Study Reveals Stronger Genetic Link to TRD

by Denis Storey
April 9, 2024 at 12:33 PM UTC

A new study has revealed a connection between a family history of TRD and increased risks of suicide mortality and resistance to treatment.

Clinical relevance: A new study has revealed a connection between a family history of TRD and increased risks of suicide mortality and resistance to antidepressant treatment.

  • Nearly a third of MDD patients face TRD despite multiple medication attempts.
  • Taiwan cohort study over a decade involving 26 million citizens confirmed the genetic connection.
  • The lead author suggests early consideration of intensive treatments beyond antidepressant monotherapy.

Nearly a third of people diagnosed with major depressive disorder (MDD) struggle with treatment-resistant depression (TRD), which persists despite repeated pharmaceutical efforts.

Now, a new nationwide cohort study based out of Taiwan has revealed a surprising connection between a family history of TRD and increased risks of suicide mortality and resistance to antidepressant treatment.

The research, appearing in JAMA Psychiatry, sheds some light on the genetic underpinnings of TRD and how it might influence existing – and future – treatment approaches.

“Patients with a family history of TRD had an increased risk of suicide mortality and tendency toward antidepressant resistance,” the study’s authors wrote, “therefore, more intensive treatments for depressive symptoms might be considered earlier, rather than antidepressant monotherapy.”


The study, which spanned more than a decade – from January 2003 to December 2017 – examined data from Taiwan’s National Health Insurance Research Database. The directory covered more than 26 million citizens. While combing through the health records, the researchers targeted those with TRD and their first-degree relatives, which included more than 172,000 people.

The researchers found that first-degree relatives of TRD patients showed a notably higher risk of developing TRD themselves, compared to control individuals.

Additionally, the research team found that these relatives appeared to also be at an elevated risk for a range of other psychiatric disorders, such as schizophrenia, bipolar disorder, major depressive disorder, and anxiety, among others.

Finally, the paper also revealed a concerning trend of increased suicide mortality among first-degree relatives of individuals with TRD. The researchers noticed that these relatives typically had lower incomes and a higher burden of physical comorbidities compared to their counterparts who lacked a similar family history.

Rethinking Future TRD Treatment

Chih-Ming Cheng, MD, the study’s lead author, stressed the clinical significance of this research, suggesting that medical professionals should consider a family history of TRD as a critical risk factor for resistance to antidepressant treatment and heightened suicide risk.

Cheng added that the psychiatric community should consider a shift toward more intensive treatment approaches for depression, such as combining or altering therapies much sooner, as opposed to simply relying on antidepressant monotherapy.

This study could mark a milestone in understanding the genetic predisposition to TRD and its broader implications for mental health care. By exposing the familial transmission of the TRD phenotype and its coaggregation with other major psychiatric disorders, the research highlights the significance of tailored interventions and preventive measures in addressing mental health challenges within families.

Nevertheless, some suggest that this study ignores other critical factors.

“Like many other studies of MDD and suicide, this study looked at a multitude of contributing parameters.” Jeoffry Gordon, MD, commented on the original study. “Unfortunately, it does not examine or appreciate the contributing, confounding factor of a history of child abuse or neglect (trauma) which has no diagnostic code to abstract. It too runs in families. There are many published studies showing that child abuse or neglect (and specific types at specific ages) contribute to MDD, treatment-resistant depression, and suicide risk.”

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