is there no bottom?…

Posted on Tuesday 6 December 2016

Just when you think you’ve found the bottom of a rotten barrel, you poke through and there’s even more corruption below. Read these [because you can’t not read them]…
The Intercept
by David Dayen
December 1, 2016
by David Hilzenrath
December 1, 2016
by David Hilzenrath
December 1, 2016

POGO Recommendations
End Reliance on User Fees. One way to enhance the FDA’s independence and help prevent the problems identified in this report would be to end the FDA’s reliance on user fees. These are direct payments by manufacturers for certain services provided to them by the FDA. In return, the manufacturers count on special consideration, including faster approvals of drugs. Often “faster” means “less careful” or “less independent.” Congress should not reauthorize the Prescription Drug User Fee Act (PDUFA). Instead, it should use federal appropriations to fund all of the FDA’s work on prescription drugs.

Eliminate Requirement for FDA to Negotiate User Fees with Regulated Industry. A short term solution and a more immediate fix to the problems described in this report would be to eliminate the legislative requirement that the FDA negotiate with “the regulated industry” in advance of user fee reauthorization.

Increase Transparency of Negotiation and Consultation Meetings. In the absence of either of the previous suggested changes, Congress should require much more transparency in the user fee reauthorization process. It should open to the public the FDA’s negotiating sessions with industry and its consultation meetings with other stakeholders, including patient and consumer groups. Congress should also require online posting of live webcasts, permanent video recordings, and transcripts of those meetings. Consumer groups that do not receive funding from the pharmaceutical or biotech industries should be included in these meetings. Transparency would allow the public and Congress to better oversee the agreements the FDA negotiates with the drug industry over the agency’s funding and its approach to reviewing drugs. It would help the public and Congress determine whether additional reforms are needed to protect public health and safety.

Require Conflict of Interest Disclosure for Stakeholders. POGO’s investigation found that the vast majority of the patient advocacy groups that the FDA consulted in the latest round of user fee meetings received funding from the pharmaceutical industry. Congress should require that all stakeholders who participate in meetings with the FDA over user fee renewal disclose all potential personal and financial conflicts of interest. Those disclosures should be posted online when the meetings take place. The disclosures should include, but not be limited to, industry funding of stakeholder groups, industry representation on the boards and staffs of those groups, and board members who serve as employees or contractors to companies in FDA-regulated businesses—e.g., makers of medical devices and contract research organizations, which manage clinical trials for drug companies.
Mickey @ 2:01 PM

déjà vu…

Posted on Monday 5 December 2016

I ran across this article on a recent drive-by of this month’s journals. It seemed like an anachronism, like something from the past. But more than that, I had an uncanny déjà vu feeling about it. It took a while to recall why. Back when I was first looking at clinical trials [2010?], I found where this study had been done, but apparently was never published. I even wrote AstraZeneca asking about it [receiving no reply]. I had started to work in a clinic where it seemed like everybody I saw was taking Seroquel, and I was trying to figure out why. About that time, the news was full of Veterans suiciding, and the epidemic prescription of Seroquel [for sleep?] was implicated. Apparently the VAH consumption of that drug was off the charts. In our clinic, it took a while to get people off of Seroquel [because it works for sleep]. I thought the risk/benefit equation did not justify using a neuroleptic for sleep so I gradually changed things [and I learned a lot about Seroquel withdrawal in the process]:
by Gerardo Villarreal, Mark B. Hamner, José M. Cañive, Sophie Robert, Lawrence A. Calais, Valerie Durklaski, Yusheng Zhai, and Clifford Qualls
American Journal of Psychiatry. 2016 173[12]:1205-1212.
  Received: July 27, 2015
  Accepted: May 02, 2016 Identifier: NCT00237393
  Study Start Date: August 2003
  Study Completion Date: December 2007

Objective: This was a 12-week randomized, placebo-controlled trial to assess the efficacy of quetiapine monotherapy in the treatment of posttraumatic stress disorder [PTSD].
Method: Eighty patients were randomly assigned to treatment with either quetiapine or placebo. The primary outcome measure was the Clinician-Administered PTSD Scale [CAPS]. Secondary efficacy measures included the CAPS subscales, the Davidson Trauma Scale, the Positive and Negative Syndrome Scale [PANSS], the Clinical Global Impressions [CGI] scales for severity of Illness and improvement, the Hamilton Depression Rating Scale [HAM-D], and the Hamilton Anxiety Rating Scale [HAM-A]. Safety measurements included adverse events, vital signs, the Abnormal Involuntary Movement Scale, the Barnes Akathisia Scale, the Simpson-Angus Scale, and the Arizona Sexual Experiences Scale.
Results: After a 1-week placebo run-in, quetiapine was started at a daily dosage of 25 mg and increased to a maximum of 800 mg; the average was 258 mg [range, 50–800 mg]. Reductions in CAPS total, re-experiencing, and hyperarousal scores were significantly greater for the quetiapine group than for the placebo group. Greater improvements were also observed for quetiapine in scores on the Davidson Trauma Scale, CGI severity and improvement ratings, PANSS positive symptom and general psychopathology subscales, HAM-A, and HAM-D than for placebo. Adverse events were generally mild and expected based on prior studies of quetiapine in this and other patient population. There were no differences in safety measures between groups.
Conclusion: Quetiapine monotherapy was efficacious in the treatment of PTSD. These findings suggest quetiapine as a single agent is effective in treating military PTSD.

Presented at the 29th Annual Conference of the Anxiety Disorders Association of America, Santa Anna Pueblo, N.M., March 12–15, 2009, and the 2009 CINP Thematic Meeting, Edinburgh, April 25–27, 2009.

Funded by an investigator-initiated grant from AstraZeneca to Dr. Hamner.

Dr. Hamner has current research support from Alkermes and Pfizer; he has been the recipient of research grant support or honoraria and/or has served as a consultant for the following pharmaceutical companies: Abbott, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Forest Laboratories, Janssen, Lundbeck, Organon, Otsuka, and Sanofi-Synthlabo. Dr. Cañive has received research grant support or honoraria and/or has served as a consultant for the following pharmaceutical companies: Abbott, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Organon, Otsuka, and Sanofi-Synthlabo. The other authors report no financial relationships with commercial interests.
The study met its primary outcome parameters and racked up the requisite p-values and effect sizes to be called a positive study. There was an accompanying editorial. And Dr. Stein was as confused as I was about the almost decade lag time between the end of the actual Clinical Trial [2007] and its publication [2016].

by Murray B. Stein
American Journal of Psychiatry. 2016 173[12]:1165-1166.

…the study by Villarreal et al., also in this issue, digs up a topic thought to be long dead: the efficacy of atypical antipsychotics for PTSD. Whereas some early, small trials had suggested that atypical antipsychotics, such as olanzapine or risperidone, might be useful adjunctive [to selective serotonin reuptake inhibitors] treatment for PTSD, a large VA Cooperative Study seemed to put the nail in the coffin of that treatment option by failing to show a benefit of adjunctive risperidone on global severity of PTSD. That trial, it should be noted, did show statistically significant [though, it was argued, clinically modest] beneficial effects on hyperarousal symptoms and, in a more recent secondary analysis, sleep disturbance. Moreover, meta-analysis suggests that atypical antipsychotics can be useful in treating PTSD, and clinicians continue to believe they are efficacious and continue to prescribe them for many [up to 20% of] patients with PTSD.

Against this backdrop of high antipsychotic prescribing for PTSD in the face of limited evidence of efficacy comes this new randomized placebo-controlled trial of quetiapine as monotherapy for military-related PTSD [by Villarreal et al]. Well, not really a new study, but an old study — completed in 2008 — newly published. It is unclear why it took nearly a decade to publish the results of this positive study, but it is timely nonetheless. Albeit a fairly small trial that enrolled 80 patients, the results suggest that quetiapine can be useful in the treatment of PTSD, though the authors remind readers that adverse effects of this class of drugs must be considered in the risk-benefit ratio of whether to treat a given individual.

Whereas clinical practice should rarely be influenced by findings from a single trial, the results of this study should hasten a reinvigoration of research into the safety and efficacy of atypical antipsychotics for the treatment of PTSD. Though we yearn for a future where better and safer drugs for PTSD can be targeted for precisely the patients most likely to benefit from them with the fewest adverse effects, we are constrained to practice medicine in the present. Call it imprecision medicine if you must, but if atypical antipsychotics — administered as monotherapy or as adjunctive therapy — can help some patients with PTSD — then let’s shore up the evidence base for their utility so that we practitioners can feel less stressed about using them.
I’m obviously in the "stressed about using them" camp. I doubt this article would’ve changed that, because since then, the cases of Tardive Dyskinesia I’ve seen have been in non-psychotic people who were on antipsychotics for sleep, or augmentation, or unclear reasons. Fortunately, the TD cases aren’t common and usually slowly clear over time [or at least diminish]. But that’s just not a risk I’m willing to take. That wasn’t my main beef with Seroquel. In my hands, it was a lousy antipsychotic drug. I just couldn’t make it work. I reviewed all the FDA studies used for approval, and they were on the shaky side. And beyond that, there was one trial that they just hid from us altogether – Study 15. They put Seroquel up against Haldol in tolerability and relapse prevention and lost both in a big way [see seroquel VIII: sins of ommission…]. That study was actively covered up [see seroquel V: through the looking glass…] [don’t miss the ‘smoke and mirrors’ email!].
That’s when I personally finally began to realize just how corrupt the pharmaceutical industry had become. And I would bet that this month’s anachronistic paper wasn’t published in a timely fashion back in the day because AstraZeneca was in the news enough already and keeping a low profile. An example [note this news report was at the same time as they were presenting this PTSD study at meetings "Presented at the 29th Annual Conference of the Anxiety Disorders Association of America, Santa Anna Pueblo, N.M., March 12–15, 2009, and the 2009 CINP Thematic Meeting, Edinburgh, April 25–27, 2009"]:
Washington Post
By Shankar Vedantam
March 18, 2009

The study would come to be called "cursed," but it started out just as Study 15. It was a long-term trial of the antipsychotic drug Seroquel. The common wisdom in psychiatric circles was that newer drugs were far better than older drugs, but Study 15’s results suggested otherwise.

As a result, newly unearthed documents show, Study 15 suffered the same fate as many industry-sponsored trials that yield data drugmakers don’t like: It got buried. It took eight years before a taxpayer-funded study rediscovered what Study 15 had found — and raised serious concerns about an entire new class of expensive drugs. Study 15 was silenced in 1997, the same year Seroquel was approved by the Food and Drug Administration to treat schizophrenia…
The irony is that while this old trial is small, it’s actually one of Seroquel’s better outings. This post is here just as a reminder of how bizarre the journey has been in the world of psychopharmacology. Once, Seroquel was the blockbuster drug of all times. Now it’s rarely mentioned…
Mickey @ 10:07 PM

looking back…

Posted on Sunday 4 December 2016


Let’s face it – for as much as Congress and the evening news pundits push us to look forward to bold new medical breakthroughs, for a lot of us, this is a time for looking back over where we’ve been and cleaning up a lot of misinformation and garbled, deceitful science. And while Stanford’s John Ioannidis recurrently warns us about sloppy/deceitful research [Why Most Published Research Findings Are False] and overdoing the Meta-Analyses and Systemic Reviews [The Mass Production of Redundant, Misleading, and Conflicted Systematic Reviews and Meta-analyses], he’s also an important resource for anyone interested in looking through the Clinical Trial Retrospectoscope. A given meta-analysis might address all the comparable studies of a single drug, or further, all the drugs aiming at the same target [using the same metrics]. A Network Meta-Analysis goes further. By using the Comparator Drugs in the various RTCs, it aims to create a heirarchy of relative efficacy. Obviously, the further one gets from the primary data, the more complex and abstract the mathematical operations become, and the more room there is for error, gibberish, or both. Ioannidis is right there at hand to at least outline the pitfalls and methodology of such an undertaking in an article understandable by mortals [Demystifying trial networks and network meta-analysis].


If there is a maestro of meta-analyses for the psychiatric drugs, it’s Oxford’s Andrea Cipriani, longtime contributor to the Cochrane Collaboration Systemic Reviews. This summer, his group published a Network Meta-Analysis of the SSRI/SNRI drugs in child and adolescent depression [Comparative efficacy and tolerability of antidepressants for major depressive disorder in children and adolescents: a network meta-analysis.][see also my antidepressants in kids? a new meta-analysis…] that concluded: "When considering the risk-benefit profile of antidepressants in the acute treatment of major depressive disorder, these drugs do not seem to offer a clear advantage for children and adolescents. Fluoxetine is probably the best option to consider when a pharmacological treatment is indicated."

If you read this blog from it’s psychiatry origins [2009] to the present, the over-riding focus has been on RCTs [Randomized Clinical Trials] of Psychiatric Drugs in the post-Prozac era. And of those, Paroxetine [Paxil] Study 329 would stand out as something of a near obsession [Efficacy of Paroxetine in the Treatment of Adolescent Major Depression: A Randomized, Controlled Trial]. I make no apology for that. As a clinician, I am a psychiatrist and psychoanalyst, and practiced psychotherapy throughout my career. So case study and n=1 are very much my cup of tea. But there are other reasons this study is so prominantly mentioned. It is virtually the only study where we have the raw data, and the internal documents that allow it to be investigated thoroughly. When we did our RIAT reanalysis [Restoring Study 329: efficacy and harms of paroxetine and imipramine in treatment of major depression in adolescence], I was focused on  the efficacy analysis. That story has been often told here so I’ll move on to my point. They reported positive results in a negative trial by changing the Outcome Variables from those declared in the a priori Protocol. And spending several years immersed in that reanalysis taught me how essential pre-registration is in conducting a truly scientific study.

Since we published our paper, I have made that pre-registration of variables point over and over like it was the discovery of a new continent – because it was such a discovery at least for me. So when Ben Goldacre publicized his COMPare project and used the name OUTCOME SWITCHING to describe it, I was immediately engaged. Then I saw his data showing that most of the contemporary trials they reviewed had some version of this kind of deceit. All of a sudden, my n = {1} obsession became n = {a majority}. Yesterday I read a Commentary article about our Study 329 Restoration and the recent Network Metanalysis by Barber and Cipriani that was the clearest summary of what I’ve been trying to say myself yet – and more:
by Sarah Barber and Andrea Cipriani
Australian & New Zealand Journal of Psychiatry. 2016 Nov 17.
[Epub ahead of print]

…According to the results from this study, psychiatrists who prescribe paroxetine to a 15-year-old with major depression are practising evidence-based medicine. Or at least they were, until a major re-analysis in 2015 found no difference between paroxetine and placebo when only outcome measures pre-specified in the original study protocol were considered [Restoring Study 329: efficacy and harms of paroxetine and imipramine in treatment of major depression in adolescence]. The statistically significant findings in Study 329 original article, it emerged, relied on four new outcome measures, introduced post hoc by the sponsor. It is known that pharmaceutical industry-funded studies are more likely to show favourable efficacy results for investigational drugs than independent trials. Study 329 demonstrates how outcome-switching and selective reporting of results can be used to manipulate results…
Just a reminder that RCTs are about efficacy AND Adverse Events, and the latter aren’t discussed here but were a major piece of our restoration. But sticking to the efficacy analysis…
This is an important issue, which is at the heart of the debate in the scientific literature about evidence based medicine and, therefore, evidence-based practice. Ben Goldacre and colleagues at the Centre for Evidence-Based Medicine at the University of Oxford have been systematically investigating the issue of outcome-switching in trials published in top medical journals and sharing their results on the website They have found that poor trial reporting often masks inadequate design, and studies such as 329 are just examples of a widespread practice in all areas of medical research, not only psychiatry. This is despite the endorsement by prominent medical journals of the Consolidated Standards of Reporting Trials [CONSORT] Statement, a guideline for authors to prepare reports of trial findings, facilitating their complete and transparent reporting and aiding their critical appraisal and interpretation. Of course, good quality trials may be poorly reported. However, transparent reporting on inadequate trials will reveal deficiencies in the design if they exist, as in the case in Study 329. Among other things, CONSORT requires there to be "completely defined pre-specified primary and secondary outcome measures" and clear reporting of "any changes to trial outcomes after the trial commenced, with reasons". Both are absent in Study 329…
CONSORT is an almost universally endorsed guideline for what goes into the RCT Protocol/Study. You fill it out when you submit an article for major journals. And here are the two elements in question. Note it says "Completely defined" and "pre-specified" [elaborations highlighted in red above]:
It also says "Any changes to the trial outcomes after the trial commenced with reasons." 329 came up short there too:
While we fully support the efforts of these groups, we wish to address the needs of practicing clinicians, who want to know which is the most reliable estimate of paroxetine in young people with major depressive disorder. Individual trials and also pairwise meta-analyses are not enough. Network meta-analysis has the great advantage over standard meta-analysis of comparing all treatments against each other [even if there is no trial data comparing the interventions directly] and ranking them according to their relative efficacy or tolerability with a precise degree of confidence. Another important advantage of network meta-analysis is that the effects of sponsorship bias are distributed [and therefore diluted] across the network. The case of Study 329 is a clear demonstration of this added value. A recent network meta-analysis has compared all antidepressants for major depression in children and adolescents [Comparative efficacy and tolerability of antidepressants for major depressive disorder in children and adolescents: a network meta-analysis]. The search strategy, though, was completed in May 2015, a few months before the publication of the re-analysis of study 329. As a result, Study 329 was included with the original 2001 data biased towards paroxetine; however, the overall results from the network meta-analysis showed that paroxetine was not statistically significantly different from placebo. This is because by combining direct with indirect evidence, the bias in studies that favour the investigational drug over placebo is mitigated by the findings of other indirect comparisons in the network. Interestingly, the final results of the network meta-analysis showed that, among all antidepressants, only fluoxetine was significantly more effective than placebo. This is probably a robust result, because it is consistent with the direct and indirect evidence comparing fluoxetine with all the other compounds in the network.

Even using the unrestored results from Study329, Paxil didn’t make the grade in the Network Meta-Analysis – a nice confirmation of our results. I also found the Prozac result interesting. It was approved for adolescents before the Black Box Warning and Lily fought [unsuccessfully] to keep it off the Prozac label. Prozac remains the main drug with FDA Approval for kids. A later Lexapro/Ccelexa FDA Approval has long been questioned, particularly recently since The citalopram CIT-MD-18 pediatric depression trial: Deconstruction of medical ghostwriting, data mischaracterisation and academic malfeasance came out. I’ve personally always suspected that the Prozac result was suspicious – thinking it simply made it under the wire before people caught on that so many studies were being jury-rigged. But this independent confirmation by Network Meta-Analysis suggests that it was indeed a valid result after all. Why it should be any different than the others doesn’t make much sense, but there it is…

The obvious drawback to Meta-Analyses and particularly the Network variety is that they need a lot of trials, so one is well along the path of a drug/class lifespan before such techniques can even be used. Further, one is at the mercy of the pharmaceutical industry’s choice of the Comparators being included in the studies. Bringing up an often unmentioned fact, in most cases, these short-term industry-funded studies conducted for approval and/or commercial purposes are all we really have – the only act in town. In spite of the fact that many, many patients are taking these drugs and staying on them for long periods of time, we still pore over those early brief trials as if they are definitive clinical roadmaps rather than, at best, simply starting places. Until we figures out a way to independently harvest the enormous untapped data pool generated from ongoing clinical usage, these often questionable approval trials retain their power to hold us in their grip [as they have for several decades].

But for now, while I can agree with Ioannidis that we are inundated with a lot of unnecessary meta-this-and-thats, high quality work like this Network Meta-Analysis by Cipriani and his colleagues is exactly what’s needed right now, along with reanalyses of questionable clinical trials and ongoing monitoring of contemporary RCT reports like Goldacre’s COMPare project. Throw in a little Data Transparency, and we’re good to go. Like I said, "…this is a time for looking back over where we’ve been and cleaning up a lot of misinformation and garbled, deceitful science."
Mickey @ 3:46 PM

in the realm of hypothesis…

Posted on Thursday 1 December 2016

The Australian Doctor
by Clare Pain
28 November, 2016

Leading psychiatrist Professor Patrick McGorry’s hopes that fish oil may protect young people from developing psychosis have proved to be unfounded. In a follow-up study of more than 300 young people at high risk of psychosis, omega-3 polyunsaturated fatty acid supplements were no better than placebo in reducing transition to psychosis.

The multinational study led by Professor McGorry failed to replicate preliminary findings from a 2010 trial in 81 patients that had shown fish oil could prevent transition to psychosis among young people who took supplements for 12 weeks. At the time, Professor McGorry, executive director of Orygen, the National Centre of Excellence in Youth Mental Health, described the results as "almost too good to be true".

Nevertheless, he suggested that clinicians considered using fish oil supplementation without waiting for further trial results, and included them as an appropriate treatment recommendation in Orygen’s Australian Clinical Guidelines for Early Psychosis. However, Professor McGorry and co-researchers conceded that the new trial had “clearly failed to replicate the findings of the original”. Low rates of transition to psychosis in the new trial may have made it difficult to show a beneficial effect of omega-3 fatty acids above and beyond the background treatments such as CBT and antidepressants, Professor McGorry said.

Commenting on the finding, Professor David Castle, Chair of Psychiatry at St Vincent’s Health and the University of Melbourne, said it was what he had expecting. “I always found the original paper very difficult to accept as the final word on [prevention of psychosis with fish oil]. The proof of science is in replication," he told Australian Doctor. "There is a complete inability to change rates of conversion [to psychosis] using any intervention. Nobody has proved anything works," he added. The failure of the fish oil trial is a further setback for Professor McGorry’s push for early interventions to prevent psychosis.

In 2011, a planned trial of antipsychotics as preventive therapy against psychosis in young people was abandoned, before it was started. And in June 2016, the Federal Government announced it would phase out funding of seven Early Psychosis Youth Services run by Headspace, of which Professor McGorry is a board member. Professor McGorry has been contacted for comment
Over a century ago, Eugen Bleuler described a premorbid personality type [the Schizoid Personality] seen in many [but not all] patients who developed Schizophrenia. Since then, the hope for heading off a psychotic decompensations has rested in identifying the at risk population in advance. A few years back, there was much excitement about identifying patients at risk for psychosis in advance. Both Patrick McGorry’s group in Australia and Anthony Morrison’sand colleagues in the UK had reported success in defining a prepsychotic personality profile and were working on interventions that appeared to decrease the conversion rates. But Morrison’s definitive study was negative:
by Morrison AP, French P, Stewart SL, Birchwood M, Fowler D, Gumley AI, Jones PB, Bentall RP, Lewis SW, Murray GK, Patterson P, Brunet K, Conroy J, Parker S, Reilly T, Byrne R, Davies LM, Dunn G.
British Medical Journal. 2012 Apr 5;344

OBJECTIVE: To determine whether cognitive therapy is effective in preventing the worsening of emerging psychotic symptoms experienced by help seeking young people deemed to be at risk for serious conditions such as schizophrenia.
DESIGN: Multisite single blind randomised controlled trial.
SETTING: Diverse services at five UK sites.
PARTICIPANTS: 288 participants aged 14-35 years [mean 20.74, SD 4.34 years] at high riskof psychosis: 144 were assigned to cognitive therapy plus monitoring of mental state and 144 to monitoring of mental state only. Participants were followed-up for a minimum of 12 months and a maximum of 24 months.
INTERVENTION: Cognitive therapy [up to 26 [mean 9.1] sessions over six months] plus monitoring of mental state compared with monitoring of mental state only.
MAIN OUTCOME MEASURES: Primary outcome was scores on the comprehensive assessment of at risk mental states [CAARMS], which provides a dichotomous transition to psychosis score and ordinal scores for severity of psychotic symptoms and distress. Secondary outcomes included emotional dysfunction and quality of life.
RESULTS: Transition to psychosis based on intention to treat was analysed using discrete time survival models. Overall, the prevalence of transition was lower than expected [23/288; 8%], with no significant difference between the two groups [proportional odds ratio 0.73, 95% confidence interval 0.32 to 1.68]. Changes in severity of symptoms and distress, as well as secondary outcomes, were analysed using random effects regression [analysis of covariance] adjusted for site and baseline symptoms. Distress from psychotic symptoms did not differ [estimated difference at 12 months -3.00, 95% confidence interval -6.95 to 0.94] but their severity was significantly reduced in the group assigned to cognitive therapy [estimated between group effect size at 12 months -3.67, -6.71 to -0.64, P=0.018].
CONCLUSIONS: Cognitive therapy plus monitoring did not significantly reduce transition to psychosis or symptom related distress but reduced the severity of psychotic symptoms in young people at high risk. Most participants in both groups improved over time. The results have important implications for the at risk mental state concept.
While a smaller study of the fish oil treatment was reported as successful…
by Amminger GP, Schäfer MR, Schlögelhofer M, Klier CM, and McGorry PD.
Nature Communication. 2015 6:7934.

Long-chain omega-3 polyunsaturated fatty acids (PUFAs) are essential for neural development and function. As key components of brain tissue, omega-3 PUFAs play critical roles in brain development and function, and a lack of these fatty acids has been implicated in a number of mental health conditions over the lifespan, including schizophrenia. We have previously shown that a 12-week intervention with omega-3 PUFAs reduced the risk of progression to psychotic disorder in young people with subthreshold psychotic states for a 12-month period compared with placebo. We have now completed a longer-term follow-up of this randomized, double-blind, placebo-controlled trial, at a median of 6.7 years. Here we show that brief intervention with omega-3 PUFAs reduced both the risk of progression to psychotic disorder and psychiatric morbidity in general in this study. The majority of the individuals from the omega-3 group did not show severe functional impairment and no longer experienced attenuated psychotic symptoms at follow-up.
…however, in the report in the The Australian Doctor, Dr. McGorry announced that the definitive study did not confirm those results:
The multinational study led by Professor McGorry failed to replicate preliminary findings from a  2010 trial in 81 patients that had shown fish oil could prevent transition to psychosis among young people who took supplements for 12 weeks.
In both instances, the larger clinical trials failed to replicate not only the success in preventing psychosis, but also the validity of the target population selection criteria. These were both large clinical trials with a lot riding on the results. In the Australian effort, early detection programs were already in place [now being unfunded]. While it’s always easy to criticize failed research in retrospect, in this case it’s important to take a careful look at what happened with both the CBT and Fish Oil Clinical Trials. In my opinion, they are both examples of Translational Medicine
Translational Medicine is a rapidly growing discipline in biomedical research and aims to expedite the discovery of new diagnostic tools and treatments by using a multi-disciplinary, highly collaborative, "bench-to-bedside" approach.

… and what’s wrong with it. If there is a prepsychotic personality [and I happen to think there might be], obviously the current criteria to define it are not ready for prime time. And the rationales for either CBT or Fish Oil as preventive treatments are based mostly on speculations. Like much of our modern research, they were in a hurry to hit a home run and were not paying enough attention to simply getting on first base. Our recently departed NIMH Director, Tom Insel, was a Translational Medicine aficionado, requiring NIMH grants to be Translational, establishing Translational Centers all over the country. And he left behind a string of fly balls that never made it over the fence. I’m afraid that these efforts have the same fate.

In this case, it would seem a better use of our research funds and talent to continue to work on defining and characterizing the prepsychotic personality’s clinical characteristics using case studies, epidemiology, psychometric techniques, etc – basic research aiming towards finding a more reliable set of criteria. The existence of such a clinical entity itself still remains in the realm of hypothesis at this point.
Mickey @ 12:00 PM


Posted on Wednesday 30 November 2016

So on Thanksgiving, this blog disappeared from the Internet – lock stock and barrel. We were out of town, and I couldn’t reach the Hosting Company until Sunday. It seems that I was under a DDoS attack
A DDoS or Distributed Denial of Service is an attack against the server which uses a wide range of IP addresses to bombard the server with traffic. We have customized internal tools which mitigate these attacks automatically and they largely go un-noticed by customers. Sometimes, however when these attacks become big enough it can cause websites on the server to become slow or unresponsive for short periods of time. In these cases there are steps that must be taken manually to stop the attack and get our servers running at full speed again. DDoS attacks are not something Just Host can warn customers about beforehand. When they occur please be assured that our team is doing everything possible to restore service as quickly as possible. There are many types of DDoS attacks, however with each possible attack the best plan for our customers is to hold tight and we will restore the same level of service as quickly as possible.
…and I was told to "hold tight." Yesterday, when I checked at noon, the blog was back – unchanged. Modern life can occasionally be kind of confusing…
Mickey @ 8:25 PM

akathisia: on the high index of suspicion list…

Posted on Wednesday 30 November 2016

I’ve run across two recent commentaries on Akathisia recently. In discussing those meta-analyses of the SSRI/SNRIs as "precursors" of suicidality [Peter Gøtzsche et al], I was using multiple terms [Activation, Akathisia, Agitation, Anxiety, Agita] to talk about the broad topic of an Adverse Reaction to these drugs. My own notion of the meaning of the word Akathisia originated long ago in the era of the first generation Neuroleptic drugs [Thorazine, Stelazine, Prolixin, Haldol, etc]. It fit into a scheme of extrapyramidal reactions – an escalating sequence: dystonia, akathisa, parkinsonion reactions, tardive dyskinesia. As I recall, we thought of Akathisa as a general neuromuscular restlessness [as in the restless leg syndrome]. I don’t remember associating that term with the antidepressants of the day, but in my case, I had little hands on experience with those drugs.

I mentioned [in anecdote-based medicine… and activation, agitation, akasthisia, agita…] that I had seen infrequent but dramatic reactions [agitation] to SSRIs during my practice years, and later working in our clinic. But I had trouble linking those to the neuromuscular restlessness I knew from the neuroleptic days as Akathisia. So when I’ve written about it, I’ve been kind of muddled, sometimes using the word Akathisia, and other times being descriptive. Were these all one thing with different presentations? or a bunch of things lumped because they are similar unwanted symptoms? And beyond semantics, is there a unifying cause? I was aware that I wasn’t clear in my mind when I was writing anecdote-based medicine… and activation, agitation, akasthisia, agita…, so I was glad to see these two recent commentaries.

The first article I read is long, focused primarily on suicidality, Neuroleptic Drugs, Akathisia, and Suicide & Violence by Philip Hickey, blogger on Mad in America. But it is primarily an Antipsychiatry polemic collecting some clinical information and a bibliography of suicidality along the way. For example, it ends:
As I’ve stated many times, psychiatry is intellectually and morally bankrupt. They are adamantly resistant to anything resembling critical self-appraisal, and there are no depths of deception and spin to which they will not go, to suppress the reality and the consequences of their drug-pushing depredations. Neuroleptic and antidepressant drugs induce some individuals to take their own lives and/or the lives of others. Neuroleptic and antidepressant drugs are almost certainly the proximate causes of many of the mass shootings that have plagued our country for almost twenty years. How much longer can psychiatry sustain this dreadful, self-serving deception?…
On the other hand, the other article is a new page on David Healy’s Rxisk [Akathisia by the Rxisk Medical Team] that I found both simple and clarifying:
What is akathisia?

Akathisia is a complex side effect of various psychotropic drugs including antidepressants and antipsychotics. It is often described as a sense of inner restlessness. It can manifest as a physical discomfort or inability to remain still, but it can also be less obvious, presenting as anything from a constant and disturbing unease in the mind, through to an intense emotional turmoil. Akathisia may occur within hours of starting treatment or it may take weeks or months to appear. It can also happen when changing the dose and when stopping the drug. Akathisia is often misleadingly described as a movement disorder, but there are no involuntary movements such as in tardive dyskinesia or Parkinsonism. Akathisia is an emotional state rather than a motor disorder, and it is this emotional state that can make you feel the need to keep moving to alleviate the tension.


Symptoms can include:
  1. anxiety or agitation
  2. restlessness
  3. feeling emotionally uneasy or dissatisfied with life [dysphoria]
  4. difficulty sleeping [insomnia]
  5. distress or panic attacks
  6. difficulty sitting still; feeling a need to keep moving; pacing back and forth
  7. a feeling of wanting to jump out of your skin
  8. dark and unpleasant thoughts
It can sometimes include the emergence of strange and unusual impulses, often of an aggressive nature. It can also lead to violence and suicide. Akathisia can feel very strange and unpleasant. Sufferers often find it very difficult to explain exactly what is wrong, even though they may be in unbearable distress. In milder cases, some people don’t realize how badly they are affected by the problem until they stop the drug or lower the dose…

It goes on to discuss prevalence, diagnosis, and treatment. They mention that the symptoms are often interpreted as worsening depression. I’ve actually seen patients medicated for anxiety, ADHD, Insomnia, or Mania when the actual diagnosis is SSRI Adverse Effects – Akathisia. I’ve come to see Akathisia and withdrawal syndromes associated with the SSRIs as primo members of my high index of suspicion list and try to listen for them with every patient on SSRIs. While the majority of people don’t have them, there are plenty that do, and you perform a real service to notice [in part, because it’s so hard for the patient to describe them].

Here’s the remarkable thing to me. Over the years, I’ve recurrently looked at the package inserts, the PDR, and read numerous articles about the SSRIs, but the clarity of that quoted piece above on Rxisk has never been conveyed by any of the things I’ve read. The majority of what I know has been learned from either my own experience or from things patients have told me – hearsay. And I can’t recall any colleague mentioning the word "Akathisia" in talking about a patient, certainly not the primary care physicians I work with.

One anecdotal observation I’ve made along the way that feels like it needs to be highlighted on the high index of suspicion is insomnia. When I first started at our clinic eight years ago, it seemed like almost every patient I saw was on some kind of poly-pharmacy – multiple antidepressants, antipsychotics, anxiolytics, and they had just banned narcotics [referring all requests to pain clinics]. They were about to do the same with anxiolytics because there were so many drug-seeking people showing up. I agreed to see all the people on the latter and learned to simply say "No." I felt like a Xanax Cop, but there are some patients where those drugs are definitely useful, and I thought the ban went too far. Narcotics? Not a psychiatric drug, so I cancelled that part of my DEA license.

It took a longer time than I would’ve liked to get the medicine regimens down to something more rational, but I was pleased with the result. There was one sticky point – sleep. I’d had a whole career as a psychiatrist, and I’d never seen so many people complaining about insomnia. There were two drugs involved – Seroquel and Trazodone. The latter is an older tetracyclic antidepressant with some hypnotic properties. Apparently the PCPs were using these drugs for sleep, thinking they were doing a good thing to stay away from Benzodiazepines. So I went after the Seroquel as the more dangerous of the two, but even used Trazodone myself as an alternative. After a while, I figured out the why of a lot the insomnia. As I learned to taper the SSRIs and get people off who had been on them forever [in the cycle of stopping and restarting because of withdrawal], I noticed I heard a whole lot less about insomnia.

Anecdotes are out of vogue these days, but reading that Rxisk page, I realized that I haven’t written a Trazodone prescription in a very long time – I can’t even remember when. So from my anecdotal perspective, that epidemic insomnia problem I used to ponder about was in some measure a side effect of all the other medications, specifically the SSRIs.  There’s no way for me to know how often it’s a subtle version of Akathisia, but it’s certainly suspicious. But I do know that my  high index of suspicion list now has SSRIs in the differential diagnosis of complaints of insomnia…

UPDATE: Don’t miss Greg’s comment, a description from inside that supplements the Rxisk page!
Mickey @ 4:12 PM


Posted on Thursday 24 November 2016

With all the talk of immigration this last year, I’ve been particularly aware of my father’s childhood stories – learning English when he went to school and growing up as a poor immigrant during the Depression in the coal belt. He came South to play football in college and never went back, saying ironically, "There was so much less prejudice in the South" – which makes absolutely no sense unless you walked in his shoes. By the time I came along, there was none of the adversity so obvious in his narrative. Each Thanksgiving, I remember those stories, both the triumphs and the scars. And I will be forever grateful that his father brought his young family to live in this place…
Mickey @ 8:00 AM

the confusion of tongues…

Posted on Tuesday 22 November 2016

Major Depressive Disorder [MDD] is a term that originated in the DSM-III in 1980 as a descriptive diagnosis, a fix for perceived difficulties with the previous diagnostic system. It replaced a number of previous diagnoses that its author, Robert Spitzer, thought could not be clearly discriminated – things like depressive neurosis, the melancholic depressions, involutional depression, post-partum depression, etc. It was intended to be a category that would be separated into more clearly distinct syndromes over time. But that’s not at all what happened.

In 1987, the approval of Prozac introduced a new class of antidepressant drugs, consolidating the "medicalization" of psychiatry, opening a pipeline of new psychiatric drugs. The DSM-IV [1994] made no substantive change to the diagnosis of Major Depressive Disorder, though it had begun to be talked about as a brain disease. The third party carriers adapted payment schedules to reimburse psychiatrists for medication management only in a system known as managed care. And the era of the 1990s was officially declared to be the Decade of the Brain with a flurry of neuroscience research. Psychiatric medications aimed for the top of the sales charts.

In the first decade of the new century, psychiatry was high on neuroscience [genomics, neuroimaging, neural circuits] and there were several initiatives to locate the etiology of mental illness in the brain. Tom Insel, new NIMH Director repurposed psychiatry as Clinical Neuroscience and laid out a twenty year program for moving forward. At the same time, the APA began working on the DSM-5 with a plan to add neurobiological parameters to the diagnoses. number of settled suits against PharmaAnd as the SSRIs were only effective in a third to a half of people with the MDD diagnosis, a new disease was born – Treatment Resistant Depression [TRD]. Then came multiple schemes trying to improve the SSRIs track record, one of which was augmentation with the other new class of drugs, the Atypical Antipsychotics. But the decade didn’t end like it started as the specialty was rife with scandal – Senator Grassley’s exposure of financial corruption among academic psychiatrists in 2008 and a flurry of civil and criminal suits against pharmaceutical companies for a variety of misbehaviors leading to even more exposure.

And things haven’t gone so well in the current decade either. The pipeline was drying up for new drugs and in 2012 it became apparent that PHARMA was shutting down its CNS R&D programs altogether. The suits and scandal exposures continued. The Clinical Neuroscience initiative at the NIMH had gone nowhere and the DSM diagnostic system was abandoned there altogether for an inchoate RDoC system-maybe-to-be. The DSM-5 hopes for biologically based diagnoses were dashed by lack-of-discovery, and it was released with the same tired MDD diagnosis, little changed from the DSM-III of 1980. But in spite of expiring patents and everything else, the psychiatric drugs remain near the top of the charts.

So what’s the State of the Union? What Union? is a better question. There are many voices sounding like a  collection of competing garage bands rather than a symphony. The third party carriers including CMS [Medicare and Medicaid] seem to have bought the primacy of medications, some 80% now prescribed by Primary Care, and are hoping to extend that with Collaborative Care – a scheme where psychiatrists don’t actually see patients but rather consult with an intermediary on cases not improving [and then there’s telepsychiatry]. Organized psychiatry [the APA] is strangely quiet, but seems to be backing the Collaborative Care meme [for inapparent reasons]. The new NIMH Director is a hands-on biopsychiatrist who seems to be following Dr. Insel’s footsteps – whatever they were. The antipsychiatrists are active as ever on sites like Mad-in-America. There are skeptics and Cynics aplenty within and around psychiatry, but nothing like a cohesive group looking to sort all of this out. And yet PHARMA and the business world seem to be chugging along as if it’s still the 1990s, oblivious to what’s going on around them – Growth, growth, growth, at any cost:
By Pharmaceutical Executive Editors
Oct 24, 2016

The US market for major depressive disorders [MDD] will rise from $2.4 billion in 2015 to $4.6 billion by 2025, at an  compound annual growth rate of 6.6%, according to GlobalData. The company’s report states that the US will not only remain the largest major market for MDD drugs, but will extend its lead over other countries, primarily due to the wide-ranging availability of treatments and the commercial success of atypical antipsychotics, which generated 39% of the sales in the US market in 2015.

GlobalData analyst Christos Michaelides, Ph.D., commented: “As a class, atypical antipsychotics are due to retain their market share during the forecast period and are expected to generate sales of $1.9 billion in 2025, which will represent a little over two-fifths of the US MDD market… While Abilify generated the greatest revenue for the atypical antipsychotics in 2015, its sales will remain static during the forecast period. This will be due to increasing use of generic aripiprazole, and competition from Otsuka/Lundbeck’s Rexulti, which is due to see its US sales increase rapidly to just under $588 million by 2025.”

GlobalData estimates that five products in the late-stage pipeline will enter the MDD market in the US during the forecast period: Alkermes’ ALKS-5461, Allergan/Gedeon Richter/Mitsubishi Tanabe’s Vraylar, Axsome Therapeutics’ AXS-05, Janssen’s esketamine, and Allergan’s rapastinel. By 2025, GlobalData expects that these pipeline drugs will generate over $800 million, of which Janssen’s esketamine will achieve the greatest share.
So the  MDD that started life in 1980 as a Descriptor, then became a Disorder, then became a Brain Disease, and now seems have now morphed into yet something else – a multibillion dollar Market.  At the risk of sacrilege, I’m reminded of a biblical story – the Tower of Babel:
Genesis 11:1-9
1 And the whole earth was of one language, and of one speech. 2And it came to pass, as they journeyed from the east, that they found a plain in the land of Shinar; and they dwelt there. 3 And they said one to another, Go to, let us make brick, and burn them thoroughly. And they had brick for stone, and slime had they for morter. 4And they said, Go to, let us build us a city and a tower, whose top may reach unto heaven; and let us make us a name, lest we be scattered abroad upon the face of the whole earth. 5And the Lord came down to see the city and the tower, which the children of men builded. 6 And the Lord said, Behold, the people is one, and they have all one language; and this they begin to do: and now nothing will be restrained from them, which they have imagined to do. 7Go to, let us go down, and there confound their language, that they may not understand one another’s speech. 8 So the Lord scattered them abroad from thence upon the face of all the earth: and they left off to build the city. 9 Therefore is the name of it called Babel; because the Lord did there confound the language of all the earth: and from thence did the Lord scatter them abroad upon the face of all the earth.

According to the Old Testament, humankind was about to settle and mark its primacy by building a glorious tower to the heavens. God apparently saw this as disrespectful and arrogant, introducing the confusion of tongues – different languages [the word Babel is apparently similar to the Hebrew word for confusion]. Since the various groups could no longer communicate, they dispersed and spread over the earth.

I’m not sure that divine intervention is even necessary [or even this analogy]. Maybe disrespect and arrogance are enough in their own right to do the same things. We’ve seen enough of both in these last decades to fill a century. Whatever the case, and wherever the blame, things couldn’t be much more confused. The tower’s in ruins; the various groups no longer communicate; and we’re in no position to deal with the situation we’re about to face in the current political climate [speaking of arrogance and towers]…
Mickey @ 6:00 PM


Posted on Monday 21 November 2016

The Bookmobile came every other Saturday. And once the Bookmobile Lady got to know you, she brought wonderful things you didn’t even know existed. Two weeks is a very long time, so there was a shelf with Compton’s Pictured Encyclopedias to fill in the gaps. But neither rivaled the Downtown Library where the selection seemed infinite. When I reached the traveling age, my Saturday Quarter bought either two bus tokens [10¢ each] for a round trip to the Library + a candy bar [5¢], or the Movie Matinee with Serial [10¢] + popcorn [10¢] + a coke [5¢]. Freedom brings some tough choices!

Maybe just an old habit, but I often start with Wikipedia. In this case [Evidence-Based Medicine], it was a good choice, particularly the Limitations and Criticism section. As a simple phrase, what’s not to like about "evidence-based medicine?" What else is there? I’ll not summarize that entry, just recommend it strongly. One thing I learned was that in its modern usage, it had become all the rage in 1987 which is after I left academia proper for practice. So it’s no wonder that I was confused when people began to say "evidence-based medicine" as if it came from some stone tablet delivered from Mount Sinai.
The term "evidence-based medicine", as it is currently used, has two main tributaries. Chronologically, the first is the insistence on explicit evaluation of evidence of effectiveness when issuing clinical practice guidelines and other population-level policies. The second is the introduction of epidemiological methods into medical education and individual patient-level decision-making.
One of the consequences of this paradigm was to promote the Randomized Clinical Trial [RCT] to the level of the "gold standard" for "proof". So third party carriers used it to slash payments for any· and every·thing not backed up by an RCT. On the other hand, it was a "gold mine" for the pharmaceutical companies, a whole industry emerging to conduct [and publish] [and exaggerate] their Clinical Trials. New paradigms, no matter how helpful, can be quickly enlisted by the dark side, and the RCT is  no exception [in a way, that’s what this whole blog is about].

One downside of the evidence-based medicine model for me was the de·emphasis of individual case reports which all but disappeared from our journals – discounted as anecdotes. We had been moved from individuals to groups "…the introduction of epidemiological methods into … individual patient-level decision-making." Of course medicine draws heavily from the data from groups, but we actually see individual human beings with all their variation – the ripples in a stream. And it’s those case studies that have been the key to organizing my own medical learning. Evidence-based medicine and its guidelines tends to bring the patient to the medical group·think rather than vice versa.

And so to the point – akathisia, suicidality, violence, the SSRIs, and the last two posts [anecdote-based medicine… and activation, agitation, akasthisia, agita…]. Back when Prozac arrived, I was in a psychotherapy practice so my prescribing was minimal. But I had patients who had a reaction of sorts. They described agitation, restlessness, anxiety, disturbing thoughts and dreams, a couple said suicidal. While it didn’t happen often, it was enough for me to "ask around" about it. And since all the patients I saw had had previous treatment of some kind, I heard about something similar from others when they were medicated before I saw them – again, not common but notable. This was over the 1990s. I saw patients weekly, and they came back and told me about it. So I began to warn about that possibility [along with the more frequent than advertised decrease in libido]. I heard a couple of patients say, "And so I didn’t go back to see him!" I wondered if my patients came back and told me about it because I saw them frequently and had an ongoing relationship before I prescribed – that maybe the other colleagues I asked didn’t know about it because the patients just moved on.

I retired in 2003, the year before the black-box warning, and stayed away from medicine for about five years. When I started volunteering in a couple of rural charity clinics [adolescent and adult], I was horrified at the medications people were on and started reading – at first to catch·up, but later to catch·on [another, that’s what this whole blog is about]. And then I read about my department chairman’s shady financial connections [Dr. Charles Nemeroff]. Thus, the origins of Shortly after I started, I saw a 17 year old boy who was quite depressed. I prescribed Celexa, discussing the black-box warning I’d read about. Within a day and a half, he had a full blown episode with anxiety, agitation, suicidality, violent outbursts, etc. and his mother called. We stopped the meds and a few days later, when I saw him, he was fine. Not too long afterwards, I read of a 14 year old kid’s suicide in our weekly paper. I’d never seen the patient, but in the months that followed I had the occasion to see his therapist, a parent, his girlfriend, and several classmates. They were all devastated and with no prodding from me said the same thing, "He was different after he started that medicine [an SSRI prescribed by his PCP]."

I still prescribe SSRIs, but everyone new to the medication gets a full warning – not the mumbly warning on the television ads, but an earnest eye-to-eye warning. Since then, I’ve only used SSRIs in adolescents for OCD or Generalized Anxiety and I follow them like a Hawk. There’s no compelling evidence in the RCTs of efficacy in depresson for this group except some early Prozac RCTs. With adults, I’ve seen more cases of Akathisia – a lot for the infrequency of my practice time. No suicidality but plenty of Agitation [Agita]. I’ve heard about several other suicides that are unquestionably related but I can’t discuss them. These are the kind of anecdotes that I was trying to talk about [anecdote-based medicine…]. It used to be called clinical experience, and I count on it in myself and the doctors that take care of me and my family. So I, for one, liked Peter Gøtzsche‘s meta-analyses [activation, agitation, akasthisia, agita…]. He sees that syndrome I call Agita as a potential harbinger of a more ominous portent, and I do too. I don’t understand why it happens sometimes, and why so infrequently, but my index of suspicious is set on high and will stay there. It comes in a variety of presentations and if you prescribe a lot of these drugs, I’d recommend reading through some of the  SSRIstories just to get oriented to the syndrome. I don’t need a clinical trial for proof, there are enough anecdotes around to calibrate my radar.

Over the years, I’ve followed the campaign to get the black box warning removed  [summarized most recently  in an innovative design…]. Most of the studies are population based, evidence-based-medicine-esque, and clearly start with a conclusion. They preach safety in an area that deserves a gospel of caution. That black box warning slowed the escalation of SSRI sales and I’m glad about that. There was one study along the way about akathisia that I thought was particularly irresponsible [Antidepressant-induced jitteriness/anxiety syndrome: systematic review – 2006]. It denied that what I call Agita even happens. I know it’s off the mark, and I expect PHARMA influenced. Agita doesn’t happen often, but it’s common enough for the busy clinician to see. Just listen for the phrase, "I can’t take that stuff!"
Mickey @ 5:40 PM

activation, agitation, akasthisia, agita…

Posted on Monday 21 November 2016

The presidential election is finally over and I want to get back to where I left off last month in the post in polite company… when I said:
Articles like these are part of a great big wake-up call, and I’m not sure they’re reaching the right audience in the right ways. For the moment, I’ll just add them to the growing catalog, and pick back up next week after the national election is behind us. Right now, diversion time – World Series, Game 7!
Here’s an abbreviated reference to that article/meta-analysis:
by Andreas Ø Bielefeldt, Pia B. Danborg, and Peter C. Gøtzsche
Journal of the Royal Society of Medicine. 2016 109[10]:381-392.
Objective: To quantify the risk of suicidality and violence when selective serotonin and serotonin-norepinephrine reuptake inhibitors are given to adult healthy volunteers with no signs of a mental disorder.
Conclusions: Antidepressants double the occurrence of events in adult healthy volunteers that can lead to suicide and violence.

But in the ensuing several weeks, Peter C. Gøtzsche and others added yet a second study to the one mentioned above. This one is an analysis of some unpublished studies from a 2001-2002 EMA submission of Duloxetine for stress urinary incontinence [that was not approved]:
by Emma Maund, Louise Schow Guski, and Peter C. Gøtzsche
Canadian Medical Association Journal. First published online ahead of print on November 14, 2016.

Background: The European Medicines Agency makes clinical study reports publicly available and publishes reasons for not approving applications for marketing authorization. Duloxetine has been approved in Europe for the treatment of stress urinary incontinence in women. The reported adverse effects of duloxetine include mental health problems and suicidality. We obtained clinical study reports from the European Medicines Agency concerning use of this drug for stress urinary incontinence.
Methods: We performed a meta-analysis of 4 randomized placebo-controlled trials of duloxetine [involving a total of 1913 patients] submitted to the European Medicines Agency for marketing approval for the indication of stress urinary incontinence in women. We used data from the clinical study reports [totalling 6870 pages and including individual patient data] to assess benefits [including frequency of incontinence and changes in quality-of-life scores, such as Patient Global Impression of Improvement rating] and harms {both general harms, including discontinuation because of adverse events, and harms related to suicidality, violent behaviour and their potential precursors, such as akathisia and activation [stimulating effects such as insomnia, anxiety and agitation]}.
Results: Duloxetine was significantly better than placebo in terms of percentage change in weekly incontinence episodes [mean difference -13.56%, 95% confidence interval [CI] -21.59% to -5.53%] and change in Incontinence Quality of Life total score [mean difference 3.24, 95% CI 2.00 to 4.48]. However, the effect sizes were small, and a sensitivity analysis [with removal of one trial] showed that the number needed to treat for a Patient Global Impression of Improvement rating of "much better or very much better" was 8 [95% CI 6 to 13]. The numbers needed to harm were 7 [95% CI 6 to 8] for discontinuing because of an adverse event and 7 [95% CI 6 to 9] for experiencing an activation event. No suicidality, violence or akathisia events were noted.
Interpretation: Although duloxetine is effective for stress urinary incontinence in women, the rates of associated harm were high when individual patient data were analyzed, and the harms outweighed the benefits.

[truncated from the original]

The two papers combined report seventeen blinded clinical trials [scattered over 28 years] with some ~1300 non-depressed subjects on SSRI/SNRI drugs compared with ~1200 placebo controls. The findings of an increased signal for suicidality with these drugs have been traditionally discounted by critics with various rationales because the medications are being given to depressed people [who are suicide-prone anyway]. So here’s a large cohort of studied patients where that explanation obviously won’t fly. And in each case, the forest plots still show that the target adverse events are significantly more prevalent in the drug treatment group than in the placebo controls. The question then becomes, "What were those target Adverse Events?"

And what of the numerous and compelling case histories of suicide, homicide, violence, agitation in some people taking SSRIs/SNRIs? They are often discounted as "anecdotes" – lacking the statistical/mathematical certifcation that comes from clinical trials. They are infrequent and just don’t show up with strong signals in RCTs or population studies. So these meta-analyses are attempts at quantifying the phenomena. But again, the question becomes, "What were those target Adverse Events?" "What do they mean by precursors to suicidality?"

Here are the criteria they used in searching through the articles/reports in these meta-analyses:

[Bielefeldt et al]

[Maund et al]

In the Bielfield et al [healthy volunteers] paper, they report on "suicidal or violent events or precursors to such events" without breaking them down. And in Maund et al [duloxetine in stress incontinence] they do break them down [above]. In this latter study they mention that there were no suicidal or violent events reported in these trials [it’s worth taking a look at this paper for the suicidal info that wasn’t reported].

There was a time when I might have read these papers that talk about "suicidal or violent events or precursors to such events" yet report no actual suicidal or violent events and been mighty skeptical. But that’s not true any more – at least for me. In fact, in our recent second Paxil Study 329 paper [Study 329 continuation phase: Safety and efficacy of paroxetine and imipramine in extended treatment of adolescent major depression], we used similar criteria. Here’s a chart I made along the way that didn’t make it into the published paper [my made-up word ‘AGITA‘ being roughly similar to the "Activation" categories above]:

These two meta-analyses [Bielefeldt et al and Maund et al] follow-up on an older paper from 2000 reporting suicidality in several non-depressed healthy volunteers on an SSRI [Zoloft]:
by David Healy
Primary Care Psychiatry. 2000 6:25-28.

In the course of a randomised double-blind crossover study comparing the effects of reboxetine and sertraline in a group of healthy volunteers, two volunteers became suicidal on sertraline. This paper describes the characteristics of the reactions experienced by both subjects. These problems were associated with a combination of akathisia and disinhihition. Dysphoric or akathisic responses on their own to either drug did not lead to suicidality in this group of subjects.
The Bielefeldt et al paper mentions a suicide in a healthy volunteer in a Duloxetine Trial that wasn’t included in these meta-analyses:
"In one of the two crossover trials we excluded because we did not have data on the first period separately, a healthy volunteer committed suicide, which was mentioned in both published articles. She had received duloxetine in increasing doses for 16 days, tapered off the maximum dose of 400 mg daily very quickly [in just four days according to the design of the study] and killed herself four days later while on placebo. The authors, several of whom were employees of Eli Lilly or owned stock in the company, judged her suicide lto be unrelated to study drug treatment, although it is well known that the suicide risk is high when an antidepressant is stopped abruptly…
This case is discussed in more detail in a 2005 Slate article by Jeane Lenzer.

If there’s an area where more has been written about a single controversy than the question of suicidality/akathisia as an adverse effect of the SSRI/SNRI medications, I don’t know what it would be. Prozac was introduced in 1987, and by 1990, the issue of suicidality was soon on the front burner…
In 1990, Teicher and colleagues reported on the emergence of suicidality on fluoxetine in a group of six patients. These reports were followed-up by reports from King et al., Creaney et al. , Rothschild and Locke  and Wirshing et al., among others, reporting other cases where suicidality appeared to emerge in individuals taking fluoxetine.
from Healy2000
… where it continues to simmer to this day with a history too long to even think about summarizing. These two meta-analyses approach  one of the lingering controversies, "Can these drugs cause the Akathisia syndrome, a precursor of violence and suicidality, in normal non-depressed people." But one can almost hear the critics in the background saying, "Wait a minute. There’s no suicides, suicidality, or violence in any of these trials. You mean to say that activation, agitation, akathisia, or agita are enough for you to extrapolate forward to say they are precursors to suicide or violence? Where’s your evidence!?" And the believer might come back with, "Have you looked at all the case histories posted on SSRIstories [see also The Story of SSRI Stories] and elsewhere!?" And in another version, this kind of back and forth has gone on with the black box warnings of suicidality on all antidepressants since 2004 almost ad infinitum. What’s a practicing physician to take from all 29 years [2016 – 1987 = 29] of these dueling reports and studies?
[stay tuned…]
Mickey @ 9:00 AM