Antipsychotics May Increase Mortality Risk for Parkinson’s Patients

Numerous groups, including the Food and Drug Administration (FDA) and the Centers for Medicare and Medicaid Services, have issued concerns or warnings related to the increased risk of death when using antipsychotics to treat behavioral problems in older people with dementia.

A study published March 21 in JAMA Neurology now suggests that clinicians should also be cautious about prescribing antipsychotics to patients with Parkinson’s disease (PD). The report found that patients with PD who took antipsychotics were at greater risk of death than those who did not take the medication.

While Parkinson’s disease is primarily associated with movement defects and psychiatric problems arising from the progressive death of dopamine cells, the side effects of dopamine replacement therapy and the stress of coping with a chronic, degenerative disease are also common.

An estimated 60 percent of people with Parkinson’s disease develop psychosis over the course of their illness. (While psychosis often manifests later in life as a symptom of Parkinson’s dementia, it also happens independently.) Previous studies have shown that up to half of Parkinson’s patients are prescribed antipsychotics within seven years of their diagnosis.

To determine whether there is an increased mortality risk associated with antipsychotic use in Parkinson’s patients, a collaborative team from the University of Pennsylvania and University of Michigan compared mortality rates of nearly 8,000 Parkinson’s patients who recently began taking antipsychotic medications with 8,000 Parkinson’s patients not exposed to the medications, as documented in Veterans Health Administration data.

The authors found that the patients who started antipsychotic therapy were more than twice as likely to die within six months compared with those who were not taking the medications.

The first-generation antipsychotic haloperidol was linked with the highest mortality risk (5.08 increased odds), followed by the second-generation antipsychotic agents olanzapine (2.79), risperidone (2.46), and quetiapine (2.16). Other antipsychotics including clozapine were not prescribed to enough patients to identify risk.

About 8 percent of the patients in the analysis had received a dementia diagnosis, leading the authors to conclude that it was unlikely that dementia was a driving factor for the mortality in Parkinson’s patients taking antipsychotics.

Because antipsychotics are sometimes prescribed in palliative care settings, the authors performed a secondary analysis to remove all Parkinson’s patients who died within one month of initiating antipsychotic therapy. Even with removing these patients from the analysis, the authors found an elevated mortality rate among antipsychotic users.

University of Pennsylvania

Study coauthor Daniel Weintraub, M.D., an associate professor of psychiatry and neurology at the University of Pennsylvania’s Perelman School of Medicine, told Psychiatric News that these data are concerning given how common antipsychotic prescriptions are among Parkinson’s patients.

“In cases of severe and significant psychotic symptoms, antipsychotics are needed, but even then I think more tolerable medications like quetiapine are preferred, whereas high-potency antipsychotics should be seen as a last-ditch effort,” Weintraub said.

“Otherwise, clinicians should focus on managing any comorbid conditions like infections that might be exacerbating the problem, lower the dosage of dopamine medications if possible, or try to minimize the impact of psychosis through cognitive and behavioral techniques,” he continued.

Henry Nasrallah, M.D., the Sydney W. Souers Professor and Chair of Neurology and Psychiatry at St. Louis University, noted that these findings highlight the challenges that clinicians face when dealing with psychosis.

“Atypical antipsychotics are an improvement over first-generation drugs like haloperidol, but as this and other research has suggested, they are not completely innocent when it comes to a risk of death,” he told Psychiatric News.

However, unlike haloperidol, which has been reported to kill neurons, thus accelerating the progress of Parkinson’s, the mechanisms behind the risk of atypical antipsychotics remain murky, Nasrallah continued. “It might be related to cardiovascular or pulmonary problems, but we are not sure.”

While the results of the JAMA Neurology study may only add to the difficult choices facing Parkinson’s patients and clinicians, Nasrallah noted that a new option for the treatment of Parkinson’s psychosis may be forthcoming. Pimavanserin—a selective serotonin inverse agonist—is currently being evaluated by the Food and Drug Administration (FDA) (Psychiatric News, September 18, 2015). On March 29, an FDA advisory committee voted 12-2 that the benefits of pimavanserin outweighed the risks; an approval decision is expected in May.

“This drug has shown an ability to improve psychotic symptoms without blocking any dopamine receptors, which is unheard of in antipsychotic circles,” Nasrallah said. If the medication receives FDA approval, it could mean more options for treating psychosis with fewer adverse effects, he added.

The JAMA Neurology study was funded by an award from the Veterans Health Administration. ■