Prospective memory deficit associated with major depressive disorder: Causality, clinical impact, and potential molecular mechanisms

Prospective memory (PM) impairment is frequently observed in major depressive disorder (MDD), yet its causal relationship, clinical impact, and molecular mechanisms remain unclear. To clarify causality between MDD and PM deficits, bidirectional mendelian randomization (MR) was conducted (MDD: n = 1639572; PM deficits: n = 152605). Genetic liability to MDD significantly increased the risk of PM deficits (OR = 1.045, P < 1 × 10 −4 ), with a lack of evidence supporting a reverse causal effect. To assess clinical impact, we recruited 222 patients with MDD and 200 healthy controls (HCs). Patients with MDD showed significantly poorer PM performance across nearly all MIST subscales ( P Bonferroni < 0.05). Among 134 patients with follow-up, linear mixed-effects models revealed slower HAMD reduction in patients with PM deficits ( z = 2.287, P = 0.022). PM performance showed no significant change after treatment ( P = 0.117). To investigate potential mechanisms and therapeutics, shared targets for MDD and PM were identified through network pharmacology and summary-data-based MR, revealing Rap1 signaling as the top enriched pathway with eight core targets. Molecular docking showed relatively weak predicted affinities (mean > −7.5 kcal/mol) of commonly used antidepressants to these targets. Virtual screening of psychiatric compounds identified Hypericin, with strong affinity to the core targets (mean −9.06 kcal/mol). In conclusion, MDD may increase the risk of PM deficits, which are associated with poorer treatment response and show limited improvement following current antidepressant treatments. Rap1-related mechanisms may be involved, and Hypericin may be considered a compound for further investigation.