Antidepressants in Kids May Double Suicidality, Aggression Risk

Nancy A. Melville

February 04, 2016

The risk for suicidality and aggression in children and adolescents treated with antidepressants is doubled compared with their counterparts who do not receive antidepressants, results of a large, systematic review suggest.

Just as importantly, the study, which included 70 clinical trials, found substantial underreporting of the drugs' negative effects in pharmaceutical study reports.

"We believe ours is the first comprehensive review of randomized controlled trial data using clinical study reports for aggressive behaviour and akathisia, and our finding of the doubling of aggression in children and adolescents is novel," the authors write.

"These trials had limitations in the study design and discrepancies in reporting, which may have led to serious underreporting of harms," they add.

The authors note that in light of the fact that harms associated with antidepressants are often not included in published trial reports, this meta-analysis included evaluation of summary trial reports and 68 clinical study reports for the 70 trials. These provide detailed summaries of trial results, which were needed to gain regulatory authorization for marketing.

The findings were published online December 3 in the BMJ.

Unexpected Link to Aggression

With first author Tarang Sharma, PhD, Nordic Cochrane Centre, Rigshospitalet, Copenhagen, Denmark, the investigators evaluated data and clinical study reports corresponding to 70 trials that involed 18,526 patients.

The researchers focused on clinical study reports from European and UK drug regulators for the antidepressants duloxetine (Cymbalta, Eli Lilly and Company), fluoxetine (multiple brands), paroxetine (multiple brands), sertraline (Zoloft, Pfizer Inc), and venlafaxine (multiple brands). They also evaluated summary trial reports for duloxetine and fluoxetine from Eli Lilly's website.

The results, which were consistent with those from previous research, showed that in adults, there were no significant associations between antidepressant use and suicidality (odds ratio [OR], 0.81; 95% confidence interval [CI], 0.51 - 1.28) or aggression (OR, 1.09; 95% CI, 0.55 - 2.14). The rates were higher for akathisia (OR, 2.00; 95% CI, 0.79 - 5.04).

In children and adolescents, however, the risks for all three measures were higher (suicidality: OR, 2.39; 95% CI, 1.31 - 4.33; aggression: OR, 2.79; 95% CI, 1.62 - 4.81; akathisia, OR, 2.15; 95% CI, 0.48 - 9.65).

Previous research, including a special review from UK regulator Medicines and Healthcare Products Regulatory Agency, has shown increased suicidality in relation to the drugs. However, the findings on aggression were unexpected, Dr Sharma, told Medscape Medical News.

"The finding in aggressive behavior was novel, as that had not been investigated in the same way before," she said.

Dr Sharma noted that the study was not able to determine which drugs were associated with a higher risk.

"We cannot answer this question reliably, as we did not have the same number of trials for all the different drugs and the quality of their reporting varied," Dr Sharma said.

The analysis showed significant and potentially dangerous shortcomings in the bulk of the clinical study reports.

"These trials had limitations in the study design and discrepancies in reporting, which may have led to serious underreporting of harms," they write.

Some important outcomes on individual patient listings, for example, were buried in appendices, and even those were available for only 32 of the trials.

Summary trial reports on Eli Lilly's website listed almost all deaths. However, all suicidal ideation events were missing, and information on remaining outcomes was incomplete.

"The summary reports on Eli Lilly's website were even more unreliable than we previously suspected. Only mortality had (almost) complete information," the authors state.

Dr Sharma noted that despite known concerns about such shortcomings in data reporting, the level of discrepancies that were found was surprising.

"There is abundant previous research that indicates the problem of selective reporting and publication bias when one compares the published literature and the original clinical study data and that this is especially worse for adverse effects or harms data," she said.

"I expected some discrepancies, both with published literature and within the clinical study report itself, based on previous research done in the area, but the level of it did surprise me. The magnitude of what was buried within the appendices was quite shocking and disturbing to me."

The researchers included aggressive behavior in their evaluation of the drugs because, despite many reports of cases of aggressive behavior linked to use of the drugs, systematic research on the issue had been lacking, particularly in comparison to the higher-profile issue of suicidality.

"Perpetrators of school shootings and similar events have often been reported to be users of antidepressants, and the courts have in many cases found them not guilty as a result of drug-induced insanity," the authors write.

Prescribe With Caution

In an accompanying editorial, Joanna Moncrieff, MD, a senior lecturer with the Division of Psychiatry at University College London, United Kingdom, agreed that the study underscores the concerns about the reports that regulators use to base decisions regarding market authorization.

"To evaluate antidepressants properly, we need access to original data from trials, but we also need research that clarifies the whole range of antidepressant induced behavioural, emotional, and physical alterations following acute treatment, long term use, and withdrawal," she writes.

Dr Moncrieff commented to Medscape Medical News that clinicians should take note of the findings when prescribing.

"Doctors should be more cautious about prescribing antidepressants to everyone, and to young people especially, and regulators should put a warning on about aggressive behavior as well as suicide," she said.

The study's authors have disclosed no relevant financial relationships. Dr Moncrieff is the author of several books critical of psychopharmacologic approaches to mental disorders, including The Myth of the Chemical Cure and The Bitterest Pills: The Troubling Story of Antipsychotic Drugs.

BMJ. Published online December 3, 2015. Full text, Editorial

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