Psychopharmacology

  • Learn when to refer a patient to a psychiatrist
  • Understand the effects of medications for depression
  • Understand the effects of medications for anxiety
  • Understand the effects of medications for psychosis and schizophrenia
  • Awareness of long-term and short-term signs that signal danger for a patient using medication

It has become increasingly important for clinicians to have a firm understanding of medication for  psychological problems. Not only is there the hope of eventually being able to prescribe medications to our patients, we are also much more likely to see a patient more often and for a longer session than their psychiatrist. This makes it imperative that therapists not only understand the main effects of the medications their patients are most likely to use, they also should be aware of indications that the patient is not tolerating the medication well.

When making the referral, make certain that you obtain a signed release from the patient to discuss their personal information with the psychiatrist. I generally explain that having this permission will allow the psychiatrist and I to work more effectively with each other. I also prepare a brief statement for the psychiatrist, outlining my reasons for referral, providing my diagnosis and the symptoms that led me to make that diagnosis, a brief history of the patient, and other information about the current problems they face.  

It is crucial actively to cultivate professional relationships with local psychiatrists as well as those who practice in specialty areas, usually in the larger cities. First, it helps you have an idea about their approach to treatment and their patients. Being a friend of a psychiatrist does not necessarily mean one would refer patients to that person, instead, it means one has a clearer idea how they see their work, their patients, and how well they relate to other people. As in any profession, there are people who are good at what they do and then there are the many others who work without much concern about their own knowledge or their patients. Look for people who are open-minded and read their journals. Additionally, psychiatrists who see a large number of patients can be very useful when the patient has a complex problem with medication since a psychiatrist who has more experience will also be likely to have tried a wider variety of medications and combinations of medications than someone who has a smaller, newer practice or does not generally see patients only for medication.

Additionally, it is important that they have the ability to help people feel comfortable as well as concerned about them. Someone may be an excellent psychopharmacologist yet, if the patient does not feel comfortable talking with them, their expertise is useless. For many years my partners and I used a psychiatrist who we ironically found through different sources we trusted. Although he was not in the local area, I sent patients to him who had tried several medications without good results, those who tended to have bad side effects to other medications they had taken, and patients who were difficult to diagnose as having a specific problem but instead presented with a cluster of emotional and mental problems. While he was excellent in assessment, diagnosis, and prescribing mediations as well as being readily available if there were untoward side-effects, he struck several of my patients  as being depressed himself, or somewhat disinterested after the first consultation. Although I would not usually do this, I had come to know him fairly well so I broached the idea that we get together to discuss a particular patient. During this discussion, as I had planned, I discussed my concerns about some of my patients’ feelings about their perception of his attitude toward them. I also observed that he had mannerisms that would be taken to imply that he was not focused on the task at hand. I brought these issues up as well even though I felt awkward about doing so. I assured him that I considered him an unusually fine psychopharmacologist and more thoroughly related the changes I had seen in them since they were using medication.

Manufacturing Medication

With the advent of any new medication as well as throughout its history of use, one can find strong advocates for it, particularly among the manufacturers but also among patients who believe  they responded well to it without significant side effects. There is a lengthy literature from both sides regarding virtually any medication. While all pharmaceuticals are extensively tested in the United States, this is generally or almost exclusively done by the manufacturer who holds the patent, under what are seen as tight controls. The medications are generally tested first in small groups of people with a specific diagnosis against a placebo. While there is a vocal minority that decries the failure to treat those who are given the placebo, the sometimes deadly side effects of new and old medications certainly warrant this sort of trial. After the initial clinical trials, the manufacturer applies to distribute the medication throughout the general public. Warnings of side effects must be included in any advertizing as well as in the packaging of the medication itself.  In order to increase initial sales, pharmaceutical companies provide new medications free of charge, as “samples” to physicians to distribute to patients on a “free trial” basis. It is important to recognize that many different medications are tested, many fail to pass even the beginning trials, and few make it to the general population. It is also important, of course, to be aware that the business of pharmaceutical manufacturers is to sell medications widely, throughout the population, and thus maximize the amount of money made on its product while it is still patented and thus cannot be copied and sold by another manufacturer at a lower price. This is best done during the ealiest years of production, which are also the most risky since all side effects are not known until the medication is widely used by the population.

With the advent of any new medication as well as throughout its history of use, one can find strong advocates for it, particularly among the manufacturers but also among patients who believe they responded well to it without significant side effects. There is a lengthy literature from both sides regarding virtually any medication. While all pharmaceuticals are extensively tested in the United States, this is generally or almost exclusively done by the manufacturer who holds the patent, under what are seen as tight controls. The medications are generally tested first in small groups of people with a specific diagnosis against a placebo. While there is a vocal minority that decries the failure to treat those who are given the placebo, the sometimes deadly side effects of new and old medications certainly warrant this sort of trial. After the initial clinical trials, the manufacturer applies to distribute the medication throughout the general public. Warnings of side effects must be included in any advertizing as well as in the packaging of the medication itself.  In order to increase initial sales, pharmaceutical companies provide new medications free of charge, as “samples” to physicians to distribute to patients on a “free trial” basis. It is important to recognize that many different medications are tested, many fail to pass even the beginning trials, and few make it to the general population.

Choosing the right medication, medication dose, and treatment plan should be based on a person's individual needs and medical situation, and under a physician, preferably a psychiatrist's care while in psychotherapy. In most States it is illegal for a therapist to suggest changes in medication to the patient in most States since it implies one is practicing medicine without being a physician. Check with your State licensing board about the specific rules that apply to you to protect yourself from lawsuits should the medication trials go poorly.

Information about medications is frequently updated. Check the FDA Web site for the latest information on warnings, patient medication guides, or newly approved medications. Also listen to your patients when you ask them about the experience they are having on their medication. It has been my experience that each patient is unique in their response to the medication. Also the time it takes for the medication to begin to produce side effects and main effects is highly variable. Report any dangerous side effects to the psyciatrist. In the best cases, the psychiatrist, therapist, and patient form a team that works together so the patient is protected as well as supported in continuing to take the medication despite uncomfortable side effects because it is having a significant impact on the main problem.

Throughout this course you will see two names for medications—the generic name and in parenthesis, the trade name. An example is fluoxetine (Prozac). See the end of this document for a complete alphabetical listing of medications.

Psychiatric medications treat mental disorders. Sometimes called psychotropic or psychotherapeutic medications, they have changed the lives of people with mental disorders for the better and for the worse. Many people with mental disorders live fulfilling lives with the help of these medications. Without them, people with mental disorders might suffer serious and disabling symptoms.As a therapist, medication can make a powerful ally in treating a patient in that it can help them get back to their work more quickly and respond to psychotherapy. However, there are many problems with current medications. Most of these are inserted in a way to make them appear unimportant, yet, some of the medications commonly used can result in death or violence. It is important to keep in mind that pharmaceuticals are in the business of selling medications, not in carefully testing them and describing all possible side effects.

In my practice, many, if not most of the patients are on medication for at least part of the time they see me for psychotherapy. I advocate the use of medications as an adjunct to psychotherapy, particularly in the early stages. While some patients are able to tolerate the side effects well or perhaps simply have less strong reactions to the side effects, others have extreme reactions to medications that are not described by FDA or any other source. While therapists are to encourage their patients to stay on their medications, often it is important to question the wisdom of this and to consult with the psychiatrist about continuing a medication that seems to be doing more harm than good.

While medications are designed to treat treat the symptoms of mental disorders, they cannot cure the disorder. In the best of cases, they make people feel better so they can function.

Medications work differently for different people. Some people get great results from medications and only need them for a short time. For example, a person with depression may feel much better after taking a medication for a few months, and may never need it again. People with disorders like schizophrenia or bipolar disorder, or people who have long-term or severe depression or anxiety may need to take medication for a much longer time. Some people simply respond poorly or not at all to any available medication.

Some people get side effects from medications and other people don't. Doses can be small or large, depending on the medication, the person, and the style of the psyciatrist. Factors that can affect how medications work in people include:

Type of mental disorder, such as depression, anxiety, bipolar disorder, and schizophrenia
Age, sex, and body size
Physical illnesses
Habits like smoking and drinking
Liver and kidney function
Genetics
Other medications and herbal/vitamin supplements
Diet

Antidepressants

Serotonin Uptake Inhibitors: SSRIs

The SSRI’s or serotonin uptake inhibitors are by far the most commonly prescribed medication for treating depression in the United States. Prozac, Paxil, Zoloft, Celexa, and Luvax are somewhat different formulations of the same basic medication made and patented by Lilly Pharmaceuticals. Much less known are the other two SSRI’s that were manufactured at the same time but quickly withdrawn because of side effects. Prozac was not the first of the SSRI’s to be made, patented or used in clinical trials and sold to the public. Some variations, marketed under the names Zelmid and Indalpine caused immediate concern among the public. Zelmid appeared to have significant side effects while Indalpine was  the focus of a virulent attack by what appear to have been anti=psychiatry fringe groups. Paxil initially raised concerns about dependence. Luvox has been niche-marketed for OCD.

Prior to the origin of SSRI’s, patients with depression were frequently treated with tricyclics (TCA’s) including desipramine, trimipramine, clomipramine, and also with the MAO inhibitors. Patients with clear signs of manic-depression were given Lithium. Lithim, however, is not a patented medication and therefore is not fiercely marketed by any pharmaceutical manufacturer. The use of particular medications is often driven by pharmaceutical manufacturers rather than any consideration of effectiveness, side effects, or the effect of different classes of medications on a patient. At least one significant study has shown there is no difference in effectiveness between the far less expensive, and no longer patented tricyclics and the SSRI’s. But then, there are also studies indicating that the SSRI’s are no better than a placebo for treating depression (Judd & Boyce, 1999). Unlike the tricyclics, however, the SSRI’s do not have the potential to cause a fatal overdose but in all other ways, they perform about the same.

The SSRI’s were invented in 1967 by Paul Kielholz in Germany. He was an important psychopharmacologist who published widely and was particularly interested in the treatment of depression. He believed depression was not adequately recognized and when it was treated with medication, there was no concern about what the “right” medication was. He felt the TCA medications had different effects, making it important to select the right medication for the symptoms presented by the patient. At the time, MAOI’s were rarely used because interaction with cheese and other common foods caused dangerous reactions, leaving only TCA’s as the sole medication for treating depression. TCA’s vary in their chemical constituents, but all inhibit norepinephrine uptake (Schildkraut, 1965). Carlsson, a Swedish neurologist who specialized in research on neurotransmitter pathways in the brain and also discovered dopamine in the brain, and won a Nobel Prize for his work on Parkinson’s Disease was also very interested in the work being done on depression and the finding  of norepinephrine uptake as a main factor in medication. He agreed with Kielholz that the various tricyclics were having a variety of  different effects on the neurochemistry of the brain. While some TCA’s had drive enhancing effects on the norepinephrine system, others such as clomipramine effected the serotonin system.  Carlsson suggested that drugs that specifically inhibited the reuptake of serotonin might clarify the nature of the biochemistry involved. Testing this theory was difficult since if serotonin was merely normalized, the brain chemistry would essentially be that of a normal brain. The medications that corrected abnormalities in the serotonin system, the SSRI’s should be the most effective yet in clinical practice, they were among the weakest with substantial information that they were ineffective with severe depression. If they affected other parts of the chemistry of the brain, such as reducing panic, they might be effective across a wider range of depressive states, including those with anxiety as a significant factor. This is what they found.

Zelmid was the first SSRI. It was produced in the late 1960’s by Carlsson, Corrodi, and Berndtsson at Astra’s pharmaceutical plant in Sweden. The antihistamine chlorpheniramine molecule was manipulated to produce zimeldine and given the brand name Zelmid in 1971. It was patented in 1972. Prozac was patented in 1974. There were many problems with the initial SSRI’s during clinical trials causing one after another to be banned by governments in European countries. Short trials with patients who did not have severe depression continued to be conducted. Zelmid was first presented at a meeting in 1982. The trials on Prozac were not published until 1985 and it was not marketed until 1988. Although contracts were signed between Astra and Merck to market Zelmid in the United States in 1982, it was found that Zelmid could cause Guillain-barre Syndrome, a potentially fatal disorder, and it was withdrawn from the market. Another derivative of Zelmid was found to cause liver problems in laboratory mice. Yet another was reported as causeing aplastic anemia. The cost of testing and bringing a medication to market through the FDA was about $300 million so Astra began to have severe financial problems because of  the failure of antidepressants and other medications to be without potentially lethal side effects.

The tide against the use of SSRI’s rather than tricyclics was eventually settled by Lilly pharmaceutical manufacturers who successfully argued that the SSRI’s were safer because overdose was not a problem which would lead to death as would overdose on tricyclics. Lilly also argued that the lengthy research was leading to suicide in depressed patients who might survive if they were allowed to take Prozac. Some researchers and psychiatrists argued that effective medications were banned and discarded because “fringe groups” had magnified the incidence of side effects. No one considered that Prozac and other SSRI’s might increase the incidence of suicide in some depressed patients.

Luvox was the first serotonin reuptake inhibitor to gain international approval. It was first lauched in Europe in 1984. While the main problem initially was the higher suicide rate among users of Luvox in comparison to the older tricyclics imipramine and amitriptyline, the problem was handled by researchers and marketers who had become increasingly experienced with negotiating problems with regulators. While it was not a satisfactory treatment for patients hospitalized with depression as well as causing severe nausea in a significant number of patients. It never has been prescribed widely to depressed patients. Clomipramine is currently seen as the most powerful tricyclic and perhaps the most useful anti-depressant ever made.  It acts on both the norepinephrine and serotonin systems. The FDA initially saw it as merely a variant of other tricyclics making  it difficult to get approval. OCD was thought to be a rare disorder. This changed after research by Rapoport of NIMH showed children with OCD was far more effective than desimpramine which was at that time the most potent medication for depression. These results caused clinicians and researchers to reconsider the basis for OCD which, until that time, had been considered to be depression. Her subsequent book The Boy Who Couldn’t Stop Washing, became a bestseller. She also appeared on popular talk shows. It led to patients who had hidden their OCD to come in for help and eventually was recognized as a distinct disorder from depression. Luvox was prescribed much less often than other SSRI’s and was seen as one of the less important SSRI’s until the shootings at Columbine High School where one of the shooters, Eric Harris, was found to be on Luvox for OCD.

Celexa:
This SSRI was created by a Danish chemist in 1971 by accident as he was trying to reproduce a selective norepinephrine reuptake inhibitor rather than an SSRI. They produced the chemical phenylphtalene, a selective norepinephrine reuptake inhibitor. Two antidepressants came from this. While both were energizing, both caused the frequency of suicide attempts to increase. The company producint it, Lundbeck, backed away from it. It was suggested that the compound be converted to an SSRI since they were seen by the FDA as less likely to lead to suicide. They manufactured citalopram, now the most selective serotonin reuptake inhibitor on the market. Even though it was introduced decades after its predecessors, in Britain in 1996, the fifth of the SSRI’s, they used an effective marketing strategy: they undercut the price of other SSRI’s and they advertized it as the most selective SSRI and therefore less likely to cause side effects. Most helpful was a story in the New Yorker in which Andrew Soloman gave an account of his own depression. This was anthologized in more than 30 books. He became a major spokesman for sufferers of depression. He was one of the first to openly discuss the stimulating effects of both Zoloft and Paxil likening them to drinking 55 and 11 cups of coffee respectively. He found Celexa did not have such a high stimulating effect yet it too is very stimulating to users.

Zoloft
Pfizer’s contribution to the SSRI market,  Zoloft (sertraline) began in about 1977. The initial tests of a new series of norepinephrine uptake inhibitors was disappointing but Zelmid was reported to have antidepressant effects so the research was taken further until sertraline was invented in 1979. It did not hit the market as Zoloft until 1992 in North America, making it one of the later SSRI’s. The marketing department of Pfizer emphasized its biochemical interaction with the body and claimedto be safer than Prozac since it broke down into different compounds and more quickly. Although the data was extensive, little of it had clinical relevance. In the wars between Prozac, Paxil, and Zoloft, in the 1990’s the sales of Zoloft  began to rival those of Prozac in volume.

Paxil
Paxil (paroxetine) was developed in 1978 by a small Danish company that was running trials on another SSRI femoxetine. The problem with femoxetine was that high doses would be required, making it necessary to take more than one pill daily. Additionally, the company manufacturing it was bought and sold eventually to Glaxco which manufactures Novo-Nordisc so they had little interest in developing an antidepressant. Because a large Danish study had been run that indicated Paxil was not very effective as  an antidepressant even though it was less likely to cause suicide, its’ relative ineffectiveness made it appear  unlikely that it would become a leader in the market of antidepressants. Marketers within SmithKline Beecham coined the term SSRI. It was adopted for the entire group of compounds including Paxil, Prozac, and Zoloft.

Although the marketing of Paxil and other SSRi’s highlighted the impression that they were selective in the areas of the brain biochemistry selected, it was a complex issue. It implied that the side-effects of the non-selective tricyclics would be avoided but it also implied that parts of the brain that appeared to be involved in depression may not be affected at all by the medication, thus making it less effective overall than TCA’s. Additionally each of the medications, while chemically very similar, was being marketed for highly specific disorders. Paxil began to be marketed for panic disorder, generalized anxiety disorder and social phobia. People who saw themselves as simply shy began to be diagnosed as having social anxiety and be referred for medication to treat the newly discovered mental illness with medication rather than with the old-fashioned work of learning social skills and gradually attaining confidence by using them. Clinicians also began to see the medications as able to “fix” problems of a lifetime as soon as the medications began to work.

Paxil presented another problem. Although the SSRI’s had been consistently touted as not having any issues of dependency; when patients stopped taking the medication, they reported psychological symptoms similar to withdrawal. Psychiatrists offered various explanations for this phenomenon but it was persistent. People in Britain who were surveyed found most people thought the antidepressants were addictive. The withdrawal was called “antidepressant discontinuation syndrome” to  distinguish it from addiction or dependence. One of the main reasons for using Paxil or another SSRI for anxiety was that they were not thought to produce the same physical dependence that all benzodiazepines and barbiturates had done in treating phobias and anxiety.

The SSRI’s also became known to have a problem with patients who use the medication for a long time. They appear to have to increase the dosage to achieve the same results. Additionally, in some patients they simply stop working. The companies manufacturing the medication were not ready to admit that the medication stopped working after awhile, usually a year or so, leaving the clinician to contend with the depressed patient. Generally patients have been switched to other sorts of antidepressants or have gone on taking medication both they and the clinician considered useless while working on resolving the problems they faced.

Prozac
Lilly’s best selling antidepressant through the 1960’s was nortriptyline, a norepinephrine reuptake inhibitor. However, it had become old-fashioned in the face of the development of new medications. In 1971, biochemists synthesized a number of new compounds from antihistamines. While Carlsson used chlorpheniramine, Molloy at Lilly used diphenhydramine. They then carried out chemical testing to create new molecules to see whether the new structures that emerged would be more effective in treating depression. They produced nisoxetine, a selective norepinephrine reuptake inhibitor and moved it into clinical trials. They also tested  the other compounds in the series. David Wong, a biochemist with little experience in psychopharmacology tested a series of serotonin inhibitors. LY-82816 had the least effects on the norepinephrine system. It was reformulated as a salt so it could be dissolved in water. It merited publication in a journal as the first specifically serotonin reuptake-inhibiting drug. Thus, Wong is considered by some as the discoverer of Prozac.

By the time Prozac got its license, the crisis with the benzodiazepines had
become severe. The psychiatric and primary care worlds were receptive to
the idea that behind every case of anxiety lay a case of depression. No one
was inclined to question the idea that antidepressants were a more
scientifically rational treatment for many of the nervous states presenting in
the community than anxiolytics. There was the extra benefit to the new
antidepressants -- no one expected an antidepressant to produce dependence.
Furthermore, compared with the older antidepressants, these new drugs were
safe in overdose and therefore could be used safely in the treatment of
suicidal patients. The fact that they had never been shown to work in a
group of patients who were hospitalized for depression or suicidal or in any group of patients who were severely depressed was quite another matter.

Norepinephrine Reuptake Inhibitors (SNRIs)

Effexor (venlafaxine) is the most commonly prescribed SNRI. While SNRIs are similar to SSRIs. they are much more useful in treating generalized anxiety disorder, panic disorders, and depression in which anxiety is a significant factor. While they generally have the same side effects as the SSRIs, they differ in some significant ways. They have come to be regarded as causing dependency although not physical addiction in the user. Patients report being unable to stop taking the medication without an immediate return of the anxiety and panic.

Prior to using Effexor, a psychologist may consider using in vivo desensitization which has been shown to have very good results across all types of phobias, including social phobias.

One of my patients who is unable to take antidepressants including Effexor because of extreme side effects has been able to begin to overcome his travel anxiety by gradually driving longer distances.Initially, it was a struggle to drive from his home to my office about 10 miles distant. While it was difficult to convice him that merely driving more often and going further was difficult since he saw that as useless and possibly causing more anxiety, he eventually began to "practice driving" at least one day a week. He has made significant progress, now traveling 100 or more miles daily and up to 60 miles from his home.

Another patient with both generalized anxiety and claustrophobia became unable to work because he could not tolerate being in enclosed spaces. He was prescribed Effexor when I began to see him but after more than two months, he had not been able to return to work. I suggested he take his wife to a local building with the highest elevators in the area and practice by going up one floor at a time and repeating that until he felt comfortable, then increasing the number of floors he traveled. This was a very successful exercise and carried over to both the elevators at his job as well as the small room where workers ate their lunch. It was also helpful to have him leave the building during breaks since it provided him with the knowledge that he could leave if the situation caused too much anxiety, then return when he felt better. Acknowledging the disorder to his supervisor and peers was helpful also since he then was not chastised for avoiding work and it was understood that he had an emotional disorder that was being treated.

The most common side effects associated with SSRIs and SNRIs include:

Headache, which usually goes away within a few days.

Nausea (feeling sick to your stomach), which usually goes away within a few days.Often a patient will lose their appetite making this medication problematic for use with depressed patients who are anorexic or bulimic.

Sleeplessness or drowsiness, which may happen during the first few weeks but then goes away. Sometimes the medication dose needs to be reduced or the time of day it is taken needs to be adjusted to help lessen these side effects.

Agitation (feeling jittery).This agitation has sometimes led to violent acts including murder. Patients taking these medications should notify others in their households that they will begin taking the medication and to report any unusual effects. It may also be felt as nervous energy, similar to drinking large quantities of coffee.


Sexual problems, which can affect both men and women and may include reduced sex drive, as well as difficulties achieving climax.

Suicidal ideation, even in patients without a history of this have been shown to become suicidal when first taking SSRIs.

Tricyclic Antidepressants

Since the advent of universal use of SSRIs, tricyclic medications were used to treat depression. Like the SSRIs they became diversified in their chemical composition as well as what their best use was considered to be. They were, and still are, very effective in treating depression. In recent research, they were found to have equal, if not better effects than the SSRIs. Tofranil, desipramine, and amitriptaline are commonly prescribed tricyclics.

As discussed previously, the main reason they stopped being prescribed was that they are lethal when taken to commit suicide while the SSRIs are not. Perhaps another reason is the aggressive marketing of SSRIs and the higher profit made on medications that are patented as opposed to those that have been on the market long enough that the patent has expired. Perhaps too, patients are exposed to many advertizements in the media as are psychiatrists and clinicians that both those taking the medication and those responsible for prescribing it are trying to provide the best by providing the newest, and presumabley the best medication.

Tricyclic antidepressants can cause side effects, including:

Dry mouth.
Constipation.
Bladder problems. It may be hard to empty the bladder, or the urine stream may not be as strong as usual. Older men with enlarged prostate conditions may be more affected.
Sexual problems, which can affect both men and women and may include reduced sex drive, and problems having and enjoying sex.
Blurred vision, which usually goes away quickly.
Drowsiness. Usually, antidepressants that make you drowsy are taken at bedtime.

Bupropion

Another antidepressant that is commonly used is bupropion (Wellbutrin). Bupropion, which works on the neurotransmitter dopamine, is unique in that it does not fit into any specific drug type. It is often prescribed after the SSRIs fail to have an effect. Thus far, I have not seen a patient have any noticable decrease in either their depression or anxiety as a result of using this medication but it has done well in clinical trials when tested by the manufacturer against a placebo. It does not seem to have any significant side effects.

SSRIs and SNRIs are popular because they do not cause as many side effects as older classes of antidepressants.However, the older antidepressants may be more effective for some patients than the newer ones. Older antidepressant medications include tricyclics, tetracyclics, and monoamine oxidase inhibitors (MAOIs). For some people, tricyclics, tetracyclics, or MAOIs may be the best medications.

Most, if not all antidepressants cause side effects. They may be lengthy and impair functioning. Some may last the entire time the medication is taken. Others, such as weight gain with SSRIs gradually becomes a problem after about a year on the medication. Any unusual reactions or side effects should be reported to a doctor immediately.

Suicidal ideation as well as attempted suicide is a risk for all people taking an antidepressant. With SSRIs even those who have not shown signs of suicidal ideation prior to beginning the medication may manifest suicidal thoughts and actions. The tricyclic antidepressants, although unlikely to cause suicidal thinking in a patient who does not have suicidal thoughts prior to beginning the medication, are dangerous because they are lethal in large quantities.

MAOIs

People taking MAOIs need to be careful about the foods they eat and the medicines they take. Foods and medicines that contain high levels of a chemical called tyramine are dangerous for people taking MAOIs. Tyramine is found in some cheeses, wines, and pickles. The chemical is also in some medications, including decongestants and over-the-counter cold medicine.

Mixing MAOIs and tyramine can cause a sharp increase in blood pressure, which can lead to stroke. People taking MAOIs should ask their doctors for a complete list of foods, medicines, and other substances to avoid. An MAOI skin patch has recently been developed and may help reduce some of these risks. A doctor can help a person figure out if a patch or a pill will work for him or her.

People taking antidepressants need to follow their doctors' directions. The medication should be taken in the right dose for the right amount of time. It can take three or four weeks until the medicine takes effect. Some people take the medications for a short time, and some people take them for much longer periods. People with long-term or severe depression may need to take medication for a long time.

Once a person is taking antidepressants, it is important not to stop taking them without the help of a doctor. Sometimes people taking antidepressants feel better and stop taking the medication too soon, and the depression may return. When it is time to stop the medication, the doctor will help the person slowly and safely decrease the dose. It's important to give the body time to adjust to the change. People don't get addicted, or "hooked," on the medications, but stopping them abruptly can cause withdrawal symptoms.

If a medication does not work, it is helpful to be open to trying another one. A study funded by NIMH found that if a person with difficult-to-treat depression did not get better with a first medication, chances of getting better increased when the person tried a new one or added a second medication to his or her treatment. The study was called STAR*D (Sequenced Treatment Alternatives to Relieve Depression).

Herbal medicines used to treat depression
The herbal medicine St. John's wort has been used for centuries in many folk and herbal remedies. Today in Europe, it is used widely to treat mild-to-moderate depression. In the United States, it is one of the top-selling botanical products.

The National Institutes of Health conducted a clinical trial to determine the effectiveness of treating adults who have major depression with St. Johns wort. The study included 340 people diagnosed with major depression. One-third of the people took the herbal medicine, one-third took an SSRI, and one-third took a placebo, or "sugar pill." The people did not know what they were taking. The study found that St. John's wort was no more effective than the placebo in treating major depression.4 A study currently in progress is looking at the effectiveness of St. John's wort for treating mild or minor depression.

Other research has shown that St. John's wort can dangerously interact with other medications, including those used to control HIV. On February 10, 2000, the FDA issued a Public Health Advisory letter stating that the herb appears to interfere with certain medications used to treat heart disease, depression, seizures, certain cancers, and organ transplant rejection. Also, St. Johns wort may interfere with oral contraceptives.

Because St. John's wort may not mix well with other medications, people should always talk with their doctors before taking it or any herbal supplement.

FDA warning on antidepressants
Antidepressants are safe and popular, but some studies have suggested that they may have unintentional effects, especially in young people. In 2004, the FDA looked at published and unpublished data on trials of antidepressants that involved nearly 4,400 children and adolescents. They found that 4 percent of those taking antidepressants thought about or tried suicide (although no suicides occurred), compared to 2 percent of those receiving placebos (sugar pill).

In 2005, the FDA decided to adopt a "black box" warning label—the most serious type of warning—on all antidepressant medications. The warning says there is an increased risk of suicidal thinking or attempts in children and adolescents taking antidepressants. In 2007, the FDA proposed that makers of all antidepressant medications extend the warning to include young adults up through age 24.

The warning also says that patients of all ages taking antidepressants should be watched closely, especially during the first few weeks of treatment. Possible side effects to look for are depression that gets worse, suicidal thinking or behavior, or any unusual changes in behavior such as trouble sleeping, agitation, or withdrawal from normal social situations. Families and caregivers should report any changes to the doctor. To find the latest information visit the FDA website.

Results of a comprehensive review of pediatric trials conducted between 1988 and 2006 suggested that the benefits of antidepressant medications likely outweigh their risks to children and adolescents with major depression and anxiety disorders.5 The study was funded in part by NIMH.

Finally, the FDA has warned that combining the newer SSRI or SNRI antidepressants with one of the commonly-used "triptan" medications used to treat migraine headaches could cause a life-threatening illness called "serotonin syndrome." A person with serotonin syndrome may be agitated, have hallucinations (see or hear things that are not real), have a high temperature, or have unusual blood pressure changes. Serotonin syndrome is usually associated with the older antidepressants called MAOIs, but it can happen with the newer antidepressants as well, if they are mixed with the wrong medications.

Medications used to treat schizophrenia

Antipsychotic medications are used to treat schizophrenia and schizophrenia-related disorders. Some of these medications have been available since the mid-1950's. They are also called conventional "typical" antipsychotics. Some of the more commonly used medications include:

Chlorpromazine (Thorazine)
Haloperidol (Haldol)
Perphenazine (generic only)
Fluphenazine (generic only).

Because these medications were invented so long ago, they are no longer under a patent and can be manufactured in generic form. They are quite inexpensive. In the 1990's, new antipsychotic medications were developed. These new medications are called second generation, or "atypical" antipsychotics.

One of these medications was clozapine (Clozaril). It is a very effective medication that treats psychotic symptoms, hallucinations, and breaks with reality, such as when a person believes he or she is the incarntation of Abraham Lincoln. But clozapine can sometimes cause a serious problem called agranulocytosis, which is a loss of the white blood cells that help a person fight infection. Therefore, people who take clozapine must get their white blood cell counts checked every week or two. This problem and the cost of blood tests make treatment with clozapine difficult for many people. Still, clozapine is potentially helpful for people who do not respond to other antipsychotic medications.

Other atypical antipsychotics were developed. All of them are effective with some patients, and none so far have been shown to cause agranulocytosis. These include:

Risperidone (Risperdal)
Olanzapine (Zyprexa)
Quetiapine (Seroquel)
Ziprasidone (Geodon)
Aripiprazole (Abilify)
Paliperidone (Invega).

The antipsychotics listed here are some of the medications used to treat symptoms of schizophrenia. All of them are patented although some are reaching the end of this and are appearing as generics, making them much less expensive. Additional antipsychotics and other medications used for schizophrenia are listed in the chart at the end.

Note: The FDA issued a Public Health Advisory for atypical antipsychotic medications. The FDA determined that death rates are higher for elderly people with dementia when taking this medication. A review of data has found a risk with conventional antipsychotics as well. Antipsychotic medications are not FDA-approved for the treatment of behavioral disorders in patients with dementia.

Some people have side effects when they start taking these medications. Most side effects go away after a few days and often can be managed successfully. People who are taking antipsychotics should not drive until they adjust to their new medication. Side effects of many antipsychotics include:

Drowsiness
Dizziness when changing positions
Blurred vision
Rapid heartbeat
Sensitivity to the sun
Skin rashes
Menstrual problems for women.

Atypical antipsychotic medications can cause major weight gain and changes in a person's metabolism. This may increase a person's risk of getting diabetes and high cholesterol.1 A person's weight, glucose levels, and lipid levels should be monitored regularly by a physician while taking an atypical antipsychotic medication.                                                                                                            

Typical antipsychotic medications can cause side effects related to physical movement, such as:

Rigidity
Persistent muscle spasms
Tremors
Restlessness.
Long-term use, regardless of amount, of typical antipsychotic medications may lead to a condition called tardive dyskinesia (TD). TD causes muscle movements a person can't control. The movements commonly happen around the mouth. TD can range from mild to severe, and in some people the problem cannot be cured. Sometimes people with TD recover partially or fully after they stop taking the medication but they are the exceptions rather than the rule.

Every year, an estimated 5 percent of people taking typical antipsychotics get TD. The condition happens to fewer people who take the new, atypical antipsychotics, but the reasons why this occurs are unknown. Perhaps people who take atypical antipsychotic medication do not take them as consistently or for such a lengthy time. There may be a difference also between the people who are given the older, less expensive medication and those who are prescribed the newer, atypical drugs. Often older medications such as Haldol are given by injection and stay in the patient's system for a long time and they are then required to get another shot. Haldol currently has the highest level of patients developing TD of any. People who think that they might have TD should check with their doctor before stopping their medication.

Antipsychotics, including the atypical antipsychotics are anti-emitics. This can make them dangerous in the hands of suicidal patients since the patient can overdose on a medication that would ordinarily cause enough gastric problems that the patient will vomit and clear their system of some of the medication. Anti-psychotic medication blocks this response so if it is mixed in a "cocktail" of a variety of medications it could make the combination lethal.

Antipsychotics are usually pills that people swallow, or liquid they can drink. Some antipsychotics are injections that are given once or twice a month.

Symptoms of schizophrenia, such as feeling agitated and having hallucinations, usually go away within days for people who respond well to the medication.The deep feeling of dread experienced by so many schizophrenics also abates. Symptoms like delusions usually go away within a few weeks or months. After about six weeks, many people will see a lot of improvement.

A major exception that has been found in clinical practice is psychosis that is caused by the used of methamphetamines. Patients who have taken these drugs over a long period of time at high dosages may not respond well to any type of antipsychotic.

However, people respond in different ways to antipsychotic medications, and no one can tell beforehand how a person will respond. Sometimes a person needs to try several medications before finding the right one. Physicians and patients can work together to find the best medication or medication combination, and dose.

Some people may have a relapse—their symptoms come back or get worse. Usually, relapses happen when people stop taking their medication, or when they only take it sometimes. Other times, stress, change in enviornment, loss of a loved one, or other internal or external factors cause the relapse. Some people stop taking the medication because they feel better or they may feel they don't need it anymore. While no one should stop taking an antipsychotic medication without talking to his or her physician, patients often do. As a therapist, it is important to openly discuss this problem with the patient so they are aware you will not be angry or otherwise disappointed in them if they stop taking their medication. Usually the best approach is to discuss why the patient stopped the medication and discuss this with the physician. When the patient begins taking the medication, they should be told that they should continue until their psychiatrist advises them to stop and at that time they should gradually taper off the medication rather than stopping suddenly. It has been my experience that people go off and on any medication regardless of what they are told. They forget to take it, they decide it is too expensive, they feel they no longer need it, the side effects become too annoying, or any number of other factors. I often have no idea they stopped taking their prescribed medication until weeks or months after they have stopped yet often there is no return of the symptoms. These are lucky patients.

Antipsychotics can produce unpleasant or dangerous side effects when taken with certain medications. For this reason, all physicians treating a patient need to be aware of all the medications that person is taking. Physicians need to know about prescription and over-the-counter medicine, vitamins, minerals, and herbal supplements. People also need to discuss any alcohol or other drug use with their doctor. Since people are reluctant to do this with a psychiatrist they have just met at the consultation, the role of the referring therapist can be crucial in supplying information about legal and illegal drug use as well as herbal and other factors that may affect the ability of the prescribed medication to have a positive effect.

To find out more about how antipsychotics work, the National Institute of Mental Health (NIMH) funded a study called CATIE (Clinical Antipsychotic Trials of Intervention Effectiveness). This study compared the effectiveness and side effects of five antipsychotics used to treat people with schizophrenia. In general, the study found that the older medication perphenazine worked as well as the newer, atypical medications. But because people respond differently to different medications, it is important that treatments be designed carefully for each person.

Medications Used to Treat Bipolar Disorders

Bipolar disorder, also called manic-depressive illness, is commonly treated with mood stabilizers. Sometimes, antipsychotics and antidepressants are used along with a mood stabilizer.

Mood stabilizers

People with bipolar disorder usually try mood stabilizers first. In general, people continue treatment with mood stabilizers for years. Lithium is a very effective mood stabilizer. It was the first mood stabilizer approved by the FDA in the 1970's for treating both manic and depressive episodes.

Anticonvulsant medications also are used as mood stabilizers. They were originally developed to treat seizures, but they were found to help control moods as well. One anticonvulsant commonly used as a mood stabilizer is valproic acid, also called divalproex sodium (Depakote). For some people, it may work better than lithium.6 Other anticonvulsants used as mood stabilizers are carbamazepine (Tegretol), lamotrigine (Lamictal) and oxcarbazepine (Trileptal).

Atypical antipsychotics

Atypical antipsychotic medications are sometimes used to treat symptoms of bipolar disorder. Often, antipsychotics are used along with other medications.

Antipsychotics used to treat people with bipolar disorder include:

Olanzapine (Zyprexa), which helps people with severe or psychotic depression, which often is accompanied by a break with reality, hallucinations, or delusions7
Aripiprazole (Abilify), which can be taken as a pill or as a shot
Risperidone (Risperdal)
Ziprasidone (Geodon)
Clozapine (Clorazil), which is often used for people who do not respond to lithium or anticonvulsants.8
Antidepressants
Antidepressants are sometimes used to treat symptoms of depression in bipolar disorder. Fluoxetine (Prozac), paroxetine (Paxil), or sertraline (Zoloft) are a few that are used. However, people with bipolar disorder should not take an antidepressant on its own. Doing so can cause the person to rapidly switch from depression to mania, which can be dangerous.9 To prevent this problem, doctors give patients a mood stabilizer or an antipsychotic along with an antidepressant.

Research on whether antidepressants help people with bipolar depression is mixed. An NIMH-funded study found that antidepressants were no more effective than a placebo to help treat depression in people with bipolar disorder. The people were taking mood stabilizers along with the antidepressants.

Treatments for bipolar disorder have improved over the last 10 years. But everyone responds differently to medications. If you have any side effects, tell your doctor right away. He or she may change the dose or prescribe a different medication.

Different medications for treating bipolar disorder may cause different side effects. Some medications used for treating bipolar disorder have been linked to unique and serious symptoms, which are described below.

Lithium can cause several side effects, and some of them may become serious. They include:

Loss of coordination
Excessive thirst
Frequent urination
Blackouts
Seizures
Slurred speech
Fast, slow, irregular, or pounding heartbeat
Hallucinations (seeing things or hearing voices that do not exist)
Changes in vision
Itching, rash
Swelling of the eyes, face, lips, tongue, throat, hands, feet, ankles, or lower legs.

If a person with bipolar disorder is being treated with lithium, he or she should visit the doctor regularly to check the levels of lithium in the blood, and make sure the kidneys and the thyroid are working normally.

Some possible side effects linked with valproic acid/divalproex sodium include:

Changes in weight
Nausea
Stomach pain
Vomiting
Anorexia
Loss of appetite.
Valproic acid may cause damage to the liver or pancreas, so people taking it should see their doctors regularly.

Valproic acid may affect young girls and women in unique ways. Sometimes, valproic acid may increase testosterone (a male hormone) levels in teenage girls and lead to a condition called polycystic ovarian syndrome (PCOS).11,12 PCOS is a disease that can affect fertility and make the menstrual cycle become irregular, but symptoms tend to go away after valproic acid is stopped.13 It also may cause birth defects in women who are pregnant.

Lamotrigine can cause a rare but serious skin rash that needs to be treated in a hospital. In some cases, this rash can cause permanent disability or be life-threatening.

In addition, valproic acid, lamotrigine, carbamazepine, oxcarbazepine and other anticonvulsant medications (listed in the chart at the end of this document) have an FDA warning. The warning states that their use may increase the risk of suicidal thoughts and behaviors. People taking anticonvulsant medications for bipolar or other illnesses should be closely monitored for new or worsening symptoms of depression, suicidal thoughts or behavior, or any unusual changes in mood or behavior. People taking these medications should not make any changes without talking to their health care professional.

Other medications for bipolar disorder may also be linked with rare but serious side effects. Always talk with the doctor or pharmacist about any potential side effects before taking the medication.

For information on side effects of antipsychotics, see the section on medications for treating schizophrenia.

For information on side effects and FDA warnings of antidepressants, see the section on medications for treating depression.

How medications for bipolar disorder should be taken
Medications should be taken as directed by a doctor. Sometimes a person's treatment plan needs to be changed. When changes in medicine are needed, the doctor will guide the change. A person should never stop taking a medication without asking a doctor for help.

There is no cure for bipolar disorder, but treatment works for many people. Treatment works best when it is continuous, rather than on and off. However, mood changes can happen even when there are no breaks in treatment. Patients should be open with their doctors about treatment. Talking about how treatment is working can help it be more effective.

It may be helpful for people or their family members to keep a daily chart of mood symptoms, treatments, sleep patterns, and life events. This chart can help patients and doctors track the illness. Psychotherapists and physicians can use the chart to treat the illness most effectively.

Because medications for bipolar disorder can have serious side effects, it is important for anyone taking them to see the doctor regularly to check for possibly dangerous changes in the body.

Medications used to treat anxiety disorders
Antidepressants, anti-anxiety medications, and beta-blockers are the most common medications used for anxiety disorders.

Anxiety disorders include:

Obsessive compulsive disorder (OCD)
Post-traumatic stress disorder (PTSD)
Generalized anxiety disorder (GAD)
Panic disorder
Social phobia.

Antidepressants

Antidepressants were developed to treat depression, but they also help people with anxiety disorders. SSRIs such as fluoxetine (Prozac), sertraline (Zoloft), escitalopram (Lexapro), paroxetine (Paxil), and citalopram (Celexa) are commonly prescribed for panic disorder, OCD, PTSD, and social phobia. The SNRI venlafaxine (Effexor) is commonly used to treat GAD. The antidepressant bupropion (Wellbutrin) is also sometimes used. When treating anxiety disorders, antidepressants generally are started at low doses and increased over time.

Some tricyclic antidepressants work well for anxiety. For example, imipramine (Tofranil) is prescribed for panic disorder and GAD. Clomipramine (Anafranil) is used to treat OCD. Tricyclics are also started at low doses and increased over time.

MAOIs are also used for anxiety disorders. Doctors sometimes prescribe phenelzine (Nardil), tranylcypromine (Parnate), and isocarboxazid (Marplan). People who take MAOIs must avoid certain food and medicines that can interact with their medicine and cause dangerous increases in blood pressure. For more information, see the section on medications used to treat depression.

Benzodiazepines (anti-anxiety medications)
The anti-anxiety medications called benzodiazepines can start working more quickly than antidepressants. The ones used to treat anxiety disorders include:

Clonazepam (Klonopin), which is used for social phobia and GAD
Lorazepam (Ativan), which is used for panic disorder
Alprazolam (Xanax), which is used for panic disorder and GAD.
Buspirone (Buspar) is an anti-anxiety medication used to treat GAD. Unlike benzodiazepines, however, it takes at least two weeks for buspirone to begin working.

Clonazepam, listed above, is an anticonvulsant medication. See FDA warning on anticonvulsants under the bipolar disorder section.

Beta-blockers

Beta-blockers control some of the physical symptoms of anxiety, such as trembling and sweating. Propranolol (Inderal) is a beta-blocker usually used to treat heart conditions and high blood pressure. The medicine also helps people who have physical problems related to anxiety. For example, when a person with social phobia must face a stressful situation, such as giving a speech, or attending an important meeting, a doctor may prescribe a beta-blocker. Taking the medicine for a short period of time can help the person keep physical symptoms under control.

See the section on antidepressants for a discussion on side effects. The most common side effects for benzodiazepines are drowsiness and dizziness. Other possible side effects include:

Upset stomach
Blurred vision
Headache
Confusion
Grogginess
Nightmares.
Possible side effects from buspirone (BuSpar) include:
Dizziness
Headaches
Nausea
Nervousness
Lightheadedness
Excitement
Trouble sleeping.
Common side effects from beta-blockers include:
Fatigue
Cold hands
Dizziness
Weakness.

In addition, beta-blockers generally are not recommended for people with asthma or diabetes because they may worsen symptoms.

How medications for anxiety disorders should be taken

People can build a tolerance to benzodiazepines if they are taken over a long period of time and may need higher and higher doses to get the same effect. Some people may become dependent on them. To avoid these problems, doctors usually prescribe the medication for short periods, a practice that is especially helpful for people who have substance abuse problems or who become dependent on medication easily. If people suddenly stop taking benzodiazepines, they may get withdrawal symptoms, or their anxiety may return. Therefore, they should be tapered off slowly.

Buspirone and beta-blockers are similar. They are usually taken on a short-term basis for anxiety. Both should be tapered off slowly. Talk to the doctor before stopping any anti-anxiety medication.

Medications used to treat ADHD
Attention deficit/hyperactivity disorder (ADHD) occurs in both children and adults. ADHD is commonly treated with stimulants, such as:

Methylphenidate (Ritalin, Metadate, Concerta, Daytrana)
Amphetamine (Adderall)
Dextroamphetamine (Dexedrine, Dextrostat).

In 2002, the FDA approved the nonstimulant medication atomoxetine (Strattera) for use as a treatment for ADHD. In February 2007, the FDA approved the use of the stimulant lisdexamfetamine dimesylate (Vyvanse) for the treatment of ADHD in children ages 6 to 12 years.

Most side effects are minor and disappear when dosage levels are lowered. The most common side effects include:

Decreased appetite. Children seem to be less hungry during the middle of the day, but they are often hungry by dinnertime as the medication wears off.

Sleep problems. If a child cannot fall asleep, the doctor may prescribe a lower dose. The doctor might also suggest that parents give the medication to their child earlier in the day, or stop the afternoon or evening dose. To help ease sleeping problems, a doctor may add a prescription for a low dose of an antidepressant or a medication called clonidine.

Stomachaches and headaches.

Less common side effects. A few children develop sudden, repetitive movements or sounds called tics. These tics may or may not be noticeable. Changing the medication dosage may make tics go away. Some children also may appear to have a personality change, such as appearing "flat" or without emotion. Talk with your child's doctor if you see any of these side effects.
How are ADHD medications taken?

Stimulant medications can be short-acting or long-acting, and can be taken in different forms such as a pill, patch, or powder. Long-acting, sustained and extended release forms allow children to take the medication just once a day before school. Parents and doctors should decide together which medication is best for the child and whether the child needs medication only for school hours or for evenings and weekends too.

ADHD medications help many children and adults who are hyperactive and impulsive. They help people focus, work, and learn. Stimulant medication also may improve physical coordination. However, different people respond differently to medications, so children taking ADHD medications should be watched closely.

Are ADHD medications safe?

Stimulant medications are safe when given under a doctor's supervision. Some children taking them may feel slightly different or "funny."

Some parents worry that stimulant medications may lead to drug abuse or dependence, but there is little evidence of this. Research shows that teens with ADHD who took stimulant medications were less likely to abuse drugs than those who did not take stimulant medications.14

FDA warning on possible rare side effects

In 2007, the FDA required that all makers of ADHD medications develop Patient Medication Guides. The guides must alert patients to possible heart and psychiatric problems related to ADHD medicine. The FDA required the Patient Medication Guides because a review of data found that ADHD patients with heart conditions had a slightly higher risk of strokes, heart attacks, and sudden death when taking the medications. The review also found a slightly higher risk (about 1 in 1,000) for medication-related psychiatric problems, such as hearing voices, having hallucinations, becoming suspicious for no reason, or becoming manic. This happened to patients who had no history of psychiatric problems.

The FDA recommends that any treatment plan for ADHD include an initial health and family history examination. This exam should look for existing heart and psychiatric problems.

The non-stimulant ADHD medication called atomoxetine (Strattera) carries another warning. Studies show that children and teenagers with ADHD who take atomoxetine are more likely to have suicidal thoughts than children and teenagers with ADHD who do not take atomoxetine. If your patient is taking atomoxetine, watch his or her behavior carefully. A child may develop serious symptoms suddenly, so it is important to make parents and caregivers aware of the problems that may occur. Make certain they are aware that they or another reliable adult must pay attention to the child's behavior every day. Other people who spend a lot of time with the child  should also be told to tell a parent or responsible adult if they notice any changes in the child's behavior. Call a physician right away if your patient shows any of the following symptoms:

Acting more subdued or withdrawn than usual
Feeling helpless, hopeless, or worthless
New or worsening depression
Thinking or talking about hurting himself or herself
Extreme worry
Agitation
Panic attacks
Trouble sleeping
Irritability
Aggressive or violent behavior
Acting without thinking
Extreme increase in activity or talking
Frenzied, abnormal excitement

Any sudden or unusual changes in behavior.

While taking atomoxetine, your child should see a doctor often, especially at the beginning of treatment. Be sure that your child keeps all appointments with his or her doctor.

Most medications used to treat young people with mental illness are safe and effective. However, many medications have not been studied or approved for use with children. Researchers are not sure how these medications affect a child's growing body. Still, a doctor can give a young person an FDA-approved medication on an "off-label" basis. This means that the doctor prescribes the medication to help the patient even though the medicine is not approved for the specific mental disorder or age.

For these reasons, it is important to watch young people who take these medications. Young people may have different reactions and side effects than adults. Also, some medications, including antidepressants and ADHD medications, carry FDA warnings about potentially dangerous side effects for young people. See the sections on antidepressants and ADHD medications for more information about these warnings.

More research is needed on how these medications affect children and adolescents. NIMH has funded studies on this topic. For example, NIMH funded the Preschoolers with ADHD Treatment Study (PATS), which involved 300 preschoolers (3 to 5 years old) diagnosed with ADHD. The study found that low doses of the stimulant methylphenidate are safe and effective for preschoolers. However, children of this age are more sensitive to the side effects of the medication, including slower growth rates. Children taking methylphenidate should be watched closely.15,16,17

In addition to medications, other treatments for young people with mental disorders should be considered. Psychotherapy, family therapy, educational courses, and behavior management techniques can help everyone involved cope with the disorder. Click here for more information on child and adolescent mental health research.

Older adults

Because older people often have more medical problems than other groups, they tend to take more medications than younger people, including prescribed, over-the-counter, and herbal medications. As a result, older people have a higher risk for experiencing bad drug interactions, missing doses, or overdosing.

Older people also tend to be more sensitive to medications. Even healthy older people react to medications differently than younger people because their bodies process it more slowly. Therefore, lower or less frequent doses may be needed.

Sometimes memory problems affect older people who take medications for mental disorders. An older adult may forget his or her regular dose and take too much or not enough. A good way to keep track of medicine is to use a seven-day pill box, which can be bought at any pharmacy. At the beginning of each week, older adults and their caregivers fill the box so that it is easy to remember what medicine to take. Many pharmacies also have pillboxes with sections for medications that must be taken more than once a day.

Women who are pregnant or may become pregnant

The research on the use of psychiatric medications during pregnancy is limited. The risks are different depending on what medication is taken, and at what point during the pregnancy the medication is taken. Research has shown that antidepressants, especially SSRIs, are safe during pregnancy. Birth defects or other problems are possible, but they are very rare.

However, antidepressant medications do cross the placental barrier and may reach the fetus. Some research suggests the use of SSRIs during pregnancy is associated with miscarriage or birth defects, but other studies do not support this.20 Studies have also found that fetuses exposed to SSRIs during the third trimester may be born with "withdrawal" symptoms such as breathing problems, jitteriness, irritability, trouble feeding, or hypoglycemia (low blood sugar).

Most studies have found that these symptoms in babies are generally mild and short-lived, and no deaths have been reported. On the flip side, women who stop taking their antidepressant medication during pregnancy may get depression again and may put both themselves and their infant at risk.20,21

In 2004, the FDA issued a warning against the use of certain antidepressants in the late third trimester. The warning said that doctors may want to gradually taper pregnant women off antidepressants in the third trimester so that the baby is not affected.22 After a woman delivers, she should consult with her doctor to decide whether to return to a full dose during the period when she is most vulnerable to postpartum depression.

Some medications should not be taken during pregnancy. Benzodiazepines may cause birth defects or other infant problems, especially if taken during the first trimester. Mood stabilizers are known to cause birth defects. Benzodiazepines and lithium have been shown to cause "floppy baby syndrome," which is when a baby is drowsy and limp, and cannot breathe or feed well.

Research suggests that taking antipsychotic medications during pregnancy can lead to birth defects, especially if they are taken during the first trimester. But results vary widely depending on the type of antipsychotic. The conventional antipsychotic haloperidol has been studied more than others, and has been found not to cause birth defects.23,24

After the baby is born, women and their doctors should watch for postpartum depression, especially if they stopped taking their medication during pregnancy. In addition, women who nurse while taking psychiatric medications should know that a small amount of the medication passes into the breast milk. However, the medication may or may not affect the baby. It depends on the medication and when it is taken. Women taking psychiatric medications and who intend to breastfeed should discuss the potential risks and benefits with their doctors.

Decisions on medication should be based on each woman's needs and circumstances. Medications should be selected based on available scientific research, and they should be taken at the lowest possible dose. Pregnant women should be watched closely throughout their pregnancy and after delivery.

Alphabetical List of Medications

This section identifies antipsychotic medications, antidepressant medications, mood stabilizers, anticonvulsant medications, anti-anxiety medications, and ADHD medications. Some medications are marketed under trade names, not all of which can be listed in this publication. The first chart lists the medications by trade name; the second chart lists the medications by generic name. If your medication does not appear in this section, refer to the FDA Web site. Also, ask your doctor or pharmacist for more information about any medication.

Medications Organized by Trade Name
Trade Name Generic Name FDA Approved Age
Combination Antipsychotic and Antidepressant Medication    
Symbyax (Prozac & Zyprexa) fluoxetine & olanzapine 18 and older
Antipsychotic Medications    
Abilify aripiprazole 13 to 17 for schizophrenia and bipolar;
18 and older for schizophrenia,
bipolar mania, and depression
Clozaril clozapine 18 and older
Fanapt iloperidone 18 and older
fluphenazine (generic only) fluphenazine 18 and older
Geodon ziprasidone 18 and older
Haldol haloperidol 3 and older
Invega paliperidone 18 and older
Loxitane loxapine 18 and older
Moban molindone 18 and older
Navane thiothixene 18 and older
Orap (for Tourette's syndrome) pimozide 12 and older
perphenazine (generic only) perphenazine 18 and older
Risperdal risperidone 13 and older for schizophrenia;
10 and older for bipolar mania and mixed episodes;
5 to 16 for irritability associated with autism
Seroquel quetiapine 18 and older, for schizophrenia and bipolar disorder
Stelazine trifluoperazine 18 and older
thioridazine (generic only) thioridazine 2 and older
Thorazine chlorpromazine 18 and older
Zyprexa olanzapine 18 and older

Trade Name Generic Name FDA Approved Age
Antidepressant Medications (also used for anxiety disorders)    
Anafranil (tricyclic) clomipramine 10 and older (for OCD only)
Asendin amoxapine 18 and older
Aventyl (tricyclic) nortriptyline 18 and older
Celexa (SSRI) citalopram 18 and older
Cymbalta (SNRI) duloxetine 18 and older
Desyrel trazodone 18 and older
Effexor (SNRI) venlafaxine 18 and older
Elavil (tricyclic) amitriptyline 18 and older
Emsam selegiline 18 and older
Lexapro (SSRI) escitalopram 18 and older; 12 - 17 (for major depressive disorder)
Ludiomil (tricyclic) maprotiline 18 and older
Luvox (SSRI) fluvoxamine 8 and older (for OCD only)
Marplan (MAOI) isocarboxazid 18 and older
Nardil (MAOI) phenelzine 18 and older
Norpramin (tricyclic) desipramine 18 and older
Pamelor (tricyclic) nortriptyline 18 and older
Parnate (MAOI) tranylcypromine 18 and older
Paxil (SSRI) paroxetine 18 and older
Pexeva (SSRI) paroxetine-mesylate 18 and older
Prozac (SSRI) fluoxetine 8 and older
Remeron mirtazapine 18 and older
Sarafem (SSRI) fluoxetine 18 and older for premenstrual dysphoric disorder (PMDD)
Sinequan (tricyclic) doxepin 12 and older
Surmontil (tricyclic) trimipramine 18 and older
Tofranil (tricyclic) imipramine 6 and older (for bedwetting)
Tofranil-PM (tricyclic) imipramine pamoate 18 and older
Vivactil (tricyclic) protriptyline 18 and older
Wellbutrin bupropion 18 and older
Zoloft (SSRI) sertraline 6 and older (for OCD only)

Trade Name Generic Name FDA Approved Age
Mood Stabilizing and Anticonvulsant Medications      
Depakote divalproex sodium (valproic acid) 2 and older (for seizures)
Eskalith lithium carbonate 12 and older
Lamictal lamotrigine 18 and older
lithium citrate (generic only) lithium citrate 12 and older
Lithobid lithium carbonate 12 and older
Neurontin gabapentin 18 and older
Tegretol carbamazepine any age (for seizures)
Topamax topiramate 18 and older
Trileptal oxcarbazepine 4 and older

Trade Name Generic Name FDA Approved Age
Anti-anxiety Medications
(All of these anti-anxiety medications are benzodiazepines, except BuSpar)    
Ativan lorazepam 18 and older
BuSpar buspirone 18 and older
Klonopin clonazepam 18 and older
Librium chlordiazepoxide 18 and older
oxazepam (generic only) oxazepam 18 and older
Tranxene clorazepate 18 and older
Valium diazepam 18 and older
Xanax alprazolam 18 and older

Trade Name Generic Name FDA Approved Age
ADHD Medications
(All of these ADHD medications are stimulants, except Strattera.)    
Adderall amphetamine 3 and older
Adderall XR amphetamine (extended release) 6 and older
Concerta methylphenidate (long acting) 6 and older
Daytrana methylphenidate patch 6 and older
Desoxyn methamphetamine 6 and older
Dexedrine dextroamphetamine 3 and older
Dextrostat dextroamphetamine 3 and older
Focalin dexmethylphenidate 6 and older
Focalin XR dexmethylphenidate (extended release) 6 and older
Metadate ER methylphenidate (extended release) 6 and older
Metadate CD methylphenidate (extended release) 6 and older
Methylin methylphenidate (oral solution and chewable tablets) 6 and older
Ritalin methylphenidate 6 and older
Ritalin SR methylphenidate (extended release) 6 and older
Ritalin LA methylphenidate (long-acting) 6 and older
Strattera atomoxetine 6 and older
Vyvanse lisdexamfetamine dimesylate 6 and older

Medications Organized by Generic Name
Generic Name Trade Name FDA Approved Age
Combination Antipsychotic and Antidepressant Medication    
fluoxetine & olanzapine Symbyax (Prozac & Zyprexa) 18 and older
Antipsychotic Medications    
aripiprazole Abilify 13 to 17 for schizophrenia and bipolar;
18 and older for schizophrenia,
bipolar mania, and depression
chlorpromazine Thorazine 18 and older
clozapine Clozaril 18 and older
fluphenazine (generic only) fluphenazine 18 and older
haloperidol Haldol 3 and older
iloperidone Fanapt 18 and older
loxapine Loxitane 18 and older
molindone Moban 18 and older
olanzapine Zyprexa 18 and older
paliperidone Invega 18 and older
perphenazine (generic only) perphenazine 18 and older
pimozide (for Tourette's syndrome) Orap 12 and older
quetiapine Seroquel 18 and older, for schizophrenia and bipolar disorder
risperidone Risperdal 13 and older for schizophrenia;
10 and older for bipolar mania and mixed episodes;
5 to 16 for irritability associated with autism
thioridazine (generic only) thioridazine 2 and older
thiothixene Navane 18 and older
trifluoperazine Stelazine 18 and older
ziprasidone Geodon 18 and older

Generic Name Trade Name FDA Approved Age
Antidepressant Medications (also used for anxiety disorders)    
amitriptyline (tricyclic) Elavil 18 and older
amoxapine Asendin 18 and older
bupropion Wellbutrin 18 and older
citalopram (SSRI) Celexa 18 and older
clomipramine (tricyclic) Anafranil 10 and older (for OCD only)
desipramine (tricyclic) Norpramin 18 and older
doxepin (tricyclic) Sinequan 12 and older
duloxetine (SNRI) Cymbalta 18 and older
escitalopram (SSRI) Lexapro 18 and older; 12 - 17 (for major depressive disorder)
fluoxetine (SSRI) Prozac 8 and older
fluoxetine (SSRI) Sarafem 18 and older for premenstrual dysphoric disorder (PMDD)
fluvoxamine (SSRI) Luvox 8 and older (for OCD only)
imipramine (tricyclic) Tofranil 6 and older (for bedwetting)
imipramine pamoate (tricyclic) Tofranil-PM 18 and older
isocarboxazid (MAOI) Marplan 18 and older
maprotiline (tricyclic) Ludiomil 18 and older
mirtazapine Remeron 18 and older
nortriptyline (tricyclic) Aventyl, Pamelor 18 and older
paroxetine (SSRI) Paxil 18 and older
paroxetine mesylate (SSRI) Pexeva 18 and older
phenelzine (MAOI) Nardil 18 and older
protriptyline (tricyclic) Vivactil 18 and older
selegiline Emsam 18 and older
sertraline (SSRI) Zoloft 6 and older (for OCD only)
tranylcypromine (MAOI) Parnate 18 and older
trazodone Desyrel 18 and older
trimipramine (tricyclic) Surmontil 18 and older
venlafaxine (SNRI) Effexor 18 and older

Generic Name Trade Name FDA Approved Age
Mood Stabilizing and Anticonvulsant Medications    
carbamazepine Tegretol any age (for seizures)
divalproex sodium (valproic acid) Depakote 2 and older (for seizures)
gabapentin Neurontin 18 and older
lamotrigine Lamictal 18 and older
lithium carbonate Eskalith, Lithobid 12 and older
lithium citrate (generic only) lithium citrate 12 and older
oxcarbazepine Trileptal 4 and older
topiramate Topamax 18 and older

Generic Name Trade Name FDA Approved Age
Anti-anxiety Medications
(All of these anti-anxiety medications are benzodiazepines, except buspirone.)    
alprazolam Xanax 18 and older
buspirone BuSpar 18 and older
chlordiazepoxide Librium 18 and older
clonazepam Klonopin 18 and older
clorazepate Tranxene 18 and older
diazepam Valium 18 and older
lorazepam Ativan 18 and older
oxazepam (generic only) oxazepam 18 and older

Generic Name Trade Name FDA Approved Age
ADHD Medications
(All of these ADHD medications are stimulants, except atomoxetine)    
amphetamine Adderall 3 and older
amphetamine (extended release) Adderall XR 6 and older
atomoxetine Strattera 6 and older
dexmethylphenidate Focalin 6 and older
dexmethylphenidate (extended release) Focalin XR 6 and older
dextroamphetamine Dexedrine, Dextrostat 3 and older
lisdexamfetamine dimesylate Vyvanse 6 and older
methamphetamine Desoxyn 6 and older
methylphenidate Ritalin 6 and older
methylphenidate (extended release) Metadate CD, Metadate ER, Ritalin SR 6 and older
methylphenidate (long-acting) Ritalin LA, Concerta 6 and older
methylphenidate patch Daytrana 6 and older
methylphenidate (oral solution and chewable tablets) Methylin 6 and older

Liking and wanting of drug and nondrug
rewards in active cocaine users:


Few studies have examined the subjective value attributed to drug rewards specifically as it compares with the value attributed to primary non-drug rewards in addicted individuals. The objective of this study is to assess ‘liking’ and ‘wanting’ of expected ‘drug’ rewards as compared to ‘food’ and ‘sex’ while respondents report about three different situations (‘current’,and hypothetical ‘in general’, and ‘under drug influence’).

In all, 20 cocaine-addicted individuals (mean abstinence = 2 days) and 20 healthy control subjects were administered the STRAP-R (Sensitivity To Reinforcement of Addictive and other Primary Rewards) questionnaire after receiving an oral dose of the dopamine agonist methylphenidate (20 mg) or placebo. The reinforcers’ relative value changed within the addicted sample when reporting about the ‘under drug influence’ situation (drug > food; otherwise, drug < food). This change was highest in the addicted individuals with the youngest age of cocaine use onset.

Moreover, ‘drug’ ‘wanting’ exceeded ‘drug’ ‘liking’ in the addicted subjects when reporting about this situation during methylphenidate. Thus, cocaine-addicted individuals assign the highest subjective valence to ‘drug’ rewards but only when recalling cue-related situations. When recalling this situation, they also report higher ‘drug’ ‘wanting’ than hedonic ‘liking’, a motivational shift that was only significant during methylphenidate.

Together, these valence shifts may underlie compulsive stimulant abuse upon pharmacological or behavioural cue exposure in addicted individuals. Additional studies are required to assess the reliability of the STRAP-R in larger samples and to examine its validity in measuring the subjective value attributed to experienced reinforcers or in predicting behaviour.

Key words
cue reactivity; methylphenidate; motivation; primary rewards; reinforcement; relative valence; salience

Introduction


Few studies have examined the subjective value attributed to drug rewards specifically as it compares with the value attributed to primary non-drug rewards in addicted individuals. In the current study, we, therefore, asked the following question: how do addicted individuals subjectively value expected drug versus non-drug reward?

The literature suggests three possibilities:

(A) Animal research suggests that after chronic drug administration the value of a drug reward is increased (Ahmed, et al., 2002; Ahmed and Koob, 1998), whereas that of a nondrug reward is decreased (Grigson and Twining, 2002). Similarly, human cocaine-addicted subjects but not controls showed reduced activation of corticolimbic brain areas when viewing an erotic (non-drug) video than when exposed to a cocaine video (Garavan, et al., 2000). (B) In contrast, other human studies show blunted subjective responses to drug rewards (intravenous methylphenidate) suggesting reductions in the subjective value of drug reward in addicted individuals (Volkow, et al., 1997). (C) Yet, another possibility is that of a generally drug-sensitised brain reward circuit where heightened drug motivation may ‘spillover’ to non-drug rewards (Robinson and Berridge, 2003). Here, evidence from animal studies suggests that drug sensitization can increase the incentive value of other rewards, such as sucrose or other foods, a sexually receptive female (for male rats), and conditioned stimuli for such rewards (Fiorino and Phillips, 1999a; b; Nocjar and Panksepp, 2002; Taylor and Horger, 1999; Wyvell and Berridge, 2001). Similarly, in human addicted individuals, evidence suggests that some cocaine-addicted individuals are hypersexual (Washton and Stone-Washton, 1993) and some substancedependent individuals may be hyper-responsive to money rewards (Bechara, et al., 2002), rating $10 to be equally valuable to $1000 (Goldstein, et al., 2007).

These discrepancies may in part relate to the dissociation between the subjective value of an expected reward (before it is received) and the perception of the reward at time of consumption (when it is received/experienced). These discrepancies may also relate to how valence/salience is defined. For example, in most self-administration or neuroimaging studies, drugrelated valence is assessed as craving or drug ‘wanting’. In contrast, in theoretical accounts of drug addiction, the incentive motivational aspects of drugs are hypothesized to be dissociated from their hedonic effects; ‘wanting’ drugs (e.g., how much an animal will work to acquire a drug) increases to pathological levels without a parallel increase in drug ‘liking’ (Robinson and Berridge, 1993; 2001; 2003).

This specific hypersensitivity (i.e., sensitization) to the incentive motivational (i.e., ‘wanting’) effects of drugs (and drug-related stimuli) is hypothesized to ultimately lead to increasingly compulsive patterns of drug-seeking and drug-taking behaviour. Our primary goal in the current study was to design a brief questionnaire of the perceived subjective value attributed to expected/hypothetical drugs and other primary reinforcers (food and sex) by cocaine-addicted individuals. We also aimed to distinguish subjective appraisal of drug ‘wanting’ from drug ‘liking’ (hedonic ratings of pleasantness). Given that reward value may differ depending on the availability of drug-related cues (Shaham, et al., 2003), we inquired not only about the ‘current’ (laboratory) setting but also about two reallife situations (‘in general’ and ‘under drug influence’; the latter hypothetical situation was presumed to be most cue reactive).

We hypothesized that cocaine-addicted individuals would provide (1) overall higher ratings for drug versus food or sex, especially when recalling the ‘under drug influence’ situation; (2) higher drug ‘wanting’ than drug ‘liking’ ratings, especially during the effects of oral methylphenidate. This latter hypothesis rests on previous results from our laboratory showing that methylphenidate enhances saliency of events by increasing dopamine in both drug-addicted (Volkow, et al., 1999a) and drug-naive (Volkow, et al., 1999b) individuals.

Methods

Participants

The sample consisted of 20 cocaine-addicted subjects and 20 healthy comparison subjects. The groups did not differ in distributions of sex and race or in mean education and general intellectual functioning (Table 1). Group differences in age and history of cigarette smoking were accounted for as further described in Results. Cocaine-addicted subjects were those who met DSM-IV criteria for active cocaine dependence and had at least a 6-month history of cocaine abuse (at least 2 g of cocaine per week – smoked or intravenous routes of administration) (see Table 1 for drug use variables). Exclusion criteria were history of a neurological disease of central origin, head trauma causing loss of consciousness > 30 min, psychiatric disease (apart from cocaine dependence for the cocaine-addicted subjects), medical conditions that may have altered cerebral function, glaucoma, cardiovascular disorders, arrhythmia and hypertension as verified by a medical and neurological examination of all subjects. Subjects were also excluded for presence of any psychoactive drugs or their metabolites (other than cocaine for the cocaine-addicted subjects, indicating cocaine use within the past 72 h) as verified by a urine drug screen (a triage urine panel, Biopsych™) performed the morning of each study day. Women who were pregnant (urine pregnancy test: STAT) or breastfeeding were also excluded. Exclusion criteria for the control subjects were the same, except any history of drug abuse or dependence or a positive urine screen for any drugs was prohibitive.

Subjects were fully informed of the nature of the research and provided a written consent for their involvement in this study in accordance with the local Institutional Review Board.

Procedure
A brief measure (Sensitivity To Reinforcement of Addictive and other Primary Rewards; STRAP-R) was devised (Table 2). Subjects were asked to think about their favourite food, sexual activity and drug or alcohol without reporting the exact stimulus/activity to the interviewer such that privacy was maintained (and demand characteristics reduced) at all times. For ‘liking’, subjects rated ‘How pleasant would it be to eat it (food), do it (sex) or use/ drink it (drug)’. For ‘wanting’, subjects rated ‘How much do you want to eat it (food), do it (sex) or use/drink it (drug)’. The same questions were repeated for three different situations: ‘current’, ‘in general’, and hypothetically while ‘under drug influence’ of their favourite drug.a A Likert-type scale was used for all questions, ranging from 1 (‘somewhat’) to 5 (‘extremely’). Question order was fixed across all study subjects (Table 2). a

The meaning of ‘under drug influence’ probably differs as a function of drug use history (control subjects may have thought about marijuana, alcohol, cigarettes or coffee or experimentation with other drugs). an expected response given the experimental environment). However, in contrast to the control subjects, this interaction in the cocaine group was also driven by (1) ‘food’ ratings in the ‘under drug influence’ situation, now lowest as compared to the other rewards and (2) ‘sex’ ratings that were significantly decreased in the ‘under drug influence’ as compared to the ‘in general’ situation (‘drug’ was similarly rated in both these situations). There were no associations between the STRAP-R ratings during placebo with age or history of cigarette smokingIV. Methylphenidate, cocaine-addicted subjects

The same pattern of results was observed under methylphenidate, although now a question (‘liking’ > ‘wanting’) and a situation × question interaction were also significant (Fs > 14.9, ps < 0.01) (Figure 4). This latter interaction was explained by higher ‘liking’ than ‘wanting’ ratings across all, but the ‘under drug influence’ situation, where the opposite pattern was observed: here, ‘wanting’ ratings exceeded ‘liking’ ratings (t19 = −3.2, p < 0.01). Follow-up paired t-tests showed that this effect was unique for the ‘drug’ ratings (t19 = −2.3, p < 0.05) (in contrast, recall the main effect of question in the healthy control subjects, where ‘liking’ always exceeded ‘wanting’, even while rating ‘drug’ ‘under drug influence’ during methylphenidate, t19 = 4.1, p < 0.01, Figure 2). There were no
associations between the STRAP-R ratings during methylphenidate with age or history of cigarette smoking in the cocaineaddicted individuals.

Correlations


To further understand this pattern of results in the cocaineaddicted individuals, where ‘drug’ ratings were higher than ‘food’ or ‘sex’ ratings ‘under drug influence’ and where ‘drug’ ‘wanting’ exceeded drug ‘liking’ ‘under drug influence’ during methylphenidate, we performed correlations between several selected dependent variables with drug use variables (listed in Table 1). Specifically, we chose to calculate the difference between ‘under drug influence’ ratings for ‘drug’ and the other reinforcers (averaged across placebo and methylphenidate, and across ‘liking’ and ‘wanting’) and also the difference between ‘under drug influence’ ‘wanting’ and ‘liking’ for ‘drug’ vis-à-vis the other reinforcers during methylphenidate only. A correlation between the differential ‘under drug influence’ ‘drug’ versus ‘food’ ratings with age of cocaine use onset was significant (r = −0.70, p < 0.01) (Figure 5); there was a similar trend for duration of use (r = 0.53, p < 0.05). The former correlation survived corrections (with partial correlations) for age, history of cigarette smoking and mean number of cigarettes smoked per day (rs > −0.70, ps < 0.001). The other correlation remained at a trend level across all these analyses.

Of interest were also the correlations between ‘liking’ and ‘wanting’, especially ‘under drug influence’ during methylphenidate. In the control subjects, these correlations were significant for all three rewards (rs > 0.63, p < 0.01). In contrast, in the cocaine-addicted individuals, ‘liking’ and ‘wanting’ were significantly intercorrelated for ‘food’ and ‘sex’ only (rs > 0.83, p < 0.0001) but not for ‘drug’ (r = −0.04, p > 0.9) ratings. These correlations provide support for the ANOVA results reported above (IV) further indicative of a dissociation between ‘drug’ ‘wanting’ and ‘liking’ ‘under drug influence’ during methylphenidate in the cocaine-addicted individuals.

Discussion


Using the newly developed STRAP-R questionnaire, we describe two main findings. First, the relative value of the three expected reinforcers (food, sex, drug) was uniquely modulated by the reported situation in the cocaine-addicted individuals. Specifically, ratings of ‘food’ exceeded ratings of ‘drug’ during the ‘current’ situation; similarly, ratings of ‘food’ and ‘sex’ exceeded ratings of ‘drug’ when reporting about an ‘in general’ situation. In contrast, when reporting about the ‘under drug influence’ situation, this pattern was reversed. In this situation ratings of ‘drug’ exceeded ratings of the other expected reinforcers (statistically significant for ‘food’) only in the drug-addicted group. The specificity of this unique reinforcer value shift to the ‘under drug influence’ situation may reflect conditioned responses to cue-induced increases in dopamine; in line with the current results, we previously suggested these conditioned responses to trigger an intense desire for cocaine, possibly exceeding desire for all other non-drug reinforcers (Volkow, et al., 2006). In general, these STRAP-R results add to an impressive body of work on the subjective effects of drugs in addicted individuals (Fox, et al., 2005; Gawin, 1991; Lasagna, et al., 1955; Leyton, et al., 2005; Von Felsinger, et al., 1955). Our current results provide further evidence in support of the possibility that in addiction, drug

A correlation between the STRAP-R and cocaine use onset in cocaine-addicted individuals. Differential STRAP-R ratings for ‘drug’ minus ‘food’ ‘under drug influence’ (averaged across ‘liking’ and ‘wanting, placebo and methylphenidate) plotted against age of onset of cocaine use in
20 cocaine-addicted individuals.


Under the Influence

The value of food, sex and drugs in cocaine-addicted individuals during methylphenidate. Mean STRAP-R ratings (± standard error of the mean) for three reported situations: (A) current; (B) in general and (C) hypothetical ‘under drug influence’ in 20 cocaine-addicted subjects as a function of three reinforcers (food, sex, drug) and two questions (‘liking’, ‘wanting’) during 20 mg oral methylphenidate. The STRAP-R in cocaine abusers reward value is increased (Ahmed, et al., 2002; Ahmed and Koob, 1998), whereas non-drug reward value is decreased (Grigson and Twining, 2002). Evidence for the other two possibilities (blunted versus sensitised value) remains to be tested
with direct group comparisons and with consumatory (versus expected) rewards.

Of note is the fact that the low ratings of ‘food’ ‘under druginfluence’ in the cocaine-addicted subjects may be indicative of cocaine’s acute anorexigenic effects [and followed by episodes of rebound hunger (Williamson, et al., 1997)]. In contrast, in the healthy control subjects, food value may not have decreased when recalling the ‘under drug influence’ situation, as these individuals may have been imagining how they felt under the effects of marijuana. Nevertheless, a significant negative
correlation with age of cocaine use onset, whereby the largest drug > food shift characterised the cocaine-addicted individuals with the youngest age of cocaine use onset, suggests this value shift may represent a cumulative (and not acute) effect of drug use. One could also entertain the possibility that this drug > food relative value differential may be a factor that predisposes individuals to more intense early drug experimentation and subsequent development of drug addiction.

Our second finding is partially consistent with the drugrelated sensitization concept of the incentive motivation model (Robinson and Berridge, 1993; 2001; 2003). Consistent with this model, cocaine-addicted individuals reported ‘wanting’ drugs more than ‘liking’ drugs. However, this result was significant only when subjects recalled drug-related situations during methylphenidate (a similar trend was observed during placebo). The specificity of this ‘drug’ ‘wanting’ > ‘liking’ motivational shift to the ‘under drug influence’ situation (recall of the last time the individual was high/buzzed) and its enhancement by methylphenidate, a dopamine agonist and stimulant, suggest the impact on results of the following factors: (A) heightened arousal/autonomic reactions (Carter and Tiffany, 1999; Ehrman, et al., 1992; Glautier and Drummond, 1994; Margolin, et al., 1994; Sinha, et al., 2000); (B) ‘fresher’ memory traces of drug effects (Lee, et al., 2006); (C) increased craving/desire/drug-urges (Garavan, et al., 2000; Madden, et al., 1997; Robbins, et al., 1992; Volkow, et al., 2006); (D) dopaminergic amplification of stimuli salience (Volkow, et al., 2002; Volkow, et al., 2004); or (E) an interaction between these factors (Brody, et al., 2002). Overall, this shift (or dissociation between ‘drug’ ‘wanting’ and ‘liking’) may contribute to compulsive drug use even when the substance is no longer pleasurable (Fischman, et al., 1985). With few exceptions (Willner, et al., 2005), most human studies in drug users appear to similarly support the incentive motivation model.

For example, an alcohol prime (but not a juice prime) increased alcohol ‘wanting’ in heavy and light
social-drinkers as measured by increased alcohol consumption; however, priming did not increase alcohol ‘liking’ as measured by taste ratings (Hobbs, et al., 2005). Correspondingly, Lambert, et al. (2006) reported a dissociation of ‘wanting’ from ‘liking’ in adult cocaine users who were studied prospectively from childhood into adulthood. Exposure to both stimulant treatment (for symptoms of attention deficit and hyperactivity disorder) and regular cigarette smoking predicted the highest ‘wanting’ for cocaine (self-report of ‘always wanted more’) and the lowest ‘liking’ (self-reported global positive effects from cocaine) (Lambert, et al., 2006). A recently developed computer-based experimental procedure similarly showed a unique pattern of dissociations between ‘wanting’ (forcedchoice photographic procedure) and ‘liking’ (pleasantness ratings) of food stimuli in 60 healthy individuals depending on their state (hungry versus after an ad-libitum meal) (Finlayson, et al., 2007). Our current parallel results indicate that the STRAP-R could provide a rapid alternative to these more time consuming experimental procedures, especially when administered in combination with a salience-enhancing agent (such as the dopamine agonist methylphenidate). Study limitations: (A) Given the experimental differences between the study groups, we analysed results separately for the cocaine addicted versus control subjects; direct comparisons with a healthy control group undergoing the same experimental protocol remain to be performed; (B) the psychometric properties of this instrument need to be tested in larger samples; it would be of particular interest to study whether the STRAP-R ratings predict behaviour [e.g., selection of drug
over monetary rewards (Madden, et al., 1997)] and (C) results need to be tested in other drug using groups, such as those with longer withdrawal periods (Grimm, et al., 2003), in recreational cocaine users and in users of other drugs such as marijuana, alcohol, opiates or methamphetamine (Newton, et al., 2005).

For future uses of the STRAP-R, the following changes could be implemented: (A) ask about specific reinforcers to reduce potential inter-subject variability; (B) administer the questioquestions in a randomised order or consider reversing the order of the questions, asking first about ‘wanting’ then about ‘liking’; (C) allow subjects to rate experiences as negative, which will allow studying reward avoidance or the effect of negative reinforcement; and most importantly (D) obtain the STRAP-R ratings during actual reinforcement experience.

For example, the STRAP-R could be used to test reinforcer deprivation (e.g., food-deprived healthy control subjects compared with drug-withdrawn addicted individuals) or reinforcer consumption (eating versus drug intoxication).

In summary, results of this brief questionnaire, the STRAP-R, developed based on translation of principles from basic animal research, suggest a shift in the valuation of drugs as compared to other primary rewards in cocaine addiction. This shift is most clearly expressed when subjects are in a cue-related context (behaviourally: when reporting an ‘under drug influence’ situation; and more so, pharmacologically: during methylphenidate). In this cue-related context, drug valence exceeds that of food or sex, a potent social reinforcer; here, drugs are also wanted more than they are liked. This relative paling of other rewards in the environment, and the increase in the drug’s incentive motivation over its hedonic properties, may predispose the drug-addicted individual to compulsive drug use, uninterrupted by the promise of attaining other no-longer salient rewards. These results, thus, support our working hypothesis that drug-addicted individuals disproportionately attribute salience, or value, to their drug of choice with a concomitant decrease in the value of other primary
rewards (Goldstein and Volkow, 2002), an impairment that is expressed when recalling or during a drug cue-induced situation.


Acknowledgements
This study was supported by grants from the National Institute on Drug Abuse (to RZG: 1R01DA023579 and R21DA02062); Laboratory Directed Research and Development from U.S. Department of Energy (OBER); National Institute on Alcohol Abuse and Alcoholism (2RO1AA09481); and General Clinical Research Center (5-MO1-RR-10710). Notice: This manuscript has been authored by Brookhaven Science Associates, LLC under Contract No. DE-AC02-98CHI-886 with the U.S. Department of Energy. The United States Government retains, and the publisher, by accepting the article for publication, acknowledges, a world-wide license to publish or reproduce the published form of this manuscript, or allow others to do so, for the United States Government purposes.

FDA warning on antidepressants
Antidepressants are safe and popular, but some studies have suggested that they may have unintentional effects, especially in young people. In 2004, the FDA looked at published and unpublished data on trials of antidepressants that involved nearly 4,400 children and adolescents. They found that 4 percent of those taking antidepressants thought about or tried suicide (although no suicides occurred), compared to 2 percent of those receiving placebos (sugar pill).

In 2005, the FDA decided to adopt a "black box" warning label—the most serious type of warning—on all antidepressant medications. The warning says there is an increased risk of suicidal thinking or attempts in children and adolescents taking antidepressants. In 2007, the FDA proposed that makers of all antidepressant medications extend the warning to include young adults up through age 24.

The warning also says that patients of all ages taking antidepressants should be watched closely, especially during the first few weeks of treatment. Possible side effects to look for are depression that gets worse, suicidal thinking or behavior, or any unusual changes in behavior such as trouble sleeping, agitation, or withdrawal from normal social situations. Families and caregivers should report any changes to the doctor. To find the latest information visit the FDA website.

Results of a comprehensive review of pediatric trials conducted between 1988 and 2006 suggested that the benefits of antidepressant medications likely outweigh their risks to children and adolescents with major depression and anxiety disorders.5 The study was funded in part by NIMH.

Finally, the FDA has warned that combining the newer SSRI or SNRI antidepressants with one of the commonly-used "triptan" medications used to treat migraine headaches could cause a life-threatening illness called "serotonin syndrome." A person with serotonin syndrome may be agitated, have hallucinations (see or hear things that are not real), have a high temperature, or have unusual blood pressure changes. Serotonin syndrome is usually associated with the older antidepressants called MAOIs, but it can happen with the newer antidepressants as well, if they are mixed with the wrong medications.

Psychopharmacology of anxiety disorders
Giovanni B. Cassano, MD
Giovanni B. Cassano, Department of Psychiatry, Neurobiology, Pharmacology, and Biotechnology, University of Pisa, Pisa, Italy ;
Nicolò Baldini Rossi, MD
Nicolò Baldini Rossi, Department of Psychiatry, Neurobiology, Pharmacology, and Biotechnology, University of Pisa, Pisa, Italy ;
Stefano Pini, MD*
Stefano Pini, Department of Psychiatry, Neurobiology, Pharmacology, and Biotechnology, University of Pisa, Pisa, Italy ;
© 2002 LLS
This is an open-access article distributed under the terms of the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Exposure of the general population to a 1:4 lifetime risk of disabling anxiety has inspired generations of fundamental and clinical psychopharmacologists, from the era of the earliest benzodiazepines (BZ) to that of the selective serotonin reuptake inhibitors (SSRIs) and related compounds, eg, the serotonin and norepinephrine reuptake inhibitors (SNRIs). This comprehensive practical review summarizes current therapeutic research across the spectrum of individual disorders: generalized anxiety disorder (GAD), panic disorder (PD) and agoraphobia (social anxiety disorder), compulsive disorder (OCD), phobic disorder (including social phobia), and posttraumatic stress disorder (PTSD). Specific diagnosis is a precondition to successful therapy: despite substantial overlap, each disorder responds preferentially to specific pharmacotherapy. Comorbidity with depression is common; hence the success of the SSRIs, which were originally designed to treat depression. Assessment (multidomain measures versus individual end points) remains problematic, as-frequently-do efficacy and tolerability The ideal anxiolytic remains the Holy Grail of worldwide psychopharmacologic research.

Keywords: generalized anxiety disorderpanic disordersocial anxiety disorderposttraumatic stress disorderobsessive compulsive disorderbenzodiazepineantidepressant

Anxiety disorders are the most common and among the most disabling of mental disorders in adults and adolescents.Although many are highly circumscribed fears of mild-to-modcratc severity, it has been estimated by the Epidemiological Catchment Area (RCA) study that approximately one quarter of people will experience severe symptoms, disability, and handicap as a consequence of anxiety disorders at some time during their lifetime. These disorders are associated with significant morbidity and increased mortality, probably as a consequence of increased suicide rates among sufferers. The direct and indirect costs to the health service and economy are considerable. Although persons who suffer from anxiety disorders are high consumers of all types of health services, only a minority receive specific help

The spectrum of anxiety disorders includes generalized anxiety disorder (GAD), panic disorder (PD) and agoraphobia, obsessive-compulsive disorder (OCD), phobic disorder (including social phobia), and posttraumatic stress disorder (PTSD). With the discovery of new psychotropic medications, specific diagnosis within this spectrum is essential because each of these disorders responds to specific pharmacotherapy. The approach to anxiety should also recognize that anxiety and depression are often comorbid conditions.

Selective serotonin reuptake inhibitors (SSRIs), which were designed to treat depression, are also effective for many anxiety disorders. They have revolutionized the treatment of anxiety, replacing chronic use of benzodiazepines (BZs). SSRIs are effective for OCD, PDs, phobias, PTSD, and GAD (see Table I). Other antidepressants, including tianeptine, have proven effective in adjustment disorders in which both anxiety and depression are involved. Doses of SSRIs for anxiety disorders could be higher than those used for depression, but must be started at lower doses to minimize the shortterm agitation sometimes experienced with these medications. The patient should be counseled that side effects often diminish with time and also that empirical switching to another SSRI may be necessary.

Table I.
Common medications used in the treatment of anxiety. FDA, Food and Drug Administration; GAD, generalized anxiety disorder; OCD, obsessive-compulsive disorder; PD/AG, panic disorder/agoraphobia; PTSD, posttraumatic stress disorder; SAD, social anxiety ...

Although tricyclic antidepressants (TCAs) have been used with success in anxiety disorders (Table I),drowsiness, anticholinergic side effects, and toxicity have made these medications less popular. Also, monoamine oxidase inhibitors (MAO Is) are effective for anxiety, but their dietary restrictions and side-effect profile have limited their use.

BZs are the oldest, class of medications used to treat anxiety. Although they have the advantage of rapid onset of action, they carry the risk of dependence, sedation, and tolerance. Withdrawal syndromes resulting in rebound anxiety, even reactions as severe as delirium tremens, are possible. BZs should be avoided in patients with a past, history of substance abuse, personality disorder, or dosage escalation. These medications are ideal for patients who experience infrequent bouts of anxiety or episodes of anxiety-related insomnia.

Buspirone is a. nonbenzodiazepine indicated for GAD. In head-to-head trials, it works as well as BZs for GAD, but has a slower onset, of action and lacks sedative properties. It is therefore less useful for the anxious patient who needs a sedative. It does not impair alertness and lacks abuse potential.

A number of well-controlled clinical trials support the empirical evidence of effective pharmacotherapy of anxiety disorders. However, the ideal anxiolytic does not. exist, and current research into some new compounds is very active and promising. Pharmacological treatment evidence for each anxiety disorder will be briefly reviewed.

Generalized anxiety disorder

Benzodiazepines

Several studies have documented that BZs are more effective than placebo in GAD.5-9 There is also evidence that BZs may be more effective on specific GAD symptoms, particularly the somatic/autonomic symptoms in contrast to the psychic symptom cluster, which includes apprehensive worry and irritability.10For example, several studies have shown that irritability may worsen in conjunction with high-potency BZs,11 and that low levels of depressive symptoms may predict a less favorable response to BZs.9 Other data suggest that, although they respond less well to BZs, psychic symptoms may be more responsive to other drugs altogether, such as buspirone or imipramine.9-10,12 Overall, BZs still remain a widely used treatment option for GAD, partly no doubt because of their rapid onset of action, with maximum effect achieved within 2 weeks, and their generally good tolerance9,10; however, there are few controlled data to support continued benefits of BZs in the long term in GAD. Information from some 6 to 8 months' maintenance therapy trials have found continued efficacy over time,14-17 but since GAD is often a long-term and unremitting disorder,18 it needs to be stated that pharmacotherapy, whether with BZs or other drugs, may need to continue for many years in a significant, number of patients.

Results generally show that approximately 70% of patients will respond to adequate BZ treatment (up to 40 mg/day of diazepam or equivalent for at least 3-4 weeks), but less than two thirds will achieve remission of symptoms. In long-term use, tolerance to side effects does occur, but tolerance to the anxiolytic effect of the BZs does not appear.19 With regard to dependence and withdrawal, compounds with a slower onset, of action, for example, oxazepam, have little reinforcing potential, while those with a long half -life, for example, diazepam and chlordiazepoxide, have a lower propensity to produce withdrawal symptoms, even if stopped abruptly. Anyway, discontinuation of acute treatment should be slow because of the potential for rebound anxiety and/or clinical relapse, and an adequate pretreatment assessment should be an important step to evaluate whether a subject would be suitable for BZ therapy, including previous history of withdrawal, liability of abuse, or likelihood of poor compliance. For this reason, and because of the high prevalence of comorbid depression, attention has focused also on different medications and antidepressants as potential treatment for GAD (Table II).

Generalized anxiety disorder (GAD): therapeutic strategies. BZ, benzodiazepine; SSRI, selective serotonin reuptake inhibitor; TCA, tricylic anti-depressant.

Azapirones

Ilic first pharmacological treatment for GAD beyond BZs was the azapirone buspirone, a partial 5-hydroxytryptamine (serotonin, 5-HT)-lA (5-HT1A) agonist, which decreases the function of postsynaptic 5-HT2 receptors. It has been demonstrated to show efficacy in GAD10,20-22 and has been associated with maintenance of efficacy over a period of several months.15,16

Buspirone is given in two or three divided doses up to 60 mg/day, and its effect is usually not apparent until 2 to 3 weeks into treatment, in contrast to the almost immediate effects of BZs. It is not sedating like the BZs; it is not associated with psychomotor impairment, tolerance, dependence, or withdrawal; and it docs not interact with alcohol.

The drug works well when there are conspicuous symptoms of worry, apprehensive tension, and irritability, and where depressive symptoms are intermixed with anxiety,23 while it is less effective than BZs on somatic and autonomically driven symptoms. Patients who have had previous good responses to BZs do not appear to respond as well to buspirone, probably due to the lack of sedative effect, and inability to alleviate BZ withdrawal symptoms, but starting buspirone 2 to 3 weeks before tapering the BZs has produced better results.

Other azapironc drugs have been assessed in GAD, like gepirone, ipsapirone, and more recently flesinoxan and tandospirone, but with more equivocal results.

Antidepressants

Although antidepressants are now well-established treatments of choice in several anxiety disorders (eg, PD, social phobia, OCD, and PTSD), their role in the treatment of GAD remains unclear. Little attention has been given to the fact, that several studies have provided encouraging support for their efficacy. Perhaps the obscurity of these findings relates to the general uncertainty about the nature of GAD, its constantly changing criteria, and the apparent, belief that it is a highly placebo-responsive disorder. Early retrospective analyses of subjects with anxiety neurosis have supported the possible efficacy of tricyclic drugs in GAD-like states. Further controlled trials by Kahn et al, Hoehn-Saric et al, and Rickels et al have provided evidence for the benefit of imipramine and trazodone in GAD. Imipramine was more effective than diazepam on psychic anxiety symptoms, and it would also be expected to have significant, antidepressant effects. Its reuptake-inhibiting effects on serotonin and norepinephrine confer a double advantage relative to some of the more selective compounds mentioned above.

Trazodone, a serotonin reuptake inhibitor (SRI) and 5-HT2 receptor antagonist, has also been found to be effective and remains a little-used, but potentially effective drug for the disorder at doses of up to 400 mg/day, with doses of 200 to 300 mg/day often being sufficient. However, due to its side-effect profile, trazodone is unlikely to be a first choice, but can be a useful backup drug for more difficult, to treat, or nonresponsive patients. Its hypnotic properties are also useful where insomnia is a major problem.

Nefazodone is a combined SRI, 5-HT2 antagonist, and weak adrenergic antagonist, which may also be beneficial in GAD. Nefazodone enjoys the advantage of greater patient acceptability and tolerability than trazodone. One open-label study in GAD has suggested benefit, for this drug, as is also the case for the SSRI paroxetine.

The most, recent, development in the pharmacotherapy of GAD, largely out of consideration of the results of the studies with TCAs, has been the controlled comprehensive trials with venlafaxine, a serotonin and norepinephrine reuptake inhibitor (SNRI). In five placebo-controlled 8-week trials, venlafaxine has demonstrated efficacy significantly greater than placebo in the treatment, of GAD patients without, accompanying depression. Venlafaxine (75, 150, and 225 mg/day) produced greater effects than placebo after 1 week of the study, and these improvements were maintained throughout the remainder of trialsThese findings were replicated in a large 6-month trial evaluating long-term treatment of GAD. Although most of the improvement on venlafaxine occurred in the first 4 weeks, subjects continued to improve over the 6-month period. Current trials have not established an optimal dosage for venlafaxine in the treatment of GAD, with positive results observed at dosages as low as 37.5 mg/day. However, data suggest that 75 to 150 mg/day is probably the most appropriate dosage range. Mild side effects including nausea, insomnia, dry mouth, and dizziness were principally seen at the initiation of treatment and cleared up over time.

Another double-blind, 8-week study compared venlafaxine (up to 150 mg/day), with buspirone (up to 30 mg/day), and placebo in outpatients with GAD. Both drugs were superior to placebo, but venlafaxine showed an earlier effect and advantage over buspirone in secondary outcome measures, notably the Hamilton Depression Scale anxiety subscore.

The results of these studies indicate that antidepressants offer promise in GAD, even if they appear to be better in treating psychic anxiety symptoms, while BZs are probably superior in treating the somatic symptoms.

Other drugs

Several other drugs have been assessed in GAD. The well-established anxiolytic effects of BZs are modified by several drawbacks, primarily of physical dependence, withdrawal symptoms, and sedation. The development of partial agonists at the y-aminobutyric acid (GAB A)/ BZ receptor complex offers some potential advantages over the traditional BZs. These BZ-like compounds should be effective anxiolytics, but less likely to produce sedation, tolerance, withdrawal, abuse liability, memory impairment, and ethanol potentiation. These newly developed compounds are either BZ derivatives or of a different, chemical structure, that is, imidazopyridine and P-carbolines. The most comprehensively studied has been the P-carboline abecarnil. In an initial double-blind trial, Ballenger et al demonstrated clinical efficacy at doses in the range of 3 to 9 mg/day, without withdrawal symptoms after short-term treatment. Further placebocontrolled studies have shown modest treatment effects; however, at higher doses, there is some evidence of withdrawal symptoms.

Hydroxyzine, an antihistaminergic compound, has been reported to produce improvement in 60% to 90% of patients with GAD. It can be very sedating when high doses are used (50 and 100 mg qid),but a more recent study showed that it can be effective at low doses (50 mg/day) as well. After 5 weeks of treatment, 86% of the patients improved compared with 47% with placebo, and the drug was well tolerated.

β-Blockers have been used for the treatment of some anxiety disorders, but the evidence so far does not support, their use in GAD.

Finally, anecdotal experiences report, potential value of kava and passionflower extract in the treatment, of GAD.

Panic disorder

Benzodiazepines

Alprazolam, the first licensed BZ for the treatment of panic, was studied in a large multinational placebo-con trolled trial (Cross National Collaborative Panic Study) conducted in two 8-week phases: during the first it was compared with placebo, and then it was compared with both placebo and imipramine. Patients showed significant improvements in all major symptom areas, like number of panic attacks, avoidance behavior, and residual anxiety between attacks, with improvements also maintained in longer-term studies. Other high-potency BZs, such as clonazepam and lorazepam, showed similar efficacy. BZs are usually well tolerated and they have a rapid onset of action (1-2 weeks). Potential problems with long-term use of BZs in PD are tolerance, dependence, and withdrawal symptoms on discontinuation, but a 2.5-year naturalistic follow-up study found little evidence of tolerance to the antipanic effect of alprazolam, and efficacy was maintained without, dose escalation.

Although some studies have failed to observe a difference between alprazolam and imipramine in treatment of the common comorbid depressive symptoms, several large meta-analyses have suggested a reduced efficacy for the BZs compared with TCAs and antidepressants in general (Table III). 

Table III.
Panic disorder (PD): therapeutic strategies. BZ, benzodiazepine; SSRI, selective serotonin reuptake inhibitor; TCA, tricylic antidepressant.

Antidepressants

Early in the 1960s, investigators documented that imipramine and the MAOIs, particularly phenelzine,were both effective treatments of PD.Other TCAs also proved effective, especially clomipramine, and the improvement, was not dependent on the treatment of concurrent, affective symptoms. Following the demonstration of efficacy of the non-SSRI clomipramine, a number of large randomized trials have now demonstrated the efficacy of SSRIs in PD,both in comparison with placebo and clomipramine. Well-controlled trials provided evidencethat fluvoxaminc, paroxetine, citai opram, sertraline, and fluoxetine have similar efficacies, although comparison trials between different. SSRIs are generally lacking. A recent, effect-size analysis of controlled studies of treatment for PD also revealed no significant, differences between SSRIs and older antidepressants in terms of efficacy or tolerability in short-term trials.As has been observed in all the trials, effective treatments reduce all the symptoms of PD, the frequency and severity of panic attacks, agoraphobic avoidance, anxiety, and comorbid depression. Although there are different responses of each of these symptoms to these treatments (eg, agoraphobic avoidance is the most difficult to treat), successful treatments effectively reduce all these aspects of the PD syndrome, but appropriate outcome measures for PD still remain a problem. Reduction of panic-attack frequency has been widely utilized, but has been unreliable as a single measure, and most investigators now use multidomain measures.

The percentage of patients who become free of panic attacks is generally 50% to 80% in acute trials lasting 6 to 8 weeks with various medications. In patients who are treated for longer periods, this percentage most, often rises. It is generally true that, the longer PD patients are treated, the more complete and comprehensive is their response. In the large Cross-National Collaborative Panic Study, after 8 to 1 2 months of treatment, three fourths of patients were free of panic attacks. In a large 12-month comparison of paroxetine and clomipramine, the panic-free rates were 85% and 72%, respectively, rising from about 55% at 3 months. The anxiety that PD patients experience between panic attacks can be considerable.

This anxiety is reduced by all effective therapies with little difference between treatments. In a similar fashion, most effective treatments decrease the common comorbid depressive symptoms, again generally with little difference between treatments.

Agoraphobia is probably the most treatment-resistant symptom in PD. Although effective pharmacotherapy does significantly reduce agoraphobia avoidance, in vivo exposure is often employed to reduce avoidance behaviors. There is no standard measure employed in the literature of improvement, in agoraphobic avoidance, making comparisons across studies and treatments difficult. Nonetheless, in a review of 16 studies,remission of agoraphobia occurred in ranges varying from 18% to 64%, and in a 12-month naturalistic study, 69% of patients became free of avoidance.

Improvement in agoraphobic avoidance occurs with all the effective treatments, probably more or less equally, although this has not been rigorously studied. The BZs are as effective as antidepressants in reducing avoidance, although effects begin earlier with the BZs. Improvement is seen as early as the first, or second week with BZs and as early as the fourth week with the antidepressants, although improvement in agoraphobia is often the last portion of the syndrome to respond, and patients continue to improve for at least 3 to 6 months. Recent trials suggest that a significant response to antidepressants may occur in the first 2 to 4 weeks, which is earlier than previously thought. An important phenomenon in the early stages of treatment (both with TCAs and SSRIs) could be the paradoxical and transient increase in anxiety and number of panic attacks, the so-called “jittering syndrome.” To initiate treatment at a very low dose, or to cover this first, period with a high-potency BZ, such as clonazepam or alprazolam, could be useful approaches.

Dietary restrictions and side effects have limited the use of MAO Is, but the introduction of the reversible inhibitors of monoamine oxidase A (RIMAs), such as moclobemidc, renewed the interest, in this class of agents. The results, though, so far are conflicting, with an 8-week study showing efficacy for moclobemide in PD,and another one failing to do so. A small case series suggested that venlafaxine may be effective in the treatment of PD, and mirtazapine provided good evidence both in an open-label study with a single-blind placebo run-in period, and in a 8-week double-blind comparison with fluoxetine.Reboxetinc, a selective norepinephrine reuptake inhibitor was effective and well tolerated in an 8-week, placebo-controlled, double-blind trial, with a significant reduction in the mean number of panic attacks and phobic symptoms at doses of 6 to 8 mg/day.

Other drugs

Buspirone in PD failed to show any efficacy even at high doses (60 mg/day).Pagoclone, a cyclopyrrolone that is believed to act as a partial agonist, at the GABAA/BZ receptor provided some preliminary evidence in a crossover trial with placebo. β-Blockers provided conflicting results, with some positive small crossover trials, but a negative double-blind trial of propranolol with alprazolam and placebo. Initial evidence suggested that gabapentin and sodium valproate may be effective in PD, while carbamazepine is not.Also Ca-channel blockers have shown mixed results.

Social anxiety disorder

Benzodiazepines

There is a limited number of controlled studies testing BZs in the treatment of social anxiety disorder. Clonazepam was shown to be effective in one 10-week, double-blind trial versus placebo, with 78% of patients responding to an average dosage of 2.4 mg/day. Almost 85% of patients had some response, with 50% having a marked response and 50% having a moderate one. There has been only one double-blind study of alprazolam, in which Gelernter et a! compared alprazolam (mean dose 4.2 mg/day) with phenelzine, cognitive behavioral group therapy, and placebo over a 12-week period. Only 38% of patients on alprazolam were considered responders at end point compared with 69% on phenelzine, 24% on cognitive behavioral group therapy, and 20% on placebo.

Versiani ct alconducted a 12-weck, double-blind study to compare bromazepam (mean dose 21 mg/day) to placebo, with a response rate of 83% of patients on active drug versus 20% of patients on placebo.

Antidepressants

Only anecdotal evidence supports the efficacy of TCAs for the treatment of social anxiety disorder,mainly due to early observations that, patients with atypical depression with marked interpersonal sensitivity and sociophobic features show a better response with MAOIs than TCAs.

There were three early controlled trials in which phenelzine (up to 90 mg/day) was found to be quite effective, with 64% of patients obtaining clinically significant responses, which increased when treatment was extended to 4 months. These results were replicated by Heimbergetal in 1998.

In a comparison between phenelzine and moclobemide, phenelzine appeared roughly equivalent, but appeared to work faster. By week 16, 91% of the phenelzine patients versus 82% of moclobemide patients were nearly asymptomatic, although moclobemide was better tolerated. In the Gelernter et altrial, phenelzine was also better than alprazolam in terms of efficacy.

As mentioned above, RIMAs have also been studied. Brofaromine (up to 150 mg/day) was promising and roughly comparable to moclobemide, with response rates of 80%, 78%, and 50%. Moclobemide, after the promising results of Versiani et al, produced a less robust, result, in the large multicenter controlled study that followed, in which 600 mg/day was superior to placebo (47% of responders compared with 34% receiving placebo). Another large multicenter trial, as well a single study,failed to confirm the efficacy of this drug in social anxiety.

Certainly the greatest amount of carefully controlled data are from the recent, paroxetine studies. In multicenter, double-blind, placebo-controlled, 12-week trials in severely symptomatic patients with social phobia, 55% of patients had a marked or moderate response at a mean dosage of 36.6 mg/day. Scores on the liebowitz Social Anxiety Scale fell about 40% on paroxetine (30.5 points). Differences were observed in the second week and throughout the remainder of the trial. These positive findings were confirmed by Baldwin et al and Allgulander.

Other controlled trials with SSRIs include fluvoxamine, sertraline, fluoxetine,venlafaxine, and nefazodone. In these trials, the clinically significant response rates of patients were in the 42% to 77% range.

Finally, open trials of citalopram and buproprion have suggested that these drugs may be effective in the treatment, of social anxiety disorder, but controlled studies are needed to confirm preliminary results.

Other drugs

Buspirone has been shown to be effective as a primary treatment in two thirds of patients in early trials, as well as an augmenting agent with SSRIs.One controlled trial failed to find significant, differences between buspirone and placebo. Also the P-blocker atenolol, despite early promise, proved ineffective when tested in patient populations with generalized symptoms of social phobia. Pindolol was no more effective than placebo in augmenting the effects of paroxetine treatment for generalized social phobia.

High doses of gabapentin (3600 mg/day) provided encouraging preliminary results in a 14-week, placebo-controlled study. Pregabalin, a follow-up compound of the G ABA agonist, gabapentin, is being developed for the potential treatment of several central nervous system disorders and anxiety, including social anxiety disorder.

Posttraumatic stress disorder

Benzodiazepines

PTSD is a complex syndrome occurring after one or more traumatic events and involves multiple anxiety symptoms, including flashbacks, emotional numbing, avoidance of the reminders of the event, and so forth. This disorder was first recognized after military combat, but is now seen frequently after rape, assault, and accidents. Although there is no established pharmacotherapy for PTSD, there are multiple medications that seem to be effective in reducing these symptoms, particularly flashbacks, phobic avoidance, depression, anxiety, startle reaction, impulsivity, and hypervigilance (Table IV). BZs seem to be helpful in suppressing hyperarousal symptoms. The first placebo-controlled trial was conducted by Braun et alusing alprazolam up to 6 mg/day. Although the core symptoms of the syndrome (intrusion and avoidant/numbing symptoms) did not improve significantly compared with placebo, they reported a positive effect in subjective well-being and a reduction in anxiety, irritability, and insomnia. Open trials with alprazolam and clonazepam came to similar results, but with drawal symptoms were particularly severe, especially considering the substantial comorbidity of PTSD with alcohol and drug abuse.

Posttraumatic stress disorder (PTSD): therapeutic strategies. SSRI, selective serotonin reuptake inhibitor; TCA, tricylic antidepressant.

O'Brien and Nutt hypothesized that early BZ treatment of trauma survivors may protect toward future development, of PTSD, but the data are still controversial, especially concerning how soon after the event treatment has to be started to offer this protection.

Antidepressants

TCAs have been shown to be helpful in three controlled trials. Imipramine (up to 300 mg/day) decreased intrusive thoughts, nightmares, and flashbacks with no effect on numbing or avoidance in an 8-week study.

Amitriptylinc (up to 300 mg/day) has also been shown to reduce avoidance and anxiety in an 8-week trial, but it had no effect in the re-experiencing of intrusive thoughts and images. Desipramine failed to show any advantage over placebo in a 4-weck study, but at relatively low doses compared with the two previous trials. Moreover, as highlighted by Friedman, TCAs have been tested mainly on samples of veterans with severe chronic PTSD, while SSRIs and MAOIs have been tested in nonveteran samples. An important finding arising from these studies is the lack of placebo response in PTSD compared with other anxiety disorders.

MAOIs have also been shown to be effective (phenelzine up to 75 mg/day) in reducing intrusive thoughts and flashbacks after 8 weeks of treatment,but other trials have failed to observe positive effects.MAOIs appear to produce moderate to good clinical improvement, primarily affecting PTSD intrusive recollections, flashbacks, and nightmares, while hyperarousal, numbing, and avoidance behavior are scarcely affected. In addition, the usual dietary and medication restrictions of the MAOIs are more problematic in this patient group, given the high incidence of substance abuse. Early trials with combat, veterans suggest, that the reversible MAOI moclobemide is promising.

SSRIs have been observed to be helpful in open studies, especially with fluoxetine up to 80 mg/day.This has been confirmed in a placebo-controlled trial of veteran and civilian trauma victims.Approximately two thirds of patients experienced decreases in the core symptoms of PTSD including hyperarousal, numbing, avoidance, and intrusive images. Pcnava et al conducted an effect-size analysis of controlled studies where fluoxetine showed the biggest effect compared with the other antidepressant and BZs studied so far.

Sertraline has also been reported effectivein longterm treatment and paroxetine (20-40 mg/day) was superior than placebo in two recent 12-week, doubleblind studies.

Nefazodone (350-450 mg/day) has been shown to significantly improve most, symptoms, including intrusive thoughts, avoidant behaviors, emotional numbing, nightmares, sleep, depression, and anger, and there is only anecdotal evidence for improvement with trazodone.

Other drugs

The anticonvulsant carbamazepine has been shown to decrease flashbacks, hyperarousal, and impulsivity. Lithium and valproic acid may be helpful as well, particularly in patients with poor impulse control. Open-label topiramate and gabapentin appeared effective as add-on therapy for chronic PTSD.

Buspirone (15-35 mg/day) was reported to be effective in reducing anxiety, insomnia, flashbacks, and depressed mood in three PTSD war veterans after 2 weeks of treatment.

Some case reports with atypical neuroleptics and an open-label study with olanzapine have been positive for the treatment of the core symptoms and the psychotic symptoms that PTSD patients may exhibit.Open-label propranolol (120-160 mg/day) improved hyperarousal, sleep, nightmares, explosiveness, and psychosocial functioning in 11 out of 12 Vietnam veterans,and acute, posttrauma propranolol may have a preventive effect on subsequent PTSD.

The α1-adrenergic antagonist prazosin and α2-adrenergic agonists clonidine and guanfacine also provided some preliminary promising results.

Obsessive-compulsive disorder

Benzodiazepines

BZs are not a first-choice treatment for OCD (Table V), and few data exist, to date. Clonazepam, a BZ that, also affects serotonergic transmission, was compared with clomipramine and clonidine in a crossover, double-blind study with each treatment lasting for 6 weeks. The first two drugs were equally effective, while clonidine was largely ineffective. Clonazepam provided an early improvement (2-3 weeks), unrelated to changes in anxiety, and there was a significant cross-response between clomipramine and clonazepam, with patients who failed on clomipramine showing a clinically significant response to clonazepam.

Obsessive-compulsive disorder (OCD): therapeutic strategies. BZ, benzodiazepine; MAOI, monoamine oxidase inhibitor; SNRI, serotonin and norepinephrine reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor; TCA, tricylic antidepressant.

Antidepressants

Pharmacological investigations have demonstrated that OCD responds selectively to drugs that act as potent inhibitors of the synaptic reuptake of serotonin. The first medication demonstrated to be effective in OCD was clomipramine (150-250 mg/day) with 40% of patients (versus 4% for placebo) having a clinically significant decrease in symptoms independently of its antidepressant effect.Subsequently, all of the SSRIs have been shown to be effective, including fluvoxaminc (100-300 mg/day), fluoxetine (20-80 mg/day), paroxetine (40-60 mg/day), sertraline (50-200 mg/day), and citalopram (2060 mg/day).Most recent controlled trials find that about 50% of patients experience a 25% to 35% drop in scale scores of OCD, primarily utilizing the Yale-Brown Obsessive Compulsive Scale (Y-BOCS).This magnitude of change typically results in significant improvement in function; however, interfering symptoms usually persist. Relative efficacy between the SRIs has been difficult to determine. Two meta-analysis suggested greater efficacy for chlorimipramine; however, these trials were performed over a 7- to 10-year time period, during which placebo rates rose significantly, making any conclusion suspect. In fact, in several head-to-head trials, clomipramine was found to have equal efficacy to fluoxetine, paroxetine, and sertraline, with SSRIs being better tolerated than clomipramine. A more recent meta-analysis generally failed to find any significant, difference between the SRIs, although it again suggested some advantage for clomipramine. However, this metaanalysis involved many of the trials mentioned above and has the same problem in interpretation. There was no observed difference in a trial comparing fluvoxaminc, paroxetine, and citalopram.

Due to their similar effects, it is difficult to choose between SSRIs, and the selection of a drug largely depends upon personal preference, even if the possibility of a drug interaction or the various pharmacokinetic profiles could influence the choice. Dosages of these medications have often been described as being significantly higher than antidepressant dosages (eg, 60-80 mg/day fluoxetine); however, in large carefully controlled trials, there has been no observed significant difference between response to higher and lower dosages for the SSRIs (eg, 50 and 200 mg/day sertraline). This clinical impression may well relate to the slow onset of effectiveness with many patients taking 10 to 12 weeks to improve (longer than 4-8 weeks for depression), during which physicians continue to raise the patients' doses, mistakenly thinking it was the increased dose, not time, that was responsible for improvement. For this reason, it is helpful to warn patients about this from the outset, and slowly titrate doses upwards to avoid side effects.

Many patients will not respond or will partially respond to the first SSRI, but will respond to another antiobsessional agent. Therefore, sequential trials are frequently required, which easily can take up to a year to accomplish.

Limited available evidence suggests that, when effective pharmacotherapy is discontinued, most patients (90%) do relapse.Therefore, current practice is to continue effective pharmacotherapy for at least 1 to 2 years or indefinitely. In a large extension study by Greist et al, 118 patients who had responded to 12 weeks' treatment with either sertraline or placebo continued their treatment, in a double-blind way, for 40 weeks. Therapy gains with sertraline were maintained with continued medication as long as they remained on active medication, without tolerance developing. The 59 patients who completed this study were followed up for a second year on open-label sertraline, whereupon they showed additional clinical improvements. Another trial with paroxetine demonstrated continued efficacy for 12 months in the majority of patients.

The effectiveness of potent SRIs is now well established in the treatment of OCD, but despite these advances, nearly 40% to 60% of patients experience minimal to no improvement, in symptoms with these treatments. Furthermore, in patients who do respond to SRIs, the degree of improvement, is often incomplete, with few patients experiencing full symptom remission. For these reasons, attempts to augment or improve the average response with pharmacological strategies targeting serotonergic or other neurotransmitter systems are routine. There is no agent that is routinely effective as an augmenting agent, although there is some support for clonazepam, clonidine, trazodone, nefazodone, tryptophan, and pindolol.There is clear evidence of benefit for traditional neuroleptics and more recently the atypical neuroleptics (eg, risperidone, olanzapine, and quetiapine), principally in the patients with OCD who have comorbid tic disorders. Intravenous clomipramine has also been shown to be more effective than oral administration.

Two controlled studies were performed to test the MAOI phenelzine efficacy in OCD. The first one found phenelzine (up to 75 mg/day) and clomipramine (up to 225 mg/day) both effective with no significant difference between the two drugs, while another one comparing phenelzine (60 mg/day) with fluoxetine (80 mg/day) and placebo found that phenelzine was no better than placebo.

Other drugs

Buspirone produced an effect, similar to clomipramine in a small double-blind study with 18 patients,but the results from controlled trials of buspirone augmentation to SRIs were less encouraging.

Inositol (18 mg/day) was superior to placebo and well tolerated in a short-term, double-blind, controlled trial with crossover design performed in OCD.

Lithium has been suggested to further reduce obsessivecompulsive symptoms when added to therapy with antidepressants, although controlled studies have not substantiated these observations, and gabapentin was reported to further reduce OC symptoms when added in an open-label manner to ongoing fluoxetine (30-100 mg/day) treatment, in five OCD patients.

Selected abbreviations and acronyms

BZ benzodiazepine
GAB γ-aminobutyric acid
GAD generalized anxiety disorder
MAOI monoamine oxidase inhibitors
OCD obsessive-compulsive disorder
PD panic disorder
PTSD posttraumatic stress disorder
RIMA reversible inhibitor of monoamine oxidase A
SNRI serotonin and norepinephrine reuptake inhibitor
SRI serotonin reuptake inhibitor
SSRI selective serotonin reuptake inhibitor
TCA tricyclic antidepressant

The Impact of Psychopharmacology on Contemporary Clinical Psychiatry

Gustavo H Vázquez, MD, PhD1

Abstract

Clinical psychiatric evaluations of patients have changed dramatically in recent decades. Both initial assessments and follow-up visits have become brief and superficial, focused on searching for categorical diagnostic criteria from checklists, with limited inquiry into patient-reported symptomatic status and tolerability of treatments. The virtually exclusive therapeutic task has become selecting a plausible psychotropic, usually based on expert consensus guidelines. These guidelines and practice patterns rest mainly on published monotherapy trials that may or may not be applicable to particular patients but are having a profound impact, not only on modern psychiatric practice but also on psychiatric education, research, and theory.

Keywords: clinical psychiatry, psychiatric diagnosis, psychiatric treatments

In visits to North America, as well as in experiences in South America, I have been struck by observations of changes in clinical psychiatric interviews in recent years, in various settings. Typically, they are very brief, involve minimal personal interaction, and are marked by the pervasive intrusion of ever-present computers. The content of interviews, particularly during follow-up visits, often consists of routine and superficial questions from a memorized checklist, completed within a few minutes, followed by encouragement to continue the same medicines and instruction to make an appointment to return for a similar visit in perhaps 2 months. Even initial assessments of new patients are remarkably brief and focused on seeking criteria (again from a memorized checklist) to generate a categorical diagnosis based on DSM or the ICD criteria that are considered standard. Once a patient has been placed in one or more tentative diagnostic pigeonholes, there inevitably follows a prescription, as the treatment selected is nearly always medicinal. As noted by Dr David M Gardner in his In Review paper in this issue, at best, treatment selection appears to be based on guidelines derived by the consensus of so-called experts, rather than the personal expertise of the prescribing clinician. These phenomena are not unique to the Americas, and appear to be commonplace internationally.

In the contemporary rush toward genetic, molecular, and imaging studies in the elusive search for diagnostic and therapeutic answers to pressing but unanswered clinical questions, psychopathology appears increasingly to be considered a nonscientific method, even in European academic centres that formerly led such inquiry. More generally, there seems to be a growing lack of interest in clinical details of the experiences of individual psychiatric patients, or in the impact of both symptoms and life circumstances on patients and their families. This trend has profound implications for adequate diagnostic, prognostic, and therapeutic understanding of patients as individuals with an illness and for giving them competent care.

To recapitulate, current trends in clinical psychiatry include the following:

  1. increasingly brief clinical assessments;
  2. reliance on simplified and potentially misleading diagnostic schemes based largely on symptom checklists and somewhat arbitrarily rigid criteria for growing numbers of proposed but inadequately established psychiatric disorders;
  3. the increasingly routine assumption that picking the right psychotropic is the main therapeutic task; and then,
  4. brief and infrequent follow-up encounters.

It is hard to avoid the impression that these trends are encouraged by the domination of psychiatric therapeutics by use of medicinal treatments. Their benefits, appropriately, are highly valued but typically limited, and their adverse effects are often less than trivial; rarely do they represent adequate, let alone comprehensive, clinical care. In turn, the clinical approaches noted surely are strongly encouraged by efforts to limit the costs of clinical care, often in the service of greater efficiency. These trends are having a profound impact, not only on the nature of modern psychiatric practice but also on psychiatric education, research, and theory, as noted by Dr Ross J Baldessarini in his Guest Editorial. Adequate and fair assessment of such trends is complicated. Valuable, even revolutionarily, improvements in the treatment of patients with major psychiatric disorders have been achieved by generally effective, reasonably well-tolerated, and usually affordable psychotropics. However, the question remains, are these gains being compromised by largely unanticipated tendencies toward more impersonal and less comprehensive care of individual patients with complex clinical problems?

Psychiatry may be particularly vulnerable to pressures that encourage briefer clinical encounters, reliance on diagnostic checklists, and treatment largely limited to prescription-writing. Such trends affect general medicine as well, but seem to be less effectively resisted, and more disruptive to traditional clinical practices in psychiatry. Other medical and surgical specialties are considered to deal more with acute life-and-death issues, and to be worthy of greater proportions of available resources. In reality, however, there is an abundance of disabling, life-threatening and -shortening aspects of major psychiatric illnesses, including high rates of suicide, especially in the young, as well as greater mortality with general medical disorders in older psychiatric patients. Sometimes increased mortality has even been associated with the use of prescribed psychotropics.

Since the 1950s, psychiatry has been waiting for the striking and impressive advances in neuroscience to transform psychiatry into a more medical or biological discipline. Such efforts seek to regain greater affiliation to general medicine, and perhaps ultimately to replace mental illness with brain disease. Although there have been major advances in the past half-century in clinical and basic psychopharmacology, and stunning advances in basic and clinical neuroscience generally, a neurobiological foundation of major mental illnesses, specifically as a means of improving diagnosis and prognosis, and for guiding development of innovative treatments, is still awaited.

Another notable recent trend is that innovation in psychopharmacologically based therapeutics has slowed substantially. Laboratory-based, basic psychopharmacology and neuroscience continue apace, but fundamental innovation leading to new drug products for the treatment of mental illnesses that are superior in effectiveness and tolerability, or fundamentally different from older drugs, has remained elusive. This circumstance has led increasing numbers of pharmaceutical corporations to shift their efforts and investments to other areas or to disappear through mergers. Companies that continue in psychopharmacology often rely on modest variations on old pharmacodynamic actions and known drugs, including marketing of isomers or active metabolites, or agents designed and selected to mimic previously successful products rather than arising from fundamental and scientifically predicted and guided innovation. In turn, the lack of compelling and relevant pathophysiologies, let alone etiologies, of most psychiatric disorders limits efforts at rational therapeutic innovation and encourages reliance on principles arising from largely serendipitous earlier discoveries.

Highlights

  • There is a growing lack of interest in phenomenological aspects and clinical details of the experiences of individual psychiatric patients.
  • Contemporary psychiatric therapeutics is based mainly on pharmacotherapy dictated by guidelines and algorithms arising from corporate-sponsored drug trials designed for commercial purposes.

Another apparent corollary of the difficulties of therapeutic innovation in psychiatry is reflected in the current state of psychiatric nosology. There is pressure to maximize potential markets by retaining overly broad diagnostic concepts, such as major depressive disorder, as well as by the implausible proliferation of psychiatric disorders to several hundred in recent editions of the DSM. Moreover, some psychotropics are promoted for a growing range of conditions. Examples include expanding indications of antidepressants to various anxiety-related disorders, and even some somatic conditions, and of antipsychotics to the treatment of mania and depression.

In addition to broadening of drug indications in pursuit of industrial marketing efforts as well as hoped-for clinical benefits, there also are risks of overgeneralizing about classes of drugs. For example, dividing antipsychotics into typical and atypical agents, based on their relative risks of some adverse neurological effects, is unsatisfactory and can be misleading: neither drug group is homogeneous, based on chemistry, pharmacodynamics, or on beneficial or adverse clinical effects., Moreover, broadening of potential indications for particular types of psychotropics can contribute to degrading the relation of drug selection to diagnosis and to adequate understanding of typically complex, individual psychiatric patients. I have heard trainees comment—only partly in jest—that detailed and individualized clinical assessments represent wasted time and effort, in that the choice of treatment for virtually any psychotic disorder, including schizophrenia, acute psychosis, mania, many types of depression, and perhaps even some anxiety disorders, is the use of a modern antipsychotic.

Such conclusions and practices often appear to be supported by available evidence, as interpreted by regulatory agencies, aggressively promoted in industrial marketing campaigns, accepted by respected journals, and recommended in expert guidelines. Increasingly, however, evidence of the clinical value and safety of a drug arises from studies aimed less at identifying ideal clinical applications and limitations than at supporting the licensing and marketing aims of pharmaceutical manufacturers. Such aims are entirely legitimate and to be expected, but have only limited bearing on clinical decision making and therapeutic practice. Subjects studied in experimental treatment trials often are highly selected and sometimes poorly representative of many clinically encountered patients. Moreover, even well-designed and -conducted, and fairly analyzed and reported, RCTs yield averaged findings that may or may not apply reliably to subgroups or to more complex individual patients.

Moreover, much of the evidence of clinical effectiveness in a particular target population is based on short-term studies, sometimes with relatively brief continuation. All too often, effective treatments are discontinued after partial clinical recovery, resulting in a relapse that is commonly misinterpreted as proof of long-term prophylactic benefit.In addition—again based on statements of expert authorities— long-term care is often considered adequate, with continued use of an initially prescribed drug or perhaps with serial trials of other agents of similar type. Such oversimplification of clinical practice and avoiding detailed, individualized, and flexible longitudinal assessments of patients with typically complex, changeable, and only partially treatment-responsive illnesses can only further degrade the quality of psychiatric care.

Despite wide distribution of reports arising from RCTs sponsored, designed, and analyzed by manufacturers of products studied, a striking lack of critical and clinically relevant information arises from them with which to evaluate or optimize clinical applications of psychopharmacological treatments for individual patients. Even academic reviews and assessments of available treatments are heavily constrained by relying on clinical therapeutics research findings that are almost entirely supported by manufacturers of products tested and only partly relevant to clinical practice. Potential RCTs participants typically are excluded if they have multiple medical and psychiatric illnesses, substance abuse, poverty or homelessness, engage in risky behaviours, or have other characteristics commonly encountered in the real world of everyday practice. In addition, the assessments employed in treatment RCTs almost always involve changes in scores on standardized symptom-rating scales rather than evaluations of improved functioning, overall health, and patient satisfaction. Adverse effects of treatments continue to be identified almost entirely by passively acquired reports from study participants or incidental observations by their clinicians, rather than by prospective, preplanned, systematic, and explicit assessments, with a high risk of undercounting uncommon adverse events. Again, outcome measurements in RCTs characteristically lack a high degree of relevance to the complex clinical problems presented by most psychiatric patients or their responses to treatment, and tend to submerge analyses of potentially important subgroups into broad, generalized, averaged conclusions that are far more applicable to marketing than clinical aims.

Moreover, findings from even well-designed and -analyzed RCTs represent average trends that are typically combined by methods of meta-analysis (averages of averages) in which each trial counts as a single observation. Almost always, such data analyses fail to distinguish effectively or convincingly one marketed product from another of similar type by efficacy or safety and say nothing about clinically nonaverage patients, or those from dissimilar sociocultural backgrounds. Data included in summary analyses most often involve findings favourable to particular commercial products Efforts to include negative or unfavourable, often unpublished, study findings are sometimes made, but usually inconsistently and incompletely, or without critical peer review.

An additional shortcoming of scientific assessments of treatments is that clinical practice typically, and increasingly, involves empirically applied combinations of treatments aimed at dealing with the substantial proportions of patients whose responses to monotherapies are unsatisfactory or short-lived. This practice of empirical polytherapy is also encouraged by the concept of comorbidity, or presence of separately diagnosed clinical disorders, which may, instead, be manifestations of a single illness. Rarely are specific combination treatments evaluated for their relative effectiveness, safety, and cost, compared with monotherapies, or are monotherapies themselves tested for effects on various conditions that are considered comorbid.

Traditionally, both individual and meta-analyzed RCTs have avoided consideration of subgroups that may respond particularly well or poorly, or have especially low or high risks of adverse responses. This circumstance may sometimes be motivated by fear of market segmentation, and commercial longing for large, but oversimplified, markets. Paradoxically, emphasis on broad indications suggests a lack of appreciation of potential marketing advantages to be gained by being distinguished by proof (with regulatory recognition) of being particularly effective for specific subgroups of patients. Such distinctions can matter for marketing as well as for clinical care as most drugs within a class appear to be quite similar in average efficacy and tolerability—at least as evaluated with pooled, averaged responses.

In conclusion, several trends in contemporary clinical practice involving psychotropics for patients with psychiatric disorders are noted. They include increasingly brief and frankly superficial clinical assessments, disincentives to invest in deeper understanding of individual patients, reliance on simplistic checklists for categorical diagnosis, and as a substitute for individualized clinical evaluation, along with treatment based on pharmacotherapy dictated by guidelines and algorithms that are not likely to be developed independent of manufacturers of products considered. These trends, in large part, are encouraged by apparent therapeutic efficiency of psychotropics in an atmosphere of cost-containment. They have led to an overall decline of clinical curiosity—a regrettable and evidently ubiquitous characteristic of contemporary clinical practice in psychiatry internationally. Modern pharmacotherapy has had a profound, but mixed, impact on clinical practice and on psychiatric education and training. It includes unprecedented therapeutic gains while encouraging brief contacts and relatively superficial clinical understanding of individual patients. These trends have profoundly discouraged formerly standard efforts to exercise real interest aimed at understanding complex human problems, and to work imaginatively, flexibly, and adaptively to develop, modify, and pursue adequate clinical care for individual patients whose needs are likely to change over time.

A Systemic Review and Experts’ Consensus for Long-acting Injectable Antipsychotics in Bipolar Disorder

This is an Open-Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Bipolar disorder (BD) is a major psychiatric disorder that is easily misdiagnosed. Patient adherence to a treatment regimen is of utmost importance for successful outcomes in BD. Several trials of antipsychotics suggested that depot antipsychotics, including long-acting first- and second-generation agents, are effective in preventing non-adherence, partial adherence, and in reducing relapse in BD. Various long-acting injectable (LAI) antipsychotics are available, including fluphenazine decanoate, haloperidol decanoate, olanzapine pamoate, risperidone microspheres, paliperidone palmitate, and aripiprazole monohydrate. Due to the increasing number of BD patients receiving LAI antipsychotics, treatment guidelines have been developed. However, the clinical applicability of LAI antipsychotics remains a global cause for concern, particularly in Asian countries. Expert physicians from Taiwan participated in a consensus meeting, which was held to review key areas based on both current literature and clinical practice. The purpose of this meeting was to generate a practical and implementable set of recommendations for LAI antipsychotic use to treat BD; target patient groups, dosage, administration, and adverse effects were considered. Experts recommended using LAI antipsychotics in patients with schizophrenia, rapid cycling BD, BD I, and bipolar-type schizoaffective disorder. LAI antipsychotic use was recommended in BD patients with the following characteristics: multiple episodes and low adherence; seldom yet serious episodes; low adherence potential per a physician’s clinical judgment; preference for injectable agents over oral agents; and multiple oral agent users still experiencing residual symptoms.

Keywords: Bipolar disorder, Long-acting injectable antipsychotics, Risperidone, Consensus

BACKGROUND

Bipolar disorder (BD) is a major psychiatric disorder that is easily misdiagnosed. It is a life-long illness characterized by recurrent and fluctuating episodes of depression and mania. In addition to causing disability and functional impairment, BD also increases all-cause mortality. Antipsychotics are efficacious in treating BD in both adults and youths. Although lithium and anticonvulsants are the first-line treatments for BD, there is growing evidence in favor of atypical antipsychotics as efficacious treatment options.

MAIN SUBJECTS

Insight into BD Patient Treatment Adherence

Patient adherence to a treatment regimen is of utmost importance for successful outcomes in BD. However, up to half of patients with BD are non-adherent or only partially adherent to antipsychotic treatment.Non-adherence and partial adherence both also appear to play a significant role in BD relapse. Several antipsychotic trials suggested that depot antipsychotics, including long-acting first- and second-generation agents, are effective in reducing relapse in BD. In the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study, 74% of patients with schizophrenia discontinued their prescribed drug use within 18 months due to either poor tolerability or lack of efficacy.However, patients and their families may choose long-acting injectable (LAI) antipsychotics over oral formulations to decrease the frequency and severity of relapse, or for convenience. Gutiérrez-Rojas et al. conducted a retrospective and naturalistic study consisting of patients with a Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV) BD diagnosis, which suggested that avoiding a delay in diagnosis and enhancing treatment adherence might be important targets for reducing BD recurrence.

LAI Antipsychotics for BD Treatment

In the early years of antipsychotic drug therapy, it became clear that depot formulations of antipsychotic drugs, which can maintain therapeutic plasma levels for several weeks, could partially solve the problem of non-adherence. Although patients treated with second-generation antipsychotics showed moderately better therapy adherence than those treated with older drugs, long-acting formulations were also required for second-generation antipsychotics. When patients were switched to the LAI form, objective clinical efficacy that exceeded that of oral atypical antipsychotics was observed in clinical studies (as per psychiatric symptom scores and relapse data). Further, patients accepted the LAI dosing, and experienced fewer extrapyramidal side effects.

Fluphenazine decanoate

Fluphenazine decanoate is a first-generation LAI that has a relatively short duration of action. The initial test dose is 12.5 mg. Maintenance doses are in the range of 12.5–100 mg, given every 2–5 weeks. Doses that are substantially less than 25 mg every 2 weeks greatly increase the risk of relapse.

Haloperidol decanoate

Haloperidol decanoate is a first-generation LAI for which it is possible to administer a loading dose so that no overlapping taper is required. Doses of around 100 mg every 4 weeks are likely optimal; relapse prevention is not improved by higher doses. Similar to fluphenazine decanoate, haloperidol decanoate is relatively inexpensive.

Olanzapine pamoate

Olanzapine pamoate is a second-generation LAI. Clinicians in the United States who administer olanzapine pamoate must enroll in a national registry that documents the incidence of rare but serious adverse drug events, particularly orthostatic hypotension and post-injection delirium/sedation syndrome (0.1% incidence) at every injection. Patients should be observed for 3 hours after every dose, and oral medication overlap may be necessary in some cases. These monitoring difficulties and the expense may limit olanzapine LAI use, even in patients who are likely to benefit.

Risperidone microspheres

Risperidone microspheres, a second-generation LAI, dosing usually begins at 25 mg or 37.5 mg, according to the dose of previously received antipsychotics. Supplementary oral antipsychotic treatment is required for 3 weeks after the first risperidone LAI (Risperdal® Consta®; Janssen Pharmaceuticals, Inc., Titusville, FL, USA). Dosing is only licensed at 2-week intervals, although there is emerging evidence that monthly dosing might be effective. The maximum licensed dose is 50 mg every 2 weeks

Paliperidone palmitate

Paliperidone was approved by the United States Food and Drug Administration (FDA) for the treatment of schizoaffective disorder in 2009. For patients naïve to oral paliperidone or injectable risperidone, overlapping oral taper is necessary.

Aripiprazole monohydrate

FDA approved aripiprazole monohydrate LAI for the treatment of schizophrenia on February 28, 2013. To maintain therapeutic concentration, concurrent use of oral aripiprazole or other antipsychotic is recommended for 14 days. The available strengths are 300 and 400 mg.

First-generation LAI antipsychotics are not approved for use in BD. Among second-generation LAI antipsychotics, only risperidone LAI has been studied and approved for BD maintenance treatment. Although first-generation LAI antipsychotics may be effective in reducing manic relapses, they may increase the risk of worsening depression. Further studies are needed in BD patients to determine the usefulness of new LAI antipsychotics, including olanzapine pamoate, paliperidone palmitate and aripiprazole monohydrate.

Risperidone is a benzisoxazole derivative atypical antipsychotic indicated for the treatment of bipolar mania. The efficacy of risperidone monotherapy for the acute treatment of mania has been demonstrated in several trials, which showed that risperidone monotherapy is superior to placebo and equivalent to haloperidol. Evidence supporting the use of risperidone LAI for BD includes: several nonrandomized, open-label studies; one randomized, open-label trial; and two adequately powered randomized, double-blind trials. These studies showed that risperidone LAI was effective in preventing relapse during bipolar maintenance treatment. In double-blind studies, risperidone LAI was associated with reduced relapse rates, increased time to relapse, and greater control of clinical symptoms during maintenance treatment following initial stabilization, compared with oral medication treatment or placebo injection.

Yatham et al. were the first to employ a randomized design in a Canadian 6-month prospective open-label pilot trial. Forty-nine patients with BD I or II were treated with a mood stabilizer and an oral second-generation antipsychotic at baseline, and were then randomized to either continue their respective antipsychotic regimens (n=26) or to be switched to risperidone LAI (n=23). The switch-over to risperidone LAI did not cause significant changes in efficacy or safety parameters, indicating its therapeutic equivalence to oral antipsychotic add-on therapies.Similar results were found in various subsequent trials, which are summarized in Table 2.

Characteristics of clinical trials of risperidone LAI in bipolar disorder

Two randomized controlled trials investigated the efficacy of risperidone LAI monotherapy for the prevention of treatment-emergent episodes in patients that experienced a manic/mixed index episode after successful stabilization on oral risperidone and who were then switched to risperidone LAI. Over 2 years, Quiroz et al.compared risperidone LAI monotherapy against placebo injections in 303 patients who were stabilized for 6 months on risperidone LAI after a manic/mixed index episode. Most of the patients in the risperidone LAI group (77%) remained on the minimum dose of 25 mg every 2 weeks. In the risperidone LAI group, 42 of 140 patients (30%) experienced recurrence during double-blind treatment versus 76 of 135 (56%) in the placebo group. Patients in the risperidone LAI group were less than half as likely to experience a recurrence as patients in the placebo group. Time to recurrence for elevated mood episodes was significantly longer in the risperidone LAI group than in the placebo group, but time to recurrence for depressive episodes did not differ. The second study was conducted in an enriched population by Vieta et al., and included an olanzapine arm in addition to risperidone LAI and placebo arms to increase the assay sensitivity. Time to recurrence of an elevated (hypomanic, manic, or mixed) mood episode was significantly longer with risperidone LAI compared with placebo. There was no significant difference in time to recurrence of a depressive episode between risperidone LAI and placebo. However, olanzapine was significantly superior to both risperidone LAI and placebo in all primary outcome variables.

Advantages and Limitations of LAI Antipsychotics

First-generation LAI medications are advantageous because medication delivery ensures the administration of the prescribed dose. Efficacy benefits are mostly due to the fact that the injectable form increases treatment adherence. However, there are important limitations to the long-term use of first-generation typical antipsychotics in patients with BD, including risk of extrapyramidal side effects and tardive dyskinesia, which may exceed that of patients with schizophrenia, and the potential for treatment-emergent exacerbation of depressive symptoms. Other disadvantages specific to LAI antipsychotics are complications at the injection site, such as nodules and indurations, muscle granulomas, fibrosis, abscess formation, and oil accumulation after repeated injections. These problems, which are observed in up to a quarter of patients, are associated with concentrated preparations, higher doses, larger volumes, weekly injections, and prolonged treatment.

Risperidone LAI, the only second-generation LAI antipsychotic approved for BD treatment, shows good tolerability across all studies. However, dose-related extrapyramidal effects, sedation, weight gain, and prolactin elevation may occur during long-term treatment.

Acute Treatment vs. Relapse Prevention in BD

The goal of acute treatment in BD is to stabilize the patient’s mood, whereas the goal of maintenance treatment is to prevent relapse. Some frequently used FDA-approved agents for acute mania include aripiprazole, carbamazepine, divalproex, lithium, olanzapine, paliperidone, quetiapine, and risperidone. Agents used for bipolar depression include lamotrigine, lithium, modafinil, olanzapine plus fluoxetine, pramipexole, and quetiapine. FDA-approved agents for BD maintenance treatment include: aripiprazole, lamotrigine, olanzapine, and Risperidone® Consta® as monotherapies; asenapine, oxcarbazepine, quetiapine, and ziprasidone as add-on agents to lithium or valproate. Patients with poor adherence or those who will not accept long-term oral treatment are given a LAI formulation as the first-line treatment. BD patients for whom second-generation LAIs are an effective treatment are candidates for second-generation LAIs, either as monotherapy or combination therapy. First-generation LAIs are not recommended for maintenance treatment. When switching from an oral antipsychotic (first or second generation) to an LAI form, it is recommended to start with the oral antipsychotic for the length of time required to obtain an effective dose and good tolerance before switching to the LAI form.

Treatment Guidelines

Canadian Network for Mood and Anxiety Treatments (CANMAT) guidelines

As per CANMAT guidelines for the management of patients with BD, 2013 update: “lithium, lamotrigine, valproate, olanzapine, quetiapine, aripiprazole, long-acting risperidone injection, and adjunctive ziprasidone continue to be first-line options for maintenance treatment of bipolar disorder”.

American Psychiatric Association (APA) guidelines

Lithium and valproate have the best supportive evidence for maintenance treatment use, with possible alternatives being lamotrigine, carbamazepine, or oxcarbazepine. When patients are already being treated with a maintenance medication or fail to respond to initial treatment, the APA guidelines advise optimization of the maintenance medication, followed by addition of an antidepressant (i.e., lamotrigine, paroxetine, or bupropion). As these guidelines were originally published in 2002 and have yet to be updated, there is no mention of LAI antipsychotics as effective agents for BD treatment.

British Association for Psychopharmacology (BAP) guidelines

For long-term treatment, lithium monotherapy should be considered, which is effective against both manic and depressive relapse, although it is more effective in preventing mania. If lithium is ineffective or poorly tolerated, other options to consider include aripiprazole, carbamazepine, oxcarbazepine, lamotrigine, olanzapine, quetiapine, or valproate, based upon the patient’s clinical condition. Antipsychotics are prescribed for some patients in LAI formulations, as monotherapy or in combination with other agents. Risperidone LAI may be useful in poorly compliant bipolar patients at high risk of manic relapse.

World Federation of Societies of Biological Psychiatry (WFSBP) guidelines

As per the 2012 update of WFSBP guidelines for the long-term biological treatment of BD: “different scenarios have to be examined separately: prevention of mania, depression, or an episode of any polarity, both in acute responders and in patients treated de novo. Treatment might differ in Bipolar II patients or Rapid cyclers, as well as in special subpopulations.” Several medications have been identified as preventive against new manic episodes, whereas the current state of research into the prevention of new depressive episodes is less satisfactory. Lithium continues to be the substance with the broadest base of evidence across all available treatments.

National Institute for Clinical Health and Excellence (NICE) guidelines

According to NICE guidelines, long-acting intramuscular injections of antipsychotics (‘depots,’ LAIs) are not recommended for routine use in BD. They may be considered for people who were treated successfully for mania with oral antipsychotics, but have had a relapse because of poor adherence.

Texas Medication Algorithm Project (TMAP)

These guidelines do not clearly mention the use of depot formulations in the treatment of bipolar disease.

The Taiwan consensus of pharmacological treatment for BD

The Taiwanese Society of Biological Psychiatry and Neuropsychopharmacology (TSBPN) initiated the Taiwan consensus of pharmacological treatment for BD. The purposes of the consensus were to enhance international collaboration, research, and education. During the maintenance phase, Taiwan recommendation grade (RG-T) 1 includes: lithium, lamotrigine, valproic acid, and carbamazepine as monotherapy options; and lithium or valproic acid plus quetiapine, lithium plus divalproex, and lithium plus carbamazepine as combination/augmentation or adjunctive/add-on therapy. RG-T 2 includes risperidone LAI as a monotherapy or combination therapy due to the weight gain side-effect and because it is less efficacious in preventing depressive episodes.

Expert Opinions from Taiwan

A consensus meeting, involving expert physicians from Taiwan, reviewed key areas based on literature and clinical practice. With an increasing number of BD patients receiving LAI antipsychotics, several treatment guidelines were developed. However, clinical applicability of LAI antipsychotics remains a global cause for concern, particularly in Asian countries. Therefore, the purpose of this meeting was to compile literature and clinical experiences from Taiwan and to put together a practical and implementable set of recommendations on how to use LAI antipsychotics in the treatment of BD. The recommendations cover LAI antipsychotic use, including target patient group, dosage, administration, and adverse effects.

The experts recommend using LAI antipsychotics in patients with schizophrenia, rapid cycling BD, BD I, and bipolar-type schizoaffective disorder. LAI antipsychotics are equally important for inpatients and outpatients. However, greater adherence and convenient usage makes them more important for outpatients with BD. LAI antipsychotic use is recommended in patients with: (1) multiple episodes and low adherence; (2) seldom but serious episodes; (3) low adherence potential as per a physician’s clinical judgment; (4) a preference for injectable agents instead of oral agents; and (5) multiple oral agent usage and remaining residual symptoms.

The experts are of the opinion that LAI antipsychotics can be used both as a monotherapy and as an adjunctive therapy. Risperidone LAI is indicated as a monotherapy or as an adjunctive therapy to lithium or valproate for the maintenance treatment of BD I. Evidence supporting the use of LAI risperidone consists of several clinical trials that demonstrated its efficacy in relapse prevention. In a multicenter, double-blind, placebo-controlled study to show the effectiveness of risperidone LAI as a monotherapy, the inclusion criteria were adult patients who met DSM-IV criteria for BD I, and who were stable on medication or experiencing an acute manic or mixed episode. Time to relapse was delayed in patients receiving risperidone LAI monotherapy as compared to placebo. Another multi-center, randomized, double-blind, placebo-controlled trial was conducted to show the effectiveness of LAI risperidone as an adjunctive treatment. The inclusion criteria were adult patients who met DSM-IV criteria for BD I and who experienced at least four mood disorder episodes that required psychiatric/clinical intervention in the previous 12 months, including at least two episodes in the 6 months prior to the start of the study. Time to relapse was delayed in patients receiving adjunctive therapy with risperidone LAI as compared to placebo. The expert group was of the opinion that the inclusion criteria in these clinical trials may not always be applicable in clinical practice. In clinical practice, LAI antipsychotics can be used for patients with recurrent episodes and in patients experiencing the acute phase and who are unwilling to use oral agents.

The attending experts agreed that dosage and administration of LAI antipsychotics should follow the results of clinical trials and prescription information. Based on clinical judgment, some patients may need a lower initial dose or longer injection interval. According to the expert’s clinical experiences, a steady clinical state can still be maintained even after dose and/or interval modification. If a patient is more prone to extrapyramidal symptoms (EPS) based on his/her medical history, initiating treatment with lower dose LAI antipsychotics is appropriate. The expert group was of the opinion that the injection interval for home care patients should follow the prescription information (i.e., 2-week interval for risperidone LAI). On the contrary, for outpatients, a longer duration injection interval may be used (e.g., 3–4 weeks for risperidone LAI) with a higher dose. This modification is based on the experts’ clinical experience; its validity is unknown at present. However, although dosing is licensed only at 2-week intervals, emerging literature evidence suggests that monthly dosing might be effective. The experts also stressed the need for combining oral risperidone in inpatients while switching to risperidone LAI during the first 3 weeks. There is no need to combine oral risperidone in outpatients who are receiving steady maintenance treatment.

In a recent open-label, 28-week, randomized, controlled trial conducted on stable patients with schizophrenia treated with risperidone or olanzapine oral formulation, the oral risperidone dose was reduced by 50% at 4 weeks and then maintained. The results of this 6-month pilot study suggested that a 50% dose reduction could improve cognitive function in stable schizophrenic patients. However, there is a need to confirm the finding through larger scale trials with longer follow-up periods in schizophrenia, and the relevance of the findings in BD. To manage common adverse reactions (e.g., EPSs) that arise during the post-switch period, experts indicate that risperidone LAI adverse events are generally the same as those with oral risperidone. Some experts point out that clinicians should proceed with caution in using risperidone LAI in BD patients, as BD patients are more prone to have EPS as compared to schizophrenic patients. If a depression episode occurs during risperidone LAI treatment, the experts recommend following the bipolar depression treatment guidelines. Reducing the dosage of risperidone LAI is not required.

The attending experts also discussed the fact that risperidone LAI has not been studied in children younger than 18 years, and that the long-term effects of risperidone on growth and sexual maturation should be evaluated further in children and adolescents. Doses should be similar for otherwise healthy elderly patients as for nonelderly patients. Elderly patients should receive special instructions on nonpharmacological interventions that help to reduce the occurrence of orthostatic hypotension.

CONCLUSIONS AND FUTURE PROSPECTS

First-generation LAI antipsychotics cause high rates of extrapyramidal side effects and tardive dyskinesia, among other adverse effects, and potentially induce depression. Risperidone LAI, the only second-generation LAI antipsychotic recommended for BD treatment, has important advantages over first-generation drugs with respect to movement disorders. However, its use is complicated and its clinical utility is compromised by excessively delayed release. Further studies with the new LAI antipsychotics (e.g., olanzapine pamoate, paliperidone palmitate, and aripiprazole monohydrate) are needed in BD patients.

Omega-3 Polyunsaturated Fatty Acids in Prevention of Mood and Anxiety Disorders

Abstract

Psychiatric disorders in general, and major depression and anxiety disorders in particular, account for a large burden of disability, morbidity and premature mortality worldwide. Omega-3 polyunsaturated fatty acids (PUFAs) have a range of neurobiological activities in modulation of neurotransmitters, anti-inflammation, anti-oxidation and neuroplasticity, which could contribute to psychotropic effects. Here we reviewed recent research on the benefits of omega-3 PUFA supplements in prevention against major depression, bipolar disorders, interferon-α-induced depression patients with chronic hepatitis C viral infection, and posttraumatic stress disorder. The biological mechanisms underlying omega-3 PUFAs’ psychotropic effects are proposed and reviewed. Nutrition is a modifiable environmental factor that might be important in prevention medicine, which have been applied for many years in the secondary prevention of heart disease with omega-3 PUFAs. This review extends the notion that nutrition in psychiatry is a modifiable environmental factor and calls for more researches on prospective clinical studies to justify the preventive application of omega-3 PUFAs in daily practice.

Keywords: Omega-3 (N-3) polyunsaturated fatty acids (PUFA), Depression, Anxiety disorders, Psychotic disorders, Clinical trials

INTRODUCTION

Psychiatric disorders remain the leading cause of morbidity and mortality, accounting for 37% of healthy life years lost globally and five of the top ten causes of Disability Adjusted Life Years (DALY).Furthermore, a considerable proportion of people with mental health problems remain untreated. For example, in the USA 67% and in Europe 74% of people with mental illness are untreated. Due to stigmatization and cultural differences, the situation is even worse in Asian countries.

Rapid urbanization and an overall transition from traditional lifestyles have been linked to increases in both physiological and mental illness. Although the psychophysiological responses to environment determinants of urbanization and modernization are complex, the emerging evidence suggests that nutrition is a critical factor for the increasing prevalence and incidence in psychiatric disorders. For example, epidemiological, biological and clinical studies implicate that omega-3 fatty acids are important in the development and treatment of various mental illness, including mood and anxiety disorders.

Omega-3 polyunsaturated fatty acids (PUFAs) (also known as n-3 fatty acids or “fish oil”) are essential macro-nutrients and must be obtained from dietary sources because the body cannot synthesize them effectively.The major types of omega-3 PUFAs are eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), and their precursor, alpha-linolenic acid (ALA). EPA and DHA are found primarily in fatty fish, such as salmon, and in fish-oil supplements. Sources of ALA include flax seed, canola, soybean, walnuts, and leafy green vegetables. Fish-oil supplements are among the most widely used dietary supplements. Omega-3 PUFAs may provide a range of neurobiological activities via modulation of neurotransmitters, anti-inflammation, anti-oxidation and neuroplasticity, which could contribute to their psychotropic effects.

Early intervention and primary prevention is considered as the best strategies for the crisis of under-treatment and under-effectiveness because a majority of patients refuse to take medications due to adverse effects and/or stigmatization. In fact, some researchers are now proposing that high-risk populations could be helped much sooner, by being alert to signs that unfold during months or even years preceding onset of diseases.Nutrition is a modifiable environmental factor that might be important in prevention medicine. For example, the use of omega-3 PUFAs in the secondary prevention of heart disease has been endorsed by the American Heart Association since 2002. This article reviews recent research on the benefits of omega-3 PUFA supplements in prevention of psychiatric disorders.

MAIN SUBJECTS

Omega-3 PUFAs in Depression and Bipolar Disorders

Psychiatric disorders based on current diagnostic systems are clinically and biologically heterogeneous. The heterogeneity is also reflected by current classification systems for antidepressant drugs (Fig. 1). For example, if the classification is based on serotonin reuptake, the agents with conflicting effects, such as the selective serotonin reuptake inhibitors (SSRI; e.g., fluoxetine or venlafaxine) and enhancers (SSRE; e.g., tianeptine) or the norepinephrine-dopamine reuptake inhibitors (NDRIs; e.g., bupropion), could all work as antidepressants. Interestingly, two common pathways, neuroprotection and anti-inflammation, have been found to be associated with all the antidepressant drugs.More importantly, these two common mechanisms link to antidepressant effects not only for drugs but also for non-pharmacological treatment omega-3 PUFAs. Indeed, the effects on neuroprotection and anti-inflammation support the promising hypothesis of psychoneuroimmunology of mood and anxiety disorders and provide an excellent interface between “mind” and “body”.

Omega-3 polyunsaturated fatty acids (PUFAs) share the common biological mechanisms of anti-inflammation and neuroplasticity with current antidepressant agents. The heterogeneity of depression could be reflected by the limits of pharmacotherapy and pharmacological ...

The PUFAs hypothesis is enlightening a promising path to discover, at least partially, the unsolved of depression. Firstly, it has been observed that countries with a high consumption of fish diet appear to have a lower prevalence of major depressive disorder (MDD)  and bipolar disorders (BD), implying a preventive effect of omega-3 PUFA on mood disorders. Secondly, patients with MDD have lower levels of n-3 PUFAs in tissues of blood and brain. In our recent meta-analytic review including 3,318 subjects, the results further support omega-3 fatty acid deficits in MDD by showing a significant decrease in the levels of EPA (effect size [ES]=−0.18, p=0.004), DHA (ES=−0.35, p=0.0002) and total n-3 PUFA (ES=−0.51, p<0.0001).

The deficits in omega-3 PUFA levels have been reported in other populations with mood disorders, including lower DHA and total n-3 PUFAs in postpartum depression  and lower DHA and EPA in social anxiety disorder. In the elderly patients, lower DHA and higher AA, n-6/n-3, AA/EPA, and AA/DHA ratios were associated with depressive disorders compared to healthy volunteers. In samples of patients with acute coronary syndromes, the depressed patients had lower DHA, total DHA and EPA; and higher AA, n-6/n-3, AA/EPA and AA/DHA than those without depression. Interestingly, lower DHA levels before starting interferon (IFN)-α therapy predicted IFN-α-induced depression in patients with chronic hepatitis C viral (HCV) infection.

Six case-control studies have shown lower omega-3 PUFA status in erythrocyte membranes or plasma in patients with BD. Compared to healthy controls, significantly decreased DHA levels have been described in both manic patients under treatment and in medication-free patients. Moreover, Ranjekar et al.ound significantly decreased omega-3 ALA and EPA levels in erythrocyte of BD patients compared to age-matched healthy controls. Manic symptom severity was negatively correlated with plasma levels of EPA and AA. Clayton et al.have reported that erythrocyte DHA levels were negatively correlated with depressive symptoms in children and adolescents with BD. However, the findings could not be replicated in a recent study about the correlation between the severity of affective symptoms and omega-3 PUFA status in medication-free BD patients. Interestingly, healthy first-degree relatives of BD patients had also a trend towards decreased blood omega-3 PUFA levels.

Omega-3 PUFAs have been reported to be effective in the treatment of BDs. In a pioneer randomized-controlled trial, omega-3 PUFAs showed prophylactic effects in the 4-month course of BD, with longer periods of clinical remission as compared to placebo. The prophylactic effects seen in this study suggest antidepressant effects. Specifically, in our re-examination of the data reported by Stoll et al., we found that all “non-completed (recurrent)” cases (3 out of 14 cases) in the omega-3 group developed manic episodes, whereas the depressive symptoms in all but 1 of the non-completed cases (10 out of 16 cases), in the placebo group worsened. This observation suggests that omega-3 PUFAs could prevent depression but not mania in patients with BD. Till now, some clinical trials have been reported to support the antidepressant effect of omega-3 PUFAs on bipolar depression, but the results are not all consistent.

Several independent groups reported meta-analytic reviews and clinical trials to support that omega-3 PUFAs were more effective than placebo, or as effective as conventional antidepressant medication fluoxetine, in treating patients with MDD. However, three meta-analyses from the two groups did not support the omega-3 PUFAs’ antidepressant effects when heterogeneous populations (e.g., community individuals with only non-clinical depressive symptoms) were included. However, these studies need to read and interpreted with caution for several limitations, such as pooling heterogeneous populations, using self-rating scales rather than structured interviews for clinical diagnosis, and implementing different intervention methods.Omega-3 PUFAs have antidepressant (statistical) effects in patients with the Diagnostic and Statistical Manual of Mental Disorders (DSM)-defined MDD but not “mood-improving” effects on symptomatic individuals in which the diagnosis was not confirmed.Meta-analyses, just like randomized clinical trials, may be affected by potential biases in terms of selection of trials (or patients) for analysis.

The beneficial effects of n-3 PUFA in depression are further supported in pre-clinical studies of animal and cellular models. N-3 PUFAs are associated with a preventive and reductive effects of depression-like behaviours in animal model in rats. In addition, the level of brain DHA is negatively correlated to the immobility time and is positively correlated to the swimming time. We proposed several biological mechanisms of the antidepressant effect of n-3 PUFAs in previous reviews, including: (1) neurotransmitter regulations, (2) anti-inflammation and anti-oxidation, and (3) neuroplasticity effects.

Omega-3 PUFAs in Prevention of IFN-induced Depression

Due to the heterogeneity of depression, half of patients with MDD fail to achieve remission with optimized medication treatmentand every antidepressant treatment is expected to have only modest effects. For example, the effect sizes of omega-3 PUFAs range from 0.17–0.23 in treating DSM-defined MDD patients. However, the effect sizes of current standard antidepressant drugs are not much better. In an excellent meta-analytic review, the effect sizes are 0.11 for mild to moderate, 0.17 for severe, and 0.47 for very severe type of MDD As omega-3 PUFAs are safe and well accepted and the current anti-depressant drugs have significant adverse effects, it is of great clinical important to identify patients to treat or high-risk subjects to prevent with this safe and yet effective natural component. There is one example to demonstrate the potential preventive effect of omega-3 PUFAs in specific high-risk population of major depression induced by IFN-α therapy.

IFN-α is the standard therapy for HCV infection; however, its clinical impact is reduced by its common and severe neuropsychiatric adverse effects. For example, up to 30% of patients develop IFN-α-induced major depression. Finding the best strategy to prevent IFN-α-induced depression will improve clinical outcome, but previous clinical trials with SSRIs have had mixed results. In addition, SSRI-induced gastrointestinal bleeding is concerned in HCV patients, who may already have esophageal varices, cirrhosis, low platelet count, and tendency toward bleeding. Furthermore, the use of antidepressants in patients receiving IFN-α therapy has been associated with rare but severe adverse effects, including retinal haemorrhaging and cotton-wool spots,bone marrow suppression, hepatotoxicity,and manic episodes.As most patients receiving IFN-α do not develop clinically significant depression, the routine pre-treatment with anti-depressant drugs might expose patients to unnecessary medications. More importantly, we have previously demonstrated that lower omega-3 PUFA levels in the peripheral blood are associated with an increased risk of developing IFN-α-induced depression over the following weeks.Taking together, we conducted a 2-week, double-blind, placebo-controlled trial, to test the differential effects of the omega-3 PUFAs in the prevention of IFN-α-induced depression.

Two hundred and seven patients with HCV were screened, 162 of them consented to participate and were randomized to the study to receive EPA, DHA or placebo, and all of them completed the two-week trial; 152 participants were followed throughout the 24 weeks of IFN-α treatment, and were included in the analysis. Compared with placebo, the incident rates of IFN-α-induced depression were significantly lower in EPA-, but not in DHA-treated patients (rates: 10% and 28%, respectively, vs. 30% for placebo). Both EPA and DHA pre-treatment significantly delayed the onset of IFN-induced depression (average weeks of onset: 12.0 and 11.7, respectively, vs. 5.3 for placebo). EPA and DHA were both well tolerated in this population. The study shows that EPA appears to be effective in the prevention of IFN-induced depression and suggests that omega-3 PUFAs are potentially a suitable preventive strategy for a wider pool of patients with depression associated with inflammation.

Omega-3 PUFAs in Prevention of Anxiety Disorders

Some preclinical data support omega-3 PUFA as an effective treatment of anxiety disorders. For example, Song et al. found that an EPA-rich diet could reduce the development of anxiety-like behaviors in rat as well as normalizing dopamine levels in the ventral striatum. Regarding therapeutic intervention, Fux et al. conducted a placebo-controlled cross-over trial of adjunctive EPA treatment in patients with obsessive-compulsive disorder (OCD). Eleven patients with OCD were randomly allocated to begin 6 weeks of placebo followed by 6 weeks of 2 g/d of EPA or EPA followed by placebo. Unfortunately they found no benefit of EPA augmentation on symptoms of anxiety, depression and obsessive-compulsiveness. Similarly, 2 g/d of EPA augmentation was ineffective in relieving anger, hostility, or depressive symptoms among seven posttraumatic stress disorder (PTSD) patients in open-label case series. These 2 studies are unfortunately limited by small sample sizes.

Buydens-Branchey et al.conducted a randomized-controlled trial and showed the daily administration of 2,250 mg/d of EPA plus 500 mg/d of DHA for 3 months was accompanied by significant decreases in anger and anxiety scores compared to placebo group in 22 substance abusers. They also showed that these changes were associated with increases in plasma levels of both DHA and EPA but an increase in EPA was more robustly correlated with low end-of-trial anxiety symptom and an increase in DHA was more robustly correlated with low end-of-trial anger symptom. These studies suggested that EPA might be effective in control of anger and anxiety, but more well-designed larger studies focusing on specific condition are needed to clarify the efficacy of omega-3 PUFA.

Haberka et al. conducted a randomized non-placebo controlled trial to determine the efficacy of 465 mg/d EPA plus 375 mg/d DHA on top of the regular pharmacotherapy in 52 patients with post myocardial infarction. They found that omega-3 PUFA supplementation revealed additional effects on decreasing depressive and anxiety symptoms. In a randomized double-blind controlled trial, Kiecolt-Glaser et al.firstly showed that omega-3 PUFA supplementation could reduce inflammation and anxiety among healthy young adults who faced stressful major examination. The medical students who received 2,085 mg/d of EPA and 348 mg/d of DHA for 12 weeks showed a 14% decrease in stress-stimulated interleukin 6 production and a 20% reduction in anxiety symptoms compared to subjects who received placebo. No significant change in depressive symptoms was shown between the two groups. These studies suggested that EPA rather than DHA might be efficacious in selective prevention of anxiety under serious physical condition or stressful situation.

Despite that many clinical trials testing efficacy of omega-3 PUFA in anxiety disorders have been done, the investigation about preventive intervention is still lacking. Recently, we administered 1,470 mg/d of DHA plus 147 mg/d of EPA for 12 weeks in accidentally injured patients to prevent PTSD. We found a beneficial effect of omega-3 PUFAs for minimizing PTSD symptoms compared with the hypothetical means in our previous data. In April 2011 when Japan was hit by the Great East Earthquake, we conducted a randomized non-placebo controlled trial in medical rescue workers during the acute distressing phase to determine whether omega-3 PUFA can attenuate PTSD symptoms compared to psycho-education alone. Although there were no significant differences between the two groups, we found the benefit of 1,568 mg/d of DHA and 157 mg/d of EPA for attenuating PTSD symptoms in women.In addition, we recently reported a result of a randomized double-blind controlled trial to prevent PTSD among 110 accidentally injured patients admitted to an intensive care unit. All patients received psycho-education and were randomly assigned to receive 1,470 mg/d of DHA plus 147 mg/d EPA or placebo for 12 weeks. Unfortunately we did not find significant differences in PTSD symptoms at 3-month follow-up visits between the two groups (Matsuoka, revision under review).

Biological Mechanisms Underlying Omega-3 PUFAs’ Psychotropic Effects

The brain is highly enriched with omega-3 PUFAs and their derivatives, which regulate several biological processes, such as neurotransmission, cell survival and neuroinflammation, and thereby mood and cognition. The beneficial effects of omega-3 PUFA in preventing depression and anxiety are supported in pre-clinical studies of animal and cellular models. For example, omega-3 PUFAs are associated with a preventive effect of depression-like and anxiety-like behaviors in animal model in rats. In addition, the level of brain DHA is negatively correlated to the depression-like behaviors, measured by immobility time in the forced-swimming test. Although the biological mechanisms underlying the psychotropic effects of omega-3 PUFAs are not fully understood, we summarize a few possible explanations.

The role of omega-3 PUFAs in neurotransmission

The change in omega-3 PUFA concentrations in the brain, induced by chronic deficiency in dietary omega-3 PUFAs, could lead to an increase in serotonin 2 (5-HT2) and decrease in dopamine 2 (D2) receptor density in the frontal cortex. The upregulation of 5-HT2A/C receptors and downregulation of dopamine receptors are thought to play a role in the pathophysiology of depressionn addition, higher cerebrospinal fluid levels of 5-hydroxy-indoleacetic acid (5-HIAA), a metabolite of serotonin and an indicator of brain serotonin turnover, has been shown to be associated with high plasma concentration of omega-3 PUFAs among healthy subjects. Biochemical studies have also shown that omega-3 PUFAs increased cerebrospinal fluid 5-HIAA releases, which are commonly associated with the improvement of depression and anxiety symptoms.

The role of omega-3 PUFAs in anti-inflammation and anti-oxidation

The inflammation theory of depression has been supported from several lines of evidence including increasing inflammatory biomarkers in clinical depressed patients and the observed behavioral changes related to inflammatory changes. Upon activation, microglia, the resident macrophages of the brain, up-regulate expression of detrimental factors of reactive oxygen species such as nitric oxide via inducible nitric oxide synthase (iNOS) and induce oxidative stress, contributing to neuropsychiatric pathogenesis.On the other hand, expression of anti-oxidative enzymes like heme oxygenase-1 (HO-1) can reverse oxidative stress and may characterize antidepressant mechanisms.Omega-3 PUFAs are anti-inflammatory and anti-oxidative, and therefore could be beneficial in depression and anxiety.

The role of omega-3 PUFAs in neuroplasticity

Various chronic antidepressants, which are the current standard treatments, increase adult hippocampal neurogenesis,and animal studies suggest that the behavioral effects of chronic antidepressants may be mediated by an induction of neuroplasticity and neurogenesis in the brain. EPA has been shown to increase cortical concentrations of N-acetyl aspartate, a putative marker of neuronal integrity and function, thereby protecting against excitotoxic apoptosis in a small clinical study.In addition, pre-clinical studies have shown that omega-3 PUFAs promote hippocampal neurogenesis in adult animals Moreover, omega-3 PUFAs may modulate neurotrophins,– which might be a direct mechanism to mediate neurogenesis and antidepressant effects.

SUMMARY

Nutrition is a modifiable environmental factor that might be important in prevention medicine. Omega-3 PUFAs are well tolerated and accepted, and have been applied for many years as the secondary prevention in various chronic medical diseases and mental disorders. In this review, we found that the clinical evidence about omega-3 PUFAs’ preventive benefits on mood and anxiety disorders is supported by their regulatory effects on immunomodulation, anti-inflammation, signal transduction, neurotransmission and neuroprotection. Our current review calls for more prospective clinical trials in identified high-risk populations to justify the preventive application of omega-3 PUFAs in daily practice.

Holistic Consideration of Patients with Schizophrenia to Improve Medication Adherence and Outcomes

Lan-Ting Lee,1 Kao Chin Chen,1,2 Wei Hung Chang,1,3 Po See Chen,1,2 I Hui Lee,1,2,3 and Yen Kuang Yang1,2

Abstract

Although several algorithms have been applied to treat patients with schizophrenia, their clinical use remains still limited, because most emphasize the prescription of antipsychotics. A new algorithm with a more holistic approach to treating patients with schizophrenia, to be used before applying traditional prescribing guidelines, was thus proposed by an expert team of Taiwanese psychiatrists. In this algorithm, several important treatment tasks/modalities are proposed, including long-acting injection anti-psychotics, shared decision-making, a case management system, compulsory treatment by law, community rehabilitation programs, the patients’ feeling about their health care professionals (patients’ behaviors) and their attitude/knowledge of their conditions/illness. This study proposes that evaluating the medication adherence of patients can be determined by two key domains, namely patients’ behaviors and attitudes. Based on different levels of their behaviors (X-axis) and attitude/knowledge (Y-axis), it is possible to categorize patients with schizophrenia into six subgroups, for which various different interventions, including the use of antipsychotics, could be applied and integrated. Further research is needed to assess the applicability of this treatment algorithm in clinical settings.

Keywords: Schizophrenia, Algorithms, Antipsychotics, Holistic therapies

INTRODUCTION

Although several algorithms have been applied to treat patients with schizophrenia, their clinical use remains still limited, because most emphasize the prescription of antipsychotics. A new algorithm with a more holistic approach to treating patients with schizophrenia, to be used before applying traditional prescribing guidelines, was thus proposed by an expert team of Taiwanese psychiatrists.

MAIN SUBJECTS

Antipsychotics

Schizophrenia is a neurodegenerative disease with a high level of relapse. The alternating nature of the illness can damage the brain, and structural abnormalities can be found even in the early phase of the disease, including ventricular enlargement and cortical atrophy.Psychosocial and clinical impairments can become more prominent in patients with schizophrenia as the disease progresses. Therefore, it is important to provide intensive biopsychosocial interventions to improve long-term outcomes. The primary goal of treating schizophrenia is to prevent relapses and restore socio-occupational functioning to the individual’s premorbid level. While it is well known that discontinuous use of antipsychotics can significantly increase the relapse rate of schizophrenia, this remains relatively high, from 41% to 97%,particularly in the early phase of the condition, when it is approximately 53.7% to 81.9%.The most common cause of relapse is a lack of medication adherence. Antipsychotic discontinuation in patients with schizophrenia increases the risk of relapse by five times.One strategy for dealing with patients who relapse due to medication discontinuation is the use of long-acting injectable (LAI) medications, as some individuals find it easier to receive an injection at 2- to 4-week intervals than remembering to take a pill once or twice a day.Indeed, several studies have demonstrated that LAI antipsychotics may maintain medication adherence and prevent relapse.– However, the majority of psychiatrists use LAI antipsychotics very conservatively, particularly in Asian countries.

Shared Decision-making

A related issue is how best to persuade patients to improve their medication adherence and accept LAI anti-psychotics, and to this end shared decision-making (SDM) can be a very useful approach when treating individuals with chronic illnesses. SDM aims to decrease the informational and power asymmetry between health care professionals (HCPs) and patients by increasing the latters’ awareness and control regarding treatment decisions that affect their well-being. For example, one study conducted an analysis of a nonrandom sample of 69 prescriber-patient conversations recorded during treatment visits. The conversations flowed freely in a number of steps, and LAI therapy was introduced with either a positive (benefits of LAIs and success stories of other patients) or a punitive approach (adherence problems and scare tactics). Patients had favorable, neutral, or resistant/concerned responses, and resistance was often related to negative feelings about injections. HCPs addressed such resistance by overcoming patient objections to LAIs (e.g., by explaining the therapeutic effects of LAIs compared to their oral counterparts) and invited patients to process of making decision. As a result, more than half (58%) of LAI-naïve patients agreed to start LAI treatment following these office visits. If the decision was made to initiate LAI therapy, HCPs selected a specific LAI to prescribe with minimal patient input. The adherence for medication was poor in the follow-up study.

While most psychiatrists agree that SDM can lead to better outcomes than other strategies, few actually apply SDM in their clinical practice, because it is seen as time-consuming or requiring additional training. Despite these concerns, it has been demonstrated that the benefits of SDM are in fact even greater than clinicians expected before applying this approach.

Continuity of Care and the Case Management System

In addition to pharmacological interventions, individuals coping with schizophrenia often require a wide range of other services in order to meet their basic needs, such as those for food, shelter, and clothing. A case manager (CM) is also needed to monitor patient drug adherence. Various types of treatment and rehabilitation programs are also required and need to be integrated in order for effective outcomes to be achieved. Moreover, different countries should develop culture-sensitive rehabilitation programs, because mental disorders are perceived differently in various areas. Ideally, these services should be delivered in an uninterrupted flow over time until they are able to cope or compensate for the disabilities caused by schizophrenia. Continuity of care is essential for patients with schizophrenia in all stages of the disease, but particularly for hospitalized patients in acute wards, and the main goal of continuity of care is preventing relapse. To ensure the effective integration of various types of programs it is necessary to apply a case management system and provide continuity of care. The CM is the key person in any case management system, and it is their job to examine whether patients have accepted and taken their (LAI) medications, and to work to ensure adherence if they have no being doing so. In addition, CMs also provide social support and play an important role in social resource integration to foster the independence of patients living in the community. Since there are limited resources for treating mental illness, it is important to develop a strategy that serves individuals with different needs. In other words, it is necessary to identify the best candidates for receiving CM services before patients are discharged.

Compulsory Treatment by Law

Some individuals with severe mental disorders have a lack of insight into their condition, and compulsory admission can be initiated if they are considered a danger to themselves or others. Compulsory admission allows the patient to be hospitalized for 30–60 days, depending on the related laws. In some circumstances, although the risk of suicide or homicide is significantly reduced, subjects with schizophrenia continue to show a lack of insight during their compulsory hospitalization. In some countries, discharge comes with a compulsory community treatment order to ensure that these subjects receive regular treatment in their communities. In this situation, LAI antipsychotics are the first drug of choice. For those patients with clearly lack insight into their own conditions, psychosocial interventions should be used in conjunction with medication.

Designing an Algorithm before Applying Traditional Prescribing Guidelines

Since January 2014, more than 30 Taiwanese experts have held several consensus meetings regarding treatment strategies that may lead to greater success in achieving therapeutic goals for Taiwanese patients with schizophrenia. We reached a consensus that in addition to the important role of prescriber-patient interactions in SDM and patients’ explanatory model (EM) for their illness, patient characteristics should be taken into account to design holistic and individualized treatment plans. Based on the literature, we developed a new algorithm (Fig. 1) that is suitable for treating patients with schizophrenia before applying traditional prescribing guidelines.Such an algorithm could be implemented in both hospital and community-based case management settings. Medication adherence can be determined by two main dimensions: behavior (regularly visiting clinics or frequently approaching HCPs) and attitude/knowledge (a favorable response to his/her disease or understanding the nature of his/her disease). Behavior and attitude are two distinct constructs. In clinical practice, some patients may regularly “show off” in clinical settings and consent to receive LAI medication, but they have no very clear ideas about their illness. However, even patients who regularly visit clinics may not regularly take their medication. Therefore, we feel that behavioral patterns should be considered when selecting treatments and interventions (X-axis in Fig. 1). Patient attitude/knowledge (Y-axis in Fig. 1) also influences behavior, and changing/improving patients’ attitude/knowledge is thus a primary goal in successful treatment programs. HCPs may start this process by assessing patients’ attitudes and behavior, and then identifying appropriate intervention strategies. Patients’ negative attitudes can be related to low levels of insight into their conditions, and are regarded as the primary cause of treatment non-adherence. Insight can be divided into three levels: correct and sufficient knowledge about schizophrenia (no cognitive deficit), partial insight/mild cognitive deficit (e.g., compromised memory), and absolute lack of insight (severe cognitive deficit, e.g., impaired awareness of illness or anosognosia). An anosognosia-like phenomenon is not unusual in patients with schizophrenia, and can explain why many do not take their medications and refuse any treatment, as they fail to recognize that they are ill and in need of medical care.

New clinical practice algorithm based on patient behavior and understanding of treatment. I–VI, subgroups I–VI; LAI, long- acting injectable; Pt, patient; HCP, health care professional.

Subgrouping Individuals with Schizophrenia Based on Behavior and Attitude

Fig. 1 shows that the behavior and attitude of individuals in subgroup I lead them to respond favorably to a simple treatment strategy. For subgroup II, which does not take medication despite acceptance, logistic problems should be considered, and environmental interventions may improve adherence. Subgroup II’s attitude/knowledge is sufficient, but their behavior toward HCPs or treatment is not always positive. For such individuals, the case management system should be initiated and combined with certain counseling techniques, such as motivation enhancement or SDM. For subgroup III, although their behavior is positive toward HCPs and treatment, cognitive deficits (e.g., impaired memory) can lead to poor adherence. In addition to assigning a CM, these patients could benefit from participating in educational programs, in which cartoon-like tools and aids are often preferable to more realistic approaches. Those patients with mild cognitive deficits and negative behavior patterns toward HCPs or treatment are categorized as subgroup IV. For this subset of patients, a case management system should be simultaneously considered along with LAI medication, because CM reminders to take oral medication are often ineffective. In subgroup V, patients may exhibit an anosognosia-like phenomenon, even though their behavior toward treatment is positive. The strategy used with these patients is similar to that employed for subgroup IV (i.e., CM combined with LAI medication). In subgroup VI, the patient is absolutely unaware of their illness. Therefore, while these individuals have neither accepted nor started to take LAI medication, it is also very unlikely that they will accept any recommendation to do so. Even when compulsory hospitalization is needed for patients at risk of suicide or homicide, some have a persistent lack of insight after being discharged from inpatient units. In this situation, the case management system, LAI medication, and compulsory community treatment should be considered to prevent episodes in which the patients are a danger to themselves or others. Meanwhile, it is highly recommended that rehabilitation programs should be introduced and applied for all subgroups.

Duration of Illness/Explanatory Model

The above algorithm was proposed for individuals with schizophrenia whose caregivers or they themselves have suffered from the impact of this disease. However, in the early phase of the disease the patients and those around them might have no idea about the nature or prognosis of schizophrenia, or be reluctant to accept such a diagnosis. The patients’ EM for schizophrenia is dynamic, and can influence their help-seeking behaviors. Moreover, the EM pattern might change depending on the treatment response to various different treatment modalities (Fig. 2 Since the treatment response to schizophrenia is slower than that seen with many other diseases, HCPs should be more patient in working to help patients to understand and accept their illness before applying the above algorithm.
The dynamic process of illness progression. Explanatory model (EM), which is composed of the various notions about condition and its treatment that are held by all those engaged in the clinical process. The EM scope was determined based on the interactions ...

CONCLUSIONS

The use of long-term medication treatment is a well-established response for individuals with schizophrenia. However, before applying the traditional algorithm for using antipsychotics, different modalities with regard to the EM of patients and their caregivers should be considered. HCPs thus need to understand/explore the EM and apply SDM for each patient and their caregivers before recommending any treatment modality. In this context, considering the patients’ attitudes to and background knowledge of their disease and medication are essential, because, in addition to prescribing medication, combining various different modalities can be very effective for treating different patient groups. However, further research is needed to assess the applicability of this treatment algorithm in clinical settings.

Clinical Predictors of Drug Response in Patients with Obsessive-Compulsive Disorder

Chan-Hyung Kim,1 Jae-Wook Jeong,2 Eun Ju Kim,2 Yoon Shick Shin,3 Ho Suk Suh,4 Hong Shick Lee,5 and Min-Seong Koo2

Abstract

Objective

The aim of this study was to evaluate which clinical variables might influence the antiobsessional responses to proserotonergic drugs in a sample of patients with obsessive-compulsive disorder (OCD).

Methods

Two hundred forty-nine patients with DSM-IV OCD under-gone mean 13-month treatments with selective serotonin reuptake inhibitors. According to the treatment response, defined as a reductions of the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) total score ≥35%, patients were divided into two groups.

Results

One hundred fourteen patients responded to the treatment and the other one hundred thirty five patients did not. Responders had a significant long duration of medication in YUMC OCD clinic, short total duration of past treatment in other institutes, and higher frequency of drug naïve cases and lower baseline Y-BOCS scores.

Conclusion

The pre-treatment factors including total duration of past treatment, drug naïve or not, baseline OCD symptoms and the factor of duration of the treatment may influence drug treatment response in OCD patients.

Keywords: Obsessive-compulsive disorder, Clinical predictors, Drug response, Treatment duration

INTRODUCTION

Obsessive-compulsive disorder (OCD) is a mental disorder consisting of repetitive thoughts and compulsions. Recently, selective serotonin reuptake inhibitors (SSRI) have been used to improve the prognosis for OCD. However, 40-60% of OCD patients do not respond to SSRIs. Research about clinical predictors, including clinical and demographic factors, has been conducted to develop treatment guidelines and predict the prognoses of OCD patients who show resistance to this kind of treatment. Several of the major prognostic factors were age at onset,presence of tics social phobia,personality disorders, hoarding, other types of OCD, initial severity of OCD symptomsfamily history of OCD, insight,sex, and others. A recent paper showed the anti-obsessional and clinically predictive effects of sertraline, but no studies have satisfactorily identified clinical predictors. Additionally, these studies addressed only a few partial factors and did not adequately identify the effects of various clinical factors on treatment response. Analyses of the effects of clinical and sociodemographic factors have suggested that information about clinical factors collected during initial patient evaluations can predict treatment responses and prognoses. We conducted a retrospective chart review study to investigate clinical predictors of responses to treatment with SSRIs according to sociodemographic and clinical factors.

METHODS

Subjects

This study included 249 patients with OCD who visited the YUMC (Yonsei University Medical Center) OCD clinic from October 1997 to October 2002. The subjects included participants 16-55 years of age who were diagnosed with OCD according to the criteria in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV), and who provided informed consent for participation in this study. Exclusion criteria were 1) women who did not use contraception and had some possibility of being pregnant; 2) women who were pregnant or breast feeding; 3) those with a current or previous organic, neurological, or substance use disorder; and 4) patients with abnormal CBC values, urine analysis, liver function test, electrolytes, and EKGs.

Evaluation of Clinical Manifestations

The Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) has been used to evaluate the severity of symptoms of patients with OCD. All patients were observed for 3-72 months, with an average observation period of 12.9 months (SD=13.8).

Pharmacotherapy

OCD symptoms were treated with drugs such as fluoxetine (40-80 mg/day), sertraline (100-150 mg/day), paroxetine (40-60 mg/day), and clomipramine (150-300 mg/day). Benzodiazepines (alprazolam, clonazepam, lorazepam), mirtazapine, and trazodone were added if necessary for treating the OCD symptoms and comorbid disorders of each patient.

Statistical Analysis

Sociodemographic parameters and clinical variables were analyzed according to sex and previous responses to treatment. Continuous variables were analyzed with Student's t-test, and nominal variables were analyzed with chi-square tests. Participants were categorized into two groups according to clinical response. Those demonstrating at least a 35% improvement in scores on the Y-BOCS were placed into the responder group, and others were placed into the non-responder group. Groups were analyzed according to sociodemographic and clinical variables. Logistic regression analysis was performed to investigate the clinical predictors of drug response. All statistical analyses were conducted using SPSS version 10.0 (SPSS Inc., Chicago, NJ, USA) for Windows.

RESULTS

Sociodemographic and Clinical Characteristics of Subjects (Table 1)

Table 1
Characteristics of the total sample

The total sample consisted of 249 participants, including 180 males (72%) and 66 females (27%). The average age of subjects was 30.78 (SD=11.53) years, the average age of onset of OCD was 21.42 (SD=9.69) years, and the average duration of OCD was 102.21 (SD=82.05) months. The average total score on the total Y-BOS was 29.22 (SD=6.93); 65 (26.1%) participants suffered from a mood disorder, 61 (24.5%) met criteria for a personality disorder, 39 (15.7%) had anxiety disorders, 18 (7.2%) had tic disorders, and 3 (1.2%) suffered from somatoform disorder. Additionally, 30 (12.0%) reported a family history of OCD, and 10 (4.0%) had a family history of tic disorders.

Differences Between Responder and Non-Responder Groups in Terms of Clinical Parameters and Sociodemographic Factors (Table 2)

Characteristics of the sample according to clinical response

The comparison of the sociodemographic and clinical characteristics of responders and non-responders revealed significant differences in baseline Y-BOS scores (t=2.245, df=164, p=0.016), duration of receiving medication at the YUMC OCD clinic (t=3.262, df=163, p=0.001), duration of previous treatment at other institutions (t=2.044, df=151, p=0.043), and initial drug-naïve status (λ2=6.538, df=1, p=0.001). However, no significant differences between responders and non-responders were observed in terms of sex, age, age at onset, duration of illness, comorbid disorders, family history of OCD, family history of tic disorders, and level of insight.

Clinical Subtypes and Comorbid Disorders of Patients with OCD (Table 3)

As noted above, 65 participants had comorbid mood disorders (26.1%) such as depression, 39 had anxiety disorders (15.6%), 61 had personality disorders (24.5%), and 18 had tic disorders (7.2%). No significant difference between responders and non-responders were observed in terms of comorbid disorders. Twenty-four responders met criteria for mood disorders (21.0%), 24 for personality disorders (21.0%), 21 for anxiety disorders (18.4%), and one for somatoform disorder (0.9%). The non-responders group included 41 participants with mood disorders (30.3%), 37 with personality disorders (27.4%), 12 with anxiety disorders (9%), and two with somatoform disorder (1.5%).

Differences Between Responders and Non-Responders according to Clinical Subtype of OCD (Table 4)

Table 4
Subtypes of Obsessive symptoms according to clinical response

The total sample of 249 patients included 60 (24.1%) participants with the checking subtype of OCD, 59 (23.7%) with the washing subtype, 28 (11.2%) with the pathological doubt subtype, 17 (6.8%) with the symmetry and precision subtype, and 15 (6.0%) with the aggressive subtype. No significant differences between responders and non-responders were observed in terms of subtype. Among responders, 33 (28.9%) had the washing subtype, 21 (18.4%) had the checking subtype, 12 (10.5%) had the pathological doubt subtype, and 12 (10.5%) had the symmetry and precision subtype. The non-responders group included 39 (28.9%) with the checking subtype, 26 (19.2%) with the washing subtype, 16 (11.9%) with the pathological doubt subtype, and 9 (6.7%) with the counting subtype.

Clinical Predictors of Drug Responses in OCD Patient According to the Logistic Regression Analysis (Table 5)

Table 5

The clinical predictors of drug responses were investigated using logistic regression to analyze the parameters that differentiated between responders and non-responders. Total baseline scores on the Y-BOCS, duration of receiving medication at the YUMC OCD clinic, duration of previous treatment at other institutions, and status as drug-naïve before the study were chosen as independent variables, and clinical symptomatology was selected as the dependent variable. The analysis showed that the duration of receiving medication at the YUMC OCD clinic was the most significant predictor of drug response and that the duration of previous treatment at other institutions, status as drug-naïve before the study, and total baseline scores on the Y-BOS were also significant clinical predictors

DISCUSSION

This study investigated the major clinical predictors of drug responses among OCD patient. For this purpose, we examined various parameters that potentially influence the treatment of OCD, including the sociodemographic characteristics and initial clinical status of patients visiting the YUMC OCD clinic. According to this study, the duration of pharmacological treatment at the YUMC OCD clinic exerted the strongest influence on treatment response. Additionally, duration of treatment at other institutions, prior drug-naïve status, and baseline Y-BOS scores were also found to be significant predictors of response to medication (Table 2).

These results may be understood in terms of the time needed for medication, education, and other types of treatment to show effectiveness. According to studies conducted by Grimshaw and Goodwin et al.on the appropriate medication duration for OCD patients, most therapeutic effects appear within the first year. Thus, this study's use of 13 months as the average period of observation was consistent with the other reports. However, additional longer-term research on the importance of medication duration is required because this study was limited to an average of only 13 months.

This study investigated predictors according to the clinical profiles obtained during initial visits to our facility. The duration of previous treatment at other institutions, previous drug-naïve status, and baseline Y-BOS scores were found to be important clinical predictors of medication response. Given that more responders than non-responders had been drug-naïve or had received medication only briefly in the past, we can hypothesize that inappropriate anti-obsessional pharmacotherapy may decrease the effect of treatment. That fewer responders initially reported severe symptoms and that the number of responders increased as the duration of pharmacological treatment increased indicated that longer periods of medication are required for patients with more severe obsessive-compulsive symptoms. This finding is consistent with the study conducted by de Haan et al., which showed that OCD patient with severe symptoms needed more medication than did OCD patients with mild symptoms.

This study found no relationship between treatment response and sex. Because the ratio of male to female participants was 180:69, additional research with a more evenly divided sample is necessary. Additionally, no significant differences in treatment response related to comorbid psychopathology, including the presence of personality disorders, was observed in this study (Table 2). However, the finding of significant differences between responders and non-responders with respect to the presence of depression and obsessive-compulsive personality disorder requires further study.

No significant differences in treatment response according to clinical subtype of OCD was observed in this study; however, the washing subtype was the most prevalent subtype in the responder group, and the checking subtype was the most prevalent subtype in the non-responder group. No differences in treatment response was observed between those with the hoarding and those with the somatization subtypes, which has been suggested as significant distinction in terms of predicting treatment response in patients with OCD. Additionally, no significant differences in clinical responses were observed according to level of insight or presence of family history of tic disorders.

Thus, the duration of receiving medication at the YUMC OCD clinic, the duration of previous treatment at other institutions, prior drug-naïve status, and baseline Y-BOS scores are the major clinical predictors of responses to medication among patients with OCD.

This study has the following limitations. First, no double-blind control group was used. Second, because this research was based on a natural follow-up of data obtained from patients who visited only the YUMC OCD clinic, these results may not be generalizable to all OCD patients. Third, patients received various types of medications. More accurate clinical results will require the use of a standardized treatment protocol. Indeed, a standardized medication regimen that is most effective for Korean patients with OCD needs to be developed by conducting comparison studies on treatment with various medications.

Finally, this study is limited by its inability to study long-term treatment effects because, although some patients were followed for 72 months, the average treatment duration was 13 months. Thus, a longer-term follow-up study among a consistent group of patients is required. Despite these restrictions, this study contributed to the literature by broadly examining the role of sociodemographic and clinical factors as predictors of the treatment response of patients with OCD and by suggesting areas warranting further research in the future.

Transcriptional Mechanisms of Drug Addiction

Eric J. Nestler

Abstract

Regulation of gene expression is considered a plausible mechanism of drug addiction given the stability of behavioral abnormalities that define an addicted state. Numerous transcription factors, proteins that bind to regulatory regions of specific genes and thereby control levels of their expression, have been implicated in the addiction process over the past decade or two. Here we review the growing evidence for the role played by several prominent transcription factors, including a Fos family protein (ΔFosB), cAMP response element binding protein (CREB), and nuclear factor kappa B (NFκB), among several others, in drug addiction. As will be seen, each factor displays very different regulation by drugs of abuse within the brain's reward circuitry, and in turn mediates distinct aspects of the addiction phenotype. Current efforts are geared toward understanding the range of target genes through which these transcription factors produce their functional effects and the underlying molecular mechanisms involved. This work promises to reveal fundamentally new insight into the molecular basis of addiction, which will contribute to improved diagnostic tests and therapeutics for addictive disorders.

Keywords: Transcription factors, Nucleus accumbens, Ventral tegmental area, Orbitofrontal cortex, Chromatin remodeling, Epigenetics

INTRODUCTION

The study of transcriptional mechanisms of addiction is based on the hypothesis that regulation of gene expression is one important mechanism by which chronic exposure to a drug of abuse causes long-lasting changes in the brain that underlie the behavioral abnormalities that define a state of addiction. A corollary of this hypothesis is that changes induced in the functioning of several neurotransmitter systems, and in the morphology of certain neuronal cell types in the brain, by chronic drug administration are mediated in part via changes in gene expression.

Of course, not all drug-induced neural and behavioral plasticity is mediated at the level of gene expression, as we know the crucial contributions of translational and posttranslational modifications and protein trafficking in addiction-related phenomena. On the other hand, regulation of gene expression is one central mechanism and likely to be particularly crucial for the life-long abnormalities that characterize addiction. Indeed, transcriptional regulation provides a template on top of which these other mechanisms operate.

Work over the past ~15 years has provided increasing evidence for a role of gene expression in drug addiction, as several transcription factors - proteins that bind to specific responses elements in the promoter regions of target genes and regulate those genes' expression - have been implicated in drug action. According to this scheme, shown in Fig. 1, drugs of abuse, via their initial actions at the synapse, produce changes within neurons that signal to the nucleus and regulate the activity of numerous transcription factors and many other types of transcriptional regulatory proteins. A These nuclear changes gradually and progressively build with repeated drug exposure and underlie stable changes in the expression of specific target genes which, in turn, contribute to the lasting changes in neural function that maintain a state of addiction.

Transcriptional actions of drugs of abuse. Although drugs of abuse act initially on their immediate protein targets at the synapse, their long-term functional effects are mediated in part via regulation of downstream signaling pathways which convertge ...

This review focuses on several transcription factors, which have been shown to play important roles in addiction. We focus further on drug-regulated transcription factors within the brain's reward circuitry, areas of brain that normally regulate an individual's responses to natural rewards (e.g., food, sex, social interaction), but are corrupted by chronic drug exposure to cause addiction. This brain reward circuitry includes dopaminergic neurons in the ventral tegmental area of the midbrain and the several regions of limbic forebrain they innervate, including nucleus accumbens (ventral striatum), prefrontal cortex, amygdala, and hippocampus, among others. As will be seen, the vast majority of research on transcriptional mechanisms of addiction to date has concentrated on the nucleus accumbens.

FosB

FosB is encoded by the FosB gene and shares homology with other Fos family transcription factors, which include c-Fos, FosB, Fra1, and Fra2. These Fos family proteins heterodimerize with Jun family proteins (c-Jun, JunB, or JunD) to form active activator protein-1 (AP1) transcription factors that bind to AP1 sites present in the promoters of certain genes to regulate their transcription. These Fos family proteins are induced rapidly and transiently in specific brain regions after acute administration of many drugs of abuse (Fig. 2). These responses are seen most prominently in nucleus accumbens and dorsal striatum, but also seen in several other brain areas. All of these Fos family proteins, however, are highly unstable and return to basal levels within hours of drug administration.

Distinct temporal properties of drug regulation of ΔFosB vs. CREB. (A) ΔFosB. The top graph shows several waves of Fos family proteins (comprised of c-Fos, FosB, ΔFosB [33 kD isoform], Fra1, Fra2) induced in nucleus accumbens by ...

Very different responses are seen after chronic administration of drugs of abuse (Fig. 2). Biochemically modified isoforms of ΔFosB (Mr 35-37 kD) accumulate within the same brain regions after repeated drug exposure, whereas all Fos family members show tolerance (that is, reduced induction compared with initial drug exposures). Such accumulation of ΔFosB has been observed for virtually all drugs of abuse, although different drugs differ somewhat in the relative degree of induction seen in nucleus accumbens core vs. shell, dorsal striatum, and other brain regions.At least for some drugs of abuse, induction of ΔFosB appears selective for the dynorphin-containing subset of medium spiny neurons - those that predominantly express D1 dopamine receptors - within striatal regions. The 35-37 kD isoforms of ΔFosB dimerize predominantly with JunD to form an active and long-lasting AP-1 complex within these brain regions, although there is some evidence from in vitro studies that ΔFosB may form homodimers.Drug induction of ΔFosB in the nucleus accumbens seems to be a response to the pharmacological properties of the drug per se and not related to volitional drug intake, since animals that self-administer cocaine or receive yoked drug injections show equivalent induction of this transcription factor in this brain region. In contrast, ΔFosB induction in certain other regions, for example, orbitofrontal cortex, requires volitional drug administration.

The 35-37 kD ΔFosB isoforms accumulate with chronic drug exposure due to their extraordinarily long half-lives. As a result of its stability, the ΔFosB protein persists in neurons for at least several weeks after cessation of drug exposure. We now know that this stability is due to two factors: 1) the absence in ΔFosB of two degron domains, which are present at the C-terminus of full length FosB and all other Fos family proteins and target those proteins to rapid degradation, and 2) the phosphorylation of ΔFosB at its N-terminus by casein kinase 2 and perhaps other protein kinases. The stability of the ΔFosB isoforms provides a novel molecular mechanism by which drug-induced changes in gene expression can persist despite relatively long periods of drug withdrawal. We have, therefore, proposed that ΔFosB functions as a sustained "molecular switch" that helps initiate and then maintain an addicted state.

Role in Addiction

Insight into the role of ΔFosB in drug addiction has come largely from the study of bitransgenic mice in which ΔFosB can be induced selectively within the nucleus accumbens and dorsal striatum of adult animals. Importantly, these mice overexpress ΔFosB selectively in the dynorphin-containing medium spiny neurons, where the drugs are believed to induce the protein. ΔFosB-overexpressing mice show augmented locomotor responses to cocaine after acute and chronic administration. They also show enhanced sensitivity to the rewarding effects of cocaine and of morphine in place conditioning assays, and self-administer lower doses of cocaine, and work harder for cocaine, than littermates that do not overexpress ΔFosB. Additionally, ΔFosB overexpression in nucleus accumbens exaggerates the development of opiate physical dependence and promotes opiate analgesic tolerance.In contrast, ΔFosB expressing mice are normal in several other behavioral domains, including spatial learning as assessed in the Morris water maze.Specific targeting of ΔFosB overexpression to the nucleus accumbens, by use of viral-mediated gene transfer, has yielded equivalent data.

In contrast, targeting ΔFosB expression to the enkepahlin-containing medium spiny neurons in nucleus accumbens and dorsal striatum (those that predominantly express D2 dopamine receptors) in different lines of bitransgenic mice fail to show most of these behavioral phenotypes.In contrast to overexpression of ΔFosB, overexpression of a mutant Jun protein (ΔcJun or ΔJunD) - which functions as a dominant negative antagonist of AP1 mediated transcription - by use of bitransgenic mice or viral-mediated gene transfer, produces the opposite behavioral effects. These data indicate that induction of ΔFosB in dynorphin-containing medium spiny neurons of the nucleus accumbens increases an animal's sensitivity to cocaine and other drugs of abuse, and may represent a mechanism for relatively prolonged sensitization to the drugs.

The role played by ΔFosB induction in other brain regions is less well understood. Recent studies have shown that ΔFosB induction in orbitofrontal cortex mediates tolerance to some of the cognitive-disrupting effects of acute cocaine exposure, which might serve to further promote drug intake.

FosB Target Genes

Since ΔFosB is a transcription factor, it presumably produces this interesting behavioral phenotype in nucleus accumbens by enhancing or repressing expression of other genes. Using our inducible, bitransgenic mice that overexpress ΔFosB or its dominant negative ΔcJun, and analyzing gene expression on Affymetrix chips, we demonstrated that - in the nucleus accumbens in vivo -ΔFosB functions primarily as a transcriptional activator, while it serves as a repressor for a smaller subset of genes. This study also demonstrated the dominant role of ΔFosB in mediating the genomic effects of cocaine: ΔFosB is implicated in close to one-quarter of all genes influenced in nucleus accumbens by chronic cocaine.

This genome-wide approach, along with studies of several candidate genes in parallel, have established several target genes of ΔFosB that contribute to its behavioral phenotype. One candidate gene is GluA2, an AMPA glutamate receptor subunit, which is induced in nucleus accumbens by ΔFosB. Since GluA2-containing AMPA channels have a lower overall conductance compared to AMPA channels that do not contain this subunit, the cocaine- and ΔFosB-mediated upregulation of GluA2 in nucleus accumbens could account, at least in part, for the reduced glutamatergic responses seen in these neurons after chronic drug exposure.

Another candidate target gene of ΔFosB in nucleus accumbens is the opioid peptide, dynorphin. Recall that ΔFosB appears to be induced by drugs of abuse specifically in dynorphin-producing cells in this brain region. Drugs of abuse have complex effects on dynorphin expression, with increases or decreases seen depending on the treatment conditions used. We have shown that induction of ΔFosB represses dynorphin gene expression in nucleus accumbens.Dynorphin is thought to activate κ opioid receptors on ventral tegment area (VTA) dopamine neurons and inhibit dopaminergic transmission and thereby downregulate reward mechanisms. Hence, ΔFosB repression of dynorphin expression could contribute to the enhancement of reward mechanisms mediated by this transcription factor. There is now direct evidence supporting the involvement of dynorphin gene repression in ΔFosB's behavioral phenotype.

Still additional target genes have been identified. ΔFosB represses the c-Fos gene which helps create the molecular switch - from induction of several short-lived Fos family proteins after acute drug exposure to the predominant accumulation of ΔFosB after chronic drug exposure - cited earlier. In contrast, cyclin-dependent kinase-5 (Cdk5) is induced in the nucleus accumbens by chronic cocaine, an effect that we have shown is mediated via ΔFosB.Cdk5 is an important target of ΔFosB since its expression has been directly linked to increases in dendritic spine density of nucleus accumbens medium spiny neurons,in the nucleus accumbens that are associated with chronic cocaine administration. Indeed, ΔFosB induction has been shown more recently to be both necessary and sufficient for cocaine-induced dendritic spine growth.

More recently, we have used chromatin immunoprecipitation (ChIP) followed by promoter chip (ChIP-chip) or by deep sequencing (ChIP-seq) to further identify ΔFosB target genes. These studies, along with the DNA expression arrays cited earlier, are providing a rich list of many additional genes that may be targeted - directly or indirectly - by ΔFosB. Among these genes are additional neurotransmitter receptors, proteins involved in pre- and postsynaptic function, many types of ion channels and intracellular signaling proteins, proteins that regulate the neuronal cytoskeleton and cell growth, and numerous proteins that regulate chromatin structure. Further work is needed to confirm each of these numerous proteins as bona fide targets of cocaine acting through ΔFosB and to establish the precise role that each protein plays in mediating the complex neural and behavioral aspects of cocaine action.

CREB

Cyclic AMP response element binding protein (CREB) is one of the most studied transcription factors in neuroscience and has been implicated in diverse aspects of neural plasticity. It forms homodimers that can bind to genes at cyclic AMP response elements (CREs), but primarily activates transcription after it has been phosphorylated at Ser133 (by any of several protein kinases), which allows recruitment of CREB-binding protein (CBP) that then promotes transcription. The mechanism by which CREB activation represses the expression of certain genes is less well understood.

Both psychostimulants (cocaine and amphetamine) and opiates increase CREB activity, acutely and chronically - as measured by increased phospho-CREB (pCREB) or reporter gene activity in CRE-LacZ transgenic mice - in multiple brain regions, including the nucleus accumbens and dorsal striatum.The time course of this activation is very different from that exhibited by ΔFosB. As depicted in Fig. 2, CREB activation is highly transient in response to acute drug administration and reverts to normal levels within a day or two after withdrawal. In addition, CREB activation occurs in both the dynorphin and enkephalin subtypes of medium spiny neurons. In contrast to cocaine and opiates, CREB shows more complicated and varied responses to other drugs of abuse.

Experiments involving the inducible overexpression of CREB or a dominant negative mutant in bitransgenic mice or with viral vectors have shown that activation of CREB - in striking contrast to ΔFosB - in the nucleus accumbens decreases the rewarding effects of cocaine and of opiates as assessed in place conditioning assays. Nevertheless, CREB activation, like ΔFosB induction, promotes drug self-administration.Importantly, effects with dominant negative CREB have been validated with inducible knockdowns of endogenous CREB activity. It is interesting that both transcription factors drive volitional drug intake; presumably ΔFosB does so via positive reinforcement, whereas CREB induces this phenotype via negative reinforcement. The latter possibility is consistent with considerable evidence that CREB activity in this brain region causes a negative emotional state.

CREB activity has been directly linked to the functional activity of nucleus accumbens medium spiny neurons. CREB overexpression increases, whereas dominant-negative CREB decreases, the electrical excitability of medium spiny neurons.Possible differences between dynorphin and enkephalin neurons have not yet been explored. The observation that viral-mediated overexpression of a K+ channel subunit in the nucleus accumbens, which decreases medium spiny neuron excitability, enhances locomotor responses to cocaine suggests that CREB acts as a break on behavioral sensitization to cocaine by upregulating neuron excitability.

Drugs of abuse activate CREB in several brain regions beyond the nucleus accumbens. One example is the ventral tegmental area, where chronic administration of cocaine or opiates activates CREB within dopaminergic and non-dopaminergic neurons. This effect seems to promote or attenuate the rewarding responses of drugs of abuse depending on the subregion of the ventral tegmental area affected.

Numerous target genes for CREB have been identified, through both open-ended and candidate gene approaches, which mediate these and other effects on nucleus accumbens medium spiny neurons and the resulting CREB behavioral phenotype. Prominent examples include the opioid peptide dynorphin, which feeds back and suppresses dopaminergic signaling to the nucleus accumbens as stated earlier.Also implicated are certain glutamate receptor subunits, such as the GluA1 AMPA subunit and GluN2B NMDA subunit, as well as K+ and Na+ ion channel subunits, which together would be expected to control nucleus accumbens cell excitability. BDNF is still another target gene for CREB in nucleus accumbens, and it too is implicated in mediating the CREB behavioral phenotype. CREB induction also has been shown to contribute to cocaine's induction of dendritic spines on nucleus accumbens medium spiny neurons.

CREB is just one of several related proteins that bind CREs and regulate transcription of target genes. Several products of the cyclic AMP response element modulator (CREM) gene regulate CRE-mediated transcription. Some of the products (e.g., CREM) are transcriptional activators, whereas others (e.g., ICER or inducible cyclic AMP repressor) function as endogenous dominant negative antagonists. In addition, several activating transcription factors (ATFs) can influence gene expression in part by binding to CRE sites. Recent studies have implicated these various transcription factors in drug responses. Amphetamine induces ICER expression in nucleus accumbens, and overexpression of ICER in this region, by use of viral-mediated gene transfer, increases an animal's sensitivity to the behavioral effects of the drug.This is consistent with findings, cited above, that local overexpression of dominant negative CREB mutants or local knockdown of CREB exerts similar effects. Amphetamine also induces ATF2, ATF3, and ATF4 in nucleus accumbens, while no effect is seen for ATF1 or CREM. ATF2 overexpression in this region, like that of ICER, increases behavioral responses to amphetamine, while ATF3 or ATF4 overexpression has the opposite effect. Very little is known about the target genes for these various CREB family proteins, an important direction for future research.

NFκB

Nuclear factor-κB (NFκB), a transcription factor that is rapidly activated by diverse stimuli, is best studied for its role in inflammation and immune responses. It has more recently been shown to be important in synaptic plasticity and memory. NFκB is induced in the nucleus accumbens by repeated cocaine administration, where it is required for cocaine's induction of dendritic spines of nucleus accumbens medium spiny neurons. Such induction of NFκB contributes to sensitization to the rewarding effects of the drug. A major goal of current research is to identify the target genes through which NFκB causes this cellular and behavioral plasticity.

Interestingly, cocaine induction of NFκB is mediated via ΔFosB : ΔFosB overexpression in nucleus accumbens induces NFκB, while overexpression of the ΔcJun dominant negative blocks cocaine induction of the transcription factor. Regulation of NFκB by ΔFosB illustrates the complex transcriptional cascades involved in drug action. As well, NFκB has been implicated in some of the neurotoxic effects of methamphetamine in striatal regions. The role of NFκB in medium spiny neuron spinogenesis has recently been extended to stress and depression models, a finding of particular importance considering the comorbidity of depression and addiction, and the well-studied phenomenon of stress-induced relapse to drug abuse.

MEF2

Myocyte enhancing factor-2 (MEF2) was discovered for its role in controlling cardiac myogenesis. More rerecently, MEF2 has been implicated in brain function. Multiple MEF2 isoforms are expressed in brain, including in nucleus accumbens medium spiny neurons, where they form homo- and heterodimers that can activate or repress gene transcription depending on the nature of the proteins they recruit. Recent work outlines a possible mechanism by which chronic cocaine suppresses MEF2 activity in the nucleus accumbens in part through a D1 receptor-cAMP-dependent inhibition of calcineurin, a Ca2+-dependent protein phosphatase. Cocaine regulation of Cdk5, which is also a target for cocaine and ΔFosB as stated earlier, may be involved as well. This reduction in MEF2 activity is required for cocaine induction of dendritic spines on medium spiny neurons. An important focus of current work is to identify the target genes through MEF2 produces this effect.

FUTURE DIRECTIONS

The transcription factors discussed above are just a few of many that have been studied over the years in addiction models. Others implicated in addiction include the glucocorticoid receptor, nucleus accumbens 1 transcription factor (NAC1), early growth response factors (EGRs), and signal transducers and activators of transcription (STATs). As just one example, the glucocorticoid receptor is required in dopaminoceptive neurons for cocaine seeking. The goal of future research is to obtain a more complete view of the transcription factors induced in nucleus accumbens and other brain reward regions in response to chronic exposure to drugs of abuse and to define the range of target genes they influence to contribute to the behavioral phenotype of addiction.

The other major goal of future research is to delineate the precise molecular steps by which these various transcription factors regulate their target genes. Thus, we now know that transcription factors control gene expression by recruiting to their target genes a series of co-activator or co-repressor proteins which together regulate the structure of chromatin around the genes and the subsequent recruitment of the RNA polymerase II complex which catalyzes transcription For example, recent research has demonstrated that the ability of ΔFosB to induce the cdk5 gene occurs in concert with the recruitment of a histone acetyltransferase and related chromatin remodeling proteins to the gene.In contrast, the ability of ΔFosB to repress the c-Fos gene occurs in concert with the recruitment of a histone deacetylase and presumably several other repressive proteins such as a repressive histone methyltransferase Given that hundreds of chromatin regulatory proteins are likely recruited to a gene in concert with its activation or repression, this work is just the tip of the iceberg of vast amounts of information that need to be discovered in the years ahead.

Epigenetic mechanisms of ΔFosB action. The figure illustrates the very different consequences when ΔFosB binds to a gene that it activates (e.g., Cdk5) versus represses (e.g., c-Fos). At the Cdk5promoter (A), ΔFosB recruits histone ...

As progress is made in identifying target genes for drug-regulated transcription factors, this information will provide an increasingly complete template that can be used to guide drug discovery efforts. It is hoped that new medication treatments will be developed based on these dramatic advances in our understanding of transcription mechanisms that underlie addiction.

Association between Alcoholism Family History and Alcohol Screening Scores among Alcohol-dependent Patients

Abstract

Objective

Several tests can be used to screen for alcohol dependence (AD), a prevalent disease with a heterogeneous etiology. As some patients with AD have a strong familial tendency in this regard, a family history of alcohol use disorders can affect the outcomes of screening tests and diagnostic evaluations for AD. In this study, we evaluated associations between a family history of alcohol use disorders and evaluations using the Cut down, Annoyed, Guilty, Eye-opener (CAGE) test, Alcohol Use Disorder Identification Test (AUDIT), and Diagnostic and Statistical Manual of Mental Disorders-fourth edition (DSM-IV) diagnostic criteria among patients with AD.

Methods

We recruited 487 male patients with AD from eight hospitals in Korea. Patients were evaluated using the CAGE, AUDIT, and DSM-IV diagnostic criteria. Patients with and without family histories were compared in terms of these assessment tools.

Results

Drinking initiation, uncontrollable drinking, and problem drinking occurred earlier and CAGE "annoyed" scores were higher in patients with a family history. Alcohol problems before the age of 25 years, frequency of spontaneous or compulsive alcohol-seeking behavior, and frequencies of psychological dependence and guilt related to alcohol use were also higher.

Conclusion

Earlier drinking problems, higher scores on specific items of the CAGE, and AUDIT, and meeting more diagnostic criteria indicate more dependent, harmful drinking by patients with AD who have a family history of this condition. Clinicians should consider patients' family history of alcohol use disorders when screening for AD to identify the correct diagnosis and develop appropriate treatment plans for these patients.

Keywords: Alcohol use disorders, Family history, Cut down, Annoyed, Guilty, Eye-opener test, Alcohol Use Disorder Identification Test, Diagnostic and Statistical Manual of Mental Disorder-fourth edition

INTRODUCTION

According to a survey on mental disorders conducted by the Korean Ministry of Health and Welfare, the lifetime prevalence of alcohol use disorders, including alcohol dependence (AD) and abuse, is 13.4% among the Korean population, which makes it the single most prevalent mental disorder. Specifically, one of five male adults (20.7%) has suffered from an alcohol use disorder more than once. Excessive drinking damages health and leads to economic losses, which have estimated at up to 15 trillion KRW (13.9 billion USD) per year in Korea. In this context, alcohol drinking has become an important health issue, and preventing and treating alcohol-related problems have been emerged as a vital national task.Early detection and effective and intensive treatment of those who are at risk from alcohol is a more effective approach to decreasing the damage from this condition than is trying to address the problem at a later stage. Healthcare centers and educational institutions in Korea have recommended distributing self-report tests and screening instruments.The tools most widely used in Korea to screen and diagnose alcohol use disorders include the Cut down, Annoyed, Guilty, Eye-opener (CAGE) test, the Alcohol Use Disorder Identification Test (AUDIT), the Michigan Alcoholism Screening Test, and the Diagnostic Statistical Manual of Mental Disorder fourth edition (DSM-IV) diagnostic criteria for alcohol use disorders.

Alcohol use disorders are caused by interactions among genetic, social, and environmental factors. Genetic factors, in particular, are the most important risk factors for AD, and these presumably account for 60% of the variance, with environmental factors accounting for 40%. Patients with AD with a family history of alcohol use disorders show severe physical problems and high levels of antisocial behavior due to their problematic use of alcohol. However, no research has been published on how a family history of alcohol use disorders relates to each item on the screening tests or to each of the diagnostic criteria for AD, and questions about whether patients with AD with a positive family history should be evaluated differently from patients without such a family history during the screening or diagnostic process remain unanswered.

The purpose of this study was to compare differences in data from items on the CAGE and the AUDIT and from the DSM-IV diagnostic criteria for AD according to family history of alcohol use disorders and to investigate how a family history of alcohol use disorders is related to the clinical characteristics of patients with AD.

METHODS

Subjects

The sample included male patients aged 20-80 years who met the DSM-IV diagnostic criteria for AD according to more than two psychiatrists at Hallym University Hangang Sacred Heart Hospital and seven other hospitals in Korea between March 2008 and January 2012. In total, 487 patients participated in the study after listening to a complete description of the study and voluntarily signing an informed consent form. The study was approved by the institutional review board of Hallym University Hangang Sacred Heart Hospital.

The exclusion criteria were: 1) substance use disorder involving a substance other than alcohol, nicotine, or caffeine; 2) current or past history of major psychiatric disorders, such as schizophrenia or mood disorders; 3) major medical conditions other than alcohol-related disorders; and 4) the presence of severe behavioral or communication problems that would make a clinical examination difficult.

Research Methods and Tools

We collected data on participants' demographic characteristics including age, level of education, marital status, occupation, and religion. Participants also responded to questions about their drinking history and completed the CAGE to examine age, problems, and other variables related to drinking and the AUDIT to investigate alcohol consumption, harmful drinking, and hazardous drinking.

1. Questionnaire about drinking history

This self-report 16-item questionnaire examines personal characteristics related to drinking. It includes questions about the age at which various drinking habits emerged and the presence of alcohol use disorders in first-degree relatives (parents and siblings) of patients.

2. Cut down, Annoyed, Guilty, Eye-opener (CAGE) test

This survey was developed by Ewing in 1984. Individuals who endorse two items may have serious alcohol-related issues and should obtain a consultation. Individuals who endorse more than three items should receive clinical treatment or be hospitalized due to severe alcoholism.

3. Alcohol Use Disorder Identification Test (AUDIT)

This tool was developed by the World Health Organization (WHO) in 1989 and is used to identify individuals who may be in danger due to their drinking problems. The test consists of 10 questions that measure three domains: drinking frequency and amount, hazardous drinking, and harmful drinking. In 2001, WHO defined scores between 8 and 16 as indicative of dangerous drinking that requires simple advice, scores between 16 and 20 as indicative of the need for a simple consultation and continuous observation, and scores higher than 20 as indicative of the need for a special consultation and assessment for problem drinking.

One Korean study using the AUDIT categorized scores of 12-14 points as indicative of problem drinking, including physical and psychosocial problems; those of 15-25 points as indicative of an alcohol use disorder; and those of 26 points or more as indicative of AD. Additionally, Jeon proposed criteria that defined problematic drinking as 8-11 points for males and 4-11 points for females, harmful drinking as 12-25 points (15-25 points for alcohol abuse), and AD as scores higher than 26.

Statistical Analysis

Baseline differences in demographic characteristics, responses to CAGE and AUDIT items, and endorsement of diagnostic criteria between patients with a family history of alcohol use disorders in first-degree relatives (parents and siblings) and without a family history were compared using t-tests for continuous variables and χ2 tests for categorical variables. The data are summarized as mean±standard deviation (SD) after normality was evaluated using Levene's test. Correlation coefficients were used to investigate correlations involving drinking history, including family history, the CAGE, the AUDIT, and the diagnostic criteria.

As the correlation analyses revealed several associations between demographic characteristics, items on the CAGE and AUDIT, and diagnostic criteria, on the one hand, and age, on the other, a multinomial logistic regression analysis for categorical variables and a univariate general linear model for continuous variables were used to correct for the confounding effects of age.

Data were analyzed using the PASW Statistics software (ver. 18.0; IBM Co., Armonk, NY, USA). Two-sided α=0.05 was considered to indicate statistical significance.

RESULTS

Patient Characteristics

According to the data, 141 patients with AD had a family history of alcohol use disorders, whereas 346 did not. The average age of patients with a family history was 46.08, whereas it was 48.93 in patients with no family history (t(480)=3.208, p=0.001). Patients with a family history started drinking at a younger age (t(479)=2.556, p=0.001) and reported drinking dyscontrol (t(449)=2.568, p=0.012) and behavioral problems during a drunken state (t(382)=3.418, p=0.001) at earlier ages than did patients with no family history. However, we found no significant difference between the groups in terms of educational level, marital status, occupation, religion, or smoking

Demographic and clinical characteristics of patients with alcohol dependence (AD) with and without a family history (FH) of alcohol use disorders

CAGE Items in Relation to Family History of Alcohol Use Disorder

We compared patients with AD with and without a family history in terms of their responses to each item on the CAGE. Patients with a family history had significantly higher scores on "annoyed" than did patients with no family history (t(1)=4.659, p=0.031), and the average total CAGE scores of patients with a family history were markedly higher than were those of patients with no family history (t(316.9)=1.863, p=0.063). The two patient groups did not significantly differ with regard to the other items (Table 2).

CAGE scores of patients with alcohol dependence (AD) with and without a family history (FH) of alcohol use disorders

AUDIT Items in Relation to Family History of Alcohol Use Disorder

We compared patients with AD with and without a family history in terms of their responses to each AUDIT item. In particular, the scores of patients with a family history were significantly higher than were those without such a history on AUDIT items 4 (impaired control over drinking), 5 (increased salience of drinking), 6 (morning drinking), 8 (blackouts), and 9 (alcohol-related injuries). The average total AUDIT scores of patients with a family history were higher (mean=28.46, SD=7.04) than were those of patients with no family history (mean=25.70, SD=7.30; t(524)=4.094, p<0.001). The two groups did not differ significantly with respect to other items (Table 3).

AUDIT scores of patients with alcohol dependence (AD) with and without a family history (FH) of alcohol use disorders

DSM-IV Diagnostic Criteria in Relation to Family History of Alcohol Use Disorder

We compared patients with AD with and without a family history in terms of the DSM-IV diagnostic criteria. Patients with a family history were more likely than those without such a history to endorse items 1a (need for markedly increased amounts of alcohol to achieve intoxication or desired effect), 1b (markedly diminished effect with continued use of the same amount of alcohol), 3 (frequent consumption of alcohol in larger amounts or over a longer period than was intended), 5 (a great deal of time spent engaging in activities necessary to obtain alcohol, use alcohol, or recover from its effects), and 6 (abandonment of or reduction in important social, occupational, or recreational activities because of alcohol use). The groups did not differ significantly in terms of other items (Table 4).

Endorsement of DSM-IV diagnostic criteria by patients with alcohol dependence (AD) with and without a family history (FH) of alcohol use disorders

DISCUSSION

The purpose of this study was to investigate associations between a family history of alcohol use disorders and scores on the CAGE and AUDIT and endorsement of DSM-IV diagnostic criteria among alcohol-dependent patients.

Patients with AD with a family history obtained higher scores on the "annoyed" item of the CAGE, leading to higher total CAGE scores in this group than in patients with no family history. This suggests that patients with a family history of alcohol use disorders are exposed to a family environment in which family members are sensitive to and critical of the drinking of other family members, resulting in annoyance about being blamed for drinking. Patients with AD commonly use defense mechanisms involving projection, turning against others, and denial. These defenses are related to low levels of insight about drinking,which renders the comments made by family members about drinking more annoying. Some studies have shown that AD leads to criticism and negative feelings among family members regarding alcohol-related issues, yielding decreased conversation, which interferes with the development of non-verbal social skills, including the ability to express emotions and rapidly respond to reactions from other people.It has been reported that children raised in an environment without emotional support face a greater risk of abusing alcohol in adulthood. This may be interpreted as evidence supporting the role of alcohol use disorders in the creation of an overall family atmosphere and as indicative of the harmful impact of these disorders on normative emotional development and problems related to alcohol use among children. These phenomena contribute to a vicious cycle in which the family history of alcoholism is perpetuated. Thus, it would be useful to further investigate responses to the "annoyed" item among patients with AD with a family history of alcohol use disorders.

Patients with a family history of alcohol use disorders obtained higher scores on AUDIT items 4, 5, and 6, which inquired about the symptoms of AD, on items 8 and 9, which addressed harmful drinking, and on the AUDIT as a whole. This may show that problems related to AD and harmful drinking are more strongly related to family history than are those related to hazardous drinking. This is consistent with studies concluding that a family history of alcohol use disorders is related to the development and chronicity of AD.The AUDIT is more accurate and effective than other screening tests in distinguishing harmful drinking and alcohol use disorder, with a sensitivity of 51-97% and a specificity of 78-96%. However, it is difficult to use for screening in primary care setting because it includes 10 questions, is complex, and takes a long time to answer. Many studies have focused on developing shorter tests summarizing the AUDIT items in the service of simple and easy application. Brief versions of AUDIT include the AUDIT-C, which includes items 1-3, and the AUDIT-PC with AUDIT items 1, 2, 4, 5, and 10. Additionally, AUDIT-3,with AUDIT item 3 alone, and AUDIT-5, with AUDIT items 2, 3, 5, 9, and 10, are widely used in clinical settings. However, these abbreviated versions of the AUDIT usually consist of questions related to hazardous alcohol use and are more useful in screening for less severe hazardous drinkers than for severe harmful alcohol users.Furthermore, scores on the dependence subscale of the AUDIT may increase the likelihood of meeting criteria for a diagnosis of AD. When using a brief version of the AUDIT with patients with a family history of alcohol use disorders, we should not overlook the risk of neglecting factors related to AD and harmful drinking.

In this study, the DSM-IV diagnostic criteria include more items related to tolerance for alcohol-dependent patients with a family history, including drinking more than before and drinking more than expected or longer than intended, compared with patients with no family history. Furthermore, patients with a family history devote more time to drinking, which leads them to give up or reduce important social, occupational, and recreational activities. It may be inferred that patients with AD with a family history are used to watching other family members drink at home and that this accustoms them to drinking, which leads to excessive drinking and failure in the performance of other activities.

The limitations of this study include difficulties generalizing results for hospitalized patients to all patients with AD. The reliability of the results may be increased by recruiting patients from various treatment settings and the community. Additionally, self-report screening tests are limited due their use of subjective methods and the possible difficulties experienced by respondents in understanding the questions. Moreover, participants may provide unrealistically positively responses to such questionnaires, under-reporting the severity of their condition by minimizing or denying their symptoms due to poor insight and use of defense mechanisms such as denial and projection.

AD is a heterogeneous disease. Many researchers have tried to examine and identify subtypes of AD to determine the causes of and treatments for each clinical subtype. Understanding the various subtypes of AD could help in providing individualized treatment for patients. Data on a family history of alcohol use disorders obtained from the CAGE and AUDIT and use of the diagnostic criteria for AD may be useful for subtyping and individualizing the treatment of AD.

This study found several differences between patients with AD with and without a family history of alcohol use disorder in terms of responses to the CAGE, AUDIT, and the DSM-IV diagnostic criteria: the data showed increased annoyance, AD symptoms, harmful drinking, and tolerance and reduced recreational and social activities among patients with AD with a family history of alcohol use disorders. The earlier drinking problems, higher scores on specific items of the CAGE and AUDIT, and endorsement of more diagnostic criteria among patients with AD with a family history imply greater dependence and more harmful drinking in these patients than in patients with AD with no family history. Thus, these characteristics should be considered in the process of screening, diagnosing, and treating patients with AD with a family history of alcohol use disorder. Clinicians should consider a family history of alcohol use disorders in the process of screening for and diagnosing AD to facilitate the appropriate assessment and treatment of these patients.

Pharmacogenetic Aspects of Antipsychotic Drug-induced Weight Gain - A Critical Review

Treatment with several antipsychotic drugs can result in weight gain, which may lead to further morbidity such as type 2 diabetes and cardiovascular disease via the development of metabolic syndrome. These important and problematic metabolic consequences of antipsychotic drug treatment probably reflect a pharmacological disruption of the mechanisms involved in control of food intake and body weight. The extent of weight gain following antipsychotic drug treatment shows substantial variability between individuals, due in part to genetic factors. Common functional polymorphisms in many candidate genes implicated in the control of body weight and various aspects of energy and lipid metabolism have been investigated for association with weight gain in subjects receiving antipsychotic drug treatment, and with metabolic pathology in chronic schizophrenia. Perhaps the strongest and most replicated findings are the associations with promoter polymorphisms in the 5-HT2C receptor and leptin genes, although many other possible genetic risk factors, including polymorphisms in the fat mass and obesity associated (FTO) gene and genes for the alpha2A adrenoceptor and melanocortin4 receptor, have been reported. Genome-wide association studies (GWAS) have also addressed antipsychotic-induced weight gain and other indicators of metabolic disturbances. However there is as yet little consistency between these studies or between GWAS and classical candidate gene approaches. Identifying common genetic factors associated with drug-induced weight gain and its metabolic consequences may provide opportunities for personalized medicine in the predictive assessment of metabolic risk as well as indicating underlying physiological mechanisms.

Keywords: Schizophrenia, Metabolic syndrome, Diabetes mellitus, Genetic polymorphism, Genetic association studies

INTRODUCTION

There is no doubt that, despite their side effects and limited efficacy, antipsychotic drugs have provided relief and symptom control for a substantial proportion of people with schizophrenia and related psychotic disorders as well as, more recently, bipolar mania. The introduction of the second generation, "atypical" antipsychotics provided a further valuable advance. These drugs provide an improved tolerability, with a reduction in extrapyramidal motor symptoms, and some of these drugs also show evidence of increased efficacy.

However, along with the increased use of these second generation antipsychotics has come an increasing awareness of an important and limiting adverse effect, that of weight gain and its metabolic consequences. This is not particularly new; weight gain has been recognised as a side effect of antipsychotic drug treatment since the introduction of chlorpromazine in the 1950s. Although long recognised as problematic, the full impact of drug-induced weight gain on the physical and psychological health of those receiving antipsychotic drug treatment has only recently been fully acknowledged. One factor that perhaps obscured the importance of antipsychotic-induced weight gain was concern over motor side effects, which drove the development of the newer drugs. However, it is probably no coincidence that this has occurred when there is an increasing awareness of the "obesity epidemic" and its consequences for the general population.

But overweight is substantially more frequent in those receiving antipsychotic drug treatment than in the rest of the population. Yet its dangers are as great; it can rapidly develop into obesity, with concurrent dyslipidemia and impaired glucose tolerance which may eventually result in type II diabetes. A further consequence of these adverse effects can be cardiovascular disease, which is likely to contribute to the reduced life expectancy and increased incidence of cardiovascular death among people with severe mental illness. Furthermore, the perception of weight gain as a result of taking antipsychotic drugs may contribute towards treatment non-adherence, with inevitable consequences in increasing risk of relapse. Thus antipsychotic drug-induced metabolic disturbance is one of the greatest concerns of current psychiatric pharmacotherapy.

The antipsychotic drugs demonstrate differences in the extent of the weight gain that they can induce. Some, like aripiprazole and ziprasidone show little effect above placebo levels, while olanzapine and clozapine can frequently induce profound weight gain; several other drugs including chlorpromazine, risperidone and quetiapine, show, on average, intermediate levels of weight gain.

It is very apparent to the practising clinician that there can be profound differences between individuals in their susceptibility to drug-induced weight gain and which cannot be explained by differences in drug treatment or life-style factors. Such individual differences strongly suggest the involvement of genetic factors, and this is supported by evidence from studies of siblings and twin pairs. Weight gain following antipsychotic treatment studied in pairs of siblings and monozygotic twins showed greater concordance in the twin pairs, interpreted as evidence for drug-induced weight gain having a strong genetic contribution, estimated at 60-80%.

Thus pharmacogenetics, the study of the influence of genetic variation on the effects of drug treatment, has the potential to identify much of what may underlie individual differences in the metabolic consequences of antipsychotic treatment. This research has been progressing steadily and with some success for over a decade, although we have yet to reach the stage at which genetic testing can provide effective indicators of individual risk for drug-induced weight gain. This article will provide a brief review and critique of the major pharmacogenetic factors associated with this metabolic risk and how they may relate to the physiological mechanisms underlying their clinical effects. It will not therefore be an exhaustive and comprehensive review and listing of genetic association studies of antipsychotic weight gain, such as that recently published,but will concentrate on the major replicated findings with some physiological relevance and on findings from the recent developments in methodology that drive pharmacogenomic research.

Initial research approaches identified common sites of variation, primarily single nucleotide polymorphisms (SNPs) or insertion/deletion sequences, in the DNA of one or a small number of "candidate" genes for study of their association with the clinical phenotype - in this case drug-induced weight gain. Choice of candidate genes is hypothesis-driven, whereby genes are usually selected on the basis of their coding for a protein that is known to be, or is potentially, involved in the functional effect of the drug and/or in the underlying physiological processes. Thus genetic factors can influence drug action in several ways, by being involved in pharmacokinetic processes or a variety of pharmacodynamics mechanisms including, but not necessarily restricted to, sites of drug action.

Modern techniques have allowed pharmacogenetics to develop beyond the study of SNPs in one or a few candidate genes to the investigation of large numbers of genes across the whole of the genome, While these genome-wide association studies (GWAS) offer great power in identifying novel genetic associations they are not without limitations; as well as being free of hypotheses based on presumed mechanisms, they present difficulties in the handling and statistical analysis of large amounts of data.

THE TARGET PHENOTYPES AND CANDIDATE GENES

This review will concentrate primarily on genes related to pharmacodynamic mechanisms, although it is recognised that pharmacokinetic genes may also be strong candidates for influencing adverse metabolic effects. Functional variants in metabolic enzymes, notably the widely-studied cytochrome P450 enzymes, can influence drug concentrations, drug availability and the ratio of active drug to metabolites (both active and inactive). Similarly, any functional genetic variability in systems influencing drug distribution, such as the p-glycoprotein pump, which can act to remove certain antipsychotic drugs from the brain, will also influence drug availability at sites of action. All effects on drug disposition will inevitably have effects on drug action, potentially influencing weight gain where this side effect is sensitive to drug concentration in the therapeutic range. To some extent pharmacokinetic variability may be ameliorated by dose titration, although this may not be true if drug effects are complicated by the presence of active metabolites. One aspect of studying pharmacodynamic gene candidates is that the findings can provide indications as to the underlying pharmacological and physiological mechanisms in a field that is as yet incompletely understood.

The pharmacogenetics of weight gain and, to a lesser extent, its related metabolic consequences such as hyperlipidemia and type 2 diabetes have been investigated in some detail. The most-studied candidate genes derive from the underlying receptors considered to mediate drug effects on food intakeand at which several of the antipsychotic drugs may act: notably but not exclusively the serotonin 5-HT2C and histamine H1 receptors. In addition, further candidates are provided by the various proteins involved in the control of food intake, energy metabolism and fat deposition. These include circulating hormones such as leptin, ghrelin and adiponectin, the hypothalamic neuropeptides and related receptors, the cannabinoid system and other factors involved in glucose and lipid disposition and metabolism.

Where positive pharmacogenetic associations have been identified in such candidate genes, the precise mechanism whereby a SNP might result in effects on, say, food intake is rarely understood. The functional mechanisms of genetic polymorphisms are often uninvestigated. However it is often assumed, often without direct evidence, that they influence functional activity, expression or regulation of the gene product, or are in linkage disequilibrium with other SNPs that do so. The former effect might be true for certain missense coding region SNPs, while polymorphisms in 5' promoter sequences may affect the binding of transcription factors, thereby disrupting the control of gene expression and resulting in abnormal expression and regulation of the gene product. The same may be true of SNPs affecting microRNA sites in 3' regions, or those that have no clear functionality, such as synonymous SNPs in the coding region, but may influence transcript stability and disposition through effects on mRNA secondary structure. But it is important to reiterate that there is often no direct evidence for such effects and underlying mechanisms frequently remain obscure.

PHARMACOGENETIC FINDINGS

The first and most replicated study to demonstrate a clear, and relatively strong, pharmacogenetic association of a candidate gene with antipsychotic drug-induced weight gain investigated a 5-HT2C receptor gene (HTR2C) promoter polymorphism (-759C/T) in drug-naive Chinese patients. After 10 weeks' treatment there was a highly significant association of genotype with weight gain in which those patients carrying the minor T allele (22% of the sample) were protected from substantial (>7%) gain in weight following initial treatment with risperidone or chlorpromazine with a relative risk of 3.45. This has, despite some failed replications, also been observed in several further studies including a European first-episode cohort receiving risperidone or olanzapine, in chronic patients receiving olanzapineand in patients receiving clozapine. Thus the findings generalise to different drugs, including those with both high (clozapine and olanzapine) or relatively low (risperidone) affinity for the 5-HT2C receptor. A recent study and meta-analysis confirms the effect of the -759 SNP, and also indicates the missense polymorphism Ser23Cys associates with antipsychotic-induced weight gain. However, this latter effect will have little influence in some ethnic sub-groups; the 23Ser allele has a very low frequency in Asian populations. The -759C/T polymorphism, along with other promoter region polymorphisms of HTR2C with which it is in linkage disequilibrium, appears to be functional in influencing gene expression.

Another candidate gene repeatedly demonstrating a positive association with antipsychotic drug-induced weight gain is that for leptin, an anorexigenic hormone secreted by adipose tissue. This gene has a promoter region polymorphism influencing the secretion of leptin and which is associated with obesity.In two drug-naive populations also investigated for the HTR2C association, antipsychotic weight gain was associated with this -2548A/G polymorphism, although in each study its influence on weight gain emerges later than that of the HTR2C SNP, findings which may differentiate initial and longer term effects on drug-induced physiological changes resulting in fat deposition. These findings have been confirmed in many further reports of antipsychotic-induced weight gain and obesity; one recent study in a large Taiwanese sample exemplifies this in showing the leptin -2548A/G polymorphism associated with measures of obesity and other metabolic pathology in patients with schizophrenia. Authors of a recent report have pointed out the discrepancies between studies - for example the two papers cited above report opposite effects of the -2548A/G genotypes influencing weight gain - and suggest heterosis (with a greater effect of the heterozygous genotype than either homozygote) may underlie the inconsistencies observed, although ethnicity or other factors may play a role. Calculations from the combined leptin and HTR2C genotype effect reported by Templeman et al.indicate that, along with baseline measures of body mass index, this genetic variability can account for a substantial proportion of the variance in weight gain. Interestingly, this study indicated that both the HTR2C and leptin SNPs influence leptin secretion as determined by its blood concentrations. As well as supporting a role for leptin in the mechanism of antipsychotic drug-induced weight gain, this finding points to an unexplored influence of the 5-HT2C receptor on leptin secretion.

Recent advances in the pharmacogenetics of antipsychotic-induced weight gain have been comprehensively reviewed elsewhere; here I shall highlight some of the more interesting findings which may be understood in terms of possible physiological mechanisms. While the 5-HT2C receptor and leptin genes have accumulated the most consistent evidence in support of their roles as risk factors for antipsychotic-induced weight gain, a large number of further candidate genes have been investigated, notably those for other receptors that may mediate some of the metabolic effects of antipsychotic drugs. Unsurprisingly there have been many negative findings, including importantly SNPs in genes for the dopamine D2 and histamine H1 receptors,although both of these also have more recent positive reports.

Other candidates that have demonstrated replicated positive associations with weight gain on antipsychotic drugs include the α2A adrenoceptor gene and two factors relating to synaptic transmission: SNAP25and the G-protein beta3 subunit (GNB3) genes.Evidence for an effect of HTR2A SNPs on antipsychotic-induced weight gain has been inconsistent, although a study carried out on patients treated with olanzapine showed that a combination of HTR2A and HTR2C SNPs with SNPs in GNB3 and the beta3 adrenoceptor gene were associated with olanzapine-induced weight gain, with significant additive effects. Brain-derived neurotrophic factor (BDNF) has a role in the regulation of food intake and there is a reported association of the functional val66met SNP in males.Similarly the role of cannabinoids in food intake and appetite is likely to underlie the reported associations of genes for the CB1 receptor and fatty acid amide hydrolase in antipsychotic weight gain. Very recently, SNPs in the melanocortin4 receptor gene, a risk factor for obesity, have been shown to be associated with antipsychotic-induced weight gain in both treatment-naïve and chronic subjects and a measure of obesity. Another risk factor for obesity, the fat mass and obesity associated (FTO) gene, is reportedly not associated with initial weight gain in first-episode patients; in very recent findings we confirm this observation but also find that it is associated with body mass in chronically-treated patients, where the effect of the FTO gene appears substantially enhanced after long term treatment with antipsychotic drugs (Reynolds et al., unpublished observations). The important and independent Clinical Antipsychotic Trials in Intervention Effectiveness (CATIE) trial of the relative effects of several antipsychotic drugss a valuable sample source for pharmacogenetic studies. A recent study of this cohort also identified an association of weight gain with a SNP in FTO, as well as with two other significant genes.

Results from GWAS and other multiple SNP approaches contrast substantially with those from such studies of single candidate genes. The first genome-wide linkage study was successful in identifying a possible genetic indicator underlying antipsychotic drug-induced obesity.These authors identified linkage in the region of the gene for pro-melanin-concentrating hormone, which is involved in the hypothalamic control of food intake; a subsequent study identified association of obesity in patients treated with olanzapine with a polymorphism in this candidate gene.

The CATIE cohort has also been investigated by GWAS for pharmacogenetic associations with a variety of metabolic outcomes. Unfortunately, none of the genes associated with the 21 SNPs identified as significant in this report had previously been found to associate with metabolic consequences of antipsychotic drug treatment, even in studies employing the same sample! However two of these genes, MEIS2 and PRKAR2B, respectively associated with risperidone effects on waist and hip circumference and clozapine effects on triglycerides, have reportedly been previously implicated in metabolic function.

Genetic factors in genes that influence serum lipids, such as those for apolipoprotein and lipoprotein lipase, have been studied in one report, with small associations with weight gain being identified. A DNA microarray candidate-gene approach has led to the identification of further genetic factors that might contribute to antipsychotic-induced hyperlipidemia, with polymorphisms in genes for acetyl-coenzyme A carboxylase α and neuropeptide Y emerging as promising candidates. Antipsychotics interact with genes controlled by sterol regulatory binding element protein transcription factors, and a strong association has been identified between antipsychotic-induced weight gain and polymorphisms in one of these transcription factors, also a risk gene for obesity, insulin-induced gene 2. Although this finding is not fully replicated, others have reported association of this gene with metabolic pathology including elevated fasting plasma glucose.

An elevation in fasting glucose is indicative of glucose intolerance, a precursor of diabetes. There have been relatively few investigations into the genetic factors determining the individual differences in liability to antipsychotic drug-induced diabetes. There are at least two different processes here: that associated with the often acute onset, reversible diabetes occurring independent of elevations in body fat mass and underlying the rare occurrences of ketoacidosis, and the type 2 diabetes that is a long-term consequence of obesity and the development of metabolic syndrome. Although these are two different physiological consequences of drug treatment, it is notable that the drugs with the greatest effect on weight gain, clozapine and olanzapine, are also particularly associated with the rapid-onset diabetes. This acute effect has not been investigated genetically; the longer-term consequences have been studied primarily in terms of the emergence of metabolic syndrome. One study reported an association with the leptin promoter SNP, but not with the -759C/T HTR2C SNP; however an interaction between the two polymorphisms was observed. Another group did find, and replicated, association of metabolic syndrome with another HTR2C SNP and with the α2A adrenoceptor gene.

CONCLUSIONS

Substantial effort has been spent in attempting to determine the genetic associations with the metabolic consequences of antipsychotic drug treatment, in the search for predictive factors that might be used to identify individual risk of these problematic adverse effects. As yet, only a few risk factors have been reproducibly identified in candidate gene studies, including SNPs in the leptin and HTR2C genes, and none of these genes have consistently emerged from GWAS.

Such variability and apparent inconsistency is common throughout the pharmacogenetic literature; as yet the larger GWAS have not proven to be more reliable in providing consistent findings. There are many reasons for this; one important factor is that many studies do not have the statistical power to identify what are often relatively small effects and which will inevitably introduce variability between studies. Sample differences in terms of ethnicity are an obvious further factor, while differences in treatment history and, important for the current topic, in diet and other life style factors may also contribute.

Future work will thus need to resolve these many inconsistences and discrepancies between studies that are apparent in the current literature. Despite the rapid advancements in technology, research approaches remain somewhat naïve; there will need to be a greater recognition that analysis of additive gene effects, gene-gene interactions and perhaps also gene-environment interactions will be important in understanding properly the various genetic risk factors contributing to the emergence of drug-induced metabolic pathology. However, as the opportunity for genotyping large numbers of SNPs in large samples becomes cheaper and more accessible, findings from further GWAS studies will, we hope, converge to give us consistent results. Identifying such results will open up opportunities for predictive genetic testing in personalised medicine, once the validity and, importantly, utility in the clinic of this pharmacogenetic approach are established. Moreover, while we recognise that candidate genes are often chosen on the basis of a known relationship with the mechanism of drug action, identifying novel genetic associations with weight gain and metabolic pathology may well provide clues as to the underlying pharmacological and physiological processes.

Additional Reading:

Principles in Using Medication with Children

Sexual Dysfunction during Treatment of Major Depressive Disorder

Psychopharmacologic Treatment of Borderline Personality Disorder

Treatments for Autism Spectrum Disorder

Recommendations about the Use of Psychotropic Medications for Children

 

 

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