Genetic and clinical characteristics of treatment-resistant depression using primary care records in two UK cohorts

Abstract Treatment-resistant depression (TRD) is a major contributor to the disability caused by major depressive disorder (MDD). Using primary care electronic health records from UK Biobank and EXCEED studies, we defined MDD and TRD, providing an easily accessible approach to investigate their clinical and genetic characteristics. MDD defined from primary care records was compared with other measures of depression and validated using the MDD polygenic risk score (PRS). Using prescribing records, TRD was defined from at least two switches between antidepressant drugs, each prescribed for at least six weeks. Clinical-demographic characteristics, SNP-heritability and genetic overlap with psychiatric and non-psychiatric traits were compared in TRD and non-TRD MDD cases. In 230,096 and 8,926 UKB and EXCEED participants with primary care data, respectively, the prevalence of MDD was 8.7% and 14.2%, of which 13.2% and 13.5% was TRD (2,430 and 159 cases), respectively. In both cohorts, MDD defined from primary care records was strongly associated with MDD PRS, and in UKB it showed overlap of 72%-88% with other MDD definitions. In UKB, TRD and non-TRD heritability was comparable (h 2 SNP = 0.25 [SE=0.04] and 0.19 [SE=0.02], respectively). TRD was positively associated with the polygenic risk score (PRS) of attention deficit hyperactivity disorder and negatively associated with the PRS of intelligence compared to non-TRD. It was more strongly associated with unfavourable clinical-demographic variables than non-TRD. This study demonstrated that MDD and TRD can be reliably defined using primary care records and provides the first large scale population assessment of the genetic, clinical and demographic characteristics of TRD.