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
Starting Up (Volume One): 4. Pharmacology
(Bulletin 36)

             The term “psychopharmacology” was introduced in 1920 by David Macht, an American pharmacologist at Johns Hopkins University, for describing the effects of the antipyretics, quinine and acetylsalicylic acid on neuromuscular coordination tests (Macht 1920). The term was used as a synonym for “pharmacopsychology,” a term introduced in 1892 by Emil Kraepelin for describing the “psychic effects” of morphine, alcohol, paraldehyde, chloral hydrate, ether and amyl-nitrate (Kraepelin 1892). The scope of psychopharmacology was gradually extended to all experimental investigations of the psychometric and “psychic” effects of drugs. By the 1940s, with the availability of lysergic acid diethylamide, psychopharmacology embraced research with psychotomimetics (also referred to as hallucinogens, psychodysleptics, psychotopathics, etc.; by the 1950s it included clinical investigations of the therapeutic effects of a rapidly growing number of new psychotherapeutic drugs used in the treatment of mental disorders (Ban 2004).

            Simultaneously, with the availability of effective psychotropic drugs in mental pathology, such as chlorpromazine, reserpine, meprobamate, imipramine and iproniazid, there was a shift in the understanding of the nature of synaptic transmission from a purely electrical to a chemically mediated event and by the end of the 1950s seven neurotransmitters had been identified in the central nervous system: acetylcholine, epinephrine, dopamine, γ-amino butyric acid, norepinephrine, serotonin, i.e., 5-hydroxytryptamine and substance P (Ban 1996). Recognition of chemical mediation at the site of the synapse, coupled with the introduction of the spectrophotofluorometer,an instrument with a resolution power to detect drug-induced changes in the concentration of neurotransmitter monoamines and their metabolites, led to the development of neuropharmacology, a branch of pharmacology that deals with the detection and identification of structures responsible for the psychotropic effects of centrally acting drugs (Bowman, Caulfield and Udenfriend1955). Previously, research dealing with centrally acting drugs was restricted to behavioral pharmacologyand neurophysiological measures, spectrophotofluorometry, however, provided direct access to the detection of the biochemical changes that might be responsible for therapeutic effects (Simon 1988). Spectrophotofluorometry also opened the path for the development of neuropsychopharmacology, a new discipline that studies the relationship between neuronal and mental processing in the brain with the employment of centrally acting drugs (Ban 2004).

            The first neuropharmacological studies with the aid of spectrophotofluorometry revealed: (1) that administration of reserpine, a Rauwolfia alkaloid, produced a decrease in brain serotonin and norepinephrine levels; (2) that administration of iproniazid, an inhibitor of the enzyme responsible for the breakdown of monoamines,increased brain serotonin levels; (3) that pre-treatment with iproniazid attenuated reserpine-induced depletion of serotonin and catecholamines; and (4) that only those Rauwolfia alkaloids and benzoquinolizines(a group of synthetic substances) that depleted serotonin had tranquilizing or sedating action (Besendorf and Pletscher1956; Brodie, Shore and Pletscher 1956;   Carlsson Rosengren, Bertler  and Nilsson 1957; Holzbauer and Vogt 1956; Pletscher 1956, 1957;  Pletscher, Shore and  Brodie1955; Zeller et al. 1952).  A possible relationship between mood and cerebral monoamine levels was based on clinical reports which indicated that treatment with iproniazid induced euphoria, a feeling of well-being, in some tubercular patients, whereas treatment with reserpine induced depressed mood or dysphoria in about 15% of hypertensive patients (Flaherty1972; Freis 1954; Mueller et al.1955; Selikoff, Robitzek and Orenstein 1952). The “birth” of neuropsychopharmacology in the mid-1950s was the result of combining these clinical observations with findings in neuropharmacological research (Ban 2008). The foundation of the new discipline was tenuous. There were reports that isoniazid, the parent substance of iproniazid, had similar effects on mood to those of iproniazid without virtually any effect on monoamine oxidase activity (Delay, Laine and Buisson 1952; Salzer and Lurie 1953, 1955). There was also a report on the favorable effects of reserpine in anxious and depressed patients (Davies and Shepherd 1955; Healy 1997).

            One of the first to recognize that neuropsychopharmacology opened up a new perspective in the understanding of psychiatric illness was Abraham Wikler, an American psychiatrist (Wikler 1957). In his monograph on The Relation of Psychiatry to Pharmacology, he suggested that studying the mode of action of psychotropic drugs with known therapeutic effects might provide information on the biochemical basis of mental disorders (Hollister 1996). By generating information on molecular changes in psychiatric illness, findings in neuropsychopharmacological research were to guide the development of rational drug treatments. The notion that drugs with known therapeutic effects might provide the key for bridging the gap between neuronal processing and mental pathology has remained the driving force for research in the new field.

            By the end of the 1950s the “neurotransmitter era,” the first epoch in the history of neuropsychopharmacology, had taken form. Research in the pathophysiology and treatment of mental illness had become guided by knowledge derived from the effect of psychotropic drugs on neurotransmitter dynamics and metabolism (Ban and UchaUdabe 2006; Pletscher2006).

References:

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

Ban TA. Academic psychiatry and the pharmaceutical industry. Prog Neuropsychopharmacol Biol Psychiatry 2006; 30: 429 – 41.

Ban TA. Fifty years chlorpromazine. A historical perspective. Neuropsychiat Dis Treat 2007; 3: 483–8.

Ban, T.A. The birth of neuropsychopharmacology. Neuropsychopharmacol Hung 2008; 3 (Suppl 2): S12–3.

Ban TA, UchaUdabe R. The Neurotransmitter Era in Neuropsychopharmacology. In: Ban TA, UchaUdabe R. editors. The Neurotransmitter Era in Neuropsychopharmacology. Buenos Aires: Polemos; 2006. p. 265 – 74.

Besendorf H, Pletscher A. BeeinflussungzentralerWirkungen von Reserpin und 5-Hydroxytryptamin durchIsonikotinsäurehydrazide. HelvPhysiolPharmacol Acta 1956; 14: 383–90.

Bowman RL, Caulfield PA, Udenfriend S. Spectrophotometric assay in the visible and ultraviolet. Science 1955; 122: 32–3.

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

Carlsson A, Rosengren E, Bertler A, Nilsson, J. Effects of reserpine on the metabolism of catecholamines. In: Garattini S, Ghetti V, editors. Psychotropic Drugs. Amsterdam: Elsevier; 1957. p. 363–72.

Davies DL, Shepherd M. Reserpine in the treatment of anxious and depressed patients. Lancet 1955; 2: 117–20.

Delay J, Laine B, Buisson JF. Note concernantl’action de l’isonicotinyl dans le traitement des étatsdépressives. Ann Med Psychol (Paris) 1952; 110; 689–92.

Flaherty JA. The psychiatric use of isonicotinic acid hydrazide: a case report. Del Med J 1952; 24: 298–300.

Freis ED. Mental depression in hypertensive patients treated for long periods with large doses of reserpine. N Engl J Med 1954; 251: 1006–8.

Healy D. The Antidepressant Era. Cambridge: Harvard University Press; 1997. p. 72 – 4.

Hollister LE. Review of Wikler’s The Relation of Psychiatry to Pharmacology. In: Ban TA, Ray OS, editors. A History of the CINP. Nashville: JM Productions; 1996. p. 339 – 43.

Holzbauer M, Vogt M. Depression by reserpine of the noradrenaline concentration in the hypothalamus of the rat. J Neurochem 1996; 1: 8–11.

Kraepelin E. Über die BeeinflussungeinfacherpsychischerVorgängedurcheinigeArzneimittel. Jena: Fischer; 1892.

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Mueller JC, Pryor WW, Gibbons JJ, Orgain ES. Depression and anxiety occurring during Rauwolfia therapy. JAMA 1955; 159: 836–9.

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Pletscher A. Release of 5-hydroxytryptamine by benzoquinolizine derivatives with sedative action. Science 1957; 126: 507–8.

Pletscher A. The dawn of the neurotransmitter era in neuropsychopharmacology. In: Ban TA, UchaUdabe R, editors. The Neurotransmitter Era in Neuropsychopharmacology. Buenos Aires: Polhemos; 2006. p. 27–37.

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

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Salzer HM, Lurie ML. Depressive states treated with isonicotinyl hydrazide (isoniazid). Ohio State Med J 1955;51:437–41.

Selikoff IJ, Robitzek FH, Orenstein GG. Treatment of pulmonary tuberculosis with hydrazine derivatives of isonicotinic acid. JAMA 1957; 150: 973–80.

Simon P. Behavioural pharmacology. In: Ban TA, Healy D, Shorter E, editors. The Rise of Psychopharmacology and the Story of CINP. Budapest: Animula; 1998. p. 131–4.

Wikler A. The Relation of Psychiatry to Pharmacology. Baltimore: Williams and Wilkins; 1957.

Zeller EA, Barsky JR, Fouts W, Kirchheimer WP, Van Orden LS. Influence of isonicotinic acid hydrazide (INH) and 1-isonicotinyl l-2-isopropyl hydrazide (IINH) on bacterial and mammalian enzymes. Experientia 1952; 8: 349–50.

September 20, 2018