This study involved analysis of QResearch – a large UK primary care database. The patient sample comprised 238,963 adults with a first diagnosis of depression documented between Jan 2000 and July 2011. Those who received antidepressants but who did not have a diagnosis of depression were not considered, to reduce the risk of indication bias. Those with a diagnosis of schizophrenia, bipolar disorder or other psychosis were also excluded.
A total of 87.7% of the cohort received one or more prescriptions for an antidepressant. SSRIs were the most commonly prescribed class (78% citalopram or fluoxetine), followed by tricyclic and related antidepressants (77% amitriptyline or dosulepin) and the group of other antidepressants (91% venlafaxine or mirtazapine).
The overall incidence of suicide (based on 198 cases during five years) was 22 per 100,000 person years. The rates during treatment with antidepressants were similar for SSRIs and tricyclic and related antidepressants. Rates were however higher during treatment with other antidepressants when compared to SSRIs (adjusted hazard ratio 2.64, 1.74 to 3.99; p<0.001). The number of suicide events was small, which led to imprecise estimates. An analysis of the most commonly prescribed individual drugs found an increased risk for mirtazapine (3.70, 2.00 to 6.84; P<0.01) and venlafaxine (2.23, 1.14 to 4.39; P=0.02), when compared with citalopram. The absolute risk of suicide over one year ranged from 0.02% for amitriptyline to 0.19% for mirtazapine.
After excluding patients with a personal history, the incidence of attempted suicide or self-harm was 613 per 100,000 person years. The associations were similar to those seen with suicide – rates for SSRIs and tricyclic/related antidepressants did not differ significantly, but they were higher during treatment with other antidepressants (1.80, 1.61 to 2.00). The hazard ratios appeared to increase with dose for all classes. Analysis of individual drugs found that the hazard ratios for venlafaxine, trazodone and mirtazapine were increased compared with citalopram; whereas that for amitriptyline was reduced. The absolute risk of attempted suicide or self-harm over one year ranged from 1.02% with amitriptyline to 2.96% for mirtazapine.Hazard ratios were highest in the first 28 days after starting treatment and also in the first 28 days after stopping treatment; these findings emphasise the need for careful monitoring of patients during these periods.
As this is an observational study the findings may reflect indication biases and residual confounding from severity of depression and differing characteristics of patients prescribed these drugs.
Limitations of this study include the possibility of channelling bias (selection of drug depends on patient characteristics), lack of detailed information on depression severity and changes over time, lack of information on other potential confounding variables (e.g. drug misuse, family history), misclassification of drug use (patients may not have taken the prescribed antidepressant), and misclassification of outcomes. In addition the number of suicide events was small, and so the power to detect smaller differences between different groups/ agents was low; the authors therefore recommend extreme caution when interpreting results for individual drugs.
Based on their findings, the authors recommend that patients taking drugs such as mirtazapine and venlafaxine (and possibly trazodone) need particularly close monitoring during treatment and shortly after stopping. They do however acknowledge that the observed increased risks with these drugs may be due to patients having different characteristics or more severe disease rather than it being a causal effect. They say that if their findings are confirmed, then current guidelines on the treatment of depression may need to be revised.
An editorial notes that the study does not address how individual patients will respond to particular antidepressants, but as multiple studies have identified a small potential signal that venlafaxine and mirtazapine are linked to a greater risk of suicide and self-harm at a population level, clinicians should exercise caution when prescribing these drugs in patients at high risk for suicide Nevertheless, clinical trials also indicate that venlafaxine and mirtazapine are at least as effective as SSRIs in alleviating symptoms of depression, so in view of the mixed evidence, tools are needed to help clinicians predict how individual patients will respond to particular antidepressants. The editorial advises that for now, clinicians must exercise caution when prescribing all antidepressants and carefully weigh up the potential risks and benefits on a case by case basis before treatment.