07/23/19

The Brute Facts of Depression Genetics

1996 was in the midst of the golden years for associating serotonin and depression. SSRIs like fluoxetine (Prozac, 1987), sertraline (Zoloft, 1991), paroxetine (Paxil, 1992) and fluvoxamine (Luvox, 1994) were on the market. Citalopram (Celexa, 1998) and escitalopram (Lexapro, 2002) would join them over the next six years. A study was published in 1996 claiming to have identified a gene, 5-HTTLPR, that was a “potential genetic susceptibility factor for affective disorders” like depression. The chemical imbalance or serotonin imbalance theory of depression was a self-evident fact, promoted by the pharmaceutical companies in their consumer advertisements, like this one for Prozac:

When you’re clinically depressed, one thing that can happen is the level of serotonin (a chemical in your body) may drop. So you may have trouble sleeping. Feel unusually sad or irritable. Find it hard to concentrate. Lose your appetite. Lack energy. Or have trouble feeling pleasure…to help bring serotonin levels closer to normal, the medicine doctors now prescribe most often is Prozac®.

But with the growth and acceptance of critiques of the chemical imbalance theory like those of Lacasse and Leo in “Antidepressants and the Chemical Imbalance Theory of Depression: “The number of websites making such claims dropped, with some websites going dark or minimalist as the drug patent ran out.” Newer medications altered their rhetoric to say they were “adjusting” or “affecting” neurotransmitter levels instead of “correcting a chemical imbalance.” Psychiatrists like Ronald Pies distanced themselves from the chemical imbalance theory, saying it was “always a kind of urban legend,” but never a theory that well-informed psychiatrists believed. It was simply “a little white lie,” according to Dr. Pies. (editor’s note: it is more correct to say Lacasse and Leo said Dr. Pies said it was simply “a little white lie.” More on this later.) Lacasse and Leo further noted: “We can’t help but notice that the silence of psychiatry regarding chemical imbalance only ended when the profits had been extracted from the SSRI marketplace.”

But interest in the 5-HTT gene persisted. In 2003 Caspi et al. published a paper on the influence of life stress on depression moderated by the 5-HTT serotonin transporter. Then, as noted by Scott Alexander in his blog, “5-HTTLPR was found to directly affect the reactivity of the HPA axis, the stress processing circuit leading from the adrenal glands to the brain.” Studies began to show an association with other psychiatric disorders such as seasonal affective disorder, insomnia, anxiety, even psychosis. Researchers began to suspect that genes like 5-HTTLPR may also moderate how we respond to life events.

A meta-analysis looked at 54 studies of the interaction and found “strong evidence that 5-HTTLPR moderates the relationship between stress and depression, with the s allele associated with an increased risk of developing depression under stress (P = .00002)”. This relationship was then independently re-confirmed for every conceivable population and form of stress. Depressed children undergoing childhood adversity. Depressed children with depressed mothers. Depressed youth. Depressed adolescent girls undergoing peer victimization. They all developed different amounts of depression based on their 5-HTTLPR genotype.

There were studies on how 5-HTTLPR and stress interacted with gender, parenting, decision-making, single motherhood and more. There were also studies of its relevance in antidepressant treatment, specifically with citalopram and fluvoxamine. “A meta-analysis of 15 studies found that 5-HTTLPR genotype really did affect SSRI efficacy (p = 0.0001).” Psychiatrists were urged to test for 5-HTTLPR before treating patients. However, as Dr. Alexander concluded after reading Border et al.’s study: “ALL OF THIS IS LIES.”

The authors said that given what we now know about polygenicity, studies of individual single-nucleotide polymorphism (SNP) like Caspi et al. does with the 5-HTTLPR gene require samples of around 34,000 people to detect an effect. “So any study with fewer than 34,000 people that says anything about specific genes is almost definitely a false positive.” The median size for the above discussed studies was 345.

We examined multiple types of associations between18 highly studied candidate genes for depression and multiple depression phenotypes. The study was very well powered compared with previous candidate gene studies, with Ns ranging from 62,138 to 443,264 across subsamples. Despite the high statistical power, none of the most highly studied polymorphisms within these genes demonstrated substantial contributions to depression liability. Furthermore, we found no evidence to support moderation of polymorphism effects by exposure to traumatic events or socioeconomic adversity.

Attempting to be fair to the psychiatric research community, Alexander said over the past fifteen years many people have voiced concerns with 5-HTTLRP findings. One study that failed to replicate findings was published in 2009. Risch et al. concluded “This meta-analysis yielded no evidence that the serotonin transporter genotype alone or in interaction with stressful life events is associated with an elevated risk of depression in men alone, women alone, or in both sexes combined.” Alexander further said that Border et al. did not prove every single 5-HTTLPR study was wrong. However, it did cast doubt upon them.

The authors of this paper are geneticists who are politely trying to explain how genetics works to psychiatrists. They are arguing that single genes usually matter less than people think. They do an analysis of depression to demonstrate that they know what they’re talking about, but the points they are making apply to insomnia, nostalgia, and everything else. So all the studies above are at least questionable.

Before placing this in an “anti-psychiatry” box and dismissing it, consider the implications of how this happened. This was shoddy science, plain and simple. And “since crappy science will find whatever it’s looking for—it was appropriately discovered that yes, changes in the serotonin transporter gene caused depression.” Alexander said the magnitude of the problem is not just a minor difference in methodology along the lines of sometimes failing to get an effect in a cold room, when the original study occurred in a hot room. It is more like “you can get an entire field with hundreds of studies analyzing the behavior of something that doesn’t exist.”

Another issue is the implications the findings have for antidepressant pharmacogenomic testing. Remember the reference to studies on 5-HTTLPR and antidepressant treatment? Assuming their validity, your psychiatrist could order a genetic test to see which antidepressant is right for you. These tests have become part of care in some hospitals, they’ve insinuated themselves into psychiatry residency programs; they’ve become part of high-priced concierge medical systems. GeneSight, one of the most popular tests, uses seven genes—one of which contains the 5-HTTLPR as a subregion. “But since the only reason we thought that they might [work] was because of evidence they affected depression, and now it seems they don’t affect depression, it’s less likely that they affect antidepressant response too.”

Remember, GeneSight and their competitors refuse to release the proprietary algorithms they use to make predictions. They refuse to let any independent researchers study whether their technique works. They dismiss all the independent scientists saying that their claims are impossible by arguing that they’re light-years ahead of mainstream science and can do things that nobody else can. If you believed them before, you should be more cautious now. They are not light-years ahead of mainstream science. They took some genes that mainstream science had made a fuss over and claimed they could use them to predict depression. Now we think they were wrong about those. What are the chances they’re right about the others? Yes, GeneSight has ten or twenty studies proving that their methods work. Those were all done by scientists working for GeneSight. Remember, if you have bad science you can prove whatever you want.

Even in science, there is no such thing as a brute, uninterpreted fact.

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(Revised on 7/28/2019)

There has been an ongoing dispute since the original Lacasse and Leo article linked above over what Dr. Pies said in his article for Medscape, “Nuances, Narratives, and the ‘Chemical Imbalance Debate in Psychiatry.” Apparently, the original article did use the phrase ‘little white lie,’ but was revised after others took note of Dr. Pies’ use of the phrase. According to Philip Hickey, PhD who was writing for Mad in America, the third paragraph of the article originally read:

“Now, if you were to give credence to a recent online polemic posing as investigative journalism, you would probably choose the first or second statement. In the narrative of the antipsychiatry movement, a monolithic entity called ‘Psychiatry’ has deliberately misled the public as to the causes of mental illness, by failing to debunk the chemical imbalance hypothesis. Indeed, this narrative insists that, by promoting this little white lie, psychiatry betrayed the public trust and made it seem as if psychiatrists had magic bullets for psychiatric disorders. (Lurking in the back-story, of course, is Big Pharma, said to be in cahoots with Psychiatry so as to sell more drugs).”

The article now has “simplistic formulation” instead of ‘little white lie.’ Dr. Pies did acknowledge he failed to put the phrase ‘little white lie’ in quotes and took responsibility for the omission (See his letter to the editor, “Response to Lacasse and Leo” attached with the above-linked article by Lacasse and Leo: “Antidepressants and the Chemical Imbalance Theory of Depression”). Dr. Pies did say in his letter:

I would regard such a statement [“Your emotional problem is due to simply to a chemical imbalance”] as simplistic and reductionistic, and would never shrug it off—as Lacasse and Leo imply—as “a little white lie.” Lacasse and Leo may have made an innocent mistake in attributing this expression to me, owing to two online versions of my “Nuances” article (2014a, 2014b).

Dr. Pies further said the American Psychiatric Association’s 1978 “Position Statement on Active Treatment” declared, “Psychiatric disorders result from the complex interaction of physical, psychological, and social factors and treatment may be directed toward any or all three of these areas.” He concluded this was precisely what he and most of his academic colleagues have been teaching for the last thirty years. However, Philip Hickey addressed the nuances of this dispute in his article linked above and then summarized his conclusions on the ‘little white lie’ issue as follows:

So, to summarize the “little white lie” issue:

In the original Psychiatric Times and Medscape articles, Dr. Pies characterized the spurious chemical imbalance theory as “this little while lie”. There was nothing in the wording of this statement to suggest that this was anything other than his own position.

At some point in the next few weeks [Dr. Hickey’s article was dated November 17, 2015], Dr. Pies realized that his statement was inaccurate, or that he had misexpressed himself, and made an appropriate correction in the Psychiatric Times article, but not in the Medscape piece.

In October 2015, Drs. Lacasse and Leo, accurately and appropriately, attributed the “little white lie” phrase in the Medscape article to Dr. Pies.

Sometime in the last two weeks, the Medscape article was amended to read “simplistic formulation”.

On November 4, 2015, Dr. Pies unjustly accused Drs. Lacasse and Leo of misattributing the phrase to him.

Dr. Pies read my article and expressed concern (see the Disqus comments below) that what I said above was erronous: “It was simply ‘a little white lie,’ according to Dr. Pies.” As the above additions to this article show, he seems to have unintentionally implied it in his original Medscape article which read, “by promoting this little white lie, psychiatry betrayed the public trust and made it seem as if psychiatrists had magic bullets for psychiatric disorders.” The revision of little white lie with simplistic formulation is clearer without leading to the misquoting of Dr. Pies that Lacasse and Leo, and me following their lead, made. Drs. Lacasse and Leo in their “Response to Daniel Carlat (2015) and Ronald Pies (2015)” said they accept Dr. Pies and his statement that he does not endorse calling the chemical imbalance theory a “little white lie” and appreciate his acknowledgement of making an editorial error. I do as well and appreciate his bringing it to my attention.

Dr. Pies went on to refer to a recent article he wrote on April 30, 2019 for Psychiatric Times, “Debunking the Two Chemical Imbalance Myths, Again.” Coincidentally, Philip Hickey published a critique of that article on Mad in America, “The Chemical Imbalance Theory: Dr. Pies Returns, Again” on July 22, 2019, the day before my article here was scheduled to be published, July 23, 2019. The two myths that Dr. Pies debunked were 1) psychiatric disorders in general are caused by a “chemical imbalance” in the brain; and 2) that “Psychiatry” as a profession endorsed the first myth, deliberately and knowingly lying to countless, unsuspecting patients.

See the two articles for more specific details. But clearly, the dispute over whether or not psychiatry (lower case “p”) as a profession endorsed the chemical imbalance myth is still a valid critique, and not simply a myth. Dr. Hickey noted the American Psychiatric Association published a 2005 brochure called “Let’s Talk Facts About Depression.” It is apparently no longer available on the APA website, but is available other places by searching for the title. The link here is to a copy Dr. Hickey placed on the Mad in America website. The brochure does say several factors play a role in the onset of depression, biochemistry, genetics, personality and environmental factors. Yet under the biochemistry factor it states,

Abnormalities in two chemicals in the brain, serotonin and norepinephrine, might contribute to symptoms of depression, including anxiety, irritability and fatigue. Other brain networks undoubtedly are involved as well; scientists are actively seeking new knowledge in this area.

And in response to the question, “How Is Depression Treated?,” under Medication it states, “Antidepressants may be prescribed to correct imbalances in the levels of chemicals in the brain.” These statements were published fourteen years ago, long before the current dispute. But they illustrate how at least one of the two chemical imbalance “myths” of Dr. Pies is not quite as debunked as he thinks it should be. And there is perhaps a clarification needed in his “Debunking” article, where he initially says “The first [myth] holds that mental illnesses (psychiatric disorders) in general are caused by ‘a chemical imbalance’ in the brain—the so-called “chemical imbalance theory” (CIT).” Then two paragraphs later seems to expand the myth to mean belief in a GUT, grand unified theory of mental illness in general: “Scientifically speaking, there never was a network of validated hypotheses capable of sustaining a full-blown, global ‘chemical imbalance theory’ of mental illness in general.”

I think it is worth repeating here that even in science, there is no such thing as a brute, uninterpreted fact. Here I am thinking of a ‘brute fact’ consistent with how Cornelius Van Til, a theologian understands it. See “The Limits of Human Reason” for more on this.

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.

09/25/18

Rewiring the Adolescent Brain with Antidepressants

A depressed teenager walking towards the light

Research has shown that the earlier in life a person begins to use drugs, the more likely they are to develop serous problems as they mature. The interaction of early social and biological risk factors needs to be considered in assessing the developmental progression of later in life problems like addiction. “The fact remains that early use is a strong indicator of problems ahead, including addiction.” While this is a noncontroversial perspective on how recreational drug use effects adolescent brain development, what about the effects of antidepressants and other psychiatric drugs on the developing brains of adolescents?

As our brains develop, our experiences reduce excess neural connections while simultaneously strengthening those that are used more often. The more we repeat any thinking or behavior pattern, the more it becomes habitually entrenched. If we repeatedly have a specific thinking pattern or do a particular behavior over and over again, the neurons in our brains strengthen that learning sequence, becoming what we refer to as a habit. “The more we actually do of whatever we do, the more ‘habitual’ that learning will become.” This is known as Hebbs Law, “Neurons that fire together, wire together.” When you combine Hebb’s Law with early drug use and the still maturing adolescent brain, you have a ready-made recipe for disaster.

image credit: NIDA

The above images of brain development are found in the NIDA (National Institute on Drug Abuse) discussion of “Drug Use and Addiction.” The images are for normal children and teens from the age of 5 to 20. Scientists think the process of brain maturation, depicted as the yellow to blue transition, corresponds to the steady reduction in gray matter volume seen during adolescence. Note that the pre-frontal cortex is the last area of the developing brain to mature. Environmental forces, like drug use, help determine which connections wither and which are reinforced. This is a process that can “cut both ways” as not every habit reinforced by Hebb’s Law is desirable.

One of the brain areas still maturing during adolescence is the prefrontal cortex—the part of the brain that allows people to assess situations, make sound decisions, and keep emotions and desires under control. The fact that this critical part of a teen’s brain is still a work in progress puts them at increased risk for making poor decisions, such as trying drugs or continuing to take them. Introducing drugs during this period of development may cause brain changes that have profound and long-lasting consequences.

There is a euphoric effect from drugs that is still poorly understood, but it seems to be related to surges of neurotransmitters in parts of the brain’s reward circuit (i.e., the basal ganglia and amygdala). Some drugs cause a surge of neurotransmitters that are significantly greater than the normally occurring bursts produced naturally with healthy pleasurable activities such as eating, or social interaction. “Just as drugs produce intense euphoria, they also produce much larger surges of dopamine, powerfully reinforcing the connection between consumption of the drug, the resulting pleasure, and all the external cues linked to the experience.” Simply put, surges of dopamine “teach” the brain to seek drugs at the expense of other goals and activities.

For the brain, the difference between normal rewards and drug rewards can be likened to the difference between someone whispering into your ear and someone shouting into a microphone. Just as we turn down the volume on a radio that is too loud, the brain of someone who misuses drugs adjusts by producing fewer neurotransmitters in the reward circuit, or by reducing the number of receptors that can receive signals. As a result, the person’s ability to experience pleasure from naturally rewarding (i.e., reinforcing) activities is also reduced.

One of the brain’s areas within its pleasure or reward center is the amygdala, which regulates emotions such as anxiety and depression, as well as having a role in the development of recreational drug addiction discussed above. While antidepressants won’t “shout” at the reward center in the same way cocaine or alcohol does, the individual who uses an antidepressant will experience a similar, if less radical, adjustment of their neurotransmitters and/or receptors. Consider what this could mean in the developing brain of an adolescent using an antidepressant that inhibits the uptake of serotonin (SSRI) or serotonin and norepinephrine (SNRI).

I have no training in medicine or neuroscience. But it seems logical to infer from the above that the long-term use or abuse of any drug which influences the neurotransmitter and/or receptor balance of the brain—cocaine, alcohol, antidepressants or other psychiatric medications—will influence brain function in the way described above. If studies show that “long-term drug use impairs brain functioning,” which the NIDA article claimed, this is equally true for recreational or psychiatric drugs. The question is, to what extent does the use of psychiatric medications like antidepressants effect the development of the adolescent brain?

A study by Lugo-Candelas et al. published in JAMA Pediatrics looked at the association between fetal brain development and prenatal exposure to SSRIs. Their findings suggested there was an association between prenatal SSRI exposure and fetal brain development, “particularly in brain regions critical to emotional processing.” The researchers said there was a need for “further research on the potential long-term behavioral and psychological outcomes of these neurodevelopmental changes.” In her review of the Lugo-Candelas et al. study for Mad in America, Bernalyn Ruiz said: “Overall, this study presents evidence that prenatal exposure to SSRI’s can affect infant neurodevelopment and may be associated with increased susceptibility to anxiety disorders, hyperactivity and maladaptive processing.”

A 2016 study by Cipriani et al. published in The Lancet concluded that the risk-benefit profile of antidepressant use in the acute treatment of major depression with children and adolescents did not seem to offer a clear advantage. The researchers said that fluoxetine (Prozac) was probably the best pharmacological treatment option. The study did not look at long-term antidepressant use as there has not been enough previous research to analyze, according to Cipriani. A STAT News review of the Cipriani et al. study quoted child psychiatrist Jon Jureidini as saying the study’s evidence for Prozac’s effectiveness was weak. He said the vast majority of children do not need to be medicated for depression.

What we’re up against is the marketing enterprise of the pharmaceutical industry combined with wishful thinking on the part of doctors and parents that there might be a good, simple solution for adolescent distress. . . . It’s something we need to take very seriously, but we don’t need to make it into a medical condition when it most times isn’t.

David Healy, Joanna Le Noury and Jon Jureidini wrote about their review of the benefits and risks of the use of antidepressants in children and adolescents for the International Journal of Risk & Safety in Medicine. They examined a total of 20 pediatric antidepressant studies conducted since 1990 and classified them as positive or negative according to the studies’ primary outcomes. In a review of the Healy, Le Noury and Jureidini study for Mad in America, Rebecca Troeger noted the authors found that all 20 trials performed between 1990 and 2005 were negative on primary outcome measures. That included the two fluoxetine (Prozac) trials “that provided the foundation for the drug’s regulatory approval” for use with children and adolescents. There was also evidence of an “excess of suicidality on active treatment” with these trials. “Of the 15 studies conducted since 2006 reviewed by the authors, nearly all were negative on primary outcome measures.”

At a global health conference in Aberdeen Scotland, Dr. Healy said every one of these trials produced more harms than benefits. Children became suicidal who would not have been suicidal if they had been kept off of antidepressants. He said if you follow the evidence, no one should be using these drugs. “At the same time, in teenagers, these drugs have become the most commonly used drugs.” The available evidence seems to question the wisdom and effectiveness of antidepressant use with children and adolescents.

07/24/18

Doubling Up On Depression

Photo by Kat Jayne from Pexels

Alkermes seems to be presenting contradictory opinions when it comes to promoting two of its drugs. When discussing Vivitrol, its extended release injectable version of naltrexone, Alkermes refers to it as “nonaddictive.” This is in contrast to other FDA-approved addiction medications such as methadone or buprenorphine, which are opioids. Alkermes has also persisted in its attempts to get ALKS 5461 approved by the FDA as an adjunctive medication to treat major depression. The active ingredient in ALKS 5461 is buprenorphine and Alkermes has emphasized that upon discontinuation of ALKS 5461 there was no evidence of withdrawal.

The conundrum is rhetorically-based and not scientific. Buprenorphine is classified as a Schedule III controlled substance, meaning it has “a moderate to low potential for physical and psychological dependence.” Yet when ALKS 5461 is being promoted, research findings conclude “There was no evidence of withdrawal upon discontinuation of treatment with ALKS 5461.” Michael Thase, the Alkermes poster presenter for ALKS 5461 at the 2018 American Psychiatric Association annual conference was quoted by Healio as saying, “there was essentially no hint whatsoever of opiate-like withdrawal or discontinuation symptoms.”

But when buprenorphine is a medication-assisted treatment (MAT) in competition with Vivitrol, it is described by Alkermes and its lobbyists as being addictive in contrast to naltrexone, the ingredient in Vivitrol, which is not addictive. STAT News published an article written by Daniel Wolf, the director of international harm reduction development at the Open Society Foundation. Wolf cited and linked investigations by the New York Times, National Public Radio and ProPublica noting how Alkermes promoted Vivitrol at the expense of other MAT drugs like buprenorphine. One example, found in the NPR article, was where the Indiana Senate passed a bill approving the use of “a federal Food and Drug Administration-approved long acting, nonaddictive medication for the treatment of opioid or alcohol dependence.” The only drug approved by the FDA that meets that description is Vivitrol.

An investigation by NPR and Side Effects Public Media has found that in statehouses across the country, and in Congress, Alkermes is pushing Vivitrol while contributing to misconceptions and stigma about other medications used to treat opioid addiction.

Wolfe noted for STAT News that the investigations he cited showed how Alkermes marketers and lobbyists derided the daily administration of methadone and buprenorphine. The pitch is apparently working, as the sales of Vivitrol rose 600% between 2011 and 2017. Legislators in 15 states have written Vivitrol (by brand name) into their laws. And multiple jurisdictions now require drug offenders to agree to use the medication if they want to avoid imprisonment. In effect, state established Drug Courts have become “Vivitrol courts.”

Alkermes highlighted Vivitrol’s properties as an opioid antagonist. This means it blocks (instead of activating) the effects of opioids like methadone, burpernorphine and heroin on opioid receptors in the brain. Naltrexone, the active ingredient in Vivitrol, will not get you high. Methadone and buprenorphine can be used alone or in conjunction with other drugs to produce a high. Their differences as MAT treatment are illustrated in the following graphic, which was found in the NPR article.

Turning to ALKS 5461, we see that Alkermes had a series of setbacks as it attempts to have the FDA approve ALKS 5461 as an adjunct treatment for major depression. As FierceBiotech noted, Alkermes failed to meet their primary endpoints in two of three phase 3 clinical trials for ALKS 5461. “But Alkermes used the success of the third trial to paint the overall dataset as supportive of the efficacy of ALKS 5461.” What Alkermes did is use its statistical analysis of the second failed clinical trial (FORWARD-4) to discover a significant result within a subpopulation of the study that wasn’t targeted by its primary endpoint. They then modified their methodology and analysis of the third clinical trial (FORWARD-5) to match the post-hoc analysis and it successfully showed a statistical significance.

In previous articles, “Nearsighted Drug Development” and “The ‘Hotel California’ Effect,” I said this seemed like cheating, even though it was allowed. Alkermes then wanted the FDA to count its failed FORWARD-4 trial as a successful one, based on its post hoc statistical analysis. So far the FDA hasn’t bought the Alkermes attempts to justify its claims. In late January of 2018 Alkermes submitted a New Drug Application to the FDA for ALKS 5461. The company claimed ALKS 5461 “demonstrated a consistent profile of antidepressant activity, safety and tolerability in the adjunctive treatment of MDD.”

Then on April 2, 2018, the FDA informed Alkermes it was refusing to review the NDA application for ALKS 5461, saying there was “insufficient evidence of overall effectiveness for the proposed indication.” They wanted to see “additional well-controlled clinical trials” prior to the resubmission of ALKS 5461, disagreeing with the Alkermes attempt touse the success of the third trial to the overall dataset as supportive of ALKS 5461 efficacy. The FDA also wanted a bioavailability study to generate more bridging data between ALKS 5461 and buprenorphine. Alkermes disagreed with the FDA’s conclusions and planned to request a Type A meeting where they could clarify what additional information the FDA needs. FierceBiotech said:

The FDA’s refusal to buy into that line of thinking is a blow to people in Alkermes and beyond. Having talked up the strength of the dataset, Alkermes CEO Richard Pops and his colleagues emerge from the setback with dented reputations. More broadly, the FDA’s refusal to even review the data is a blow for any biotech hoping the arrival of Scott Gottlieb, M.D., as commissioner would usher in an era in which the FDA waves through drugs with patchy data packages.

Two weeks later, the FDA rescinded its refuse-to-file letter. FierceBiotech said: “The company did not provide the FDA with additional data or analyses and the agency expects to return a decision by Jan. 31, 2019.” Alkermes CEO Richard Pops said the FDA’s initial refusal was based on a “misunderstanding” of the NDA submission. He declined to say what the FDA initially thought was missing from the NDA. “I think it just took a while to get that lens focused the right way for FDA to accept the file.”

While ALKS 5461 is back on schedule, the FDA’s about-face is by no means a guarantee of success—the agency has deemed the data complete enough for review, but could still reject it.

At the May 2018 American Psychiatric Association Annual Meeting, Alkermes presented a poster on its research into the “Long-Term Efficacy, Safety and Tolerability of Adjunctive ALKS 5461 in Patients With Major Depressive Disorder.” The reported results of a completed long term study (NCT02141399) were that 49% of the 1454 enrolled patients completed the 1-year study, 11% discontinued due to an adverse event. The remission rate, defined as a score of 10 or less on the MADRS-10, was 52.5%. Time to remission was 59.0 days. Adverse events occurring with a frequency of less than 10% were nausea, headache, constipation, dizziness and somnolence (drowsiness). “There was no evidence of withdrawal upon discontinuation of treatment with ALKS 5461.”

Overall, ALKS 5461 showed durability of antidepressant effect up to 52 weeks of treatment in patients with MDD. ALKS 5461 was well tolerated with an AE profile consistent with that reported in the short-term trials.

These results were repeated in Healio: “ALKS 5461 well-tolerated in major depression” and in Psychiatry Advisor: “Novel Buprenorphine Combinayion Therapy Shows Efficacy for MDD in Long-Term Trial.” Psychiatry Advisor has links to the Alkermes clinical trials referenced, which are all completed, but none had reported their results by June 1, 2018. Michael Thase’s report in Healio seemed to be in conflict with the research program noted above by FierceBiotech, unless he was counting the recently completed long term study. He said: “The research program for this compound has included a number of double blind studies, of which two are unequivocally positive; these data are being reviewed by the FDA for a possible indication as an adjunct to antidepressants.”

FierceBiotech pointed out where two of three clinical trials phase 3 clinical trails failed to meet their primary endpoints. And the third had its methodology and analysis modified after post-hoc analysis of the second clinical trial showed statistical significance in a subpopulation. Can the results be “unequivocally positive” when the primary endpoint for one of the positive studies was changed after it had begun?

There are some questions I have with regard to the assertion there was “no evidence of withdrawal upon discontinuation” for the long term study. What specifically were the researchers looking for as “evidence of withdrawal”? And when was the assessment done—immediately upon conclusion of the 52-week study?

Mood swings with bouts of anxiety or depression are common side effects with buprenorphine withdrawal. Granted, the buprenorphine dose is relatively small at 2 mg, but the time period of use at 52 weeks was long. “Buprenorphine withdrawal symptoms last longer for those who use buprenorphine for longer periods of time or at higher doses.” See “A Double-Edged Drug” for more on buprenorphine withdrawal.

However, psychological withdrawal symptoms can last for many months after cessation. It is recommended that you join a support group or see a psychologist who can help see you through the protracted or post acute withdrawal symptoms (PAWS). Many heavy buprenorphine users experience PAWS. With continued use of buprenorphine, there comes a point where the brain produces in an inadequate amount of neurotransmitters in the body. People going through buprenorphine PAWS manifest long lasting changes in the brain as a result of long term use. These changes are slower to reverse and can persist for many months, depending on the frequency and amount of past dosing.

Another thing to remember is that Suboxone (buprenorphine and naloxone) and ALKS 5461 (buprenorphine and samidorphin) appear to be biochemical twins. Also remember where employees of Alkermes have characterized buprenorphine as “addictive.” And the addictive potential of buprenorphine has not been entirely neutralized by its combination with Alkermes’ patented opioid antagonist, samidorphin (ALKS 33).

In “The Coming Depression Apocalypse,” I said I’m concerned the use of ALKS 5461 for treatment resistant depression would generate a population of individuals dependent upon buprenorphine. The problems coming off of ALKS 5461 would eclipse what we now know happens with SSRI withdrawal. A New York Times article said originally, antidepressants were supposed to be used short term for episodic mood problems—six to nine months. Now, almost 7% of Americans have been using antidepressants for at least five years. Patients who try to taper off antidepressants often find withdrawal symptoms are so severe they cannot stop. “Nearly half who tried to quit could not do so because of these symptoms.”

Coupling buprenorphine withdrawal in ALKS 5461 to the known issues with antidepressant withdrawal compounds the problems these medications were supposed to treat. And within the biochemical worldview, these symptoms will be reinterpreted as evidence of the underlying depression and proof the individual needs to remain on ALKS 5461 and/or 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.”

01/5/18

In the Dark About Antidepressants

In 2011, antidepressants were the third most commonly prescribed medication class in the U.S. Mojtabai and Olfson noted in their 2011 article for the journal Health Affairs that much of the growth in the use of antidepressants was driven by a “substantial increase in antidepressant prescriptions by nonpsychiatric providers without an accompanying psychiatric diagnosis.” They added how the growing use of antidepressants in primary care raised questions “about the appropriateness of their use.” Despite this concern, antidepressant prescriptions continued to rise. By 2016, they were the second most prescribed class of medications, according to data from IMS Health.

A CDC Data Brief from August of 2017 reported on the National Health and Nutrition Examination Survey. The Data Brief provided the most recent estimates of antidepressant use in the U.S. for noninstitutionalized individuals over the age of 12. As indicated above, there was clear evidence of increased antidepressants use from 1999 to 2014. 12.7% of persons 12 and over (one out of eight) reported using antidepressant medication in the past month. “One-fourth of persons who took antidepressant medication had done so for 10 years or more.”

Women were twice as likely to take antidepressants. And use increased with age, from 3.4% among persons aged 12-19 to 19.1% among persons 60 and over. See the following figures from the CDC Data Brief. The first figure notes the increased use of antidepressants among persons aged 12 and over between 1999 and 2014. You can see where women were twice as likely to take antidepressants as men.

Figure 1

The second figure shows the percent of individuals aged 12 and over who took antidepressant medication in the past month between 2011 and 2014. Note how the percentages increase by age groups for both men and women, with the highest percentages of past month use for adults 60 and over for both men and women.

Figure 2

The third figure shows the length of antidepressant use among persons aged 12 and over. Note that while 27.2% reported using them 10 years or more, 68% reported using antidepressants for 2 years or more. “Long-term antidepressant use was common.” Over the fifteen-year time frame of the data, antidepressant use increased 65%.

Figure 3

The widespread use of antidepressants documented above is troubling when additional information about antidepressants is considered. A February 2017 meta-analysis done by Jakobsen et al., and published in the journal BMC Psychiatry, found all 131 randomised placebo-controlled trials “had a high risk of bias.” There was a statistically significant decrease of depressive symptoms as measured by the Hamilton Depression Rating Scale (HDRS), but the effect was below the predefined threshold for clinical significance of 3 HDRS points. Other studies have indicated that differences of less than 3 points on the HDRS are not clinically observable. See “Antidepressant Scapegoat” for more information on the HDRS. Jakobsen et al. concluded:

SSRIs might have statistically significant effects on depressive symptoms, but all trials were at high risk of bias and the clinical significance seems questionable. SSRIs significantly increase the risk of both serious and non-serious adverse events. The potential small beneficial effects seem to be outweighed by harmful effects.

In his review of the Jakobsen et al. study for Mad in America, Peter Simons noted where these results add to a growing body of literature “questioning the efficacy of antidepressant medications.” He pointed to additional studies noting the minimal or nonexistent benefit in patients with mild or moderate depression; the adverse effects of antidepressant medications; the potential for antidepressant treatment to potentially worsen outcomes. He concluded:

Even in the best-case scenario, the evidence suggests that improvements in depression due to SSRI use are not detectable in the real world. Given the high risk of biased study design, publication bias, and concerns about the validity of the rating scales, the evidence suggests that the effects of SSRIs are even more limited. According to this growing body of research, antidepressant medications may be no better than sugar pills—and they have far more dangerous side effects.

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. That is because there has been repeated underreporting and even fraud in reporting suicides, suicide attempts and suicidal thoughts in placebo-controlled trials. He added that the FDA has contributed to the problem by downplaying the concerns, choosing to trust the drug companies and suppressing important information.

He pointed out 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. Yet the individual responsible for the FDA’s 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 the 2001 study.

In “Precursors to Suicidality and Violence in Antidepressants” Gøtzsche co-authored a systematic review of placebo-controlled trials in healthy adults. The study showed that “antidepressants double the occurrence of events that can lead to suicide and violence.” Maund et al. (where he was again a co-author) demonstrated that the risk of suicide and violence was 4 to 5 times greater in women with stress incontinence who were treated with duloxetine (Cymbalta).

Although the drug industry, our drug regulators and leading psychiatrists have done what they could to obscure these facts, it can no longer be doubted that antidepressants are dangerous and can cause suicide and homicide at any age. Antidepressants have many other important harms and their clinical benefit is doubtful. Therefore, my conclusion is that they shouldn’t be used at all. It is particularly absurd to use drugs for depression that increase the risk of suicide when we know that psychotherapy decreases the risk of suicide. . . . We should do our utmost to avoid putting people on antidepressant drugs and to help those who are already on them to stop by slowly tapering them off under close supervision. People with depression should get psychotherapy and psychosocial support, not drugs.

Peter 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.” Breggin 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.

Vera Sharav, “a fierce critic of medical establishment,” the founder and president of the Alliance for Human Research Protection (AHRP), testified at the 2006 hearing. She reminded the Advisory Committee that the FDA was repeating a mistake they had made in the past. She said in the past the FDA withheld evidence of suicides from the Advisory Committee. German documents and the FDA’s own safety review showed an increased risk of suicides in Prozac. “Confirmatory evidence from Pfizer and Glaxo were withheld from the Committee.” Agency officials “obscured the scientific evidence with assurances.”

What the FDA presented to you is a reassuring interpretation of selected data by the very officials who have dodged the issue for 15 years claiming it is the condition, not the drugs. What the FDA did not show you is evidence to support that SSRI safety for any age group or any indication. They are all at risk. They failed to provide you a complete SSRI data analysis. They failed to provide you peer-reviewed critical analyses by independent scientists who have been proven right. FDA was wrong then; it is wrong now. Don’t collaborate in this. [But they eventually did]

Breggin commented that the FDA controlled and monitored the original pediatric studies because the drug companies did not do so on their own and failed to find a risk of antidepressant-induced suicidality in any age group. “Why would the FDA assume these same self-serving drug companies, left on their own again, would spontaneously begin for the first time to conduct honest studies on the capacity of their products to cause adult suicidality?”

In a linked document of two memos written by an Eli Lilly employee in 1990, Dr. Breggin noted where the individual questioned the wisdom of recommendations from the Lilly Drug Epidemiology Unit to “change the identification of events as they are reported by the physicians.” The person went on to say: “I do not think I could explain to the RSA, to a judge, to a reporter or even to my family why we would do this especially to the sensitive issue of suicide and suicide ideation. At least not with the explanations that have been given to our staff so far.” Those suggestions included listing an overdose in a suicide attempt as an overdose, even though (here he seems to be quoting from a policy or procedural statement) “when tracking suicides, we always look at all overdose and suicide attempts.” Eli Lilly brought the first SSRI, Prozac, to market in 1986.

Next time you hear someone say that the FDA studies only showed increased suicidality in children and young adults as opposed to adults, remember that the adult studies, unlike the pediatric studies, were not controlled, monitored or validated by the FDA. This is one more example of the extremes the FDA will go to in order to protect drug companies and their often lethal products.

The problems with antidepressants, most of which are SSRIs—selective serotonin reuptake inhibitors—were at least partially known as Prozac and its cousins were being developed and brought to market in the early 1990s. As the above discussion indicated, there seems to have been a disregard of the potential for multiple negative side effects from their use, up to and including the various forms of suicidality. The sleight-of-hand done by the drug companies, and apparently the FDA, means that many individuals are in the dark about the adverse side effects stemming from their SSRI medications.

12/5/17

Pick Your Poison: Diabetes and Psych Meds

The American Diabetes Association said 30.3 million Americans, 9.4% of the population, had diabetes in 2015. There are 1.5 million news cases of diabetes diagnosed each year. It is the 7^th leading cause of death in the U.S. with 79,535 death certificates in 2015 listing it as the underlying cause of death. A total of 252,806 death certificates listed diabetes as an underlying or contributing cause of death. If the number of deaths from diabetes were equal to 252,806, it would be the third leading cause of death in the US, according to the CDC … and psych meds increase the risk for diabetes.

SSRIs have been associated with an increased risk of diabetes, as Yoon et al. noted in “Antidepressant Use and Diabetes Mellitus.” The researchers ruled out depression itself as a potential confounding variable in the relationship between antidepressants and diabetes. Their findings suggested that antidepressant drug treatment and not the depression increased the risk of diabetes mellitus (DM). “Given the widespread use of antidepressants, the implications of the increased risk are serious.”

The authors noted that while there is disagreement as to the reason for the association between antidepressant use and DM risk, some studies “propose that antidepressants may bio-pharmacologically affect glucose homeostasis and insulin sensitivity.” In “Use of Antidepressants Linked to Diabetes,” Peter Simons of Mad in America noted a study that has supported that hypothesis. A study led by Raymond Noordam and published in The Journal of Clinical Psychiatry, found the use of SSRIs in nondiabetic participants was associated with lower insulin secretion and an increased risk of insulin dependence in type 2 diabetes in older adults.

It is biologically plausible that SSRIs decrease insulin secretion and that this might, therefore, be a mechanism underlying the previously observed association between SSRIs and increased risk of type 2 diabetes. Consequently, type 2 diabetes patients treated with SSRIs might also have a higher risk to develop insulin dependence, a condition associated with an increased risk of mortality.

The researchers also found that participants already diagnosed with diabetes who were taking antidepressants were twice as likely to start insulin treatment than those who did not take antidepressants. They said: “our data might suggest that progression of type 2 diabetes during the use of SSRIs is accelerated.” Simons commented how the higher mortality rate for individuals who require insulin treatments made this “a particularly alarming finding.”

This new study provides additional convincing evidence that although SSRIs are commonly believed to have fewer risks of adverse effects than TCAs, they still carry significant risk. This appears to be particularly relevant when it comes to patients with diabetes. Whenever antidepressant medication is considered, patients and prescribers should carefully weigh the potential risks and benefits.

There was an updated meta-analysis published in PLos One, “The Risk of New-Onset Diabetes in Antidepressant Users.” Their meta-analysis found an increased risk factor of 1.27 between exposure to antidepressants and new-onset diabetes. When they restricted the analyses to higher quality studies, the relative risk was higher. The researchers noted their findings were in line with two previous meta-analyses that reported “a 1.5-fold increase of diabetes among AD [antidepressant] users.” In an interview with Endocrinology Advisor, the lead investigator of the study extrapolated that given a 13% prevalence rate of antidepressant use in the US, a 1.3-fold increase in diabetes risk would translate to over 1 million cases of diabetes that could be due to concurrent antidepressant use.

Pharmacy Times reported in “Atypical Antipsychotic-Induced Type 2 Diabetes” that patients with schizophrenia were at an increased risk of developing metabolic disorders like type-2 diabetes mellitus (T2DM). Schizophrenic patients had a number of risk factors for T2DM, including family history, increased body mass index (weight gain), a sedentary lifestyle and the use of atypical antipsychotics. There have been several proposed mechanisms for the association of diabetes and atypical antipsychotics, one being the weight gain associated with the medications.

A 2006 study by Alvarez-Jiménez et al. found that 78.8% of patients taking atypical antipsychotics experienced a weight gains greater than 7%, the cut off for clinically meaningful weight gain in the study. In 2004 the FDA required a warning be placed in the medication guides of all atypical antipsychotics warning of the increased risk of hyperglycemia and diabetes.

Patients with schizophrenia are at increased risk of developing metabolic disorders like type 2 diabetes. This is due to a number of factors, including the treatment of schizophrenia with atypical antipsychotics. There are several potential mechanisms behind antipsychotic-induced diabetes, including the weight gain associated with these medications, the effects on pancreatic receptors and/or glucose transporters, or some other cause not yet discovered. Most likely, it is a combination of these effects. Of the atypical antipsychotics, clozapine [Clozaril] and olanzapine [Zyprexa] are associated with the highest incidence of metabolic dysfunction, whereas ziprasidone [Geodon] and aripiprazole [Abilify] are considered to be the least risky.

In “Antipsychotic-Induced Diabetes Mellitus” published in U.S. Pharmacist, Chhim et al. reported there are several metabolic consequences with antipsychotic use, including weight gain, hyperglycemia (abnormally high blood glucose) and dyslipidemia (an abnormal amount of triglycerides, cholesterol and/or fat phospholipids in the blood). The association of type 2 diabetes mellitus (T2DM) and antipsychotic use is supported by retrospective epidemiologic studies as well as post-marketing assessment. Data indicate the prevalence of diabetes and obesity is 1.5 to 2 times higher in people diagnosed with schizophrenia or affective disorders than the general population.

The authors noted that diabetes was reaching epidemic proportions worldwide, and the contributions of medications to the development of hyperglycemia and other metabolic problems was getting more attention. “Pharmacists are in a unique position to counsel and encourage appropriate self-monitoring in patients receiving certain drugs, such as antipsychotics, that can contribute to the development of weight gain, hyperglycemia, and dyslipidemia.” They can encourage patients to report adverse events to other health care providers and seek therapeutic substitutions, counseling, and/or treatment for the adverse events.

Another resource addressing these concerns, one that was cited in “Antipsychotic-Induced Diabetes Mellitus,” is the “Consensus Development Conference on Antipsychotic Drugs and Obesity and Diabetes.” This is a joint consensus statement from the American Diabetes Association, the American Psychiatric Association, the American Association of Clinical Endocrinologists, and the North American Association for the Study of Obesity to help reduce the risk of developing diabetes, cardiovascular disease, and other complications of diabetes.

There was a large longitudinal study done in Denmark by Rajkumar et al. that found in addition to the high risk for diabetes conferred by schizophrenia on individuals, “the risk is further increased by both first-generation and second-generation antipsychotics.” Reporting on the study for Mad in America, Bernalyn Ruiz said the authors said the prevalence of diabetes was 4 to 5 times greater in people diagnosed with schizophrenia. “After adjusting for potential confounders, the risk was elevated threefold compared to those without a schizophrenia diagnosis.” No differences were seen between first-generation and atypical antipsychotics.

This large nationwide study confirmed endogenous risk for diabetes among individuals diagnosed with schizophrenia, with risks increasing significantly when antipsychotics are prescribed.

The bottom line is that in addition to their other adverse effects, there is credible scientific evidence that antidepressants and antipsychotics increase the risk of diabetes among individuals taking them. So when you’re advised to use one of these classes of psychiatric medications, it’s a bit like being asked to pick your poison.

Faith Seeking Understanding

Charles Sigler, D.Phil.

Tag Archives: antidepressants