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Psychopharmacology

Contributed by: David J. Nutt, Peter L. Carlton

Publication year: 2014

A discipline that merges psychology, which studies cognition, emotion, and behavior, and , which characterizes the effects of drugs. In focusing on understanding drugs that affect processes, especially thinking, feeling, and action, with a particular emphasis on those drugs that affect abnormalities in thought, affect (mood), and behavior, is closely related to .

Understanding the effects of drugs on psychological processes entails examining the regulation of these drugs by neurotransmitters, because drugs mediate their actions through changing these transmitters. See See also:

PHARMACOLOGY See ; PHARMACY See ; PSYCHOLOGY .

Psychopharmacology is concerned with four major classes of drugs that are of clinical significance in controlling four major categories of psychiatric disorders: anxiety, depression, mania (), and .

However, the scope of psychopharmacology is not limited to drugs and encompasses the study of other brain processes, including those that underlie medical conditions such as and dementias, as well as those involved in sleep, attention, , and cognition. See See also: ADDICTIVE DISORDERS ; BRAIN ; COGNITION ; SLEEP AND

DREAMING .

Anxiety

Anxiety is a normal, future-oriented emotional state with motivational value. However, if anxiety becomes excessive in magnitude or duration, it can interfere significantly with normal functioning and thus becomes a medical syndrome. It has been estimated that 2–4% of the general population suffers from an anxiety disorder at any , with lifetime rates of up to 20%, and these may require psychiatric attention and treatment with an anxiolytic drug. There are two major groups of anxiolytics—those that act quickly (fast-acting, drugs) and those that work more slowly. Of the fast-acting anxiolytics, the [for example, diazepam ® (Valium, )] are the most commonly used because they are the safest; however, in the past, and related drugs (for example, meprobamate) were used.

A major advance in understanding the benzodiazepines was the identification of the cellular sites at which these drugs act—the so-called receptors. These receptors are part of the for the neurotransmitter gamma-aminobutyric acid (GABA), which is the main inhibitory chemical in the brain. The benzodiazepines and other related drugs share a biochemical property in that all augment the activity of GABA; however, this augmentation occurs in different ways, which explains why barbiturates are more toxic than AccessScience from McGraw-Hill Education Page 2 of 6 www.accessscience.com

benzodiazepines. These drugs are , so they can be used to promote sleep. Other sedative drugs, such as antihistamines, are sometimes used to reduce anxiety.

Slower-acting anxiolytics include drugs that are also and others such as that act on the receptors for the neurotransmitter . A more recent approach to reducing anxiety is one that focuses on channels to reduce neurotransmitter release, through the use of drugs such as pregabalin. See See also:

ANXIETY DISORDERS See ; TRANQUILIZER .

Depression

The symptoms of depression can include sadness, hopelessness, despair, and irritability. Suicidal thoughts and attempts are common, and sometimes result in completed . In addition, physical symptoms such as loss of appetite, sleep disturbances, and psychomotor agitation (for example, restlessness, hand wringing, and pacing) are often associated with depression. When depression becomes so pervasive and intense that normal functioning is impaired, medication may be indicated. It has been estimated that as much as 15% of the population will require antidepressant medication at some time in their lives.

There are two major groups of antidepressant drugs, which share the property of elevating the level of the neurotransmitter serotonin or (or both). The first group comprises drugs that act to block the of these neurotransmitters into nerve cells—if they work on serotonin, they are called selective ® serotonin reuptake inhibitors [SSRIs, for example, fluoxetine (Prozac, )]; if they work on norepinephrine, then they are called nor- reuptake inhibitors (NRIs, for example, reboxetine). Some antidepressant drugs

(for example, and older tricyclic antidepressants) block the uptake of both neurotransmitters, and this may result in somewhat greater clinical efficacy. Bupropion is an antidepressant that is effective in increasing norepinephrine as well as increasing (a neurotransmitter in the brain); this latter effect probably explains why it is also useful in quitting smoking, because dopamine deficiency may to withdrawal symptoms.

The antidepressant drugs in the second group, which are less often prescribed, are called inhibitors because their major biochemical effect is to inhibit an called monoamine oxidase, which breaks down serotonin and norepinephrine. Therefore, by inhibiting monoamine oxidase, the levels of serotonin and norepinephrine are increased.

The antidepressants typically require at least several weeks of chronic administration before they become effective in alleviating depression, which is thought to reflect the need for adaptive changes in neurotransmitter receptors and second messengers to occur. When used properly over time, they can maintain efficacy for many years, and their main role is now to prevent further episodes of depression from occurring. They also work in alleviation of the anxiety disorders, probably by the same mechanisms of changing neurotransmitter levels, but AccessScience from McGraw-Hill Education Page 3 of 6 www.accessscience.com

they affect other brain regions rather than the ones involved in depression. See See also: AFFECTIVE DISORDERS ;

NORADRENERGIC SYSTEM .

Mania (bipolar disorder)

Manic episodes are characterized by hyperactivity, grandiosity, flight of ideas, and irritability. Some affected patients may be euphoric, whereas others 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, which vary from many years to hardly any time at all.

Mania can be life-threatening and needs urgent medical involvement. It can be brought under control by using mood stabilizers, such as or sodium valproate, or by antipsychotic drugs because they block dopamine, which is thought to be elevated in mania. Prevention of further episodes is the key requirement of treatment because of the damage that both manic and depressive episodes cause to family and work life; thus, maintenance therapy with mood stabilizers such as those already mentioned or lamotrigine (which may be better at preventing depressive relapse) is necessary. See See also: BIPOLAR DISORDER ; PSYCHOTHERAPY .

Schizophrenia

Schizophrenia is the most common form of ; it incorporates a broad range of symptoms that can include bizarre delusions, hallucinations, incoherence of thought processes, and inappropriate affect (the so-called positive symptoms), as well as major impairments of cognitive social and work functions (the negative symptoms). It affects about 1% of the population in all countries and ethnic groups.

The positive symptoms of schizophrenia are thought to be a result of excessive dopamine release in the limbic system and can be controlled, to 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 people treated for schizophrenia. However, treatment is only partially successful, because normal functioning is not completely restored in most patients. In general, the negative symptoms are less responsive to treatment and tend to dominate the long-term outcome.

Antipsychotic drugs fall into three main classes: typical, atypical, and dopamine partial . Typical drugs include haloperidol, atypicals include clozapine and olanzapine, and the only partial currently in clinical practice is aripiprazole. Although different antipsychotic drugs have different kinds and degrees of side effects, all share a common biochemical action, which is to attenuate the activity of dopamine. The reduction in dopamine activity produced by the antipsychotics is thought necessary for their antipsychotic effects and accounts directly for their adverse effects on motor behavior. This occurs because dopamine is known to be present in high concentrations in the nigrostriatal system, which is an anatomically defined dopamine system of the brain that is AccessScience from McGraw-Hill Education Page 4 of 6 www.accessscience.com

intimately involved in the regulation of movement. The motoric side effects fall into two general classes. The first class includes motor restlessness (akathisia) and symptoms that are very similar to those of Parkinson’s disease. In general, these disturbances can be managed by adjunctive medication with other drugs. Such control is not yet possible for the second class of movement disorder, called tardive dyskinesia, which is a disturbance typically including involuntary movements that most often affect the tongue and the facial and neck muscles but can also include the digits and trunk.

For typical antipsychotics, there is a small therapeutic window between the antipsychotic effects and the motoric ones, which makes avoiding the latter quite difficult. The atypicals and partial agonists have a wider window, but patients suffer from other unwanted actions, especially weight gain and diabetes. Because the treatment of schizophrenia is usually life-long, prevention and management of side effects can become a major concern. See See also: PSYCHOSIS ; SCHIZOPHRENIA .

Laboratory analysis of physiological mechanisms

The mechanisms by which different drugs exert their clinical effects on behavior remain to be determined. Four major factors make this challenging: (1) The multiplicity of variables that control behavior typically cannot be simply measured. (2) Each of these variables can interact with others, so the behavioral consequences of one interaction are not the same as the consequences of another interaction. (3) It may be that different mechanisms control similar behaviors; therefore, patients, all labeled as schizophrenic, for example, may share many behaviors that are actually mediated by different underlying processes. (4) Much of the research cannot be undertaken in humans, especially for ethical reasons, and hence laboratory models must be developed in infrahuman species. However, psychopharmacology offers a powerful means of cross-translating these research questions among species, as the neurotransmitter mechanisms are largely conserved across all mammals. Indeed, this is a major reason for the development and strength of the discipline.

The development of laboratory models is itself a formidable task, because the disorders that must be mimicked are uniquely human, which is in contrast to most other disorders. Unlike a disorder such as diabetes, there are no direct analogs of mania, depression, or schizophrenia in laboratory animals; however, some progress has been made in this arena, especially now that genetic studies in humans can be readily replicated in mice using molecular biological transgenic approaches. Although anxiety can be produced in the laboratory, the extent to which such anxiety truly mirrors anxiety in humans is uncertain, because the measurement of anxiety in humans is determined not just by physiological changes but mostly by their verbal report.

These problems can be partially circumvented by showing that drug-induced behavioral changes in the laboratory have properties that are parallel to those seen in the clinic. For instance, if chronic, but not acute, administration of a drug produces clinical change, then chronic, but not acute, administration of that drug should produce behavioral change in the laboratory. In addition, if clinical change is selectively induced by one group of drugs, then the laboratory behavior also should be selectively sensitive to that one group, but not to other groups AccessScience from McGraw-Hill Education Page 5 of 6 www.accessscience.com

of drugs. For example, behavior in a laboratory animal that changes only after chronic, not acute, treatment with both lithium and valproate (but not other drugs) could have promise as a model of mania. As more and more of the characteristics of clinical change are paralleled in laboratory behavior, the greater are the chances that such laboratory behavior will serve as a useful baseline for the elucidation of underlying physiological mechanisms.

New imaging techniques such as positron emission tomography (PET) and magnetic resonance imaging (MRI) have begun to allow more direct inquiry into the sites of actions of drugs in the brain, and these can be applied in animal studies as well. For instance, studies of patients who have anxiety have found that there are relative deficits in the GABA receptors in the brain regions that regulate anxiety. If similar deficits are induced in mice, then anxiety also is produced. A reduction in serotonin receptors has been found in patients who have depression, whereas there is evidence for excessive release of dopamine in a proportion of patients who have schizophrenia. By producing similar changes in animals that mimic the clinical picture, this also has allowed new treatments to be tested. See See also: MEDICAL IMAGING ; NEUROBIOLOGY .

David J. Nutt, Peter L. Carlton

Keywords psychopharmacology; pharmacology; psychology; anxiety; depression; mania; schizophrenia; imaging

Bibliography

J. Geddes et al., Relapse prevention with antidepressant drug treatment in depressive disorders: A systematic review, Lancet , 361:653–661, 2003 DOI: http://doi.org/10.1016/S0140-6736(03)12599-8

S. Kapur, Psychosis as a state of aberrant salience: A framework linking , phenomenology, and pharmacology in schizophrenia, Am. J. Psychiatry , 160:13–23, 2003

DOI: http://doi.org/10.1176/appi.ajp.160.1.13

D. J. Nutt and A. L. Malizia, New insights into the role of the GABA(A)-benzodiazepine receptor in psychiatric disorder, Br. J. Psychiatry , 179:390–396, 2001 DOI: http://doi.org/10.1192/bjp.179.5.390

D. J. Nutt et al., The other face of depression, reduced positive affect: The role of in causation and cure, J. Psychopharmacol. , 21:461–471, 2007 DOI: http://doi.org/10.1177/0269881106069938

Additional Readings

T. Chang and M. Fava, The future of psychopharmacology of depression, J. Clin. Psychiatr. , 71(8):971, 2010

DOI: http://doi.org/10.4088/JCP.10m06223blu AccessScience from McGraw-Hill Education Page 6 of 6 www.accessscience.com

A. Cooke et al., Effects of competition on endurance performance and the underlying psychological and physiological mechanisms, Biol. Psychol. , 86(3):370–378, 2011

DOI: http://doi.org/10.1016/j.biopsycho.2011.01.009

J. D. Preston, J. H. O’Neal, and M. C. Talaga, Handbook of Clinical Psychopharmacology for Therapists , 6th ed.,

New Harbinger Publication, Oakland, CA, 2010

J. Rhoads and P. J. M. Murphy, Clinical Consult to Psychopharmacology for Primary Care Providers , Springer,

New York, 2012

J. Wegmann, Psychopharmacology: Straight Talk on Mental Health Medications , 2d ed., Premier Publishing &

Media, Eau Claire, WI, 2012

American Society of Clinical Psychopharmacology

Pacific Neuropsychiatric Institute