Daniel M. Keller, PhD

June 23, 2015

SAN DIEGO — The use of antipsychotic (AP) medication to treat psychosis in Parkinson's disease (PD) increases the risk for all-cause death, and the risk varies with the AP class and the specific drugs within a class, a study shows.

"The antipsychotics users had a hazards ratio between 2 and 3 compared with non–antipsychotic users in terms of 6-month mortality, so they were that much more likely to die," Daniel Weintraub, MD, from the Philadelphia Veterans Affairs Medical Center and associate professor of psychiatry in the Perelman School of Medicine of the University of Pennsylvania in Philadelphia, told Medscape Medical News.

He presented the study findings here at the International Parkinson and Movement Disorder Society (MDS) 19th International Congress.

The study included data on patients with PD in the national Veterans Affairs administrative database between 1999 and 2010. The cohort was largely male.

Using 31 exclusion criteria, matching factors, and covariates, the researchers formed a matched control cohort of non–AP users. They compared 180-day mortality of AP users with that of nonusers, from which hazard ratios were calculated. There were 7877 matched pairs.

The antipsychotics users had a hazards ratio between 2 and 3 compared with non–antipsychotic users in terms of 6-month mortality, so they were that much more likely to die Dr Daniel Weintraub

All APs Raised Mortality Risk

No class of AP (typical vs atypical) or specific drug was without risk for death.

"Some people might assume [the newer, atypical ones] have a lower risk, and yes, they did have a lower risk, but the risk for atypical antipsychotics was elevated as well, compared with nonusers," Dr Weintraub said.

Table. Mortality Risks by Antipsychotic Class and Specific Drug (Intention-to-Treat Analysis)

Class or Drug Hazard Ratio P Value
No antipsychotic use 1.0
Atypical antipsychotic 2.26 <.001
Typical antipsychotic 3.65 <.001
Haloperidol 5.08  
Other typical 1.82 .07
Olanzapine 2.79 <.001
Quetiapine 2.16 <.001
Risperidone 2.46 <.001
Other atypical 1.19 .62


Whether the analysis was done by intention to treat or by exposure to drug, the patterns were largely the same. Adjustments were made for measurable confounders related to PD severity and comorbidities.

The only typical AP relatively commonly prescribed was haloperidol. Three atypical APs commonly prescribed were quetiapine, olanzapine, and risperidone.

Quetiapine represented almost 70% of AP prescriptions in the cohort, and although the mortality risk was lowest with quetiapine, it was still about double the risk compared with no AP use.

Haloperidol, olanzapine, and risperidone were all associated with higher mortality risks than quetiapine.

The researchers found similar results when they excluded patients who died within the first 2 weeks or 4 weeks of AP exposure to eliminate patients who were at imminent risk for death when therapy was initiated.

Dr Weintraub next plans to look at National Death Index data for causes of death and also to examine hospitalization and outpatient visit data to see whether there was increased morbidity associated with AP use.

Psychosis in PD is common, affecting 60% of patients, with half of them receiving treatment with APs. The study did not include any patients who had psychosis but were not treated for it in order to investigate the mortality risk of PD psychosis alone. Psychosis was included as a covariate here to control for it; however, there was no strict matching of treated vs nontreated patients with PD psychosis.

The value of treating psychosis in PD needs to be balanced against the mortality risk.

Calling it "a very important study in Parkinson's disease," Michael Okun, MD, professor of neurology and co-director of the Center for Movement Disorders and Neurorestoration at the University of Florida in Gainesville and national medical director of the National Parkinson Foundation, commented to Medscape Medical News that "patients should be aware that treatment of Parkinson's related psychosis can be life-changing and life-saving in some cases."

He said clinicians "tend to use drugs such as clozapine, quetiapine, and possibly a new agent, pimavanserin. If you can preserve optimal treatment of the motor symptoms of Parkinson's and also suppress psychosis, the risk-benefit ratio usually favors treatment."

Dr Okun noted that the increased mortality with AP use in patients with PD psychosis parallels findings of their use in non-PD patients with psychosis.

Dr Weintraub and colleagues recommend developing and testing new APs as well as nonpharmacologic strategies for managing psychosis in PD.

The research was federally funded through the Department of Veterans Affairs. Dr Weintraub and Dr Okun have disclosed no relevant financial relationships.

International Parkinson and Movement Disorder Society (MDS) 19th International Congress. Abstract 482. Presented June 16, 2015.


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