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

Abstract

The aim of this article is to discuss the validity of relapse prevention trials and the issue of withdrawal confounding in these trials. Recommendations for long-term antidepressant treatment are based almost exclusively on discontinuation trials. In these relapse prevention trials, participants with remitted depression are randomised either to have the antidepressant abruptly discontinued and replaced by inert placebo or to continue active treatment. The drug–placebo difference in relapse rates at the end of the maintenance phase is then interpreted as a prophylactic drug effect. These trials consistently produce remarkable benefits for maintenance treatment. However, the internal validity of this trial protocol is compromised, as research has shown that abruptly stopping antidepressants can cause severe withdrawal reactions that lead to (or manifest as) depression relapses. That is, there is substantial withdrawal confounding in discontinuation trials, which renders their findings uninterpretable. It is not clear to what degree the drug–placebo separation in relapse prevention (discontinuation) trials is due to withdrawal reactions, but various estimations suggest that it is presumably the majority. A review of findings based on other methodologies, including real-world long-term effectiveness trials like STAR*D and various naturalistic cohort studies, do not indicate that antidepressants have considerable prophylactic effects. As absence of evidence does not imply evidence of absence, no definitive conclusions can be drawn from the literature. To enable a thorough risk–benefit evaluation, real-world effectiveness trials should not only focus on relapse prevention, but also assess antidepressants’ long-term effects on social functioning and quality of life. Thus far, reliable long-term data on these outcome domains are lacking.

The ‘patient voice’: patients who experience antidepressant withdrawal symptoms are often dismissed, or misdiagnosed with relapse, or a new medical condition

“…17 However, in these studies, withdrawal effects from the rapid discontinuation of antidepressants are ignored, inflating the apparent rate of relapse recorded in this group, therefore exaggerating the perceived 'relapse prevention' properties of antidepressants. 20,41 Given these methodological flaws this evidence has been described as 'uninterpretable' and NICE guidance based on this evidence should be updated appropriately, acknowledging the lack of robust evidence for relapse prevention properties. 20 Minimisation of these methodological flaws has led to antidepressants being presented as more effective than is warranted by existing data.…”

“…20,41 Given these methodological flaws this evidence has been described as 'uninterpretable' and NICE guidance based on this evidence should be updated appropriately, acknowledging the lack of robust evidence for relapse prevention properties. 20 Minimisation of these methodological flaws has led to antidepressants being presented as more effective than is warranted by existing data. 20,38,42,43 As a consequence of the minimisation of their withdrawal effects, as well as a number of their other side effects (perhaps reflected in the infrequency with which GPs discuss these issues with patients), antidepressants have also been regarded as more safe that is warranted by existing data.…”

“…5,15,16 Consequently, both RCPsych and NICE have updated their guidance to recognise that antidepressant withdrawal can be more severe and longlasting than previously recognised; symptoms can last 'months or more' and can be 'more severe for some patients'. 1,4,17 Mistaking withdrawal for relapse or another medical condition It has also been noted in several reviews of antidepressant withdrawal symptoms that such reactions can be mistaken for relapse of the underlying condition for which the antidepressant was originally prescribed, [18][19][20] and this has been highlighted in the DSM-5 21 ; however, the degree to which this occurs has never been quantified. 22 Furthermore, previous accounts have highlighted that when antidepressant withdrawal is not recognised it may be mistaken for the onset of another medical illness, including stroke, other neurological conditions, infectious disease and adverse effects of other medications the patient is taking, leading to unnecessary and expensive interventions and management.…”

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.…”

“…In another analysis, Hengartner remarks that scientific evidence for long-term antidepressant treatment rests "almost exclusively" on relapse-prevention trials and also observes "unequivocally positive" results of such trials. 69 The advantages of the relapse-prevention design for non-curative drugs having smallish effects relative to placebo stand out: randomization is applied to a highly selected sample (no placebo responders, no noncompliers, no victims of serious adverse events) after an open-label period where dosages have been optimized. Earlier observers of this design also noted that it overestimated efficacy and underestimated long-term toxicity, 70,71 but its first applications in psychopharmacology were to determine whether a significant withdrawal syndrome occurred upon abrupt discontinuation of benzodiazepines and lithium.…”