Selective Serotonin Reuptake Inhibitors and Suicidality: A Guide for the Perplexed

Can J Psychiatry. 2009;54(2):72-74. The rate of suicidal adverse events is elevated around 2-fold in drugs, relative to placeboes, in clinical trials of antidepressants in children, adolescents, and young adults.1,2 Since the FDA's black box warning in 2003-2004, there has been a decline in the prescription rate of antidepressants, with no compensatory increase in referrals for psychotherapy in the United States.3 Families, patients, and clinicians are uncertain about how to balance the benefits and risks of antidepressants. In this brief review, the clinical significance of suicidal events is discussed along with the factors that may increase or attenuate the risk, possible explanations for this phenomenom, the benefits and risks of antidepressants, the public health implications of a decline in the use of SSRIs, and recommendations for clinicians. Suicidal adverse events are treatment-emergent increases in suicidal ideation or an actual suicide attempt. In more than 4300 participants in pediatric antidepressant clinical trials, there have been no deaths by suicide, and most of these events were increases in suicidal ideation, rather than actual suicide attempts. The actual risk difference for the occurrence of an event is not large. While the FDA initially reported a risk difference of 2%, a more recent re-analysis included more recently conducted trials found a risk difference of only 0.9%, which translates to a NNH of 121.1,2 Moreover, during the period of time when the rate of SSRI prescriptions was increasing, youth suicide rates were declining.4 One cannot necessarily infer a causal relation between the increase in the use of SSRIs in adolescents and a decline in the adolescent suicide rate. However, if antidepressants were associated with an increased risk for suicide, one would have expected an increase in adolescent suicide, which clearly was not the case. The nature of assessment for suicidal events has also been questioned. In most clinical trials, suicidal events are not surveyed systematically, but are reported spontaneously. In fact, in the subset of clinical trials that had systematic assessment, there was no difference between medication and placebo regarding systematically assessed suicidal ideation.2 However, other reports have shown similar rates of events, whether using usual adverse event reporting methods or by deriving the occurrence of events from systematically assessed measures of self-reported suicidal ideation. 5'6 Predictors of suicidal adverse events include previous suicidal behaviour and higher baseline levels of suicidal ideation, anger, and irritability.5 In the Treatment of Adolescent Depression Study,6 the rate of suicidal events was lower in the combination of antidepressant and CBT than in medication alone; however, in other clinical trials of more severely or chronically depressed youth, no protective effect was found for combination treatment.6,7 No relation has been established among dosage, adherence pattern, medication type, and risk for events, and while some promising pharmacogenetic findings have been reported, there is currently no clinical applicability of these findings. Several hypotheses, all unproven, have been advanced to explain the increased rate of suicidal events in antidepressant-treated patients, compared with those on placebo. These have included induction of akathisia, disinhibition, increasing energy of the patient to the point where he or she can actually make an attempt, induction of mania or a mixed state, or withdrawal from medication as a result of nonadherence, with induction of dysphoria and suicidality. The adage of suicidal behaviour coming as a consequence of improvement in mood is not consistent with data showing a high correlation between severity of suicidal ideation and severity of depression; further, most reported suicidal events were not attempts, but were increases in suicidal ideation. The induction of a mixed state can certainly lead to suicidal ideation and behaviour; however, while the risk of a suicidal event is higher in adolescents than in children, the risk of mania after treatment with an antidepressant is higher in younger children. …