1 Boring Old Man

NETWORK META-ANALYSIS: John Ioannidis

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.

Lessons learned from Restoring Study 329: Transparent reporting, open databases and network meta-analyses as the way forward

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…

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 COMParetrials.org. 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…

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].

Hopes of preventing psychosis with fish oil flounders: study

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

Early detection and intervention evaluation for people at risk of psychosis: multisite randomised controlled trial.

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

[full text on-line]

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.

Longer-term outcome in the prevention of psychotic disorders by the Vienna omega-3 study.

by Amminger GP, Schäfer MR, Schlögelhofer M, Klier CM, and McGorry PD.

Nature Communication. 2015 6:7934.

[full text on-line]

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.

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.

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.

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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.

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?…

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

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.

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. And 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.

Depression Drugs Sales in the US to Reach $4.6 billion by 2025

PharmExec.com

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.

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.

^{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!}

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 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 1boringoldman.com. 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.

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!

Precursors to suicidality and violence on antidepressants: systematic review of trials in adult healthy volunteers

by Andreas Ø Bielefeldt, Pia B. Danborg, and Peter C. Gøtzsche

Journal of the Royal Society of Medicine. 2016 109[10]:381-392.

[full text on-line]

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.

Considering benefits and harms of duloxetine for treatment of stress urinary incontinence: a meta-analysis of clinical study reports

by Emma Maund, Louise Schow Guski, and Peter C. Gøtzsche

Canadian Medical Association Journal. First published online ahead of print on November 14, 2016.

[full text on-line]

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]:

Emergence of antidepressant induced suicidality

by David Healy

Primary Care Psychiatry. 2000 6:25-28.

[full text online]

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.

"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…

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

The classic Psychologist laboratory animal study involves genetically identical rats living in cages divided into two groups – one control group and one with some experimental intervention. Blinded observations of some pre-defined outcome parameter are recorded and the groups compared statistically at the end of the study. By making everything about the groups exactly the same, you can reasonably conclude that any differences in the outcome parameters are caused by the intervention. In another variation, one might have a single group with a control period of observations, then a second period making the intervention – comparing the control period to the experimental period. Whatever the case, the point is to aim for uniform groups with the only difference being the intervention – control vs experimental.

And then there are the Ethologists who do just the opposite. They often try not to interfere or make their presence known at all. So they sit in trees in the jungle and watch the animals in their natural habitat [or even become a part of it eg Dian Fossey]. Their books tend to be about one individual or a small group – more like a case study or a family study. And the tables, graphs, and statistics aren’t so prominent as they are in the works of the laboratory based scientists. They’re replaced by narrative descriptions.

1. Hypothesis Testing Research versus Material-Exploration

Scientific research and reasoning continually pass through the phases of the well-known empirical-scientific cycle of thought: observation – induction – deduction – testing [observe – guess – predict – check]. The use of statistical tests is of course first and foremost suited for “testing”, i.e., the fourth phase. In this phase one assesses whether certain consequences [predictions], derived from one or more precisely postulated hypotheses, come to pass. It is essential that these hypotheses have been precisely formulated and that the details of the testing procedure [which should be as objective as possible] have been registered in advance. This style of research, characteristic for the [third and] fourth phase of the cycle, we call hypothesis testing research.

This should be distinguished from a different type of research, which is common especially in [Dutch] psychology and which sometimes also uses statistical tests, namely material-exploration. Although assumptions and hypotheses, or at least expectations about the associations that may be present in the data, play a role here as well, the material has not been obtained specifically and has not been processed specifically as concerns the testing of one or more hypotheses that have been precisely postulated in advance. Instead, the attitude of the researcher is: “This is interesting material; let us see what we can find.” With this attitude one tries to trace associations [e.g., validities]; possible differences between subgroups, and the like. The general intention, i.e. the research topic, was probably determined beforehand, but applicable processing steps are in many respects subject to ad-hoc decisions. Perhaps qualitative data are judged, categorized, coded, and perhaps scaled; differences between classes are decided upon “as suitable as possible”; perhaps different scoring methods are tried along-side each other; and also the selection of the associations that are researched and tested for significance happens partly ad-hoc, depending on whether “something appears to be there”, connected to the interpretation or extension of data that have already been processed.

When we pit the two types so sharply against each other it is not difficult to see that the second type has a character completely different from the first: it does not so much serve the testing of hypotheses as it serves hypothesis-generation, perhaps theory-generation — or perhaps only the interpretation of the available material itself.

An Anecdote: A young pregnant woman presented to the ER of our UK military hospital one evening with a severe URI and sore throat. She was given symptomatic medications and started on penicillin. The next day [a Sunday], she returned with a skin rash thought to be a reaction to the penicillin, and it was stopped. By Monday when she returned, the rash covered her body and she was admitted with a diagnosis of Stevens-Johnson Syndrome.  We had two Internists, an Ophthalmologist, a Dermatologist, and we were 25 miles away from Addenbrooks Hospital in Cambridge who supplied a steady stream of expert consultants throughout her hospital stay. When we were finally able to send her back to the US months later, she’d survived what amounted to massive burns; she was blind; she’d lost her child; she survived kidney failure and was off of peritoneal dialysis. I heard from her about a year later excited to say that she was beginning to regain some of her sight. The young general medicine officer who’d initially given her the penicillin [at her request] saw her every day over those months, and after his military service, he became an Ophthalmologist – an interest he developed while following her eye-care with the British consultants. After the fact, one never knows if this kind of maelstrom was from the original viral infection or the penicillin  – both listed as possible causes in such cases. And I, for one, have never seen another such case. With an incidence of single digits per million people per year, many physicians have never seen this illness. I expect that those of us involved in this case see her every time we consider antibiotics for a sore throat or see a penicillin reaction.

In the overwhelming majority of cases, penicillin doesn’t have any effect on the course of a sore throat, whether caused by the Streptococci organisms or not. If, however, it is a Strept Throat, there was a time when the result might well be Scarlet Fever, Rheumatic Fever, Acute Glomerulonephritis – conditions that had long term and often ominous consequences. That penicillin shot has virtually eliminated those once common illnesses – a medical miracle. But the reason to get a culture to be sure it’s a Strept Throat first instead of treating all Sore Throats as Strept Throats is another kind of prevention – to minimize the possibility of cases like the one described above [among other things].

Manufacturers tell FDA why they should be able to promote drugs and devices off label

by Jeanne Lenzer

British Medical Journal. 2016 355:i6098

Manufacturers have told the US Food and Drug Administration [FDA] that restricting their ability to engage in “truthful and non-misleading speech” about off-label uses of drugs and devices infringes their rights to free speech. The comments were made during hearings held in Washington, DC, on 9 and 10 of November on whether to allow manufacturers to promote drugs and medical devices for uses not approved by the FDA. Public comment on the proposal to loosen off-label promotion is open until 9 January 2017. One in every five prescriptions in the US is estimated to be for off-label use. For example, the use of certain antibiotics in children, which have been tested and approved in adults, is one commonly accepted off-label use. But manufacturers are generally prohibited from promoting off-label use, with the exception of “safe harbor” activities, such as distributing reprints of peer reviewed journal articles that may discuss unapproved uses. Industry has sued the FDA in some cases where the FDA sought to limit their off-label activities and has scored some successes in court.

Approximately 60 speakers addressed the FDA. Robert Califf, commissioner of the FDA, opened the hearings by saying that the agency had historically restricted off-label promotion to ensure the efficacy and safety of vaccines, biologics, animal and human drugs, and medical devices. He said that some off-label promotions had had “devastating consequences.” As an example, he cited the case of atypical antipsychotic drugs, which were approved for the treatment of schizophrenia and bipolar disorder, but which some companies promoted to treat dementia and behavioral problems in elderly people “using tactics that obscured the absence of reliable evidence.” He said that “subsequent clinical trials showed an increased incidence of death” among elderly people when used in this off-label manner. Califf left the door open to the need for expanded off-label promotion, however, when he said that an “evidence gap” existed for information that was not available on a product label and that additional information might help healthcare providers make better decisions for patients.

About two dozen industry representatives, surrogates, insurers, and patient groups, including Pharmaceutical Research and Manufacturers of America, the Biotechnology Innovation Organization, and the Advanced Medical Technology Association, presented after Califf. They said that discussions between industry and healthcare providers, as well as payers, about emerging uses of drugs or devices not approved by the FDA were necessary for providers to plan formularies and fee schedules, to gain information about rapid developments in medicine that do not appear on product labels, and for doctors to learn about treatments for rare conditions for which randomized controlled trials were not feasible.

Advocates of off-label promotion said that the FDA needed to loosen the levels of evidence necessary to conduct discussions with healthcare providers. John Kamp, executive director of the Coalition for Healthcare Communication, said that manufacturers should not have their arms “tied behind their back” by such restrictions. He said that the FDA’s rules were vague, and he urged the agency to allow industry to use “postapproval clinical trials … post hoc analyses, subpopulation analysis, observational data, real world evidence, and physician treatment guidelines” to support claims about off-label uses. These presenters were followed by public interest groups and patients who said that they were harmed by off-label uses of drugs and devices promoted by manufacturers…

The FDA requires two well-conducted clinical trials demonstrating statistically significant results in favor of a drug for efficacy approval. While this is a permissive standard, the FDA at least adheres to one important element of analysis not strictly enforced by journal editors or in other venues – they require statistical separation in the declared a priori defined primary outcome variables for approval. On the other hand, this request for the FDA to  "allow industry to use ‘postapproval clinical trials … post hoc analyses, subpopulation analysis, observational data, real world evidence, and physician treatment guidelines’ to support claims about off-label uses" is literally a listing of areas where efficacy has regularly been misreported using "outcome switching" among the many other methods of introducing bias. Given industry’s track record over the last several decades, it is the height of hubris to even suggest such changes.

hu·bris (hybrs)
n.
Overbearing pride or presumption; arrogance: “There is no safety in unlimited technological hubris” [McGeorge Bundy].

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hubris. [n.d.]. The American Heritage® Dictionary of the English Language, Fourth Edition.