by Thomas A. Ban
In 1808, Dalton’s postulation that the elementary units of all matters in the universe are indivisible atoms rendered the chemical structure of drugs definable and led to the birth of pharmacology, organic chemistry, and the pharmaceutical industry. Starting in the 1850s, several centrally acting drugs were introduced, and by the end of the 19th century subcutaneously administered morphine, usually combined with hyoscine, was widely used in psychiatry for controlling excitement, agitation and aggression; chloral hydrate and paraldehyde for calming and inducing sleep; and potassium bromide for relieving anxiety, restlessness and tension.
Developments in pharmacotherapy continued in the 20th century with the introduction of barbiturates (Ban, 1969) and amphetamines (Bradley, 1937); and with the demonstration of the therapeutic effect of nicotinic acid, in cerebral pellagra, penicillin, in syphilitic general paralysis, and thiamin, in Korsakoff’s syndrome. By the end of the 1940s psychosis due to cerebral pellagra, and dementia due to cerebral syphilis virtually disappeared, and the prevalence of dysmnesias markedly decreased in psychiatric hospitals (Ban, 1971).
Pharmacotherapy of mental illness received a great impetus in the1950s from the demonstration of the therapeutic effect of lithium in mania; chlorpromazine and reserpine in psychosis and especially schizophrenia; methylphenidate in hyperactive children; meprobamate in anxiety; and iproniazid and imipramine in depression. The search for structurally and pharmacologically similar drugs led to the introduction of a steadily increasing number of centrally acting drugs. By the end of the 1970s there were about 50 psychotropic drugs with demonstrated therapeutic efficacy in clinical use. They were classified as neuroleptics, psychostimulants, anxiolytic-sedatives, and antidepressants. Since then, their number almost doubled with two new classes, “mood stabilizers,” and “cognitive enhancers,” added. (Ban 2004).
Simultaneously with the introduction of the first set of psychotropic drugs, the spectrophotofluorimeter was introduced, providing a means for the detection of the underlying biochemical changes of pychotropic effects. Spectrophotofluorimetry triggered research in neuropharmacology, the discipline focused on the mode of action, and especially on he molecular changes affected, by psychotropic drugs.
Developments in the neuropharmacology of antidepressants began in the mid-1950s with the demonstration that iproniazid, increased, whereas reserpine decreased cerebral monoamine concentrations. Since iproniazid, a monoamine oxidase inhibitor (MAOI), used at the time in the treatment of tuberculosis, induced euphoria in some patients, and reserpine, used at the time in the treatment of hypertension, induced depression, it was hypothesized that depression and elation, are mediated by the neurotransmitter monoamines, serotonin (5-HT) and norepinephrine (NE). Instead of testing this hypothesis, several MAOI drugs were introduced in the late 1950s and early 1960s for the treatment of depression, and the “reserpine reversal” screen was developed for identifying potential antidepressants. Employment of “reserpine reversal” led to the recognition that in animals selectively depleted from NE, desipramine, an active metabolite of imipramine that selectively blocks NE reuptake, had no longer reversed reserpine effects. Since imipramine, the prototype of tricyclic antidepressant was shown to interfere with the reuptake of NE it was hypothesized that NE re-uptake inhibition was the culprit of imipramine’s “antidepressant” (reserpine-reversing) effect. Again, instead of testing this hypothesis, several NE reuptake inhibitor (NARI) antidepressants were introduced during the 1960s and ‘70s. The shift in neuropharmacological theory from NE- to 5-HT reuptake inhibition began in the early 1980s after the demonstration of a correspondence between imipramine binding sites and 5-HT binding sites in the human platelet and in the hypothalamus of the rat. It culminated in the 1990s and by the end of the 20th selective serotonin reuptake inhibitors (SSRIs) dominated the treatment of depression (Ban 2004).
Developments in the neuropharmacology of neuroleptics began in the mid-1950s with Laszlo Gyermek’s finding that chloprpromazine (CPZ) has antiserotonin effects, and the demonstration of a relationship between the antiserotonin effect and the tranquilizing action of phenothiazines (Gyermek, Lazar and Csak (1956). Interest began to shift from anti-serotonin to anti-dopamine effects in the 1960s with Carlsson and Lindqvist’s (1963) inference from their findings that catecholamine – dopamine (3-methoxytyramine) (D) receptor blockade is an essential feature in the mechanism of action of CPZ and haloperidol. By the time of the demonstration of dopamine receptor blockade in the mid-1970s, dopamine receptor blockers, haloperidol-like drugs, dominated treatment of schizophrenia. Interest in the anti-serotonin effect of neuroleptics was dormant for well over two decades until the demonstration in the 1980s that clozapine, an effective neuroleptic, has higher affinity to the 5-HT2A receptors, than to the D2 receptors. Introduction of clozapine into treatment in the 1980s signaled the beginning of the return to chlorpromazine-type of neuroleptics with higher affinity to the 5-HT2A receptors than to the D2receptors, after a long dominance of haloperidol type of “incisive “ neuroleptics with higher affinity to the D2 receptors than to the 5-HT2A receptors. The term “incisive” was coined by a group of psychiatrists in Lyon in the late-1950s to separate neuroleptics which produce marked extrapyramidal signs, like prochlorperazine, from the sedative neuropleptics, like chlorpromazine. By the end of the 20th century, clozapine-type of neurolepics, referred to as “atypical neuroleptics,” dominated treatment of schizophrenia.
In so far as antidepressants are concerned, drug development did not stop with the SSRIs. In the late 1990s a series of new antidepressants emerged. One of the first of these new drugs was venlafaxine, and one of the last so far was reboxetine. With the introduction of venlafaxine, a nonselective, but prevailingly 5-HT reuptake inhibitor, the mirror image if imipramine, a nonselective, but prevailingly NE reuptake inhibitor, a full circle of NE and 5-HT reuptake inhibitor antidepressants was completed. With the introduction of reboxetine, a NARI, the circle opened in the early 1960s with the introduction of desipramine, was reopened in the late 1990s virtually unchanged (Ban, 2001).
The difficulties encountered in the demonstration of the therapeutic effect of chlorpromazine in schizophrenia, and imipramine in depression have brought to attention the heterogeneity in pharmacological responsiveness within these diagnostic categories, and triggered research in psychopharmacology, the discipline concerned with the psychopathology affected by psychotropic drugs. . But instead of developing a methodology for resolving the heterogeneity by identifying the treatment responsive subgroups, a methodology with the employment of the randomized clinical trial (RCT) was adopted for the demonstration of therapeutic efficacy of psychotropic drugs in pharmacologically heterogeneous populations.
To increase the sensitivity of the methodology for the detection of therapeutic effects during the 1980s multi-center, centrally coordinated clinical investigations designed with power statistics replaced single-center, isolated clinical trials. Multi-center efficacy studies led to a flood of semi-finished psychotropic drugs, with more and more extended indications prescribed for a wider and wider population without any orientation points from clinical psychopharmacological research that might predict in which patient any of the drugs has therapeutic effects.
The problem was further compounded by findings in meta-analyses which indicated that none of the antidepressants drugs developed during five decades was superior in efficacy to imipramine, the first effective antidepressant; none of the antipsychotics were found to be superior to CPZ, the first effective antipsychotic; and none of the mood stabilizers to lithium, the first effective mood stabilizer (Ban, 2001). In fact, there were some findings which indicated that response rates with the SSRIs, introduced in the 1980s and 1990s, might be lower than with imipramine, the first TA introduced in the mid-1950s. In terms of adverse effects, SSRIs have a different side effect profile from the TCAs; they produce more frequently agitation, anxiety, diarrhea, insomnia, nausea and vomiting, whereas TCAs produce more frequently dry mouth, dizziness and constipation (Ban, 2001).
In so far as antipsychotics are concerned undoubtedly, the propensity to develop acute and chronic extrapyramidal signs and hyperprolactinemia, is significantly lower with the primarily 5-HT2A receptor blockers, but 5-HT2A receptor blockers are not necessarily safer than the primarily D2 receptor blockers, because of their considerably higher propensity to induce cardiac complications and metabolic side effects.
The lack of progress in developing more effective or selective drugs for the treatment of schizophrenia focused attention on Frank Fish’s (1964) study with the employment of Leonhard’s (1957) classification conducted in the mid-1960s in which 3 of 4 patients with unsystematic schizophrenia, and 1 of 4 patients with systematic schizophrenia responded favorably to neuroleptic phenothiazines. These findings were complemented in the 1980s with the results of a multinational survey in which the prevalence of tardive dyskinesia in the treatment responsive unsystematic schizophrenic population was 4.5%, and in the treatment refractory systematic schizophrenic population over 20% (Guy, Ban and Wilson, 1985, 1986).
The possibility that in some forms of schizophrenia neuroleptics might not just be ineffective, but may also be harmful (Ban, 1990), coupled with concerns that in some forms of depression, or in some people with certain personality structure, SSRIs may lead to suicide (Healy, 2003), has created concerns about the indiscriminate use of psychotropic drugs.
Research in neuropsychopharmacology --the discipline in which the study of the mode of action of psychotropic drugs provides information on the pathophysiology of psychiatric disease-- is dependent on drugs with well defined therapeutic effects. Hence, interpretation of findings in neuropsychopharmacological research has remained compromised because of the heterogeneity in pharmacological responsiveness within psychiatric diagnoses to the same psychotropic drug.
There are two diagnostic instruments with the potential to recognize subpopulations within current consensus based classifications: the Diagnostic Criteria for Research Budapest-Nashville (Petho, Ban et al., 1988) and the Composite Diagnostic Evaluation System (Ban, 1989), but so far no pharmacologically homogeneous populations have been identified with these instruments. Until the time such populations are identified, the use of “nosologic homotypes” offers a possibility of obtaining interpretable findings in neuropsychopharmacoloical research in mental illness.
Nosologic homotypes are identical in elementary units, i.e., psychopathologic symptoms, of mental illness, and are assigned the same position in the “nosologic matrix” constructed in view of “nosologic organizing principles.” The elementary units of mental illness are psychopathologic symptoms. Each form in which the pathologic experiences appear (psychopathologic symptom), represent a distinct pathology in the processing of mental events, and each distinct “psychopathologic symptom profile,” is a potential phenotype of a mental disorder. The formal characteristics of the “onset” (sudden versus insidious), “course” (episodic or continuous), and “outcome” (recovery or defect), of the mental syndrome reflect the pathologic process in its “dynamic totality.” The “dynamic totality” of the pathological process, together with the “holistic character” of the clinical picture (monomorphous, polymorphous, amorphous), provides a structure that is determined by the illness (Ban, 1987). It is in terms of this structure that each mental illness is defined and assigned a distinct place in the “nosologic matrix,” based on three nosologic organizing principles.
The first organizing principle of psychiatric nosology is the “inclusiveness,” or “totality” of the psychopathologic process. Its origin can be attributed to Esquirol’s adoption of the distinction between “insanity proper” and “partial insanity” in 1838. The second organizing principle is “course” and “outcome” of the psychopathologic process Its’ origin might be attributed to Kraepelin’s separation of “manic-depressive insanity,” an episodic and remitting illness from “dementia praecox,” a continuous and progressing disease in 1899. The third organizing principle is “polarity.” Its origin is in the 1950s can be attributed to Leonhard’s (1957) adoption of the distinction between “multiform-polymorphous” and “simple-momorphous” psychiatric disease.
Since “nosologic homotypes” are more homogenous populations in terms of psychopathology than any of the diagnostic populations identified to-date, the information collected by the “nosological homotyping” could serve as the starting point for an empirically derived classification of mental illness. Considering that “nosologic homotypes” are based on the “abnormal forms” in which the pathologic experiences appear and psychotropic drugs are defined in terms of their effect on “signal transduction” in the brain, empirically derived “nosologic homotypes” provide clinical entities which are suitable for testing hypotheses relevant to the relationship between “processing of mental events,” and “signal transduction” in the central nervous system.
Employment of “nosologic homotyping,” could open up a new perspective for translating pharmacological actions into clinical effects.
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Thomas A. Ban
August 29, 2013