Wednesday, 01.04.2020

Thomas A. Ban
Neuropsychopharmacology in Historical Perspective
Education in the Field in the Post-Neuropsychopharmacology Era
Background to An Oral History of the First Fifty Years

Volume 10: Postscript

(Bulletin 73)

 

         The 10-volume Oral History series of the American College of Neuropsychopharmacology (ACNP) is based on the transcripts of 235 videotaped peer interviews with 213 clinicians and basic scientists who contributed to the development of the field of neuropsychopharmacology during the first epoch of its development (Ban 2011a). The original collection of videotapes is stored in the Louise M. Darling Biomedical Library of the University of California in Los Angeles (UCLA), at the UCLA-ACNP Center for the Study of the History of Neuropsychopharmacology.

         The transcripts in this series and the videotapes are not identical. To clarify ambiguous information in the interviews, the transcripts of the videotapes were edited. Furthermore, to ascertain that that the edited transcripts express interviewees’ contributions and thoughts as closely as possible, interviewees were allowed to correct and, if necessary, revise their text.  Additions by interviewees in the course of their revision were restricted to research contributions or events that occurred before the date of the interview. 

         The interviews cover a wide range of topics.

         To sort out the great variety of information on the videotapes, each transcript was assigned by the series editor to one of 10 volumes, each volume dedicated to a different area of research. In each volume the story of neuropsychopharmacology is told from a different vantage point (Ban 2011b). The differences in perspective on the history of the field are reflected in the “contributions profile” of each interviewee included in the volume presented by the volume editor; the introductions to the volume presented by the volume editors pull together the individual presentations (Ban 2011c,d,e,f,g,h.i,j,k,l; Blackwell 2011a,b,c; Fink 2011a,b; Gershon 2011a,b; Katz 2011a,b;  Kleber 2011a,b;  Levine 2011a,b; Salzman 2011a,b; Shorter 2011a,b; Sulser 2011a,b).

         Each volume in the series is connected to the next by the preface of the series editor. By identifying interviewees’ salient research contributions and placing this work in the context of the development of the field, they draw together the information in the interviews into a micro- and macro-history of neuropsychopharmacology from the early 1950s to the end of the 1990s (Ban 2011c,d,e,f,g,h,i,j,k,l).

 

Neuropsychopharmacology

 

         The series concludes with a “Postscript” in which the first epoch in the history of neuropsychopharmacology, the “neurotransmitter era,” is discussed in a historical perspective (Ban and Ucha Udabe 2006a,b). It is pointed out that the birth of “neuropsychopharmacology,” the discipline that studies the relationship between neuronal and mental events with centrally acting drugs, was triggered in the late 1950s,  by the introduction of a series of therapeutically effective psychotropic drugs in mental illness and by the development of a technology for tracking in the brain the relevant molecular changes to their mode of action. It is emphasized that progress in the field depends on interaction between basic scientists and clinical researchers (Ban 2011e, m).

         To facilitate progress in the field by the early 1960s two major neuropsychopharmacology associations were founded: Collegium Internationale Neuro-Psychopharmacologicum (CINP) in 1957 and ACNP in 1961. The objective of both associations was “to encourage and promote scientific study, teaching and application of neuropsychopharmacology” by providing a platform for neuropharmacologists and psychopharmacologists to interact. It was envisaged that interaction would narrow the gap and harmonize activities between the two disciplines, but this did not happen. Instead, as time passed the gap between basic and clinical research widened. By the mid-1980s it was so wide that communication between neuropharmacologists and psychopharmacologists became difficult. By the end of the 20th century, for the clinical researchers, the technical language spoken by basic scientists became virtually incomprehensible and for the basic scientists the clinical information generated by psychiatrists did not provide the necessary feedback for their work. The breakdown in communication interfered with progress in neuropsychopharmacological research and the development of drugs for the treatment of mental illness (Ban 2011b,m). In the ACNP the changes in the constitution of membership paralleled this development. In the initial membership of both Colleges clinical researchers were in majority. But as time passed this was no   longer the case.  In the ACNP, by the 1990s, researchers with representation from a wide variety of disciplines from molecular biology to social epidemiology, outnumbered clinical researchers in the membership (Ban 2011b,m).

 

Psychotropic Drugs

           

         Pharmacotherapy in psychiatry began in the second half of the 19th century with the use of morphine, apomorphine and hyoscine for controlling excitement, agitation and aggression; paraldehyde and chloral hydrate for calming and inducing sleep; and potassium bromide for relieving restlessness, anxiety and tension. As a result of the introduction of these drugs, by the 1890s the milieu in psychiatric hospitals was transformed. In the first half of the 20th century a series of sedative barbiturates and stimulant amphetamines were introduced, followed by two vitamins, nicotinic acid and thiamin; an antibiotic, penicillin; and an anticonvulsant, diphenylhydantoin. By virtually eliminating patients with cerebral pellagra and cerebral syphilis and markedly reducing the number of institutionalized patients with epilepsy and the Wernicke-Korsakoff amnestic syndrome, the introduction of these drugs transformed the diagnostic distribution of hospitalized psychiatric patients (Ban 2006, 2011b).

         The story covered in this series begins after this prelude, with the introduction of the first set of psychotropic drugs for the pharmacological treatment of mental illness in the 1950s. It included lithium for manic-depressive disease; chlorpromazine for psychoses and especially for the schizophrenias; meprobamate for anxiety states; and iproniazid and imipramine for depressive illness. The commercial success of these drugs stimulated the pharmaceutical industry to further develop psychotropic drugs and by the end of the 1950s there were 22 similar drugs available for use in psychiatry. In the years that followed their number grew and by the end of the 20th century, when our story ends, they were 53 psychotropic drugs, including 28 anti-psychotics, 13 antidepressants, 10 anxiolytics and three mood stabilizers available for clinical use in Canada for example, with a few more in some European countries and a few less in the United States. In the course of this process the primary site of psychiatric practice shifted from the hospitals to the community (Ban 2006, 2011b).

         The therapeutic success of the first set of psychotropic drugs in some patients stimulated research to study their mode of action in the hope that it would provide the necessary information on the pathophysiology of mental disease for developing more selective and effective psychotropic drugs. This, again, did not happen. None of the newer drugs were more effective than the prototypes introduced in the 1950s. In fact, as time passed, instead of becoming more selective the clinical indications of individual psychotropic drugs widened instead of narrowed. By the end of the 20th century the indication of many antipsychotics was extended to bipolar disorder and the indication of many antidepressants to anxiety disorders (Ban 2006, 2011e,m).

 

Neuropharmacology

 

         The driving force for these developments was first behavioral pharmacological research that developed behavioral screens for identifying drugs similar to the prototypes, followed by  neuropharmacological research that studied the mode of action of psychotropic drugs in the brain. The idea was that a better understanding of the action of these substances would lead to more effective drugs with fewer side effects (Ban 2011c,e; Shorter 2011a; Sulser 2011a)

         Instrumental to the shift in pharmacological research from behavioral pharmacology to neuropharmacology in the early 1960s was the prior detection of chemical neurotransmitters in the brain, the recognition of chemical transmission in the central nervous system and the introduction of the spectrophotofluorimeter. The new instrument had the resolution power to show that the administration of reserpine decreased, whereas the administration of iproniazid increased, the level of serotonin, norepinephrine and their metabolites in the brain. At the time these experiments were conducted it was already known that the monoamine neurotransmitters, serotonin and norepinephrine, were present in the brain. It was also known that iproniazid inhibited  the enzyme monoamine oxidase and produced euphoria in some tubercular patients and that reserpine produced depression in a few hypertensive patients (Ban 2011e,g; Gershon 2011a,b; Sulser 2011a,b). 

         Early neuropharmacological research with psychotropic drugs was focused on the mode of action of antipsychotics and antidepressants (Ban 2011g; Gershon 2011a,b).

         Research with antipsychotics began in the mid-1950s with the discovery of a linear relationship between the sedative and peripheral antiserotonin effect of chlorpromazine and its congeners. Additionally, a linear relationship was discovered between their mg/kg potency in pharmacological tests (and corresponding dose requirement in treatments) and their extrapyramidal effects. The turning point in antipsychotic development was the finding that the nialamide-induced accumulation of O-methylated metabolites of dopamine and norepinephrine was increased in mice treated with chlorpromazine and haloperidol. The postulation in 1963 of a relationship between an assumed dopamine receptor blockade and neuroleptic effects led to a shift from chlorpromazine-type neuroleptics to haloperidol-type neuroleptics which have greater affinity to dopamine receptors. By the time the dopamine hypothesis was formulated in the mid-1970s, haloperidol-type neuroleptics dominated the treatment of schizophrenias. Then, to undo the harm done by extrapyramidal side effects and especially tardive dyskinesia, haloperidol-type neuroleptics were by and large replaced during the 1990s by clozapine and clozapine-type neuroleptics, which have a low propensity to induce extrapyramidal signs (at the price of producing metabolic side effects). Since clozapine-type neuroleptics, similar to chlorpromazine, have stronger affinity to serotonin receptors than to dopamine receptors, by the end of the 20th century the control of psychosis and treatment of schizophrenia was back to square one, where it started in the early 1950s (Ban 2006, 2011e). 

         Neuropharmacological research with antidepressants ran a parallel course with antipsychotics. It began in the late 1950s with the discovery that imipramine has noradrenergic, serotonergic and anticholinergic properties. Then in 1960, research with antidepressants in the brain began with the demonstration that imipramine and amitriptyline blocked norepinephrine re-uptake into neurons. It continued with the finding that imipramine’s reserpine-reversal was suspended after depletion of catecholamines. The formulation of a catecholamine hypothesis of depression in the mid-1960s encouraged the replacement of imipramine-type, non-selective, but prevailingly norepinephrine reuptake inhibitors, with selective, desipramine-type, norepinephrine re-uptake inhibitors in the treatment of depression. The turning point in antidepressant development was the recognition that norepinephrine re-uptake inhibitors become serotonin re-uptake inhibitors by halogenation; that an intact serotonin system is prerequisite for β-adrenoreceptor down regulation; and the 1980 demonstration of a correspondence between imipramine binding sites and serotonin binding sites in the human platelet and in the hypothalamus of the rat. The shift from tricyclic antidepressants to selective serotonin re-uptake inhibitors began in the 1980s and by the end of the 1990s selective serotonin re-uptake inhibitors dominated treatment of depression. While their dominance in prescription practices continued, with the introduction of venlafaxine, a non-selective, but prevailingly serotonin re-uptake inhibitor, a full circle in antidepressant development was completed; with the introduction of reboxetine, a selective norepinephrine re-uptake inhibitor, the circle that had opened in the early 1960s with desipramine, was reopened in the late 1990s without offering a single antidepressant that was clinically more effective or selective than imipramine, the prototype of monoamine uptake inhibitors introduced in 1957 (Ban and Lehmann 1963; Ban, Gaszner, Aguglia et al. 1998).Yet, by the time the circle was closed, the conceptual framework of psychiatry was transformed from psychological to biological (Ban 2006, 2011e).

         While neuropharmacological research failed to drive psychotropic drug development, by the late 1950s it provided the missing link to understand  that the neuronal network of the brain, charted out at the turn of the 20th century, functioned by monoamine neurotransmitter release from vesicles at the pre-synaptic site of the synaptic cleft. The subsequent mapping of neurotransmitter pathways in the neuronal network in the 1960s, together with the accumulating knowledge on the role of the different pathways in mental activity, made it feasible to start studying the relationship between neuronal and mental processing in the brain. In the years that followed, a steadily growing number of neurotransmitters were detected in the brain and interest shifted from norepinephrine, serotonin and dopamine to glutamate and γ-aminobutyric acid, the most extensively distributed excitatory and inhibitory neurotransmitters in the central nervous system. Furthermore, it was recognized that some of the neuropeptides function in the brain as neurotransmitters; that glial cells are also involved in neurotransmitter re-uptake and not only nerve cells; and that communication within the brain is not restricted to wiring - synaptic transmission that uses chemical transmitters - but also includes a volume transmission occurring in the extracellular fluid that uses trophic factors, ions and gases as neurotransmitters (Ban and Ucha Udabe 2006a,b; Fuxe and Agnati 2006; Sulser 2011a,b).

         During its first 50 years, neuropharmacology research moved from the study of psychotropic drugs in pre-synaptic events in the 1960s to the study of membrane receptors in the 1970s, to second messenger mediated activation of protein kinases in the 1980s and to early gene expressions in the 1990s (Sulser 2011b).

         By the end of the 20th century it was recognized that the primary targets of psychotropic drugs in the brain are all encoded by genes that have been identified. Thus, at this point, the neurotransmitter era, the first epoch in the history of neuropsychopharmacology ended and a new epoch, the molecular genetic era in neuropsychopharmacology, began (Ban 2002; Ban and Ucha Udabe 2006a,b). As the populations within psychiatric diagnoses remained pharmacologically heterogeneous, neuropsychopharmacologists in the new era were confronted with the dilemma of whether to follow a pharmacogenomic approach guided by the genome or to follow a pharmacogenetic approach guided by a prior identification of pharmacologically homogeneous psychiatric populations, a dilemma similar to the one that confronted us 50 years before (Ban 1969, 2002, 2011m).

 

Clinical methodology

 

         The dilemma of methodology first arose in the late 1950s when early psychotropic drugs focused attention on the pharmacological heterogeneity within psychiatric diagnoses. To meet the requirements of neuropsychopharmacological research, there was a need for a re-evaluation of psychiatric diagnostic concepts (Ban 1969). Yet, this did not happen. Instead, a statistical approach, the randomized clinical trial (RCT), was adopted for the demonstration of therapeutic efficacy in pharmacologically heterogeneous populations (Ban 1987, 2006, 2011f; Levine 2011a).

         A RCT requires reliable clinical end points and instruments for the assessment of change. To meet these requirements consensus-based diagnoses and psychiatric rating scales were adopted. The methodology was further strengthened by the adoption of power statistics to prevent Type II or β-error owing to insufficient sample sizes. By the 1990s multi-center clinical investigations designed with power statistics replaced single-center trials in the development of psychotropic drugs. This clinical methodology was eminently suited for the demonstration of therapeutic efficacy in a pharmacologically heterogeneous diagnostic population even if only a small proportion of patients in the sample were responsive to the drug. It was with the help of this methodology that pharmacotherapy became the primary form of treatment for the schizophrenias, depressions, bipolar disease and dementias.  By the end of the 20th century pharmacotherapy with psychotropic drugs dominated treatment in psychiatry (Ban 2006, 2011m; Levine 2011a).

         As the use of psychotropic drugs developed with this methodology increased, psychopathology was gradually replaced by psychiatric rating scale variables and psychiatric nosology gave way to consensus-based diagnostic algorithms. By the end of the 20th century, a new generation of psychiatrists grew up well-founded in molecular genetics and brain imaging without any knowledge of psychopathology and psychiatric nosology, the disciplines that provide the foundation of modern psychiatry. As a result, research in neuropsychopharmacology, as well in the molecular genetics of psychiatric disorders, is conducted without benefitting from the homogeneity of clinical end-points that psychopathology and psychiatric nosology can offer (Ban 2002).  Furthermore, the confounding of psychopathology with abnormal behavior led to an enlargement of the psychiatric populations within diagnostic groups and an extension of the scope of psychiatry to include, in addition to pathologies in mental processing, behavioral anomalies with compromised social functioning (Ban 1987).  Simultaneously, treatment in psychiatry became evidence-based, albeit the evidence for demonstrated efficacy that was stipulated by regulatory authorities has made drugs available for clinical use even if only one in four patients was expected to respond favorably. As the pharmacological heterogeneity within psychiatric diagnoses precluded the linking of pharmacodynamic action of drugs to their effect on mental pathology, in the selection from drugs for treatment the primary consideration was their differential propensity for inducing side effects (Ban 2006).

         Dissatisfaction with the inadequacy of diagnostic concepts in classifications of mental illness led initially to attempts to replace clinical diagnoses by biological indicators, e.g., biochemical and endocrine measures; then, in the mid-1980s, it was recognized that without being linked to a well-defined clinical entity, these measures “hang in the air” (Ban 1987). Re-conceptualization of mental illness in terms of discrete neurobiological deficits offered promise, but the alternative phenotypes of schizophrenia identified as the abnormality of smooth pursuit eye movements and P-50 evoked response deficit were encountered several times more frequently in the general population than the schizophrenias. On the positive side,  “pharmacological dissection” using iproniazid and other non-selective monoamine oxidase inhibitors led to the delineation and separation of “atypical depression” from the other depressions and with imipramine to the delineation and separation of panic disorder from the other anxiety disorders. “Composite diagnostic evaluations” provide a capability to detect therapeutic effects in prototype-based diagnoses covered up by consensus-based diagnoses as, for example, “vital depression,” the form of endogenous depression that helped to uncover imipramine’s antidepressant effect; and  “affect-laden paraphrenia,” the form of schizophrenia in which more than four in five patients were found, in the mid-1960s, highly responsive to neuroleptics. Finally, “nosologic homotyping” provides the most homogeneous populations of illness, in terms of psychopathology and psychiatric nosology, that psychopharmacology can offer for neuropsychopharmacologic research (Ban 2007; Klein 1973).

 

Psychopharmacology

 

         The roots of psychopharmacology are in the observation in the mid-1840s that “dawamsec,” an electuary of hashish, had a different effect on the melancholic than on the regressed (aliéné stupide) and on the demented. This observation translates in our current frame of reference into the hypothesis that the proteins encoded by genes in the different diagnostic populations in psychiatry are different, as they respond differently to the same psychotropic drug (Ban 2002; 2011m). The clinical identification of these differentially responding populations to the same drug has remained to-date a target of psychopharmacology research (Ban 2002; 2006).

         The scope of the field was extended with the introduction of pharmacopsychology in the 1890s, to the study of the effects of drugs on performance tests. Then, with the introduction of phenomenological psychopathology in the early years of the 20th century, the study of psychomimetics on the subjective experiences of mental life began. While phenomenologic explorations with psychomimetics so far has not contributed to psychopharmacology, psychometrics, at the core of pharmacopsychology, was instrumental in developing the clinical methodology used in the past 50 years in the testing of the therapeutic efficacy of psychotropic drugs (Ban 2011g,m; Gershon 2011a,b).

         The scope of psychopharmacology was further extended to study the effects of psychomimetic and psychotherapeutic drugs. Studies with psychomimetics began in the early years of the 20th century. By the end of the 1950s it was recognized that the psychopathology induced by mescaline, lysergic acid diethylamide, dimethyltryptamine and phencyclidine resembled the schizophrenias, whereas the psychopathology-induced with Ditran resembled the organic psychoses. In the 1960s studies on the psychopathology induced by psychomimetics was complemented with studies on their neuropharmacology. As interest in neuropharmacology shifted from monoamine to amino acid neurotransmitters, research with phencyclidine, an antiglutamate that blocks NMDA receptors, was intensified  (Ban 2011g; Gershon 2011a,b).  

         Studies with psychotherapeutics ran parallel with psychomimetics. Research with these drugs started in the mid-1930s with the discovery that intravenous sodium amobarbital in a low dose could relieve transiently catatonic stupor and psychogenic mutism (Ban 1969, 2011m). Subsequently, it was revealed that those unresponsive to treatment with amobarbital might respond to intravenous methamphetamine or parenteral chlorpromazine. By the end of the 1930s it was discovered that d,l amphetamine was effective in both the treatment of narcolepsy and the control of hyperactive children. It was also reported that it could induce psychosis. In the mid-1950s it was recognized that the majority of amphetamine-induced psychoses resemble paranoid schizophrenia (Ban 2011m; Gershon 2011a,b)

         In the 1970s a new area of psychopharmacology research emerged: the testing of neuropsychopharmacological hypotheses. The findings in this area of research are supportive of the dopamine hypothesis of schizophrenia and the serotonin hypothesis of depression. Administration of methylphenidate, a dopamine agonist, produced exacerbation of psychopathology in some patients with chronic schizophrenia, and administration of p-chlorophenylalanine, a serotonin synthesis inhibitor, reversed the therapeutic effect of tricyclic antidepressants in some depressed patients, whereas the administration of α–methylparatyrosine, a catecholamine synthesis inhibitor, did not. Furthermore, physostigmine, an acetylcholinesterase inhibitor, improved memory in normal subjects. This finding - together with the early discovery that tetrahydroacridine, another acetylcholinesterase inhibitor - reversed the mental disintegration induced by Ditran, an anticholinergic substance, and with the demonstration of decreased acetylcholine levels in the brain in Alzheimer’s disease - triggered  the development of acetylcholinesterase inhibitors for the treatment of Alzheimer’s dementia.  The first acetylcholine cholinesterase inhibitor “cognitive enhancers” for Alzheimer’s disease, were introduced in the 1990s (Ban 2011f; Gershom 2011a,b).

         Today, molecular genetic research is moving rapidly ahead in the hope of developing a  better understanding of and more effective treatments for psychiatric disorders. It is hoped that by presenting this 10-volume series repetition of what went wrong in the first 50 years will be prevented and that neuropsychopharmacology in its second epoch will enjoy new success.

 

References:

 

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June 20, 2019