Tag: discontinuation syndrome

03/1/22

Withdrawal or Relapse When Tapering Antidepressants?

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The number of antidepressant prescriptions written in primary care has continued to increase, and patients are remaining on them for longer durations of time. Yet research into maintaining or discontinuing antidepressants (ADs) in this setting has been almost nonexistent. “Maintenance or Discontinuation of Antidepressants in Primary Care,” published in September of 2021 in The New England Medical Journal, examined the relapse rates of primary care patients who expressed a desire to discontinue their antidepressant. The researchers, G. Lewis and L. Marston et al, found that patients who chose to discontinue their antidepressant therapy had a higher risk of relapse than those who maintained their current medication. However, others believed the results were misleading, because the authors misinterpreted withdrawal effects as relapse.

Lewis, Marston et al found that patients assigned to discontinue their antidepressant medication had a higher frequency of depression relapse than those who maintained their medication through the 52 weeks of follow-up done by the study. Eligible patients were between 18 and 74, and had reported at least two prior episodes of depression. All patients had been receiving and adhering to their daily regimens and had been taking their ADs for more than two years. The main exclusion criterion for the study was current depression. They investigated three SSRIs, fluoxetine (Prozac), citalopram (Celexa) and sertraline (Zoloft), which have similar pharmacologic profiles and similar mechanisms of activity, and mirtazapine (Remeron).

Relapse occurred in 39% of the patients in the maintenance group, while 56% of the patients in the discontinuation group relapsed. Quality-of-life measures and symptoms of depression, anxiety, and medication withdrawal were generally worse in patients who discontinued their ADs. “By the end of the trial, 39% of the patients in the discontinuation group had returned to taking an antidepressant prescribed by their clinician.” See the figures below.

In a critique published in The BMJ of Lewis, Marston et al, Mark Horowitz, Joanna Moncrieff and Beth Parkin said their conclusion that continuing antidepressants reduced the chance of relapse was not warranted. “Because the authors neglected to account for the possibility of antidepressant withdrawal effects being mis-classified as relapse, a fundamental problem in discontinuation trials.” Although the antidepressants were discontinued more slowly than in previous studies, the 8 weeks of discontinuation was still a relatively short taper for patients who had been taking the drugs for more than 2 years. While the approach was consistent with recommendations at the time of the trial (half the dose for one month, then half the dose every second day for one month, before stopping), they are no longer in line with the current guidance from the Royal College of Psychiatrists on Stopping antidepressants.

Antidepressant withdrawal symptoms overlap with most domains of the depression scale used to detect relapse in the study. There was also a high correlation between mean differences on the withdrawal scale and means differences on the depression scale and anxiety scale. “Together, with the overlap of withdrawal symptoms with measures of mood and relapse, this suggests that the withdrawal symptoms may account for the increase in symptom scores and relapse rate.” The reverse would be unlikely, since withdrawal symptoms included physical symptoms that were not intrinsically related to depression—dizziness, electric shocks, and headache. “Occam’s razor would suggest one condition causes several symptoms rather than requiring several conditions.”

Confounding withdrawal with relapse is consistent with the finding that most relapses occurred when withdrawal effects were at their peak, “within 6-12 weeks of when the drugs were stopped (at week 8).” Ninety percent of the total difference in relapse rates between the two arms of the study were present 12 weeks after the drugs were stopped, although this accounts for only 27% of the total follow-up time. Additionally, patients stopping fluoxetine had fewer withdrawal effects than other antidepressants, likely because of its longer elimination half-life. These patients relapsed 25% less than people stopping citalopram and sertraline, “again suggesting withdrawal effects.”

Anxiety and depression scores were the same for both groups at the end of the study. While 44% of the discontinued group had returned to their medication by this time, there was no difference in symptom scores—even with twice as many people on antidepressants in the maintenance group. “This suggests that discontinuation of antidepressants did not worsen mood after the period in which withdrawal symptoms had settled.” There were only small differences in DESS scores (Discontinuation-Emergent Signs and Symptoms) by the end of the 52 week study. Lastly, 71% of the patients in the discontinuation group correctly guessed their allocation to placebo; possibly because of experiencing withdrawal symptoms and then expecting they would get worse.

As there was no effort made to manage the potential confounding of relapse by withdrawal the current study suffers the same flaws as previous discontinuation studies and cannot provide evidence of the benefits of long-term treatment, only the difficulties of stopping it. The authors could resolve some of these concerns by analysing the correlation of withdrawal symptoms with mood scores and relapse amongst individual patients to verify if withdrawal symptoms might account for relapse. They could also re-analyse their data by excluding patients who experienced significant withdrawal symptoms (e.g. modified DESS ≥ 2) from qualifying for a diagnosis of relapse. This would provide a more robust measure of relapse, reducing the potential for the misclassification of relapse as withdrawal. They could also test whether unblinding was associated with relapse.Uncritical interpretation of this study may lead to the erroneous conclusion that antidepressants should be continued to prevent relapse, when in reality all they may be doing is preventing withdrawal symptoms. The more accurate conclusion would be that such symptoms are temporary withdrawal symptoms that can be minimised by stopping the drug more gradually, as recognised by the authors in media interviews, although not in the published paper.

Additional responses in The BMJ supported these points. Bryan Shapiro said, “Dr. Horowitz offers a valid critique of this discontinuation trial—that is, the confounding of illness relapse with antidepressant withdrawal symptoms.” Gary Singh Marlowe said, “For many patients who have been on anti-depressants for more than a few years a 2-month tapering period is insufficient.” Singh Marlowe said practitioners like him have “become increasingly aware that many of the symptoms these patients experience on stopping their anti-depressants are due to the drug withdrawal itself rather than a return of the ‘illness.’” See “Withdrawal Symptoms Cloud Findings of Antidepressant ‘Relapse’ Trial” by Peter Simon on the Mad in America website for more discussion of the Horowitz, Moncrieff and Parkin critique.

Concern that antidepressant withdrawal symptoms are being confounded with relapse symptoms of depression are not just coming from Mad in America and Horowitz, Moncrieff and Parkin. The Mental Elf reported on a systematic review done by the Cochrane Common Mental Health Disorders group on studies where antidepressants were taken for 6 months or more and then discontinued. Relapse rather than discontinuation was the primary outcome for 31 of 33 studies. Only one study reported data on withdrawal symptoms.

All included trials were at high risk of bias. The main limitation of the review is bias due to confounding withdrawal symptoms with symptoms of relapse of depression. Withdrawal symptoms (such as low mood, dizziness) may have an effect on almost every outcome including adverse events, quality of life, social functioning, and severity of illness.

Because of this flaw, the Cochrane group was not able to conclude whether any of the discontinuation strategies were safe and effective, also noting none of them employed tapering protocols beyond a few weeks. The Cochrane authors also doubted the validity of the evidence base for antidepressant continuation, as it depended “on the same and similar studies thoroughly confounded by withdrawal, which is probably mistaken for relapse.”

Consequently, it is unclear to what degree misclassified withdrawal symptoms contributed to “relapse” rates. Research suggests this could pertain to most relapses (El-Mallakh 2012; Greenhouse 1991; Hengartner 2020; Recalt 2019; Rosenbaum 1988). Moreover, withdrawal symptoms may have an effect on almost every outcome including adverse events, quality of life, social functioning, severity of illness, and anxiety and depression scores. For example, low mood and other withdrawal symptoms may register on the Hamilton Rating Scale for Depression (HAM-D) – the prioritised measure for depressive symptoms – and may result in people falsely allocated to having “severe” depressive symptoms.

Based on the review, the Cochrane review authors advised clinicians that:

  • Because of confounds, the evidence is unreliable for either discontinuation approach or risk of relapse after discontinuation.
  • It is unclear how long antidepressant treatment has to be maintained after remission. Current guidelines are based on consensus rather than evidence.
  • Evidence is lacking for appropriate discontinuation approaches for those who do not have “recurrent” depression, the elderly, and those taking antidepressants for anxiety.
  • The effect of short tapering regimens (≤ 4 weeks) was similar to abrupt discontinuation. Clinicians should expect to taper much slower, perhaps using liquid drug forms or tapering strips, while closely monitoring for withdrawal symptoms.
  • To taper effectively, clinicians will need to recognise withdrawal symptoms. Withdrawal symptoms differ from relapse or recurrence in timing of onset (within days rather than weeks), a rapid reversal after reintroduction of the antidepressant, and the emergence of somatic and psychological symptoms different from the original illness (e.g. shock-like sensations, dizziness, pronounced insomnia). Utilising the Discontinuation-Emergent Signs and Symptoms (DESS) Scale (PDF) may be helpful in monitoring reductions in dosage. When the patient’s DESS score returns to baseline after a reduction, further reduction is appropriate.
  • Mark Horowitz, who is a researcher and psychiatrist, was quoted in an article discussing the Cochrane review on Mad in America. He said:

For me, this is such a critical issue both from a personal and a professional perspective. I’m one of the hundreds of thousands of people who have had or are having long, difficult, and harrowing battles coming off long-term depressants because of the severity of the withdrawal effects. And yet, rather than being able to find or access any high-quality evidence or clinical guidance in this situation, I could only find useful information on peer support sites where people who had gone through withdrawal from antidepressants themselves have been forced to become lay experts. Since then, the Royal College of Psychiatrists has taken a great step forward in putting out guidance on Stopping Antidepressants in 2020. However, there is still a lack of research and, therefore, evidence in this area on what works for different people. I want other people to have the evidence base to come off without the same trouble I had.

American psychiatry has fallen behind Britain in protecting its citizens from the potential for iatrogenic harm of antidepressants. In May of 2018, the All-Party Parliamentary Group for Prescribed Drug Dependence published “Antidepressant Dependency and Withdrawal.” At the bottom of the first page is a disclaimer that says this is not an official publication of the House of Commons or the House of Lords. Yet it seems to have influenced the Royal College of Psychiatrists to make public the above linked information for anyone who wants to know more about “Stopping Antidepressants in 2020.”

The Executive Summary of “Antidepressant Dependency Withdrawal” said it was incorrect to view antidepressant withdrawal as largely mild, self-limiting (typically resolving between 1-2 weeks) and of short duration. Available research showed that antidepressant withdrawal reactions are widespread, with incidence rates ranging from 27% to 86%. Nearly half of those experiencing withdrawal described it as severe. Approximately 25% of antidepressant users experienced withdrawal reactions for at least 3 months after cessation; many experienced AD withdrawal for longer than 6 months.

Antidepressants fulfill the criteria for dependency-forming medications within the DSM, the ICD, and the WHO’s definition of dependency. “It is more reasonable to classify antidepressants as potentially dependency-forming medications than not.” Not only do they cause withdrawal in a large proportion of users, there is evidence antidepressants generate tolerance in up to 25% of users. About a third of antidepressant users report being “addicted”, according to their own understanding of the concept.

“The escalation of long-term antidepressant use combined with the misdiagnosis of withdrawal reactions warrants serious concern.” The length of AD use has doubled over the past decade, fueling a rise in prescriptions for the drugs. The evidence suggests this lengthening duration may be partly rooted in “the underestimation of the incidence, severity and duration of AD withdrawal reactions.” This underestimation may have led to many withdrawal reactions being misdiagnosed as relapse or as failure to respond to treatment with AD medications.

There is one final observation to make about the Lewis, Marston et al study. “Maintenance or Discontinuation of Antidepressants in Primary Care,” was of 150 general practices in the United Kingdom, and yet it was published in the prestigious American journal, The New England Journal of Medicine. I wonder if the researchers were attempting to reach a more receptive and less critical audience than if they had published in a prestigious British journal like The BMJ, which did publish the critique of Horowitz, Moncrieff and Parkin.

04/16/19

Antidepressant “War” Games

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When James Davies and John Read published a systematic review of antidepressant withdrawal effects in the peer-reviewed journal, Addictive Behaviors, they drew media attention to the growing debate over antidepressant withdrawal. Their findings represented “a public health issue of significant proportions.” After decades of silence, the media attention was surprising. But critiques of their review denied and minimized the problem.

Joseph Hayes and Sameer Jauhar responded to the Davies and Read review on the Mental Elf blog: “Antidepressant withdrawal: reviewing the paper behind the headlines.” Hayes and Sameer said when they looked carefully at the Davies and Read review it did not accurately portray the data. “Whilst withdrawal effects are high for certain drugs (paroxetine, venlafaxine), when stopped abruptly, this happens very rarely in clinical practice and guidelines are in placed to address this.”  In response, Davies and Read invited Hayes and Sameer to submit their critique to Addictive Behaviors for a proper peer-review. They also said they disagreed with many of Hayes and Sameer’s arguments:

The fact that there was not more and better research for us to review speaks volumes about whether the prescribing professions have taken the issues seriously. In particular, many of RCT studies employed treatment durations and follow-up protocols that may significantly underestimate withdrawal incidence and duration. Hayes and Jauhar seem particularly concerned about whether our inclusion of surveys may have biased our estimates that 56% experience withdrawal symptoms when coming off and 46% of those describe them as severe. We readily concede, as we did in the review, that our estimates are indeed estimates, based on the best available evidence. They may be off by 5% or even perhaps as much as 10%, lower or higher.

Their estimates were that 56% of those who attempt to come off of antidepressants experience withdrawal. Forty-six percent of those individuals described the effects of withdrawal as severe; and it was not unusual for the withdrawal effects to last for several months. Davies and Read concluded current guidelines underestimated the severity and duration of antidepressant withdrawal.

We recommend that U.K. and U.S.A. guidelines on antidepressant withdrawal be urgently updated as they are clearly at variance with the evidence on the incidence, severity and duration of antidepressant withdrawal, and are probably leading to the widespread misdiagnosing of withdrawal, the consequent lengthening of antidepressant use, much unnecessary antidepressant prescribing and higher rates of antidepressant prescriptions overall. We also recommend that prescribers fully inform patients about the possibility of withdrawal effects.

James and Davies further said using the term ‘discontinuation syndrome’ to characterize antidepressant withdrawal ran contrary to the evidence. The term is misleading, since it wrongly separated antidepressant withdrawal from other CNS (central nervous system) drug withdrawals and minimized the vulnerabilities from SSRIs. Antidepressant withdrawal could occur without discontinuation, for example, with a decrease in medication.

There can also be a misdiagnosis of withdrawal. Re-emergent symptoms of depression and anxiety regularly occur with antidepressant withdrawal and are misread as evidence of a relapse. This leads to drugs being reinstated and a more negative prognosis being used.

Withdrawal can also be misdiagnosed in other ways: as failure to respond to treatment (e.g. where covert non-adherence is mistaken as the condition worsening, leading to dose increase or drug switching); or as bipolar I or II (e.g. where ‘manic’ of ‘hypomanic’ withdrawal reactions are misdiagnosed as the early onset of bipolar); or as the result of switching medications (e.g. where withdrawal reactions are misdiagnosed as side-effects of the new antidepressant).

Concern with antidepressant withdrawal led The New York Times to publish two articles: “Many People Taking Antidepressant Discover They Cannot Quit” and “Antidepressant and Withdrawal: Readers Tell Their Stories.” In “Many People,” the authors noted how the long-term use of antidepressants has more than tripled since 2000. Nearly 25 million adults “have been on antidepressants for at least two years, a 60 percent increase since 2010.” The drugs were initially approved for short-term use; to get through a crisis. “Even today, there is little data about their effects on people taking them for years, although there are now millions of such users.”

The Times article looked at data gathered since 1999 as part of the National Health and Nutrition Examination Survey. See the chart below. “‘What you see is the number of long-term users just piling up year after year,’ said Dr. Dr. Mark Olfson, a professor of psychiatry at Columbia University.”  Peter Kramer, a psychiatrist and author of books such as: Listening to Prozac, said he thought the decision to use or not use antidepressants was a cultural one—how much depression should someone have to live with? “I don’t think that’s a question that should be decided in advance.”

Antidepressants are not harmless; they commonly cause emotional numbing, sexual problems like a lack of desire or erectile dysfunction and weight gain. Long-term users report in interviews a creeping unease that is hard to measure: Daily pill-popping leaves them doubting their own resilience.

In the second NYT article, “Readers Tell Their Stories,” the authors said more than 8,800 people responded to their invitation to tell The Times of their experience with long-term antidepressant use. They said by the mid-1990s drug makers had convinced the FDA that antidepressants reduced the risk of relapse in people with chronic, recurrent depression and should be taken long-term. Then beginning in 1997, pharmaceutical companies were allowed to advertise directly to consumers. This coincided with the popularization of the “chemical imbalance theory” of depression by drug company marketers and some researchers.

In truth, the theory has scant basis. No one knows the underlying biology of depression or any mood disorder. But that shift — along with a change in federal regulations, in 1997, allowing drug makers to advertise directly to consumers — helped undermine the stigma associated with depression and mood disorders generally.

Ronald Pies and David Osser also responded critically to the Davis and Read systematic review in Psychiatric Times, “Sorting Out the Antidepressant ‘Withdrawal’ Controversy.”  They said they don’t deny that severe reactions can occur when antidepressants are stopped suddenly, “we also believe that fears of such “excruciating” experiences are greatly overstated, in the context of proper psychiatric care.” Pies and Ossler redirected the blame onto primary care physicians, who prescribe nearly 80% of antidepressants. “Moreover, as critics of these drugs rightly point out, it is very hard to find detailed, professionally approved guidelines for tapering and discontinuation of antidepressants.”

Pies and Osser disagreed with the implication that antidepressants were “addictive” drugs. “We strongly disagree with that characterization and do not believe that SSRI/SNRI discontinuation/withdrawal symptoms should be lumped together with those of clear-cut drugs of abuse, such as alcohol and barbiturates.” They said there was no conclusive evidence of pathophysiological mechanisms underlying SSRI/SNRI withdrawal similar to drugs of abuse such as alcohol, opioids, barbiturates or benzodiazepines. Craving, compulsive use, intentional overuse, and “getting high” are not characteristic of SSRI/SNRI antidepressants.

In their view, the vast majority of serious withdrawal symptoms occurred when the tapering period of SSRIs/SNRIs was less than 1 or 2 months. “This may be particularly the case when the patient has taken the medication for a year or longer.”

We believe, based on our extensive experience with antidepressants, that serious withdrawal symptoms are extremely rare when tapering periods of 2 to 6 months are used. However, we acknowledge that such long tapering periods are probably uncommon in general medical practice, and even in most psychiatric settings.

Davies and Read responded to Pies and Osser in a letter published in Psychiatric Times, “The International Antidepressant Withdrawal Crisis: Time to Act.”  They thought Pies and Osser had a biased reading of their systematic review and a selective use of the literature in order to “reassure professionals that antidepressant withdrawal is minimal and easily manageable.” Their opinion was that when clinicians started from the false presumption that a problem was rare, “this can become a self-fulfilling prophecy that minimizes the problem in perpetuity.” They reminded us that in the 1960s and 1970s it was the clinical experience of note psychiatrists that benzodiazepines were not addictive.

They pointed out how the three types of studies in their review did not differ greatly in terms of withdrawal incidence. They gave the weighted averages of each as: 57.1% in online surveys; 52.5% for naturalistic studies; and 50.7% for short randomized controlled trials. Similar findings from the differing methodologies strengthened confidence in the overall estimate. “In fact, findings from the three methodology types demonstrate that it is broadly safe to conclude that at least half of people suffer withdrawal symptoms when trying to come off antidepressants.”

Davies and Read concluded their review by saying antidepressant withdrawal reactions were widespread. Current clinical guidelines in the U.S. and U.K. are in need of correction, “as withdrawal effects are neither mostly ‘mild’ nor ‘self-limiting’ (i.e. typically resolving over 1–2 weeks), but are regularly experienced far beyond what current guidelines acknowledge.”  The lengthening duration of antidepressant use has fueled the increase of antidepressant prescriptions over the same time period.

The evidence set out suggests that lengthening use may be partly rooted in the underestimation of the incidence, severity and duration of antidepressant withdrawal reactions, leading to many withdrawal reactions being misdiagnosed, for example, as relapse (with drugs being reinstated as a consequence) or as failure to respond to treatment (with either new drugs being tried and/or dosages increased). This issue is pressing as long-term antidepressant use is associated with increased severe side-effects, increased risk of weight gain, the impairment of patients’ autonomy and resilience (increasing their dependence on medical help), worsening outcomes for some patients, greater relapse rates, increased mortality and the development of neurodegenerative diseases, such as dementia.

Before the Davies and Read review, this debate about antidepressants was largely ignored in the media. But “A systematic review into the incidence, severity and duration of antidepressant withdrawal effects” brought the debate into the media spotlight and demanded a response from conventional psychiatry. On January 23, 2019, Jahaur and Hayes finally published their critique of the Davies and Read review in Addictive Behaviors (as Davies and Read had invited) with the title: “The war on antidepressants.” Sometime afterwards, the article was removed with the following caveat: “The publisher regrets that this article has been temporarily removed. A replacement will appear as soon as possible at which time the reason for the removal of the article will be specified, or the article will be reinstated.”

As of March 16th, when I’m publishing this article, there is no information on why the publisher temporarily removed the article. Michael Hengartner, writing for Mad in America, attempted to explain how the debate turned into such a heated dispute, into a “war.” He traced the origins of the debate back to a February 24, 2018 article to The Times by Wendy Burn and David Baldwin that affirmed: “any unpleasant symptoms experienced on discontinuing antidepressants have resolved within two weeks of stopping treatment.” (See “The Lancet Story on Antidepressants” Part 1 and Part 2 for more). Several academics and psychiatrists, including Davies and Read, challenged the two-week “discontinuation” claim made by Burn and Baldwin. A formal complaint was made to the UK Royal College of Psychiatrists, asserting that the public was being misled over antidepressant safety. Hengartner said:

Given that the biomedical treatment approach constitutes the foundation of modern psychiatry, it was not further surprising that challenging the long-term safety of antidepressants caused discomfort (and, in my view, also disbelief and even denial) within academic psychiatry.

The dispute spilled over into social media, with Jauhar, Hayes and Read trading barbs on Twitter. The Twitter exchanges increased in its aggressive tone, “with ad hominem attacks” made by both sides. Hengartner said he entered the debate in order to point out how Jauhar and Hayes had been exceptionally fierce and reproachful. “In my view, their critique was not only offending, but I also think that some of the most serious charges were unsubstantiated.” Perhaps this tone from Jauhar and Hayes led to “The war on antidepressants” being temporarily removed from the Addictive Behaviors website. “Moreover, the allegation that both the presentation of the results and the conclusions drawn from the data are severely flawed is unwarranted (or at least grossly exaggerated).” His concluding paragraph nicely captured the debate:

Davies and Read put the claim that withdrawal symptoms affect only a small minority and typically resolve within 2 weeks to the test. They provide evidence that withdrawal effects occur in about half of all antidepressant users and that withdrawal is experienced as severe in about half of those concerned. These findings clearly contradict the preferred narrative in mainstream psychiatry. The media widely disseminated these inconvenient findings and soon the review by Davies and Read was fiercely attacked by academic psychiatry in the person of Jauhar and Hayes, who contend that the review was flawed and systematically biased. However, most allegations did not stand up to scrutiny and turned out to be greatly exaggerated or even false. In the interest of the patients who are currently experiencing withdrawal reactions and the many more who will suffer withdrawal effects in the future, we need to end this “war.” Academic psychiatry must address these problems and conduct thorough research on withdrawal reactions. Instead of declaring war, psychiatry should offer solutions on how it wants to combat severe and persistent antidepressant withdrawal. And it is important that psychiatry and clinical psychology reconcile, because, ultimately, we are on the same mission. Our purpose is to help people with mental health problems. Let’s not forget this, even amidst fierce scientific debates.