Antidepressants may increase suicide risk

The U.S. Food and Drug Administration (FDA) issued a “black box” warning , the most serious type of warning, in Oct. 2004, alerting clinicians about the increased risk of suicidal ideation or suicidal behavior in children and adolescents treated with antidepressants.

However, according to a Feb. 2016 study by Dr. Christian Bachmann in European Neuropsychopharmacology, the prescription rate of antidepressants for U.S. youth still increased between 2005 and 2012 from 1.3 percent to 1.6 percent. Sertraline was the most widely utilized antidepressant among U.S. youth, with markedly increased antidepressant use among teenagers from 15 to 19 years old.

According to Bachmann and his collaborators, there is no substantial evidence indicating a surge in mental health disorders among youth to account for the heightened prescription rate. Instead, he speculated that the growing use of mental health services and the limited availability of psychotherapy services may have been contributing factors to the steady increment of antidepressant use.

In many clinical guidelines, psychotherapy is recommended as the first-line treatment for children and adolescents suffering from a mental health disorder. Yet some patients and physicians, as Bachmann and co-authors note, may prefer antidepressant use because they believe that medication could realize treatment goals more quickly.

A recent study, however, has demonstrated that psychotherapy should indeed be the first stage of treatment. Lead author Dr. Andrea Cipriani, associate professor at the Department of Psychiatry of the University of Oxford, and fellow researchers showed in their June 8 publication in The Lancet that among 14 antidepressants, only fluoxetine (Prozac) is significantly more effective than a placebo in treating major depressive disorder among children and adolescents.

In this study, the research team conducted a network meta-analysis review of antidepressants and compared and ranked them according to their efficacy and tolerability. The researchers searched PubMed, Web of Science and other databases for published as well as unpublished double-blind randomized trials that had tested the effect of antidepressants compared to a placebo or another antidepressant in children and adolescents with a primary diagnosis of major depressive disorder.

Among the clinical trials found in the search which concluded on May 31, 2015, 34 trials were deemed eligible for the purpose of this study. These trials involved 14 antidepressants and 5,260 children and adolescents who were about nine to 18 years old.

In addition to the efficacy and tolerability of these antidepressants, secondary outcomes of interest to the research team included increased risk of suicide as well as the quality of evidence in the clinical trials. To assess the reliability of the data, the researchers conducted a systematic evaluation of evidence with the Cochrane risk of bias tool and the GRADE system.

Upon reviewing the clinical trials, the research team discovered that fluoxetine was the most effective as well as the best tolerated antidepressant, albeit with a medium effect on depressive symptoms. Fluoxetine was also the only medication found to be more potent than a placebo. The least effective antidepressant was nortriptyline, and the worst tolerated was imipramine. Duloxetine, sertraline and venlafaxine were also found to have lower tolerability than a placebo.

With regard to secondary outcomes, suicidality could not be comprehensively assessed for all 14 antidepressants due to the lack of reliable data. Nonetheless, from available information, the research team deduced that venlafaxine significantly increased suicidality among youth.

From the systematic evaluation of clinical trial data, the researchers were able to derive these vitally important revelations concerning antidepressants for major depressive disorder among youth. However, Cipriani and collaborators could not be sufficiently confident in the accuracy of their findings due to the low quality of evidence in the clinical trials.

Thirty of the 34 trials (88 percent) indicated a high to moderate risk of bias, while only four (12 percent) were of low risk. The research team also suspected that several studies suffered from selective reporting of data and overestimation of the treatment efficacy. The team also noted that 22 of the 34 studies (65 percent) were funded and likely influenced by pharmaceutical companies.

Since the researchers could not be assured of either the accuracy or the validity of the clinical trial results, they could not assert from their review the exact extent to which an antidepressant such as fluoxetine is more effective than a placebo at reducing depressive symptoms in children and adolescents. According to Cipriani and fellow authors of the study, the validity of clinical study results could not be confirmed without access to raw clinical trial data.

Due to this uncertainty concerning the quality of evidence, the research team does not advise any pharmacological treatment to be the first intervention in major depressive disorder among children and adolescents. Instead, youth are urged to first seek psychological treatment. If psychotherapy services are unavailable, then fluoxetine should be considered as an option, considering its relative effectiveness and tolerability. The other 13 antidepressants, based on this study, do not seem to be suitable for youth consumption.

Even with the use of fluoxetine, the authors of this study warn that children and adolescents should be closely monitored, especially at the beginning, for the development of side effects. The extent to which these findings and recommendations apply to adults remains to be substantiated, but the researchers emphasize the need for well-designed and transparent clinical studies concerning antidepressant use in all population sectors. Further study is also encouraged for the development of new therapeutic options for major depressive disorder.