Studies using death certificates have indicated an excess of sudden cardiac deaths among users of antipsychotic drugs compared to the general population, but may have underestimated the presence of other known causes of sudden and unexpected death.

To assess the cause and risk factors for sudden death discovered by contemporaneous investigation of all deaths occurring over a 26-year period (1984–2009) in adult patients registered for care in one large psychiatric hospital in New York.

Circumstances of death, psychiatric diagnoses, psychotropic drugs and past medical history were extracted from the root cause analyses of sudden unexpected deaths. After the exclusion of suicides, homicides and drug overdoses, explained and unexplained cases were compared regarding clinical variables and the utilization of antipsychotics.

One hundred cases of sudden death were identified among of 119, 500 patient-years. The death remained unexplained in 52 cases. The incidence of unexplained sudden death was 125/100,000 (95% CI 88.9–175.1/100,000) patient-years in 2005–2009, 53/100,000 (95% CI 31.7–88.5/100,000) patient-years in 1999–2004 and 7/100,000 (95% CI 3.7–19.4/100,000) patient-years in 1984–1998. Explained and unexplained cases were similar regarding psychiatric diagnoses and treatment with any psychotropic class, including first- and second-generation antipsychotics. Dyslipidemia (p = 0.012), diabetes (p = 0.055) and co-morbid dyslipidemia and diabetes (p = 0.008) were more common in the unexplained than in the explained cases.

In a consecutive cohort of psychiatric patients, the unexplained sudden deaths were associated with known risk factors for coronary artery disease, but not with higher utilization of first- or second-generation antipsychotics.