psychopharmacology

n.
The branch of pharmacology that deals with the study of the actions, effects, and development of psychoactive drugs.

psychopharmacologic psy'cho·phar'ma·co·log'ic (-kə-lŏj'ĭk) or psy'cho·phar'ma·co·log'i·cal (-ĭ-kəl) adj.
psychopharmacologist psy'cho·phar'ma·col'o·gist n.

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A discipline that merges the subject matter of psychology, which studies cognition, emotion, and behavior, and pharmacology, which characterizes different drugs. Thus, psychopharmacology focuses on characterizing drugs that affect thinking, feeling, and action. In addition, psychopharmacology places particular emphasis on those drugs that affect abnormalities in thought, affect, and behavior, and thus has a relationship to psychiatry. Psychopharmacology is predominantly, but not exclusively, concerned with four major classes of drugs that are of clinical significance in controlling four major categories of psychiatric disorder: anxiety, depression, mania, and schizophrenia.

Anxiety is an emotional state that can range in intensity from mild apprehension and nervousness to intense fear and even terror. It has been estimated that 2–4% of the general population suffer from an anxiety disorder at some time. Although anxiety in some form is a common experience, it can become so intense and pervasive as to be debilitating; it may therefore require psychiatric attention and treatment with an anxiolytic drug. There are three major groups of anxiolytics. Members of the first group are called propanediols; meprobamate is the most widely used. The second group is the barbiturates, of which phenobarbital is the most generally prescribed. The third group, most frequently prescribed, is the benzodiazepines, the best known of which is diazepam.

A major advance in understanding the benzodiazepines was the identification of the cellular sites at which these drugs act (so-called benzodiazepine receptors). The distribution of these receptors in the brain has also been found to have a striking parallel to the distribution of the receptors for a naturally occurring substance called gamma-amino butyric acid (GABA). Furthermore, it is known that GABA has a ubiquitous inhibitory role in modulating brain function. Most importantly, it is now clear that benzodiazepines share a biochemical property in that all augment the activity of GABA. See also Anxiety disorders; Serotonin; Tranquilizer.

The symptoms of depression can include a sense of sadness, hopelessness, despair, and irritability, as well as suicidal thoughts and attempts, which are sometimes successful. In addition, physical symptoms such as loss of appetite, sleep disturbances, and psychomotor agitation are often associated with depression. When depression becomes so pervasive and intense that normal functioning is impaired, antidepressant medication may be indicated. It has been estimated that as much as 6% of the population will require antidepressant medication at some time in their lives.

There are two major groups of antidepressant drugs. Members of the first group are called heterocyclics because of their characteristic chemical structures. Members of the second group, which are less often prescribed, are called monoamine oxidase inhibitors. See also Monoamine oxidase.

The antidepressants typically require at least several weeks of chronic administration before they become effective in alleviating depression. This contrasts with the anxiolytics, which are effective in reducing anxiety in hours and even minutes. Another difference between these two classes of drugs is that the anxiolytics are more likely to be efficacious: anxiolytics are effective in the vast majority of nonphobic, anxious patients, whereas the antidepressants are effective in only about 65–70% of depressed patients. See also Affective disorders.

Manic episodes are characterized by hyperactivity, grandiosity, flight of ideas, and belligerence; affected patients appear to be euphoric, have racing thoughts, delusions of grandeur, and poor if not self-destructive judgment. Periods of depression follow these episodes of mania in the majority of patients. The cycles of this bipolar disorder are typically interspersed among periods of normality that are, in most cases, relatively protracted.

Mania can usually be managed by chronic treatment with lithium salts and can be expected to be effective in 70–80% of the individuals treated. Furthermore, the period of depression that typically follows the manic episode can usually be prevented, or at least attenuated, if lithium treatment is maintained after the manic phase has subsided. Any periods of depression that do occur can be managed by antidepressant drugs. Lithium is no longer the only drug used in the management of mania. Carbamazepine, an anticonvulsant that is used in the treatment of epilepsy, is also useful in the treatment of periods of mania.

Schizophrenia is a form of psychosis; it incorporates a broad range of symptoms that can include bizarre delusions, hallucinations, incoherence of thought processes, inappropriate affect, and grossly disorganized movements. It affects 1–2% of the population. The symptoms of schizophrenia can be controlled, in varying degrees, by a large group of drugs called antipsychotics. Symptom management requires chronic medication and can be expected in about 80% or more of the schizophrenics treated. However, management is only partially successful in that normal functioning is not completely restored in most patients.

The antipsychotics have a broad range of side effects among which are disturbances of movement that fall into two general classes. The first class includes an array of symptoms very like those characteristic of Parkinson's disease. The second class of movement disorder is called tardive dyskinesia. Signs of this disturbance typically include involuntary movements that most often affect the tongue and facial and neck muscles but can also include the digits and trunk.

Although different antipsychotic drugs have different kinds and degrees of side effects, all share a single biochemical action: they all attenuate the activity of dopamine, a naturally occurring substance in the brain. The reduction in dopamine activity produced by the antipsychotics directly accounts for their effects on motor behavior. It is to be expected, therefore, that disrupted dopamine activity in this system would produce disturbances of movement. It is less clear, however, whether reduced dopamine function is also a factor in the process by which these drugs control psychotic (including schizophrenic) symptoms. See also Schizophrenia.

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n

The scientific study of the effects of drugs on behavior and normal and abnormal mental functions.

The use of drugs that act on the mind is as old as the recorded history of man. Alcohol in the form of fermented beverages such as mead was probably already popular in the palaeolithic age, about 8000 bc, and grape wine from about 400–300 bc. Opium is referred to in Sumerian tablets of around 4000 bc, and marijuana was known in China at 2737 bc. The hallucinogenic properties of the magic mushroom (teonanacatl) were known from 1000 bc in Mexico, while in northern Europe and Asia the inebriant properties of the fly agaric mushroom, Amanita muscaria, feature in Norse legends. The concept that drugs can be used medically to restore mental health is, in contrast, the result of a very recent revolution in pharmacology, following the discovery in the 1950s of new classes of drugs, the tranquillizers and antidepressants, and their widespread use in the treatment of mental illness.

Staggering quantities of psychoactive drugs are now consumed for medical purposes. About half of the female population of the United Kingdom over the age of 60 regularly uses sedative drugs to put them to sleep each night. Benzodiazepines in the form of Valium (diazepam) and related substances by day, and Mogadon (nitrazepam) and Dalmane (flurazepam) for night sedation, have largely replaced barbiturate sedatives and hypnotics. The success of these 'tranquillizers' can be gauged by the astonishing quantity consumed, amounting to tens of billions of doses throughout the world each year. These substances have a definite although mild calming effect, they relieve anxiety and diminish aggression, and they are relatively safe — in contrast to the barbiturates, which all too commonly lead to death from overdose. Because these newer drugs are relatively safe, and since almost all of us feel anxious from time to time, the extravagant success of the benzodiazepines during the 1960s and 1970s is not hard to understand. More recently, with the recognition that prolonged use of benzodiazepines can lead to addiction, there has been a growing reaction to their widespread use.

The most remarkable modern development in this field, however, is the discovery of drugs that are successful in the treatment of some of the fundamental symptoms of psychosis and depression. The first drug found to have such effects in schizophrenic patients was chlorpromazine (Largactil, Thorazine), and from this a large number of other so-called 'major tranquillizers' with similar effects have been developed. Since the first favourable reports on chlorpromazine appeared in France in 1952, such drugs have been adopted widely for the treatment of schizophrenia. More than 100 million schizophrenic patients have been treated with chlorpromazine since 1953. The major tranquillizers have definite beneficial effects on some of the most fundamental symptoms of schizophrenia: patients show less disordered thinking, suffer from fewer delusions and hallucinations, exhibit more appropriate emotional behaviour. They are not simply quietened or sedated, and indeed other sedative drugs such as the 'minor' tranquillizers (benzodiazepines) do not exhibit these effects. It is not surprising that the massive use of chlorpromazine and similar drugs has had an enormous impact on the treatment of schizophrenia. (For further discussion, see schizophrenia: evidence for a neurochemical basis.) The mental institutions have been transformed from sombre places with a largely custodial function to hospitals with open doors in which community therapy and rehabilitation techniques have been introduced. The number of patients so severely ill as to need more or less permanent hospitalization has also diminished strikingly — to the extent that separate psychiatric hospitals may no longer be necessary in future.

Other groups of drugs have been discovered to have beneficial effects in treating the melancholia of depressed patients. Two major classes of antidepressants have been introduced since the late 1950s — one derived from the substance iproniazid and the other from imipramine. Both groups of compounds have beneficial effects in depression, although these actions are usually less dramatic than those seen with the antipsychotic drugs. A remarkable discovery, made by Dr John Cade in Australia in 1949, has been that the symptoms of mania can often be treated very effectively by administration of small doses of an inorganic salt — lithium carbonate. Continued treatment with lithium carbonate reduces the frequency of recurrence of manic episodes in individuals who would otherwise show a regular cycle of such illness.

The problems of madness have not been solved by the drugs — we still do not understand what causes schizophrenia or depression, or even the nature of these illnesses. The idea that abnormalities in brain chemistry may underlie mental illness has, however, derived strong support from the finding that psychosis can be treated with simple chemicals. Much research effort is currently directed towards discovering precisely how the antipsychotic and antidepressant drugs alter brain chemistry. It is now widely accepted that antipsychotic drugs act by blocking the effects of one of the chemical transmitter substances used by brain cells to transmit signals to one another. The transmitter blocked by chlorpromazine and related drugs is dopamine, and this finding has suggested the possibility that in schizophrenia excessive amounts of dopamine secreted in the brain might represent an immediate causative factor for the psychotic state. (See dopamine neurons in the brain.) On the other hand, antidepressant drugs seem to act by enhancing the effects of other chemical transmitter substances, noradrenaline (norepinephrine) and serotonin, in the brain — suggesting that these chemicals may be available in abnormally low amounts in the brains of depressed people.

In general, however, our knowledge of the mode of action of many psychoactive drugs is limited. This applies particularly to nicotine, cannabis, and the hallucinogens, but both barbiturates and alcohol act as central nervous system depressants. With respect to barbiturates and benzodiazepines it is likely that their depressant effects on neural activity are mediated by the neurotransmitter gamma-aminobutyric acid (GABA), but other neurotransmitters may also be involved. Rather surprisingly, less is known about the precise mode of action of alcohol on the brain beyond the fact that it appears to depress synaptic transmission.

The fact that simple chemical substances can have such profound influences on the state of the mind, as between madness and sanity, between depression and euphoria, between normal perception and the vivid hallucinations induced by lysergic acid diethylamide (LSD), has obvious philosophical implications for the relation between the mind and the chemistry of the brain. It is clear that subtle changes in brain chemistry can have profound effects on the state of consciousness, and it behoves us to understand more of such subtleties.

Drugs are also consumed very widely for non-medical reasons. Of these alcohol, nicotine, and caffeine are relatively universal — others, whose use is strictly controlled by legislation, such as the hallucinogens, barbiturates, amphetamines, marijuana, phencyclidine, cocaine, and opiates, are, nevertheless, also quite widely taken. These compounds have a bewildering variety of different psychic effects. Alcohol and barbiturates are depressants, leading to a feeling of relaxation, loss of inhibition, and to inebriation and sleep. Others are stimulants, such as nicotine and the more powerful amphetamines; these are performance-enhancing drugs. LSD, mescaline, phencyclidine, and the many other hallucinogens are in a class apart because these compounds can produce bizarre changes in perception — they replace the present world with another that is equally real but different, often with vivid sensory hallucinations. There are other drugs whose actions are primarily euphoriant, notably cocaine, morphine, heroin and other opiate drugs, and — in a milder form — marijuana. They replace the present world with one in which the individual experiences no problems, and often intense pleasure. The most powerful euphoriants, the opiates and cocaine, are medically dangerous drugs — largely because their continued use leads inevitably to tolerance and addiction, i.e. larger and larger doses become necessary to achieve the desired effects, and the organism becomes physically dependent on continued drug use, so that stopping the drug may precipitate very unpleasant withdrawal symptoms. It should be remembered, however, that morphine and related opiates still have important medical uses in the control of pain. Opium has long been regarded as a sovereign remedy for the relief of pain and other symptoms. As Thomas Sydenham, the English physician, wrote at the end of the 17th century, 'I cannot forbear mentioning with gratitude the goodness of the Supreme Being who has supplied afflicted mankind with opiates for their relief'. Almost certainly it is the insanitary habits and unsterile modes of use as well as the actions of the drugs as such that make opiates such a hazard to the life and health of the addict today.

We may one day discover how to eliminate the problem of addiction, and we will then be faced with the difficult decision as to whether 'safe' euphoriant drugs should be allowed widespread availability and use. Several millennia of experience with alcohol suggests that strict control of the availability of such substances would inevitably be needed. The 'soma' of Aldous Huxley's Brave New World may be nearer than is generally realized. There is little doubt that legislation controlling the use of marijuana will gradually become less prohibitive, and that modern plant breeding could work wonders with the Indian hemp plant to produce 'super-pot'. It is also clear that society has not yet decided what its attitudes should be to the general availability of chemically induced pleasure.

(Published 1987)

— Les Iverson

Bibliography
• Iversen, L. L., Iversen, S. D., and Snyder, S. H. (eds.) (1975–84). Handbook of Psychopharmacology, vols. i–xviii.
• Iversen, S. D., and Iversen, L. L. (1981). Behavioral Pharmacology (2nd edn.).
• Ray, O. S. (1972). Drugs, Society and Human Behavior.

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