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 (h2SNP) 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 h2SNP 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.

Lifetime depression and age-related changes in body composition, cardiovascular function, grip strength and lung function: sex-specific analyses in the UK Biobank

“…Lifetime depression was assessed as part of the MHQ using a modified version of the depression module of the Composite International Diagnostic Interview Short Form (CIDI-SF) and defined according to DSM-5 criteria for major depressive disorder ( Supplementary Material 1 ) [ 107 ]. To achieve maximum coverage of the UK Biobank study, we also included in our definition or lifetime depression individuals who had reported during the nurse-led interview at baseline that a doctor had told them that they had depression (field 20002), participants who reported in response to a single-item question on the MHQ that a professional (doctors, nurse or person with specialist training such as psychologist or therapist) had diagnosed them with depression (field 20544), participants with a hospital inpatient record containing an ICD-10 code for depression (F32-F33; Supplementary Material 2 ), participants with a primary care record containing a Read v2 or CTV3 code for depression (see [ 108 ] for diagnostic codes and data extraction procedures), and those who were classified as individuals with probable depression according to Smith et al [ 109 ] based on additional questions that were introduced during the later stages of the baseline assessment ( Supplementary Material 3 ). We excluded individuals with any record of bipolar disorder or psychosis.…”

“…Healthy controls were defined as individuals who did not meet our criteria for lifetime depression and did not have a record of other mental disorders: (i) no “schizophrenia”, “mania / bipolar disorder / manic depression”, “anxiety / panic attacks”, “obsessive compulsive disorder”, “anorexia / bulimia / other eating disorder”, “post-traumatic stress disorder” reported during the nurse-led interview at baseline (field 20002); (ii) no mental disorders reported in response to the single-item question on the MHQ (field 20544); (iii) no self-reported current psychotropic medication use at baseline ( Supplementary Material 4 ) [ 100 ]; (iv) no linked hospital inpatient record that contained any ICD-10 Chapter V code except organic causes or substance use (F20-F99); (v) no primary care record containing a diagnostic code for mental disorders [ 108 ]; (vi) not classified as individual with probable bipolar disorder according to Smith et al [ 109 ]; (vi) no Patient Health Questionnaire-9 (PHQ-9) sum score of ≥5, which was assessed as part of the MHQ.…”

Comorbid Chronic Pain and Depression: Shared Risk Factors and Differential Antidepressant Effectiveness

“…Geneticbased methods can also aid in further examination of our findings by performing discovery genome-wide association studies (GWAS) of comorbid chronic pain and depression to determine individuals' polygenic risk irrespective of whether they have developed chronic pain or not. Furthermore, GWAS will enable: (i) the elucidation of causality between chronic pain and treatment response by using methods such as Mendelian randomization; and (ii) replication in antidepressant treatmentresistant depression cohorts with primary care and genotype data (120).…”

The Validity of Brief Phenotyping in Population Biobanks for Psychiatric Genome-Wide Association Studies on the Biobank Scale

“…For example, the UK Biobank was initiated as a study of later-life general health and morbidity [16]. Psychiatric phenotyping has become feasible as the UK Biobank has matured [17][18][19][20]. Some such phenotyping has been achieved through medical record linkage, which has numerous complexities beyond the scope of this editorial [21,22].…”