Examining ketamine effects on depression, neuroplasticity, and inflammation in Veterans with Parkinson's disease

Veterans Affairs Med Ctr San Francisco, San Francisco CA

Investigators

Abstract

Parkinson’s disease (PD) is a complex, disabling neuropsychiatric disorder with growing impact on Veterans in terms of prevalence and disability. Depression in PD (dPD) is common, a stronger predictor of quality of life than the hallmark motor symptoms of the illness, and associated with accelerated decline and elevated risk of suicide. Unfortunately, current treatments have limited efficacy for dPD. This may stem from the widespread brain degeneration in PD that likely contributes to the etiology and maintenance of depressive symptoms. Thus, improving outcomes for the growing Veteran PD population requires developing new treatments that address dPD’s complex pathophysiology. Evidence suggests that impaired neuroplasticity and elevated inflammatory activity may be high-yield targets for novel antidepressants. Impairment in long-term potentiation (LTP), a basic mechanism of neuroplasticity that depends on glutamatergic signaling at the N-methyl-D- Aspartate receptor (NMDAR), has been specifically implicated in depression. Abnormal glutamatergic signaling is a significant contributor to disease progression in PD: overactive glutamatergic transmission and excessive NMDAR activation impair LTP in animal models and diminished “LTP-like” plasticity is found in PD patients. Dysregulated inflammation, known to play a central role in PD pathophysiology, is linked to these neuroplasticity deficits. The immune system is hypothesized to drive PD progression through “immunoexcitotoxicity”, wherein inflammation up-regulates glutamate levels and the NMDAR; this glutamatergic overstimulation impairs synaptic plasticity and induces cell death. Ketamine, an NMDAR antagonist and robust antidepressant, may offer a promising new approach to treating dPD. Ketamine not only reduces depressive symptoms, but also has neuroplasticity-enhancing and anti-inflammatory effects that have been observed in both preclinical and clinical studies. Recent preclinical work also suggests that ketamine can improve mood and offer neuroprotection in PD. Thus, ketamine may have the potential to reduce depression in PD while also targeting key components of PD pathophysiology, thereby having disease-modifying effects. To date, no published studies have examined the effects of ketamine in humans with PD. To address this gap, we propose a randomized, placebo-controlled study evaluating the effects of a single infusion of ketamine versus placebo (remimazolam) in Veterans with dPD (N=80). We hypothesize that ketamine will have a strong safety and tolerability profile and improve depressive symptoms within 24 hours (Aim 1). Further, its antidepressant effects will be associated with modulation of both impaired neuroplasticity (Aim 2) and elevated inflammatory activity (Aim 3). To test these hypotheses, we will use clinical assessments (of adverse events, Veteran- reported tolerability, and depression), non-invasive brain stimulation techniques to quantify changes in LTP-like neuroplasticity, and blood-based cytokine measurement to quantify changes in systemic inflammation. The proposed study will provide clinical efficacy data and elucidate ketamine’s mechanisms of action in PD using accessible, neuroscience-informed markers of neuroplasticity and inflammation. Findings will lay the groundwork for a multi-site Merit-funded trial. The study is well-aligned with VA priorities to promote cross- disciplinary efforts by psychiatry and neurology to improve outcomes for Veterans with PD. The training plan will allow the candidate to develop new skills in: (1) design and conduct of clinical pharmacologic trials focused on the Veteran PD population; (2) using transcranial magnetic stimulation (TMS) to efficiently assess neuroplasticity; and (3) using peripheral cytokine assays to assess systemic inflammatory activity. Training will also expand the candidate’s knowledge of high-yield scientific areas including PD pathophysiology, the role of impaired neuroplasticity in neuropsychiatric illness, and psychoneuroimmunology. This CDA-2 program will allow the candidate to launch a career as a VA physician-scientist focused on accelerating the development of new pharmacologic treatments for serious neuropsychiatric disorders through mechanistic clinical trials.