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
Neuropharmacology (Volume Three): 2. Psychotropic drugs
(Bulletin 41)


          Psychotropic drug development has been closely linked to neuropharmacological research and for about 30 years it was dominated by studies on the effect of drugs on neurotransmitter mediated signal transduction in the brain. 




          Developments in the neuropharmacology of neuroleptics(antipsychotics) began in the mid-1950s with the demonstration of a linear relationship between the sedative and the anti-serotonin (5HT) effect of chlorpromazine (CPZ) and its congeners (Gyermek, Lazar and Csak 1956).

          In the late 1950s neuroleptics were divided into “sedative,” or CPZ-type, and “incisive,” or prochlorperazine-type drugs (Lambert, Perrin, Revol et al. 1959).There was no difference in therapeutic efficacy between the two groups, but “incisive” neuroleptics were more potent on a mg per kg basis and produced more frequent and severe extrapyramidal signs (EPS) (Freyhan 1961).

          In the early 1960s dopamine (DA) receptor blockade was implicated in the mode of action of neuroleptic drugsand antagonism to the effects of amphetamine, a dopamine agonist,was used as a pharmacological screen for the detection of potential antipsychotic drugs (Carlsson and Lindqvist 1963; Haase and Janssen 1965).By the mid-1960s “incisive” neuroleptics dominated the treatment of schizophrenia. During the 1970s their dominance was perpetuated by the demonstration that they block dopamine-D2 receptors and the formulation of the DA-hypothesis of schizophrenia (Seeman, Chan-Wong, Tedesco and Won 1975; Seeman, Lee, Chan-Wong and Wong 1976; Snyder 1976; Snyder, Creese and Burt 1975).

          In the late 1970s the steadily growing number of patients with tardive dyskinesia turned interest to thioridazine, a piperidyl side chain containing sedative neuroleptic. Treatment with thioridazine induced considerably less frequent and severe EPS than treatment with incisive neuroleptics, but thioridazine produced cardiac conductance changes (Ban and St. Jean 1964; Kelly, Fay and Laverty 1963). 

          In the early 1970s clozapine, a substance with an even lesser propensity to induce EPS than thioridazine, was introduced in Europe (Angst, Jaenicke, Padrutt and Scharfetter 1971).  In the mid-1970s clozapine was withdrawn from clinical use (in most countries) because of 18 cases of agranulocytosis, including eight fatal cases, encountered in Finland (Idanpaan-Heikkila, Alhave, Olkimora and Palva 1975).

          In the mid-1980s clozapine was re-introduced and became the prototype of a series of so-called “atypical neuroleptics.” Atypical neuroleptics differ from “typical neuroleptics” like haloperidol by their lesser propensity to induce EPS and higher affinity to serotonin 5HT2A receptors than to dopamine-D2 receptors. They also have a broader receptor profile than “typical neuroleptics.” Thus, “atypical neuroleptics” are similar to CPZ-type of “sedative neuroleptics” drugs with a broad receptor profile and higher affinity to serotonin-5HT2 receptors than to dopamine-D2 receptors (Lehmann and Ban 1997).




          Developments in the neuropharmacology of iproniazid-like antidepressants began in the mid-1950s with the findings that iproniazid, a monoamine oxidase (MAO) inhibitor (MAOI), increased 5HT and norepinephrine (NE) in the brain and produced euphoria in some patients treated for tuberculosis (Selikoff, Robitzek and Orenstein 1952).In the late 1950s several MAOIs were introduced in the treatment of depression. By the early 1960s hepatotoxicityand hypertensive criseswere encountered with some of these drugs (Blackwell 1963; Zimmerman, Rosenblum, Korn and Feldman 1959).

          Deprenyl (selegiline), the first selective inhibitor of the Type B iso-enzyme of MAO, was developed in the mid-1960sand moclobemide, a selective inhibitor of the Type A iso-enzyme, in the mid-1970s (Ban 2001; Birkmayer, Riederer, Youdim and Linauer 1975; Wiesel, Raafaub and Kettler 1985).  

          Developments in the neuropharmacology of imipramine-like antidepressants began in the late 1950s with the demonstration that imipramine, a tricyclic substance, has antihistaminic, anticholinergic, noradrenergic and serotonergic properties (Domenjoz and Theobald 1959).It reversed reserpine-induced sedation, hypothermia, ptosis and diarrhea (Ban 1974, 1981).In the early 1960s reserpine reversal was introduced as a pharmacological screen for the identification of imipramine-like antidepressants. About the same time, both imipramine and amitriptyline, the two available tricyclic antidepressants at the time were found to block NE reuptake into neurons (Axelrod, Whitby and Hertting 1961). Since reserpine-reversal with desipramine (DMI), the demethylated metabolite of imipramine, a selective NE re-uptake blocker, was more potent than with imipramine and imipramine’s reserpine reversal was suspended by the administration of α-methyl-metatyrosine, a substance that blocked the formation of NE, the possibility was raised that NE and not 5HT is the neurotransmitter involved in the antidepressant effect of these drugs (Sulser 1998).In the mid-1960s the catecholamine hypothesis of affective disorders was formulated and several NE re-uptake inhibitor antidepressants (NARIs), including DMIand maprotiline, were introduced (Amin, Brahm, Bronheim, Klingner, Ban and Lehmann 1973; Ban and Lehmann 1962; Schildkraut 1965). Then, in the 1970s, it was recognized that NE re-uptake inhibitors convert into 5HT reuptake inhibitors by halogenation (Carlsson, Berntsson and Corrodi 1997).  It was also shown that an intact 5HT system was a prerequisite for ß-adrenergic receptor down regulation, a common characteristic in the mode of action of DMI-type of antidepressants (Sulser 2004). Simultaneously with this development, the pharmacological concept of depression was extended by the introduction of the “behavioral despair-learned helplessness, swimming survival - test” in the screening for antidepressants. The new test was based on a “stress model,” instead of the reserpine-model of depression.   

           In 1980 a correspondence was shown between imipramine binding sites and 5HT binding sites in the human plateletand in the hypothalamus of the rat (Langer, Moret, Raisman et al. 1980; Paul, Rehavi, Skolnick and Goodwin 1980).Introduction of a series of selective 5HT re-uptake inhibitors (SSRIs) followed and by the 1990s SSRIs became the main stream in the treatment of depression (Baghai, Grunze and Sartorius 2007).  By the end of the 20th century with the introduction of venlafaxine, a non-selective, but prevailingly 5HT re-uptake inhibitor, a full complement of monoamine re-uptake inhibitors was completed (Ban 2004).With the introduction of reboxetine, a selective NE reuptake inhibitor, the circle opened in the early 1960s with the introduction of DMI was reopened (Ban, Gaszner, Aguglia, et al 1998).


          Drugs used in the treatment of depression at the end of the 20th century:

·SSRIs (citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline);

·NARIs (amoxapine, lofepramine, maprotiline,nortriptyline, reboxetine, viloxazine);

·double, 5HT and NE, re-uptake inhibitors (SNRIs) (amitriptyline, dibenzepine, dosulepine/dothiepin, doxepin, duloxetine, imipramine, melitracen, milnacipran, protriptyline); serotonin modulators (SMAs) (trazodone and nefazodone);

·noradrenergic and selective   serotonergic drugs (NaSSAs)(mianserin and mirtazepine);

·a DA receptor antagonist (trimepramine); a dopamine and NE re-uptake inhibitor (DNRI) (bupropion);

·and a glutaminergic modulator (GM) (tianeptin.)


          Anxiolytic Sedatives


          The development of anxiolytic sedatives began in 1950 with the synthesis of meprobamate,a propanediol preparation that depressed multineuronal reflexes by accelerating acetylcholine breakdown at the synaptic cleft (Berger 1954; Lehmann and Ban 1970) The substance was introduced in 1955 and became the first “blockbuster drug” (Tone 2009).

          In the early 1960s chlordiazepoxide, diazepam and several other benzodiazepine preparations were introduced and within a few years virtually replaced meprobamate in the treatment of anxiety (Cohen 1970).In the late 1970s benzodiazepine receptors were identified and it was shown that benzodiazepines acted on the GABA neurotransmitter system (Baastrup and Squires 1978; Sigel 2002).During the 1990s SSRIs replaced benzodiazepines as the primary treatment of anxiety disorders.


          Mood Stabilizers


           The development of mood stabilizers began in the late 1940s with the re-introduction of lithium into psychiatry by John Cadeand the demonstration in the mid-1960s that lithium has mood stabilizing effects (Baastrupand Schou 1967; Cade 1949).

          In the mid-1970s, based on clinical observations, it was suggested that the anticonvulsants carbamazepineand sodium valproate could also stabilize mood (Lambert, Caraz, Borselli and Bouchardy 1975; Okuma, Kishimoto, Inoe et al. 1973).

          In the late 1970s it was discovered that carbamazepine-controlled amygdala kindled seizures and in 1980 it was demonstrated that in the action of sodium valproate the GABA system was involved (Evans, von Zerssen, Kessling et al. 1980).

          In the 1990s several more drugs were introduced as mood stabilizers, including the anticonvulsant lamotrigine, as well as some atypical neuroleptics, like quetiapine and risperidone (Altamura, Salvador, Malara et al. 2003; Calabrese, Suppes, Bowden, et al. 2000; Healy2008; Vieta, Gasto, Colom et al.2006).


          Cognitive Enhancers


          The development of cognitive enhancers began in the mid-1950s with the discovery that tetrahydroaminoacridane (THA), a cholinesterase inhibitor, controlled aberrant-behavior induced by atropine, an anticholinergic drug. Interest in THA was revived in the 1970s with William Summers report on the effect of THA in Alzheimer’s disease (AD)and with the demonstration that physostigmine, a short acting cholinesterase inhibitor, enhanced cognition in Stanford students (Sommers 2006).  In the 1990s several cholinesterase inhibitors, including galantamine,rivastigmine, and donepezil were introduced in the treatment of AD (Finkel 2004; Loneman, Green, Kirby et al. 2008; Razay and Wilcock 2008).




Altamura DB, AC, Salvadori D, Madaro D, Santini A, Mundo E. Efficacy and tolerability of quetiapine in the treatment of bipolar disorde: preliminary evidence from a 12-month open label study. J Affect Dis 2003; 76: 267-71.

Amin MM, Brahm E, Bronheim LA, Klingner A, Ban TA, Lehmann HE. A double-blind comparative clinical trial with Ludiomil (Ciba 34,276B) and amitriptyline in newly admitted depressed patients. Curr Ther Res 1973; 15: 691-73.

Angst J, Jaenicke U, Padrutt A, Scharfetter C. Ergebnisse eines doppelblindversuch von HF-1854 (8-Chlor-11-[4-methyl-1-piperazeninyl]-5H-dibenzo [b,e] (1,4) diazepin) im Vergleich zu Levomepromazin. Pharmacopsychiatry 1971; 4: 192-200.

Axelrod J, Whitby LB, Hertting G. Effect of psychotropic drugs on the uptake of 3H norepinephrine by tissues. Science 1961; 133: 383-4.

Baastrup PC, Schou M. Lithium as a prophylactic agent: Its effect against recurrent depression and manic depressive psychosis.  Arch Gen Psychiatry 1967; 16: 162-72.

Baastrup C, Squires RF. Brain specific benzodiazepine receptors. The British Journal of Psychiatry 1978; 133: 249 – 60.

Baghai TC, Grunze H, Sartorius N. Antidepressant medications and other treatments of depressive disorders: a CINP Task Force report based on a review of evidence. The International Journal of Neuropsychopharmacology 2007; 10 (Supplement 1): S1-S207.

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

Ban TA. Pharmacotherapy of depression: a historical analysis.  Journal of Neural Transmission 2001; 108: 707-16

Ban TA. Neuropsychopharmacology and the history of pharmacotherapy in psychiatry. A review of developments in the 20th century. In: Ban TA, Healy D, Shorter E, editors. Reflections on Twentieth-Century Psychopharmacology.  Budapest: Animula; 2004. p. 697-720.

Ban TA, Gaszner P, Aguglia E, Batista R, Castillo A, Lipcsey A, Macher J-P, Torres Ruiz A, Vergara L. Clinical efficacy of reboxetine: A comparative study with desipramine with methodological considerations. Human Psychopharmacology 1998; 13 (Supplement): S29-S39.

Ban TA, Lehmann HE. Clinical trial with desmethylimipramine (G-35020), a new antidepressive compound. Canadian Medical Association Journal 1962; 1020-1

Ban TA, St.Jean A. The effect of phenothiazines on the electrocardiogram. J Can MedAssoc 1964; 91; 537-40.

Berger FM. The pharmacological properties of 2-methyl-2-n-propyl -1, 3 propanediol dicarbamate (Miltown), a new interneuronal blocking agent. J Pharmacol Exp Ther 1954; 112: 413-23.     

Birkmayer W, Riederer P, Youdim MB, Linauer W. The potentiation of the anti-akinetc effect after L-dopa treatment by an inhibitor of MAO-B. J Neurol Transm 1975; 36: 303-16. 

Blackwell B. Hypertensive crisis due to MAOI. Lancet 1963; 2: 849-53.

Cade J. Lithium salts in the treatment of psychotic excitement.  Med J Aust. 1949; 2; 349-52.

Calabrese J, Suppes T, Bowden C, Sachs GS, Swann AC, McElroy SL, Kusumaker V, Ascher JA, Earl NL, Greene PL, Monaghan ET. A double-blind placebo controlled prophylaxis study of lamotrigine`in rapid cycling bipolar disorsder. Lamictal 614 Study Group. J Clin Psychiatry 2000; 61:  841-50.

Carlsson A, Berntsson P, Corrodi H. Zimelidine. Belgian Patent Number 781.105, March 23, 1972. In: Healy D. The Antidepressant Era. Cambridge: Harvard University Press; 1997. p. 201.

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

Cohen IM. The Benzodiazepines. In: Ayd FJ, Blackwell B, editors. Discoveries in Biological Psychiatry. Philadelphia/Toronto: JP Lippincott Company; 1970. p. 130-41.

Domenjoz R, Theobald W. Zur Pharmacolgie des Tofranil. Arch Int Pharmacodyn 1959; 120: 450-89.

Emrich HM, von Zerssen D, Kissling W, Möller HJ, Windorfer A. Effect  of sodium valproate on mania: The GABA hypothesis of affective disorders. Arch Psychiatr Nervenkr 1980; 229: 1-16.

Finkel SI. Effects of rivastigmine on behavioral and psychological symptoms of dementia in Alzheimer’s disease. Clin Ther 2004; 26: 980-90.

Freyhan F. The influence of specific and non-specific factors on the clinical effects of psychotropic drugs. In: Rothlin E, editor. Neuropsychopharmacology. Amsterdam/London/New York/Princeton: Elsevier Publishing Company; 1961. p. 189-203.

Gyermek L, Lázár GT, Csák Zs. The antiserotonin action of chlorpromazine and some other phenothiazine derivatives.  Arch Int Pharacodyn 1956; 107: 62-74.

Haase AJ, Janssen PAJ. The Action of Neuroleptic Drugs.  Amsterdam: North Holland Publishing House; 1965

Healy D. Mania. A Short History of Bipolar Disorder. Baltimore: The Johns Hopkins University; 2008. p. 135-60.

Idanpaan-Heikkila J, Alhave E, Olkimora M, Palva J. Clozapine and agranulocytosis.  Lancet 1975; 1: 611-2.

Kelly HR, Fay JE, Laverty SG. Thioridazine hydrochloride (Mellaril): the effect on the electrocardiogram and a report on two fatalities with electrocardiographic abnormalities. J Can Med Assoc 1963; 89: 546-7

Lambert P-A, Carraz G, Borselli S, Bouchardy M. Le dipropylacetamide dans le traitement de la psychose  maniaco-depressive.  Encephale 1975; 1: 25-31.

Lambert P, Perrin J, Revol L, Achaintre A, Balvet P, Beaujard M, Berthier C, Broussolle P, Requet A. Essai de classification des neuroleptiques d’après leurs activités psychpharmacologiques et cliniques. In: Bradley PB, Deniker P, Radouco-Thomas C, editors. Neuropsychopharmacology. Amsterdam/London/New York/Princeton: Elsevier Publishing Company; 1959. p. 619-24.

Langer SZ, Moret C, RaismanR, Dubokovitch ML, Briley M. High affinity 3H-imipramine binding in rat hypothalamus associated with uptake of serotonin but not of norepinephrine. Science 1980; 210: 1133-5.

Lehmann, HE, Ban TA. Pharmacotherapy of Tension and Anxiety. Springfield: Charles C. Thomas; 1970  

Lehmann HE, Ban TA. The history of the psychopharmacology of schizophrenia. Can J Psychiatry 1997; 42: 152-62.

Loveman E, Green C, Kirby J, Takada A, Picot J, Payne E, Clegg A. The clinical and cost effectiveness of donepezil, rivastigmine galantamine and memantine for Alzheimer’s disease. Health Technical Assessm 2008; 10: 1-16.

Okuma T, Kishimoto A, Inoe K, Matsumoto  H, Ogura A, Matsushita T, Nakao T, Ogura C. Antimanic and prophylactic  effects of carbamazepine  (Tegretol)  on manic depressive psychosis: A preliminary report.  Folia Psychiatr Neurol Jpn 1973; 27: 283-97.

Paul SM, Rehavi M, Skolnick P, Goodwin FK. Demonstration of high affinity binding sites for [3-H] imipramine  in human platelets. Lif Sci 1980; 26: 953-9.

Razay G, Wilcock GK. Galantamine in Alzheimer’s disease. Expert Review of Neurotherapeutics 2008; 8: 9-17.

Schildkraut JJ. The catecholamine hypothesis of affective disorders: a review of supporting evidence. Am J Psychiatry 1965; 122: 509-22.

Seeman P, Chau-Wong M, Tedesco J, Won K. Brain receptors for antipsychotic drugs and dopamine direct binding assays. Proc Natl Acad Sci USA. 1975; 72: 4376- 80.

Seeman P, Lee T, Chau-Wong M, Wong K. Antipsychotic drug doses and neuroleptic/dopamine receptors. Nature (London) 1976; .261: 717-9.

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

Sigel A. mapping of the benzodiazepine recognition sites on GABA receptors. Curr Top Med Chem 2002; 2: 833-9.

Snyder SH. The dopamine hypothesis of schizophrenia. Focus on the dopamine receptor. Am J Psychiatry 1976; 133: 140-4.

Snyder S, Creese L, Burt  DR. The brain’s dopamine receptor: labeling with [3H] dopamine and [3H] haloperidol. Psychopharmacol Commun 1975; 1: 663-73.

Sulser F. The 1960s. My early years with tricyclics. In: Ban TA, Healy D, Shorter E, editors. The Rise of Psychopharmacology and The Story of CINP. Budapest: Animula; 1998. p. 81-3.

Sulser F. Becoming a psychopharmacologist: New drugs and new concepts.  An autobiographical account. In: Ban TA, Shorter E, Healy D, editors. Reflections on Twentieth-Century Psychopharmacology. Budapest: Animula; 2004. p. 299-307.

Summers WK. Tacrine and Alzheimer treatments. J Alzheimers Dis 2006; 9: 443-5.

Tone A. The Age of Anxiety. New York: Basic Books; 2009

Vieta E, Gasto C, Colom F, Reiares M,  Martinez-Aran  A,  Benabarre A, Akiskal HS.  Role of risperidone in bipolar II: and open 6-month study J Affect Disord 2001; 67: 213-9

Wiesel F, Raafaub A, Kettler R. Pharmacokinetics of oral moclobemide in healthy human  subjects and effects on MAO activity in platelets  and excretion of urine monoamine metabolites. European Journal of Clinical Pharmacology 1985; 28: 89-95.

Zimmerman HJ, Rosenblum L, Korn J, Feldman PE. Some preliminary clinical and biochemical aspect of liver function in patients receiving iproniazid. Annals of the New York Academy of Science 1959; 80: 915-27.


October 25, 2018