Brief reportRe-analysis of the earliest controlled trials of imipramine
Introduction
Tricyclic antidepressants started with imipramine, synthesized and patented by Franz Häfliger and Walter Schinder in 1951 (US Patent 2,554,736) at CIBA-Geigy Laboratories in Basel as a chemical analog of the tricyclic antipsychotics (Baldessarini 2013). Antidepressant properties of imipramine were first suggested by clinical observations led by Roland Kuhn at the Münsterlinger Psychiatric Clinic in Switzerland in 1957, with considerable initial skepticism about its clinical efficacy (Kuhn, 1958, Tondo,). By early 1960s, several of the earliest controlled clinical trials in modern psychopharmacology had been carried out to test the clinical impression that imipramine was an effective and tolerable antidepressant. FDA approval for clinical use of imipramine in 1959 was followed by rapid appearance of a series of chemically and pharmacologically related compounds (Baldessarini, 2013). A landmark review of early, controlled trials of imipramine and of its pharmacology was reported in 1965 by two of the founders of modern clinical psychopharmacology, Gerald Klerman and Jonathan O. Cole (1965).
We carried out an updated analysis of the 1965 review to compare early with modern randomized controlled trials of antidepressant drugs that have continued to appear over the past half-century (Undurraga and Baldessarini, 2012). Such agents are among the most widely used, and so, among the most clinically and industrially important of all classes of drugs (Healy, 1997, Baldessarini, 2013).
Section snippets
Methods
We obtained copies of 26 studies of early controlled clinical trials of imipramine reviewed by Klerman and Cole (1965). Studies included for further analysis involved placebo controls and reported response rates that were defined by the authors using different methods, ranging from symptom-rating scales to clinical impressions, though presumably balanced in drug and placebo arms in each trial. When outcomes were quantified or categorized, we routinely excluded the lowest values of questionable
Results
Of 26 studies cited in the early review by Klerman and Cole (1965), we found 18 trials that compared the tricyclic antidepressant imipramine to a placebo control and reported responder rates for drug versus control arms (Table 1). All placebos were inactive except that three studies (Daneman, 1961, Weintraub and Aronson, 1963, Uhlenhuth and Park, 1964) used small doses of atropine (0.3–1.4 mg/day) to mimic antimuscarinic side-effects, and Fahy et al. (1963) used anesthetic doses of a barbiturate
Discussion
Responses to the first tricyclic antidepressant in its earliest controlled trials were much larger than in 122 antidepressant trials reported between 1980 and 2010 (Undurraga and Baldessarini, 2012). The pooled drug/placebo RR from the early trials of imipramine was 2.17 (CI: 1.87–2.51; Table 1), or 2.02 (1.43–2.85) based on meta-analysis (Fig. 1), compared to only 1.42 (1.38–1.48) in the modern antidepressant trials. Similarly, the early estimated NNT was 3.1 (2.1–5.8), compared to the
Role of funding source
Funding sources had no involvement in the preparation of this report.
Conflict of interest
Dr. Vieta is a consultant or grant recipient with: Almirall, Astra-Zeneca, Bristol-Myers-Squibb, Eli Lilly, Forest Research Institute, Gedeon Richter, Glaxo-Smith-Kline, Janssen-Cilag, Jazz, Lundbeck, Merck, Novartis, Otsuka, Pfizer, Sanofi, Servier, Schering-Plough, Takeda, and United Biosource Corporations. No other authors or immediate family members have financial relationships with pharmaceutical or biomedical corporations that might represent potential conflicts of interest in the work
Acknowledgments
Supported in part by a Josep Font Research Grant from the Hospital Clínic of Barcelona (to JU), by the Instituto de Salud Carlos III through the Centro para la Investigación Biomédica en Red de Salud Mental (CIBERSAM; to JU, EV), a grant from the Bruce J. Anderson Foundation and by the McLean Private Donors Psychopharmacology Research Fund (to RJB). Dr. Baldessarini directs the program in psychopharmacology at McLean Hospital founded by Jonathan O. Cole, M.D., in the 1980s.
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