For millions of people, the journey to find an antidepressant that works is a frustrating trial-and-error process. A new study looked at the genetics of over 135,000 people who were prescribed these medications to understand why some people don't respond. The researchers found two new genetic locations associated with not responding to common antidepressants like SSRIs and SNRIs. They also found that the genetics of non-response were linked to other psychiatric traits and, in a negative way, to cognitive traits and feelings of well-being. The study used this genetic information to suggest some existing drugs that might be worth testing further for people who don't respond to first-line treatments. It's crucial to remember this is a genetic association study—it shows a link, not a cause. The findings are early and need to be confirmed. The drugs they highlighted are just candidates for future research, not proven solutions. This work helps map the complex biology behind treatment resistance, but it doesn't change how doctors prescribe antidepressants today.
Meta-analysis identifies two genomic loci associated with antidepressant non-response in 135,471 individualsWhy do antidepressants fail for some people? New genetic clues emerge
AI-generated summary of the cited source, checked by automated accuracy review. How we work
Key Takeaway
Note: Genetic associations with antidepressant non-response require replication and validation before clinical application.
This genome-wide association meta-analysis examined genetic factors in antidepressant non-response using data from 135,471 individuals prescribed antidepressants, including 25,255 non-responders and 110,216 responders. The study focused on identifying genomic loci associated with non-response to antidepressant treatment, primarily SSRIs and SNRIs, compared to treatment responders.
The analysis identified two novel loci: rs1106260 associated with non-response to SSRIs, and rs60847828 associated with non-response to both SSRIs and SNRIs. The study also found significant polygenic prediction in independent samples and reported genetic correlations, with positive associations between non-response and most psychiatric traits, and negative associations with cognitive traits and subjective well-being. Exact effect sizes, p-values, and confidence intervals for these findings were not reported.
Safety and tolerability data were not reported in this genetic analysis. The authors note this is an association study that does not establish causation, and all findings require replication and validation. The practice relevance is limited to suggesting that meta-analyses using real-world measures can improve discovery of variants associated with non-response, and that shortlisted drugs based on bioinformatics analyses warrant further investigation for potential to reduce depressive symptoms in non-responders.
What this means for you:
Early genetic clues found for why antidepressants fail, but it's not a test yet. More on Major Depressive Disorder
No significant association between BDNF genotypes and remission in major depressive disorder patients treated with antidepressants
Genetic markers do not predict antidepressant success in major depression
This meta-analysis review examined 599 Caucasian patients with a major depressive episode treated with SSRIs, SNRIs, or TCAs. The analysis f…
A large review found that specific genetic markers do not predict who will recover from depression when taking common antidepressant medicat…
Heterogeneous definitions and clinical inconsistencies currently hinder the accurate identification of treatment-resistant depression
New ways to define treatment resistant depression are emerging
This narrative review examines the phenotypic definition of treatment-resistant depression (TRD) and its associated biological correlates. T…
Doctors struggle to treat some types of depression because the current definition is inconsistent. New research looks at how biology and beh…
Bidirectional link between cannabis use disorder and major depressive disorder affects over 3 million individuals
Depression and cannabis use disorder often go hand in hand for millions of people
This meta-analysis examines the bidirectional association between cannabis use disorder and major depressive disorder across psychiatric and…
A massive analysis of over 3 million people shows depression and cannabis use disorder are closely linked, with higher rates of each conditi…
Public health interventions improve mental health in young people in LMICs: systematic review
Public health interventions improve mental health in young people in LMICs
A systematic review of 30 studies found that public health interventions, including digital health, improved mental health outcomes in young…
A review of 30 studies finds that public health interventions, including digital tools, can improve mental health in young people in low-inc…
View Original Abstract ↓
Antidepressants exhibit a considerable variation in efficacy, and increasing evidence suggests that individual genetics contribute to antidepressant treatment response. Here, we combined data on antidepressant non-response measured using rating scales for depressive symptoms, questionnaires of treatment effect, and data from electronic health records, to increase statistical power to detect genomic loci associated with non-response to antidepressants in a total sample of 135,471 individuals prescribed antidepressants (25,255 non-responders and 110,216 responders). We performed genome-wide association meta-analyses, genetic correlation analyses, leave-one-out polygenic prediction, and bioinformatics analyses for genetically informed drug prioritization. We identified one novel locus (rs1106260) associated with non-response to selective serotonin reuptake inhibitors (SSRIs), and one novel locus (rs60847828) associated with non-response to SSRIs and serotonin-norepinephrine reuptake inhibitors (SNRIs) and showed significant polygenic prediction in independent samples. Genetic correlation analyses show positive associations between non-response to antidepressants and most psychiatric traits, and negative associations with cognitive traits and subjective well-being. In addition, we investigated drugs that target proteins likely involved in mechanisms underlying antidepressant non-response, and shortlisted drugs that warrant further replication and validation of their potential to reduce depressive symptoms in individuals who do not respond to first-line antidepressant medications. These results suggest that meta-analyses of GWAS utilizing real-world measures of treatment outcomes can increase sample sizes to improve the discovery of variants associated with non-response to antidepressants.
Genotype-Guided SSRI Prescribing Shows No Short-Term Benefit but Higher Remission at 6 Months
Genetic Testing Helps Some Depression Patients Feel Better Long Term
Related in Genetics & Precision Medicine
Polygenic risk scores validate IL-1 signaling role in childhood asthma, supporting IL1R1 antagonist repurposing
New data links specific proteins to asthma risk in children
This meta-analysis of two family-based cohorts found that externally derived asthma polygenic risk scores (GBMI-PRS) are valid in children a…
Researchers found that certain genetic markers and protein levels can help identify the underlying causes of childhood asthma.
19 genome-wide significant loci identify genetic architecture and high correlations with other substance use disorders
Genes linked to stimulant addiction found in largest study yet
This meta-analysis of 709,369 individuals identifies 19 genome-wide significant loci associated with Stimulant Use Disorder. The study also …
Scientists found 19 genetic regions tied to stimulant addiction, including one linked to obesity. The study of over 700,000 people also show…
Pfkelch13 mutations occur in 6% of Plasmodium falciparum isolates across various African regions
New Data Shows Regional Differences in Malaria Drug Resistance
This meta-analysis of observational cohort studies evaluates the prevalence of pfkelch13 mutations in Plasmodium falciparum isolates from pa…
New research reveals varying levels of a specific genetic mutation that may link to reduced effectiveness of malaria treatments across Afric…
Long-read sequencing yields 4.5% more diagnoses in unresolved rare disease cases
New genetic test solves mysteries for hundreds of patients with rare disorders
A systematic review of 9 studies found that long-read whole genome sequencing (lrWGS) provided a definitive diagnosis in 4.5% of 646 previou…
A review of 646 cases shows long-read whole genome sequencing finds answers where standard tests failed, identifying structural changes and …
From Other Specialties
Meningeal Immune System Offers New Target for Glioblastoma Immunotherapy
New approach targets the immune system to treat brain tumors
This systematic review explores how targeting the meningeal immune system, including dural lymphatics and rBAMs, could overcome current barr…
A new strategy focuses on the area where brain tumors meet the body's defenses to improve how immunotherapy works for glioblastoma.
A 6 dimension and 42 item system provides early risk assessment for high-risk diabetic feet
Experts Develop New Risk Assessment System for Diabetic Feet
This expert consultation and guideline describes the development of an early risk assessment system for high-risk diabetic feet. The consens…
A new assessment system identifies risk factors like nerve damage and circulation to help manage and prevent complications in patients with …
Rapid advancements in imaging and blood-based biomarkers are transforming the diagnosis and management of ADRD
New guidelines help doctors tell delirium from dementia
This clinical guideline provides a narrative review on the evolving diagnostic and treatment landscape for Alzheimer's disease and related d…
Delirium is acute and fluctuating; dementia is chronic. New guidelines help doctors tell them apart.
ACTH and vigabatrin achieved full seizure control in a patient with Ververi-Brady syndrome
ACTH and Vigabatrin Show Promise for Rare Epilepsy Syndrome
This case report describes a 5-month-old male infant with Ververi-Brady syndrome and infantile epileptic spasms syndrome. The patient achiev…
A new gene variant linked to Ververi-Brady syndrome showed positive results when treated with a combination of ACTH and vigabatrin.