by Thomas A. Ban

INTRODUCTION

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).

PSYCHOTROPIC DRUGS

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).

NEUROPHARMACOLOGY

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 20^th 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 20^th 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).

PSYCHOPHARMACOLOGY

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.  

NEUROPSYCHOPHARMACOLOGY

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.

Selected references

Ban TA.  Psychopharmacology. Baltimore: Williams & Wilkins; 1969

Ban TA. Nicotinic acid in psychiatry. Canadian Psychiatric association Journal 1971; 16: 413-31.

Ban TA.Prolegomenon to the clinical prerequisite : psychopharmacoogy and the classssification of mental disorders. Progr Neuro-psychopharmacol Biol Psychiatry 1987; 11: 527-80.

Ban TA. Composite Diagnostic Evaluation of Depressive Disorders. Nashville: JM Productions; 1989.

Ban TA. Clinical pharmacology and Leohard;’s classifcatin of endogenous psychoses. Psychopatholo 1990; 23: 331-8.

Ban TA. Pharmacotherapy of mental illness. A historical analysis. Prog Neuro-Psychopharmacol & Biol Psychiat  2001; 23: 709-27.

Ban TA. Neurpsychopharmacology and the history of pharnmacotherapy in psychiatry a review of developments in the 20^th century. In: Ban TA, Healy, Shorter E, eds. Reflections on twentieth-century psyhopharmacology. Budapest: Animula; 2004, pp. 697-720.

Bradley CB. The behavior of children receiving Benzedrine. Amer J Psychiatry 1937; 94: 577-80.

Carlsson A, Lindqvist M. Effect of chloprpomazine or haloperidol on formation of 3-methoxytyramine and omtanephrine  in mouse brain. Acta Pharmacol Toxicol 1963; 20: 140 - 4.

Esquirol JED. Des Maladies Mentales Considerees Sous les Raports  Medical Hygienique et Medico-Legal. Paris: Baillière; 1838.  

Fish F. The influenèce of he tranquilizer on th Leonhard schizophrenic syndromes.  Encephale 1964; 53: 245-9.

Guy W, Ban TA, Wilson WH. An international survey of tardive dyskinesia. Prog Neuro-psychopharmacol & Biol Psychiat 1985; 9: 401-5.

Guy W, Ban TA, Wilson WH, The prevalence of anormal involuntary movements`in hronic schizophrenia. Int Clin Psychopharmacol 1986; 1: 134-44.

Gyermek L, Lazar GT, Csak Zs. The antiserotonin action of chlorpromazine and some other phnothiazine derivatives. Arch Int Phamacodyn 1956; 107: 62-74.  

Healy D. Let Them Eat Prozac. Toronto: james Lorimer & Company Ltd; 2003.

Kraepelin E. Psychiatrie. Ein Lehrbuch für Studierende und Ärzte. 6 Auflage. Leipzig: Barth; 1899.

Leonhard K. Aufteilung de endgenen Psychosen. Berlin: Akademie-Verlag; 1957.

Petho B, Ban TA, et al. DCR Budapest-Nashille in the diagnosis and classification fuctional psychoses. Psychopathology 1988; 21; 153-239.

Thomas A. Ban
August 29, 2013

Samuel Gershon: Events and Memories.

Bernard Lerer’s comments

        I came to Detroit in 1982 to work with Sam Gershon at Lafayette Clinic. I had completed my residency in psychiatry two years earlier and then did a research fellowship with Robert (Haim) Belmaker at Ezrath Nashim Hospital in Jerusalem. I met Sam in 1981 during one of his visits to Israel and talked to him about my interest in the biology of depression and bipolar disorder and the mechanism of action of ECT. Sam offered me a fellowship on the spot. Without even checking other options, I made arrangements to do my training with Sam in Detroit. When I arrived in July 1982 and started work Sam did not assign me to any projects. Instead, he listened to my ideas and helped me implement what I wanted to do.

        My first study was an open trial of the tetracycline antibiotic, demeclocycline, in patients with acute mania.  The study was motivated by the focus of the Belmaker group on inhibition of adenylate cyclase as a possible mechanism of action of lithium in bipolar disorder. Since demeclocycline inhibits adenylate cyclase and causes diabetes insipidus, as does lithium, a trial of demeclocycline in mania was an excellent test of the hypothesis. Unfortunately, good ideas do not always pay off. Demeclocycline did not have any effect on manic symptoms. Very soon I had used up all my credit with the nursing staff as manic patients receiving the drug did not improve and then grew significantly worse. Sam supported me as best he could but it soon became clear that the study had to be disbanded.

        My next clinical research venture was also in bipolar disorder and was enthusiastically supported by Sam. While with the Belmaker group in Jerusalem I had been part of a study that compared add-on of the anticonvulsant, carbamazepine, to placebo add-on in patients with “excited psychosis.” Bipolar manic and schizoaffective manic patients as well schizophrenia patients with manic-like symptoms were included in the study. The addition of carbamazepine was significantly better than placebo (Klein, Bental, Lerer and Belmaker 1984).

        Encouraged by these results I wanted to undertake a randomized controlled trial  (RCT) comparing lithium and carbamazepine in patients with acute mania. Sam liked the study because it could test his hypothesis that patients with “typical” bipolar disorder, characterized by predominant mood symptoms in the acute phases and high quality remissions, are those who respond best to lithium. Having rehabilitated my stature with nursing staff, Norman Moore and I set out to do the study. The fact that both drugs worked equally well helped keep the peace on the ward. We published the results in the Journal of Clinical Psychiatry (Lerer, Moore, Meyendorff et al. 1987). As the first RCT of carbamazepine versus lithium in mania it aroused a lot of interest. The number of patients was not large enough to substantively test Sam’s hypothesis but there definitely was a trend for those patients who responded to lithium to be more “typical” in their clinical picture as well as during remission than those who responded to carbamazepine.

        Another study I initiated with Sam’s encouragement also supported a different profile of action of lithium and carbamazepine in bipolar disorder. It had been previously shown that pretreatment with lithium inhibited the mood enhancing effects of stimulants in euthymic patients with bipolar disorder. Together with Elaine Meyendorff, I examined the effect of carbamazepine pretreatment on methylphenidate-induced behavioral activation and euphoria. Seven euthymic bipolar patients received two weeks of pretreatment with carbamazepine or placebo in a double-blind crossover design. After each pretreatment period, the subjects received methylphenidate, 30 mg i.v.; mood and behavior changes were monitored for a period of five hours after each infusion. Methylphenidate induced a striking psychostimulant effect that was not attenuated by carbamazepine pretreatment. This clearly differs from the effect of lithium in the same paradigm and supports the hypothesis of different therapeutic profiles for lithium and carbamazepine in bipolar disorder (Meyendorff, Lerer, Moore et al. 1985; Lerer, Moore, Meyendorff et al. 1985).

        I did a lot more in those amazing years in Detroit. In 1984 I received deeply appreciated recognition of my preclinical studies on the mechanism of action of ECT (encouraged and supported by Sam) for which I was awarded the A.E. Bennet Prize for Preclinical Research in Biological Psychiatry (Lerer 1984).

        I returned to Israel in 1984 and never forgot Sam’s dictum regarding “typical bipolarity” and its exquisite responsiveness to lithium. I have taught this approach to my students and see it regularly in my clinical work. I am firmly convinced there is a population of bipolar patients who respond extraordinarily well to lithium and are never ill again after starting the drug.

        At this time I am in the process of conducting an extensive, systematic analysis of all available data comparing carbamazepine and lithium in bipolar disorder. I am working with two talented younger colleagues in the Department of Psychiatry at Hadassah – Hebrew University Medical Center in Jerusalem. Beyond assessing the overall effect of carbamazepine as compared to lithium, one of our cardinal objectives is to determine whether there are unique characteristics that differentiate patients who respond to the two drugs.

        More than 40 years after they were first expressed to me, Sam’s ideas remain a powerful motivating factor for my own research and that of others in psychopharmacology and biological psychiatry. And that is only a drop in the ocean of his achievements.

References:

Klein E, Bental E, Lerer B, Belmaker RH.  Combination of carbamazepine and haloperidol versus placebo and haloperidol in excited psychoses: A controlled study. Archives of General Psychiatry 1984; 41:165-70. 

Lerer B.  Studies on the role of brain cholinergic systems in the therapeutic mechanisms and adverse effects of ECT and lithium (Winning Paper, A.E. Bennet Award, Basic Science, 1984). Biological Psychiatry 1985; 20:20-40.

Lerer B, Moore N, Meyendorff E, Cho S-R, Gershon S.  Carbamazepine and lithium: Different profiles in affective disorders? Psychopharmacology Bulletin 1985; 21:18-22.

Lerer B, Moore N, Meyendorff E, Cho S-R, Gershon S.  Carbamazepine versus lithium in mania: A double blind study. Journal of Clinical Psychiatry 1987; 48:89-93.

Meyendorff E, Lerer B, Moore N, Bow J, Gershon S.  Methylphenidate infusion in euthymic bipolars: Effect of carbamazepine pretreatment. Psychiatry Research 1985; 16:303-8.

July 9, 2020