FROM THE MAJOR DEPRESSIVE DISORDER CLINICAL KNOWLEDGE CENTER
The Black Hole of the Black Box for Antidepressants

by Mary Ann Stephens, PhD

Depression is a common and treatable illness. In 2006, 15.8 million adults (7.2% of persons aged 18 or older) reported having at least one Major Depressive Episode (MDE) in the past year.(1) The mainstay of pharmacotherapy for major depression are antidepressant (AD) medications, including SSRIs, SNRIs, tricyclic antidepressants, and novel agents such as bupropion. In the STAR*D trial, one-third of those with major depression became symptom-free, and 10-15% reduced symptomatology by half after initial treatment with ADs. For non-responders who switched to another AD, an additional 25% became symptom-free.(2)

Like all medications, AD have side effects that may limit their use under some circumstances or in some patients. The most common side effects are headache, nausea, dry mouth, and constipation, which although distressing, are not life-threatening and are often transient or tolerable. On the other hand, there has been a long-standing debate over whether these medications also may increase the risk of suicide, and this requires more careful analysis of risks and benefits.

Suicide rates are higher in depressed patients. About 60% of deaths attributed to suicide were in people who were depressed.(3) Although the majority of these suicides occurred in patients who simply were not adequately treated,(4) others occurred in those whose primary symptoms were managed. In almost 300 trials reviewed by the FDA, there were 5.1 suicides per 10,000 subject years in the adult population studied but a key point is that suicide rates did not differ between AD and placebo overall. Nevertheless, suicide death is traumatic for patients' families, clinicians, and loved ones who are affected by suicide.

This debate over whether AD increases suicide is unlikely to be resolved in the near future and consensus may never be reached. Consequently, the ensuing debate about what to do with the possibility of AD-induced suicide also is unresolved.

In 2004, the FDA reviewed data showing that antidepressants increased the risk of emerging suicidality by 4% in children on AD compared to 2% on placebo – but no actual cases of suicide were reported. Although the analyses were based on studies of five selective serotonin reuptake inhibitors (SSRIs) (citalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline) and four additional ADs (bupropion, mirtazapine, nefazodone, and venlafaxine), these findings led to the FDA's mandate to include a "black box" warning on the labeling of all AD about the increased risk of suicide in children, because the available data were not adequate to exclude any single medication from the increased risk.

In the wake of these findings, the FDA reviewed data on suicidality and AD use among adults in Dec 2006. The causal link between AD and suicidality was less clear for adults, but there was some evidence to suggest that adults between the ages of 18 and 24 may be more likely to have increased risk of suicidality while on AD relative to placebo.(5) Data from 295 randomized controlled trials and more than 77,380 patients were analyzed by two independent groups within the FDA (the safety and the biometrics groups), each using different data analytic strategies. Overall, suicidality rates did not statistically differ between AD (62%) and placebo conditions (72%). However, when separate analyses were conducted across age groups, an age-dependent decrease in risk for suicidality emerged. AD were protective against suicidality for people 65 and older; their risk was reduced by 61% among those randomly assigned to AD. In contrast, risk of suicidality was higher among younger patients. The risk for suicidality almost doubled for 18-24 year-olds assigned to AD. Because an absence of risk could not be demonstrated, the FDA directed that the black box warning on all AD product labeling be revised to include young adults.

With the broadening of the black box warning to include both children and young adults, many clinicians and patient advocacy groups fear that access to these medications will become restricted among the very population who may be in most need of them. Indeed, several recent studies support these fears. Following the initial black box warning, rates of diagnosis of pediatric depression were 32% lower than would have been predicted on the basis of historical data dating back to 1999,(6) with a concomitant decline in prescriptions for AD for children and adolescents.(6-8) Yet, despite decreased use of AD, there was a sharp and unprecedented increase – 14% - in suicide rates.(7) Further, a meta-analysis of 27 pediatric trials using AD to treat major mood disorders, obsessive-compulsive disorders (OCD), and non-OCD anxiety disorders found that the benefits of the AD appeared to outweigh the risks from suicidality.(9)

Perhaps in anticipation of a similar reaction to the revised black box warning, the FDA included labeling cautions about the dangerous consequences of untreated depression. The goal of the warning is to encourage the careful, well-monitored use of ADs, especially in the initial 1-2 months of pharmacotherapy when signs of suicidality are most likely to emerge.(10) Untreated depression can have catastrophic consequences, and until definitive data emerge on the suicide risk association with ADs, clinicians prescribing antidepressants to children and young adults should be proactive in assessing changes in suicidality, and communicate closely with patients and their families to educate them about the warning signs of suicidal behavior. The best tool for the prevention of suicide is close monitoring of all patients with major depression and consistent use of screening tools in practice. Please join us on January 30th for a neuroscienceCME TV activity to address this very important topic. Click here for activity details.

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