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Fava, 2018 Discontinuing Antidepressant Drugs: Lesson from a Failed Trial and Extensive Clinical Experience

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Discontinuing Antidepressant Drugs: Lesson from a Failed Trial and Extensive Clinical Experience

Fava G.A.a,b,c · Belaise C.a,c



Scholten et al. [1] reported on the first randomized controlled trial that attempted to prevent relapse in patients with remitted anxiety disorder who discontinued antidepressant drugs (AD) by use of a cognitive-behavioral therapy (CBT) relapse prevention group compared to treatment as usual. The patients who were assigned to CBT received 8 group sessions of relapse prevention, targeting vulnerability factors and discontinuation symptoms. AD were tapered every 2 weeks within 4 months according to a fixed schedule. In the control group (treatment as usual), tapering and discontinuation of AD were carried out without CBT, in individual sessions, according to the same schedule [1]. Primary outcomes were occurrence/reoccurrence of any anxiety disorder or major depressive disorder. Secondary outcome was the success rate of discontinuation of AD. Seventy-three patients were enrolled. Over 16 months there were no significant differences between the CBT group and the treatment as usual group in any of the primary and secondary outcome measures. Despite guidance, only 36% of all participants succeeded in discontinuing AD, and only 28% did not have recurrence. One patient committed suicide. The trial was stopped prematurely for ethical reasons and futility [1]. However, it was certainly not futile and provided important insights into discontinuing AD.


As the authors commented [1], the guidelines’ recommendations to discontinue AD were found neither feasible nor effective in their sample. The investigators, while convinced to apply the best evidence, found out that they had been simply misguided. Withdrawal symptoms and syndromes may occur during and despite slow tapering, do not magically vanish after a couple of weeks from discontinuation and may persist for a long time, leading to postwithdrawal syndromes [23]. In this trial [1], the CBT group was thus stopped when it was more needed, as we are going to discuss below. Further, withdrawal symptoms and syndromes were not adequately assessed and addressed; they might have been misidentified as the occurrence of an anxiety disorder. That specific trial was bound to fail, but alternative routes may be feasible. We will describe the approach to discontinuing AD that we have developed over the years. It has not been tested in controlled trials but may inspire new research efforts in an area that badly needs investigation.

Edited by Altostrata
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So, at best, approximately 28% of individuals can discontinue at a rapid taper over 4 months.

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That's the most comprehensive analysis I've seen. Very sobering. 

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Twenty years ago, this journal anticipated the current medical scenario dominated by corporate interests which result in self-selected academic oligarchies that influence clinical and scientific information. 


Members of special interest groups, by virtue of their financial power and close ties among themselves, have the task of systematically preventing dissemination of data which may be in conflict with their interests.


Corporate powers fused with academic medicine to create an unhealthy alliance that works against objective reporting of clinical research, sets up meetings and symposia with the specific purpose of selling the participants to sponsors, and substantially controls journals, medical associations, and related foundations (through direct support and/or advertising). The growth of evidence-based medicine, with its emphasis on systematic reviews and guidelines, provided an ideal ground for multiplying the effects of financial conflicts of interest in medicine.


In the early nineties, when the reports on withdrawal syndromes upon discontinuing SSRI began to appear, it was crucial to downplay such occurrences. At that time, the commercial plan was to extend the use of SSRI to other psychiatric disorders and to prolong their administration to the longest possible time. Awareness of the occurrence of dependence would have run counter to such a strategy. A concerted action became operational:


(a) Withdrawal reactions were promptly renamed as discontinuation syndromes, as if they were different from what was known about other psychotropic drugs, such as BZD. There was no evidence to support that dependence was different with SSRIs and SNRIs. Indeed, in our clinical experience it is far more difficult to discontinue a drug such as paroxetine or venlafaxine than any BZD. Both physicians and patients were taught that the problem could have appeared only with abrupt discontinuation of AD and that, if symptoms arose, they had to be considered signs of relapse, with prompt readministration of the AD.


(b) BZD, because of their widespread use and their limited cost, were a major obstacle to the introduction of the new AD in anxiety disorders. In anxiety disorders, when directly compared to AD, BZD were found to be more or as effective and with fewer side effects. 
A commercial war was thus started: the dependence potential of BZD was dramatized, and their prescription was hindered in all possible ways, despite the clinical value of this class of medication. Physicians thus learned that BZD were bad and could cause dependence, whereas AD were devoid of such effects. This was probably the most spectacular achievement of propaganda in psychiatry.


(c) Prolongation of pharmacological treatment with the claim to maintain the clinical responses obtained in the short term was another commercial target for SSRI and SNRI. The evidence supporting this strategy was mainly based on clinical trials where remitted patients were randomized to drug continuation or placebo, without any differentiation between withdrawal syndromes and relapse. Thus, in the group that underwent drug tapering and discontinuation, we have no way to know how many of the relapses were actually withdrawal and postwithdrawal syndromes. As a result, the efficacy of AD in preventing relapse in depression compared to placebo relies on hiding the existence of withdrawal syndromes that are misinterpreted as new illness episodes.


(d) Special interest groups operating in funding agencies and medical journals made sure that iatrogenic components of depression could not get attention and funding, even though these phenomena may explain a large part of clinical outcomes, such as chronicity.


An important research question arises with withdrawal phenomena related to SSRI and SNRI: are these distressing but self-limiting reactions or are they signs of something else? They may be manifestations of behavioral toxicity (the oppositional model of tolerance), potentially related to loss of clinical effects, increased vulnerability to relapse, resistance when treatment is reinstituted, unresponsiveness, paradoxical effects.


A major consequence of these commercial strategies has been that patients experiencing anguish and mental pain of withdrawal syndromes have not received appropriate medical attention and have been forced to refer themselves to websites, groups, associations, which had the recognized merit of providing support but could not offer the medical competence that was required, particularly as to medical comorbidities. Professional organizations and scientific societies have major responsibilities in not assuring proper care to people in need of it.”

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