Ultrapositivistic Psychopharmacology Era 1970present

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Modern biological psychiatry started in 1952 when the French psychiatrists Jean Delay and Pierre Deniker first evaluated the efficacy of chlorpromazine (trade name Tho-razine) in a variety of psychiatric disorders and found it to be highly effective for ameliorating schizophrenic symptoms. This breakthrough was based on the recent discovery of surgeon Henri Laborit that such drugs were effective presurgical sedatives, and also potentially effective in controlling the agitation of various psychiatric disorders including schizophrenia. The robust calming effects and specific reductions in the positive symptoms of schizophrenia (e.g., delusions, hallucinations, and inappropriate moods) were so impressive that the use of chlorpromazine swept through psychiatry. The number of schizophrenics that had to be chronically institutionalized diminished precipitously as soon as these agents came into widespread use.

With the recognition that one of the main targets of these agents were recently characterized dopamine systems of the brain (Arvid Carlsson, 2001, Nobel Prize in 2000), and the discovery of the various receptor molecules for dopamine transmitters, the specificity and potency of antipsychotics were honed by creative pharmacologists such as Paul Janssen in Belgium (discoverer of haloperidol, or Haldol, and also risperidone, or Risperdal). This led to our current array of atypical antipsychotics (Chapter 10), which can also alleviate some of the negative symptoms of schizophrenia (the anhedonic flattening of affect, the social isolation, and cognitive impairments often characterized as "formal thought disorders"). These newer drugs also have the advantage of few troublesome long-term side effects such as motor dyskinesias that consistently emerged after long-term treatment with the earlier, more potent anti-dopaminergic antipsychotics. Within a few years of the discovery of chlorpromazine, antidepressants were developed, on the heels of the serendipitous discovery that certain drugs for tuberculosis gave many patients extra enthusiasm and psychic energy [the monoamine oxidase (MAO) inhibitor isoniazid and iproniazid].

Other molecules (e.g., the tricyclic imipramine) were soon discovered to be effective in treating depressive disorders and eventually panic attacks (Klein and Rabkin,

1981). With advances in neurochemistry, the two types of antidepressant effects were narrowed to classes of molecules that could inhibit MAO or block reuptake of synap-tically released biogenic amines, especially of norepinephrine and serotonin (Julius Axelrod, Nobel Prize in 1970 for "discoveries concerning the humoral transmitters in the nerve terminals and the mechanism for their storage, release, and inactivation"). This eventually led to increasingly specific agents, until we now have an abundance of selective serotonin reuptake inhibitors (SSRIs) that effectively stabilize a variety of Axis I as well as some Axis II disorders (Chapter 8), with few troublesome side effects (except for occasional emotional numbing and diminished pleasure responses such as anorgasmia). Still the long-term therapeutic mechanisms remain uncertain.

Various benzodiazepine antianxiety agents came into use in the 1960s, directly developed from preclinical animal studies that initially observed sedation and antiaggressive effects with chlordizepoxide (Librium). At this same time, the even earlier preclinical and clinical work on lithium by John Cade (1949) in Australia was gradually crafted into a treatment for manic-depressive disorders by Mogens Schou (1992) in Denmark.

These great passages of the psychopharmacology revolution have been retold many times, but never as comprehensively as in the excellent three-volume series entitled The Psychopharmacologists by David Healy (1996, 1998, 2000). The history of this fascinating era is detailed through a series of personal interviews with the main protagonists of the biological psychiatry revolution. In those first-person accounts, the reader can try to sort out the many controversies, linkages between lines of thought and battles over priority.

The clinical successes of the 1950s rapidly led to the characterization of various neurochemical systems in the brain [especially of acetylcholine, dopamine, nore-pinephrine, serotonin, and gamma-aminobutyric acid (GABA)] and the emergence of preclinical psychopharmacology disciplines that sought to characterize how these drugs operated (for summaries, see Charney et al., 1999; D'Haenen et al., 2002). It became routine to evaluate all new molecules in animals, often with classical behaviorist techniques that were not based on any theoretically coherent ideas about how psy-chobehavioral systems might be organized in the brain. Indeed, the behaviorists who became "opinion leaders" in pharmaceutical firms, had an active dislike of psychological theorizing and often of the brain itself. Inputs and outputs were deemed more important than the brain/mind matters that intervened.

Cranking out simple positivistic drug behavior relationships was deemed of sufficient predictive power to guide drug development. Eventually, when techniques for measuring receptor binding kinetics were developed, one could utilize test-tube assays to predict the efficacy of psychotropic agents (Snyder, 1980). Many researchers concluded it was unnecessary to worry much about psychological constructs in generating medications that could effectively treat mental disorders. An atheoretical study of input-output relations sufficed, and thus we still know little about how most of the psychiatric medicines in common use help create mental environments that are conducive to therapeutic change. This has been common in medicine where serendipitous practical advances often precede any substantive understanding.

Most of the successes of biological psychiatry have arisen from our ability to manipulate just a few neurochemical systems (Fig. 1.1). This is now understandable. There exist a limited number of "state-control" neurochemical systems that arise from discrete brainstem nuclei and ramify widely in the brain, affecting many mind functions in fairly predictable ways: catecholamines such as norepinephrine (NE) and dopamine (DA) facilitate information transmission and energize affective responses (both positive and negative), and serotonin systems generally diminish and narrow the lines of information transmission, thereby perhaps decreasing the acute effects of both negative and positive instinctual and cognitive urges. The GABA system operates through much more widely dispersed clusters of small interneurons (as well as a few long axoned pathways) to generally dampen the arousability of the brain. Hence facilitation of GABA can have striking effects on various types of overarousal ranging from anxiety to epilepsy. A brief synopsis of the biological psychiatry revolution would look approximately like this (adapted from Panksepp, 1998, p. 117):

NOREPINEPHRINE (Function: Sustains high signal/noise ratios in sensory processing areas)

SEROTONIN (Function: Reduces impact of incoming information and cross-talk between sensory channels)

NOREPINEPHRINE (Function: Sustains high signal/noise ratios in sensory processing areas)

SEROTONIN (Function: Reduces impact of incoming information and cross-talk between sensory channels)

(Function: Maintains psychomotor & motivational focus and arousal) DOPAMINE

Ch1 - Ch4 (Function: Mediates attention and arousal in all sensory systems) ACETYLCHOLINE

(Function: Maintains psychomotor & motivational focus and arousal) DOPAMINE

Ch1 - Ch4 (Function: Mediates attention and arousal in all sensory systems) ACETYLCHOLINE

Figure 1.1. Parasagittal depiction of the dispersion of biogenic amine [dopamine (DA), norepinephrine (NE) and serotonin] and acetylcholine systems in the rat brain. LC, locus coeruleus; DB, dorsal NE bundle; VB, ventral NE bundle; CN, caudate nucleus; AC, anterior commissure; OB, olfactory bulb; CTX, cortex; BG, basal forebrain; HC, hippocampus; TH, thalamus; SC, superior colliculus; IC, inferior colliculus; NS, nigrostriatal DA pathway; ML/MC, mesolimbic and mesocor-tical DA pathways; HY, hypothalamus. ''A'' designations indicate major NE and DA cell groups; ''B'' designations indicate major serotonin/raphe cell groups; ''CH'' designations indicate major cholinergic cell groups. [This figure is reprinted from Panksepp (1998), Affective Neuroscience, with the permission of Oxford University Press.]

'Of the drugs currently used to alleviate depression, some prolong the synaptic availability of biogenic amine transmitters, while others slow degradation. In the former class are the many tricyclic antidepressants that can inhibit norepinephrine, serotonin, or dopamine reuptake at synapses. More recently, other specific reuptake inhibitors have been developed, perhaps the most famous being the SSRIs. Representatives of the other major class of drugs inhibit the enzyme monoamine oxidase (MAO) that normally helps degrade biogenic amines following release. MAO inhibitors are less commonly used than the reuptake inhibitors because they have more side effects, such as the increased toxicity of certain foods that are high in the amino acid tyramine. However, recent developments (e.g., discovery of several forms of MAO in the brain) have yielded some safer and more specific drugs of that class. Some of them, such as phenelzine, are also quite effective for other disorders, such as "social phobias," the strong discomfort that some people feel during social interactions.

The class of drugs known as antipsychotics generally dampens DA activity. Since there are several different DA receptors, modern work has sought to more specifically target the D2 receptors, which are present in abnormally high quantities in the schizophrenic brain. Most antipsychotics are receptor blockers, which means that they prevent dopamine from having normal physiological interactions with its receptor. Other drugs that stimulate receptors are called agonists; such drugs can promote schizophrenic symptoms. For instance, the indirect agonists such as cocaine and amphetamines can induce sufficiently strong paranoid symptoms that psychiatrists have difficulty distinguishing them from the real thing.

Most modern antianxiety agents interact with their own receptor, a benzodiazepine receptor, which can facilitate GABA activity in the brain. More recently, some totally new types of antianxiety agents have been discovered, such as buspirone, which interact with serotonin receptors. With the revelation of the role of many other neuropeptides in the genesis of anxiety, perhaps specific anxieties, it is likely that even more specific antianxiety agents will be developed in the future.

Many investigators presently believe that functional psychiatric disorders result from neurochemical imbalances (i.e., lack of regulation) among many transmitter systems as opposed to a pathology in a single one, so there may be many ways to restore overall balance. The recent discovery of a large number of neuropeptide transmitter and receptor systems has opened the door to the development of a new generation of psychiatric medicines, which may modify discrete mood states and associated behavioral tendencies.'

It is also now widely recognized that the qualities of the therapist—his or her capacity for empathy—are as important for the efficacy of psychotherapy as any specific mode of treatment (Beutler et al., 1994). That is generally not thought to be the case for current biological interventions, where actions of drugs on specific chemical systems are believed to be the decisive factor in the efficacy of treatments, but many agents do work for several different diagnostic categories. For instance, SSRIs alleviate anxiety, panic attacks, and obsessive-compulsive disorders (Chapters 11, 12, 13, and 16). This may partly reflect the simple fact that broadly distributed neurochemical systems, such as the biogenic amines, are bound to influence practically all emotions and mental activities. Few emotion-specific therapies presently exist, but they may arise from the currently ongoing neuropeptide revolution (Chapter 21).

The systematic evaluation of all therapies is stymied by the existence of robust placebo effects that seem to emerge from our mysterious mental ability to improve when we simply perceive that we are being helped (Peters, 2001). In part, such effects are mediated by brain chemicals such as the endogenous opioids, which are influential in regulating pleasure and positive social feelings (Panksepp, 1998). Although some drugs and psychotherapies have effects on similar brain systems (e.g., Baxter et al., 1992), they are typically thought to access different aspects of the brain/mind. While the beneficial effects of psychotherapies are surely initiated through the higher functions of the mental apparatus (i.e., symbolically, through neocortical language functions that are uniquely human), drug therapies modulate tonic levels of arousability more directly within basic brain/mind operating systems that we share with the other animals. The convergence appears to be in the modulation of the neurodynamic tone of middle-level emotional systems of the "limbic brain."

The enormous success of the biological psychiatry revolution has led to a variety of practical socioeconomic dilemmas, related largely to the high efficacy of the available agents. They include the problems of managed care and profit-driven programs. Under such a system there are pressures to reduce type 1 errors as much as possible (i.e., the prescription of expensive therapies, when in fact they are not necessary). However, these same economic pressures tend to promote type 2 errors (i.e., claims that certain therapies are not effective, when in fact they are). Perhaps we should also be concerned about "type 3" errors (i.e., where certain high-priced drugs are aggressively pushed forward when equally effective low-priced drugs are available). When enormous economic factors come to bear on therapeutics, there is bound to be controversy about efficacy and optimal courses of action. If one can't demonstrate which treatment is unambiguously best, there is bound to be a heightened tendency by some (i.e., drug providers) to go for the more expensive options, while others (i.e., drug receivers) prefer to go for the cheaper alternatives. This makes the issue of psychiatric diagnostics and prognostics an increasingly contentious and politicized affair.

These concerns have filled the pages of important psychiatric journals for the past decade. The flagship journal in the Western Hemisphere remains the American Journal of Psychiatry (with its immediate predecessor, The American Journal of Insanity), which has now been summarizing psychiatric thought for almost a century and a half. The massive recent progress of the field can be dated by the appearance of increasingly biologized journals: first, the Archives of General Psychiatry in 1959 near the beginning of the psychopharmacology revolution, and then Biological Psychiatry in 1969, when the brain systems (e.g., biogenic amines and GABA) accounting for the initial wave of enthusiasm became well-recognized as major topics of neuroscientific inquiry. Many others have followed. We are presently at the threshold of the next great phase of the biological psychiatry revolution—with the harnessing of neuropeptidergic and molecular biological knowledge just around the corner. We can only imagine the new challenges that will need to be faced.

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