Objective: To assess the psychiatric effects of SYN120 in patients with Parkinson’s disease dementia (PDD).

Background: SYN120 is a dual antagonist of serotonin (5-HT6 and 5-HT2A) receptors. The 5-HT6 receptor modulates numerous neurotransmitters and facilitate learning and memory processes, while the 5-HT2A receptor mediates psychiatric symptoms, including depression, apathy and psychosis.

Methods: A Phase 2a randomized, double-blind, placebo-controlled, parallel-group, 16-week study was conducted at 20 PSG sites in PDD patients taking a cholinesterase inhibitor. Eligible patients (i.e., meeting UKPDSBBC + NINDS/NIMH Working Group Criteria for PDD) were randomized 1:1 to SYN120 100 mg daily or placebo. The key efficacy endpoints assessing cognition are reported elsewhere. Secondary endpoints included the following psychiatric measures: SCOPA-SLEEP, Parkinson’s Disease-Adapted Scale for Assessment of Positive Symptoms (SAPS-PD), and the Neuropsychiatric Inventory (NPI).

Results: Eighty-two PDD patients were randomized and started study treatment, of whom 77 were included in the modified ITT efficacy sample (SYN120=36, placebo=41). Treatment groups were well matched at baseline. From baseline to week 16, the NPI-Apathy/Indifference score significantly improved on SYN120 (-47% on SYN 120 vs. +30% on placebo; p=0.003). Numerical improvements with SYN120 compared to placebo were also noted for NPI-Irritability/Lability (effect size [ES] = 0.23; p=0.08), NPI-Anxiety (ES=0.28; p=0.09), and SCOPA-SLEEP nighttime sleep (ES=0.47; p=0.05) items. Across the full efficacy sample, 40% (SYN120=13, placebo=20) of participants were rated as having apathy/indifference symptoms at baseline. Restricting analysis to those 33 participants, the apparent benefits from SYN120 was greater (-63% on SYN 120 vs. +3% on placebo on NPI-Apathy/Indifference; p<0.001). 

Conclusions: SYN120 treatment in PDD patients was associated with potential improvements in apathy (most prominently), sleep, anxiety, and irritability/lability. While these are secondary outcomes supported by post-hoc analysis, the apparent effect of SYN120 on apathy in PDD patients is consistent with expected effect of inhibiting 5-HT2a receptors and worthy of further investigation.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/impact-of-syn120-a-dual-5-ht6-5-ht2a-antagonist-on-psychiatric-symptoms-in-patients-with-parkinsons-disease-dementia-results-from-a-phase-2a-study/