Inflammation as a Pathophysiologic Pathway to Anhedonia: Mechanisms and Therapeutic Implications

Anhedonia, characterized by a lack of motivation, interest, or ability to experience pleasure, is a prominent symptom of depression and other psychiatric disorders and has been associated with poor response to standard therapies. One pathophysiologic pathway receiving increased attention for its potential role in anhedonia is inflammation and its effects on the brain. Exogenous administration of inflammatory stimuli to humans and laboratory animals has reliably been found to affect neurotransmitters and neurocircuits involved in reward processing, including the ventral striatum and ventromedial prefrontal cortex, in association with reduced motivation. Moreover, a rich literature including meta-analyses describes increased inflammation in a significant proportion of patients with depression and other psychiatric illnesses involving anhedonia, as evident by elevated inflammatory cytokines, acute phase proteins, chemokines, and adhesion molecules in both the periphery and central nervous system. This endogenous inflammation may arise from numerous sources including stress, obesity or metabolic dysfunction, genetics, and lifestyle factors, many of which are also risk factors for psychiatric illness. Consistent with laboratory studies involving exogenous administration of peripheral inflammatory stimuli, neuroimaging studies have further confirmed that increased endogenous inflammation in depression is associated with decreased activation of and reduced functional connectivity within reward circuits involving ventral striatum and ventromedial prefrontal cortex in association with anhedonia. Here, we review recent evidence of relationships between inflammation and anhedonia, while highlighting translational and mechanistic work describing the impact of inflammation on synthesis, release, and reuptake of neurotransmitters like dopamine and glutamate that affects circuits to drive motivational deficits. We will then present insight into novel pharmacological strategies that target either inflammation or its downstream effects on the brain and behavior. The meaningful translation of these concepts through appropriately designed trials targeting therapies for psychiatric patients with high inflammation and transdiagnostic symptoms of anhedonia is also discussed.