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). Primary care electronic health records provide an easily accessible approach to investigate TRD clinical and genetic characteristics. MDD defined from primary care records in UK Biobank (UKB) and EXCEED studies was compared with other measures of depression and tested for association with MDD polygenic risk score (PRS). Using prescribing records, TRD was defined from at least two switches between antidepressant drugs, each prescribed for at least 6 weeks. Clinical-demographic characteristics, SNP-based heritability (h²_SNP) and genetic overlap with psychiatric and non-psychiatric traits were compared in TRD and non-TRD MDD cases. In 230,096 and 8926 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, respectively. In both cohorts, MDD defined from primary care records was strongly associated with MDD PRS, and in UKB it showed overlap of 71-88% with other MDD definitions. In UKB, TRD vs healthy controls and non-TRD vs healthy controls h²_SNP was comparable (0.25 [SE = 0.04] and 0.19 [SE = 0.02], respectively). TRD vs non-TRD was positively associated with the PRS of attention deficit hyperactivity disorder, with lower socio-economic status, obesity, higher neuroticism and other unfavourable clinical characteristics. 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.

Fig. 1. Definition of MDD and TRD in both cohorts.

Selection of individuals with depression and treatment-resistant depression (TRD) in EXCEED and UKB primary care data (A) and other measures of depression used as comparison in UKB (B). MDD major depressive disorder, SU substance use, AD antidepressant.

Fig. 2. PRS of psychiatric disorders and risk of depression in UKB.

Association between polygenic risk scores (PRS) for psychiatric disorders and depression phenotypes in UKB, showing odds ratios (OR) and 95% confidence intervals (PRS were standardized). SR-depression self-reported depression diagnosed by a professional, CIDI-SF Composite International Diagnostic Interview Short Form, GP general practitioner, BP bipolar disorder, MDD major depressive disorder, SCZ schizophrenia.

Fig. 3. Overlap among different measures of depression in UKB.

Percentage of UK Biobank participants having at least one, at least two or zero depression codes in primary care data who endorsed other measures of depression (ICD depression based on hospital records, Smith depression, self-reported (SR) depression diagnosed by a professional, depression according to the Composite International Diagnostic Interview Short Form (CIDI-SF) and help-seeking depression based on having seen a general practitioner (GP) or psychiatrist for depression-anxiety, see Supplementary Methods). The number of overlapping subjects is reported on top of each bar. See Supplementary Table 4 for further details on these comparisons.

Fig. 4. Psychiatric comorbidities in TRD and non-TRD in UKB.

Psychiatric comorbidities in patients with treatment-resistant depression (TRD) and without TRD according to primary care records in UK Biobank. OCD = obsessive-compulsive disorder.

Fig. 5. GCTB SNP heritability estimates in UKB.

GCTB estimates of SNP-based heritability (SNP-h2), negative selection (S), and polygenicity (proportion of variants with non-zero effects, Pi), for the stringent classification of TRD and non-TRD (≥two diagnostic codes for depression), and a less stringent classification including cases with at least one diagnostic code for depression in UK Biobank.