“Anhedonic depression” as a novel, mechanism-based subtype of depression -- Treatment implications for precision psychiatry

Treatment of depression is hampered by the failure to identify distinct symptom profiles with distinct pathophysiologies that differentially respond to distinct treatments. We posit that "anhedonic depression" is a subtype that responds to specific mechanism-based treatments.

We aim to show that anhedonic depression is characterized by dysregulated reward systems mediated via a hypodopaminergic state and inflammation, and that this depression subtype can be addressed by specific treatment choices targeting these pathways.

We investigate potential upstream mechanisms driving inflammation and changes in dopamine metabolism, including alterations in the gut microbiota, intestinal permeability and cellular stress.

We will use several well-characterized cross-sectional and prospective (interventional) patient cohorts, some of which are already completed and data ready to analyze.

Our Aims are to: (i) identify specific mechanisms underlying anhedonic depression (ii) investigate blood/brain/feces biomarkers of anhedonic depression, iii) test the efficacy on anhedonic depression of three different interventions targeting separate biological pathways hypothesized to cause anhedonic depression (pramipexole - a dopamine-agonist; probiotics - live bacteria with beneficial effects on microbiota & gut barrier function; eicosapentaenoic acid -enriched omega-3 - fatty acids with anti-inflammatory properties).

We believe that our proposal has the potential to advance precision psychiatry.