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SPECIAL ISSUE: PSYCHOPHARMACOLOGY AND PSYCHOSOMATIC RESEARCH |
Department of Psychiatry, University of Michigan, 1500 East Medical Center Drive, Ann Arbor, MI 48109-0118
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INTRODUCTION |
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 TOP INTRODUCTION MONOAMINE THEORIESTHE NEW-AND-IMPROVED MONOAMINE...CONTENTS OF THIS ISSUECLINICAL IMPLICATIONS AND THE...REFERENCES |
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"O true apothecary! Thy drugs are quick."—Romeo and Juliet, William Shakespeare
Although Psychosomatic Medicine has traditionally published primarily original research communications, there has always been a strong interest in the clinical side, ie, in responding to the needs of clinicians often referred to as "consultation-liaison practitioners." One of the most important of these needs is an up-to-date understanding of medications, especially their use in the patient who is suffering from both medical and psychiatric disorders but more broadly in psychiatric syndromes generally. The goal of this special issue is to respond to this need. Like the benefits described in the first quote cited above, but unlike the negative and unfortunate effects alluded to in the second quote, the psychopharmacologist at the millennium has many effective and well-tolerated medications available.
In considering how to approach this topic and what to include, it seemed unnecessary to review the standard use of standard medications in the more common psychiatric disorders. Such reviews are widely available, and new ones are constantly appearing. It seemed more useful to go beyond what is standard practice now to try to anticipate and predict the near future. What substances, what physiological factors, what basic science advances are likely to be involved in new understanding of how mental disorders develop and new methods of psychotropic drug treatment? As guest editor of this special issue, I have attempted to make such prognostications. Of course, only a small number of the possibilities could be included in one issue. Another editor probably would have arrived at a different, although overlapping, list of topics for inclusion.
I recruited 22 authors to prepare nine review articles. Descriptions of these articles are provided below. Before addressing the articles, however, I want to provide brief background information and an update of the monoamine theory of mental disorders. Although it is oversimplified and not fully accurate in its original form, the monoamine theory has probably provided the heuristic basis for more research into the pathophysiology of mental disorders and the mechanisms of action of psychotropic drugs than any other theory in the history of psychopharmacology. It continues to guide research and, in modified form, seems to remain valid.
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MONOAMINE THEORIES |
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TOPINTRODUCTIONMONOAMINE THEORIESTHE NEW-AND-IMPROVED MONOAMINE...CONTENTS OF THIS ISSUECLINICAL IMPLICATIONS AND THE...REFERENCES |
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Monoamines have been implicated in the pathophysiology of a number of psychiatric disorders. The most extensively studied associations are dopamine with schizophrenia and norepinephrine, epinephrine, and serotonin with depression and anxiety. There is some, albeit weaker, evidence of the involvement of monoamines in mania as well as dopamine in affective disorders generally and in substance abuse. Of all of these, the earliest and most studied was the putative association between depression and the catecholamines.
Evidence of the probable association between depression and the catecholamines came originally from two sets of observations in the 1950s and 1960s. First, reserpine, a drug used to lower blood pressure, was reported to do two things, deplete monoamine levels in the brain and induce depression in a significant number of individuals, although this effect was recently called into some doubt (1). Later, it was reported that ß-adrenergic blocking drugs, which also produce a condition in the brain that is functionally similar to monoamine depletion, also produced depression, although this observation has also been questioned (2).
Second, two classes of drugs found to be effective antidepressants, tricyclics and monoamine oxidase inhibitors, were found to raise effective concentrations of the amines at the postsynaptic level, either by blocking presynaptic reuptake of the amine neurotransmitters (tricyclics) or by blocking metabolic degradation of the amines (monoamine oxidase inhibitors). These two types of early observations suggested that depression was due to a low level of monoamines and that functionally raising the level would provide an antidepressant effect. Once this monoamine theory of depression was formulated (3), investigators sought additional evidence, typically in two places. First, were the actual monoamine levels in depressed patients depleted? Second, were the monoamines involved in the control of physiological systems related to symptoms associated with depression, eg, sleep or weight and appetite? The answers to both questions seemed to be "yes" (4, 5), but the results of studies looking at the relationship between amine levels and depression have not always supported this theory (6).
Although the original focus of research was on depression, the involvement of the monoamines in other psychiatric disorders has been of great interest. One theory suggested not only that depression was associated with monoamine depletion but also that mania was associated with excess. Data supporting an elevation of monoamines in mania have been inconsistent.
There is a theory that dopamine is related to the pathophysiology of schizophrenia. This theory arises from the observation that all drugs that have been shown to improve schizophrenic symptoms influence dopamine levels. It is noteworthy that such drugs typically are beneficial for psychotic symptoms from many different causes (eg, psychotic depression, psychotic mania, and delirium). In other words, these drugs may be more generally antipsychotic than antischizophrenic, suggesting that dopamine is involved in psychosis generally rather than schizophrenia specifically.
Monoamine changes are also believed to be associated with several of the anxiety disorders, especially panic disorder (7). This idea grew out of four general observations. First, the symptoms of anxiety (at least the somatic symptoms) are very similar to the symptoms produced by activation of the sympathetic part of the autonomic nervous system, and the major neurotransmitter in that system is the catecholamine norepinephrine. Second, medications that decrease anxiety include drugs that affect the monoamines. Third, normal stress, which includes anxiety-like symptoms, produces sympathetic activation, including increases in systemic catecholamine levels. Finally, study of individuals with panic disorder has produced some evidence of adrenergic activation involving catecholamine changes.
In summary, the oldest and most extensively studied idea is that there is a functional depletion of the monoamines, especially norepinephrine and serotonin, in depression. Additional theorizing and research has implicated schizophrenia (or psychosis more generally), anxiety disorders (especially panic disorder), and mania (perhaps). A variety of other psychiatric disorders not reviewed here (eg, eating disorders) have also been hypothesized to have pathophysiological changes involving the monoamines. How or where might abnormalities in monoamine function be found in these disorders, and how might psychopharmacology, including drug treatment, be involved?
If the monoamines are involved in psychiatric and other brain disorders, how might that occur? There are many possibilities. Some of the most likely are mentioned here. The actual amount of the chemical itself could be altered. This could be true in terms of absolute amount of substance present or in terms of the "active pool" (the monoamine available to act as neurotransmitter at a given time). These factors relate to synthesis, storage, release, reuptake, and degradative metabolic mechanisms. Alternatively, the receptor system for the monoamine in question could be abnormal in its function. This could be due to an abnormal number or function of the postsynaptic receptors, presynaptic autoreceptors, and/or monoamine transporter molecules.
An issue related to somatic treatment effects is germane here. All somatic treatments for depression and other psychiatric disorders, including electroconvulsive therapy, take at least 1 to 2 weeks and typically 1 month or more for the full effect to occur. Assuming that treatment provides benefit by reversing an underlying abnormality associated with the etiopathology of the disorder (an assumption that may not be correct), processes such as those described above that change in this time domain would seem to be most likely to be involved.
A second important issue, which is often neglected in discussions of possible underlying mechanisms of disorders involving the brain, is the placebo effect. Many disorders and symptoms of such illnesses are alleviated by placebos (8). Depression, eg, is highly responsive to placebo treatments. Leaving aside the erroneous assumption that placebo responsiveness implies the disorder is in any way less "real," it would nonetheless seem that improvement in the very poor understanding that is now available about how, at a physiological level, placebos work, might give important hints as to the underlying abnormalities present in these highly placebo-responsive disorders.
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THE NEW-AND-IMPROVED MONOAMINE THEORY |
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TOPINTRODUCTIONMONOAMINE THEORIESTHE NEW-AND-IMPROVED MONOAMINE...CONTENTS OF THIS ISSUECLINICAL IMPLICATIONS AND THE...REFERENCES |
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Until very recently, all drugs that have been reported to benefit depression affected the monoamines. Although this may reflect, at least in part, the practice of pharmaceutical companies screening and testing for a particular purpose (eg, antidepressant effects) only substances known to have effects similar to drugs previously shown to be effective (ie, effects on monoamine systems), it also reflects the enormous importance of the monoamines in the pathophysiology of depression. Recently, a substance P antagonist was reported to have antidepressant properties (20). Thus, even though the monoamine theories remain of vital importance and dominance, it is noteworthy that nonmonoamine neurotransmitters are implicated as well.
The summary of the monoamine theory of psychiatric disorders given above is extremely abbreviated. In its simplest form, the monoamine theory says that levels of monoamines are abnormal in various psychiatric brain disorders. The theory becomes modified in a variety of ways as the factors listed above are added—potential abnormalities in receptors and second messenger systems, modulatory effects on other systems, etc. And, of course, there is not really one monoamine theory, as I have used the term, but several, addressing the different individual monoamines (mainly norepinephrine, dopamine, and serotonin) and the different disorders in question separately. The reader in search of more detail can use the references provided as an entrance to this extensive literature. This brief summary has been provided here because of its importance to both the history and current practice of clinical psychopharmacology and the psychopharmacological sciences. It also provides some background for the articles in this special issue.
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CONTENTS OF THIS ISSUE |
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TOPINTRODUCTIONMONOAMINE THEORIESTHE NEW-AND-IMPROVED MONOAMINE...CONTENTS OF THIS ISSUECLINICAL IMPLICATIONS AND THE...REFERENCES |
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Knowledge of mechanisms of the pharmacological action of drugs is sometimes perceived as less important, or at least of less practical value, than other pharmacological topics, such as dose and duration of treatment needed for efficacy and side effects and potential drug interactions. Although it may not be necessary to know the underlying mechanistic information to treat every patient one sees, it is frequently highly valuable. For example, understanding how, and therefore why, drug interactions occur makes it much easier to anticipate which drug combinations are most likely to be problematic. In other words, rather than trying to remember the many hundreds or thousands of psychotropic drug interactions that have been reported, to say nothing of the many thousands of others that have an increased likelihood of occurring but have never made it to the literature, those combinations that pose the highest risk can often be anticipated or predicted from "first principles" of drug action. Pharmacological mechanisms, including mechanisms of drug action, are addressed in these first four articles.
Clinicians often believe they do not have the "luxury" of spending time to learn the history of the medical field they work in; this includes psychopharmacology. In the first article, Domino (21) offers the theory that many of the drugs we use, indeed, many whole classes of these drugs, arose from structural modifications of drugs that had antihistaminic effects, right up to and including the selective serotonin reuptake inhibitors. Any clinical psychopharmacologist who wishes to understand why we have the drugs we have would do well to read this historical piece. So would the clinician who wonders why we don’t have other drugs that we wish for. Perhaps just as the monoamine theory has influenced which drugs have been developed, so has the molecular structure of drugs that have antihistaminic effects.
At a very simple level, drug action in the brain and elsewhere can be divided into substances that affect membrane channels related to ion fluxes, those that influence second-messenger systems, and those that do other things, such as have direct effects on mechanisms of gene expression. In the second article, Chen et al. (22) review data on the known mechanisms by which drugs that have antidepressant or mood-stabilizing effects operate. In general, these drugs influence signal transduction and, secondarily, gene expression through effects on second-messenger systems. These observations tend to support the monoamine theory because monoamine neurotransmitters and neuromodulators typically interact with receptors that activate second-messenger systems. Understanding these systems allows the clinician to understand one way by which the drugs being used are likely to be providing symptom relief.
When drugs are prescribed, the clinician often will recommend that the patient take the medication with a specific frequency at specific times of day. This recommendation will usually depend on the half-life of the drug and the pattern of side effects, eg, sedating medications are usually taken at night. Rarely do we ask, "Will this drug have more beneficial effects if given at one time of day than another?" Early data indicate that such a question should be asked. For example, it seems that the therapeutic index of a drug, ie, the ratio of the dose range producing unwanted toxic effects to the dose range producing the desired beneficial effects, may vary across 24 hours because of circadian changes of various physiological functions in the patient. In the third article, Nagayama provides an introduction to this relatively new area of chronobiology (23). This is a topic to watch. It seems likely that within 5 years or less, optimal prescribing practices will include such considerations for at least some of the psychotropic drugs we use.
The final article in this section, by Torres and Horowitz (24), focuses on drug addiction. Recent research is beginning to link mechanisms of action of drugs of abuse, such as cocaine, ethanol, and morphine, to activation of specific signal transduction pathways that activate specific genes in the brain. For example, involvement of mesocorticolimbic dopamine, a monoamine, has been implicated in brain reward systems associated with drug self-administration in animals. Pharmaceutical agents that modify the actions of this dopaminergic system in appropriate ways might become drugs of tremendous value in the armamentarium of the clinical psychopharmacologist.
The articles in this special issue are not intended as a review of standard treatment methods. There are, however, treatment issues that are addressed because they are less standard. In one case, the disorders under consideration are less commonly encountered. In the second case, the issue of whether usual treatment of a common psychiatric disorder can affect the course of a medical disorder is addressed.
The first article, by Tsai, focuses on the treatment of autism (25). Autism is not a common disorder, and the pharmacological treatment of autism is often done by psychiatrists with specialized training in child psychiatry. It is for just that reason that reviews of drug treatment methods for autism are less commonly seen than reviews for many of the other psychiatric disorders. It was also for that reason that this review was included. Autism is a psychotic disorder. The psychopharmacology expert should have, at a minimum, a working knowledge of how to treat psychotic disorders generally. That includes autism, and that is why this review is here.
The second article addresses an issue of immediate importance and relevance to the consultation-liaison practitioner. Recent studies have reported that the presence of depression significantly increases the likelihood that a person with coronary artery disease will have a cardiac event. It especially raises the risk of reinfarction in the first several months after a myocardial infarction. Carney et al. (26) address the question of whether treatment of depression can decrease the likelihood that such cardiac events will occur.
The third group of articles addresses the use of substances as therapeutic agents that are new or of less familiarity to the practicing clinician than the usual drugs in the psychopharmacological armamentarium. These include gonadal steroids, glucocorticoids, and various natural products.
In the first manuscript, Epperson et al. (27) focus on the potential uses of gonadal steroid agents to treat mood disorders in women. The results they review indicate that estrogenic and androgenic agents may be of use but that progesterone seems not to be useful for mood disorders.
Hyperactivity of the hypothalamic-pituitary-adrenocortical axis might be the most robust psychobiological finding that exists in biological psychiatry. The second article, by Wolkowitz and Reus (28), reviews data indicating that antiglucocorticoid drugs, ie, drugs that lower cortisol levels, can be of benefit in some people who have major depression.
The last article in this section is by Fugh-Berman and Cott (29). These authors review data addressing the efficacy of various herbs and dietary supplements for a number of psychobiological dysfunctions, such as memory and mood changes. They note that for at least a few of these substances, randomized, controlled clinical trials have demonstrated benefit.
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CLINICAL IMPLICATIONS AND THE FUTURE |
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TOPINTRODUCTIONMONOAMINE THEORIESTHE NEW-AND-IMPROVED MONOAMINE...CONTENTS OF THIS ISSUECLINICAL IMPLICATIONS AND THE...REFERENCES |
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The history of clinical psychopharmacology seemed to follow the "punctated equilibrium" model, if I might borrow a concept from evolutionary biology. Before the 1950s, there were few effective and specific treatments for any psychiatric disorder. The first antipsychotics arrived in the early 1950s, and most of the additional typical neuroleptics were available within the next decade. In the 1950s and early 1960s, the benzodiazepines replaced earlier, "dirtier," sedative anxiolytic agents, and the tricyclic and monoamine oxidase inhibitor antidepressants arrived. The first mood stabilizer, although already in use in Europe for 20 years, did not reach the US market until 1970. In short, the 1950s were the years for the early antipsychotics; the 1960s, for tricyclic antidepressants and benzodiazepine anxiolytics; and the 1970s, for the mood stabilizer lithium. In the 1980s, clinical psychopharmacology rested, if I might this time borrow from the book of Genesis. (In the early 1980s, it was discovered that the "antidepressants" were also very effective anxiolytics, but this did not involve the introduction of any new drugs.)
In its most simple form, this is the history of the clinical arena until the late 1980s: active development of a class of drugs for a particular set of indications, followed by years or decades in which no new novel drugs for that set of indications appeared. In the late 1980s, the introduction of fluoxetine (Prozac) revolutionized clinical psychopharmacology practice, not because this selective serotonin reuptake inhibitor and those that followed it were more effective for depression and anxiety (they are not) but primarily because they were safer and easier to use because of their more benign side effect profiles. (They also have a different, somewhat broader list of indications.) Nonpsychiatric physicians became more comfortable in treating depression and anxiety disorders. This occurred at the same time that managed care organizations began to expect primary care physicians to refer patients less frequently to specialists, including psychiatrists, and to treat themselves more of the disorders they encountered in patients.
In this special issue I have tried to look around some of these corners, and it is not by accident that I put the more basic science articles before the more clinical ones, where the reader will encounter them first. It is tempting to skip them, to look only a little ways ahead, just around the next corner. I do it myself all the time, and that is, perhaps, all that is absolutely necessary for the busy practicing clinician. But the clinician who wishes to look a little farther, to extend his or her intellectual reach, will be richly rewarded for the effort expended to absorb these basic science pieces. This basic science is an important part of our future, a future that will be here before we know it.
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TOPINTRODUCTIONMONOAMINE THEORIESTHE NEW-AND-IMPROVED MONOAMINE...CONTENTS OF THIS ISSUECLINICAL IMPLICATIONS AND THE...REFERENCES |
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