DEVELOPING TREATMENTS FOR THE NON-MOTOR SYMPTOMS OF PARKINSON'S DISEASE

The non-motor mood symptoms associated with Parkinson’s disease (PD) are associated with increased disability and accelerated disease progression. But standard serotonergic-based antidepressants have limited efficacy for PD depression, and there has been little progress in understanding its pathology or evaluation of new treatments. With an increased understanding of the PD-related pathology in mood-related circuitry there is a growing interest in developing plasticity-enhancing interventions such as ketamine and 5HT2A targeting drugs as treatments for the mood and other non-motor symptoms associated with PD. In this panel Shlomi Raz will present data on a Non-hallucinogenic serotonin 5HT2A/2C receptor agonist AB-300 that was assessed in the tetrabenazine (TBZ) progressiveratio rodent model, a validated paradigm for probing motivational dysfunction that parallels non-motor symptoms of apathy and depression in Parkinson’s disease. TBZ reliably induced a marked reduction in motivated responding, reflected by fewer lever presses and rewards earned. AB-300 significantly reversed these deficits, with the strongest and most consistent improvements seen at 5 mg/kg and particularly within the low-motivation subgroup—an analogue for patients with prominent apathy. Bupropion served as a positive control and confirmed assay sensitivity. These results show that AB-300 restores goal-directed behavior in an established translational model of apathy, supporting its advancement into the Phase Ib PD trial where non-motor symptoms, including apathy and motivational loss, are key readouts alongside motor outcomes. Psilocybin shows early promise for treating mood dysfunction associated with depression, but its potential benefit in PD is unclear, as safety concerns have excluded people with neurodegenerative disease from previous trials. Ellen Bradley will present findings on psilocybin’s effects from the first open-label pilot study in PD (NCT04932434). 12 participants with mild to moderate stage PD plus depression and/or anxiety (mean age 63.2 ± 8.2 years, 5 women) received psilocybin (one 10 mg followed by one 25 mg dose) paired with a course of psychotherapy. Tolerability, preliminary efficacy, and changes in emotional and cognitive experience were examined using natural language processing of psychotherapy session content. The design of a recently initiated randomized placebo controlled trial funded by the Michael J Fox Foundation (MJFF) exploring the efficacy of psilocybin in PD will also be discussed. Measures of synaptic plasticity has been demonstrated to be lower in individuals with PD. Sophie Holmes will present the results of a study demonstrating this using PET imaging and then present newly collected data from a second recently completed MJFF funded study of ketamine treatment of PD. The results of of the 50 person randomized controlled trial will be presented for the first time in a national meeting. The treatment with ketamine demonstrated both statistical and clinically meaningful benefits over placebo on the primary endpoint of week-8 MADRS. Secondary outcome measures also largely favored ketamine treatment over placebo. Overall, the treatment was relatively well tolerated, further suggesting a potential role for ketamine in the treatment of the Parkinson’s associated mood symptoms. Lastly, Daniel Weintraub will serve as the discussant helping to provide perspective on the relevant neurobiology, unmet need, and meaningfulness of the data presented.

Learning Objective 1: To familiarize the audience with the prominent non-motor symptoms of Parkinson’s disease and the novel treatment approaches being tested for the treatment of non-motor symptoms of Parkinson’s disease.

Learning Objective 2: To outline the preclinical and clinical emerging data suggesting possible novel treatment effects of the non-motor symptoms associated with Parkinson’s disease.

References

Shi Y, Dobkin R, Weintraub D, Cho HR, Caspell-Garcia C, Bock M, Brown E, Aarsland D, Dahodwala N.Association of Baseline Depression and Anxiety with Longitudinal Health Outcomes in Parkinson’s Disease. Mov Disord Clin Pract. 2024 Sep;11(9):1103-1112 Bradley ER, Sakai K, Fernandes-Osterhold G, Szigeti B, Ludwig C, Ostrem JL, Tanner CM, Bock MA, Llerena K, Finley PR, O’Donovan A, Zuzuarregui JRP, Busby Z, McKernan A, Penn AD, Wang ACC, Rosen RC, Woolley JD.Psilocybin therapy for mood dysfunction in Parkinson’s disease: an open-label pilot trial. Neuropsychopharmacology. 2025 Jul;50(8):1200-1209