Tag Archives: Council for Evidence-Based Psychiatry

10/22/19

Fighting or Fueling Suicide with Antidepressants?

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

08/13/19

Following the Leader with Antidepressants

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

04/20/18

The Lancet Story on Antidepressants, Part 2

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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 24th, 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.”

10/14/15

Antipsychotic Big Bang

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Duff Wilson wrote in “Side Effects May Include Lawsuits” that antipsychotics were a niche product for decades. Yet they have recently generated sales that have surpassed that of “blockbusters like heart-protective statins.” In the 1990s, pharmaceutical companies began marketing them for much broader uses than the original FDA approved uses for more serious mental illnesses, like schizophrenia and bipolar disorder. A Scientific American article reported that pediatric prescriptions for atypical antipsychotics rose 65%—from 2.9 million to 4.8 million—between 2002 and 2009. And a New York Times article noted that federal investigators have found widespread overuse of psychiatric drugs by older Americans with Alzheimer’s disease.

There are two more facts to introduce you to about neuroleptics or atypical antipsychotics. First, in 2008, antipsychotics sales reached $14.6 billion, making them the biggest selling therapeutic class of drugs in the U.S. Second, each of the following pharmaceutical companies that marketed antipsychotics has been investigated for misleading marketing under the False claims Act. All their neuroleptics—Risperdal (risperidone; Johnson & Johnson), Zyprexa (olanzapine; Eli Lilly), Seroquel (quetiapine; AstraZeneca), Geodon (ziprasidone; Pfizer), and Abilify (aripiprazole; Bristol-Myers Squibb and Otsuka)—are now off patent.

The primary use off-label use of neuroleptics for the elderly and with children has been for behavioral control. A recent study commissioned by the Pennsylvania Department of Human Services found that children between the ages of 6 and 18 who were in foster care was four times higher than other youth in Medicaid. More than half of these youth had a diagnosis of ADHD. “This is concerning, as the majority of these youth did not have another diagnosis that clinically indicated the use of antipsychotics.” Risperidone was the most frequently prescribed antipsychotic medication among the youth. However, Abilify and Seroquel grew to exceed risperodone over the course of the study. Zyprexa was the least commonly used antipsychotic among all youth.

A trade group for nursing homes, The American Health Care Association, indicated that while antipsychotics helped some dementia patients who have hallucinations or delusions, “They also increase the risk of death, falls with fractures, hospitalizations and other complications.” The American Psychiatric Association, among others pointed to a JAMA Psychiatry study that showed mortality risks increased in patients given antipsychotics to reduce their symptoms of dementia. Another study published in Health Policy said the benefits and harms of using antipsychotic medications in nursing homes should be reviewed.

Antipsychotic medication use in nursing home residents was found to have variable efficacy when used off-label with an increased risk of many adverse events, including mortality, hip fractures, thrombotic events, cardiovascular events and hospitalizations.

Another “add on” area for neuroleptic use is when it is used with an antidepressant for “treatment resistant” depression. On BuzzFeed, Cat Ferguson reported how the sale of antipsychotics such as Abilify, and Zyprexa “skyrocketed” as they were approved to treat depression as an add-on medication. Seroquel is not FDA approved to treat major depression, but along with Abilify and Zyprexa is approved to treat bipolar depression in adults. Zyprexa and Seroquel are approved for some indications of bipolar disorder in adolsecents, but Abilify is only used off label with bipolar children, having “low or very low evidence of efficacy.” See the Psychopharmacology Institute for more information on these drugs and their approved and off-label uses.

Ferguson quoted a few psychiatrists expressing concern about the antipsychotic boom, and there are some surprises given other stands they’ve taken. Allen Frances, the former chair for the DSM-IV, agreed there has been heavy marketing of antipsychotics. He thought they are prescribed too quickly for depression and without clear indication of their efficacy. He added there seemed to be pressure from the pharmaceutical companies. He said: “These drugs should have a narrow indication, and instead they’ve become the highest revenue-producing drugs in America.”

Over the past few years Allen Frances has become an outspoken critic of some psychiatric practices, including the overuse of antipsychotics and antidepressants. He’s also been critical of the DSM-5. He’s even written Saving Normal to address his concerns with psychiatry and psychiatric practice. Search for his name here to find several articles where he is mentioned.

I was surprised and encouraged to see Jeffrey Lieberman, the chair of psychiatry at the Columbia University College of Physicians and Surgeons express concern with the over prescribing of antipsychotics. Lieberman has positioned himself as defender of psychiatry and psychiatric practice, recently publishing Shrinks. You can also search his name here to see other articles interacting with his book and position on psychiatry. Lieberman said that antipsychotic medication should be used sparingly in treating nonpsychotic disorder, including depression. He said: “I think there’s the possibility that antipsychotics are overprescribed, not just for depression, but in other areas.”

My point is that when two prominent psychiatrists with opposing views on many areas of psychiatry and psychiatric practice agree that antipsychotics are overused, pay attention. Both Frances and Lieberman have pointed out elsewhere how pharmaceutical marketing strategies contribute to this problem, but some pharma companies and representatives put the blame back on doctors. An Eli Lilly spokesperson said pharmaceutical companies aren’t responsible for how their drugs are used by doctors. “Physicians make prescribing decisions, not pharmaceutical companies. . . . While certainly we inform doctors of the benefits and risks of our medicine, it’s really up to physicians to prescribe the right medicine.”

But this attempt to deflect responsibility onto physicians is a cop out when you consider the marketing done by pharmaceutical companies for their products. In this YouTube advertisement for Abilify as an antidepressant add-on, you see how Bristol-Myers Squibb actively encouraged individuals to “ask your doctor if Abilify is right for you.” Pay attention to the fact that the first thirty seconds verbally describes how Abilify can help, while the rest of the 90-second commercial has the woman and her family going on a picnic while the adverse side effects are described.

Another problem is that all clinical trials for drug approval are done over short periods of time—six or eight weeks—antipsychotics included. But what are the long-term consequences of antipsychotics? As Dan Iosifescu, the director of the Mood and Anxiety Disorders Program at Ichan School of Medicine at Mount Sinai Hospital said, “It’s just a fallacy to take short-term data and extrapolate it for long term.” His bottom line is that antipsychotics tend to be helpful in the short term, but can have major consequences in the long term.

Thomas Glasen, writing in Schizophrenic Bulletin, weighed the pros and cons of medication treatment for psychosis. In the case for medication, he noted that the benefits of medication were profound. The therapeutic power of antipsychotic medication had been validated in countless studies and was now the primary treatment of schizophrenia. “In today’s climate, treating schizophrenia without medication mobilizes high anxiety among treaters for the safety of their patients from irrationality and for the safety of themselves from litigation.” However, in the case against medication, Glasen said:

Antipsychotics obscure the pathophysiology of psychosis by altering the neurobiology of the brain and the natural history of [the] disorder. . . . Medication can be lifesaving in a crisis, but it may render the patient more psychosis-prone should it be stopped and more deficit-ridden should it be maintained.

So how do individuals on long-term antipsychotics do? In Anatomy of an Epidemic, Robert Whitaker described Martin Harrow’s presentation of a long-term study funded by NIMH on sixty-four individuals diagnosed as schizophrenic between 1975 and 1983. Whitaker had just reviewed a series of studies questioning whether there was a long-term benefit to the use of antidepressants before discussing the Harrow study. He then said: “If the conventional wisdom is to be believed, then those who stayed on antipsychotics should have had better outcomes.” Harrow found that after two years, there was evidence that the off-med group was doing slightly better than the group on drugs.

Then, over the next thirty months, the collective fates of the two groups began to dramatically diverge. The off-med group began to improve significantly, and by the end of 4.5 years, 39 percent were “in recovery” and more than 60 percent working.

The outcomes for the medication group worsened and this divergence continued. At the fifteen-year follow up, 40 percent of those off drugs were in recovery and more than half were working; only 28 percent suffered from psychotic symptoms. “In contrast, only 5 percent of those taking antipsychotics were in recovery, and 64 percent were actively psychotic.” The 2007 Harrow study can be found here. Harrow said that not only was there a significant difference in global functioning between the two groups, 19 of the 23 (83%) schizophrenic patients with uniformly poor outcome after fifteen years were on antipsychotics.

symptomsHarrow et al. (2014) continued his study and reported data in Psychological Medicine at the twenty-year stage of his follow-up schedule. Here he investigated whether multi-year treatment with antipsychotics reduced or eliminated psychosis; and whether the results were superior to individuals in the non-medicated group. The data showed that the pattern noted above by Whitaker in Harrow’s 2007 report continued: “A surprisingly high percentage of SZ prescribed antipsychotic medications experienced either mild or more severe psychotic activity.”  The figure to the left, originally from the 2014 Harrow et al. report, shows that 68% of the medication group experienced psychotic activity, while only 8% of the off-med group experienced any psychotic activity. The source of the figure was a slide reproducing the Harrow data in a presentation by Robert Whitaker at the “More Harm than Good” conference sponsored by the Council for Evidence-Based Psychiatry (CEP). The slides and videos of the presentation can be found here.

Harrow et al. thought the high percentage of the medication group experiencing psychotic activity was influenced by two factors. One was the high vulnerability to psychosis of many schizophrenic patients, leading to a high risk of psychosis. But that begs the question of how the medication group in the study had such a high number of patients “at risk of psychosis.” Given the above data, their second factor seems to have been the more important factor: prolonged use of antipsychotics (or partial dopamine blockers) may produce a medication-generated build-up of supersensitive dopamine receptors or excess dopamine receptors.

The production of excess or supersensitive dopamine receptors would then be an iatrogenic, drug induced effect from the long-term use of antipsychotics. The brain increases or sensitizes the receptors, thus compensating for the blockade of original receptors in the postsynaptic neuron. Again, drawing from Whitaker’s presentation slides at the CEP conference, it would look like this:

dopamine

The above presentation of Harrow’s data and the discussion from Whitaker’s CEP presentation seem to affirm Glasen’s thesis that antipsychotics could alter the neurobiology of the brain. Antipsychotics reduce the activity of dopamine systems, stimulating the increase of receptors. When the antipsychotic is tapered or withdrawn, this would not immediately diminish the number of additional dopamine receptors produced by the brain to compensate for the dopamine blocking action of the antidepressant. With decreased antipsychotic levels, the result would be increased activation of the postsynaptic neurons because of the greater number receptors to absorb dopamine.

The person’s symptoms could intensify through the increased absorption of dopamine because of this disregulation of the dopamine system. In other words, tapering off of antipsychotics could activate symptoms like mania, paranoia and hallucinations because of the chemical imbalance produced by the medication. The experience of mania from a too sudden withdrawal of an antipsychotic is in this view, likely a withdrawal or discontinuation symptom instead of proof that the person needs to remain on an antipsychotic because they have a chemical imbalance. Robert Whitaker’s conclusion in Anatomy of an Epidemic was:

What the scientific literature reveals is that once a person is on an antipsychotic, it can be very difficult and risky to withdraw from the medication, and that many people suffer severe relapses. But the literature also reveals that there are people who can successfully withdraw from the medications and that it is this group that fares best in the long term.