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?”

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.

01/8/19

Antidepressant Fall From Grace, Part 2

In 1995 Irving Kirsch and Guy Sapirstein set out to assess the placebo effect in the treatment of depression. Like most people, Kirsch used to think that antidepressants worked—the active ingredient in the antidepressant helped people “cope with their psychological condition.” They weren’t surprised to find a strong placebo effect in treating depression; that was their hypothesis and the reason to do the study. What did surprise them was how small the drug effect was—the difference between the response to the drug and the response to the placebo. “The placebo effect was twice as large as the drug effect.”

Along with Thomas Moore and others, Kirsch then did an analysis of data submitted to the FDA for approval of the six most widely prescribed antidepressants approved between 1987 and 1999: fluoxetine (Prozac), paroxetine (Paxil), sertaline (Zoloft), venafaxine (Effexor), nefadozone (Serzone) and citalopram (Celexa). The researchers found that 80% of the response to medication was duplicated in placebo control groups. The mean difference between drug and placebo was clinically negligible. You can read more about this study in Prevention & Treatment, “The Emperor’s New Drugs.”

When they published their findings, Kirsch sad he was pleasantly surprised by the consensus about their findings. “Some commentators argued that our analysis had actually overestimated the real effect of antidepressants.” One group of researchers said the minimal difference between antidepressant treatment and controls was a “dirty little secret” that had been known all along. “The companies that produce the drugs knew it, and so did the regulatory agencies that approve them for marketing. But most of the doctors who prescribe these medications did not know it, let alone their patients.”

According to Irving Kirsch, pharmaceutical companies have used several devices to present their products as better than they actually are. First they will withhold negative studies from publication. While publication bias effects all areas of research, it is acutely problematic with drug trials. “Most of the clinical trials evaluating new medications are sponsored financially by the companies that produce and stand to profit from them.”

The companies own the data that come out of the trials they sponsor, and they can choose how to present them to the public — or withhold them and not present them to the public at all. With widely prescribed medications, billions of dollars are at stake.

Positive studies may be published multiple times, a practice known as “salami slicing.” Often this is done in ways that makes it difficult for reviewers to recognize the studies were done on the same data. The authors may be different. References to the previous publication of the data are often missing. Sometimes there are minor differences in the date used between one publication and another. Sometimes positive data is cherry-picked from a clinical trial and published, giving the impression that the drug seemed more effective than it really was. For more information on this issue, see: The Emperor’s New Drugs: Exploding the Antidepressant Myth by Irving Kirsch.

Published in 2004, the STAR*D study (Sequenced Treatment Alternatives to Relieve Depression) was a multisite, multistep clinical trial of outpatients with nonpsychotic major depression. It was designed to be more representative of the real world use of antidepressants than typical clinical trials; and to show the effectiveness of antidepressants in the best of circumstances. STAR*D was funded by the NIMH at a cost of $35 million dollars and took six years to complete. It was hailed as the “largest antidepressant effectiveness trial ever conducted.” Robert Whitaker described it as follows:

The STAR*D trial was designed to test whether a multistep, flexible use of medications could produce remission in a high percentage of depressed outpatients. Those who didn’t get better with three months of initial treatment with an SSRI (citalopram) then entered a second stage of treatment, in which they were either put on a different antidepressant or given a second drug to augment an antidepressant. Those who failed to remit in step two could go on to a step three, and so on; in total, there were four treatment steps.

According to the NIMH, in level 1, about one-third of participants became symptom-free. In level 2, about 25% of participants became symptom-free. So a half of the participants in the STAR*D study became symptom-free after two treatment levels. “Over the course of all four treatment levels, almost 70 percent of those who did not withdraw from the study became symptom-free.” However, there was a progressive dropout rate: 21% withdrew after level 1; 30% after level 2; and 42% after level 3.

An overall analysis of the STAR*D results indicates that patients with difficult-to-treat depression can get well after trying several treatment strategies, but the odds of beating the depression diminish with every additional treatment strategy needed. In addition, those who become symptom-free have a better chance of remaining well than those who experience only symptom improvement. And those who need to undergo several treatment steps before they become symptom-free are more likely to relapse during the follow-up period. Those who required more treatment levels tended to have more severe depressive symptoms and more co-existing psychiatric and general medical problems at the beginning of the study than those who became well after just one treatment level.

The message communicated to doctors and the public was that STAR*D showed that antidepressants enabled 67% of depressed patients to recover. Robert Whitaker said an article in The New Yorker commented this “effectiveness rate” was “far better than the rate achieved by a placebo.” But this “cumulative” remission rate of 67% was in fact a theoretical rate that assumed those who dropped out of the study would have the same remission rates as those who remained. “They [also] included remission numbers for patients who weren’t depressed enough at baseline to meet study criteria, and thus weren’t eligible for analysis.” Irving Kirsch said the STAR*D symptom remission was temporary for most: “Approximately 93 percent of the patients who recovered relapsed or dropped out of the trial within a year.”

Recently, Kirsch and others acquired the STAR*D raw data through the MIMH and reanalyzed the HRSD (Hamilton Rating Scale for Depression) results. The HRSD was identified by the original as the primary outcome measure for STAR*D. “Yet the outcome that was presented in almost all the study papers was the QIDS (Quick Inventory of Depressive Symptomatology), a measure made up especially for the STAR-D study, with no prior or subsequent credentials.” The QIDS was devised as a way of tracking symptoms during the course of treatment NOT as an outcome measure. And the original study protocol stated it should not be used as an outcome measure.

Analysis of the HRSD data in STAR*D failed to reach the threshold required for a minimal improvement. “It is also below average placebo improvement in placebo-controlled trials of antidepressants.” The STAR*D results were about “half the magnitude of those obtained in standard comparative drug trials.” Commenting on STAR*D in his book, The Emperor’s New Drugs, Irving Krisch said:

This is a rather bleak picture of the effects of antidepressant treatment. In the best of circumstances—which is what the trial was designed to evaluate—only one out of three depressed patients showed a lasting recovery from depression, and since there was no evaluation of what the recovery rate might have been with placebo treatment, there was no way of knowing whether their recovery was actually due to the medication they had been given.

In her review of the Kirsch reanalysis of the STAR*D study, Joanna Moncrieff said STAR*D suggests that in real life situations, people who take antidepressants do not do very well. “In fact, given that for the vast majority of people depression is a naturally remitting condition, it is difficult to believe that people treated with antidepressants do any better than people who are offered no treatment at all.” She thought this might be the reason the results of the main outcome measure (the HRSD) remained unpublished for so long—and also an explanation for the substitution of the QIDS as an outcome measure. In the original STAR*D analysis:

Whether this was deliberate on the part of the original STAR-D authors or not, it was certainly not made explicit. There should surely be uproar about the withholding of information about one of the world’s most widely prescribed class of drugs. We must be grateful to Kirsch and his co-authors for finally putting this data in the public domain.

According to data gathered by the CDC, 10.7% of all U.S. adults in 2011-2014 reported using an antidepressant in the past 30 days. This is 5.9 times the reported usage for 1988-1994. Demographically, the percentages of U.S. adults who used antidepressants increased with age. The percentages of women using antidepressants were also consistently higher then men for all age groups. Yet their effectiveness in treating depression has been shown to be little better than a placebo. And given that they have a multitude of adverse effects—even the SSRIs—in most cases, no medication may be better than an antidepressant.

See “Dirty Little Secret” and “Do No Harm with Antidepressants” on this website for more information on the antidepressant research of Irving Kirsch. See “The Lancet Story on Antidepressants,” Part 1 and Part 2 for more on the ongoing debate over the effectiveness of antidepressants. See “Antidepressant Fall From Grace, Part 1” for a brief history of antidepressants.

01/1/19

Antidepressant Fall From Grace, Part 1

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.

04/20/18

The Lancet Story on Antidepressants, Part 2

While introducing his review on The Mental Elf of a Lancet study by Cipriani et al., “Comparative efficacy and acceptability of 21 antidepressant drugs,” Andre Tomlin commented how it had been a rough few months where “anti-antidepressant voices” really hit the mainstream. Neuroskeptic thought the study was a nice piece or work, but had very little new information. He also thought the media hype over it was “frankly bananas.” In Part 1 of this article, I looked at the more positive responses to the Cipriani et al. study. Here we will look at the rest of the story from the “anti-antidepressant voices.”

Turn to Part 1 if you want to hear what The Mental Elf and Neuroskeptic had to say about the Cipriani et al. study first. Here we’ll look at the thoughts of Peter Gøtzsche, Joanna Moncrieff and the Council for Evidence-Based Psychiatry.

Tomlin seems to question Gøtzsche’s ‘evidence,’ that antidepressants actually kill people who take them. But turn to “In the Dark About Antidepressants” or “Psychiatry Needs a Revolution” for more on Gøtzsche’s ‘evidence’ on the harm from antidepressants before you dismiss his claims. Remember that Peter Gøtzsche is a careful medical researcher and the Director of the Nordic Cochrane Center. Along with 80 others, he helped start the Cochrane Collaboration in 1993, which is “a global independent network of researchers, professionals, patients, carers, and people interested in health.”

In “Rewarding the Companies that Cheated the Most in Antidepressant Trials, “ Dr. Gøtzsche’s opening comment was: “It is well known that we cannot trust the data the drug companies publish, and it seems that, in psychiatric drug trials, the manipulations with the data are particularly pronounced.” He described, with supporting citations, how half the deaths and suicides that occur in randomised drug trials are not published. When independent researchers have the opportunity to analyze trial data themselves, “the results are often markedly different to those the companies have published.” He then said:

Fraud and selective reporting are of course not limited to the most serious outcomes but also affect other trial outcomes. Several of the authors of a 2018 network meta-analysis in the Lancet are well aware that published trial reports of depression pills cannot be trusted. I therefore do not understand why they are authors on this paper.

He noted how most of the data analyzed by the Cipriani et al. study came from published trials reports, “which we know are seriously unreliable for depression trials.” Gøtzsche pointed out where one of the coauthors for the study had previously coauthored a study showing that “the effect of depression pills was 32% larger in published trials than in all trials in FDA’s possession.” In his opinion, the meta-analytic analysis of the Cipriani et al. study had no clinical value and was “so complicated that it is impossible to know what all this leads to. But we do know that statistical maneuvers cannot make unreliable trials reliable.”

In addition to the doubtful effect of antidepressants noted in the study (see Part 1), Gøtzsche thought ranking the drugs according to their effect and acceptability was a futile exercise. “My thought was that the authors had rewarded those companies that had cheated the most with their trials.” He said it was highly unlikely that some depression pills were both more effective and better tolerated than others.

One doesn’t need to be a clinical pharmacologist to know that this seems too good to be true. Drugs that are more effective than others (which is often a matter of giving them in higher, non-equipotent doses), will usually also be more poorly tolerated.

The reality is that despite serious flaws in depression drug trials, “the average effect is considerably below what is clinically relevant.” That was demonstrated in the Cipriani et al. study and has been shown in several other studies. Examples of the serious flaws noted by Gøtzsche included: “[a] lack of blinding because of the conspicuous adverse effects of the pills, cold turkey in the placebo group because people were already on depression pills before they were randomised, industry-funding, selective reporting and data massage.” He concluded the benefits to harm of depression pills meant that placebo was better than the drug.

Joanna Moncrieff was appalled at the almost universally uncritical coverage given to the Cipriani et al. study. In her article, “Challenging the new hype about antidepressants,” she noted where John Geddes, one of the study’s coauthors, said only one in six people with depression receive effective treatment; and he wanted to make that six out of six. By her calculations, if 9% of the UK population is already taking antidepressants, “and they only represent 1 in 6 of those who need them, then 54% of the population should be taking them. I make that another 27 million people!” Dr. Moncrieff went on and noted once again, that despite the hype, there was nothing groundbreaking in this latest meta-analysis. “It simply repeats the errors of previous analyses.”

The analysis consists of comparing ‘response’ rates between people on antidepressants and those on placebo. But ‘response’ is an artificial category that has been arbitrarily constructed out of the data actually collected, which consists of scores on depression rating scales, like the commonly used Hamilton rating Scale for Depression (HRSD). Analysing categories inflates differences (3). When the actual scores are compared, differences are trivial, amounting to around 2 points on the HRSD, which has a maximum score of 54. These differences are unlikely to be clinically relevant, as I have explained before. Research comparing HRSD scores with scores on a global rating of improvement suggest that such a difference would not even be noticed, and you would need a difference of at least 8 points to register ‘mild improvement’. [See her article for the noted citations and a link to her previous discussion on the HRSD]

Participants in a clinical trial can deduce whether or not they are in the experimental group with the antidepressant medication by recognizing the side effects with antidepressant medication “(e.g. nausea, dry mouth, drowsiness and emotional blunting) irrespective of whether or not they treat depression.” If that happens, these participants may then receive an amplified placebo effect by knowing they are taking an active drug rather than an inactive placebo. “This may explain why antidepressants that cause the most noticeable alterations, such as amitriptyline, appeared to be the most effective in the recent analysis.”

She also pointed out ‘real world’ studies showing the long-term effects of people treated with antidepressants. “The proportion of people who stick to recommended treatment, recover and don’t relapse within a year is staggeringly low (108 out of the 3110 people who enrolled in the STAR-D study and satisfied the inclusion criteria).” Several studies have found that the outcomes for people treated with antidepressants “are worse than the outcomes of people with depression who are not treated with antidepressants.” Moncrieff said calling to increase the use of antidepressants, as Geddes did, will not address the problem of depression and will only “increase the harms these drugs produce.”

As the debate around the [media] coverage highlighted, many people feel they have been helped by antidepressants, and some are happy to consider themselves as having some sort of brain disease that antidepressants put right. These ideas can be reassuring. If people have had access to balanced information and decided this view suits them, then that is fine. But in order for people to make up their own minds about the value or otherwise of antidepressants and the understanding of depression that comes in their wake, they need to be aware that the story the doctor might have told them about the chemical imbalance in their brain and the pills that put it right, is not backed up by science [see her article for a link to this topic], and that the evidence these pills are more effective than dummy tablets is pretty slim.

The Council for Evidence-Based Psychiatry also pointed out “the new research proves nothing new.” Further, they cited where the Royal College of Psychiatrists (RCP) represented the Cipriani et al. study as “finally putting to bed the controversy on anti-depressants.”

This statement is irresponsible and unsubstantiated, as the study actually supports what has been known for a long time, that various drugs can, unsurprisingly, have an impact on our mood, thoughts and motivation, but also differences between placebo and antidepressants are so minor that they are clinically insignificant, hardly registering at all in a person’s actual experience.

Then on February 24^th, the President of the Royal Collage of Psychiatry and the Chair of its Psychopharmacology Committee stated in a letter to The London Times that: “the vast majority of patients, any unpleasant symptoms experienced on discontinuing antidepressants have resolved within two weeks of stopping treatment.” This led to a “Formal Complaint to the UK Royal College of Psychiatrists” when Professor John Read and others wrote to the RCP disputing that claim. The formal complaint stated:

To mislead the public on this issue has grave consequences. People may be misled by the false statement into thinking that it is easy to withdraw and may therefore try to do so too quickly or without support from the prescriber, other professionals or loved ones. Other people, when weighing up the pros and cons of starting antidepressants may make their decision based partly on this wrong information. Of secondary concern is the fact that such irresponsible statements bring the College, the profession of Psychiatry (to which some of us belong), and – vicariously – all mental health professionals, into disrepute.

The complaint cited several research papers documenting how withdrawal effects from antidepressants “often last far longer than two weeks.” The cited research included a study done by the Royal Collage of Psychiatry (RCP) itself, “which found that withdrawal symptoms were experienced by the majority (63%), generally lasted for up to 6 weeks and that a quarter reported anxiety lasting more than 12 weeks. Within 48 hours of the misleading statement in The Times, the survey results were removed from the RCP website, as was a leaflet by the RCP on antidepressant withdrawal. You can listen to a podcast interview with Professor John Read here. There is a link to the RCP leaflet and The Times article there as well.

Stay tuned; this controversy isn’t over yet. In conclusion, to paraphrase Paul Harvey, “Now you know the rest of the Lancet story on antidepressants.”

04/10/18

The Lancet Story on Antidepressants, Part 1

The Lancet recently published a new paper reporting on a large-meta-analysis of studies on antidepressants done by Cipriani et al., “Comparative efficacy and acceptability of 21 antidepressant drugs.” All 21 antidepressants reviewed in the study were found to be more effective than placebo. Various news agencies, referred to it as “a groundbreaking study;” or as confirming “that antidepressants are effective for major depressive disorder (MDD);” and, “New study: It’s not quackery—antidepressants work. Period.” But the excitement and conclusions noted here seem to have been overdone and a bit premature.

Let’s start with the articles quoted in the first paragraph. The author of an article for The Guardian thought the “groundbreaking” Lancet study showed antidepressants were effective; and “we should get on with taking and prescribing them.” The upshot for him was that the millions of people taking antidepressants (including him) “can continue to do so without feeling guilt, shame or doubt about the course of treatment.” Doctors should feel no compunction about prescribing these drugs. “It’s official: antidepressants work.”

An article for bigthink, “New study: It’s not quackery—antidepressants work. Period,” also thought the Cipriani et al. study was helping to put some of the debate about the effectiveness of antidepressants to bed. Again the reported result was that all antidepressants performed better than placebos. The bigthink author related that in order for a drug to be considered “effective, it had to reduce depression symptoms by at least 50 percent,” which would be an astounding discovery for even one antidepressant, let alone all 21. But that was no quite how the Cipriani et al. study authors defined drug efficacy for their study. The authors said efficacy was the “response rate measured by the total number of patients who had a reduction of ≥50% of the total score on a standardised observer-rating scale for depression,” not a 50% or greater reduction in depressive symptoms. Cipriani was then quoted as saying: “We were open to any result. This is why we can say this is the final answer to the controversy.”

The opening sentence of an article on the Medscape website, “Confirmed: Antidepressants Work for Major Depression,” said: “A large meta-analysis confirms that antidepressants are effective for major depressive disorder (MDD).” Here we find the correct description of efficacy in the study: “Results showed that each studied antidepressant was significantly more efficacious, defined as yielding a reduction of at least 50% in the total score of a standardized scale for depression, than placebo after 8 weeks.” Two additional quotations of Cipriani from a press release about the study are given, suggesting while antidepressants can be an effective tool, they shouldn’t necessarily be the first line of treatment. “Medications should always be considered alongside other options, such as psychological therapies, where these are available.”

Reflecting on these three articles, I thought the Guardian and bigthink articles weren’t as careful as they could have been in their rhetoric about the results of the Cipriani et al. study. Although the Medscape article was more nuanced, it also seemed to lead to the same conclusions as the Guardian article, namely: “The demonstration of the extent of antidepressant superiority over placebo reassures patients and health-care professionals of the efficacy of [this] treatment despite high placebo response rates.” But is this conclusion by the Medscape article accurate? In the discussion section of the Cipriani et al. study, the authors said: “We found that all antidepressants included in the meta-analysis were more efficacious than placebo in adults with major depressive disorder and the summary effect sizes were mostly modest.” Further on was the following:

It should also be noted that some of the adverse effects of antidepressants occur over a prolonged period, meaning that positive results need to be taken with great caution, because the trials in this network meta-analysis were of short duration. The current report summarises evidence of differences between antidepressants when prescribed as an initial treatment. Given the modest effect sizes, non-response to antidepressants will occur.

It does not seem the study conclusively found that antidepressants work for major depression. The authors even said in some individuals antidepressants won’t be effective. Now look at the following two assessments of the Cipriani et al. study from an individual (Neuroskeptic) and an organization (The Mental Elf) that I have found to be fair, nuanced and helpful in their assessments of research into psychiatric and medication-related issues.

The Mental Elf article does have a positive title: “Antidepressants can help adults with major depression” and an overall positive assessment, but there were some clear limitations noted as well. First, gleaning results from the study, it reported the most effective antidepressants studied were: agomelatine (Valdoxan, Melitor, Thymanax), amitriptyline (Elavil), escitalopram (Lexapro), mirtazapine (Remeron), paroxetine (Paxil), venlafaxine (Effexor) and vortioxetine (Brintellix). And it noted the least effective ones studied were: fluoxetine (Prozac), fluvoxamine (Luvox), reboxetine (Edronax) and trazodone (many different brand names). The most tolerable antidepressants were: agomelatine, citalopram (Celexa), escitalopram, fluoxetine, sertraline (Zoloft) and vortioxetine. And the least tolerable were: amitriptyline, clomipramine (Anafranil), duloxetine (Cymbalta), fluvoxamine (Luvox or Faverin), reboxetine (Edronax and others), trazodone and venlafaxine.

The included data only covered a short time period—8-weeks of treatment. So the results may not apply to longer-term antidepressant use. “And some antidepressant side effects occur over a prolonged period, so positive results should be interpreted with caution.” Another concern the author noted was that seventy-eight percent of the trials included in the study were funded by pharmaceutical companies. While industry funding was not associated with substantial differences in response or dropout rates, non-industry funded trials were limited and many trials did not report or disclose their funding.

Another 73% of the included trials were rated as having a moderate risk of bias, with 9% rated as a high risk of bias and only 18% as having a low risk of bias. Significantly, the review pointed out the study did not address specific adverse events, withdrawal symptoms, or when antidepressants were used in combination with other non-drug treatments—information most patients would have found useful. Nevertheless, the Mental Elf reviewer thought the study struck a nice balance between “strong evidence that antidepressants work for adult depression” while “accepting the limitations and potential biases” in the study.

Neuroskeptic who wrote “About that New Antidepressant Study,” thought that while it was a nice piece of work, it told very little new information and had a number of limitations. He thought the media reaction to the paper was “frankly bananas.” He put the effectiveness ratings into perspective by pointing out the “mostly moderate” effect size was .30 on the Standardized Mean Difference (SMD) measure, where .2 was ‘small’ and .5 was ‘medium.’ “The thing is, ‘effective but only modestly’ has been the established view on antidepressants for at least 10 years.” He then cited a previous meta-analysis that found the overall effect size to be almost identical—.31! He then turned to the findings of Irving Kirsch’s research with antidepressants, saying:

Cipriani et al.’s estimate of the benefit of antidepressants is also very similar to the estimate found in the notorious Kirsch et al. (2008) “antidepressants don’t work” paper! Almost exactly a decade ago, Irving Kirsch et al. found the effect of antidepressants over placebo to be SMD=0.32, a finding which was, inaccurately, greeted by headlines such as “Anti-depressants ‘no better than dummy pills.”The very same newspapers are now heralding Cipriani et al. as the savior of antidepressants for finding a smaller effect…

The media hype has been “frankly bananas” about the Cipriani et al. study. More balanced reviews by Neuroskeptic and The Mental Elf thought it was “a nice piece of work” and “a nice balance” between the evidence that antidepressants work for adults with depression while accepting “the limitations and potential biases” in the data. The hype is claiming clear effectiveness for a measure that only shows modest effectiveness over the short-term of 8 weeks. Ironically, the trumpeted findings of Cipriani et al are actually lower than those of Irving Kisrch (.32), who pointed out that the SMD criterion suggested by NICE (National Institute for Health and Care Excellence) was .50. Kirsch et al. said: Thus, the mean change exhibited in trials provides a poor description of results.”

Be sure to read Part 2 of “The Lancet Story on Antidepressants” to see what anti-antidepressant voices have to say about the Cipriani et al. study. For more information on the antidepressant research by Irving Kirsch, see: “Dirty Little Secret” and “Do No Harm with Antidepressants.”

Faith Seeking Understanding

Charles Sigler, D.Phil.

Tag: antidepressant effectiveness