Biomedical Psychiatric Therapeutics

Carolina

Introduction

John M. Davis

This is a textbook on physical treatments in psychiatry, principally psychotropic drugs and electroconvulsive treatment (ECT). Although psychiatry has lagged behind general medicine in the development of pharmacotherapies, this lag represents only a modest number of years when considered in the context of the history of medicine from antiquity to the present. In the past 50 years, general medicine has seen the development of a substantial number of safe and efficacious drug treatments for a variety of disorders. Physical treatments in psychiatry had their beginning before World War II with the development of ECT and the serendipitous discovery that amphetamine has a beneficial effect on children with what at that time was called hyperactive behavior. The antimanic effect of lithium was discovered in 1949, but chemotherapy and psychiatry really became one with the discovery of the antipsychotic properties of chlorpromazine and reserpine in 1952. Their use became widespread throughout the world in the late 1950s and early 1960s.

The discovery of effective treatments has substantially altered the fate of mental patients. In real life, it is rare that any treatment completely prevents illness or produces a permanent cure in every patient all the time, although this does occur on occasion. For example, smallpox as a disease has been completely eliminated from the world. More typically, drugs suppress a disorder, but continuous administration is necessary to prevent recurrences. Even though the miracle antibiotics may produce a dramatic cure in a patient with an infectious disease, they do not prevent recurrences in patients who have suitable predisposing factors.

It is relevant, therefore, to ask: What is the increment in therapeutics achieved through the use of drugs in psychiatry? Such a question is semi-quantitative. For any new treatment, one can ask: How well do patients do, now that we have this new treatment, in comparison to how they would have done with the older treatment? For comparison, let us take the first two antibiotics discovered: penicillin and streptomycin. At the time streptomycin was discovered, the standard treatment for tuberculosis was a prolonged period of bed rest in a sanatorium. In a controlled trial done by the British Medical Research Council, patients were randomly assigned to regimens of streptomycin plus bed rest or bed rest alone. Two out of three patients recovered with streptomycin, and one out of three recovered with standard treatment. At the time penicillin was discovered, sulfur was the standard treatment for pneumococcal pneumonia, and approximately 11% of patients were dying. With penicillin, the death rate was reduced to 6%. For both of these antibiotics, then, the increment to medical practice was either to double the number of patients who made a reasonable recovery (tuberculosis) or to cut by 50% the number of patients who died (pneumococcal pneumonia).

How well do the psychiatric drugs perform in comparison? To quantify this, we use the percentage of patients who do relatively well with the new treatment in comparison with the percentage who do well with the standard treatment. The National Institute of Mental Health (NIMH) double-blind study of antipsychotics found that about 30% of patients showed a reasonable recovery with placebo, but this recovery rate could be increased to about 70% with the use of antipsychotic drugs, more than doubling the efficacy. It is, of course, important to remember that there is a qualitative distinction in that continuous administration of drugs in psychiatry is generally required to prevent relapses. It is relevant to note that about 35 double-blind studies on the maintenance use of antipsychotic drugs to prevent relapse found that in four to six months about 53% of patients relapsed on placebo. This can be reduced to 20% by maintenance antipsychotic drugs. Again, drugs produce a doubling of the number of patients doing relatively well. Similarly, in 30 double-blind studies on imipramine for depression, approximately 65% of patients recovered with imipramine in three or four weeks and only 32% recovered with placebo. Seven studies on maintenance tricyclics to prevent recurrence showed that, in approximately four to six months, half the patients relapsed on placebo but one-fourth relapsed when treated with maintenance antidepressants. Similarly, in seven double-blind studies of lithium for unipolar and bipolar recurrent affective disease, 4 out of 5 patients relapsed in six months or a year, whereas only 1 out of 3 relapsed when treated with maintenance medication. In terms of producing an increment in the number of patients who do well with our present chemotherapy in comparison with the numbers who would have done as well without these new innovations, we have nothing to be ashamed of in psychiatry.

With the development of such effective pharmacotherapies, the need arises for adequate textbooks in which the medical student, the house officer, and the practitioner can learn about drug treatment of mental illness and related topics. This book admirably fulfills these needs and serves as a means of updating the practicing psychiatrist. In addition, many primary care physicians, internists, and other practitioners who see a great variety of patients with major psychiatric problems in fact do a fair amount of psychiatric chemotherapy. This text is ideal for introducing the general physician to psychotropic drugs. In addition to primary learning, the text provides an excellent review for psychiatrists preparing for board examinations and is comprehensive enough to serve as a general reference text for the practicing psychiatrist.

The authors have a gift for concise, declarative statements, and the text is very readable. It is a clearly written, medium-length book that can be read in the time it would take to read a much shorter but less skillfully written book. This textbook covers the basic chemotherapy of anxiety, the affective disorders, and schizophrenia. It also has a chapter on ECT. Although the effectiveness of modern pharmacotherapy is such that ECT is not now used as much as it once was, at present there is clearly a role for ECT in psychiatry. With the increasing age of our population, the care of a wide variety of dementias and deliriums becomes an increasingly important problem, and this topic is well covered. In recent years, it has become apparent that some patients who have chronic pain are in fact suffering from depressions, and this text reviews the new information on chronic pain.

With any innovation of treatment, there is always a price to pay in side effects. These are covered here in the various chapters on the specific treatments. Drug–drug interactions are a consequence of having many drugs in medicine but, like side effects, the physician must learn to cope with these, and this topic is reviewed in a separate chapter. Unfortunately, both prescription and nonprescription drugs can lead to psychiatric complications, and the psychiatrist deals with many patients who are suffering from mental disorders either as a consequence of drugs their physician administers or consequent to self-administration of nonprescription medications, as well as the abuse of drugs. With any technological advances, there are new problems to solve, and it is important that physicians be trained in how to handle these new problems.

The discovery of effective drug treatments has other consequences for the practice of psychiatry. Biological psychiatrists are studying the mechanisms by which drugs produce their beneficial effects. My work, for example, has focused on looking at the common denominators of the biologic mechanisms of actions of the drugs that can either benefit a given psychiatric disorder or produce a psychiatric disorder as a complication. For example, reserpine when used to treat hypertension can cause depression, and we now know that it lowers brain norepinephrine levels. Virtually all drugs used to treat depression can potentiate norepinephrine. This line of reasoning led to the catecholamine hypothesis of depression. A similar line of reasoning has implicated serotonin and acetylcholine in depression. This general paradigm led to the development of the so-called dopamine theory of schizophrenia.

In addition to adding to our general knowledge of biologic factors, the medical model has sharpened diagnostic distinctions and led to the development of laboratory tests for mental illness. Knowledge about the clinical pharmacology of drugs may allow us to use drugs more effectively. Plasma-level monitoring may be helpful with dose adjustment, in understanding the various mechanisms, and in evaluating the seriousness of overdose. This text covers the use of laboratory results in psychiatry. Psychiatry has developed the technology to measure the effectiveness of psychotropic drugs (quantitative rating scales with known reliability, double-blind design, random assignment, and so on). The development of this technology has enhanced the development of psychiatry as a scientific specialty.

This book also covers future directions in biologic psychiatry. In using the drugs, physicians must also deal with patients psychologically, and this text covers psychodynamic and psychoanalytic considerations relevant to the medically oriented psychiatric treatments. This is an important textbook in fulfilling a training need so practitioners and students can gain a better understanding of the various medically oriented therapies and be able to use these treatments with greater understanding and, hence, a greater degree of efficacy and safety.

I

GENERAL TREATMENT APPROACHES

CHAPTER 1

Chemotherapy of Anxiety

John L. Sullivan, Paula D. Sullivan, Steve Mahorney and Richard L. Goldberg

Publisher Summary

This chapter discusses anxiety and its general treatment approaches. Anxiety can be viewed as an adaptive mechanism that has survival value if it falls within a normative range. Anxiety reflects a complex emotional response to a variety of human circumstances. It is generally regarded as an unpleasant feeling that is similar in certain respects to fear. At pathologic levels, anxiety reflects an emotional response to danger that is disproportionate to the objective degree of the threat, and the psychophysiologic manifestations of anxiety may resemble extreme fear and panic. The development of medicinals to treat pathologic anxiety constitutes a major contribution to 20th century psychiatry. Although there are still important questions to be answered regarding the most effective utilization of anxiolytics in clinical practice, general guidelines have been developed to significantly reduce abuse and potential toxicity of these compounds. Furthermore, advances in the understanding of the neurochemical mechanism of action of anti-anxiety agents and the metabolic basis of anxiety promise to productively increase the understanding of the interrelationships between brain function and behavior. Although the various benzodiazepines are currently considered to be most effective for treating pathologic anxiety in a variety of settings, specific uses have been proposed for heterocyclic antidepressants, monoamine oxidase inhibitors, β-blockers, antihistamines, and, perhaps, neuroleptics, and clonidine to increase the specificity and sensitivity of the therapeutic armamentarium. Other than that, work with other classes of compounds that demonstrate anxiolytic properties such as thiazolopyridazines and azaspirodecanediones continues to refine the ability to provide effective and safe chemotherapy for the anxiety disorders.

The nature and meaning of anxiety have provided an issue for speculation, observation, and experimentation since the earliest periods of civilization. Normal anxiety is often considered to be a warning signal that serves to protect psychobiologic functioning. However, for reasons that are poorly understood, anxiety can reach dimensions that threaten the integrity of psychobiologic functioning and thus constitute a pathologic condition. For example, adaptive as well as creative behaviors appear to be more successful if there is an optimal element of anxiety, but pathologic anxiety can incapacitate such behaviors to the extent that they become ineffective. Anxiety stems from anticipation of impending danger in which the source and character of the danger cannot be clearly defined, whereas fear is an emotional reaction to a specific and known danger (1). Both of these emotional reactions are responses to organismic stress. Thus, anxiety can be viewed as an adaptive mechanism that has survival value if it falls within a normative range.

Anxiety itself reflects a complex emotional response to a variety of human circumstances. It is generally regarded as an unpleasant feeling that is similar in certain respects to fear. At pathologic levels, anxiety reflects an emotional response to danger that is disproportionate to the objective degree of the threat, and the psychophysiologic manifestations of anxiety may resemble extreme fear and panic. Because anxiety is a phenomenon which is often difficult to evaluate and quantify, exact figures about its prevalence and magnitude within any given social group are difficult to obtain. In large measure, we must rely on subjective reports of anxiety, since there are few widely accepted and objectively verifiable composite measures for the phenomenon. A number of self-rating and observer-rating tests that measure specific, subjective impressions, and behavioral variables have been designed to quantify some of the more commonly agreed upon manifestations of anxiety.

A distinction that has gained some popularity in recent years is the differentiation between state anxiety and trait anxiety. State anxiety concerns an emotion felt at a given time in response to a specific circumstance or set of circumstances, whereas trait anxiety refers to a personal characteristic of an individual, including a baseline of anxiety and susceptibility to anxiety in response to stress. According to this concept, state anxiety can be superimposed on trait anxiety, and the results of treatment may vary in these two types. Although this concept of anxiety has theoretical implications, the evaluation of potentially therapeutic agents that are effective in alleviating anxiety (anxiolytics) relies in large measure on the determination of generally excessive anxiety at the time of treatment.

The central role of anxiety in subjective and objective human behaviors states has been appreciated for millenia by philosophers, but Sigmund Freud was the first to attempt to explain anxiety in scientific terms. Freud conceived that anxiety was fundamentally composed of inherited biologic factors that were influenced significantly by developmental and social factors, and that perturbations in any or all of these systems could result in pathologic anxiety, as manifested in a variety of psychopathologic states. Unfortunately, much of Freud’s work remained in the theoretical realm during his lifetime because of the relative technical inadequacies of psychobiologic inquiry that prevailed during his lifetime.

The notion that anxiety can be conceptualized as a functional state subject to maladaptive influence suggests that abnormal anxiety may result in symptomatic disease states in much the same way that adrenal tumor or cardiogenic shock may result in hypertension or hypotension, respectively. Most of the knowledge that we have acquired about the phenomenon of pathologic anxiety has emphasized the consequences of excessive amounts of anxiety. Therefore, the development of medicinals to treat pathologic anxiety has focused on pharmacologic compounds that serve as effective antianxiety