Antipsychotics for Schizophrenia Linked to Lower Mortality Risk?

It's widely assumed antipsychotics increase the risk of cardiovascular disease (CVD) and early death in patients with schizophrenia. However, new findings suggest the opposite is true and that long-term use of these agents may actually reduce the risk of CVD and death.

Investigators followed more than 62,000 residents of Finland for up to 20 years and found that the cumulative mortality rate during periods in which antipsychotics were used was considerably lower than periods in which antipsychotics were not used.

"This is the longest follow-up ever of patients taking antipsychotics, and what we saw again was that those patients who have schizophrenia and don't take antipsychotics die at a faster rate than people who do take antipsychotics," coauthor Christoph Correll, MD, professor, Institute of Behavioral Science, Feinstein Institute for Medical Research, Manhasset, New York, told Medscape Medical News.

"Although antipsychotics surely have side effects that can increase metabolic risks, the illness itself has a greater side effect burden, and the illness itself outperforms in a bad [way]...the risk of antipsychotics, in terms of cardiovascular burden," said Correll, who is also the medical director of the Recognition and Prevention Program, Department of Psychiatry, Zucker Hillside Hospital, New York City.

The study was published online January 10 in the World Journal of Psychiatry.

Knowledge Gap

Individuals with schizophrenia have a shorter average life expectancy compared with the general population. Antipsychotic use is associated with short-term adverse cardiometabolic events, but there is a "lack of knowledge" about whether long-term use of these agents is associated with greater physical morbidity and mortality, the investigators note.

Correll noted that there is some previous evidence suggesting antipsychotics may reduce all-cause mortality. However, he added, these studies were of shorter duration.

The study population data came from the nationwide Hospital Discharge register and included all individuals hospitalized because of schizophrenia in Finland between 1972 and 2014.

The investigators followed patients with schizophrenia who were taking antipsychotics for up to 20 years. They used hospitalization data on physical illness "as a marker for severe physical morbidity." The dataset also allowed them to assess all-cause mortality as well as death from cardiovascular causes or suicide.

The researchers studied an "incident cohort" consisting of first-episode patients with schizophrenia who had not taken antipsychotics during the year preceding the index hospitalization (n = 8719; mean age, 41.2 years; 56.2% male) as well as the full cohort, which the researchers refer to as the "prevalent" cohort. It included 62,250 patients with a mean age of 46.8 years; of these individuals, 50.2% were male.

Although both cohorts were followed for up to 20 years, the median follow-up times for the prevalent and incident cohorts were 14.1 years (interquartile range, 6.9-20.0) and 10.1 years (interquartile range, 5.0-14.3), respectively.

The study included five outcomes of interest. Of these, two focused on physical illnesses and three were mortality-related outcomes, including all-cause mortality, cardiovascular mortality, and death by suicide.

To eliminate selection bias, the researchers compared antipsychotic use and non-use periods in the same individual using a stratified Cox model and assessed mortality outcomes using "traditional" between-individual Cox multivariate models.

There was no difference in somatic and cardiovascular hospitalization rates between the use vs non-use periods for the same patient (adjusted hazard ratio [aHR], 1.00; 95% CI: 0.98 - 1.03; and aHR, 1.00; 95% CI: 0.92 - 1.07, respectively).

When researchers looked at specific antipsychotics, they found that long-acting injectable (LAI) fluphenazine was associated with the highest decreased risk of somatic hospitalizations, whereas quetiapine, olanzapine, risperidone, and aripiprazole were associated with a "slightly increased risk."

Similarly, there was no increased risk of cardiovascular hospitalization between periods of each individual's use or non-use of antipsychotic, and again, LAI fluphenazine performed best. In fact, LAI fluphenazine monotherapy was associated with a significantly decreased risk of cardiovascular hospitalization (aHR, 0.46; 95% CI, 0.32 - 0.68).

Clozapine Advantage

During the follow-up period, all-cause mortality was significantly lower in patients taking any antipsychotic compared with those taking no antipsychotic, according to Kaplan–Meier analyses.

Cumulative mortality rates up to 20 years for non-use vs any use were 46.2% vs 25.7%, respectively (P < .0001).

In particular, those treated with clozapine had the lowest all-cause mortality rate, at 15.6% (P < .0001).

Closer analysis revealed that the aHR for all-cause mortality during antipsychotic use vs non-use was lower in the prevalent vs incident group.

Cardiovascular mortality was also significantly lower during any antipsychotic use compared with non-use in the prevalent as well as incident cohorts (aHR, 0.62; 95% CI, 0.57 - 0.67; and aHR, 0.83; 95% CI, 0.63 - 1.09, respectively).

Although no individual antipsychotic was associated with increased risk of cardiovascular death, LAI olanzapine and oral flupentixol were both associated with a significantly reduced risk compared with no use (aHR, 0.14; 95% CI, 0.02 - 1.01; and aHR, 0.24; 95% CI, 0.11 - 0.54, respectively).

Suicide mortality was also lower in patients taking antipsychotics, compared with periods of non-use, in both the prevalent (aHR, 0.52; 95% CI, 0.43 - 0.62) and incident cohorts (aHR, 0.50; 95% CI, 0.33 - 0.74).

The "most beneficial mortality outcome" was associated with use of clozapine in all three types of death:

All-cause mortality (aHR, 0.39; 95% CI, 0.36 - 0.43).
Cardiovascular mortality (aHR, 0.55; 95% CI, 0.47 - 0.64).
Suicide mortality (aHR, 0.21; 95% CI, 0.15 - 0.29).

Correll suggested several reasons why schizophrenia without antipsychotic treatment might increase the risk for mortality and CVD.

"Ongoing psychosis and stress increase cortisol, which then worsens cardiovascular illness," he said.

In addition, patients who are not taking antipsychotics aren't monitored as frequently for cardiovascular symptoms as their counterparts who are prescribed these medications, he added.

"Controversial" Findings

Commenting on the study for Medscape Medical News, Mark Olfson, MD, PhD, Elizabeth K. Dollard Professor of Psychiatry, Medicine, and Law, and professor of epidemiology, Columbia University Medical Center, New York City, said the "new findings raise the possibility that long-term antipsychotic medications of adults with schizophrenia may not only be less harmful to cardiovascular health than widely assumed, but actually protective."

"In perhaps the most startling finding, the authors report that among 20 antipsychotic medication classes examined, long-acting injectable olanzapine, which is generally regarded as one of the most metabolically aggravating antipsychotic medications, was the most strongly associated with reducing cardiovascular mortality risk," he added.

Olfson, who was not involved with the study, offered a cautionary note.

"Before accepting this controversial finding, it is important to consider the possibility that healthy user effects may bias their results," he said.

He noted that it is the "propensity for patients who receive one treatment to also seek other treatments or engage in other healthy behaviors." Therefore, "not adjusting for these other changes can lead to the inference that antipsychotic medications are having stronger protective effects than is actually the case."

Correll emphasized that these findings "do not mean we shouldn't use antipsychotics with lower cardiovascular risk or minimize these side effects, but basically these side effects shouldn't deter us from using antipsychotics because not using antipsychotics is even worse."

The study was conducted by researchers from Finland, the United States, and Germany, and financed with grants from the Finnish Ministry of Social Affairs and Health through a development fund for Niuvanniemi Hospital. Disclosures for the authors are listed in the article. Correll has been a consultant and/or advisor to or has received honoraria from Alkermes, Allergan, Angelini, Gedeon Richter, Gerson Lehrman Group, IntraCellular Therapies, Janssen/J&J, LB Pharma, Lundbeck, MedAvante-ProPhase, Medscape, Neurocrine, Noven, Otsuka, Pfizer, Recordati, Rovi, Sumitomo Dainippon, Sunovion, Supernus, Takeda, and Teva. Olfson has reported no relevant financial relationships.

World Psychiatry. Published online January 10, 2020. Abstract

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