Effects of pharmacological dopamine modulation on motivation and motor function in major depression characterized by low-grade inflammation

• Applicants: Dr. Woo Ri Chae; Professor Dr. Christian Otte
• Subject Area: Biological Psychiatry
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 517382576

Major depressive disorder (MDD) is a leading cause of disability worldwide and has many adverse mental and somatic health consequences including cardiometabolic diseases. However, about one third of patients do not achieve full remission from depression even after multiple antidepressant treatments – potentially due to its clinical heterogeneity. Chronic low-grade inflammation is present in more than a quarter of patients with MDD, is associated with treatment resistance, and may represent the underlying substrate linking depression and cardiometabolic diseases. A large body of evidence on depression heterogeneity point to an “immunometabolic” subtype characterized by the clustering of immunometabolic dysregulations with atypical behavioral symptoms related to energy homeostasis. Motivational and motor impairments reflected by symptoms of anhedonia and psychomotor retardation in MDD are closely related to alterations in energy homeostasis, are associated with increased inflammation, and may be a direct consequence of the impact of inflammatory cytokines on mesolimbic dopamine (DA) signaling. The definition of anhedonia currently encompasses both a motivational “wanting” and a hedonic “liking” aspect, while only the “wanting” aspect is shown to be DA-dependent. Psychomotor retardation reflects deficits in motor behavior as well as cognitive performance and is associated with reduced DA function. Patients with MDD show reduced willingness to exert effort for reward (“reward motivation”) and the ability to learn through positive reinforcement (“reward learning”) as well as reduced gait and psychomotor processing speed. Low-grade inflammation is expected to additionally impair those functions. Pharmacological stimulation of DA in healthy individuals increases reward motivation and reward learning, especially in those with low baseline DA levels. Furthermore, DA enhancement has been shown to improve gait and psychomotor processing speed in elderly patients with MDD. In the proposed project, we will examine the effect of DA stimulation on motivation and motor function in patients with MDD and healthy controls and the role of inflammation using a double-blind, randomized, placebo-controlled, cross-over design. If successful, our study would provide crucial evidence that pharmacologic strategies that increase DA may effectively treat inflammation-related symptoms of anhedonia and psychomotor retardation in MDD. Similar pharmacological strategies may have clinical utility in other neuropsychiatric populations with increased inflammation as well.

• DFG Programme: Research Grants