ArticleNeuropsychopharmacology : official publication of the American College of Neuropsychopharmacology2021
Transcriptome-wide association study of treatment-resistant depression and depression subtypes for drug repurposing.
Article in Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers, 1 of them a synthesis that pooled it.
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Who cites it
25 citing papers in PubMed, 1 synthesis or guideline pooled it, 46 citations in OpenAlex.
- Metabolic activity of CYP2C19 and CYP2D6 on antidepressant response from 13 clinical studies using genotype imputation: a meta-analysis.Translational psychiatry · 2024Pooled it
- Mendelianization: Concentrating Polygenic Signal Into a Single Causal Locus.Genetic epidemiology · 2026Article
- Ethnobotanical Uses and Phytochemical, Pharmacological, Behavioral, and Toxicological Effects ofMolecules (Basel, Switzerland) · 2026Review
- Preliminary clinical and electrophysiological findings of NAc/ALIC deep brain stimulation strategy for treatment-resistant depression.iScience · 2026Article
- The HPA axis and kynurenine pathway: exploring the role of stress and neuroinflammation in treatment-resistant depression.Pharmacological reports : PR · 2026Review
- Comparative polygenic predispositions of treatment-resistant depression in East Asian and European populations.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2026Article
- Analysis of Genomic and Transcriptomic Data Revealed Key Genes and Processes in the Development of Major Depressive Disorder.International journal of molecular sciences · 2025Article
- Systematical Comparison Reveals Distinct Brain Transcriptomic Characteristics in Depression Models Induced by Gut Microbiota Dysbiosis and Chronic Stress.Molecular neurobiology · 2025Article
- Treatment-resistant depression: role of genetic factors in the perspective of clinical stratification and treatment personalisation.Molecular psychiatry · 2025Review
- Increased TMEM106B levels lead to lysosomal dysfunction which affects synaptic signaling and neuronal health.Molecular neurodegeneration · 2025Article
- Genetic Correlates of Treatment-Resistant Depression.JAMA psychiatry · 2025Article
- Leveraging pleiotropy for the improved treatment of psychiatric disorders.Molecular psychiatry · 2025Review
- Multiome-wide Association Studies: Novel Approaches for Understanding Diseases.Genomics, proteomics & bioinformatics · 2024Review
- Meta-analysis of CYP2C19 and CYP2D6 metabolic activity on antidepressant response from 13 clinical studies using genotype imputation.medRxiv : the preprint server for health sciences · 2023Article
- Metabolomic Investigation of Major Depressive Disorder Identifies a Potentially Causal Association With Polyunsaturated Fatty Acids.Biological psychiatry · 2023Article
- Are mGluR2/3 Inhibitors Potential Compounds for Novel Antidepressants?Cellular and molecular neurobiology · 2023Review
- Integrating genetics and transcriptomics to study major depressive disorder: a conceptual framework, bioinformatic approaches, and recent findings.Translational psychiatry · 2023Review
- The Melanocortin System: A Promising Target for the Development of New Antidepressant Drugs.International journal of molecular sciences · 2023Review
- In Silico Analysis of Ferroptosis-Related Genes and Its Implication in Drug Prediction against Fluorosis.International journal of molecular sciences · 2023Article
- Pyroptosis-related genes prognostic model for predicting targeted therapy and immunotherapy response in soft tissue sarcoma.Frontiers in pharmacology · 2023Article
Corrections and comments
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Authors and funding
5 authors at 2 institutions in 2 countries.
Funding
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.