Gustafsson, T. T., Taipale, H., Lahteenvuo, M., Tanskanen, A., Svirskis, T., Huoponen, S., & Tiihonen, J. (2025). Cause-specific mortality in treatment-resistant major depression: Population-based cohort study. Journal of Affective Disorders, 368, 136–142.

Key Takeaways

A cohort study of 176,942 individuals with major depressive disorder (MDD) found that those with treatment-resistant depression (TRD) had a 17% higher all-cause mortality rate than those with non-TRD major depression.
The increased mortality in the TRD group was mainly due to external causes, such as accidents and suicides, particularly unintentional poisonings.
TRD individuals who met the TRD criteria within eight months of their initial antidepressant treatment trial had an increased risk of suicide.
The study highlights the need for enhanced evaluation, monitoring, and management of self-harm risks in individuals with TRD, especially those not responding to initial treatments.

Rationale

Major depressive disorder (MDD) is a serious mental health condition associated with increased mortality due to various causes.

Treatment-resistant depression (TRD) is a severe form of MDD characterized by the failure of multiple antidepressant treatment trials that have been adequate in terms of duration and dose.

Previous research has shown that TRD is associated with increased mortality, but it is unclear whether this applies to all causes of death or just external causes like suicides.

This large, population-based cohort study aimed to investigate cause-specific mortality associated with TRD in a representative sample of individuals diagnosed with MDD.

The study sought to address the gap in knowledge regarding the specific causes of mortality in TRD and contribute to a better understanding of the long-term prognosis of this condition.

Method

This study utilized a population-based cohort design, leveraging Finnish nationwide registers to identify individuals diagnosed with MDD and track their cause-specific mortality.

Procedure

Researchers identified individuals with a diagnosis of MDD who were treated with antidepressants between 2004 and 2016.

TRD was defined as having more than two adequate antidepressant treatment trials within two years of the initial prescription.

The study followed these individuals for cause-specific mortality, considering factors like sex, age, depression severity, treatment history, and comorbidities.

Sample

The sample included 176,942 individuals with MDD, of whom 11% met the criteria for TRD.

The majority of participants were women (63%), and the median age at the index diagnosis was 40 years.

Measures

The primary outcome was all-cause mortality, categorized into natural and external causes.

External causes included accidents and suicides, while natural causes encompassed cardiovascular diseases, cancer, and other natural causes.

Covariates such as sex, age, depression severity, history of antidepressant use, and the presence of comorbidities were also considered.

Statistical Measures

Cox proportional hazard models were used to analyze the data, with results presented as hazard ratios (HR) and their 95% confidence intervals (CI).

Logistic regression models were employed to examine the associations between covariates and TRD status, with results presented as odds ratios (OR) and their 95% CI.

Results

TRD was associated with a 17% higher all-cause mortality rate compared to non-TRD major depression.

This increase was primarily attributed to a higher mortality rate from external causes, particularly accidents and suicides.

No significant difference was found in mortality due to natural causes between the TRD and non-TRD groups.

The study also found that deaths due to drug overdoses were more common in the TRD group, while alcohol poisonings were more common in the non-TRD group.

Insight

This study provides valuable insights into the cause-specific mortality associated with TRD.

The key finding that TRD is associated with increased mortality due to external causes, particularly suicides and unintentional poisonings, underscores the importance of early identification and aggressive management of TRD.

This study extends previous research by demonstrating that the increased risk of suicide in TRD is particularly pronounced in individuals who meet the TRD criteria within a relatively short period after their initial treatment.

The findings suggest that rapid failure of sequential treatment trials should be considered a red flag, prompting enhanced monitoring and intervention to prevent self-harm.

Future research could explore the specific factors that contribute to the increased risk of external causes of mortality in TRD, such as the role of specific symptoms, comorbidities, and treatment approaches.

Clinical Implications

The findings of this study have significant implications for clinical practice and future research.

Clinicians should be vigilant in monitoring individuals with TRD for signs of suicidal ideation and self-harm behaviors, especially in those who experience rapid treatment failure.

Early intervention and aggressive management of TRD are crucial to mitigate the risk of mortality.

Future research should focus on identifying predictors of treatment resistance and developing more effective interventions for TRD, with the ultimate goal of improving the prognosis and reducing mortality in this high-risk population.

Strengths

The study has several strengths, including its large sample size, population-based design, and use of comprehensive nationwide registers, which enhance the generalizability of the findings.
The use of Cox proportional hazard models allows for the examination of time-to-event data, providing a more nuanced understanding of the relationship between TRD and mortality.
Additionally, the study’s detailed analysis of cause-specific mortality offers valuable insights into the specific causes of death associated with TRD.

Limitations

The definition of TRD, based on the number of treatment trials, may not perfectly capture the complexity of treatment resistance.
The study relied on routine data, which may lack detailed information on treatment adequacy and individual symptom profiles.
Additionally, the study was conducted in Finland, and the generalizability of the findings to other populations may be limited.

Reference