I took a several week unpaid leave of absence from blogging and email commerce to do a number intense project. I found that I just couldn’t do it if I thought about anything else. I finished the part that had to be done yesterday, and look forward to returning to my normal mental life. Looking over all the accumulated emails, I ran across one from a medical school friend who sent me a blurb from his literature [he’s an Emergency Medicine physician]. It was in Emergency Medicine Today:
hat tip to Ferrell… 
Antidepressants Appear To Be Much More Dangerous For Kids, Teens Than Reported In Medical Journals, Review Finds.HealthDay reports, “Antidepressants appear to be much more dangerous for children and teens than reported in medical journals, because initial published results from clinical trials did not accurately note instances of suicide and aggression,” a review published Jan. 27 in the BMJ suggests. Researchers arrived at that conclusion after analyzing data from “68 clinical study reports from 70 drug trials that involved more than 18,500 patients.” The clinical studies “involved five specific antidepressants: duloxetine [Cymbalta], fluoxetine [Prozac], paroxetine [Paxil], sertraline [Zoloft] and venlafaxine [Effexor].”
According to Medical Daily, “the limitations in both design and reporting of clinical trials may have led to ‘serious under-estimation of the harms.’” The study authors concluded, “The true risk for serious harms is still uncertain.” The Telegraph [UK] also covers the story.
At first I thought it was an acknowledgement of our recent article [Restoring Study 329: efficacy and harms of paroxetine and imipramine in treatment of major depression in adolescence], but it was better than that. It was an article from the Nordic Cochrane Center about the potential adverse effects in adolescents from SSRIs – another log on the fire:
by Tarang Sharma, Louise Schow Guski, Nanna Freund, and Peter C. GøtzscheBritish Medical Journal. 2016 352:i65
Objective: To study serious harms associated with selective serotonin and serotonin-norepinephrine reuptake inhibitors.Design: Systematic review and meta-analysis.Main outcome measures: Mortality and suicidality. Secondary outcomes were aggressive behaviour and akathisia.Data sources: Clinical study reports for duloxetine, fluoxetine, paroxetine, sertraline, and venlafaxine obtained from the European and UK drug regulators, and summary trial reports for duloxetine and fluoxetine from Eli Lilly’s website.Eligibility criteria for study selection: Double blind placebo controlled trials that contained any patient narratives or individual patient listings of harms.Data extraction and analysis: Two researchers extracted data independently; the outcomes were meta-analysed by Peto’s exact method [fixed effect model].Results: We included 70 trials [64 381 pages of clinical study reports] with 18 526 patients. These trials had limitations in the study design and discrepancies in reporting, which may have led to serious under-reporting of harms. For example, some outcomes appeared only in individual patient listings in appendices, which we had for only 32 trials, and we did not have case report forms for any of the trials. Differences in mortality [all deaths were in adults, odds ratio 1.28, 95% confidence interval 0.40 to 4.06], suicidality [1.21, 0.84 to 1.74], and akathisia [2.04, 0.93 to 4.48] were not significant, whereas patients taking antidepressants displayed more aggressive behaviour [1.93, 1.26 to 2.95]. For adults, the odds ratios were 0.81 [0.51 to 1.28] for suicidality, 1.09 [0.55 to 2.14] for aggression, and 2.00 [0.79 to 5.04] for akathisia. The corresponding values for children and adolescents were 2.39 [1.31 to 4.33], 2.79 [1.62 to 4.81], and 2.15 [0.48 to 9.65]. In the summary trial reports on Eli Lilly’s website, almost all deaths were noted, but all suicidal ideation events were missing, and the information on the remaining outcomes was incomplete.Conclusions: Because of the shortcomings identified and having only partial access to appendices with no access to case report forms, the harms could not be estimated accurately. In adults there was no significant increase in all four outcomes, but in children and adolescents the risk of suicidality and aggression doubled. To elucidate the harms reliably, access to anonymised individual patient data is needed.
Since the article is online, I’ll skip the details and say why I liked it, over and above it being another loud message about the potential harms of SSRIs in adolescents as well as the pressing need for Data Transparency in Clinical Trials:
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The reference came from a primary care newsletter. Non-psychiatrist physicians prescribe the majority of the SSRIs, and that’s where this information about harms belongs. Hopefully the news is finally spreading.
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The heavy lifting in this article was done by students working with Dr. Gøtzsche at the Nordic Cochrane Center. We desperately need for this kind of critical evaluation of Clinical Trials to be coming from the world of young researchers and physicians rather than just from us old guys.
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They did this meta-analysis using a large number of Complete Study Reports[ CSRs] they got from the European Medicines Agency [EMA]. Again, great news that they could get them. And there was more, they got to see the wide variability in what was in those reports and how variable they were with raw data – clarifying that in lobbying for Data Transparency, we need to specify that they have actual data.
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They emphasize the point that that the CSRs are not enough to evaluate harms. We absolutely need to have access to the Case Report Forms [CRFs] where the data was originally transcribed. We couldn’t have done our Paxil Study 329 article without them.
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Their findings mirrored ours from Paxil Study 329, but they had information from many more studies than just our one source. It is a more general commentary.
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It’s always great to hear from an old friend from the time when the world was young [among many other things, ironically, we were lab partners in pharmacology lab a little over 50 years ago]…
But happy talk aside, we shouldn’t even have to be fighting for honesty and transparency is the scientific literature. That ought to be a given. As a young guy, I noticed that the elders always talked about the good old days when things were better and I resolved not to do that when I got old. In the main, I have been able to hold to that resolution. But with this issue of the Clinical Trial articles in the medical literature, I can’t stick to my guns. I can’t remember ever having to keep one eye always cocked, looking for signs that I’m being taken for a ride by a distorted, commercially biased production. It really was better in the old days…
Check out this letter to the editor at Current Psychiatry I wrote about today, and decide if the writer is on the mark, or not
http://www.currentpsychiatry.com/index.php?cHash=c67b8b67d1f331dec64d13414e41275d&id=22373&trendmd-shared=1&tx_ttnews%5Btt_news%5D=455913
Leave you with this from the link:
“If all of the medications developed since 1990 disappeared, I believe I could be as effective a psychiatrist as I am today. The simple, sad fact is that there have been no major psychopharmacotherapeutic advances in the past 30 years. Yes, there have been changes in side-effect profiles and improvements around the edges, so to speak, but no fundamental changes in effectiveness since the introduction of clozapine.”
Hope your absence from the Net was worth your time and efforts. Again, I think it a nice gesture to tell readers you will be gone for some predetermined period of time so we won’t have to come here and then conclude, “oh man, he is still in abstention…”
At least you did’t have to deal with 30 inches of snow, I assume…
I think that you have to consider the source.
I don’t think any rehash of old trials trumps the successful use of these medications for decades by any clinical psychiatrist.
It is almost like we are supposed to be surprised by side effects or the fact that the medication we prescribe actually work.
Any study that suggests that and comes across as sensational at this late stage seems to lack validity to me.
“I can’t remember ever having to keep one eye always cocked, looking for signs that I’m being taken for a ride by a distorted, commercially biased production. It really was better in the old days.”
I am not sure when those good old days were, but it sure seems to me that throughout the 90s when I had my intro to psychiatry there was constant manipulation of science in favor of marketing. Look at every phase 3 clinical trial conducted with the new generation of antipsychotics. Risperidone was compared to 20 mg of haloperidol, olanzapine to 15 mg +/- 2.5 mg of haloperidol, quetiapine to 12 mg of haloperidol. Until the 7-arm sertindole trial (which was not published for years after the FDA declined on this drug), there was no honest reckoning of these drugs against a reasonably dosed comparator. Finally a large VA trial and the NIMH CATIE studies showed that second gen. were not superior to first gen antipsychotics. Meanwhile, for at least a decade, you had hired ‘experts’ telling everyone how superior these drugs were to the old drugs. US State governments were lobbied on behalf of psychiatric patients to pay for the new treatments and funds were shifted from hospitals to pills. Our already weak inpatient infrastructure was further ravaged to pay for therapies that turned out to be not much better than the drugs that were pennies. Perhaps it was better in the 1960s through the 1980s, but I am skeptical.
Many thanks for your thoughts, Daniel.
Here is a link from an economist reporting from observations made way back in 2003. http://www.nber.org/papers/w9626
An experienced psychiatrist with whom I occasionally converse says he sees a great deal of antidepressant-induced suicidality in teens and adults.
He has a regional reputation (San Francisco Bay Area) for skill in “difficult” cases, other psychiatrists refer such to him. Quite frequently, he finds the problem is iatrogenic and the solution is minimizing drugs.
He is one of the very, very few psychiatrists expert in tapering and treating withdrawal syndrome.
“Our already weak inpatient infrastructure was further ravaged to pay for therapies that turned out to be not much better than the drugs that were pennies. Perhaps it was better in the 1960s through the 1980s, but I am skeptical”
Sorry – but the weak inpatient structure was ravaged by managed care – it had nothing to do with the pharmaceutical industry.
It is still being ravaged by the managed care industry.
“But happy talk aside, we shouldn’t even have to be fighting for honesty and transparency is the scientific literature. That ought to be a given.”
My null hypothesis is that institutions eventually always become corrupt because by my observation I have yet to see an exception. It’s also that the base state of humanity is venal and greedy and that honesty and transparency do have to be fought for because all virtue has to be fought for.
Obviously I am not a Rousseauist. Sade won that argument. So did Freud over Carl Rogers in my opinion. So did Mick Jagger over the Mamas and Papas (look at the family dysfunction that phony optimism led to). So did the science of genetics which pretty much showed we are pretty much chimpanzees with better language skills, and an occasional capacity to think about the future and things like ethics.
This is actually a recipe for objectivity as well as happiness. If one goes through life expecting people to be honest and unbiased, one is in for a world of hurt. But Buddha covered all of this many centuries ago without the benefit of sponsored double blind trials.