Antidepressant withdrawal – the tide is finally turning

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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.

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Hengartner

2020

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“…However, this position is no longer tenable in view of current evidence that indicates that the clinical phenomena pertain to withdrawal syndromes and do not differ from those that occur with other psychotropic drugs. 40 – 45 Hengartner et al remarked that the first systematic review on SSRI appeared only in 2015, 40 , 46 and the first on serotonin-noradrenaline reuptake inhibitors (SNRI) in 2018, 42 after nearly 200 meta-analyses on the efficacy of new generation antidepressants. The withdrawal syndrome encompasses a broad range of somatic symptoms (e.g.…”

Section: The Clinical Foundations Of the Model Of Oppositional Toleramentioning

confidence: 99%

“…However, in due course after their introduction, more pronounced problems occurred with most of the newer antidepressants. 40 – 46 It would seem that, with both types of drugs, that withdrawal reactions and post-withdrawal syndromes may ensue, despite slow tapering. Yet, even though loss of clinical effect and paradoxical reactions may occur also with long-term treatment with benzodiazepines, other vulnerabilities that have been described with AD (resistance, switch to mania or hypomania, refractoriness) are unlikely to occur with benzodiazepines.…”

Section: The Oppositional Model As a Conceptual Clinical Frameworkmentioning

confidence: 99%

May antidepressant drugs worsen the conditions they are supposed to treat? The clinical foundations of the oppositional model of tolerance

Fava

2020

In recent years there has been a considerable debate on antidepressant drugs. Continued drug treatment with antidepressant medications may stimulate processes that run counter to the initial acute effects of a drug. The oppositional model of tolerance may explain loss of treatment efficacy during maintenance treatment and the fact that some side effects tend to occur only after a certain time. These processes may also direct the illness into a treatment-unresponsive course, including manifestations of bipolar disorder or paradoxical reactions. When drug treatment ends, oppositional processes no longer encounter resistance, resulting in potential onset of new withdrawal symptoms, persistent post-withdrawal disorders, hypomania, and resistance to treatment if it is reinstituted. In all these cases, antidepressant medications may constitute a form of iatrogenic comorbidity, which increases chronicity and vulnerability to depressive episodes. Antidepressant medications are essential drugs for the treatment of major depressive episodes. They are less likely, however, to provide protection for relapse prevention. Current prescription practices need to be reformulated in light of consideration of vulnerabilities and adverse effects of treatment. The oppositional model of tolerance provides a conceptual framework for weighing all these elements in the individual case. The model does not appear to apply to all patients who undergo treatment with AD, but only to a part of them. Studying the variables that are associated with such occurrence in certain patients and not in others would be one of the most important tasks of current therapeutic research. Current diagnostic systems in psychiatry do not consider the iatrogenic components of psychopathology, and can be applied to only patients who are drug free. They are suited for a patient who no longer exists: most of the cases that are seen in psychiatric clinical practice receive psychotropic drugs and such treatment is likely to affect prognosis and treatment choices.

“…12,13,23,24 To avoid the costs and risks associated with unnecessary long-term antidepressant treatment and misdiagnosis of withdrawal, 25–28 a better understanding and proper recognition of antidepressant withdrawal syndromes are required. 15,29,30…”

Section: Introductionmentioning

confidence: 99%

Protracted withdrawal syndrome after stopping antidepressants: a descriptive quantitative analysis of consumer narratives from a large internet forum

Hengartner

Schulthess

Sørensen

et al. 2020

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Background: Protracted withdrawal syndrome (PWS) after stopping antidepressants (frequently also referred to as post-acute withdrawal syndrome or PAWS) has been described in a few case reports. However, a detailed quantitative analysis of specific symptom manifestations in antidepressant PWS is still lacking. Methods: We extracted patient narratives from a large English-language internet forum SurvivingAntidepressants.org , a peer support site concerned about withdrawal from antidepressants. PWS was ascertained based on diagnostic criteria proposed by Chouinard and Chouinard, specifically ⩾6 months of continuous antidepressant use, with emergence of new and/or more intense symptoms after discontinuation that last beyond the initial 6 weeks of acute withdrawal. We assessed medication history, outcome of PWS, and the prevalence of specific symptoms. Results: In total, n = 69 individual reports of protracted withdrawal were selected for analysis. At time of the subjects’ most recent reports, duration of PWS ranged from 5 to 166 months, mean = 37 months, median = 26 months. Length of time on the antidepressant causing protracted withdrawal ranged from 6 to 278 months, mean = 96 months, and median = 79 months. Throughout the withdrawal experience, affective symptoms, mostly anxiety, depression, emerging suicidality and agitation, were reported by 81%. Somatic symptoms, mostly headache, fatigue, dizziness, brain zaps, visual changes, muscle aches, tremor, diarrhea, and nausea were reported by 75%. Sleep problems (44%) and cognitive impairments (32%) were mentioned less frequently. These broad symptom domains were largely uncorrelated. Conclusion: PWS or PAWS from antidepressants can be severe and long-lasting, and its manifestations clinically heterogeneous. Long-term antidepressant exposure may cause multiple body system impairments. Although both somatic and affective symptoms are frequent, they are mostly unrelated in terms of occurrence. Proper recognition and detection of PWS thus requires a comprehensive assessment of medication history, duration of the withdrawal syndrome, and its various somatic, affective, sleep, and cognitive symptoms.