Navigating the Neurochemical Maze of Antidepressant Withdrawal

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A systematic review and meta-analysis on antidepressant discontinuation found that while one in three people reports symptoms upon stopping, half are likely due to the nocebo effect. Severe symptoms are rare, affecting only about 3% of those discontinuing. Credit:

Expectations contribute to symptoms following discontinuation of antidepressants.

How difficult is it to stop taking antidepressants? If countless Internet posts and multiple scientific studies are to be believed, discontinuing these medications is highly problematic, and doctors often underestimate the difficulties involved. However, it is unclear how common discontinuation symptoms actually are. Researchers from Charité – Universitätsmedizin Berlin and University Hospital Cologne have now conducted a systematic review and meta-analysis. In their article in The Lancet Psychiatry, they conclude that one in three people reports symptoms after discontinuing antidepressant treatment, but half of those symptoms are attributable to negative expectations (the nocebo effect).

Exploring the Nocebo Effect in Antidepressant Withdrawal

Antidepressants are not habit-forming, at least according to the formal definition. Unlike “true” addictive substances, for example, taking them does not cause the body to require higher and higher doses to achieve the same effect. Even so, many patients report symptoms such as dizziness, headache, or insomnia when they stop taking these mood medications. The phenomenon went largely unremarked by researchers for years, but there are now a relatively large number of studies seeking to quantify the extent of discontinuation symptoms.

Varied Results in Discontinuation Studies

“The results of these studies vary, in some cases widely,” says Prof. Christopher Baethge, a researcher at the Department of Psychiatry and Psychotherapy at University Hospital Cologne and the Faculty of Medicine at the University of Cologne. “There has been a great deal of discussion, some of it quite emotional, within the research community and the general public alike in recent years about how prevalent and severe the discontinuation symptoms actually are.” A look at prescription figures shows just how relevant this topic is. According to the most recent Arzneiverordnungs-Report, which summarizes data on drug prescriptions, nearly 1.8 billion daily doses of antidepressants were prescribed in Germany in 2022.

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How difficult it is to get off antidepressants is often discussed emotionally. A meta-analysis now sheds light on how common discontinuation symptoms actually are. Credit: © Charité | Romy Greiner

Comprehensive Meta-analysis Brings Clarity

To answer that question more reliably than before, a team led by Christopher Baethge and Dr. Jonathan Henssler, head of the Evidence-Based Mental Health research group at the Department of Psychiatry and Neurosciences at Charité, conducted a systematic review of existing studies and re-analyzed them in what is known as a meta-analysis. As the first study of its kind, it provides the soundest assessment to date of the consequences of stopping antidepressant treatment. “Our analysis shows that on average, one in three people will experience symptoms after stopping antidepressant treatment,” Henssler says. “However, only half of these symptoms are in fact attributable to the drug itself.”

Placebo Influence and Real Discontinuation Symptoms

For their paper, the researchers reviewed more than 6,000 studies. They then selected 79 of them and re-analyzed the results of those trials using statistical methods. In the end, they analyzed data on about 21,000 people, who had received either an antidepressant or a placebo and then been surveyed regarding the prevalence of discontinuation symptoms. Some 31 percent of the patients treated with an active drug reported discontinuation symptoms, but so did 17 percent of those who had received a placebo alone.

“Drug effects can be ruled out in the placebo group, which means the symptoms either arose by chance, independently of the treatment, or they are the product of the nocebo effect,” Henssler explains. The nocebo effect is often considered the mirror image of the placebo effect. It explains the observation that inactive treatments can be associated with “side effects.” These effects are triggered purely by the expectation that the treatment that people think they are receiving will have negative effects.

Incidence and Severity of Discontinuation Symptoms

“When we take non-specific symptoms and the effect of expectations into account, about one in six or seven people is affected by discontinuation symptoms that occur as an actual consequence of antidepressant medication,” Henssler says, summing up the study’s results. “In most cases, the symptoms are mild. The vast majority of those affected will be able to discontinue antidepressants without relevant symptoms. This means that in most cases, there is no need for a lengthy or gradual tapering process.”

Managing and Mitigating Severe Withdrawal Symptoms

The study found that severe discontinuation symptoms are experienced by one in 35 people, or nearly three percent of those affected. These kinds of symptoms were more common after discontinuing treatment with the drugs imipramine, paroxetine, venlafaxine, and desvenlafaxine. There was not yet enough information on hand for the researchers to assess the situation for a number of widely used antidepressants.

As Baethge points out, “It’s important for all people wishing to discontinue treatment with antidepressants to be monitored and counseled by healthcare professionals and to receive individual support in the case of withdrawal symptoms. Joint decision-making between the patient and prescriber even before a course of treatment begins is the foundation of good treatment. We hope our data will support patients and healthcare professionals and help alleviate some of the uncertainty surrounding these issues today.”

For more on this study, see Breaking Free From Antidepressants: Study Uncovers the Risks of Discontinuation Symptoms.

Reference: “Incidence of antidepressant discontinuation symptoms: a systematic review and meta-analysis” by Jonathan Henssler, Yannick Schmidt, Urszula Schmidt, Guido Schwarzer, Tom Bschor and Christopher Baethge, 5 June 2024, The Lancet Psychiatry.
DOI: 10.1016/S2215-0366(24)00133-0

The 79 studies considered in the meta-analysis included both randomized placebo-controlled trials and observational studies conducted without a control group. Of the 21,002 patients involved in the studies, 16,532 had received an antidepressant, and 4,470 a placebo. In addition to the researchers from Charité and University Hospital Cologne, researchers at the Medical Center – University of Freiburg and University Hospital Carl Gustav Carus, in Dresden, were involved in the meta-analysis.

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