To Örebro University

BACKGROUND: Psychotic major depressive disorder (MDD), a subtype of MDD characterised by psychotic symptoms that occur exclusively during mood episode, is clinically significant yet underexplored genetically due to its rarity. This study comprehensively examines the genetic basis of psychotic MDD and elucidates its position within the mood-psychotic spectrum.

METHODS: This population-based cohort study used Swedish and Danish registry data for over 5.1 M individuals born between 1958 and 1993/1996. Specialist-diagnosed psychotic MDD was defined using ICD-10 sub-codes of MDD, F32.2/F32.3. We estimated familial aggregation/coaggregation using generalised estimating equations, heritability and genetic correlations using structural equation modelling. We also analysed ∼30,000 genotyped MDD cases from the UK Biobank and a Swedish cohort to explore which polygenic risk score (PRS) may predispose individuals to psychotic MDD.

FINDINGS: With over 10,000 psychotic MDD identified from the two nationwide patient registers, this study highlights the familial aggregation of psychotic MDD, co-aggregation with mood and psychotic disorders, and its stronger genetic correlation with schizophrenia compared to non-psychotic MDD. The familial risks increased with closer biological relatedness, suggesting genetic influence. Pedigree-heritability of psychotic MDD was 30.17% (95% CI 23.53-36.80%). While the genetic correlation between psychotic and non-psychotic MDD was high (0.82, 95% CI 0.73-0.92), the psychotic subgroup showed a higher genetic correlation with schizophrenia than non-psychotic MDD (0.67 vs 0.46, p-value 7.55∗10-4). Within 30,000 genotyped MDD cases, individuals with psychotic MDD had higher mean PRS for schizophrenia and BD but a lower MDD PRS than non-psychotic MDD. PRS for BD type-I was associated with increased odds of psychotic MDD, while BD type-II PRS showed no significant association with psychotic MDD.

INTERPRETATION: This study provides evidence for the genetic basis of psychotic MDD, underscoring its unique position bridging the spectrum of mood and psychotic disorders. These findings advance our understanding of the aetiology of psychotic MDD and contribute to the limited body of evidence on this phenotype by utilising large-scale population-based data.