Objective: To investigate synaptic loss in Parkinson’s Disease depression (PDd) using PET and [¹¹C]UCB-J (a marker for synaptic density) and present the initial blinded findings of the first clinical trial investigating ketamine’s antidepressant effects in PDd.

Background: Depression is the most common psychiatric condition in Parkinson’s disease (PD). We hypothesize that synaptic loss in underpins depression and that ketamine, having  synaptogenic properties, will effectively treat depression in PD.

Method: Ten people with PDd (age: 61 ±  7 years; 4 men) and twelve people with PD but without depression (age: 62 ± 6 years; 5 men) were imaged with [¹¹C]UCB-J PET. The primary outcome measure was binding potential (BP_ND: calculated from SRTM2), calculated using the centrum semiovale as the reference region. Two-tailed t-tests were used to determine between-group differences in BP_ND, and Pearson’s correlation was used for association with depressive symptoms, assessed using the Montgomery-Asberg depression rating scale (MADRS). In a separate ongoing clinical trial, a total of 50 PDd individuals will be randomized to receive six infusions of either ketamine (0.5mg/kg) or placebo, with MADRS score being the primary outcome measure. We present preliminary trial data from 24 people with PDd (62 ±  9), 11 men, 13 women, mean MADRS: 25± 4), treated with either ketamine or placebo.

Results: We observed significantly lower synaptic density in the PDd vs. PD group in the dorsolateral prefrontal cortex (dlPFC), anterior cingulate and hippocampus (p<0.05); and a significant negative correlation between MADRS and [¹¹C]UCB-J in the dlPFC (r= -0.64, p=0.004). Initial blinded results from the clinical trial indicate robust reductions in depression severity following ketamine or placebo (66% responders, 54% in remission), with evidence of sustained effects at 1 month follow-up (50% responders, 38% in remission).

Conclusion: We observed a distinct lower synaptic density in mood-related circuitry in PDd, which could represent a target for synaptogenic treatment interventions such as ketamine. Although blinded, the preliminary findings of our ongoing clinical trial show a robust reduction in depression symptoms suggesting that ketamine is a promising intervention for PDd.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/distinct-pattern-of-synaptic-loss-in-parkinsons-disease-depression-and-initial-findings-from-the-yale-ketamine-pd-ket-pd-trial/