Aiding and Abetting Anhedonia: Impact of Inflammation on the Brain and Pharmacological Implications

Immune targets for therapeutic development in depression: towards precision medicine

“…Although the glutamate signal is predominantly intracellular, these data are compatible with evidence from preclinical models in which pro-inflammatory cytokines and microglial activation can alter glutamate release and transport, resulting in increased extracellular glutamate concentrations 112 . Neuroinflammation thus has been hypothesized to play a role in neurotoxicity via its downstream effects on glutamate metabolism 113 . However, many factors other than inflammation can alter glutamate levels, and MRS in vivo can only resolve the minor peak of glutamate resonance in relatively large (~1 cm 3 ) volumes of tissue.…”

“…Inflammatory cytokines have been shown to exert a direct effect on mesolimbic dopamine transmission that is associated with a reduced willingness to expend effort for reward as well as with a reduced capacity for reward learning 144 . This effect, at least partly, involves a reduction in the availability of dopamine precursors, as neuroimaging and in vivo microdialysis studies in humans and/or non-human primates indicate that inflammatory cytokines such as IFNα reduce dopamine release in the ventral striatum, in association with depressive symptoms including anhedonia and psychomotor slowing 113 . In a non-human primate model, this effect could be reversed by administering the dopamine precursor, levodopa 145 .…”

“…Among the unmet psychiatric needs associated with biomarkers of inflammation 113 , anhedonia itself predicts antidepressant non-response, as observed in the Genome-Based Therapeutic Drugs for Depression (GENDEP) 2 and the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) 178 studies. Beyond anhedonia, other clinical phenotypes have been associated with different aspects of inflammation.…”

“…Ultimately, the development and adoption of immune-targeted therapeutics for depression may disrupt the conventional, syndromic categorization of MDD and focus instead on transdiagnostic symptom dimensions, such as anhedonia, that may be particularly salient in some clinically defined subgroups of patients and more specifically related to tractable immune mechanisms 113 .…”

Progress and challenges in research of the mechanisms of anhedonia in major depressive disorder

“…One study found that provision of exogenous inflammatory stimulation to humans and experimental animals or a state of chronic endogenous inflammation leads to a lack of motivation in subjects, subsequently leading to anhedonia. 38 Imaging studies further revealed that the elevated plasma CRP level in patients with MDD was significantly related to the decreased functional connectivity and elevated glutamate level in the brain’s reward circuit, as well as the symptoms of anhedonia. 39 A recent study found that increased levels of inflammatory factors in the central nervous system were positively correlated with the increased levels of inflammatory factors in plasma (r=0.855), as well as the symptoms of anhedonia in patients with MDD.…”