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Objectives The treatment of Parkinson disease (PD) psychosis remains a challenge. Only a few treatments eliciting significant relief of psychotic symptoms have passed the test of randomized controlled trials. Methods Here, we conducted a review of the literature on the effect of antidepressants on PD psychosis. Because there is no randomized controlled trial that assessed the antipsychotic effects of antidepressants in PD, only case reports, case series, and open-label trials were available to review. Because of the scarce literature, statistical analysis could not be performed. Results The following antidepressants alleviated hallucinations in PD: amoxapine, citalopram, clomipramine, escitalopram, mianserin, mirtazapine, and venlafaxine. The antidepressants were generally well tolerated, with the exception of amoxapine, which exacerbated parkinsonism. Conclusions Whereas the conclusions that can be drawn on the efficacy of antidepressants at reducing PD psychosis are limited because of the poor quality of the reported studies, it is encouraging to notice that there are positive anecdotal reports. Further studies are needed to confirm the potential of these drugs and also to determine if a subtype of patients or of psychotic features may be more likely to be improved by antidepressants.

l‐3,4‐Dihydroxyphenylalanine (l‐DOPA) is the most effective treatment for Parkinson's disease (PD), but its use over a long period is marred by motors complications such as dyskinesia. We previously demonstrated that selective metabotropic glutamate 2/3 (mGlu2/3) receptor activation with LY‐354,740 alleviates dyskinesia in the 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP)‐lesioned marmoset and the 6‐hydroxydopamine (6‐OHDA)‐lesioned rat. Here, we sought to determine the role played by selective mGlu2 activation in the anti‐dyskinetic effect of mGlu2/3 stimulation and have investigated the effect of the highly selective mGlu2 positive allosteric modulator LY‐487,379 at alleviating established, and preventing the development of, l‐DOPA‐induced dyskinesia in the 6‐OHDA‐lesioned rat. First, dyskinetic 6‐OHDA‐lesioned rats were administered l‐DOPA in combination with LY‐487,379 (0.1, 1 and 10 mg/kg) or vehicle, and the severity of dyskinesia was determined. Second, 6‐OHDA‐lesioned rats were administered LY‐487,379 (0.1 or 1 mg/kg), started concurrently with l‐DOPA, once daily for 22 days, and dyskinesia severity was evaluated weekly for four consecutive weeks. We also assessed the effect of LY‐487,379 on l‐DOPA anti‐parkinsonian effect. We found that acute challenges of LY‐487,379 0.1 mg/kg in combination with l‐DOPA, significantly diminished dyskinesia severity, by ≈54% (p < .01), when compared to vehicle. Moreover, animals treated with l‐DOPA/LY‐487,379 0.1 and 1 mg/kg during the dyskinesia induction phase exhibited milder dyskinesia, by ≈74% and ≈61%, respectively (both p < .01), when compared to l‐DOPA/vehicle. LY‐487,379 did not impair l‐DOPA anti‐parkinsonian activity. These results suggest that mGlu2 activation may be an effective and promising therapeutic strategy to alleviate the severity and prevent the development of dyskinesia.

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Background Ozanimod is an oral small molecule sphingosine 1-phosphate receptor modulator approved for relapsing forms of multiple sclerosis (RMS) and under development for ulcerative colitis (UC) and Crohn’s disease (CD). Following multiple dosing of ozanimod in healthy subjects, ozanimod and two of the active metabolites CC112273 and CC1084037 represent approximately 6%, 73%, and 15% of circulating total active drug exposure, respectively. Two separate pharmacokinetic (PK) models were developed for the most prominent metabolite CC112273 and ozanimod. CC1084037 was not modeled due to the high correlation between CC112273 and CC1084037 plasma concentrations. Therefore, this analysis aims to characterise the PK of ozanimod and the major metabolite CC112273 in UC and RMS population. Methods Subjects from 11 studies (Phase 1 to Phase 3) in healthy volunteers, RMS, and UC patients were included in this population PK analysis. The analyses included a total of 18901 concentrations from 2890 subjects for CC112273 and 18834 PK concentrations from 2977 subjects for ozanimod. A 2-compartment model was used to describe the concentration-time profiles of both ozanimod and CC112273, separately. The influence of weight, age, sex, race, disease, or smoking status and hepatic function on the PK of ozanimod and CC112273 were explored. The impact of concomitant corticosteroids on CC112273 PK were evaluated post hoc. Results While the overall apparent clearance of ozanimod was 7% lower in RMS patients compared to UC, similar exposures were observed in both populations. The most influential covariate on ozanimod PK was body weight, with a modest 23% increase in apparent clearance for a 102-kg subject relative to a 70-kg subject (Figure 1). The apparent clearance of CC112273 was 16% greater in RMS patients compared to UC patients, resulting in a slightly higher exposure for UC patients. Increasing body weight had a modest reduction in clearance, while smoking had the largest influence on CC112273 PK of approximately 108% increased clearance (Figure 2). Post-hoc results showed no impact of concomitant prednisone or prednisolone on the PK of CC112273. Other factors, including age, race, sex, or hepatic impairment did not impact the PK of ozanimod or CC112273 PK. Conclusion The population PK model of CC112273 indicates that covariates with the largest effect on CC112273 PK parameters were body weight and smoking status. However, no covariate impacted clearance by more than 25%. The PK of ozanimod and CC112273 were not meaningfully impacted by age including in the elderly, body weight, race, sex, hepatic function, or concomitant prednisone or prednisolone. Overall, the PK of ozanimod and CC112273 were comparable in UC and RMS patients.