PSYCHOPHARMACOLOGY

Psychopharmacology is defined as the use of drugs to modify mental or behavioral performance. In general, psychopharmacology is used in the treatment of biologically based mental illnesses, although there has been increased interest in using drugs to enhance performance in healthy individuals.

Psychopharmacology assumes a strong mind-brain connection, if not a complete reduction of mind to brain. However, early theories about the relationship of brain chemistry to behavior were weak and post hoc. Most drugs were discovered accidentally and adopted because of their effects on symptoms (Valenstein 1998). Only later were theories of the ways drugs act on the brain developed, followed by theories of how mental states are related to brain chemistry. Although the mechanism of action on neuronal receptors has been elucidated for many drugs, the mechanisms by which drugs influence behavior at the whole-brain level are poorly understood. There are no definitive biological markers for diagnosing mental illness, and thus diagnosis relies on a clinical judgment of whether symptoms are present.

Although theories that mental illnesses result from a specific underlying chemical imbalance are not well substantiated, they have encouraged afflicted persons to seek treatment by reducing some of the stigma associated with psychological theories of mental illness. The discovery of drugs that alleviate some of the most debilitating symptoms of mental illness also allowed deinstitutionalization to occur, resulting in much more effective, community-based treatment programs

Psychopharmacologic Agents

The major classes of psychopharmacologic agents (Schatzberg and Nemeroff 1998) are antipsychotics (also known as neuroleptics), antidepressants, anxiolytics (antianxiety agents), and mood stabilizers. In addition, cognitive enhancing drugs are receiving increasing interest and use.

ANTIPSYCHOTICS. Antipsychotics, which are used primarily for the treatment of schizophrenia, reduce symptoms such as paranoia, visual and auditory hallucinations, and delusions. The first drugs of this type—phenothiazines—initially were produced as synthetic dyes. Later research in the 1940s showed that they act on the central nervous system as antihistamines. When administered to patients with allergies, they produced side effects that included decreased muscle tone, reduced nausea, and mild elation. That led to their use to relax patients before surgery, treat Parkinson's disease, and calm agitated and manic patients. In manic patients these drugs were also found to reduce the psychotic symptoms associated with the disorder. Antipsychotics are the most successful variety of psychopharmaceutical agents, reducing symptoms in 90 percent of patients in the acute phase of the disorder. Long-term use, however, may result in negative side effects that include tardive dyskinesia, which is characterized by involuntary motor movements such as those seen in Parksinson's patients, and neuroleptic malignant syndrome, which is a potentially fatal side effect. In contrast to the typical antipsychotics, the development of atypical antipsychotics has focused on not only reducing psychotic symptoms but also on improving negative symptoms (for example, loss of motivation, social withdrawal, and affective flattening) associated with schizophrenia and reducing adverse side effects.

ANTIDEPRESSANTS. Antidepressant pharmaceuticals also were discovered fortuitously. After World War II chemical companies had a surplus of the rocket fuel hydrazine, which they began modifying in an attempt to find new compounds with properties that might be useful for medical purposes. In the course of testing one of the new compounds against tuberculosis it was found to cause euphoria as a side effect. A derivative of hydrazine was synthesized as iproniazid, and after animal testing showed that the drug increased alertness, it became a treatment for depression.

There are three primary classes of antidepressants: selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs), and tricyclics. Common SSRIs include fluoxitine (Prozac) and paroxitine (Paxil), MAOIs are exemplified by phenylzine (Nardil) and isocarboxazid (Marplan), and tricyclics include amitriptyline (Elavil) and imipramine hydrochloride (Tofranil).

All these drugs are considered equally effective in reducing depressive symptoms. The typical response rate of patients with uncomplicated unipolar depression to antidepressants is about 65 percent, compared with a 30 percent response rate on placebo. In addition to reducing current symptoms of depression these drugs appear to reduce the 50 percent relapse rate of major depressive episodes by 50 percent over the course of one year. The observed response rate with pharmacologic agents has been found to be identical to that of cognitive-behavioral psychotherapy. Treatment for depression that combines pharmacologic treatment and psychotherapy is more effective than is either modality alone (Burns 1980).

Side effect profiles or counterindications usually influence which drugs are prescribed more frequently. Side effects of SSRIs include headache, tremor, nausea, diarrhea, insomnia, agitation, nervousness, and sexual dysfunction. More important, SSRIs were found to increase suicidal behavior among adolescents, prompting the U.S. Food and Drug Administration (FDA) to mandate "black box" warnings to that effect on prescription bottles. Side effects of MAOIs include weight gain, orthostatic hypotension (drop in blood pressure when standing up quickly), delayed ejaculation, insomnia, and cholinergic side effects such as blurred vision, constipation, dry mouth, speeded heart rate, and urinary retention; MAOIs also require a diet that avoids foods with tyramine as hypertension and cerebral hemorrhage or death (rare) may occur. Side effects of tricyclics include weight gain, sexual dysfunction, cholinergic side effects, and sedation.

ANXIOLYTICS. The first drugs for treating anxiety were discovered in 1945 during testing of drugs designed to combat infectious bacteria. Those early drugs were found to be extremely habit-forming and to produce drowsiness, and ultimately were replaced by a class of antianxiety drugs called benzodiazepines (for example, alprazolam [Xanax] and diazepam [Valium]) that were discovered after an unexpected chemical reaction occurred in a compound that originally had been developed for use as a dye.

Benzodiazepines are very effective in reducing anxiety. In fact, since their introduction in the 1960s anxiolytics have been referred to as "happy pills." Eighty-two percent of patients on alprazolam show improvement compared with 42 percent on placebo. These drugs are also effective in reducing the occurrence of panic attacks. Benzodiazepines are among the most frequently prescribed drugs; however, they are habit-forming, and many of the 7 million prescriptions written yearly in the United States are in response to simple stresses of everyday life rather than debilitating conditions.

MOOD STABILIZERS. Mood-stabilizing drugs are used in the treatment of bipolar (manic-depressive) illnesses, in which patients suffer from recurrent cycles of depressive moods followed by manic periods. Lithium is the primary treatment for manic-depressive illness. Its effectiveness was discovered in the course of testing the hypothesis that uric acid would increase mania. Uric acid was difficult to work with because it was not easily soluble, and so lithium urate was used instead and surprisingly reduced mania. The FDA approved lithium treatment for mania in 1970 after a double-blind study showed that all the manic patients on lithium remained well, whereas half the patients who were switched from lithium to a placebo relapsed.

Additional double-blind, placebo-controlled studies have found that 70 to 80 percent of patients show improvement on lithium. Lithium reduces the intensity of manic and depressive episodes and decreases the overall number of episodes. Major side effects include excessive thirst and volume of urine, memory problems, tremor, and weight gain. In addition, high doses can lead to endocrine and renal complications.

COGNITIVE ENHANCERS. Cognitive-enhancing drugs are designed to improve cognitive functions such as memory and attention. Pharmacological agents to improve memory function are particularly important in slowing the memory loss observed in patients with Alzheimer's disease. The focus of this research has been on drugs that influence the brain systems involved in learning and memory. More specifically, agents are being developed to help patients retain memories that may be lost as individuals age. In clinical trials, donepezil (Aricept), rivastigimine tartrate (Exelon), and galantamine (Reminyl) all have been shown to reduce cognitive decline in the early stages of Alzheimer's. However, the measures of performance used have been very general tests of cognitive functioning, and so the exact cognitive function that is affected by these drugs is unclear. Side effects of these medications usually occur at higher doses and include gastrointestinal problems, dizziness, and headaches.

Drugs that enhance attentional functioning have been developed for the treatment of attention deficit hyperactivity disorder (ADHD). These drugs help patients maintain attention on a task over an extended period and reduce impulsive motor behaviors. Treatment for ADHD has consisted primarily of psychostimulants, including methylphenidate (Ritalin), d-amphetamine (Dexedrin), and a mixture of amphetamine salts (Adderall). Although the idea of giving stimulants to reduce hyperactivity is counterintuitive, these drugs have been shown to reduce symptoms in 70 to 80 percent of children with ADHD and are much more effective than are psychological treatments. These drugs reduce psychomotor activity and restlessness and increase a patient's ability to pay attention. Some of the more frequently reported side effects of psychostimulants include weight loss, social withdrawal, irritability, and insomnia.

With the development of these drugs interest has increased in the possibility of creating cognitive enhancers for healthy adults. Early research investigating the effects of Alzheimer's drugs on memory in healthy adults showed little to no improvement in memory function. As a result of that failure pharmaceutical companies began to focus on drugs that influence the formation of new memories and the retention of memories. However, data showing clinical effectiveness of these drugs were not available in the first years of the twenty-first century. In contrast to memory enhancement, much research suggests that healthy individuals who take methylphenidate and other psychostimulants show improvements in working memory and sustained attention. Conflicting research not only failed to replicate those improvements but found impairments in other cognitive functions. Before these drugs are prescribed for cognitive enhancement, their effects on healthy adults must be confirmed in controlled clinical trials.

Ethical Considerations

The ethical issues surrounding psychopharmacology can be grouped into four categories: research on psychopharmacologic agents, use in clinical treatment of illness, use for performance enhancement, and prophylactic or preventive use.

RESEARCH. Ethical issues in psychopharmacological research are largely the same as those in research in general and include issues related to the ethical treatment of animals, the informed consent of participants, and the appropriate use of placebos in control groups (Roberts and Krystal 2003). Because of the high commercial value of these products conflicts of interest among scientists are also important.

CLINICAL TREATMENT. Ethical issues that arise in the treatment of mental illness include informed consent (whether treatment is taking place inside or outside a research study), weighing the risks of side effects against the benefits of treatment (particularly the increased risk of suicide among adolescents taking certain antidepressants and the risks to the fetus or child of a pregnant or nursing mother receiving treatment), and access to treatment (for example, whether financial ability should determine which patients get access to newer, more expensive antipsychotics and which get cheaper, older, and less effective generic medications).

However, there are also "big picture" issues concerning what is viewed as an illness and when treatment should be directed at the individual rather than the environment. With most prescriptions for antidepressants and anxiolytics being written by general physicians rather than mental health professionals, drugs often are prescribed for dispositional characteristics or problems that are not biological in nature (for example, for persons dealing with stressful life events, grieving from a loss, or pessimistic by nature) even though psychological interventions designed to enhance coping skills could be more effective. Further, environmental change may be more effective than individual interventions in reducing the prevalence of some mental illnesses.

For example, with suicide as a leading cause of death among college students, perhaps it would be more efficacious to think about rampant depression as a problem stemming from the environment rather than from the individual. This changes the focus of treatment to modifications of the environment, (such as transition programs, peer support resources, and so on) as opposed to treating the many individuals who are suffering as a result of that environment. This amounts to taking a human factors approach to society and asking how to take what is known about cognitive strengths and limitations and use it to redesign cultural institutions to maximize productivity and benefit the individual while minimizing stress.

COGNITIVE ENHANCEMENT AND PROPHYLAXIS. Ethical questions concerning cognitive performance enhancement and prophylactic use have begun to be addressed. (President's Council on Bioethics 2003). The use of enhancing drugs when deficits are present (for example, for patients with Alzheimer's or ADHD) is subject to the same ethical questions as is the use of other psychopharmaceuticals for the treatment of illness. New ethical concerns arise when drugs are used to enhance performance in patients in whom no deficits are present (Farah, Illes, Cook-Deegan, et al. 2004) or to prevent illness when no signs of illness are present. For example, the potential risks of taking a drug are much more important in risk-benefit calculations when the patient's quality of life is high in the absence of the drug.

Questions of access and coercion also arise: With the use of Ritalin as a study aid reportedly on the rise among high school and college students, does this constitute an unfair advantage to the users? Will nonusers feel pressured to use the drugs in order to compete with users? Will those who cannot afford the drugs be left behind? In addition, general questions of what it means to be a person have been asked: To what extent is character built by coping with the limitations and imperfections present in oneself and others? Should individuals be free to experiment on themselves with such drugs? Will achieving human perfection make people happier?

Finally, with the contemporary emphasis on genetic contributions to psychiatric disorders, individuals eventually may be able to take drugs prophylactically based on genetic tests that assign an increased probability of developing a disorder. This raises concerns about whether this information should be supplied to individuals and how they will interpret the risks. It also prompts questions about how likely an outcome should be before information is given or action is taken. In light of the relative lack of understanding of brain system dysfunctioning in disorders, prophylactic use of drugs likely will become an increasingly serious issue.

ELIZABETH J. MULLIGAN ERIC D. CLAUS

SEE ALSO Emotion;Neuroethics;Psychology.

BIBLIOGRAPHY

Burns, David D. (1980). Feeling Good: The New Mood Therapy. New York: Avon. Provides a comprehensive overview of pharmacologic and cognitive-behavioral treatments for depression.

Farah, Martha J.; Judy Illes; Robert Cook-Deegan; et al. (2004). "Neurocognitive Enhancement: What Can We Do and What Should We Do?" Nature Reviews Neuroscience 5: 421–425. A response to the President's Council on Bioethics (2003). Presents an argument in support of the development and use of cognitive enhancing drugs.

President's Council on Bioethics. (2003). Beyond Therapy: Biotechnology and the Pursuit of Happiness. Washington, DC: Author.

Roberts, Laura Weiss, and John Krystal, eds. (2003). Special issue on psychopharmacology and ethics. Psychopharmacology 171(1): 1–119.

Schatzberg, Alan F., and Charles B. Nemeroff, eds. (1998). The American Psychiatric Press Textbook of Psychopharmacology, 2nd edition. Washington, DC: American Psychiatric Press.

Valenstein, Elliot S. (1998). Blaming the Brain: The Truth about Drugs and Mental Health. New York: Free Press. Presents the historical development of drugs used to treat mental illness and critically analyzes the role of the pharmaceutical industry in promoting biological theories of mental illness.