TARGETING SYNAPTIC LOSS IN PARKINSON’S DISEASE DEPRESSION WITH KETAMINE

Depression is highly prevalent in Parkinson’s disease (PD) and contributes to disability, diminished quality of life, and accelerated disease progression. Serotonergic antidepressants show limited efficacy in PD depression, and little progress has been made in clarifying its underlying mechanisms or developing targeted treatments. We hypothesize that PD -related pathology within mood -related circuitry contributes to depression in PD, and that plasticity -enhancing interventions such as ke tamine may effectively target these mechanisms. Synaptic density ([¹¹C]UCB -J PET) and functional network organization (fMRI) were measured in PD participants with depression (n=10), without depression (n=20), and healthy controls (n=18). In a parallel -design randomized clinical trial (n=51), PD participants with depression received six infusions of ketamine or placebo. A mechanistic imaging subset (13 per arm) completed pre - and post -treatment [¹¹C]UCB-J PET and fMRI. The trial database was locked on November 18, 2025, and unblinding has only just occurred. Full analyses are now underway, and complete clinical and mechanistic results will be presented in May 2026. Synaptic density was significantly reduced in mood-related regions—including the dlPFC, ACC, amygdala, and hippocampus— in PD depression compared with both PD without depression and healthy controls (all p < 0.05). Lower synaptic density in the dlPFC, amygdala, and hippocampus correlated with greater depression severity (all p < 0.05). Functional connectivity was reduced within default mode and fronto -limbic networks in PD depression. We observed a significant difference on the primary outcome —change in MADRS from baseline to post -treatment (p = 0.0063). Participants in the placebo group showed a mean reduction of –10 points, whereas those receiving ketamine demonstrated a –16-point reduction. Ketamine was well tolerated, with no serious adverse events reported. These convergent clinical and mechanistic findings suggest that synaptic and network abnormalities represent a key pathway in PD depression — one that ketamine may be well positioned to target. With unblinding now complete, this trial provides the first randomized, controlled efficacy data for ketamine in a neurodegenerative disease. The results may support ketamine as a mechanism -informed therapeutic option for PD depression and help guide broader strategies to treat neuropsychiatric symptoms in neurodegeneration.

References

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