Mortality Among Parkinson's Disease Patients Treated With Pimavanserin or Atypical Antipsychotics: An Observational Study in Medicare Beneficiaries.

OBJECTIVE: Pimavanserin, a serotonin 5-HT2 antagonist, is indicated for treatment of hallucinations and delusions associated with Parkinson's disease psychosis. In premarketing trials in patients with Parkinson's disease psychosis, 11% of patients died during open-label pimavanserin treatment. Antipsychotics, which are used off-label in Parkinson's disease psychosis, increase mortality in dementia patients. The authors compared mortality with pimavanserin and atypical antipsychotics in a large database. METHODS: This was a retrospective new-user cohort study of Medicare beneficiaries with Parkinson's disease initiating pimavanserin (N=3,227) or atypical antipsychotics (N=18,442) from April 2016 to March 2019. All-cause mortality hazard ratios and 95% confidence intervals were estimated for pimavanserin compared with atypical antipsychotics, using segmented proportional hazards regression over 1-180 and 181+ days of treatment. Potential confounding was addressed through inverse probability of treatment weighting (IPTW). RESULTS: Pimavanserin users had a mean age of approximately 78 years, and 45% were female. Before IPTW, some comorbidities were more prevalent in atypical antipsychotic users; after IPTW, comorbidities were well balanced between groups. In the first 180 days of treatment, mortality was approximately 35% lower with pimavanserin than with atypical antipsychotics (hazard ratio=0.65, 95% CI=0.53, 0.79), with approximately one excess death per 30 atypical antipsychotic-treated patients; however, during treatment beyond 180 days, there was no additional mortality advantage with pimavanserin (hazard ratio=1.05, 95% CI=0.82, 1.33). Pimavanserin showed no mortality advantage in nursing home patients. CONCLUSIONS: Pimavanserin use was associated with lower mortality than atypical antipsychotic use during the first 180 days of treatment, but only in community-dwelling patients, not nursing home residents.

Entacapone and prostate cancer in Parkinson's disease patients: A large Veterans Affairs healthcare system study.

BACKGROUND: An increased incidence of prostate cancer was observed in Parkinson's disease (PD) patients treated with entacapone during a pre-approval randomized clinical trial; the relation has not been robustly investigated in the U.S. ambulatory setting. OBJECTIVE: To investigate whether entacapone is associated with prostate cancer and to assess whether the associations are correlated with advanced disease at the time of cancer diagnosis. METHODS: Using data from the Department of Veterans Affairs healthcare system, new-user cohorts were created of PD patients treated with add-on entacapone or add-on dopamine agonist/monoamine oxidase B inhibitors between January 2000 and December 2014. Patients were followed on-treatment for occurrence of prostate cancer, identified via linkage to the VA cancer registry. RESULTS: Mean follow-up time was 3.1 and 4.0 years in the entacapone and control cohort, respectively. There were 17,666 subjects meeting study criteria (mean age, 74 (SD 8.6) years); the entacapone-treated group comprised 5,257 subjects. Twenty-three prostate cancer cases occurred in the entacapone cohort and ninety-seven in the control cohort. The overall incidence of prostate cancer was 1.8 per 1,000 person-years of risk. There was no difference in risk of prostate cancer between the cohorts for increased duration of entacapone intake (adjusted HR: 1.08; 95% confidence interval: 0.46-2.51 for cumulative exposure of ≥2 years). Time since starting drug therapy and cumulative dose (mg) also do not suggest a difference in prostate cancer risk between cohorts. CONCLUSIONS: Prolonged therapy with entacapone was not associated with increased prostate cancer incidence; however, findings suggest a higher severity of prostate cancer.

Involvement of the central somatosensory system in restless legs syndrome: A neuroimaging study.

OBJECTIVE: To investigate morphologic changes in the somatosensory cortex and the thickness of the corpus callosum subdivisions that provide interhemispheric connections between the 2 somatosensory cortical areas. METHODS: Twenty-eight patients with severe restless legs syndrome (RLS) symptoms and 51 age-matched healthy controls were examined with high-resolution MRI at 3.0 tesla. The vertex-wise analysis in conjunction with a novel cortical surface classification method was performed to assess the cortical thickness across the whole-brain structures. In addition, the thickness of the midbody of the corpus callosum that links postcentral gyri in the 2 hemispheres was measured. RESULTS: We demonstrated that a morphologic change occurred in the brain somatosensory system in patients with RLS compared to controls. Patients with RLS exhibited a 7.5% decrease in average cortical thickness in the bilateral postcentral gyrus (p < 0.0001). Accordingly, there was a substantial decrease in the corpus callosum posterior midbody (p < 0.008) wherein the callosal fibers are connected to the postcentral gyrus, suggesting altered white matter properties in the somatosensory pathway. CONCLUSION: Our results provide in vivo evidence of morphologic changes in the primary somatosensory system, which could be responsible for the sensory functional symptoms of RLS. These results provide a better understanding of the pathophysiology underlying the RLS sensory symptoms and could lead to a potential imaging marker for RLS.

Postmortem and imaging based analyses reveal CNS decreased myelination in restless legs syndrome.

BACKGROUND: Restless legs syndrome (RLS) is a neurological disorder characterized by a strong urge to move the legs and has been shown in many studies with abnormally low brain iron. Iron deficiency is associated with hypomyelination in brains of animals. Therefore we hypothesized that a myelin deficit should be present in the brains of patients with RLS. METHODS: We performed Western blot analysis on myelin isolated from RLS (n=11) and control (n=11) brain tissue obtained at autopsy for the expression of the integral myelin proteins, myelin basic protein (MBP), and proteolipid protein (PLP) and the oligodendrocyte specific enzyme 3'5'-cyclic nucleotide phosphohydrolase (CNPase). To expand the postmortem findings to in vivo, we analyzed the brains of RLS patients (n=23) and controls (n=23) using voxel-based morphometry (VBM). RESULTS: The expression of MBP, PLP and CNPase in the myelin from RLS was decreased by approximately 25% (p<0.05) compared to controls. The amounts of transferrin (Tf) and H-ferritin (H-Frt) in the myelin fraction were also significantly decreased in RLS compared to controls. The imaging analysis revealed significant small decreases in white matter volume in RLS patients compared to controls in the corpus callosum, anterior cingulum and precentral gyrus. CONCLUSION: A decrease in myelin similar to that reported in animal models of iron deficiency was found in the brains of individuals with RLS. The evidence for less myelin and loss of myelin integrity in RLS brains, coupled with decreased ferritin and transferrin in the myelin fractions, is a compelling argument for brain iron insufficiency in RLS. These data also indicate the need to look beyond the sensorimotor symptoms that typically define the syndrome and its assumed relation to the dopaminergic system. Understanding the full range of RLS pathology may help us better understand the complex, intermittent nature and diversity of the clinical features of RLS and expand our consideration of treatment options for RLS.

Altered eyeblink reflex conditioning in restless legs syndrome patients.

BACKGROUND: Restless legs syndrome (RLS) is characterized by abnormal leg sensations and an uncontrollable urge to move the lower extremities during rest periods. Evidence suggests that reflex tasks that involve sensory-motor integration may be altered in RLS patients. This led us to determine if RLS patients show alterations in a sensory-motor reflex conditioning task called differential eyeblink conditioning. METHODS: RLS subjects were washed out of treatment medication for 7 days prior to testing. Subjects (20 RLS and 19 Control) received 120 discrimination conditioning trials consisting of 60 CS+ trials (i.e., an auditory stimulus paired with the airpuff-US separated by a silent 900 ms trace interval) and 60 CS- trials (i.e., a different auditory stimulus that was NOT paired with the US). RESULTS: Control subjects showed normal differential responding to the CS+ and CS-, but the RLS patients showed little or no differential responding. A post-test questionnaire provides evidence that symptomatic interference was not responsible for the eyeblink conditioning deficits in the RLS subjects, and further suggests that neurophysiological factors were responsible for these deficits. CONCLUSIONS: Together these results suggest that deficits in eyeblink conditioning are related to the pathophysiology of RLS. The eyeblink conditioning test may also be useful for supporting a clinical diagnosis or treatment strategy for RLS.