Antipsychotics and mortality in Parkinsonism.

BACKGROUND: : The use of antipsychotic medications is associated with an increased risk of death in older adults with dementia. The risk of death in patients with preexisting parkinsonism who receive antipsychotic drugs is not known. METHODS: : Using a nested case-control design, we examined the risk of death within 30 days of newly starting antipsychotic medications among people with Parkinsonism aged 70 years and older in Ontario, Canada. Data were obtained from Ontario's healthcare administrative databases. RESULTS: : Among 5,391 individuals with parkinsonism who died during the study period (2002-2008) and a matched comparison group of 25,937 who were still alive, individuals exposed to atypical antipsychotic drugs had a higher risk of death (unadjusted odds ratio [OR] = 2.8, 95% CI: 2.1-3.8, adjusted OR: 2.0, 95% CI: 1.4-2.7). Results were similar for quetiapine use compared with no antipsychotic use (unadjusted OR: 2.5, 95% CI: 1.6-4.0, adjusted OR = 1.8, 95% CI: 1.1-3.0). Typical antipsychotics were associated with an increased odds of death compared with atypical antipsychotics (unadjusted OR = 2.4, 95% CI 1.1-5.2, adjusted OR = 2.4, 95% CI: 1.1-5.7). CONCLUSIONS: : Individuals with parkinsonism who are newly prescribed antipsychotic medications have a higher risk of death within 30 days than those who do not start these medications. Although it is not possible to establish causality, the results suggest an increased risk. It is important to be vigilant for accompanying serious medical conditions that may increase mortality in individuals requiring treatment with antipsychotics and to consider alternative approaches to treating psychosis, agitation, and aggression in this population.

MS patients report excellent compliance with oral prednisone for acute relapses.

BACKGROUND: Multiple Sclerosis is characterized by relapses separated by periods of relative quiescence. High dose intravenous corticosteroid pulses for three to five days is the current standard for the treatment of acute relapses, but recent evidence supports the use of equivalent doses of oral therapy as an alternative. The highest single dose preparation of oral prednisone is a 50mg tablet, requiring patients to take 25 tablets a day. Questions regarding compliance with this oral regimen have been raised. OBJECTIVES: To determine whether MS patients are complaint with 1,250 mg of oral prednisone daily for acute relapses. METHODS: Between November 2008 and December 2009, all patients diagnosed with an acute relapse in the London (Ontario) MS clinic were prospectively identified. If treatment with oral prednisone was initiated, subjects were given a survey to be mailed anonymously to the clinic. RESULTS: Sixty eight MS relapses were diagnosed and treated with corticosteroids in 66 patients of which 60 (58 subjects) were treated with 1,250 mg prednisone. Fifty-three (91.4%) surveys were returned. The reported compliance rate was high at 94.3% (50/53) with only one patient reporting being unable to take all the required pills due to intolerance. Most subjects (43, 86.0%) encountered at least one side effect, most commonly insomnia, mood changes and increased appetite. Two thirds of subjects (69.8%) indicated a preference for oral medication for future relapses. CONCLUSION: High dose (1,250 mg) oral prednisone is an acceptable therapy to MS patients for the treatment of acute relapses with a high rate of compliance.

Cancer incidence in a trial of an antiapoptotic agent for Parkinson's disease.

We performed a placebo-controlled trial of CEP-1347, an inhibitor of neuronal apoptotic cell death, in patients with early Parkinson's disease (PD) to determine whether long-term therapy would slow disability progression. This also provided an opportunity to monitor cancer incidence in a large cohort of PD patients followed prospectively including periods before and after patients developed disability requiring dopaminergic therapy. This was a multicenter study of 806 patients with early PD, without disability requiring dopaminergic therapy, assigned randomly to placebo or one of three doses of CEP-1347. Patients were monitored for an average of 1.8 years (1,467 patient-years) with routine cancer screening evaluations and annual skin examinations by a dermatologist. There was no significant excess of cancers among patients taking CEP-1347 compared with placebo for any cancer type (all P > 0.1). Nonmelanoma skin cancers were the most common cancer type observed. The incidence of melanomas was 20.9 times that predicted in the general population. Most melanomas occurred in patients who had never taken dopaminergic therapy. We found no evidence that CEP-1347 affected cancer incidence within 2 years of follow-up. Melanoma occurrence in our PD patients was greater than predicted compared with the general population and was unrelated to dopaminergic therapy. Clinical surveillance of PD patients for melanoma may be warranted.

A comparison of treatment thresholds in two large Parkinson's disease clinical trial cohorts.

Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism (DATATOP) and Parkinson Research Examination of CEP-1347 Trial (PRECEPT) were two clinical trials of potential disease-modifying agents for Parkinson's disease that used the time to reaching disability sufficient to require dopaminergic therapy as the primary endpoint. To compare the thresholds for initiating dopaminergic treatment for Parkinson's disease between the two studies, conducted fifteen years apart. Baseline and 12-month endpoint characteristics for subjects in the placebo arms of the two studies were compared. DATATOP placebo subjects had slightly higher total Unified Parkinson's Disease Rating Scale (UPDRS) scores at baseline than PRECEPT placebo subjects (26.1 vs. 23.6, P = 0.03). Time to endpoint was not significantly different. Mean total UPDRS scores at endpoint among those subjects reaching endpoint by 12 months were 48.4 in DATATOP and 37.5 in PRECEPT (P < 0.0001). Baseline disease severity and time to disability requiring dopaminergic therapy were similar in the DATATOP and PRECEPT trials. The threshold for starting dopaminergic treatment was lower in PRECEPT than in the earlier DATATOP study. This may relate to changes in philosophies with respect to starting treatment for Parkinson's disease, but the factors underlying this change remain to be elucidated.

Serum urate as a predictor of clinical and radiographic progression in Parkinson disease.

OBJECTIVE: To determine whether concentration of serum urate, a purine metabolite and potent antioxidant that has been linked to a reduced risk of Parkinson disease (PD), predicts prognosis in PD. DESIGN: Prospective study. SETTING: The Parkinson Research Examination of CEP-1347 Trial (PRECEPT) study, which investigated the effects of a potential neuroprotectant on rates of PD progression, was conducted between April 2002 and August 2005 (average follow-up time 21.4 months). PARTICIPANTS: Eight hundred four subjects with early PD enrolled in the PRECEPT study. MAIN OUTCOME MEASURES: The primary study end point was progression to clinical disability sufficient to warrant dopaminergic therapy. Cox proportional hazards models were used to estimate the hazard ratio (HR) of reaching end point according to quintiles of baseline serum urate concentration, adjusting for sex, age, and other potential covariates. Change in striatal uptake of iodine I 123-labeled 2-beta-carbomethoxy-3-beta-(4-iodophenyl)tropane ([(123)I]beta-CIT), a marker for the presynaptic dopamine transporter, was assessed with linear regression for a subset of 399 subjects. RESULTS: The adjusted HR of reaching end point declined with increasing baseline concentrations of urate; subjects in the top quintile reached the end point at only half the rate of subjects in the bottom quintile (HR, 0.51; 95% confidence interval [CI], 0.37-0.72; P for trend < .001). This association was markedly stronger in men (HR, 0.39; 95% CI, 0.26-0.60; P for trend < .001) than in women (HR, 0.77; 95% CI, 0.39-1.50; P for trend = .33). The percentage of loss in striatal [(123)I]beta-CIT uptake also improved with increasing serum urate concentrations (overall P for trend = .002; men, P = .001; women, P = .43). CONCLUSIONS: These findings identify serum urate as the first molecular factor directly linked to the progression of typical PD and suggest that targeting urate or its determinants could be an effective disease-modifying therapy in PD. Trial Registration clinicaltrials.gov Identifier: NCT00040404.