Investigators Seek Genetic Clues for Treatment-Resistant Depression

Efforts to find genetic underpinnings for treatment resistance depression (TRD) are gaining momentum.

The success of such investigations could lead to personalized medicine strategies for patients with TRD who, by definition, have failed on two or more treatments with different classes of antidepressants during a current episode of depression.

Investigators hope to achieve a breakthrough for the estimated 2.8 million US patients who suffer from TRD, a subset of major depressive disorder (MDD). As many as 31% of individuals with MDD have TRD, amounting to a cost of nearly $44 billion annually for treatment, according to the Journal of Clinical Psychiatry.

In the search for correlations between the incidence of TRD and an individual's genetics, investigators in Taiwan found that a family history of TRD begets an increased risk of suicide mortality and antidepressant resistance. The study, which was published in JAMA Psychiatry, was considered high-powered because it drew from electronic health records from virtually the entire population of Taiwan, which is enrolled collectively in a national health plan.

“We identified 21,046 patients with TRD, 34,467 first-degree relatives of patients with TRD, and 137,868 control individuals matched for birth year, sex, and kinship. The results demonstrated that first-degree relatives of individuals with TRD exhibited an increased risk of having TRD and significantly increased risk of other psychiatric disorders, such as schizophrenia, bipolar disorder, [attention deficit hyperactivity disorder] ADHD, [autism spectrum disorder] ASD, anxiety, and [obsessive compulsive disorder] OCD.” wrote lead author Chih-Ming Cheng, M.D., and fellow investigators. Cheng is with the Department of Psychiatry, Taipei Veterans General Hospital, in Taipei, Taiwan.

The authors recommended more intensive treatments for depression be given to individuals with a family history of TRD, and these treatments would include add-on pharmacotherapy and non-pharmacotherapy, in addition to antidepressants alone.

Findings from two recent large population studies in the United Kingdom also touched on the smoking gun genetics of TRD.

JooEun Kang, M.D., Ph.D.

The analysis of data from the UK Biobank and EXCEED studies revealed a strong correlation between TRD and attention deficit hyperactivity disorder (OR = 1.09 [1.04-1.14]), versus non-TRD.

“Our results suggested that TRD has partially distinct genetic and clinical demographic characteristics compared with non-TRD that may be helpful to identify patients who should be considered for referral to secondary care,” wrote lead author Chiara Fabbri, Ph.D., of the Social, Genetic and Developmental Psychiatry Center, Institute of Psychiatry, Psychology and Neuroscience, at King’s College London.

A recent study published in the American Journal of Psychiatry looked for clues among electronic health records of 154,433 genotyped patients across 4 biobanks.

The authors estimated the heritability of TRD at between 2.0% and 4.2%.

“Significant genetic overlap was observed with cognition, attention deficit hyperactivity disorder, schizophrenia, alcohol and smoking traits, and body mass index,” wrote lead author JooEun Kang, M.D., Ph.D., a computational biologist and resident physician at Brigham and Women's Hospital in Boston.

“Two genomewide significant loci were identified, both previously implicated in metabolic traits, suggesting shared biology and potential pharmacological implications,” she noted.

Such findings could lead to the development of more targeted therapies and help predict which treatments are most likely to be effective for individual patients.