07/19/22

The Vicious Cycle of Antidepressant Use

CDC data reported that 13.2% of adults used antidepressants in the past 30 days, and their use increased with age. A similar increase by age was apparent when antidepressant use was examined in both men and women. “In all age groups, antidepressant use was higher among women compared with men.” However, a new study suggested that antidepressant use has very little effect on patients’ health-related quality of life.

The above information on antidepressant use was taken from the CDC data brief report looking at Antidepressant Use Among Adults in the United States. Antidepressant use in the past thirty days increased among adults aged 18-39 (7.9%), then to 14.4% among adults aged 40-59, and to 19.0% among adults aged 60 and over. Disconcertingly, 20% of women between 40 and 59 almost one quarter of women 60 and over were prescribed antidepressants. Overall, antidepressant use increased from 10.6% in 2009 to 13.8% in 2018. See the following charts from the CDC data brief.

The New York Times cited these statistics in “How Much Do Antidepressants Help, Really?” It observed that clinical drug trials only follow people taking antidepressants for 8 to 12 weeks, missing the vast majority of people who take them longer. The NYT article then referenced a study published in April of 2022, “Antidepressants and health-related quality of life (HRQoL) for patients with depression.” This study compared Americans with a depression diagnosis who took antidepressants, to Americans with a depression diagnosis who did not take the medications over the course of two years.

The data came from the US National Medical Expenditures Panel Survey (MEPS). The study included all types of antidepressants—SSRIs like Prozac, SNRIs like Effexor, and older antidepressants like phenelzine. The researchers found no significant differences in the changes in quality of life reported by the two groups, suggesting “that antidepressant drugs may not improve long-term quality of life.”

A physician and epidemiologist who was not involved in the study said it was difficult to come to a conclusion on this study alone. Individuals who are prescribed antidepressants are likely more depressed than individuals who aren’t prescribed drugs. “People with more severe depression might be less likely to improve their mental quality-of-life scores over time,” for reasons that don’t correspond to the antidepressants they take. When Peter Simons reviewed the study for Mad in America, he said that critique was simply false.

The researchers used a statistical method called the difference-in-difference (D-I-D) analysis that compared each subject’s follow-up levels to their individual baseline levels for their physical and mental component summaries, (PCS and MCS). They acknowledged their study’s inability to control for the effect of the severity of depression. “However, the D-I-D analysis compare each subject’s follow-up levels to his/her individual baseline levels for the PCS and MCS and investigate the overall change for the group which should minimize the impact of this factor on the overall analysis.”

Another perceived issue with the study was that since people were taking antidepressants for an extended time, some quality-of-life improvements could have taken place before the study began following them. Omar Almohammed, a co-author of the study said it was still reasonable to expect continued increases in quality of life long after beginning an antidepressant. “If we don’t expect improvement from the continuous use of these medications, then the correct decision might be to stop the continuous use of these medications.”

But pills are often cheaper. And it can be difficult for some to access therapy because there aren’t enough providers, and mental health treatment aren’t fully covered by all insurance plans. Robert DeRubeis of the University of Pennsylvania said, “It’s not at all clear that even in the short term, pharmacological approaches, on average, are more effective than psychological ones.”

Clinical trials suggest that although antidepressants do improve depression symptoms over the first few months, their benefits are modest and are much less pronounced among people with mild depression compared with those with severe depression. (This is worrying considering that, according to one study, 73 percent of Americans prescribed antidepressants don’t even have a diagnosis of depression.) And experts are divided over whether these small benefits make a noticeable difference to people’s moods or overall functioning.

Much of this improvement is attributed to the placebo effect, rather than the medication itself. Even researchers who argue the benefits from antidepressants admit they “do not work for everybody.” And over time, they will have even less benefits. There are approximately 15.5 million Americans who have been taking antidepressants for at least five years. The longer that people take them, there will likely be increasingly smaller benefits, “in part because patients build up a tolerance to the medications.”

But there is a vicious cycle if you decide to discontinue your use of antidepressants. Too rapid of a taper can lead to antidepressant withdrawal, euphemistically called “discontinuation syndrome.” These withdrawal symptoms are sometimes seen as a depressive relapse, “proving” the need to remain on antidepressants in order to hold off a major depressive episode. They often include physical sensations such as dizziness, nausea, and “brain zaps” (an electric shock sensation in the head). In “Distinguishing relapse from antidepressant withdrawal,” Mark Horowitz and David Taylor said many withdrawal symptoms overlap with symptoms of anxiety or depressions, making it difficult to distinguish.

Their onset soon after dose reduction, the association of psychological with physical symptoms, their prompt response to reinstatement, and their typical ‘wave’ pattern of onset, peak and resolution can help distinguish withdrawal symptoms from relapse.

Giovanni Fava has researched the adverse effects of antidepressants for almost thirty years. In 1994, he said in an editorial for the journal Psychotherapy and Psychosomatics, “The field of psychopharmacology has generally neglected the issue of potential sensitization of psychiatric disease to psychotropic drug use.” In January of 2022 he released Discontinuing Antidepressant Medications, as a guide for clinicians who want to help patients withdraw from antidepressants. Fava was interviewed by James Moore about the release of his book for a Mad in America podcast.

In Discontinuing Antidepressant Medications, Fava introduced the construct of behavioral toxicity of psychotropic drugs, applying it to the field of antidepressant tapering and discontinuation. Fava said it was originally described by Alberto DiMascio and Dick Shader.

A medication that is used at the normal, average doses may become toxic to the patient and this toxicity expresses itself with phenomena such as loss of clinical effect, where the patient is doing well on antidepressant and after a while of taking medication regularly, the antidepressant no longer works. If you try to increase the dosage, it may only help for a little while. So, loss of clinical effect and hypomanic episodes—that is the medication is really working too much and brings the patient to a state of hypomania or mania which is a symptom of bipolar disorder—but also a paradoxical fact that is that the antidepressant makes you more depressed.In the book, I discuss the relationship between venlafaxine and apathy. This is an example of a paradoxical effect and resistance, the fact that these patients become resistant either to the same medication, when it’s prescribed again or to another medication. Withdrawal is part of behavioral toxicity and my view is quite different from that of other investigators in the field because as a clinician I know that all these manifestations of behavioral toxicity are related.

Fava said if you have two, or three or even four of these manifestations together, it is likely an example of behavioral toxicity. He works with the most difficult cases and explained that the longer a patient is on a medication, “The higher the toxicity that you provoke.” In other words, the antidepressant that initially was effective “has become toxic” to the patient and is causing a problem. He said it is difficult to discontinue an antidepressant if you don’t use some additional medications and psychotherapy. Discontinuing antidepressants is not something that can be applied to all patients.

So, when I discuss with a patient, I’ll say that most of the patients, 90% of the patients respond, “Please, get this medication out of my body as soon as you can.” Then, we continue with that, but a basic problem which is not only in this field but in psychiatry and in medicine today is to believe that there is a procedure we should apply to all patients, and that is clinical practice shows that it’s not possible.

Antidepressant withdrawal, discontinuation syndrome, is becoming a greater concern in American psychiatry, but it isn’t where it needs to be. In addition to Giovanni Fava, Peter Breggin has been critical of the over prescription of psychiatric medications and wrote Psychiatric Drug Withdrawal in 2013. In 2020, the Royal College of Psychiatrists published “Stopping Antidepressants,” which contains information for “anyone who wants to know more about stopping antidepressants.” In May of 2018, The All-Party Group for Prescribed Drug Dependence (in the Parliament of the U.K.) published, “Antidepressant Dependency and Withdrawal.”

The Executive Summary of that publication said it was incorrect to view antidepressant withdrawal as largely mild, self-limiting and of short duration. Antidepressants fulfill criteria for being dependency-forming medications. Around one-third of users “report being addicted to AD [antidepressants], according to their own definition of that concept.” The increase of long-term antidepressant use along with with the misdiagnosis of withdrawal reactions warrants serious concern.

The lengthening duration of AD use (which has doubled on average in the last 10 years) has fuelled rising AD prescriptions over the same time period. The evidence suggests that such lengthening duration may be partly rooted in the underestimation of the incidence, severity and duration of AD withdrawal reactions; underestimations which may have led to many withdrawal reactions being misdiagnosed as relapse or as failure to respond to treatment. It warrants serious concern that the misdiagnosis of withdrawal may be contributing to escalating long-term AD use (since drugs are being reinstated rather than withdrawn), given that long-term 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, and the development of neurodegenerative diseases, such as dementia.

For more on antidepressants on this website, try: “Withdrawal or Relapse When Tapering Antidepressants?” and “Are Antidepressants Worth the Risks?”

03/1/22

Withdrawal or Relapse When Tapering Antidepressants?

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.

08/13/19

Following the Leader with Antidepressants

In February of 2018 the international debate on antidepressants was renewed when James Davies, a co-founder of the Council for Evidence-Based Psychiatry (CEP), and his coauthors published a letter in the Times on the benefits and harms of antidepressants. This was in response to a study done by Cipriani et al that found all the 21 antidepressants reviewed to be more effective than placebo. Carmine Pariante of the Royal College of Psychiatrists said: “This meta-analysis finally puts to bed the controversy on anti-depressants, clearly showing that these drugs do work in lifting mood and helping most people with depression.” In response, the Council for Evidence-Based Psychiatry said that statement was “irresponsible and unsubstantiated, as the study actually supports what has been known for a long time,” namely that the differences between placebo and antidepressant are so minor that they are clinically insignificant. It created a media and professional firestorm that has yet to burn out, and even led to some strategic retreats by organizations like the RCP that originally hailed the results.

CEP noted how the individuals in the referenced studies were not in truly blinded clinical trials. “Most people on antidepressants experience some noticeable physical or mental alterations, and as a consequence realise they are on the active drug.” This then boosts the placebo effect, adding further questions about the so-called effectiveness of antidepressants. Irving Kirsch has published several studies demonstrating the significance of the placebo effect with antidepressants. For more on the Cipraini et al study, see “The Lancet Story on Antidepressants,” Part 1 and Part 2. For more on Irving Kirsch and the placebo effect, see “Dirty Little Secret.”

Additionally, the trials only addressed short-term use of antidepressants (8 weeks), not the long-term use which is more typical. “Around 50% of patients have been taking antidepressants for more than two years, and the study tells us nothing about their effects over the long term. In fact, there is no evidence that long-term use has any benefits, and in real-world trials (STAR-D study) outcomes are very poor.” STAR*D was the largest, longest and most expensive study of antidepressants ever conducted.

James Davies and John Read (also a member of CEP) published a systematic review in the journal Addictive Behaviors that showed antidepressant withdrawal was “more widespread, severe and long-lasting than indicated by current guidelines.” The review indicated that an average of 56% of patients who stop or reduce their antidepressants experience withdrawal symptoms, a significant proportion of whom experienced them for more than two weeks. “It is not uncommon for patients to experience symptoms for several weeks, months, or longer.” One study said 40% of patients experience symptoms for at least six weeks; another indicated that 25% experience symptoms for at least 3 months. Davies said the new review indicated what patients have known for years, “That withdrawal from antidepressants often causes severe, debilitating symptoms which can last for weeks, months or longer.”

Davies and Read noted in their paper that an implication of the higher incidence of antidepressant withdrawal and longer duration added credence to concerns that doctors were misdiagnosing antidepressant withdrawal as treatment failure. “Re-emergent symptoms of depression and anxiety are a regular feature of antidepressant withdrawal itself.” They pointed out where the RCP’s own survey, “Coming Off Antidepressants” found that the withdrawal reaction was rated severe by most people, and approximately 25% of users reported experiencing anxiety for at least 3 months after stopping their antidepressant.

The President of the Royal College of Psychiatrists, Wendy Burn, published a letter in the Times that said “We know that in the vast majority of patients, any unpleasant symptoms experienced on discontinuing antidepressants have resolved within two weeks of stopping treatment.” CEP challenged the Royal College of Psychiatrists and its president, stating they believed the statement was not evidence-based; that it misled the public. Further, they pointed out how within 48 hours of the misleading statement in the Times, the RCP removed “Coming Off Antidepressants” from its website. They suggested one interpretation of that action was the RCP was attempting keep the public from seeing evidence that contradicted what the RCP president claimed in the Times.

This was not just a dispute between CEP and the RCP over interpreting Cipriani et al. August of 2018 contained a one-two punch that broadened the debate over antidepressant ineffectiveness. The British Journal of Psychiatry published an editorial written by Gordon Parker, the founder of The Black Dog Institute, “The benefits of antidepressants: news or fake news?” that said antidepressant trials were disconnected from the real world of clinical practice. Psychological Medicine published a study by de Vries et al that analyzed the cumulative effect of publication biases on the apparent efficacy of antidepressants for the treatment of depression.

Asking if antidepressants are effective treatment for major depression is asking the wrong question. The problem, according to Gordon Parker, is that ‘major depression’ is a “domain diagnosis” for a variety of depressive illnesses. “Basically, the target diagnosis of major depression captures multiple types of depressions—some biological, some psychological, some social—and not all would be expected to respond to medication.” In other words, you lose the evidence for their effectiveness with biological causes by combining them with social and psychological ones. “For patients with depression, if you narrow down to those who have a biologically-based depressive sub-type, the antidepressants are distinctly effective.”

De Vries et al looked at the cumulative impact of biases upon on two effective treatments for depression: antidepressants and psychotherapy. They identified four major biases: study publication bias, outcome reporting bias, spin, and citation bias. Study publication bias involves not publishing an entire study. Outcome reporting bias refers to not publishing negative outcomes or switching the status of primary and secondary outcomes. “Both biases pose an important threat to the validity of meta-analyses.”

Spin uses reporting strategies that distort the interpretation of results and mislead readers. Authors conclude the treatment is effective despite non-significant results on the primary outcome. For example, by focusing on statistical significance instead of clinical significance, researchers have confirmed the efficacy of several SSRIs. Another spin technique is instead of concluding a treatment was no more effective than placebo, researchers point out how a treatment was well tolerated and effective in a sub population of the original study, say patients who had not received prior therapy. Finally, with citation bias, studies with positive results receive more citations than negative studies. This leads to greater visibility of positive results and creates an obstacle to ensuring that negative findings can be discovered. De Vries et al concluded:

The problem of study publication bias is well-known. Our examination of antidepressant trials, however, shows the pernicious cumulative effect of additional reporting and citation biases, which together eliminated most negative results from the anti-depressant literature and left the few published negative results difficult to discover. These biases are unlikely to be unique to anti-depressant trials. We have already shown that similar processes, though more difficult to assess, occur within the psychotherapy literature, and it seems likely that the effect of these biases accumulates whenever they are present. Consequently, researchers and clinicians across medical fields must be aware of the potential for bias to distort apparent treatment efficacy, which poses a threat to the practice of evidence-based medicine.

In October of 2018 a reanalysis of the STAR*D study, supported the claim of antidepressant ineffectiveness. The STAR*D study, published in 2004, attempted to mimic real world patients, recruiting from routine outpatient treatment centers. Additionally, they did not exclude patients with comorbid diagnoses, as is typically cone in clinical trials. STAR*D was funded by the NIMH at a cost of $35 million dollars and took six years to complete. The reanalysis was done by Irving Kirsch and others. The improvement found in the reanalysis was roughly half of that seen in the standard comparative drug trials. In her review of the Kirsch-led reanalysis for Mad in America, Joanna Moncrieff said STAR*D suggested that “in real life situations (which the STAR-D mimicked better than other trials) people taking antidepressants do not do very well.”

For the vast majority of people, depression naturally remits. “It is difficult to believe that people treated with antidepressants do any better than people who are offered no treatment at all.” Moncrieff speculated this may be the reason why the results of the main outcome of the STAR*D study took so long to be published. For more on the STAR*D study, see “Antidepressant Fall from Grace, Part 2.”

Then in May of 2019, the Royal College of Psychiatrists changed its position on antidepressant withdrawal. It issued a revised policy statement updating its guidance to doctors. James Davies of CEP said the changes were welcome; and if acted upon, “will help reduce the harm that is being caused to huge numbers of patients through overprescribing, inadequate doctor training and often disastrous withdrawal management.” The College called for the following changes:

There should be greater recognition of the potential for severe and long-lasting withdrawal symptoms on and after stopping antidepressants in NICE guidelines and patient information
NICE should develop clear evidence-based and pharmacologically-informed recommendations to help guide gradual withdrawal from antidepressant use
The use of antidepressants should always be underpinned by a discussion with the patient about the potential level of benefits and harms, including withdrawal
Discontinuation of antidepressants should involve the dosage being tapered, which may occur over several months, and at a reduction rate that is tolerable for the patient
Monitoring is needed to distinguish the features of antidepressant withdrawal from emerging symptoms
Adequate support services should be commissioned for people affected by severe and prolonged antidepressant withdrawal, modelled on existing best practice
There should be routine monitoring on when and why patients are prescribed antidepressants
Training for doctors should be provided on appropriate withdrawal management
Research is needed into the benefits and harms of long-term antidepressant use

These changes by the RCP with regard to antidepressants are needed in the US as well. Antidepressant withdrawal is a real concern for some individuals. Routine monitoring of when and why patients are prescribed antidepressants is needed. Support services are needed for individuals who experience severe and prolonged withdrawal. There is a need to inform patients when prescribing antidepressants of the potential benefits as well as the potential harms—including withdrawal.

Research into the potential benefits and harms of long-term antidepressant use is needed. Discontinuation of antidepressants should be done slowly, taking its cue from how well the patient is tolerating the taper. Both the patient and doctor should carefully monitor the tapering process and strive to distinguish between symptoms of antidepressant withdrawal and emerging symptoms of the underlying depressive disorder. Doctors need to be trained in appropriate tapering and withdrawal management of antidepressants.

Drawing on the above discussion, we can add the need for greater awareness of the multiple types of depressions—some biological, some psychological, some social—and the need to freely acknowledge that antidepressants won’t work for everyone. Edward Shorter makes a compelling case for distinguishing between depression and melancholia in How Everyone Became Depressed. In the pursuit of developing the evidence base for the use of antidepressants and best practice guidelines, we need to systematically eliminate the impact of bias on the publication of research results with antidepressants. Admittedly this is a problem that extends beyond just antidepressant research, see “Clinical Trial Sleight-of-Hand,” “The Reproducibility Problem” and “Reproducibility in Science” for more information.

British psychiatrists have taken the first step towards correcting errors in how they use antidepressants. Hopefully they will persist in seeing that the recommended changes are implemented. American psychiatrists and physicians need to do the same. They need to follow the lead of the RCP.

04/16/19

Antidepressant “War” Games

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 16^th, 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.

07/30/14

Getting Off the Antidepressant Merry-Go-Round

I told Allison to concentrate on my voice and imitate how I was breathing. My coworker held her head in her lap. Together we kept Allison focused until the paramedics came. Determined to stop all drug use after she came into outpatient drug and alcohol treatment, she decided to stop taking her Paxil … cold turkey. The result was a severe panic attack and ER visit.

The Center for Disease Control and Prevention (CDC) estimated that eleven percent of Americans 12 and over use antidepressants. More than 60% of those taking an antidepressant medication have taken it for 2 years or longer; 14% have taken the medication for 10 years or more. Like Allison, women between the ages of 40 and 59 are those most likely to be taking an antidepressant (22.8%). Antidepressants were the most commonly used medication by persons aged 18-44; they were the third most commonly used prescription drug by all Americans in 2005-2008.

Okay, you’re thinking you want to try to withdraw from antidepressants; but you don’t want to duplicate Allison’s experience. What should you do?

First, do some research on the growing evidence of problems with antidepressants.

Look at some of the material available on the websites “ToxicPsychiatry” by Peter Breggin and PsychRights by Jim Gottstein. Here are a few recommendations.

Start with Patient Online Report of Selective Serotonin Reuptake Inhibitor-Induced Persistent Postwithdrawal Anxiety and Mood Disorders, by Carlotta Belaise, Alessia Gatti, Virginie-Anne Chouinard, and Guy Chouinard,on Psychrights. It is a short, easy to read study of online self-reports of withdrawal symptoms and postwithdrawal symptoms that they attributed to the discontinuation of SSRI antidepressants.

Then read “Do Antidepressants Cure or Create Abnormal Brain States?” by Joanna Moncrieff, found on ToxicPsychiatry. If you want further information, try her book, The Myth of the Chemical Cure. Dr. Moncrieff effectively challenges the received wisdom of the chemical imbalance theories underlying the use medications for depression, psychosis and bipolar disorder.

If you have used antidepressants for a number of years, also read: “Now Antidepressant-induced Chronic Depression Has a Name: Tardive Dysphoria,” by Robert Whitaker. Try out his website as well, Mad in America.

You can also read two articles that I’ve written and made available here on Faith Seeking Understanding: “Antidepressant Withdrawal or Discontinuation Syndrome?” and “Antidepressants Their Ineffectiveness and Risks.”

Second, become familiar with the potential postwithdrawal side effects of antidepressant withdrawal.

There is a website of free resources at RxISK. You can research reported side effects by drug name; and you can report a drug’s side effects. But be sure to look at the “Symptoms-on-Stopping Zone.” Read about the concept of medication spellbinding coined by Peter Breggin on his ToxicPsychiatry site. Try his article, “Intoxication Anosognosia: The Spellbinding Effect of Psychiatric Drugs” or his book, Medication Madness for a more detailed discussion.

Mario Fava has developed a scale to assess withdrawal/discontinuation symptoms during an antidepressant taper. You can see a copy of his DESS Scale here; and read about antidepressant discontinuation here. You can download the original Fava article here after registering with psychiatrist.com.

Finally, don’t try this at home alone.

Read this blog post on Mad in America by Monica Cassani. Locate psychiatric support groups and websites like Beyond Meds by Monica Cassani. RxISK has published a detailed “Guide to Stopping Antidepressants.” Also read Your Drug May Be Your Problem: How and Why to Stop Taking Psychiatric Medications or Psychiatric Drug Withdrawal, both by Peter Breggin.

Make sure you have medical support and monitoring from a doctor or psychiatrist who is supportive of your attempt to taper. Someone who is president of the local chapter of NAMI and believes in the chemical imbalance theory of depression is not a good choice to supervise your drug taper. Postwithdrawal symptoms will be seen as the re-emergence of your underlying psychiatric disorder and proof you need to be on medications for life.

Tell family and friends of your decision and enlist them (those who are receptive to your decision to taper) as members of an accountability or support group. Have them read this material.

In closing, remember this warning by Dr. Peter Breggin on his website:

Most psychiatric drugs can cause withdrawal reactions, sometimes including life-threatening emotional and physical withdrawal problems. In short, it is not only dangerous to start taking psychiatric drugs, it can also be dangerous to stop them. Withdrawal from psychiatric drugs should be done carefully under experienced clinical supervision.

Faith Seeking Understanding

Charles Sigler, D.Phil.

Tag: antidepressant withdrawal

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Withdrawal or Relapse When Tapering Antidepressants?

Following the Leader with Antidepressants

Antidepressant “War” Games

Getting Off the Antidepressant Merry-Go-Round