Thomas A. Ban: Neuropsychopharmacology in Historical Perspective Education in the Field in the Post Psychopharmacology Era


Thomas A. Ban: Selective Drugs Versus Heterogeneous Diagnoses Towards a New Methodology in Psychopharmacologic Research*



        In this presentation the history of modern neuropsychopharmacology was reviewed with special reference to the impasse in pharmaco-therapeutic progress. It was postulated that a methodology for the delineation of the therapeutic profile of psychotropic drugs and identification of the treatment responsive form(s) of illness is an essential prerequisite for progress in the pharmacotherapy of mental illness.

        It is reasonable to assume that the information generated by the methodology will provide the necessary orientation points for developing therapeutically more effective and clinically more selective psychotropic drugs. It should also open the possibility to complement the current capability of tailoring drugs to receptor profiles with the capability of tailoring drugs to the different forms and subforms of mental illness.



        Psychopharmacology and neuropharmacology are two interrelated disciplines which are dedicated to the study of different aspects in the action of psychoactive drugs. Psychopharmacology is focused on illness. It deals with the detection of psychopathologic symptoms and syndromes, and the identification of nosologic entities which are affected by psychotropic drugs. Neuropharmacology is focused on drugs. It deals with the detection of the action, and the identification of the structures responsible for the psychotropic effects of centrally acting drugs (Ban 1996).

        The roots of psychopharmacology are in Moreau de Tours' (1840s) discovery that the effects of “dawamsee,” an electuary of hashish, are different in "regressed" and "depressed" patients (Moreau de Tours 1841; Caldwell 1970). The roots of neuropharmacology are in Claude Bernard's (1850s) recognition that drugs provide a "physiological scalpel" for the study of the physiology of the nervous system (Bernard 1869; Shorter 1997).

        Introduction of therapeutically effective psychotropic drugs, and the spectrophotofluorimeter (during the 1950s), led to the development of neuropsychopharmacology. There were high expectations that neuropharmacology would provide psychopharmacology a royal road to the understanding of the pathophysiology of mental illness. It was also hoped that research in psychopharmacology would generate the necessary feedback for neuropharmacology, to develop more effective and selective pharmacological treatments (Ban 1987).

        Since the introduction of the first set of new psychotropic drugs almost 50 years passed and well over 100 psychotropic drugs have become available for clinical use. Despite the numerous drugs and unprecedented progress in related fields, expectations for better treatments have not been fulfilled. There is a possibility that the improvements are covered up by the heterogeneity within psychiatric diagnoses. Another possibility is that no progress was made, because of the lack of necessary clinical feedback.

        In this paper 50 years of neuropsychopharmacological development is outlined and the impact of different factors on this development discussed. Special reference is given to the methodology of clinical research, focused on the demonstration of therapeutic effectiveness, and to the heterogeneity within the psychiatric diagnoses. The paper concludes with the postulation that a methodology for the delineation of the therapeutic profile of psychotropic drugs and identification of the treatment responsive forms of illness is an essential prerequisite for progress in the pharmacotherapy of mental illness.


Outline of development

        The history of modern neuropsychopharmacology can be divided into three distinct periods. The first (1950s) corresponds with the introduction of prototype psychotropic drugs, and the second (1960s and 70s), with the introduction of the first generation of psychotropics, identified based on structural and / or pharmacological similarities to the prototype drugs. The third, ongoing period, is characterized by the introduction of the second generation of psychotropics, developed with consideration of theories about the pathomechanism of mental illness derived from studies on the action mechanism of therapeutically effective drugs.


Development of drugs

        The first set of prototype psychotropics include four structurally distinct antipsychotics, i.e., chlorpromazine, an aliphatic phenothiazine, reserpine, an indole derivative, haloperidol, a butyrophenone, and chlorprothixene, a thioxanthene; three structurally distinct anxiolytics, i.e., meprobamate, a propanediol, hydroxyzine, a diphenylmethane, and chlordiazepoxide, a benzodiazepine; two structurally and functionally distinct antidepressants. i.e., iproniazid, a hydrazine monoamine oxidase inhibitor (MAOI), and imipramine, a dibenzazepine monoamine reuptake inhibitor (MAUI); and a mood stabilizer, i.e., lithium carbonate, an inorganic salt (Ban 1969; Usdin and Efron 1972).

        The origin of chlorpromazine and hydroxyzine are in research with antihistaminics (Caldwell 1970; Ban 1969); meprobamate, in research with antibiotics (Berger 1998); haloperidol, in research  with meperidine (Janssen 1996); lithium, in research in manic-depressive illness (Cade 1970); iproniazid, in clinical observations in tubercular patients (Selikoff, Robitzfk and Orenstein 1952; Healy 1997); reserpine, in Ayurwedic medicine (Kurland 1996); and imipramine, chlorprothixene, and chlordiazepoxide, in the search for structurally and / or pharmacologically similar drugs to meprobamate and chlorpromazine (Ban 1969; Ayd and Blackwell 1970).

        Some of the prototypes had a major impact on psychotropic drug development and by the end of the second period the number of drugs available for clinical use in the treatment of mental illness increased from 10 to 56 by the inclusion of 18 additional antipsychotics, 12 additional antidepressants, 2 additional mood stabilizers, 6 hypnotics, and 2 stimulants. During the third period, there has already been a further increase, from 56 to 75, in the drugs available for treatment, by the inclusion of 10 additional antidepressants, 6 additional antipsychotics, an additional anxiolytic, an additional hypnotic, and a cholinesterase inhibitor (Poldinger and Wider 1990).

        There are 73 psychotropic drugs available for clinical use in Canada and /or the United States today: 28 antipsychotics, primarily for the treatment of schizophrenia; 23 antidepressants, primarily for the treatment of depression; 10 anxiolytics, for the treatment of anxiety states; seven hypnotics for insomnia; three mood stabilizers for the treatment of manic-depressive illness; one stimulant, for the treatment of attention deficit disorder hyperactivity; and one cholinesterase inhibitor, for the treatment of Alzheimer's disease (Compendium of Pharmaceuticals and Specialties 1999; Physicians' Desk Reference 1999).


Advances in neuropharmacology

        Development of neuropharmacology was triggered (in the mid-1950s) by the introduction of the spectrophotofluorimeter, an instrument with the capability (resolution power) to measure the concentration of cerebral monoamines involved in neuronal transmission at the synaptic cleft (Carlsson 1998). Prior to its introduction, research, dealing with central nervous system acting drugs, was restricted to behavioral pharmacology and neurophysiological measures. Spectrophotofluorimetry provided direct access to the detection of the biochemical changes responsible for the behavioral effects.

        Developments in the neuropharmacology of antidepressants began (in the late 1950s) with the demonstration that iproniazid increased (Besendorf and Pletscher 1956), whereas reserpine decreased cerebral monoamines, i.e., serotonin (5-HT) (Pletscher, Shore and Brodie 1955, 1956), and norepinephrine (NEPA. Since iproniazid, a monoamine oxidase inhibitor (MAOI), induced euphoria in some tubercular patients (Selikoff, Robitzfk and Orenstein 1952; Healy 1997; Flaherty 1952; Crane 1956), and reserpine dysphoria in some hypertensives (Lewis 1971; Hollister 1978), the possibility was raised that the mood changes were mediated by 5-HT and / or NE (Pletscher, Shore and Brodie 1956; Brodie, Shore and Pletscher 1956; Brodie BB, Shore PA, Pletscher 1998). The postulation of a relationship between reserpine induced depletion of monoamines and depression led to the introduction of the reserpine reversal test in the pharmacological screening for potential antidepressants (Garattini 1996; Costa, Garattini and Valzelli 1960). It also provided the rational for the research which, with the employment of a radioactive isotope labelling technique, led to the finding of NE and 5-HT reuptake inhibition with tricyclic antidepressants (Axelrod, Whitby and Hertting 1961; Glowinski and Axelrod 1964).

        Developments in the neuropharmacology of antipsychotics began (in the early 1960s) with findings of an increase in the nialamide (MAOI)-induced accumulation of 3-0-methylated metabolites of dopamine (D) and NE in chlorpromazine and haloperidol treated rats. The increase in the accumulation of 3-methoxytyramine and normetanephrine was explained by a compensatory increase of tyrosine hydroxylase activity to the drug induced blockade of catecholamine receptors (Carlsson and Lindquist 1963). Postulation of a relationship between dopamine receptor blockade and antipsychotic effects (Engel 1976), led to the introduction of a series of tests, e.g., antagonism of amphetamine-induced stereotypes, antagonism of apomorphine induced vomiting, in the pharmacological screening for potential antipsychotics (Janssen 1998). It also provided the rational for the research which, with the employment of X-ray crystallography, led to the demonstration of dopamine receptor blockade with neuroleptics (Creese, Burt and Snyder 1975, 1977).

        Development of receptor binding assays (during the 1970s) opened the path for the determination of the NE and 5-HT reuptake blocking (inhibiting) potency of anti-depressants. Identification (separation) of receptor sub-types (during the 1980s) led to the determination of the dopamine-D2 and serotonin-5-HT2A blocking potency of neuroleptics, and to the delineation of the receptor profile, in terms of affinities to muscarinic-cholinergic, histamine-H1, and alpha 1 and alpha 2- adrenoreceptors, of antipsychotic and antidepressant drugs.

        Separation of receptor subtypes was further refined (during the 1980s) by the introduction of genetic technology. With the employment of receptor cloning (by the late 1990s), five subtypes of the dopamine receptor (Dl, D2, D3, D4 and D5) (Sokoloff and Schwartz 1995), 14 subtypes of the serotonin receptor (5HTIA, 5FITIB, 5HTID, 5HT1E, 5HT1F, 5HT2A, SHTB, 5HT2C, 5HT3, 5HT4, 5HTSA, 5HTSB, 5HT6 and 5HT7) (Lucas and  Hen 1995; Beres 1999), and five subtypes of the muscarinic-cholinergic receptor have been identified (Bonner, Buckcley, Young and Brann 1987). The new genetic technology opened the path for tailoring psychotropics to receptor affinities (Bischoff, Bruinink, Gunst et al. 1992).


Receptor profile of psychotropics

        At the time of its introduction (in 1952) chlorpromazine was characterized as a substance which induced cataleptic immobility, reduced spontaneous motility, and interfered with operant behavior, including intracranial self-stimulation (Ban 1969). Today, within the framework of modern receptorology, chlorpromazine is characterized as a serotonin-5HT2A and dopamine-D2 receptor blocker, with a receptor profile characterized by affinities to the histamine-HI, dopamine-D2, muscarinic-cholinergic, and alphas- and alpha2- adrenoreceptors (Richelson 1999; Richelson and Nelson 1984; Richelson, Souder, Acuna, et al. 1997).

        At the time of its introduction imipramine was characterized as a substance which increased the speed of pigeons working to obtain grain by pecking a key in the Skinner box, and decreased lever pressing on a Sidman avoidance schedule. Today, within the framework of modem receptorology, imipramine is characterized as a NE- and 5HT-reuptake blocker with a receptor profile characterized by affinities to the muscarinic-cholinergic, histamine-H1, and alpha1- and alpha2-adrenoreceptors (Richelson 1991; Bolden-Watson and Richelson 1993; Frazer 1997).

        With consideration of their receptor affinities, the 28 antipsychotic drugs available for clinical use in Canada and / or the United States for the treatment of schizophrenia, can be classified into two major categories: one with a higher affinity for the dopamine-D2 receptor than the serotonin-5-HT2A receptor, and the other with a higher affinity for the serotonin-5-HT2A receptor than the dopamine-D2 receptor. Drugs of the first category include droperidol, flupenthixol, fluphenazine, fluspirilene, haloperidol, pericyazine, perphenazine, pimozide, pipotiazine, prochlorperazine, reserpine, thioproperazine, thiothixene, trifluoperazine, and zuclopenthixol; and drugs of the second category include chlorpromazine, chlorprothixene, clozapine, loxapine, olanzapine, mesoridazine, methotrimeprazine, promazine, quietapine, risperidone, sertindol, thioridazine and ziprasidone (Richelson 1999; Richelson and Nelson 1984; Richelson, Souder, Acuna, et al. 1997).

        With consideration of their receptor affinities, the 23 antidepressants available in Canada and/or the United States for the treatment of depression can be classified into 10 categories: non-selective, prevailingly NE reuptake blockers (amitriptyline, doxepin, and imipramine); non-selective, prevailingly 5-HT reuptake blockers (clomipramine, and venlafaxine); selective serotonin reuptake blockers (fluoxetine, fluvoxamine, paroxetine, and sertraline); selective norepinephrine reuptake blockers (amoxapine, desipramine, maprotiline, nortriptyline, and protriptyline); serotonin selective - 5HT2A block with weak 5-HT reuptake inhibition - agents (nefazodone, and trazodone); noradrenaline and serotonin selective - NE-alpha-2, 5HT2A and 5HT2C block - agents (mirtazepine, and trimipramine); a selective dopamine reuptake inhibitor (bupropion); a serotonin precursor (tryptophan); non-selective MAOls (phenelzine and tranylcypromine); and a selective Type A MAOI (moclobemide). In terms of NE and/or 5-HT reuptake blocking potency, considered for a long time the essential feature in the pharmacological action of antidepressants, there is a wide variation between antidepressant drugs (Richelson 1991; Bolden-Watson and Richelson 1993; Frazer 1997; Ban 1999).


Advances in psychopharmacology

        While neuropharmacologists could embark without delay on the study of the action mechanism of psychotropic drugs, psychopharmacologists had to remove some major obstacles before moving ahead.

        Despite chlorpromazine's great success in transforming disturbed wards, it took approximately eight years from the time of Delay, Deniker and Harl's (1952) first report on the antipsychotic effect of the drug to demonstrate its superiority to placebo, in the treatment of schizophrenia (Casey, Bennett, Lindley et al. 1960; Casey, Lasky, Klett and Hollister 1960). Another four years passed before the findings in the US Veterans Administration Collaborative Studies were verified and further substantiated by the National Institute of Mental Health Psychopharmacology Service Center Collaborative Study Group (1964).

        There was also a delay in the demonstration of the therapeutic effectiveness of imipramine. It was only in 1965, i.e., eight years after Kuhn's first report on the antidepressant effect of the drug (1957), that Klerman and Cole succeeded to demonstrate its superiority to placebo in the treatment of depression (1965). Another four years passed before their findings were verified by Klein and Davis (1969), and five years before it was further substantiated by Angst (1970).

        The difficulties encountered in the demonstration of the therapeutic effectiveness of chlorpromazine and imipramine focused attention on the heterogeneity in responsiveness to pharmacological treatment within the diagnostic categories of schizophrenia and depression. It also brought to attention the need for a methodology for the demonstration of the therapeutic effectiveness of psychotropic drugs. Confronted (in the mid-1960s) with the predicament to choose between developing a methodology for the identification of the treatment responsive forms of illness to resolve the heterogeneity within the diagnoses first, or a methodology for the demonstration of therapeutic effectiveness, psychopharmacologists opted for the latter.


Methodology: demonstration of therapeutic effectiveness

        There are two essential prerequisites of a methodology for the demonstration of therapeutic effectiveness: rating scales which can detect and document changes, and diagnostic end points which communicate and can be reliably identified. It was in response to the need for documentation and rating scales that a German speaking group developed a Manual for the Assessment and Documentation in Psychopathology (AMP 1971; AMDP 1979;   Guy and Ban 1982); a Swedish team constructed a Comprehensive Psychiatric Rating Scale (CPRS) (Åsberg, Perris, Schalling and Sedvall 1978); and William Guy in the United States assembled rating scales for the assessment of change and published it in the Early Clinical Drug Evaluation Units (ECDEU) Assessment Manual (1976). Since sensitivity is an important attribute of rating scales used in measuring changes in time, and there is an inverse relationship between a comprehensive coverage of psychopathology and the sensitivity of a scale, the ECDEU Manual was to become an important source book of scales for efficacy studies with psychotropic drugs. Two of the scales included in the Manual, the Brief Psychiatric Rating Scale (BPRS) of Overall and Gorham (1962), and the Hamilton Rating Scale for Depression (HAMD) (1960), have remained the most extensively used scales in efficacy studies with antipsychotics in schizophrenia, and antidepressants in depression.

        The need for diagnostic end points was met by the 9th edition of the International Classification of Diseases (ICD-9) of the World Health Organization (released in 1977), and the Third Edition of the Diagnostic and Statistical Manual (DSM-III) of the American Psychiatric Association (released in 1980). The ICD-9 was the first international classification of mental illness, with a glossary of definitions, and the DSM-III, was the first classification of mental illness with multiaxial evaluation and operationalized diagnostic criteria. By the mid-1980s, consensus-based classifications of mental illness replaced all other diagnostic classification of mental illness in the clinical development of psychotropic drugs.

        With the availability of a generally accepted methodology, single center, isolated clinical trials were replaced by multi-center, centrally coordinated clinical investigations with sample sizes determined by power statistics. Since virtually all clinical information on psychotropics during the past decades have been generated in such large multicenter clinical studies, with individual contributions restricted to small insignificant proportions of the total sample, the impact of the methodology transcends the clinical development of psychotropic drugs. It extends into medical education by providing the only acceptable information for evidence-based medicine. It also extends into neuropharmacological research, by providing the only available feedback for those engaged in the development of new psychotropic drugs.

        Despite the major impact of the methodology on the practice of pharmacotherapy, a review of findings in clinical studies indicate that no major changes (advances) have taken place during the past decades in the pharmacotherapy of schizophrenia and depression. None of the many new antipsychotics was found to be consistently superior to chlorpromazine; and none of the many new antidepressants was found to be consistently superior to imipramine (Ban 1987; Ereshefsky 1999; Stahl 1999; Ban 1972, 1974, 1981).

        Findings in the first pooled analysis of placebo-controlled studies with imipramine in the treatment of depression (conducted in the early 1960s) indicate a 65% response rate with imipramine against a 31% response rate with placebo. The 65% response rate with imipramine implies that one can expect that 2 of 3 depressed patients treated with imipramine will improve; and the 31% placebo response rate indicates that in one of the two patients who improve, the improvement is the result of treatment with the drug. In two subsequent pooled analyses of placebo-controlled studies with imipramine, response rates were similar, i.e., 70% vs 39% (Klein and Davis 1969) and 65% vs 37% (Angst 1970).

        Response rates with neuroleptics in the maintenance therapy of schizophrenia are virtually the same as response rates with imipramine in depression. Findings of a meta-analysis (conducted in the mid-1970s) with 24 placebo-controlled clinical studies indicate that regardless of which antipsychotic used, about 30% of the patients from the active drug group, and little more than 60% from the placebo group relapse, i.e., only one or two patients, including placebo responders, benefits from treatment (Ban 1987; Davis 1975).

        Response rates with the newer antidepressants in the treatment of depression are the same or may even lower than with imipramine in the pooled analyses (conducted in the 1960s). Findings of a meta-analysis (conducted in the mid-1990s) with 300 double-blind randomized clinical trials with antidepressants, indicate a widening of the antidepressant response range from 65%-70% to 45%-79%, with a lowering of the threshold for antidepressant effects from 65% to 45% (Davis, Wang and Janicak 1993; Fawcett and Barkin 1997).

        While response rates are more or less the same with all psychotropics of the same category, it is frequently seen that a patient refractory to one antipsychotic/antidepressant responds to another. The finding that responsiveness to a second antipsychotic/antidepressant is encountered more frequently than it could be accounted for by chance and/or by a placebo effect, indicates that the therapeutic profiles of at least some of these drugs differ.


Factors with an impact on development

        Despite the recognition of possible differences between the therapeutic profile of psychotropic drugs of the same class, development of a methodology for the identification of the treatment responsive form(s) of illness, and delineation of the therapeutic profile of drugs, has been delayed. There are many contributing factors to the delay. Included among them are consensus-based classifications, sensitive rating scales and the simple fact that restriction of the indication of drugs from the broadest possible population, in which therapeutic effectiveness can be demonstrated, to the treatment responsive form(s) of illness, is contrary to the interest of the pharmaceutical industry, the primary force in the development of psychotropic drugs.

        During the years of introduction of the first generation of psychotropic drugs psychiatry was straggling to reconcile widely different orientations (from social to psychodynamics) within the field. The purpose of the first widely accepted consensus-based classifications was the creation of a common language. To accommodate the different orientations in psychiatry, the diagnostic categories in both consensus-based classifications are broad, and by accommodating the different forms of disease by a limited number of diagnoses, each of the diagnostic categories are heterogeneous to the extent that their predictive validity are low. The problems with consensus-based classifications, and especially with the DSM-III and its successors, are compounded by their rapid success. By providing the diagnostic endpoints used in the clinical development, and the approved indications in the clinical use of psychotropic drugs, consensus-based classifications have become one of the major obstacles to the identification of the treatment responsive forms of illness.

        Another major obstacle is the sensitive scales used in the demonstration of the therapeutic effectiveness of psychotropic drugs. Rating scales can be sensitized by the omission of psychopathological symptoms relevant to psychiatric nosology, which are not influenced by treatment, and / or by the retaining of only those items (variables) of a scale which show the largest changes. Montgomery and Asberg's depression scale (Perris 1986) was derived by such compromises from the CPRS. While the use of a sensitive scale helps to demonstrate therapeutic effectiveness in the shortest possible time in the smallest number of patients, the omission of some psychopathologic symptoms (variables), relevant to psychiatric nosology, precludes the possibility of finding any relevant information to the identification of the treatment responsive forms of illness by meta-analyses in the vast data bases.


Attempts to resolve heterogeneity

        Information collected in the development of psychotropic drugs during the past four decades have not provided any orientation points for resolving the heterogeneity within the diagnostic categories of schizophrenia and depression. Attempts to identify the treatment responsive form(s) of illness by linear regression equations, biological markers, pharmacological load tests and / or biochemical indicators yielded inconsistent findings (Ban 1987; 1974, 1981; Bowers 1984). By none of these means was it possible to predict which patient will respond to treatment and which patient will remain refractory.

        The contention that secondary amine antidepressants, like desipramine and nortriptyline, are more suitable for the treatment of depression with motor retardation (Kielholz 1968) (79), than tertiary amines, i.e., imipramine and amitriptyline, was not borne out by evidence. Hypotheses that depression with low urinary 3-methoxy-4-phenylglycol (MHPG) (the final metabolic end product of NE) concentrations, respond to selective NE reuptake blockers, whereas depression with low 5-hydroxy-indole-acetic acid (5HIAA) (the final metabolic end product of serotonin) concentrations in the cerebrospinal fluid (CSF), respond to selective 5-HT reuptake blockers, could not be substantiated in clinical experiments (Potter, Scheinin, Golden et al. 1985; Schatzberg 1998). By the mid-1980s it was revealed that both, desipramine, a selective NE reuptake inhibitor, and zimelidine, a 5-HT reuptake inhibitor decreased both MHPG and 5HIAA concentrations in the CSF (Potter, Scheinin, Golden et al. 1985). To date, no consistent relationship could be revealed between the NE and 5-HT blocking potencies of antidepressants and therapeutic effects.

        The contention that schizophrenic patients with excitement and agitation respond more favorably to "sedative,” phenothiazines (neuroleptics), like chlorpromazine, methotrimeprazine, and thioridazine, whereas schizophrenic patients with withdrawal and retardation respond more favorably to "activating,” "incisive,” phenothiazines (neuroleptics), like trifluoperazine, prochlorperazine and perphenazine (Lambert 1998), were not borne out by evidence (Cawley 1967; Marks 1962; Platz, Klett and Caffey 1967). The difference between "sedative" and "incisive" neuroleptics is in the frequency and severity of the dopamine-D2 receptor blockade induced extrapyramidal manifestations. In "sedative" neuroleptics, extrapyramidal signs are counteracted by relatively strong central anticholinergic effects. There is a striking similarity between the distinction of "sedative" versus "incisive" and "atypical" versus "typical" neuroleptics. The signal difference between the two distinctions is that the former (sedative vs incisive) is based on the ratio between affinities to the dopamine-D2 and muscarinic cholinergic receptors, whereas the latter (atypical vs typical) is based on the ratio between affinities to the dopamine-D2   and   serotonin-5HT2A   receptors. Accordingly, in "sedative" neuroleptics, the dopamine-D2 receptor blockade is mitigated by the blockade of the central muscarinic-cholinergic receptors, whereas in "atypical" neuroleptics, by the blockade of the serotonin-5HT2A receptors. Despite the clinical experience that treatment in many patients with an atypical neuroleptic need to be supplemented with a typical neuroleptic, atypical neuroleptics are frequently employed as the primary choice of treatment in schizophrenia (Stahl 1999). Although findings that "negative" symptoms of schizophrenia respond more favorably to atypical than to typical neuroleptics are inconsistent (Breier, Buchanan, Kirkpatrick et al. 1994; Meltzer 1996), there is steadily accumulating evidence that many treatment refractory schizophrenics fare better when switched from a typical to an atypical neuroleptic (Stahl 1999; Meltzer 1996; Kane, Honigfeld, Singer and Meltzer 1988).


Towards a new methodology

        By focusing attention on the treatment refractory schizophrenic population, atypical neuroleptics revived interest in psychopharmacological studies with Leonhard's classification (Astrup 1959; Leonhard 1957). Findings in these studies (from the late 1950s and early 1960s) indicate that responsiveness in the different forms and subforms of schizophrenia differs to the extent that only about one of four patients with systematic schizophrenia, whereas about three of four patients with unsystematic schizophrenia respond favorably to neuroleptics (Astrup 1959; Fish 1954). In one of these studies the response rate in affect-laden paraphrenia was about 85%, whereas it was below 50% in the systematic paraphrenias, and below 25% in the systematic hebephrenias (Fish 1954; Ban 1990). In keeping with these findings are case reports (from the early 1980s) indicating that discontinuation of neuroleptic treatment had no detectable effect in a couple of patients with shallow hebephrenia (Kelwala and Ban 1981a); and that administration of neuroleptics aggravated psychopathology in a patient with periodic (febrile) catatonia (Kelwala and Ban 1981b). In keeping also are the findings that neuroleptic dose requirements differ in the different forms and subforms of schizophrenia (Ban, Guy and Wilson 1984). Catatonic patients may respond favorably to very low doses, as reported in the early years of neuroleptic treatment, but develop severe neurotoxicity if the dose is increased (Baruk and Launay 1964).

        The notion that in some forms of schizophrenia neuroleptic treatment is not just ineffective, but may even be harmful, was supported by a multinational survey of tardive dyskinesia (TD) (Guy, Ban and Wilson 1985). In this survey the overall prevalence rate of TD was 13.6% with a 53% prevalence in neuroleptic refractory shallow hebephrenia, and a 4.5% prevalence in neuroleptic responsive unsystematic schizophrenia.

        In another survey, nine of 10 patients with unsystematic schizophrenia responded favorably, whereas nine of 14 patients with systematic schizophrenia responded unfavorably to neuroleptic potentiation by lithium salts. In the same survey it was noted that five of the 14 patients with systematic schizophrenia developed neurotoxicity on the combination, while in patients with unsystematic schizophrenia, neurotoxicity was not encountered at all (Prakash, Kelwala and Ban 1982).


Identification of treatment responsive forms of illness

        Recognition that in some forms of schizophrenia neuroleptics are not just ineffective, but also harmful, raised concerns about the indiscriminate use of psychotropic drugs. It also triggered interest in the identification of forms of illness which are covered up in classifications used in the clinical development of psychotropics. One of the many forms of illness identified during this process was "vital depression," a   diagnostic   concept   introduced   by   Kurt Schneider (Prakash, Kelwala and Ban 1982), characterized by corporization, disturbance of vital balance, the feeling of loss of vitality, etc. The diagnostic concept of vital depression was instrumental in the recognition of imipramine's antidepressant effect (National Institute of Mental Health, Psychopharmacology Service Center Collaborative Study Group 1964). Nevertheless, it is covered up in the DSM-III (also in DSM-III-R and DSM-IV) to the extent that even if all the possible symptoms and signs of major depression are displayed, one still would not know whether the patient qualifies for vital depression.

        The idea for developing composite diagnostic evaluations is intimately linked to the need for uncovering forms of illness covered up by consensus-based classifications. A composite diagnostic evaluation is a polydiagnostic evaluation with a structured interview based on an integrated criteria list (Ban 1989; Gaszner and Ban 1998).

        The prototype of composite diagnostic evaluations is CODE-DD, the composite diagnostic evaluation of depressive disorders. It consists of an integrated criteria list of 90 variables ("codes"), which can provide diagnoses in all the component diagnostic systems; a computer prompted structured interview with 90 sets of questions which can provide decisions, through dichotomous answering about the "presence" or "absence" of each "code"; and decision trees, i.e., specially devised algorithms, which can assign diagnoses in 25 systems of diagnostic classifications and determine the severity of the disease (Ban 1989).

        Composite diagnostic evaluations represent the first step towards the development of a methodology for the delineation of the nosologic (also psychopathologic) profile of psychotropic drugs. Composite evaluations provide a methodology for the study of the differential effect of drugs in different forms of illness, and for the identification of the treatment responsive form(s) of illness to psychotropic drugs.



AMDP. Das AMDP-System. Manual zur Dokumentation psychiatrischer Befunde. 3 Aufl. Berlin. Springer, 1979.

American Psychiatric Association. DSM-III. Diagnostic and Statistical Manual of Mental Disorders. Third Edition. Washington; 1980.

AMP. Das AMP-System. Manual zur Dokumentation psychiatrischer Befiinde. Berlin: Springer, 1971.

Angst J. Acci6n clinica de la imipramina. In: Tofranil. Berea: Stampfli y Cia; 1970, pp. 1-85.

Åsberg M, Perris C, Schalling D, Sedvall G, editors. The CPRS-Development and application of a psychiatric rating scale. Acta Psychiatr Scand 1978;(Suppl 271):69.

Astrup C. The effects of ataraxic drugs on schizophrenic subgroups related to experimental findings. Acta Psychiatr Scand 1959;34(Suppl 36):388-93.

Axelrod J, Whitby LG, Hertting G. Effect of psychotropic drugs on the uptake of H3-norepinephrine by tissues. Science 1961;133:383-4.

Ayd FJJ Jr, Blackwell B, editors. Discoveries in Biological Psychiatry. Philadelphia: Blackwell; 1970.

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

Ban TA. - Schizophrenia. A Psychopharmacological Approach. Springfield: Thomas, 1972.

Ban TA. - Depression and the Tricyclic Antidepressants. Montreal; Ronalds Federated, 1974.

Ban TA. - Psychopharmacology of Depression. Basel: Karger, 1981.

Ban TA. Prolegomenon to the clinical prerequisite: Psychopharmacology and the classification of mental disorders. Prog Neuropsychopharmacol Biol Psychiatry 1987;11(5):527-80.

Ban TA. CODE-DD Composite Diagnostic Evaluation of Depressive Disorders. Brentwood: JM Productions; 1989.

Ban TA. Clinical pharmacology and Leonhard's classification of endogenous psychoses. Psychopathology 1990;23:331-8.

Ban TA. They used to call it psychiatry. In: Interviews by David Healey. London: Chapman & Hall; 1996, pp. 587-620.

Ban TA. Selection of pharmacological treatment in depressive illness. Current findings within a historical frame of reference. Neuropsychopharmacologia Hungarica 1999;1:3-11.

Ban TA, Guy W, Wilson WH. Description and distribution of the subtypes of schizophrerha based on Leonhard's classification. Psychiatr Dev 1984;3:179-99.

Baruk H, Launay J. Les neuroleptiques et la loi des stades. Encephale 1964;53:180-3.

Beres ZS. Az antipsichotikumok receptor interakcioja, farmakodinamikaja es klinikai hatasok. Neuropsychopharmacologia Hungarica 1999;I:45-6.

Berger FM. As I remember. In: Ban TA, Healy D, Shorter E, editors. The Rise of Psychopharmacology and The Story of CINP (pp. 59-67). Budapest: Animula; 1998.

Bernard C. Des effets physiologiques de la morphine et leur combination avec ceux de chloroform. Bulletin therapeutique 1869;77:242-56.

Besendorf H, Pletscher A. Beeinflussung zentraler Wirkungen von Reserpin and 5-Hydroxytryptamin dutch lsonicotinsaurehydrazine. Helv Physiol Acta 1956;14:383-90.

Bischoff S, Bruinink A, Gunst F, Krauss J, Schauf M, Vassaut A, Maitre L. Can brain region-selective dopamine (DA) receptor blockers preferentially act on schizophenic subtypes? In: Darcourt RP, Pringuey D, Mendlewicz J, editors. 18th Collegium Internationale NeuroPsychopharmacologicum Congress Part One. New York: Raven Press; 1992, pp. 23-5.

Bolden-Watson C, Richelson E. Blockade by newly developed antidepressants of biogenic amine upake into rat brain synaptosomes. Lie Sci 1993;57:1023-29.

Bonner TI, Buckcley NJ, Young AC, Brann MR. - Identification of a family of muscarinic acetylcholine receptor genes. Science 1987;237:527-32.

Bowers MB. Family history of CSF homovanillic acid pattern during neuroleptic treatment. Am J Psychiatry 1984;41:296-8.

Breier A, Buchanan RW, Kirkpatrick B, Davis OR, Irish D, Summerfelt A, Carpenter WT Jr. Effects of clozapine on positive and negative symptoms in outpatients with schizophrenia. Am J Psychiatry 1994;151:20-6.

Brodie BB, Shore PA, Pletscher A. Limitations of serotonin-releasing activity to those Rauwolfia alkaloids possessing tranquilizing action. Science 1956;123:992-3.

Cade JFJ. The story of lithium. In: Ayd FJ Jr, Blackwell B, editors.  Discoveries in Biological Psychiatry. Philadelphia: Lippincott; 1970, pp. 218-29.

Caldwell AE. Origins of Psychopharmacology from CPZ to LSD. Springfield: Thomas; 1970.

Carlsson A. Neuropsychopharmacology. In: Ban TA, Healy D, Shorter E, editors. The Rise of Psychopharmacology and The Story of CINP. Budapest. Animula; 1998, pp. 124-5.

Carlsson A, Lindquist M. Effect of chlorpromazine or haloperidol on formation of 3 -methoxytyram ne and normetanephrine in mouse brain. Acta Pharmacol Toxicol 1963;20:140-4.

Casey JF, Bennett IF, Lindley CJ, Hollister LE, Gordon MH, Springer NN. Drug therapy in schizophrenia: a controlled study of the relative effectiveness of chlorpromazine, promazine, phenobarbital and placebo. Arch Gen Psychiatry 1960;2:210-20.

Casey JF, Lasky JJ, Klett CJ, Hollister LE. Treatment of schizophrenic reactions with phenothiazine derivatives. Amer J Psychiatry 1960;117:97-105.

Cawley RH. The present status of physical methods of treatment of schizophrenia. In: Coppen A, Walks A, editors. Recent Developments in Schizophrenia. Ashford: Headley Brothers; 1967.

Compendium of Pharmaceuticals and Specialties. The Canadian Reference for Health Professionals. 34th edition. Toronto: CK Productions; 1999.

Costa E, Garattini S, Valzelli L. Interactions between reserpine, chlorpromazine and imipramine. Experientia 1960;15:461-63.

Crane GE. The psychiatric side effects of iproniazid. American Journal of Psychiatry 1956;112:494-501.

Creese I, Burt DR, Snyder SH. Dopamine receptor binding: differentiation of agonist and antagonist states, with 3H-dopamine and 3H-haloperidol. Life Sciences 1975;17:993-1002.

Creese I, Burt DR, Snyder SH. Dopamine receptor binding predicts clinical and pharmacological potencies of antischizophrenic drugs. Science 1977;192;596-8.

Davis JM. Maintenance therapy in psychiatry. I. Asuncion Schizophrenia. Am J Psychiatry 1975;132:1237-45.

Davis JM, Wang Z, Janicak PG. A quantitative analysis of clinical drug trials for the treatment of affective disorders. Psychopharmacol Bull 1993;29:175-81.

Delay J, Deniker P, Harl JM. Utilisation en thempeutique psychiatrique dune phenothiazine d'action centrale elective (4560 RP). Ann Mediciopsychol 1952;110:112-17.

Engel J. The mode of action of psychotropic drugs. In: Advances in the Drug Therapy of Mental Illness. Geneva: World Health Organization; 1976, pp. 51-60.

Ereshefsky L. Pharmacologic and pharmacokinetic considerations in choosing an antipsychotic. J Clin Psychiatry 1999;60(Suppl 10):S20-S30,.

Fawcett J, Barkin RL. Efficacy issues with antidepressants. J Clin Psychiatry 1997;58(Suppl 6):S32-S39.

Fish EJ. The influence of the tranquilizers on the Leonhard schizophrenic syndromes. Encephale 1954;53:245-9.

Flaherty JA. The psychiatric use of isonicotinic acid hydrazide: a case report. Delaware med J 1952;24:298-300.

Frazer A. Antidepressants. J Clin Psychiatry 1997;58(Suppl 6):9-25.

Garattini S. The role of independent science in psychopharmacology. In: Ban TA, Healy D, Shorter E, editors. The Rise of Psychopharmacology and The Story of CINP. Budapest: Animula; 1996, pp. 135-57.

Glowinski J, Axelrod J. Inhibition of uptake of titriated noradrenaline in the intact rat brain by imipramine and structurally related compounds. Nature 1964;204:1318.

Guy W. ECDEU Assessment Manual for Psychopharmacology. - Pub No (ADM). (DREW No. 76-338). (Rockville: National Institute of Mental Health). Washington: United States Government Printing Office; 1976.

Guy W, Ban TA, editors and translators. The AMD-System. Manual   for   the   Assessment   and   Documentation   in Psychopathology. Berlin: Springer; 1982.

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

Gaszner P, Ban, TA. CODE-HD Composite Diagnostic Evaluation of Hyperthymic Disorders. Budapest: Animula; 1998.

Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry 1960;23:56-62.

Healy D. The Antidepressant Era. Cambridge: Harvard University Press; 1997.

Hollister LE. The beginning of psychopharmacology. A personal account. In: Ban TA, Healy D, Shorter E, editors. The Rise of Psychopharmacology and The Story of CINP. Budapest: Animula; 1978, pp. 41-44.

Janssen PAJ. Haloperidol and the butyrophenones: The early years. In: Ban TA, Ray OS, editors. A History of the CINP. Brentwood: JM Productions; 1996. pp. 440-8.

Janssen PAJ. Function and dysfunction of the basal ganglia.  In: Ban TA, Healy D, Shorter E, editors. The Rise of Psychopharmacology and The Story of CINP. Budapest: Animula; 1998, pp. 63-8.

Kane J, Honigfeld G, Singer J, Meltzer H. Clozapine for the treatment resistant schizophrenic: a double-blind comparison with chlorpromazine. Arch Gen Psychiatry 1988;45:789-96.

Kelwala S, Ban TA. Is maintenance neuroleptic therapy necessary in shallow hebephrenia? J Clin Psychiatry 1981a;42:12.

Kelwala S, Ban TA. - Febrile catatonia sustained by neuroleptics. J Univ Ottawa 1981b;6:135.

Kielholz P. Die Behandlung endogener Depressionen mit Psychopharmaka. Deutsche Chirurg Med Wschr 1968;93:701-3.

Klein D, Davis J. Diagnosis and Drug Treatment of Psychiatric Disorders. Baltimore: Williams and Wilkins; 1969.

Klerman GL, Cole J. Clinical pharmacology of imipramine and related antidepressant compounds. Pharmacol Rev 1965;17:101-41.

Kuhn R. Uber die Behandlung depressives Zustande mit einem iminodibenzylderivat (G 22,355). Schweiz med Wschr 1957;87:1135-40.

Kurland A. Reserpine. In: Ban TA, Ray OS, editors. A History of CINP (pp. 405-409). Brentwood: JM Productions; 1996.

Lambert PA. Chlorpromazine: A true story by the progress effected by the drug. In: Ban TA, Heal D, Shorter E, editors. The Rise of Psychopharmacology and The Story of CINP. Budapest: Animula; 1998, pp. 237-43.

Leonhard K. - Aufteilung der endogenen Psycosen. Berlin: Akademie; 1957.

Lewis WH. Iatrogenic psychotic depressive reaction in hypertensive patients. Am J Psychiatry 1971;124:1416-17.

Lucas JJ, Hen R. New players in the 5-HT receptor field; genes and knockout. Trends Pharmacol Sci 1995;16:246-52.

Marks J. Predrug behavior as a predictor of response to phenothiazines among schizophrenics. J Nery Ment Dis 1962;137:597-601.

Meltzer HY. Atypical antipsychotic drugs. In: Bloom FE, Kupfer D, editors. Psychopharmacology: The Fourth Generation of Progress. New York: Raven Press; 1996, pp.1277-86.

Moreau de Tours, J.   Memoire sur le traitement des hallucinations par le Datura stramonium. Paris: Rouvier et Le Bouvier; 1841.

National Institute of Mental Health, Psychopharmacology Service Center Collaborative Study Group. Phenothiazine treatment in acute schizophrenia: effectiveness. Arch Gen Psychiatry 1964;10:246-61.

Overall J, Gorham DR. The brief psychiatric rating scale. Psychological Reports 1962;10:799-812.

Perris C. Rating depression with a subscale of the CPRS. In: Sartorius N, Ban TA, editors. Assessment of Depression. Berlin: Springer; 1986, pp. 90-107.

Physicians' Desk Reference. 53rd edition. USA: Medical Economics Data Publishing Company; 1999.

Platz AR, Klett J, Caffey EM Jr. Selective drug action related to schizophrenic subtypes. (A comparative study of carphenazine, chlorpromazine, and trifluoperazine). Dis New Syst 1967;28:601-5.

Pletscher, A. - On the eve of the neurotransmitter era in biological psychiatry. In: Ban TA, Healy D, Shorter E, editors. The Rise of Psychopharmacology and The Story of CINP. Budapest: Animula; 1998, pp. 110-15.

Pletscher A, Shore PA, Brodie BB. Serotonin release as a possible mechanism of reserpine action. Science 1955;122:374-5.

Pletscher A, Shore PA, Brodie BB. Serotonin as a mediator of reserpine action in the brain. J Pharmacol Exp Ther 1956;116:84-9.

Poldinger W, Wider F. Index Psychopharmacorum. Bern: Hans Huber; 1990.

Potter MZ, Scheinin M, Golden RN, Rudorfer MV, Cowdry RW, Calil HM, Ross RJ, Linnoila M. Selective antidepressants and cerebrospnal fluid. Arch Gen Psychiatry 1985;42:1171-7.

Prakash R, Kelwala S, Ban TA. Neurotoxicity with combined administraton of lithium and a neuroleptic. Compr Psychiatry 1982;23:567-71.

Richelson E. Biological basis of depression and therapeutic relevance. J Clin Psychiatry 1991;52:(Suppl 6):S4-S10.

Richelson E. Receptor pharmacology of neuroleptics: relation to clinical effects. J Clin Psychiatry 1999;60(Suppl 10):S5-S14.

Richelson E, Nelson A. Antagonism by neuroleptics of neurotransmitter receptors of normal human brain in vitro. Eur J Pharmacol 1984;103:197-204.

Richelson E, Souder T, Acuna J, et al. - Binding studies with some new neuroleptics at human brain receptors. Biol Psychiatry 1997;41(Suppl 7):228.

Schatzberg AF. Noradrenergic versus serotonergic antidepressants: Predictors of treatment response. J Clin Psychiatry 1998;59(Suppl 14):15-18.

Selikoff IJ, Robitzfk EH, Orenstein GG. Treatment of pulmonary tuberculosis with hydrazine derivatives of isonicotinic acid. JAMA 1952;150:973-80.

Shorter E. A History of Psychiatry. New York: John Wiley & Sons; 1997.

Sokoloff P, Schwartz JC. Novel dopamine receptors half a decade later. Trends Pharmacol Sci 1995;16:270-5.

Stahl SM. Selecting an atypical antipsychotic by combining clinical experience with guidelines from clinical trials. J Clin Psychiatry 1999;(Suppl 10):S31-S41.

Usdin E, Efron DH, editors. Psychotropic Drugs and Related Compounds.  PHSP No. 1589.  Washington:  US Government Printing Office; 1972.

World Health Organization. International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM). Geneva; 1977.




I am grateful to Olaf Fjetland for his contributions in adopting this text from the published original and especially for converting referencing and references.


*Based on an article published with same title in Psychiatr Biol 1999;7(4): 177-89.


November 25, 2021