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Another View of the History of Antipsychotic Drug Discovery and Development

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Another View of the History of Antipsychotic Drug Discovery and Development Molecular Psychiatry (2012) 17, 1168–1173 & 2012 Macmillan Publishers Limited All rights reserved 1359-4184/12 www.nature.com/mp PERSPECTIVE Another view of the history of antipsychotic drug discovery and development WT Carpenter Jr1 and JM Davis2 Chlorpromazine initiated effective pharmacotherapy for schizophrenia 60 years ago. This discovery initiated or stimulated key developments in the field of psychiatry. Nonetheless, advances in pharmacotherapy of schizophrenia have been modest. Psychosis remains the primary aspect of psychopathology addressed, and core pathologies such as cognition and negative symptom remain unmet therapeutic challenges. New clinical and basic neuroscience paradigms may guide the near future and provide a more heuristic construct for novel and innovative discovery. Molecular Psychiatry (2012) 17, 1168–1173; doi:10.1038/mp.2012.121; published online 14 August 2012 Keywords: antipsychotic drugs; chlorpromazine; history; psychopharmacology; schizophrenia Efficacious therapy for persons suffering with schizophrenia and hindered the development of practical case management and related psychotic disorders was not established before the dis- supportive therapies, and created a flawed psychotherapy versus covery of the antipsychotic properties of chlorpromazine reported medication polemic. Society was sometimes viewed as causative in 1952.1 Following the remarkable success in treating and pre- of schizophrenia leading to legal efforts to impede treatment. The venting tertiary syphilis with antibiotic therapy, there was reason cumulative result was trans-institutionalization that even today is to hope for substantial therapeutic advances. Electroconvulsive represented with large schizophrenia populations in jails, prisons, therapy had been introduced and appeared effective for some homeless or in forensic psychiatric settings.7 forms of schizophrenia, especially those with catatonic features Against this historical backdrop, the chance observation that and acute psychotic episodes.2 Reserpine, an antihypertensive chlorpromazine induced a calming effect initiated a remarkable compound that was later determined to reduce storage and release period of efficacious therapy. In France, chlorpromazine was being of dopamine at a presynaptic level was tried with some success to tried as an anesthesia adjunct that might prevent shock or have benefit schizophrenia.3 other beneficial properties. Chosen as the least sedative of the Before the 1950s there were other heroic attempts, often with antihistamines available at that time, it was tested in a wide severe adverse effects and without known efficacy. These have variety of patients. When tried in patients with schizophrenia, been cataloged elsewhere.4 Prefrontal lobotomy had the broadest Delay8 initially reported their results at a psychiatric meeting in application and achieved a desired ‘calming’ effect but at the Luxemburg and then very quickly in a journal article in 1952 expense of vital emotional processing and motivational qualities. describing spectacular results in acutely psychotic schizophrenic As soon as ACTH and the corticosteroids became available to patients. The use of chlorpromazine spread very quickly administer to patients, clinicians observed beneficial effects on throughout the world. Initially it was used in a rather low many diseases, which resulted in trails to alter cortisol level in both dose, but even so in New York state hospitals, it reduced directions: of adrenalectomy, which failed to help schizophrenia, episodes of violence and days in seclusion by 90–95%. At that and cortisone administration, which was initially reported by one time, the number of state hospital beds had been rising investigator to have a beneficial effect. This was not replicated in progressively in the United States. After the introduction of subsequent open or case-controlled studies.5,6 Absence of efficacy chlorpromazine the number of beds for schizophrenia may have implication for the current interest in immunosuppres- decreased steadily. The large state hospitals, some exceeding sion and anti-inflammatory therapeutics. The asylum movement 15 000 beds, were downsized or disappeared. Clinicians noted attempted to provide more humane care, but adverse con- that in acutely psychotic patients, chlorpromazine reduced sequences of sequestration in non-therapeutic environments were excitement and some patients appeared to be recovered. associated with the long-term confinement in large institutions. Decreased emotion was associated with sustained psychotic The social psychiatry movement, initiated in England before symptoms in more chronic patients. They also noticed that the discovery of chlorpromazine, shifted clinical care closer to chlorpromazine was not very effective in dull, apathetic, patients’ natural environment, but antipsychotic drugs were to deteriorated schizophrenic patients. This early insight was lost prove invaluable to the deinstitutionalization movement. In the and only recently have negative symptoms in schizophrenia United States chronic hospital care was drastically reduced, but been identified as a separate therapeutic indication.9 Clinicians communities were inadequately prepared for the comprehensive also began to describe acute extrapyramidal side-effects, clinical and rehabilitation care and living support required. The including dystonic and dysphoric effects as well as akathisia cause of schizophrenia was sometimes conceptualized only at the and pseudoparkinsonism. Later, the significance of tardive dyskinesia psychological level. The belief in psychodynamic therapeutic was appreciated. The term ‘neuroleptic’ for chlorpromazine and 1Department of Psychiatry, Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore, MD, USA and 2Department of Psychiatry, University of Illinois at Chicago, Baltimore, MD, USA. Correspondence: Dr WT Carpenter, Department of Psychiatry, Maryland Psychiatric Research Center, University of Maryland School of Medicine, PO Box 21247, Baltimore, MD 21228, USA. E-mail: [email protected] Received 13 June 2012; accepted 5 July 2012; published online 14 August 2012 Antipsychotic drug discovery and development WT Carpenter and JM Davis 1169 subsequent dopamine antagonist drugs captured both the drug, alone, neither treatment, or both, for 6 months to 1 year tranquilization and neurological effects. after which time all patients received drug. Five-year follow-up The initial conceptualization of chlorpromazine action focused found patients not receiving drugs in the first 6 months to 1 year on its so-called ‘tranquilization effect,’ antianxiety and antiag- had double the days in hospital for the next 5 years compared gressive effects. Meprobamate was introduced in 1955 and had with those receiving initial drug treatment.20 Another study antianxiety properties, but it was recognized relatively early that showed that the patients randomized to placebo for 1 month had meprobamate was ineffective in schizophrenia. This led to the no worse outcome than those initially receiving drug, indicating conceptualization of major tranquilizers and minor tranquilizers. that brief off-medication periods did not produce lasting In the late 1960s, the term ‘antipsychotic’ was used to better morbidity.21,22 It is clear that acute treatment is efficacious and depict the behavioral effects of chlorpromazine in schizophrenic maintenance treatment substantially reduces relapse frequency. patients.10 It is also documented that periods off medication for research The history of antipsychotic drug therapy has been described can be safely and ethically conducted.23 A recent comprehen- in detail.11,12 Here, we will briefly note highlights from 1952 to sive review of placebo drug effects on course and outcome is the present with emphasis on limitations as well as advances. available.24 Two paradigm shifts to encourage discovery related to unmet 3. Scientific methodology: Historically, many treatments based on therapeutic needs in schizophrenia treatment will be presented. open trials later proved to be ineffective in controlled investiga- Following the initiation of efficacious pharmacotherapy with tions. Medicine developed the controlled randomized clinical trial chlorpromazine, four developments have had a major impact on method to provide more stringent scientific testing of efficacy schizophrenia research and treatment: hypotheses. Regarding the third major advance, the clinically observed therapeutic effect of chlorpromazine raised the question 1. Determining that efficacy was based on antipsychotic rather of standard of evidence needed to provide solid science for than tranquilizing properties; therapeutic interventions in psychiatry. This was a pressing issue 2. Identifying psychotic relapse prevention efficacy; in psychiatry, in part because of the implementation of treatments 3. Establishing scientific methodology for ascertainment of such as prefrontal lobotomy without adequate knowledge of risk/ efficacy; and benefit or patient selection. The resolution of this problem 4. Initiating the field of psychopharmacology. resulted in methodology for determining efficacy and effective- ness of treatments and assessment of adverse effects. The 1. Antipsychotic rather than tranquilizer: The major tranquilizer methodologies for the random assignment, double-blind clinical construct suggested that therapeutic success was based on trial and systematic clinical assessment tools were developed calming the patient with reduction in aggression,
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