Abstract
Major depressive disorder (MDD) is the single largest contributor to global disability and up to 20–30% of patients do not respond to at least two antidepressants (treatment-resistant depression, TRD). This study leveraged imputed gene expression in TRD to perform a drug repurposing analysis. Among those with MDD, we defined TRD as having at least two antidepressant switches according to primary care records in UK Biobank (UKB). We performed a transcriptome-wide association study (TWAS) of TRD (n = 2165) vs healthy controls (n = 11,188) using FUSION and gene expression levels from 21 tissues. We identified compounds with opposite gene expression signatures (ConnectivityMap data) compared to our TWAS results using the Kolmogorov-Smirnov test, Spearman and Pearson correlation. As symptom patterns are routinely assessed in clinical practice and could be used to provide targeted treatments, we identified MDD subtypes associated with TRD in UKB and analysed them using the same pipeline described for TRD. Anxious MDD (n = 14,954) and MDD with weight gain (n = 4697) were associated with TRD. In the TWAS, two genes were significantly dysregulated (TMEM106B and ATP2A1 for anxious and weight gain MDD, respectively). A muscarinic receptor antagonist was identified as top candidate for repurposing in TRD; inhibition of heat shock protein 90 was the main mechanism of action identified for anxious MDD, while modulators of metabolism such as troglitazone showed promising results for MDD with weight gain. This was the first TWAS of TRD and associated MDD subtypes. Our results shed light on possible pharmacological approaches in individuals with difficult-to-treat depression.
Highlights
Major depressive disorder (MDD) is the single largest contributor to global disability and the main contributor to suicide deaths, which number close to 800,000 per year [1]
These depression subtypes were defined using primary care electronic health records (EHR) of diagnostic codes and/or symptoms reported as part of the mental health questionnaire (MHQ), those assessed by the Composite International Diagnostic Interview Short Form (CIDI-SF) [21]; cases of bipolar, psychotic or substance use disorders were excluded and further details are available as Supplementary Methods
We identified three subtypes of MDD that were associated with increased treatment-resistant depression (TRD) risk after Bonferroni correction, namely MDD with weight gain (n total = 5826 and 4697 after quality control), anxious MDD (n total = 18,034 and 14,954 after quality control) and endogenous MDD (n total 1014 and 860 after quality control) (Fig. 1)
Summary
Major depressive disorder (MDD) is the single largest contributor to global disability and the main contributor to suicide deaths, which number close to 800,000 per year [1]. Certain subtypes of MDD have been associated with the risk of TRD or with a chronic course and higher disability, anxious, melancholic and atypical depression [11,12,13]. These findings confirm the hypothesis that clinical manifestations may be connected to specific biological mechanisms and to the risk of TRD. According to this hypothesis, clinical symptoms can be used to predict the risk of TRD, and to guide the prescription of targeted treatments based on patterns that are recognizable at the first clinical assessment
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