Withdrawal Confounding in Randomized Controlled Trials of Antipsychotic, Antidepressant, and Stimulant Drugs, 2000–2017

Abstract

Background: Results of relapse prevention randomized controlled trials (RCTs) which discontinue psychotropic drug treatment from some participants may be confounded by drug withdrawal symptoms. We test for the confound by calculating whether ≥50% of the difference in relapse risk between drug-discontinued and drug-maintained groups is present at discontinuation time points (DCTs) with “short” and “long” assumptions regarding onset and duration of withdrawal symptoms. Methods: In eligible RCTs of antidepressants, antipsychotics, and stimulants from 2000 to 2017 (n = 30) selected from a systematic review, differences in relapse risk were examined by arithmetic and graphical comparison of mean behavioral scores or survival plots. Results: Only 14 studies (46.6%) with 15 analyses of relapse risk provided sufficient data. Under short and long DCTs, 9 of 13 (69.2%) and 7 of 9 (77.8%) interpretable analyses, respectively, suggested a withdrawal confound. The proportion of endpoint placebo-maintenance group difference present by the DCT averaged 69.1% (range, 58.7–148.0%, n = 13) for short DCT assumptions, and 79.0% (range, 51.5–183.3%, n = 9) under long DCTs. One study (3.33%) controlled for withdraw al effects, and 1 yielded inconclusive results. Conclusions: These results support suggestions that withdrawal symptoms confound the results of relapse prevention RCTs. Accounting for such symptoms in RCTs is an ethical, scientific, and clinical imperative. Justifications for relapse prevention RCTs employing a discontinuation procedure require more scrutiny.

Withdrawal effects confounding in clinical trials: another sign of a needed paradigm shift in psychopharmacology research

“…[74][75][76] Evaluating the conflicting evidence for antidepressants' longterm effectiveness, Hengartner concluded that "there is substantial withdrawal confounding in journals.sagepub.com/home/tpp discontinuation trials, which renders their findings uninterpretable" (p. 1). 69 In previous work systematically reviewing 80 discontinuation RCTs published since 2000, 20 70% with industry funding or participation, we found that, in most RCTs, most of the difference in relapse rates between drug-continued and drugdiscontinued groups occurred soon after discontinuation, 77 when withdrawal symptoms are most likely to occur. We identified several flaws in these trials.…”

How effective are antidepressants for depression over the long term? A critical review of relapse prevention trials and the issue of withdrawal confounding

“…It is difficult to quantify the extent to which events recorded as depression relapse in maintenance studies are related to withdrawal reactions, but different estimations suggest that it is presumably the majority. 46,69,70 These findings indicate that there is substantial withdrawal confounding in relapse prevention (discontinuation) trials and that the internal validity of these studies is compromised. It follows that the results of these trials are uninterpretable.…”

“…Here, I will focus on one particular issue, that is, withdrawal confounding. 46 Various authors have stressed that prolonged antidepressant use can cause neurochemical adaptations (physical dependence) and corresponding withdrawal reactions upon dose reduction or discontinuation comparable with other central nervous system (CNS) drugs like benzodiazepines, stimulants or opioides. 18,22,47,48 There is now compelling evidence from clinical trials, observational studies and user surveys that stopping antidepressants can cause severe and persistent withdrawal reactions in a substantial portion of users.…”

“…10,[70][71][72] The findings detailed above hence indeed question the validity of relapse prevention (discontinuation) trials, of which the vast majority, noteworthy, does not attempt to differentiate relapse from withdrawal. 46,69 Of course genuine depression relapses also occur in the discontinuation (placebo) arm, but this is not the point. The fundamental issue is that events recorded as relapses could very well be, and in many cases certainly are, the result of withdrawal reactions.…”

Discontinuing psychotropic drug treatment

“…4,5 Adverse clinical effects of discontinuing psychotropic drugs also can arise in changing from active drug to placebo in clinical trials. 6,7 Pharmacodynamic mechanisms underlying discontinuation syndromes…”