Historical Insights in Psychopharmacology

The writings of two classic thinkers in psychiatry in the 19th and 20th centuries, Emil Kraepelin and Aubrey Lewis, are provided and examined for insights they provided into continuing problems in the diagnostic and treatment of psychiatric conditions today. Kraepelin was the famed great late 19th-century psychiatric leader from Germany who identified the basic distinction between schizophrenia (dementia praecox) and manic-depressive illness. He laid the foundations of much of psychiatric diagnosis that remains relevant today, and he was a committed defender of the biological approach to psychiatry, although he was conservative with the use of drugs, which were ineffective in his day. Lewis (1900–1975) was the most prominent figure in British psychiatry through most of the 20th century. He was the leader of the Institute of Psychiatry at the Maudsley Hospital for much of the middle of the 20th century. That institution in London was the most influential educational center for psychiatry in the nation. Through his leadership there, Lewis was extremely influential. He tended to be skeptical about the use of psychotropic medications, and emphasized social aspects of psychiatric illness.

Key Research Studies in Clinical Psychopharmacology

A number of key clinical research studies in psychopharmacology are presented and critiqued. They include some classic studies dating back decades, to current studies involving the most recent important studies or analyses of clinical research in psychopharmacology—such as diagnostic validators in psychiatry, a maintenance RCT of olanzapine in bipolar illness, brain effects of dopamine blockers, whether antidepressants prevent depression or not, the use of paroxetine in depression, the natural history of treated depression today, adult attention-deficit disorder, and treatment response in first-episode depression. The critiques provided often show that the claimed results of studies are different from the actual data, which need independent interpretation.

The Placebo Effect

Until the 1960s, physicians in the United States could legally prescribe “placebo” on a prescription pad and handed to a patient. It was not unethical to do so. Placebo had long been known to be an effective treatment for various medical conditions. For millennia, physicians new that many of their treatments were ineffective and that many conditions could not be treated. Instead of giving treatments that have some pharmacological properties, which meant they would have some side effects and be harmful in some way, it was viewed as more ethical to give an inert pill, a placebo, which would cause no direct pharmacological harm. The view was that the patient might get some psychological benefit from the apparent treatment. The placebo response involves two major aspects: natural history and psychological expectation. Too much attention is given to the latter and not enough to the former. Clinicians see patients improve, as in acute depressive episodes, due to natural history, but they attribute such benefit to the drugs they use, or their psychotherapeutic relationship. Often Nature deserves the credit, and clinicians need to pay more attention to the natural course of psychiatric illnesses.

The “Med Check”

A major myth in contemporary psychiatry, repeated by psychiatry residency directors and their residents, is the cliché “ ‘Psychopharm’ is easy; psychotherapy is hard.” The truth is that learning psychopharmacology is as hard as learning psychotherapy—perhaps harder, because it entails not only knowledge about medications, but knowledge and skill about diagnosis, about interviewing, and about relating to the patient. The follow-up psychopharmacology visits occur after the initial diagnostic interview. Often pejoratively called “med checks,” such visits tend to consist of brief symptom assessments, followed by pill adjustments for symptoms. Pill-for-symptom treatment is poor psychopharmacology, and therefore an inappropriate focus. Instead, follow-up visits need to be long enough to allow for attention to the interpersonal relationship, such as transference. Again, the use of psychotherapeutic methods is helpful. Such an approach will enhance adherence, the lack of which is a major aspect of treatment failure.

Drug Discovery

Newer and better medications are obtained as part of the drug discovery process, which occurs mainly in the pharmaceutical industry. This process is hampered by excessive attention to marketing demands, as opposed to scientific exploration. It also is impaired by the psychiatric profession’s mistaken ideologies, whether psychoanalytic orthodoxy in the past or DSM beliefs of the present. Wrong clinical phenotypes impair finding new pharmacological mechanisms and targeting them well to the write clinical indications. Perhaps as a consequence, no treatments have been developed in the last few decades, since DSM-III, that are more effective than prior agents. Progress for the future in drug discovery will require not just better neurobiological work, but also a new approach to clinical diagnoses in psychiatry.

Treatment versus Enhancement

The concept of “treatment” is based on a “biomedical” model of disease. In this model, illness represents a breakdown of the physical constituents of the body, leading to a functional loss of a capacity to perform typical activities of the organism. The proponent of the “enhancement” approach to the therapy of depression comes at the problem from other disease models. Any of the alternative non-biomedical models imply the conclusion that therapeutic interventions in depression should seek to enhance the functioning of the individual, rather than simply to permit redress of loss of functioning. Therefore, besides using psychotropic drugs for treatment of symptoms, many patients and clinicians seek psychotropic drugs to enhance normally variable psychological traits. This enhancement approach to practice appears to be most active in relation to the use of amphetamines to heighten attention, energy, and libido, as well as to lose weight. The use of psychotropic agents for such nonmedical uses raises some ethical questions, as well as contradicting the Hippocratic tradition of focusing medication treatment on diseases.

Treatment of Personality

The diagnosis and treatment of personality are probed. Some DSM definitions are viewed as either invalid (narcissistic personality disorder) or related to other conditions (schizotypal personality). Instead, DSM-based personality “disorders” are seen as psychoanalytic speculations, with weak empirical support, except for borderline personality and antisocial personality. Other aspects of personality are best understood as traits, rather than “disorders,” or as symptomatic changes that are acute and occur lower in the hierarchy of diagnosis than mood or psychotic states, and are caused by the latter. The common report of purported comorbidity is seen as an overestimation, with personality changes often being part of other conditions. Symptomatic treatment is seen to be questionable in benefit over risk, both for dopamine blockers and for SRIs.

Beyond Symptoms

The four classic diagnostic validators of psychiatry are appraised: symptoms, course, genetics, and treatment response/biological markers. Of these, course of illness is seen as the most important and the most neglected. The non-specificity of treatment response and the inadequacy of symptoms is emphasized. If symptoms are not the primary target for drug treatment, as the Hippocratic tradition teaches, then diagnosis becomes extremely important for the practice of clinical psychopharmacology. The role of genetics is important, but it is limited to highly genetic diseases. Related to DSM-5 and its predecessors, the application of these diagnostic validators demonstrates that most DSM diagnoses are not valid.

Monoamine Agonists (“Antidepressants”), Including Dopamine Agonists (“Stimulants”)

The drug class of monoamine agonists includes agents called antidepressants and stimulants. Monoamine agonists are the most widely used class of psychotropic drugs. There are three major monoamines, and thus three main types of monoamine agonists. We consider each in turn: the serotonin reuptake inhibitors (SRIs), norepinephrine reuptake inhibitors (NRIs), and dopaminergic agents. We also discuss the dopamine agonists—bupropion (Wellbutrin) and amphetamines (“stimulants”), as well as other new monoamine agonists. The clinical pharmacology of specific agents within each class, including their efficacy and side effects, is explored. Specific phenomena surveyed include SRI tolerance, sexual dysfunction, drug interactions, serotonin withdrawal syndrome, and suicide and akathisia.

Fundamentals of Neurobiology

This chapter examines the basic pharmacology of psychotropic drugs. Besides knowing what drugs do to certain chemicals or proteins in the brain, it is important to know where drugs affect those chemicals or proteins. There is some basic knowledge about neuroanatomy that is relevant to the clinical practice of psychopharmacology. It is accepted that neurobiology is an important factor in the etiology and pathophysiology of major psychiatric conditions—like schizophrenia and manic-depressive disease, as well as in other psychiatric clinical pictures. The general summary usually provided is that neurobiology represents a diathesis to psychiatric conditions, which is supplemented by environmental stress to produce observed clinical pictures. This mixture of genetics and environment is oversimplified in the minds of most mental health professionals. In fact, the mix depends on the illness. The biochemical neuroanatomy of the monoamines, glutamate, and GABA in the brain are discussed. Pharmacokinetic aspects of psychopharmacology are reviewed, including hepatic metabolism, drug half-lives, dosing, and tolerance and sensitization.