The conundrum of depression clinical trials: one size does not fit all.

In this paper we review the history of antidepressant (AD) development, since the discovery of imipramine in 1957 to the present day. Through this exploration we will show that the increasing placebo response is likely a red herring and that a higher magnitude of placebo response is not an adequate explanation for AD trials' high failure rates. As a better explanation for their lack of success, we will examine some of the fundamental flaws of AD clinical trials and their origins in historical forces. We focus on underpowering, which occurs as a consequence of unrealistic expectations for AD performance. In addition, we describe the lack of precision in the depression outcome measurements for the past 40 years and show how these measures contrast with those used in clinical trials of other chronic diseases, which use simpler outcome measures. Finally, we describe the role of regulatory agencies in influencing clinical trial design and how the assumption that 'one size fits all' for the past 60 years has led to flawed design of AD clinical trials.

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.

[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

The creation of the concept of an antidepressant: an historical analysis.

The concept of an "antidepressant" implies a drug that acts in a disease specific way to reverse the neuropathological basis of the symptoms of depression. However, there is little scientific research that could confirm this view. This paper reports an historical study of the emergence of the concept of the antidepressant and the social forces that influenced its adoption. Historical literature documents the increasing importance of the specificity of medical treatments in the 20th century and the increased power that they conferred on medical practitioners. In the case of depression, stimulants were used as treatment from the 1940s. During the 1950s the anti-tuberculous drugs iproniazid and isoniazid started to be portrayed as more specific than stimulants, even though their stimulant effects were well documented. When imipramine was suggested to be effective in depression, it was presented solely as acting in a disease specific way and it was soon referred to as an "antidepressant". The idea that some drugs have a specific action on the underlying basis of depression caught on rapidly and was well established by the 1960s before any evidence was available to support this view. Forces that could have driven the adoption of this view include the psychiatric profession's desire to integrate with general medicine to improve its social status and to move away from the asylum into the community. Physical interventions and drug treatments helped to boost its medical credentials and antidepressant drugs provided a convenient form of medical treatment for community-based distress. They also helped the profession to counter attacks from the antipsychiatry movement. The pharmaceutical industry too helped to establish and disseminate the view of antidepressants as disease specific treatments in order to distinguish them from non-specific drugs. This study raises questions about the view that psychiatry was transformed into a modern medical enterprise in the 1950s and 1960s by the introduction of disease specific drugs.

Contribución de la iproniazida y la imipramina al desarrollo de la psiquiatría biológica: primeras hipótesis etiopatogénicas de los trastornos afectivos / The contribution of iproniazid and imipramine to the development of biological psychiatry: the first etiopathogenic hypotheses of affective disorders

En 1957 se introdujeron en la clínica los dos primeros antidepresivos, imipramina e iproniazida, agentes de dos familias farmacológicas distintas; los antidepresivos tricíclicos y los inhibidores de la monoaminooxidasa (IMAO), respectivamente. Estos fármacos revolucionaron la práctica clínica en la asistencia psiquiátrica de la época. Pero, además, el desarrollo de la imipramina y la iproniazida supuso la introducción de nuevos métodos para la evaluación de la actividad antidepresiva de distintas sustancias y permitió avanzar en el conocimiento de la etiopatogenia de los trastornos afectivos, al posibilitar el postulado de las hipótesis monoaminérgicas de las depresiones durante la década los sesenta, que planteaban una deficiencia funcional de la neurotransmisión noradrenérgica y/o serotoninérgica, con base en el efecto bloqueador de la recaptación sináptica de estas aminas por parte de la imipramina, o la inhibición de la monoaminooxidasa, en el caso de la iproniazida. Sobre estas primeras hipótesis neurobiológicas del origen de las enfermedades mentales, se fue construyendo paulatinamente lo que hoy conocemos como psiquiatría biológica (AU)

In 1957, the 2 first antidepressants introduced into clinical practice were imipramine and iproniazid. These agents belong to 2 different pharmacologic families: tricyclic antidepressants and monoamine oxidase inhibitors (MAOI), respectively. These drugs revolutionized clinical practice in psychiatry at that time. Moreover, the development of iproniazid and imipramine required the introduction of new methods to evaluate the antidepressant activity of different substances and led to advances in the knowledge of the etiopathogenesis of affective disorders. This allowed the monoaminergic hypothesis of depression to be postulated in the 1960s, which proposed a functional deficiency in noradrenergic and serotonergic neurotransmission, based on synaptic reuptake blocking of theses amines by imipramine or monoamine oxidase inhibition by iproniazid. On the basis of these first neurobiological hypotheses on the origin of mental illness, what is currently known as "biological psychiatry" gradually developed (AU)

History and evolution of the monoamine hypothesis of depression.

The symptoms of depression can be improved by agents that act by various mechanisms to increase synaptic concentrations of monoamines. This finding led to the adoption of the monoamine hypothesis of depression, first put forward over 30 years ago, which proposes that the underlying biological or neuroanatomical basis for depression is a deficiency of central noradrenergic and/or serotonergic systems and that targeting this neuronal lesion with an antidepressant would tend to restore normal function in depressed patients. The hypothesis has enjoyed considerable support, since it attempts to provide a pathophysiologic explanation of the actions of antidepressants. However, in its original form it is clearly inadequate, as it does not provide a complete explanation for the actions of antidepressants, and the pathophysiology of depression itself remains unknown. The hypothesis has evolved over the years to include, for example, adaptive changes in receptors to explain why there should be only a gradual clinical response to antidepressant treatment when the increase in availability of monoamines is rapid. Still, the monoamine hypothesis does not address key issues such as why antidepressants are also effective in other disorders such as panic disorder, obsessive-compulsive disorder, and bulimia, or why all drugs that enhance serotonergic or noradrenergic transmission are not necessarily effective in depression. Despite these limitations, however, it is clear that the development of the monoamine hypothesis has been of great importance in understanding depression and in the development of safe and effective pharmacologic agents for its treatment.

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.