Tag: antidepressant adverse events

10/22/19

Fighting or Fueling Suicide with Antidepressants?

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England has pulled ahead of the U.S. in its willingness to recognize and act on adverse effects with antidepressants. In May of 2019, the Royal College of Psychiatrists revised its position on antidepressant withdrawal. In its “Position statement on antidepressants and depression,” it stated the routine use of antidepressants for mild and sub-threshold depressive symptoms among adults was not generally recommended. Discontinuation should be done with a slow taper in order to reduce the risk of withdrawal symptoms. “Ongoing monitoring is also needed to distinguish the features of antidepressant withdrawal from emerging symptoms which may indicate a relapse of depression.” Now there is evidence that antidepressants significantly raise the risk of suicide for adults.

In June of 2019, Hengartner and Plöderl published a study that found depressed adults who start treatment with antidepressants are 2.5 times more likely to attempt suicide when compared to placebo. The study reanalyzed the safety summaries submitted to the FDA for new generation antidepressants (SSRI, SNRI and atypical serotonergic-nonadrenergic antidepressants like Remeron (mirtazapine). They found the rate of attempted suicide was about 2.5 times higher with those adults taking antidepressants rather than placebo. CEP, the Council for Evidence-Based Psychiatry, said Hengartner and Plöderl examined all the suicides and suicide attempts recorded in the safety summaries of all antidepressant trials submitted to the FDA between 1987 and 2013.

Based on this, the study estimates the absolute risk increase in the rate of both fatal and non-fatal suicide attempts for antidepressants vs placebo to be about 0.5%, which is statistically a highly significant effect. While this study does not attempt to identify the precise cause, other studies have suggested that rare adverse drug reactions such as akathisia or extreme agitation, as well as severe withdrawal reactions upon stopping the drug, may increase the suicide risk.

Earlier analysis of the data did not reveal the increased suicide risk because the method used in those clinical trials to analyze the data was incorrect. Previous calculations were based on ‘person exposure years’ (PEY) rather than the number of patients receiving treatment. Hengartner and Plöderl said PEY was not the correct method here because it assumes that the hazards (i.e. the suicide risk) remain constant over time. Yet the evidence shows that the highest suicide risk occurred in the first four weeks after the start of treatment, as well as shortly after the drug has been stopped. “Thus, when based on the number of patients randomized rather than PEY, the data presented herein suggest that antidepressants significantly increase the suicide risk in adults with major depression.”

Writing for the Mental Elf, Douglas Badenoch agreed with this conclusion. He began his review of the study by acknowledging the difficulty of studying suicide in prospective trials because it is such a rare event. It’s hard to combine the findings of such studies because they usually look at different things. Additionally, there is a risk of attrition bias, when patients who experience adverse effects withdraw from the trials. “These factors on their own may account for the apparently contradictory findings across studies of suicide in antidepressant use in general.”

He agreed that it was problematic to use PEY as an outcome measure; that it could result in under-estimating short-term harmful effects. “Most suicide attempts occur within the first 3-4 weeks of treatment, so factoring in further exposure time to the outcome measure only serves to reduce its sensitivity.” He said patients, parents and others need to be aware of the small, although increased, risk. These risks need to be balanced against the risks of withdrawing or withholding antidepressants. Nevertheless, “There is strong evidence here that antidepressant treatment may trigger suicide in adults with depression. The use of patient-exposure-years as an outcome may have masked this short-term effect in some previous studies.”

Writing for Mad in America, Peter Simons noted that a new study in Denmark found antidepressants were ineffective in preventing suicides. Approximately 20% of participants attempted suicide after being hospitalized for depression, “whether they took antidepressants or not.” They found a significant spike in suicides right after initiating antidepressants. The incidence of suicide was 3-4 times higher during the first 28 days after initiation compared to the following year. The incidence of suicide was stable at a low level among participants not treated with antidepressants.

Hengartner and Plöderl are no strangers to critiquing antidepressants. They previously demonstrated how statistical significance with drug-placebo trials does not imply clinical significance. “A statistically significant result neither proves that the null hypothesis is false nor that the alternative hypothesis is true.” They said interpreting a statistically significant drug-placebo difference as evidence that drug work was a logical fallacy. “Thus, since statistical significance does not imply clinical significance, readers need to consider what the reported mean effect of d = 0.3 practically means.”

This effect size corresponds to around 2 points on the Hamilton Rating Scale for Depression, which was used by the clinical trials in their analysis to test for significance. Yet it is generally agreed that a difference of < 3 points, or an effect size where d = 0.5 (corresponding to < 4 HAMD-17 points) are clinically irrelevant. “Research suggests that drug-placebo differences < 3 points are undetectable by clinicians and that at least 7 HAMD-17 points are necessary for a clinician to detect a minimal improvement in a patient’s clinical presentation.” They concluded the average treatment effect of d = 0.3 must be considered undetectable and clinically insignificant in real world practice. See Figure 1 in the linked article for a chart that illustrates this.

Frequently it is said that the effect of antidepressants is comparable to other medications in general medicine. However, several medicine drugs have effect sizes where d > 0.8, where the effect size of antidepressants is d = 0.3. In addition, the general medicine drugs with small effect sizes were mostly based on objective, severe clinical outcomes, such as mortality or cardiovascular events. In contrast, efficacy with antidepressants was exclusively based on subjective symptom ratings with the HAMD-17 scale.

To provide a fair comparison of the efficacy of antidepressants and general medicine drugs, researchers should base the effect size of antidepressants likewise on a severe clinical outcome such as for instance (fatal) suicide attempts. In that case the effect size of antidepressants would be close to zero and favoring placebo. This compares very unfavorably to most general medicine drugs.

As noted above with the Royal College of Psychiatrists, there is a growing willingness to acknowledge evidence for the adverse effects and ineffectiveness of existing antidepressants. However, there is still is a well-entrenched belief in the value of antidepressants. Hengartner and Plöderl suggest that the treatment effect of antidepressants “is most likely an overestimation due to systematic biases that inflate the apparent efficacy of antidepressants.” They conclude that:

Contrary to the predominant interpretation we contend that antidepressants do not work in most patients, given that only 1 of 9 people benefit, whereas the remaining 8 are unnecessarily put at risk of adverse drug effects. To be clear, antidepressants can have strong mental and physical effects in some patients that may be considered helpful for some time, but there is no evidence that the drugs can cure depression. Insomnia, fatigue, loss of appetite, psychomotor agitation, and suicidal acts are recognized depression symptoms, but newer-generation antidepressants may cause precisely these symptoms. This is not what we would expect from drugs that effectively treat depression. Moreover, emerging evidence from well-controlled long-term pharmacoepidemiologic studies suggests that antidepressants may increase this risk of serious medical conditions, including dementia, stroke, obesity, and all-cause mortality. Antidepressants may have clinically meaningful short-term benefits in a small minority of patients, but the most recent meta-analytic evidence does not indicate that they work in the majority of patients. A careful re-evaluation of risks and benefits is therefore needed before the controversy about the utility of antidepressants can be put to bed.

So sertraline (Zoloft), paroxetine (Paxil), venlafaxine (Effexor), nefazodone (Serzone), mirtazapine (Remeron), venlafaxine ER (Effexor ER), citalopram (Celexa), escitalopram (Lexapro), duloxetine (Cymbalta), desvenlafaxine (Pristiq), trazodone ER, vilazodone (Viibryd), levomilnacipram (Fetzima), or vortioxetine (Brintellix) are of questionable efficacy, with only 1 in 9 patients gaining some benefit. Fluoxetine (Prozac) and bupropion (Wellbutrin, Zyban) were excluded from the study only because of a lack of pertinent data on PEY, not because of their efficacy. See “Following the Leader with Antidepressants” for more on the ineffectiveness of antidepressants.

But pharmaceutical companies aren’t ready to throw in the towel just yet. Instead of re-evaluating the risks and benefits with antidepressants, they are moving on to a new drug approach. In March of 2019, the FDA approved Spravato for the treatment of severely depressed patients with treatment resistant depression. This was the first legitimately new kind of depression drug since Prozac in 1988. However, there were questions with the approval process. Kaiser Health News reported there was only modest evidence of Spravato’s effectiveness. There was no information on its safety beyond 60 weeks (Spravato is a Schedule III Controlled Substance); and three patients died by suicide during the clinical trials. See “Red Flags with Spravato” and “Better Living Through Spravato?” for more on this issue.

Despite questions regarding the FDA approval of Spravato, Johnson & Johnson is now trying to add FDA approval for Spravato to treat depressed, suicidal patients. Towards that end, Janssen Pharmaceutical Companies of Johnson & Johnson announced positive results from two Phase 3 clinical studies in adult patients with active suicidal ideation. The findings were presented at the 32nd European College of Neuropsychopharmacology in Copenhagen, Denmark. While there is a growing consensus on the ineffectiveness of antidepressants and clear evidence that existing antidepressants are ineffective in treating suicidality, does it make sense to expand the approved FDA treatments for the latest antidepressant to include suicidality?

08/13/19

Following the Leader with Antidepressants

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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

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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.

01/1/19

Antidepressant Fall From Grace, Part 1

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The so-called antidepressants are not a single class of drugs; nor are they just used to treat depression. There has also been a long-running debate over their adverse effects and treatment effectiveness. After Prozac was approved as the first SSRI (selective serotonin reuptake inhibitor) in 1987, the SSRI class of antidepressants became a kind of patent medicine for treating various mood-related conditions, and was even used as a character or personality enhancement. Yet there has been an accumulation of evidence over the past twenty years that questioned whether SSRIs were more effective than placebo. Are antidepressants effective treatments for depression and are they worth the risk?

Currently, the main classes of antidepressants are SSRIs such as Prozac (fluoxetine), Zoloft (sertaline) and Celexa (citalopram); SNRIs (serotonin norepinephine reuptake inhibitors such as Effexor (venafaxine), Cymbalta (duloxetine) and Pristiq (desvenlafaxine); and NDRIs (norepinephrine-dopamine reuptake inhibitors) such as Welbutrin or Zyban (bupropion). Methylphenidate (as Ritalin, Concerta and others) is also chemically a NDRI, but is used primarily as a medication for ADHD and will not be included in the following discussion. Older classes of antidepressants include tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs) and tetracyclic antidepressants (TeCAs). Antidepressants are used to treat major depression, anxiety, obsessive-compulsive disorder (OCD), attention-deficit hyperactivity disorder (ADHD), eating disorders, chronic and neuropathic pain, bed-wetting, fibromyalgia and menopause, smoking cessation and others.

The earliest and probably most widely accepted scientific theory of antidepressant action is the monoamine hypothesis (which can be traced back to the 1950s), which states that depression is due to an imbalance (most often a deficiency) of the monoamine neurotransmitters (namely serotonin, norepinephrine and dopamine).It was originally proposed based on the observation that certain hydrazine anti-tuberculosis agents produce antidepressant effects, which was later linked to their inhibitory effects on monoamine oxidase, the enzyme that catalyses the breakdown of the monoamine neurotransmitters. All currently marketed antidepressants have the monoamine hypothesis as their theoretical basis.

In 1952 psychiatrists Max Lurie and Harry Salzer coined the term “antidepressant” to describe the action of isoniazid, a medication originally developed as a treatment for tuberculosis. Seeikoff and Robitzek experimented with another ant-tuberculosis drug, iproniazid, which had a greater psychostimulant effect, but also greater toxicity. Serious adverse effects, including liver inflammation, led to its recall as an antidepressant in 1961. These drugs are MAOIs.

A tricyclic antidepressant, Tofranil (imipramine), was also first used to treat depression in the 1950s. Another TCA, Elavil (amitriptyline), was approved in 1961. Dozens of additional TCAs were developed over time. Similar to TCAs, tetracyclic antidepressants (TeCAs) like Remeron (mirtazapine) were introduced in the 1970s. But there were problems with TCAs, including a higher risk of serious cardiovascular side effects. They also had a relatively low toxicity level, making them a suicide risk—not an attractive adverse effect for an antidepressant.

While they are biochemically similar to TCAs and have no real differences in therapeutic effectiveness, SSRIs only affect the reuptake of serotonin, not the reuptake of dopamine and norepinephrine. SSRIs also have a higher toxicity level than TCAs and a lower risk of serious cardiovascular side effects. So an argument was made for SSRIs having fewer and milder side effects than TCAs. Initially persuasive, this claim has become less credible over time.

The SSRI antidepressant craze began with the introduction of Prozac in 1987. Zoloft (sertaline) came to market in 1992, Luvox (fluvoxamine) in 1994, Paxil (paroxetine) in 1996, Celexa (citalopram) in 1998, and Lexapro (escitalopram) in 2002. All the above SSRIs are now off patent and available as generics. Yet they are among the three most commonly used classes of prescription medications in the U.S. 12.7% of persons over the age of 12 reported they took an antidepressant in the previous month, according to data from the National Center for Health Statistics. Antidepressant use is highest among females in two age groups: 40 to 59 (21.2%), and 60 and over (24.4%). The same trend was seen with males from 40 to 59 (11.6%), 60 and over (12.6%). See the linked CDC article for more information on antidepressant use among Americans.

Prozac use swept over the U.S. like a pharmaceutical wave after it was approved. It even became a drug that people took for  “cosmetic psychopharmacology,” according to psychiatrist Peter Kramer, the author of the best-selling book: Listening to Prozac. Kramer said: “If I am right, we are entering an era in which medication can be used to enhance the functioning of the normal mind. The complexities of that era await us.”

The complexities of antidepressant use from the early days included evidence of violence and suicide. Toxic Psychiatry by another psychiatrist named Peter Breggin, was published in 1991. Breggin documented reports of suicidal behavior with Prozac in both the popular press and the professional literature. “Suicidal Behavior Tied to Drug,” was published on February 7, 1991 in The New York Times. The article said two cases of suicidal behavior and fantasies (with no prior history) were reported in The New England Journal of Medicine that same day. Eli Lilly (the manufacturer of Prozac) was facing more than 50 lawsuits at the time, but denied that there was any scientific merit to the claim Prozac could prompt suicidal or violent acts.

Dr. Breggin also predicted the rise of what is now called “treatment resistant depression” with SSRIs. He said: “If Prozac can indeed alleviate depression by making more serotonin available in the brain, then with time it may produce incurable depression by making the brain relatively unresponsive to any amount of serotonin.” In 2004 the FDA finally required black box warnings to be placed on the newer antidepressants, warning of the potential for the increased risk of suicidal thoughts and behavior in children and adolescents. Despite the age qualification, the danger for adults is also present.

In an article, Breggin described “How FDA Avoided Finding Adult Antidepressant Suicidality.” Quoting the FDA report of the 2006 hearings, he noted where the FDA permitted the drug companies to search their own data for “various suicide-related text strings.” Because of the large number of subjects in the adult analysis, the FDA did not—repeat, DID NOT—oversee or otherwise verify the process. “This is in contrast to the pediatric suicidality analysis in which the FDA was actively involved in the adjudication.” He added that the FDA did not require a uniform method of analysis by each drug company and an independent evaluator as required with the pediatric sample.

Peter Gøtzsche, a Danish physician and medical researcher who co-founded the Cochrane Collaboration, wrote an article describing how “Antidepressants Increase the Risk of Suicide and Violence at All Ages.” He said that while drug companies warn that antidepressants can increase the risk of suicide in children and adolescents, it is more difficult to know what that risk is for adults. This is because there has been repeated underreporting and even fraud with reporting suicides, suicide attempts and suicidal thoughts in placebo-controlled antidepressant trials. He added the FDA has contributed to the problem by downplaying the concerns, choosing to trust the drug companies and suppressing important information.

Gøtzsche drew attention to a meta-analysis of placebo-controlled trials from 2006 where the FDA reported five suicides in 52,960 patients (one per 10,000).  See Table 9 of the 2006 report. However the individual responsible for the FDA’s 2006 meta-analysis had published a paper five years earlier using FDA data where he reported 22 suicides in 22,062 patients (which is 10 per 10,000). Additionally, Gøtzsche found there were four times as many suicides on antidepressants as on placebo in a 2001 study.

Additional adverse side effects from antidepressant use include: weight gain and metabolic disturbances; sexual dysfunction; bleeding; sleep disturbances; emotional blunting; agitation and activation; discontinuation syndrome (withdrawal); violence; and others. New research published in the journal Psychotherapeutics and Psychosomatics concluded that SNRIs should be added to the list of drugs that induce withdrawal symptoms upon discontinuation. Even a gradual withdrawal did not prevent the onset of “withdrawal phenomena” with SNRIs.

The results of this systematic review indicate that withdrawal symptoms may occur after discontinuation of any type of SNRI (venlafaxine, desvenlafaxine, duloxetine, milnacipran, or levomilnacipran). However, the prevalence of withdrawal symptoms was variable and appeared to be higher after discontinuation of venlafaxine.

See a literature review of long-term use of newer generation antidepressants (i.e., SSRIs and SNRIs and others) by Carvalho et al. You can also look at “In the Dark About Antidepressants,” Antidepressant Misuse Disorder” and “Listening to Antidepressants” on this website for more information on antidepressants and their adverse effects. For more information on the association of antidepressants and violence, see Medication Madness by Peter Breggin and “Violence and the Brain” or “Iatrogenic Gun Violence” on this website.

While not everyone will experience these adverse events, they are present for many individuals who have used or are using antidepressants. But if your depression is debilitating, are antidepressants effective enough to be worth risking their potential adverse effects? In Part 2 of “Antidepressant Fall From Grace” we will look at the debate over the efficacy of antidepressants.