Brief report
Re-analysis of the earliest controlled trials of imipramine

https://doi.org/10.1016/j.jad.2012.10.032Get rights and content

Abstract

Aims

Re-analysis of outcomes of the earliest controlled trials of imipramine for comparison to more recent findings in antidepressant trials.

Methods

Controlled trial-reports of imipramine reviewed by Klerman and Cole (1965) were re-analyzed for their methods and response rates, using random-effects meta-analytic modeling.

Findings

In 18 early trials (1959–1965), imipramine yielded a large and highly significant, pooled drug/placebo response rate-ratio (RR) of 2.17 (CI: 1.87–2.51), with an estimated number-needed-to-treat (NNT) of 3.1 (CI: 2.1–5.8), even though only 9/18 (50%) trials, individually yielded statistically significant drug-placebo differences.

Conclusions

Responses to imipramine in its earliest controlled trials were much larger than in recent antidepressant trials. Drug-placebo differences declined significantly between 1959 and 1965, with rising placebo-associated responses. Frequent failure to find superior drug-over-placebo outcomes may reflect patient characteristics and limited statistical power. Antidepressant-trial methods have become much more standardized, samples larger and more complex, and effect-sizes much smaller since the 1960s.

Limitations

Some reports did not include relevant information, diagnostic and outcome criteria varied, and only 18/30 trials included responder-rates.

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.

References (26)

  • R. Höhn et al.

    Double-blind comparison of placebo and imipramine in the treatment of depressed patients in a state hospital

    Journal of Psychiatric Research

    (1961)
  • E.H. Uhlenhuth et al.

    Influence of medication (imipramine) and doctor in relieving depressed psychoneurotic outpatients

    Journal of Psychiatric Research

    (1964)
  • H.C. Abraham et al.

    Controlled clinical trial of imipramine (Tofranil) with outpatients

    British Journal of Psychiatry

    (1963)
  • W.R. Ashby et al.

    Clinical trial of imipramine (“Tofranil”) on depressed patients

    Journal of Mental Science

    (1961)
  • R.J. Baldessarini

    Chemotherapy in Psychiatry

    (2013)
  • J.R. Ball et al.

    Controlled trial of imipramine in treatment of depressive states

    British Medical Journal

    (1959)
  • E.A. Daneman

    Imipramine in office management of depressive reactions: double-blind clinical study

    Diseases of the Nervous System

    (1961)
  • P. Fahy et al.

    Controlled comparison of electroconvulsive therapy, imipramine and thiopentone sleep in depression

    Journal of Neuropsychiatry

    (1963)
  • M. Fink et al.

    Clinical efficacy of chlorpromazine-procyclidine combination, imipramine and placebo in depressive disorders

    Psychopharmacologia

    (1965)
  • C. Friedman et al.

    Imipramine (Tofranil) in depressive states: controlled trial with inpatients

    Journal of Mental Science

    (1961)
  • Greenblatt, M., Grosser, G.H., Wexler, H., 1964. Differential response of hospitalized depressed patients to somatic...
  • D. Healy

    The Antidepressant Era

    (1997)
  • I.S. Kenning et al.

    Treatment of depressive states with imipramine hydrochloride

    Canadian Psychiatric Association Journal

    (1960)
  • Cited by (7)

    • Investigating the potential role of BDNF and PRL genotypes on antidepressant response in depression patients: A prospective inception cohort study in treatment-free patients

      2019, Journal of Affective Disorders
      Citation Excerpt :

      After the introduction of selective serotonin reuptake inhibitors (SSRIs) and other antidepressants in the 1980s, the category of depressive disorders which may be treated with antidepressants widened to include major depressive disorder (according to DSM-IV and DSM-5). This may contribute to why the effect size of treatment with an antidepressant versus placebo was substantially larger (2.17 vs. 1.42) and the number needed to treat fewer (3.1 vs. 8.0) in old (1959–1965) studies on imipramine in comparison to newer (1980–2010) antidepressant trials (Undurraga et al., 2013). The characteristics of the current disease category ‘major depression’ are likely different from the original ‘endogenomorphic depression’ (Klein et al., 1980).

    • The Rise and Fall of the Age of Psychopharmacology

      2022, Journal of Clinical Psychopharmacology
    View all citing articles on Scopus
    View full text