Who develops severe or fatal adverse drug reactions to selective serotonin reuptake inhibitors?

To ascertain the risk factors associated with the development of severe and fatal adverse drug reactions (ADRs) or intentional overdoses by patients on selective serotonin reuptake inhibitors (SSRIs).

We undertook a data analysis of Health Canada's database of Adverse Drug Reactions to SSRIs from 1986 to 1996, as well as a literature review.

Among the complete ADR reports in the SSRI database, there were no sex differences in occurrences of all ADRs (n = 1011), severe ADRs (n = 295), drug-drug interactions (n = 312), deaths (n = 87), or intentional overdoses (n = 79), when sex differences in prescription practices were considered. There were no differences in ADR rates among different SSRIs. The most common cause of death among patients taking SSRIs was intentional overdose (n = 65, 74.7%). This was reported in 47 (72.3%) women and 18 (27.7%) men. The most common drugs taken with SSRIs in patients who died of intentional overdoses were benzodiazepines, tricyclic antidepressants (TCAs), narcotics, alcohol, and diphenhydramine. Patients who had severe or fatal ADRs were more likely to be taking an SSRI with 2 or more other drugs, including alcohol. Drug combinations that included another CYP-450 drug were especially problematic. A total of 129 cardiovascular ADRs were reported, most of which were severe. These included rhythm disturbances, blood pressure perturbations, and chest pain or angina. Cardiovascular ADRs most often occurred with concomitant drug use of benzodiazepines, TCAs, histamine H2 antagonists, lithium, and calcium channel blockers. There were 3 deaths from malignant neuroleptic syndrome unassociated with intentional overdose.

SSRIs are relatively safe when their widespread use is compared with the prevalence of ADRs. SSRIs may, however, be associated with ADRs, and even death, following intentional overdose or when taken with 2 or more other drugs or alcohol (particularly another drug metabolized by CYP-450). Physicians prescribing SSRIs need to consider drug-drug interactions and carefully monitor patients with severe affective disorders, comorbid medical conditions (especially cardiovascular disease), alcohol abuse, or a history of overdosing.