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

Chiara Fabbri,Nick Shrine,Ken B Hanscombe,Louise V Wain,Louise Moles,Saskia P Hagenaars,Robert C Free,Alessandro Serretti,Catherine John,David J Shepherd,Alexander T Williams,Cathryn M Lewis,Martin D Tobin

doi:10.1038/s41380-021-01062-9

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.

Highlights

IntroductionThe study of factors determining the course of Major depressive disorder (MDD) and response to treatments has been a major research area, with the aim of providing better instruments for personalised health care and facilitate recovery, i.e., the return to the premorbid level of health and functioning, a condition associated with a reduced risk of depressive relapse [2]
Major depressive disorder (MDD) is a common psychiatric disorder affecting more than 264 million people worldwide and it is the fourth-leading cause of disability [1].The study of factors determining the course of MDD and response to treatments has been a major research area, with the aim of providing better instruments for personalised health care and facilitate recovery, i.e., the return to the premorbid level of health and functioning, a condition associated with a reduced risk of depressive relapse [2]
MDD polygenic risk score (PRS) was associated with primary care-defined MDD diagnosis (p = 6.05e–6 and p = 1.89e–71 in EXCEED and UK Biobank (UKB), respectively; Supplementary Table 3), with a similar effect size in the two cohorts (z test comparing the effect size in the two samples: z = 1.58, p = 0.11)

Summary

Introduction

The study of factors determining the course of MDD and response to treatments has been a major research area, with the aim of providing better instruments for personalised health care and facilitate recovery, i.e., the return to the premorbid level of health and functioning, a condition associated with a reduced risk of depressive relapse [2]. A substantial proportion of patients with MDD do not reach remission, even after multiple antidepressant treatments [3]. In the United Kingdom, MDD is usually treated in primary care and antidepressant treatment is recommended for moderate to severe depression [5].

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Discussion

Conclusion