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.


References
Ahmed, SH, Kenny, PJ, Koob, GF, Markou, A (2002) Neurobiological evidence for hedonic allostasis associated with escalating cocaine use. Nat Neurosci 5: 625–626.
Ahmed, SH, Koob, GF (1998) Transition from moderate to excessive drug intake: change in hedonic set point. Science 282: 298–300.
Bechara, A, Dolan, S, Hindes, A (2002) Decision-making and addiction (part II): myopia for the future or hypersensitivity to reward. Neuropsychologia 40: 1690–1705.
Brody, AL, Mandelkern, MA, London, ED, Childress, AR, Lee, GS,
Bota, RG, et al. (2002) Brain metabolic changes during cigarette craving. Arch Gen Psychiatry 59: 1162–1172.
Carter, BL, Tiffany, ST (1999) Meta-analysis of cue-reactivity in addiction research. Addiction 94: 327–340.
Ehrman, R, Robbins, SJ, Childress, AR, O’Brien, CP (1992) Conditioned responses to cocaine-related stimuli in cocaine abuse patients. Psychopharmacology (Berl) 107: 523–529.
Finlayson, G, King, N, Blundell, JE (2007) Is it possible to dissociate
’liking’ and ’wanting’ for foods in humans? A novel experimental procedure. Physiol Behav 90: 36–42.
Fiorino, DF, Phillips, AG (1999a) Facilitation of sexual behavior and enhanced dopamine efflux in the nucleus accumbens of male rats after D-amphetamine-induced behavioral sensitization. J Neurosci
19: 456–463.
Fiorino, DF, Phillips, AG (1999b) Facilitation of sexual behavior in male rats following d-amphetamine-induced behavioral sensitization.
Psychopharmacology (Berl) 142: 200–208.
Fischman, MW, Schuster, CR, Javaid, J, Hatano, Y, Davis, J (1985) Acute tolerance development to the cardiovascular and subjective effects of cocaine. J Pharmacol Exp Ther 235: 677–682.
Fox, HC, Talih, M, Malison, R, Anderson, GM, Kreek, MJ, Sinha, R (2005) Frequency of recent cocaine and alcohol use affects drug craving and associated responses to stress and drug-related cues.
Psychoneuroendocrinology 30: 880–891.
Garavan, H, Pankiewicz, J, Bloom, A, Cho, JK, Sperry, L, Ross, TJ, et al. (2000) Cue-induced cocaine craving: neuroanatomical specificity for drug users and drug stimuli. Am J Psychiatry 157: 1789– 1798.
Gawin, FH (1991) Cocaine addiction: psychology and neurophysiology. Science 251: 1580–1586.
Glautier, S, Drummond, DC (1994) Alcohol dependence and cue reactivity. J Stud Alcohol 55: 224–229.
Goldstein, RZ, Tomasi, D, Alia-Klein, N, Cottone, LA, Zhang, L, Telang, F, et al. (2007) Subjective sensitivity to monetary gradients is associated with frontolimbic activation to reward in cocaine abusers.Drug Alcohol Depend 87: 233–240.
Goldstein, RZ, Volkow, ND (2002) Drug addiction and its underlyingneurobiological basis: neuroimaging evidence for the involvementof the frontal cortex. Am J Psychiatry 159: 1642–1652.
Grigson, PS, Twining, RC (2002) Cocaine-induced suppression of saccharin intake: a model of drug-induced devaluation of natural rewards. Behav Neurosci 116: 321–333.
Grimm, JW, Lu, L, Hayashi, T, Hope, BT, Su, TP, Shaham, Y (2003) Time-dependent increases in brain-derived neurotrophic factor protein levels within the mesolimbic dopamine system after withdrawal from cocaine: implications for incubation of cocaine craving. J Neurosci 23: 742–747.
Hobbs, M, Remington, B, Glautier, S (2005) Dissociation of wanting and liking for alcohol in humans: a test of the incentivesensitisation theory. Psychopharmacology (Berl) 178: 493–499. Lambert, NM, McLeod, M, Schenk, S (2006) Subjective responses to initial experience with cocaine: an exploration of the incentivesensitization theory of drug abuse. Addiction 101: 713–725.
Lasagna, L, Von Felsinger, JM, Beecher, HK (1955) Drug-induced mood changes in man. I. Observations on healthy subjects, chronically ill patients, and postaddicts. J Am Med Assoc 157: 1006–1020.
Lee, JL, Milton, AL, Everitt, BJ (2006) Cue-induced cocaine seeking and relapse are reduced by disruption of drug memory reconsolidation.
J Neurosci 26: 5881–5887.
Leyton, M, Casey, KF, Delaney, JS, Kolivakis, T, Benkelfat, C (2005) Cocaine craving, euphoria, and self-administration: a preliminary study of the effect of catecholamine precursor depletion. BehavNeurosci 119: 1619–1627.
Madden, GJ, Petry, NM, Badger, GJ, Bickel, WK (1997) Impulsive and self-control choices in opioid-dependent patients and nondrug- using control participants: drug and monetary rewards. Exp
Clin Psychopharmacol 5: 256–262.
Margolin, A, Avants, SK, Kosten, TR (1994) Cue-elicited cocaine craving and autogenic relaxation: association with treatment outcome.
J Subst Abuse Treat 11: 549–552.
Newton, TF, De La Garza, R, Kalechstein, AD, Nestor, L (2005) Cocaine and methamphetamine produce different patterns of subjective and cardiovascular effects. Pharmacol Biochem Behav 82:
90–97.
Nocjar, C, Panksepp, J (2002) Chronic intermittent amphetamine pretreatment enhances future appetitive behavior for drug- and natural-reward: interaction with environmental variables. Behav
Brain Res 128: 189–203.
Robbins, SJ, Ehrman, RN, Childress, AR, O’Brien, CP (1992) Using cue reactivity to screen medications for cocaine abuse: a test of amantadine hydrochloride. Addict Behav 17: 491–499.
Robinson, TE, Berridge, KC (1993) The neural basis of drug craving: an incentive-sensitization theory of addiction. Brain Res Brain Res
Rev 18: 247–291.
Robinson, TE, Berridge, KC (2001) Incentive-sensitization and addiction. Addiction 96: 103–114.
Robinson, TE, Berridge, KC (2003) Addiction. Annu Rev Psychol 54: 25–53.

Citations

1. Lieberman JA, Stroup TS, McEvoy JP, Swartz MS, Rosenheck RA, Perkins DO, Keefe RS, Davis SM, Davis CE, Lebowitz BD, Severe J, Hsiao JK; Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE). Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. New England Journal of Medicine. 2005 Sep 22;353(12):1209-1223.

2. Rush JA, Trivedi MH, Wisniewski SR, Stewart JW, Nierenberg AA, Thase ME, Ritz L, Biggs MM, Warden D, Luther JF, Shores-Wilson K, Niederehe G, Fava M. Bupropion-SR, sertraline, or venlafaxine-XR after failure of SSRIs for depression. New England Journal of Medicine. 2006 Mar 23; 354(12):1231-1242.

3. Trivedi MH, Fava M, Wisniewski SR, Thase ME, Quitkin F, Warden D, Ritz L, Nierenberg AA, Lebowitz BD, Biggs MM, Luther JF, Shores-Wilson K, Rush JA. Medication augmentation after the failure of SSRIs for depression. New England Journal of Medicine. 2006 Mar 23; 354(12): 1243-1252.

4. Hypericum Depression Trial Study Group. Effect of Hypericum perforatum (St. John's wort) in major depressive disorder: a randomized controlled trial. Journal of the American Medical Association. 2002; 287(14): 1807-1814.

5. Bridge JA, Iyengar S, Salary CB, Barbe RP, Birmaher B, Pincus HA, Ren L, Brent DA. Clinical response and risk for reported suicidal ideation and suicide attempts in pediatric antidepressant treatment, a meta-analysis of randomized controlled trials. Journal of the American Medical Association. 2007; 297(15): 1683-1696.

6. Bowden CL, Calabrese JR, McElroy SL, Gyulai L, Wassef A, Petty F, Pope HG, Jr., Chou JC, Keck PE, Jr., Rhodes LJ, Swann AC, Hirschfeld RM, Wozniak PJ, Group DMS. A randomized, placebo-controlled 12-month trial of divalproex and lithium in treatment of outpatients with bipolar I disorder. Archives of General Psychiatry. 2000 May; 57(5):481-489.

7. Rothschild AJ, Bates KS, Boehringer KL, Syed A. Olanzapine response in psychotic depression. Journal of Clinical Psychiatry. 1999 Feb; 60(2):116-118.

8. Suppes T, Webb A, Paul B, Carmody T, Kraemer H, Rush AJ. Clinical outcome in a randomized 1-year trial of clozapine versus treatment as usual for patients with treatment-resistant illness and a history of mania. American Journal of Psychiatry. 1999 Aug;156(8): 1164-1169.

9. Thase ME, Sachs GS. Bipolar depression: pharmacotherapy and related therapeutic strategies. Biological Psychiatry. 2000 Sep 15;48(6):558-572.

10. Sachs G, Nierenberg AA, Calabrese JR, Marangell LB, Wisniewski SR, Gyulai L, Friedman ES, Bowden CL, Fossey MD, Ostacher MJ, Ketter TA, Patel J, Hauser P, Rapport D, Martinez JM, Allen MH, Miklowitz DJ, Otto MW, Dennehy EB, Thase ME. Effectiveness of adjunctive antidepressant treatment for bipolar depression: a double-blind placebo-controlled study. New England Journal of Medicine. Epub 28 Mar 2007; 356(17): 1771-1773.CEU

11. Vainionpaa LK, Rattya J, Knip M, Tapanainen JS, Pakarinen AJ, Lanning P, Tekay A, Myllyla VV, Isojarvi JI. Valproate-induced hyperandrogenism during pubertal maturation in girls with epilepsy. Annals of Neurology. 1999 Apr;45(4):444-450.

12. Joffe H, Cohen LS, Suppes T, McLaughlin WL, Lavori P, Adams JM, Hwang CH, Hall JE, Sachs GS. Valproate is associated with new-onset oligoamenorrhea with hyperandrogenism in women with bipolar disorder. Biological Psychiatry. 2006 Jun 1;59(11):1078-1086.

13. Joffe H, Cohen LS, Suppes T, Hwang CH, Molay F, Adams JM, Sachs GS, Hall JE. Longitudinal follow-up of reproductive and metabolic features of valproate-associated polycystic ovarian syndrome features: A preliminary report. Biological Psychiatry. 2006 Dec 15;60(12):1378-1381.

14. Wilens TC, Faraone, SV, Biederman J, Gunawardene S. Does stimulant therapy of attention-deficit/hyperactivity disorder beget later substance abuse? A meta-analytic review of the literature. Pediatrics. 2003; 111(1):179-185.

15. Swanson J, Greenhill L, Wigal T, Kollins S, Stehli A, Davies M, Chuang S, Vitiello B, Skroballa A, Posner K, Abikoff H, Oatis M, McCracken J, McGough J, Riddle M, Ghouman J, Cunningham C, Wigal S. Stimulant-related reductions in growth rates in the PATS. Journal of the Academy of Child and Adolescent Psychiatry. 2006 Nov; 45(11): 1304-1313.

16. Greenhill L, Kollins S, Abikoff H, McCracken J, Riddle M, Swanson J, McGough J, Wigal S, Wigal T, Vitiello B, Skroballa A, Posner K, Ghuman J, Cunningham C, Davies M, Chuang S, Cooper T. Efficacy and safety of immediate-release methylphenidate treatment for preschoolers with attention-deficit/hyperactivity disorder. Journal of the Academy of Child and Adolescent Psychiatry. 2006 Nov; 45(11):1284-1293.

17. Wigal T, Greenhill L, Chuang S, McGough J, Vitiello B, Skrobala A, Swanson J, Wigal S, Abikoff H, Kollins S, McCracken J, Riddle M, Posner K, Ghuman J, Davies M, Thorp B, Stehli A. Safety and tolerability of methylphenidate in preschool children with attention-deficit/hyperactivity disorder. Journal of the Academy of Child and Adolescent Psychiatry. 2006 Nov; 45(11): 1294-1303.

18. Alwan S, Reefhuis J, Rasmussen S, Olney R, Friedman J for the National Birth Defects Prevention Study. Use of selective serotonin-reuptake inhibitors in pregnancy and the risk of birth defects. New England Journal of Medicine. 2007 Jun 28; 356(26):2684-2692.

19. Louik C, Lin An, Werler M, Hernandez S, Mitchell A. First-trimester use of selective serotonin-reuptake inhibitors and the risk of birth defects. New England Journal of Medicine. 2007 Jun 28; 356(26):2675-2683.

20. Austin M. To treat or not to treat: maternal depression, SSRI use in pregnancy and adverse neonatal effects. Psychological Medicine. 2006 Jul 25; 1-8.

21. Cohen L, Altshuler L, Harlow B, Nonacs R, Newport DJ, Viguera A, Suri R, Burt V, Hendrick AM, Loughead A, Vitonis AF, Stowe Z. Relapse of major depression during pregnancy in women who maintain or discontinue antidepressant treatment. Journal of the American Medical Association. 2006 Feb 1; 295(5): 499-507.

22. U.S. Food and Drug Administration (FDA). FDA Medwatch drug alert on Effexor and SSRIs, 2004 Jun 3. Available at www.fda.gov/medwatch/safety/2004/safety04.htm#effexor.

23. Jain AE, Lacy T. Psychotropic drugs in pregnancy and lactation. Journal of Psychiatric Practice. 2005 May; 11(3): 177-191.

24. Ward RK, Zamorski MA. Benefits and risks of psychiatric medications during pregnancy. American Family Physician. 15 Aug. 2002; 66(4): 629-636.

 

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