[A 70-year history of tricyclic antidepressants]. / 70-letniaia istoriia tritsiklicheskikh antidepressantov.

For the first time the facts from the history of tricyclic antidepressants (TCA) are systematized in Russian psychiatric literature. The authors describe the history of first TCA agents, analyze the history of TCA group development based on the increase of new agents, present the history of original TCA creation in the USSR and the Eastern block countries, systemize the history of TCA classification development and review the studies on TCA neurochemical activity. An impact of TCA history on formulation of hypotheses of the pathogenesis of depression and some forms of neuroses is demonstrated. It is shown that the history of TCA creation urged the development of new groups of antidepressants.

The clinical discovery of imipramine.

The major classes of psychotropic drugs were introduced in an extraordinary decade of discovery between the late 1940s and late 1950s. In the present climate of pessimism about the absence of new drug development, it may be instructive to look back at the research methods used during that era. The study that identified the first antidepressant is a case in point. It was conducted by Roland Kuhn, a Swiss psychiatrist working in a remote psychiatric hospital. Kuhn, like the other pioneering researchers of his day, was given access to new drug entities, and the method he used to discover their clinical effects was open-minded, exploratory, comprehensive, clinical observation. The paper that reported the results of his study has not been available in English, but because of its historical significance and because Kuhn's achievement stands in such contrast to the present impasse in drug development, the authors thought that it might be informative to read about his discovery in his own words. Accordingly, one of the authors (M.R.) translated the paper into English, and they now present excerpts of that translation with the intent of encouraging reevaluation of contemporary approaches to drug discovery. By today's clinical research standards, Kuhn's method of unfettered, exploratory, clinical observation was substandard, haphazard, even messy. Yet it produced a major breakthrough-the discovery that a drug can alleviate depression-that has had a lasting impact on the treatment of depression and on the development of antidepressant drugs. Kuhn's experience might usefully inform our strategies of drug development.

CNS drug development. Part I: The early period of CNS drugs.

This column begins a new series on central nervous system (CNS) drug development. This series will review developments up to the present day and end with a forward-looking perspective on what to expect over the next 10-20 years. The goal of this series is to explain to practicing clinicians how drugs are developed and why CNS drug development is at an important juncture involving both significant challenges and opportunities. This column (Part 1) reviews the history of CNS drug development from the period before written history through the golden era (i.e., late 1940s-early 1960s) in which the first modern medications for anxiety, bipolar, depressive, and psychotic disorders were discovered by chance. It also describes the early era of rational drug development in which other agents (e.g., thioridazine, fluphenazine, haloperidol, imipramine) were developed based on those first agents. The blueprint laid down for development of antibiotics is reviewed in relation to its impact on CNS drug development. The impact of the blockbuster business model and modern marketing/sales approaches on CNS drug development is also discussed.

Monoaminergic neurotransmission: the history of the discovery of antidepressants from 1950s until today.

The 1950s saw the clinical introduction of the first two specifically antidepressant drugs: iproniazid, a monoamine-oxidase inhibitor that had been used in the treatment of tuberculosis, and imipramine, the first drug in the tricyclic antidepressant family. Iproniazid and imipramine made two fundamental contributions to the development of psychiatry: one of a social-health nature, consisting in an authentic change in the psychiatric care of depressive patients; and the other of a purely pharmacological nature, since these agents have constituted an indispensable research tool for neurobiology and psychopharmacology, permitting, among other things, the postulation of the first aetiopathogenic hypotheses of depressive disorders. The clinical introduction of fluoxetine, a selective serotonin reuptake inhibitor, in the late 1980s, once again revolutionized therapy for depression, opening the way for new families of antidepressants. The present work reviews, from a historical perspective, the entire process that led to the discovery of these drugs, as well as their contribution to the development of the neuroscientific disciplines. However, all of these antidepressants, like the rest of those currently available for clinical practice, share the same action mechanism, which involves the modulation of monoaminergic neurotransmission at a synaptic level, so that the future of antidepressant therapy would seem to revolve around the search for extraneuronal non-aminergic mechanisms or mechanisms that modulate the intraneuronal biochemical pathways.

[In memory of Roland Kuhn (1912-2005) and 50 years of imipramine]. / Erinnerung an Roland Kuhn (1912-2005) und 50 Jahre Imipramin.

Based on his clinical experience and knowledge in the humanities, phenomenology, and natural sciences, the Swiss psychiatrist and Rorschach expert Roland Kuhn discovered the specific antidepressant effect of imipramine in the treatment of vital depressive disorder. This discovery of the first tricyclic antidepressant drug shows how an education covering the various fields of psychiatry facilitates therapeutic and scientific achievements. Kuhn's methods as a psychiatrist and his papers can show present and future generations of psychiatrist ways to make new discoveries in the field of psychiatry, psychotherapy, and psychopharmacology.

La introducción clínica de la iproniazida y la imipramina: medio siglo de terapéutica antidepresiva / The clinical introduction of iproniazid and imipramine: half a century of antidepresant therapy

Los primeros fármacos antidepresivos, imipraminae iproniazida, fueron introducidos en clínica en 1957.El origen de la iproniazida, un isopropil derivado dela isoniazida, se encuentra en los agentes antituberculososque se venían utilizando desde principios de ladécada de 1950.Los primeros datos sobre los efectos de la iproniazidaen pacientes depresivos no tuberculosos fueroncomunicados por Kline y cols. en 1957, quienes valoraronsu eficacia en pacientes con depresión psicóticacrónica, abriendo las puertas al primer grupo de fármacosespecíficamente antidepresivos (los inhibidoresde la monoamino-oxidasa, IMAO). Simultaneamente,tuvo lugar otro gran avance histórico en elmanejo de la depresión: el descubrimiento de los antidepresivostricíclicos, cuyo primer exponente y prototipofue la imipramina. La historia de estos antidepresivoscomenzó en los primeros años de la década de1950, gracias al desarrollo de sustancias iminodibenzólicasestudiadas en ese momento como posiblesagentes antihistamínicos, y a la perspicacia del psiquiatrasuizo Kuhn, quien ensayó un hipotético agenteantipsicótico de la compañía farmacéutica suiza J.R.Geigy (G-22355), en 300 pacientes esquizofrénicos.Aunque su eficacia antipsicótica fue inferior a la dela clorpromazina, su actividad antidepresiva fue superiora la de cualquier sustancia conocida hasta lafecha. El nuevo fármaco, denominado imipramina,se comercializó en la primavera de 1958, y sigue siendoun agente de referencia, sobre todo en investigaciónclínica. Sin embargo, la vida comercial de laiproniazida fue corta, pues se retiró del mercadoamericano en 1961 por problemas de seguridad (ictericiay nefrotoxicidad).En cualquier caso, la importancia en la historia dela psiquiatría de estos dos agentes ha sido capital,pues abrió las puertas a un evidente fenómeno de desestigmatización de la asistencia psiquiátrica y a laincorporación de la Atención Primaria al tratamientode los problemas de salud mental

In 1957, the first antidepressant drugs introducedinto clinic were imipramine and iproniazid. Iproniazid’sorigin, an isopropyl derivative of isoniazid, was includedin anti-tuberculosis agents that were used frombeginning of the 1950 decade. The first data about iproniazideffects in depressive patients without tuberculosiswere presented by Kline’s team in 1957, whichassessed the efficacy in patients with chronic psychoticdepression,opening the door to the first group of specificallyantidepressant drug (monoamine oxidaseinhibitors, MAOI). At the same time, there was anotherhistoric advance in the management of depression: thediscovery of tricyclic antidepressants, whichimipramine was its first agent and prototype.Imipramine’s history began in the first years of thedecade of 1950, thanks to development of iminodibenzolicsubstances, studied like possible anti-hystaminergicagents in that moment, and the perceptiveness of theSwiss psychiatrist Kuhn, who tested a hypotheticantipsychotic agent of Swiss Pharmaceutical CompanyJ.R. Geigy (G-22355) in 300 schizophrenic patients.Despite its antipsychotic efficacy was lower than chlorpromazine,its antidepressant’s activity was higher thanany other substance known at this moment. New drug,called imipramine, was launched in the spring of 1958,and it continues being an agent of reference, especiallyin clinical research. Nevertheless, the commercial lifeof iproniazide was short, because it was withdrawnfrom the American market in 1961 due to safety problems(jaundice and nephrotoxicity). In any case, thesetwo agents have a great significance in psychiatric history,like that opening the door at the phenomenon ofdestigmatization of psychiatric assistance and the incorporationto primary care to treatment of mental healthproblems

Mechanism of action of antidepressant medications.

The psychopharmacology of depression is a field that has evolved rapidly in just under 5 decades. Early antidepressant medications--tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs)--were discovered through astute clinical observations. These first-generation medications were effective because they enhanced serotonergic or noradrenergic mechanisms or both. Unfortunately, the TCAs also blocked histaminic, cholinergic, and alpha1-adrenergic receptor sites, and this action brought about unwanted side effects such as weight gain, dry mouth, constipation, drowsiness, and dizziness. MAOIs can interact with tyramine to cause potentially lethal hypertension and present potentially dangerous interactions with a number of medications and over-the-counter drugs. The newest generation of antidepressants, including the single-receptor selective serotonin reuptake inhibitors (SSRIs) and multiple-receptor antidepressants venlafaxine, mirtazapine, bupropion, trazodone, and nefazodone, target one or more specific brain receptor sites without, in most cases, activating unwanted sites such as histamine and acetylcholine. This paper discusses the new antidepressants, particularly with regard to mechanism of action, and looks at future developments in the treatment of depression.

Van Gogh and lithium. Creativity and bipolar disorder: perspective of a writer/photographer.

Diana Dennison has suffered from manic depression since her teenage years in the 1960s but only realised that she had the condition when, in her 30s, she learnt that her uncle was manic depressive. Diana endured her low states with either no medication or with what was for her the unsatisfactory effect of tricyclic antidepressants. Her untreated hypomanic states cut a swathe through her life. She has never been hospitalised for her condition. Her marriage did not survive but her daughters did and she is now a proud and doting grandmother who skis and scuba dives. Only in the last 4 years did Diana seek help for the treatment of her condition. Diana is a free-lance writer, researcher and photographer.

A descoberta da imipramina e a psicoterapia: uma (re)visäo / Imipramine's discovery and the psychotherapy: a (re)vision

Duas conferências de ROLAND KUHN, pronunciadas em 1972 e 1977, respectivamente, em Belo Horizonte e Barcelona foram (re)vistas. Através das mesmas é evidenciado como a descoberta da imipramina, nas suas origens, esteve entimamente relacionada com a psicoterapia. Também é mostrado como KUHN utilizou alguns argumentos de FREUD a respeito de uma relaçao especial entre neurose e depressao, neurose e regressao e sobre as substâncias químicas responsáveis pela distribuiçao de energia no aparelho psíquico. Ao mesmo tempo, como referiu-se ao conceito de "depressao vital", enunciado por BINSWANGER, como o grande motivador conceitual ou teórico da descoberta da imipramina através da análise existencial. Ainda através do texto sao expostos argumentos de KUHN favoráveis ao emprego conjunto de psicoterapia e psicofarmacoterapia. Como enriquecimento aos argumentos do psiquiatra suíco favorável aos tratamentos combinados foram utilizadas idéias de outros autores que os consubstanciam. A (re)visao permitiu verificar que: 1) a relaçao íntima entre o emprego da imipramina e a psicoterapia é um texto histórico essencial ao conhecimento; 2) os textos de KUHN se mostram muito atuais à psiquiatria brasileira; 3) o reducionismo nesta área de grande complexidade - frente a ausência de conhecimentos mais completos - é inútil e ilógico. Como conclusao, sao considerados a origem e o tempo da descoberta da imipramina e levantadas questoes a respeito da demora no reconhecimento de textos essenciais do conhecimento psiquiátrico.

Antidepressant drugs as adjuvant analgesics.

This article reviews the history of the use of antidepressants in painful states and traces the evolution of thinking from initially considering them as antidepressants to the current concept that they have an analgesic action. The greatest part of this paper considers chronic, nonmalignant, painful states and the evidence with each for the efficacy of some of these drugs. The mechanism of action, pharmacokinetics and adverse effects are discussed. Practical suggestions are made regarding their usage. Although antidepressants are imperfect analgesics because of limited efficacy and untoward effects, they may be the only avenue of relief for a painful condition. The correct choice of agent and proper administration are critical.