SSRI Withdrawal Front Page News

By Carrie Clark

The Psychiatric Times, one of the largest online psychiatry periodicals, made antidepressant withdrawal front page news this month. In the cover article, Dr. Nicolas Badre, Professor David Cohen, and Camila Losada Strassle provide a much-needed discussion on informed consent and safe tapering, emphasizing the harm caused to patients by the frequent conflation of relapse with withdrawal.

Inner Compass Initiative is particularly proud of this achievement because Dr. Badre and Professor Cohen are senior fellows at the newly launched Inner Compass Research Institute. Over the coming months, the institute will be working to transform mental health policy, bringing critical analysis to questions of overmedicalization, prescribed harm, and holistic alternatives to conventional psychiatric treatment.

“There are so many misrepresentations and errors of reasoning in Pies and Henssler’s critique.”

The urgent need for this analysis is sharply highlighted by a critique of the cover article, also published by the Psychiatric Times. Dr. Ronald Pies and Dr. Jonathan Henssler cast doubt on the reality of antidepressant withdrawal, reject the need for slow, hyperbolic tapering, and even argue that patients should not be advised about withdrawal or managing discontinuation as part of the informed consent process. There are so many misrepresentations and errors of reasoning in Pies and Henssler’s critique that it’s difficult to know where to start.

The most glaring is the conviction that antidepressants are an effective long-term treatment for depression, preventing relapse and improving quality of life. Pies and Henssler believe that antidepressants are highly beneficial treatments, and this naturally leads them to see the risk-benefit ratio for the drugs in a favorable light. This colors everything else in their critique. The potential for withdrawal symptoms is simply less concerning to authors who believe the drugs are overwhelmingly beneficial and should be taken over the long term. This faith in extended treatment leads Pies and Henssler to argue that clinicians should not discuss discontinuation with patients at the point of prescription. They state that discontinuation should not be presented to patients “as an expected course of action.”

“It’s far from clear that antidepressants are effective long-term treatments.”

However, it’s far from clear that antidepressants are effective long-term treatments. As Badre et al. explain in their cover article, the benefit of long-term antidepressant treatment is justified on the basis of so called "relapse prevention" trials. In these trials, patients randomized to discontinue antidepressants are rapidly tapered off the drugs, increasing their likelihood of experiencing withdrawal symptoms. However, these trials typically make no effort to systematically measure withdrawal symptoms, attributing any worsening seen in the discontinuation group to “relapse” and ignoring the possibility of withdrawal altogether. As Mark Horowitz has documented, “Current discontinuation studies that are thought to demonstrate relapse prevention properties of antidepressants are likely to be confounded by withdrawal symptoms,” rendering the existing relapse prevention literature virtually meaningless.

Pies and Henssler also seem fundamentally confused about what antidepressant withdrawal symptoms actually are. At one point they assert that “antidepressant withdrawal does not produce the characteristic physiological responses seen in, for example, barbiturate, opiate, or alcohol withdrawal (eg, diaphoresis, tachycardia, myoclonus, seizures).” Embarrassingly for the authors, diaphoresis (sweating), tachycardia (elevated heart rate), and myoclonus (involuntary spasms) are all well-documented symptoms of antidepressant withdrawal syndrome. Similarly, the critique quotes Dr. Roger S. McIntyre claiming that antidepressant withdrawal symptoms are exclusively “somatic,” or physical, in nature. In fact, recognized psychological symptoms, including worsened mood, irritability, and agitation are among the most commonly observed antidepressant withdrawal symptoms and occur even in people who were given antidepressants for reasons other than mental health problems, including healthy volunteers.

McIntyre further demonstrates his ignorance when he states that “a relapse…is defined by symptom intensification on a symptom measurement tool like the…HAMD-17 [17-item Hamilton Depression Rating Scale].… I am not aware of any evidence that the antidepressant discontinuation syndrome is itself consistently correlated with symptom intensification on a clinician-reported outcome measure of depression.” Again, this is completely inaccurate. As Horowitz has written, “Withdrawal symptoms overlap with all commonly used depression rating scales” (emphasis added). If clinicians do not recognize that a patient is experiencing withdrawal, then psychological symptoms like those listed above could of course be mistaken for worsening depression on a measure like the HAMD-17.

Pies and Henssler also appear confused about the biological mechanisms that cause antidepressant withdrawal. They acknowledge, correctly, that, “antidepressants can induce homeostatic changes resulting in withdrawal symptoms during discontinuation.” Puzzlingly though, they then reject homeostatic disruption as a potential causal mechanism in delayed antidepressant withdrawal, stating that “we know of no recognized physiological mechanism that would produce a genuine withdrawal syndrome de novo, with onset after (roughly) the first month of drug discontinuation.”

“Studies have shown that the homeostatic adaptations caused by antidepressants can persist for months or years after the drugs are discontinued.”

Pies and Henssler here seem to imply that withdrawal symptoms are mediated by the length of time it takes the drug to leave the body (approximately one month), rather than the lasting effects of homeostatic change. But studies have shown that the homeostatic adaptations caused by antidepressants can persist for months or years after the drugs are discontinued. While we do not yet know why some people experience delayed onset while others do not, the persistence of homeostatic changes surely represents a logical basis from which to investigate the specific causes of delayed onset. It’s also worth noting that antidepressant treatment effects are also delayed, taking 6-8 weeks to manifest after treatment is started, and that the physiological mechanism underpinning this phenomenon is also unknown. Pies and Henssler seem comfortable with this uncertainty when it comes to starting antidepressant treatment, only becoming sceptical of delayed onset when it relates to withdrawal.

Having demonstrated that they understand neither the characteristic symptoms of antidepressant withdrawal nor the biochemical processes underlying it, it is unsurprising to find that Pies and Henssler argue that it occurs only rarely. Clinicians who cannot accurately identify the symptoms of a condition clearly lack the necessary skills to recognize it in their patients and are therefore likely to overlook it. You cannot see what you aren’t looking for.

It is certainly true that the failure to include standardized measures of withdrawal in past discontinuation studies has created uncertainty about the true frequency of antidepressant withdrawal. Pies and Henssler cite a 2019 meta-analysis that found a rate of 56% but immediately dismiss this as “inflated due to selection bias associated with the inclusion of online surveys.” Instead they prefer a meta-analysis, conducted by Henssler himself, which found a much lower rate of 3-15%.

However, the Henssler analysis has biases of its own, many of which far exceed the potential for sample bias in online surveys. As Moncrieff et al. point out:

The data that form the basis of Henssler’s review were derived from trials, which were mostly funded by drug companies to assess efficacy, in which withdrawal was assessed cursorily, most often based on spontaneously reported adverse events. The problematic nature of such data is not discussed in Henssler’s paper, even though it is known to be inconsistent and unreliable and is particularly likely to miss emotional symptoms of withdrawal.

Moncrieff et al. reanalysed Henssler’s data, including only those few studies that had used a systematic measure of withdrawal symptoms. This reanalysis found that the incidence of any withdrawal symptom was 55%, virtually the same rate as that found in the 2019 meta-analysis. In short, the claim that antidepressant withdrawal is rare is not well supported.

“This will come as a surprise to the many patients who have suffered crippling withdrawal.”

However, the belief that it is leads Pies and Henssler to argue that tapering hyperbolically to reduce withdrawal symptoms is largely unnecessary. Instead, they recommend linear tapering over 2-4 months, stating that “our own experience suggests that for the vast majority of patients, gradual tapering of antidepressant agents over 2 to 4 months does not lead to prolonged or severe withdrawal symptoms.” This will come as a surprise to the many patients who have suffered crippling withdrawal after following just such a taper. It’s also a claim that is notable for providing the expert consensus of the authors (“our own experience”) as evidence rather than any systematic proof that short linear tapers provide superior outcomes for patients.

This is ironic, given that Pies and Henssler reject slow, hyperbolic tapering on the grounds that “there are very few, if any, randomized, controlled studies using extended antidepressant tapering periods.” While this is true, there are also no controlled studies demonstrating that short, linear tapers are effective. On the contrary, some evidence suggests that up to 60% of patients may be unable to stop their antidepressants using this method. By contrast, a cluster of cohort studies have shown that tapering hyperbolically with tapering strips enables a similar proportion of patients to stop their antidepressants successfully. One study, in which 71% of participants had previously tried and failed to discontinue the drug, found that 72% were able to discontinue their antidepressant using tapering strips.

However, the part of Pies and Henssler’s critique that will be most upsetting to people who have experienced antidepressant withdrawal will be the claim that their symptoms are mainly attributable to “psychosocial factors, rather than true biological withdrawal.” The authors dismiss the reports of people who have experienced severe withdrawal as “subjective reports and patient-generated narratives,” arguing that fully half of reported antidepressant withdrawal symptoms are accounted for by the nocebo effect. The nocebo effect describes the way that negative expectations of the discontinuation process can cause the patient to imagine that they are experiencing withdrawal symptoms. These are sometimes called “psychosomatic” effects. While nocebo is a measurable effect, six randomized control trials have found an average rate of nocebo withdrawal effects of just 11.8%, far lower than the 50% suggested by Pies and Henssler. As Horowitz has pointed out:

Patients would need to be aware of the range of effects possible in order for psychosomatic symptoms to arise in the same form as “real” symptoms—who would guess that brain zaps are a symptom of withdrawal?

It’s tremendously promising to see an outlet like the Psychiatric Times covering the issue of antidepressant withdrawal. A robust exchange of different viewpoints is welcome and needed. But the quality of the debate goes down and patients and clinicians alike are done a disservice when misleading claims like those of Pies and Henssler are allowed to stand uncriticized.

Photo by by Babak Eshaghian on Unsplash.