There are a number of developments and links to share this time around, so I plan to do that in multiple parts over the next couple of days.

New research on the incidence of antidepressant withdrawal
A new systematic review and meta-analysis of the incidence of antidepressant discontinuation symptoms has been published in Lancet Psychiatry, and has generated considerable debate. It includes 79 studies (44 RCTs and 35 observational studies) covering 21K patients. Authors report:
“Incidence of at least one antidepressant discontinuation symptom was 0·31 (95% CI 0·27–0·35) in 62 study groups after discontinuation of antidepressants, and 0·17 (0·14–0·21) in 22 study groups after discontinuation of placebo. Between antidepressant and placebo groups of included RCTs, the summary difference in incidence was 0·08 [0·04–0·12]. The incidence of severe antidepressant discontinuation symptoms after discontinuation of an antidepressant was 0·028 (0·014–0·057) compared with 0·006 (0·002–0·013) after discontinuation of placebo. Desvenlafaxine, venlafaxine, imipramine, and escitalopram were associated with higher frequencies of discontinuation symptoms, and imipramine, paroxetine, and either desvenlafaxine or venlafaxine were associated with a higher severity of symptoms. Heterogeneity of results was substantial.”
Most studies were of short duration, lasting several weeks, but there were also studies looking at extended use. Duration of antidepressant therapy before discontinuation ranged up to 156 weeks, and duration of observation of discontinuation symptoms ranged up to 196 days.
This systematic review and meta-analysis is an important and long overdue contribution to the research literature. It is a valuable corrective to current discussions in two ways. One, it provides a more accurate estimate of discontinuation effects compared to early inflated estimates based on online surveys that generated considerable public alarm but were not congruent with real-world clinical experience, leading to polarized debates and clinical disbelief. Two, for those skeptical that antidepressant discontinuation effects arise with a frequency that is clinically significant, this review confirms that antidepressant discontinuation effects are indeed clinically relevant, and all clinicians working with patients on antidepressants must be knowledgeable about them and should know how to manage them. An incidence of antidepressant discontinuation symptoms of any severity being experienced by one in six patients who discontinue their medication and severe withdrawal symptoms being experienced by around one in thirty patients has more face validity, in my opinion, and better represents what happens in the clinic, but this likely under-estimates the incidence of withdrawal with years of antidepressant use. Certain antidepressants are associated with greater rates of withdrawal in this analysis, and this is also congruent with clinical practice, where most discontinuation effects are concentrated around the use of venlafaxine and paroxetine. There is still a considerable dearth of high quality clinical trials investigating antidepressant withdrawal effects, and while this present analysis appears rigorous with regards to short- and medium-term use of antidepressants, I would not be surprised if future research leads to further revision of these estimates. It is true that this review has important limitations, but it is by far the most rigorous systematic review and meta-analysis we have on this subject. Those who criticize this review on grounds of methodological rigor should be absolutely aghast at the methodological weaknesses of earlier reviews whose findings they champion. (Some of my comments were included in the STAT News story on this paper by Annalisa Merelli.)
On the issue of antidepressant withdrawal, I’ve been of the view (and have said so to that effect on numerous occasions) that the condition has generally been neglected, poorly recognized, poorly studied, and poorly managed. There are some who seem to take the view that antidepressant withdrawal is so prevalent and so serious for such a large percentage of people that the routine use of antidepressants cannot be justified. I have disagreed with such extreme views, and such positions are consistent neither with existing scientific evidence nor with clinical experience, but I remain a proponent of taking antidepressant withdrawal seriously and being open about it with patients. I think serious and protracted harm from antidepressants is experienced by a small percentage of people. For the vast majority, any withdrawal experienced is manageable with a sensible tapering strategy. But a small percentage still translates into large absolute numbers worldwide, and this suffering needs to be recognized and addressed appropriately. People experiencing severe and protracted withdrawal often require specialized strategies, such as very slow hyperbolic tapering, or concomitant use of other medications to facilitate the taper.
Lewis and Lewis are correct when they write in their commentary:
“Given that antidepressants are prescribed to many millions of people, the relatively uncommon severe withdrawal symptoms will still affect a substantial number of people. Organisations that help people stop prescription drugs have many members who have difficulty in stopping antidepressants. However, for individual clinicians, severe withdrawal symptoms will seem uncommon and most patients will likely not be troubled by antidepressant withdrawal, especially when medication is tapered over a few weeks.”
Substack Roundup
- on “The Deal With How We Pick Antidepressants and Antipsychotics,” part one and part two: “we’re probably too dismissive about antidepressant selection and excessively particular about antidopaminergic selection.”
Wil Ward for
— Universal Depression Screening Leads to Unnecessary Harm- — Scott Alexander on demons in Internal Family Systems therapy, Book Review: The Others Within Us
A complement to demons in IFS —
on psychedelic industry’s entity dilemma:“The psychedelic industry faces a dilemma. What should it say about entities? The industry wants to go from the New Age fringes and become a normal, insurance-refundable part of western healthcare. And it’s doing pretty well at that objective. However, psychedelic drugs reliably lead to entity encounters, and that’s not normal for western healthcare.”
- — A critical theory of (or for) America
- — Serotonin Inhibits Emotions. And that’s OK
- — The Weird Nerd comes with trade-offs. “there is a trend wherein Weird Nerds are being driven out of academia by the so-called Failed Corporatist phenotype... most people, while liking non-conformism in the abstract and post-facto, are not very willing to actually put up with the personality trade-offs of Weird Nerds in practice.”
- — The Modified Aberrant Salience Hypothesis (MASH) for Psychosis
I have enjoyed
’s weekly discussion of interesting publications in psychiatry on . Recommend following.
FDA Advisory Committee Vote on MDMA-Assisted Psychotherapy
As almost everyone reading this post would be aware by now, advisory committee to the US FDA voted overwhelmingly against the approval of MDMA-assisted psychotherapy for PTSD. Even though there was a large efficacy signal, numerous concerns were raised by the committee, relating to functional unblinding, the psychotherapy protocol in the study, a lack of medical tests to ensure safety post-administration (even basic stuff, like liver enzymes, duh!), abuse potential, problems with dropouts in the follow-up study, and an incident of sexual abuse by a study therapist, among other concerns! Barone on the committee expressed it very well: “it seems like there are so many problems with the data… each one alone might be okay, but when you pile them on top of each other… I think there’s just a lot of questions still”.
Josh Hardman at Psychedelic Alpha provided a detailed live account of the advisory committee meeting, which I found very helpful in developing a more granular sense of how the meeting unfolded without having to watch it myself. For overviews, you can refer to the coverage by Nature and Psychiatrist.
There have been an number of excellent commentaries on this outcome. Owen Muir (
) has been doing a multi-part series on “Saving MDMA” at (part one here, and see the archive for follow-ups). Andrew Penn () has aptly commented, “It’s not the psychedelic renaissance. It’s the psychedelic adolescence.” has made the case “MAPS (now Lykos) exploited the suggestibility-enhancing properties of MDMA to advance an evangelical mission to spiritualize humanity through the vehicle of its clinical trials… I believe that MDMA has potential as a therapeutic tool in the treatment of PTSD, but I don’t believe that MAPS designed their trials to effectively demonstrate that. In my analysis below, I assembled evidence that their particular therapy increases the risks of MDMA, especially for those with PTSD related to sexual assault and minority trauma.” has commented on “who is to blame and what happens next?,” pointing out the tension between tension between MAPS / Doblin and Lykos. STAT News has produced an excellent story (unfortunately paywalled) on “how Lykos’ MDMA research went awry” and the various problems with the research culture at Lykos/MAPS.