An Ego Boost Amidst Some Seriously Bad News About Anti-Depressants

It is not schadenfreude (taking pleasure in another’s misery) but I received an unexpected ego boost buried in shockingly bad news in a new paper + editorial on Suicide and Antidepressant Use published in the  British Medical Journal, Jan. 28, 2016 (available

Danish researchers, Tarang Sharma and colleagues, uncovered confirmation that the rate of suicidality and aggression doubles in adolescents and young adults taking selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) compared to placebo.  They dug into 70 peer-reviewed published reports, covering 18,526 patients, studying five different antidepressants.  To get to the heart of the study they found a highly statistically significant increase in aggression, suicide, and restless discomfort (akathisia) in young people…and only a trend in adults.

An additionally disheartening finding of the Sharma et al report was highlighted in the accompanying editorial by Joanna Moncrieff.  When Sharma and colleagues dug into the data, they documented significant misrepresentation in clinical reports of adverse reactions.  To quote Moncrieff,

Comparing the “results” reported in the reports with data from individual patient listings or patient narratives revealed misclassification of deaths in people taking antidepressants and misrepresentation of suicidal events. More than half of the suicide attempts and instances of suicidal ideation were coded as “emotional lability” or “worsening of depression,” for example. Summary reports published on Eli Lilly’s website were even more incomplete, listing only 10% of the suicide attempts revealed in the corresponding clinical study reports, and no instances of suicidal ideation.

As a prescribing psychiatrist, I know that SSRIs are important treatment for depressed individuals.  But for years now evidence has been accumulating that over a broad average, the SSRIs and SNRIs have a statistically modest effect on depression. Moncrieff concludes her editorial with a capsule review (so to speak) of that growing limitation:

Despite their widespread use, antidepressants are only modestly more effective than placebo in trials of depression. Measures of global clinical improvement suggest the difference is not clinically relevant or even detectable.12 Moreover, placebo controlled studies do not distinguish whether the effects of a drug are attributable to the targeting of putative underlying mechanisms or a consequence of the drug’s mind-altering effects. The blunting of emotions produced by SSRIs may directly affect depression rating scale scores, for example, and their psychoactive and physical effects may influence patient expectations, promoting an amplified placebo effect.13

Sharma et al suggest that aggressive and suicidal behavior correlates with the restless discomfort of akathisia, often labeled an “extrapyramidal side-effect” (the term isbasically medical jargon referencing the neuro-anatomical substrate of Parkinsonism).  This correlation with chemically-induced restlessness is an interesting observation in itself, suggesting that this restlessness creates a pressure to do something, to evacuate the bad feelings into destructive behavior.

About that ego boost: the explanation has a personal meaning to me, because I published the first report of extra-pyramidal symptoms associated with an SSRI in a letter way back in 1989, Brod TM, Fluoxetine and extrapyramidal side effects. Am J Psychiatry 1989; 146:1353.  I had almost forgotten about that, and had, in fact, taken the publication off my abbreviated Curriculum Vitae!

Incidentally this report comes on the heels of one last week correlating an increase in Autism Spectrum Disorder (ASD) in kids born to mothers who took SSRIs. The paper by Boukhris and colleagues was published in JAMA Pediatrics last week (JAMA Pediatr. 2016;170(2):117-124. doi:10.1001/jamapediatrics.2015.3356.)  Based on over 145,000 full-term single births registered in Quebec from 1008 to 2009, the authors determined an increased risk of  ASD in mothers taking antidepressants in the 2nd and 3rd trimesters (not first trimester).  Note that the differences were not large, but were statistically significant.  The risk of ASD in the overall population and in those whose mothers took SSRIs in the first trimester was similar, 0.7%.  But the rate increased to 1.2% in mothers who took SSRIs in the 2nd and 3rd trimesters.  

Note also that although prior studies have found increased ASD in children of depressed mothers, In an accompanying editorial in JAMA Pediatrics, Bryan King asserts,

[These findings] might also be taken as an argument that this is a drug effect rather than merely an association with depression.

Final comment for now: The controversy and concern about use of antidepressants in pregnancy is definitely not settled.  Treatment of the depressed mother has proven benefits to infant health as well as to the mother.  Alexis Link MD has commented,

I encourage us all to be thoughtful about this issue.  It can be extremely dangerous to reject the possibility of medication use during pregnancy since it can actually be life-saving for baby and mother (personal communication).

and she called my attention to a Sept. 2015 review from Harvard.   I have come across a more recentlypublished review also from Mass. General Hospital published online 5 January, 2016, with the long and intriguing title:

Absence of evidence for increase in risk for autism or attention-deficit hyperactivity disorder following antidepressant exposure during pregnancy: a replication study (Castro et al, Translational Psychiatry (2016) 6, e708; doi:10.1038/tp.2015.190

We don’t know yet which perspective will eventually dominate as more studies come in.  Personally, I’m impressed with the need for care and caution evidenced by both the Sharma and Boukhris studies.  And armed with tools of intensive psychotherapy and also neurofeedback, I know many fewer depressed women can now be well-treated without SSRI and SNRI antidepressants.

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