The researchers from Taipei Veterans General Hospital in Taiwan suggested that combining or altering therapies for depression might be considered instead of monotherapy at an earlier treatment stage for patients reporting that history.
The cohort study published in the Journal of the American Medical Association Psychiatry found that, compared with control individuals matched for birth year, sex, and kinship, first-degree relatives of individuals with TRD had an increased risk of developing TRD and increased suicide mortality.
“Antidepressant responses and the phenotype of treatment-resistant depression (TRD) are believed to have a genetic basis,” the study team explained. “Genetic susceptibility between the TRD phenotype and other psychiatric disorders has also been established in previous genetic studies, but population-based cohort studies have not yet provided evidence to support these outcomes.”
Using a nationwide insurance cohort with extremely high coverage and comprehensive healthcare data, the researchers sought to estimate the TRD susceptibility and the susceptibility between TRD and other psychiatric disorders within families.
The cohort study assessed data from the Taiwan national health insurance database across the entire population of nearly 26 million beneficiaries between January 2003 and December 2017. At the beginning of follow-up, the study included 172,335 participants—88,330 male and 84,005 female with a mean age of 22.9 years. Data analysis was performed from August 2021 to April 2023.
The researchers defined TRD as having experienced at least three distinct antidepressant treatments in the current episode, each with adequate dose and duration, based on the prescribing records. The study team then identified 34,467 first-degree relatives of the 34,467 TRD patients. The comparison group looked at nearly 134,000 first-degree relatives of participants without TRD and matched by birth year, sex, and kinship.
The results indicated that first-degree relatives of the TRD sufferers had lower incomes, more physical comorbidities, higher suicide mortality, and increased risk of developing TRD themselves (absolute risk reduction [aRR], 9.16; 95% CI, 7.21-11.63) and higher risk of other psychiatric disorders than matched control individuals. The disorders for which higher risk was found included:
• Schizophrenia (aRR, 2.36; 95% CI, 2.10-2.65)
• Bipolar disorder (aRR, 3.74; 95% CI, 3.39-4.13)
• Major depressive disorder (MDD; aRR, 3.65; 95% CI, 3.44-3.87)
• Attention-deficit/hyperactivity disorders (aRR, 2.38; 95% CI, 2.20-2.58)
• Autism spectrum disorder (aRR, 2.26; 95% CI, 1.86-2.74)
• Anxiety disorder (aRR, 2.71; 95% CI, 2.59-2.84)
• Obsessive-compulsive disorder (aRR, 3.14; 95% CI, 2.70-3.66).
“To our knowledge, this study is the largest and perhaps first nationwide cohort study to demonstrate TRD phenotype transmission across families and coaggregation with other major psychiatric disorders,” the authors suggested. “Patients with a family history of TRD had an increased risk of suicide mortality and tendency toward antidepressant resistance; therefore, more intensive treatments for depressive symptoms might be considered earlier, rather than antidepressant monotherapy.”
The researchers pointed out that MDD is considered to have a genetic component, adding that “the largest meta-analysis of genome-wide association studies (GWASs) to date targeting MDD indicated that single nucleotide variant–related heritability was estimated at approximately 8%. Similarly, the occurrence of antidepressant responses and treatment-resistant phenotype (or treatment-resistant depression [TRD]) may possess a genetic basis and be transmitted within a family. For example, first-degree relatives of patients with depression responded similarly to amin-oxidase inhibitors or imipramine for depression symptoms.”
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