Discontinuing Psychotropic Drugs from Participants in Randomized Controlled Trials: A Systematic Review

Abstract

Background and Objective: Methods and justifications for discontinuing psychotropic drugs in randomized controlled trials (RCTs), and RCTs’ acknowledgement of possible withdrawal symptoms following discontinuation, have not been examined systematically, which this review aims to do. Study Eligibility, Data Extraction, and Synthesis: Publications in MEDLINE, EMBASE, and PsycINFO (2000–2017) randomly assigning participants diagnosed with mental disorders to discontinue antipsychotic, antidepressant, anticonvulsant, antimanic, mood-stabilizing, benzodiazepine, or stimulant drugs. Authors independently extracted data, devised a typology of trials, and assessed trials’ recognition of with­drawal symptoms. Results: Eighty RCTs (70% with industry participation) discontinued drugs from 5,757 participants to investigate relapse prevention (44%), successful dis­continuation (26%), architecture of withdrawal (14%), and practicality of discontinuation (10%). RCTs of stimulants, antidepressants, and antipsychotics mostly aimed to reach conclusions about relapse prevention by testing abrupt or rapid discontinuations; RCTs of benzodiazepines mostly aimed to reduce drug use by testing longer-lasting, supportive discontinuations. In 67% of RCTs, no justification was given for the specific discontinuation strategy, which lasted under 2 weeks in 60% of RCTs. Possible withdrawal confounding of trial outcomes was addressed in 14% of eligible RCTs. Limitations: Only the published literature was searched. Conclusions and Implications: RCTs use drug discontinuation to study several key issues in psychopharmacology but infrequently justify how they implement it or acknowledge that possible withdrawal symptoms may threaten internal validity. Reappraising the use of drug discontinuation and the recognition of withdrawal symptoms in RCTs is required.

Long-term outcomes of trials in the National Institute for Health and Care Excellence depression guideline

“…8 The picture is further complicated, however, because any trial examining 'relapse' as an outcome of stopping antidepressants could be conflating relapse with withdrawal symptoms. 9 Various naturalistic cohort studies show that long-term antidepressant use has worse outcomes than short-term antidepressant use or non-pharmacological treatments. 10,11 Moreover, it appears to be difficult to stop antidepressants after extended use; 12 some patients using antidepressants may develop dependency 13 and patients using antidepressants long term report feeling addicted.…”

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

“…16 The alternative word "discontinuation" was promoted by the pharmaceutical industry to ensure that selective serotonin reuptake inhibitors (SSRIs) were not seen by physicians and the public as addictive, [17][18][19] but reports of contemporary RCTs use both words interchangeably; "withdrawal" is more common in studies of benzodiazepines and stimulants, "discontinuation" in studies of antidepressants and antipsychotics. 20 To reduce ambiguity, distinguishing between the action of reducing or stopping a drug (discontinuation) and the ensuing signs, symptoms and experiences (withdrawal) seems appropriate.…”

“…39,40 In discontinuation RCTs, attitudes and behavior of study personnel and clinical attendants are sometimes reported to have important effects on the outcomes of (especially institutionalized) patients' discontinuations. 20 First-person accounts also suggest that the economic ability to suspend one's usual duties may determine the success of discontinuation. 50 Knowledge on psychosocial contributions ("set" and "setting") to prescribed drug effects is not fully organized, 51 and rarely do RCTs complement their findings with direct evaluations of treatments by participants in their own words.…”

“…Adapted from Cohen and Recalt. 20 more severely, 28,78 even if more time may not eliminate all withdrawal risk. 79 The prevalence of abrupt or rapid discontinuations is staggering not only considering the risk of biasing study results, but in light of ethical imperatives in medicine and in human subject research to do no harm.…”

“…83,84 Of the 80 discontinuation RCTs we reviewed, 85% variously lacked basic information about symptom scores, measures of variability for those scores at important points throughout each trial, information about blinding and concealment of treatment allocation; washout; environmental factors; rationales for specific discontinuation procedures; and whether other psychotropics were concomitantly prescribed during discontinuation. 20,77 This carelessness constitutes another threat to the standing of RCTs as "gold standard" research methods; assessing RCTs solely by the data included in journal articles is like judging an iceberg only by what we see above the waterline. 85 Suggestions for current trial methodology Current conventional study designs can account for the risk of withdrawal confounding, first by replacing the abrupt switch to placebo at the start of a randomized discontinuation phase with a slow medication taper of meaningful duration.…”