The use of antipsychotic agents is an essential component in the treatment of mental illness. While data show that individuals with severe mental illness (SMI) have shortened life expectancy compared with those without SMI, concerns over the safety of antipsychotic use as a potential contributor to this increased mortality have arisen. Researchers report observing that long-term antipsychotic use is associated with lower mortality in patients with schizophrenia, and that excess mortality may be associated with other factors, including not using antipsychotics at all.

Current research published January 2020 in World Psychiatry provides reassurance that these agents are safe in the long term, and that mortality was higher during periods when patients were not using antipsychotic medications. 

Antipsychotic agents have long been available for the treatment of mental illness, with their efficacy proven in numerous randomized, controlled trials; however, such side effects as  movement disorders, including tardive dyskinesia, and more recently cardiovascular effects such QTc prolongation, metabolic syndrome, and sudden cardiac death, have potentially limited their use. 

Coauthor Jari Tiihonen, a professor of psychiatry at Karolinska Institute in Sweden, and colleagues set out to assess the association of antipsychotic use with severe physical morbidity (identified as risk of hospitalization), all-cause mortality, and cardiovascular and suicidal death among schizophrenia patients in hospitals. They explored the effect of antipsychotic use versus nonuse periods for the same patients on hospitalization-based outcomes for inpatients treated for schizophrenia between 1972 and 2014 in Finland (N = 62,250) with up to 20 years of follow-up (median 14.1 years). 

The analysis included a variety of antipsychotic agents, including first-generation antipsychotics (such as haloperidol and perphenazine) and second-generation antipsychotics (SGAs); aripiprazole (Abilify), released in the U.S. in 2002, was the newest SGA included, thus leaving out agents released after Abilify. Clozapine was included in the analysis, and the researchers commented, “Data suggest that long-term antipsychotic use does not increase severe physical morbidity leading to hospitalization, and is associated with substantially decreased mortality, especially among patients treated with clozapine.” 

The team reported that during use of any antipsychotic agent when compared with nonuse, the adjusted hazard ratios (aHRs) for cardiovascular hospitalization were 1.00 (95% CI, 0.92-1.07); 0.62 (95% CI, 0.57-0.67) for cardiovascular mortality; 0.48 (95% CI, 0.46-0.51) for all-cause mortality; and 0.52 (95% CI, 0.43-0.62) for mortality associated with death by suicide. However surprisingly, the most beneficial outcome was associated with the use of clozapine in all-cause mortality (aHR = 0.39, 95% CI, 0.36-0.43); cardiovascular mortality (aHR=0.55, 95% CI, 0.47-0.64); and suicide mortality (aHR = 0.21, 95% CI, 0.15-0.29).

“We know from previous studies that only half of those who have been discharged from hospital after their first psychotic episode with a schizophrenia diagnosis take antipsychotic drugs. Besides, there are many people with schizophrenia who are on long-term benzodiazepine medication, which is in breach of existing guidelines and is associated with increased mortality risk. Building trust and understanding towards the efficacy and safety of antipsychotic drugs is important, and we hope that this study can contribute to this end,” said Dr. Tiihonen.

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