A major systematic review published in JAMA Psychiatry last month found that while withdrawal symptoms were more common one week after ceasing antidepressants compared to placebo, clinical significance was limited.
Researchers from Imperial College London analysed 50 randomised clinical trials with nearly 18,000 participants.
Dizziness, nausea, vertigo, and nervousness were more common one week after stopping antidepressants than after stopping placebo. However, the effect size equated to one additional symptom on a standardised scale (the Discontinuation-Emergent Signs and Symptoms scale).
Moreover, the authors concluded that “the mean number of discontinuation symptoms at week 1 after stopping antidepressants was below the threshold for clinically significant discontinuation syndrome,” and depression symptoms were not associated with discontinuation.
Several experts argue that we shouldn’t be, noting that the included studies overwhelmingly involved people who had been taking antidepressants for less than 12 weeks.
The JAMA study authors acknowledge this limitation. “Participants in most studies were taking the antidepressant for a relative short period, although 6 studies had a treatment period ranging from 36 weeks to 4.5 years.”
Critics argue this point shouldn’t be dismissed.
Professor Katharine Wallis is one of them. She’s head of the Mayne Academy of General Practice at the University of Queensland Medical School, and lead of the RELEASE (REdressing Long-tErm Antidepressant uSE in general practice) study.
“The review by Kalfas et al is largely irrelevant for clinical practice in Australia.” – Professor Katharine Wallis
“The review confirms that if people take antidepressants for only 8-12 weeks, then they are unlikely to suffer much in the way of withdrawal symptoms. While this might be a useful message, it is not helpful for guiding practice today,” Professor Wallis says.
“In Australia, the average duration of antidepressant therapy is around 4 years. Half of antidepressant users take antidepressants for longer than 12 months,” Professor Wallis says.
“Thus the review does not contribute anything useful for most antidepressant users and risks denying their reality and distracting practitioners from the problems that they face when attempting to stop taking these drugs.”
The main analysis looked at 11 trials which compared withdrawal symptoms in people who ceased antidepressants with those who continued them or stopped placebo; in six of those trials, the participants had been taking antidepressants for eight weeks, in four they had been taking them for 12 weeks, and in one patients had been on them for 26 weeks.
A Healthed survey in July found that 56% of 1538 GP respondents believe the prevalence of antidepressant withdrawal symptoms is underestimated. Fifteen percent think the prevalence is overestimated, and 29% reckon it’s correctly estimated.
Australian GPs aren’t the only ones worried that the prevalence of discontinuation symptoms is being underestimated.
Writing in the Conversation, Dr Mark Horowitz, author of the Maudsley Deprescribing Guidelines, and social psychiatry Professor Joanna Moncrieff, said the JAMA review was “written by academics, many of whom have close ties to drug manufacturers,” and “risks underestimating the potential harms to long-term antidepressant users by focusing on short-term, industry-funded studies.”
Dr Horowitz and Professor Moncrieff, both also from University College London, said their own research found a clear link between duration of antidepressant use and likelihood and severity of withdrawal symptoms.
“People who had used antidepressants for more than two years were ten times more likely to have withdrawal effects, five times more likely for those effects to be severe, and 18 times more likely for them to be long lasting compared with those who had taken the drugs for six months or less,” they wrote.
“Studying what happens to people after just eight to 12 weeks on antidepressants is like testing car safety by crashing a vehicle into a wall at 5km/h – ignoring the fact that real drivers are out on the roads doing 60km/h.”
They also argue that the review’s assumption that the withdrawal-like symptoms people experience when they discontinue a placebo cancels out the effects from withdrawal effects from antidepressants, pointing out that “as was shown in another recent review, symptoms following discontinuation of a placebo tend to be milder than those experienced when stopping antidepressants, which can be intense enough to require emergency care.”
Others said the JAMA review did not adequately reflect the most commonly used antidepressants, “most studies involved limited or no withdrawal risk (e.g. vortioxetine, agomelatine).”
Last year, another systematic review and metanalysis published in the Lancet looked at 79 studies – 44 RCTs and 35 observational, covering 21,002 patients. It found the incidence of discontinuation symptoms was about 15% — and that severe discontinuation symptoms occurred in around one in 30 patients.
It too been the subject of criticism – with researchers including Dr Horowitz publishing an appraisal and reanalysis this week. They said the data in the original review are “derived from pharmaceutical industry–sponsored efficacy studies in which withdrawal was a minor consideration” and had a number of methodological flaws.
And just like the JAMA review, the Lancet review mainly included participants who had been taking antidepressants for three to six months.
Like 56% of GPs in Healthed’s survey, Professor Wallis agrees withdrawal symptoms are often underestimated. She says lack of awareness and recognition have resulted in both doctors and patients misinterpreting withdrawal symptoms as a relapse of anxiety or depression.
“The confusion is easy to understand as some symptoms of withdrawal, such as nervousness, irritability, insomnia, fatigue and agitation, can also be symptoms of anxiety and/or depression,” she explains in this article about how to safely cease antidepressants.
In addition to feeling anxious and irritable, people experiencing antidepressant withdrawal may also experience symptoms such as:
“Further, withdrawal symptoms tend to start within hours, days or sometimes weeks of stopping or decreasing antidepressant dose and can last weeks or longer, whereas any relapse of anxiety or depression usually takes longer before recurring and may be associated with life events,” she adds.
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