In a recent publication in the Journal of the American Medical Association, Johan Lundberg, MD, PhD, of the Centre for Psychiatry Research at Karolinska Institute’s Department of Clinical Neuroscience, and colleagues sought to assess the burden of TRD in a large, population-wide cohort in an area with universal healthcare by incorporating data from both healthcare categories (psychiatric and nonpsychiatric) and, further, to create a prognostic model for clinical use.

This population-based observational cohort study involved data from the Stockholm MDD Cohort for MDD episodes between 2010 and 2017 that justified predefined criteria for TRD (three or more consecutive antidepressant treatments). The data analysis was conducted from August 2020 to May 2022.

In this cohort, researchers identified 158,169 unipolar MDD episodes among 145,577 individuals between January 2012 and December 2017, which included 64.7% women with an average age of 42 years. From this initial cohort, 12,793 episodes (11%) were deemed eligible for consideration as TRD.

The primary outcomes were psychiatric and nonpsychiatric comorbid conditions, antidepressant treatments, healthcare-resource utilization, lost workdays, all-cause mortality, intentional self-harm, and TRD in the prognostic model.

The results revealed that the average time from the initiation of an MDD episode to TRD was 552 days. Additionally, of all the treatment steps, selective serotonin reuptake inhibitors were the most common class of antidepressant treatment. At some point prior to initiation of the third pharmacologic antidepressant treatment, 5,907 patients (46.2%) received psychotherapy.

Other data indicated that TRD episodes had more inpatient bed-days when compared with matched non-TRD episodes (average, 3.9 days; 95% CI, 3.6-4.1 vs. 1.3 days; 95% CI, 1.2-1.4) and more lost workdays (average, 132.3 days; 95% CI, 129.5-135.1 vs. 58.7 days; 95% CI, 56.8-60.6) 12 months after the index date.

Among TRD episodes, more commonly occurring comorbid conditions in TRD episodes included anxiety, stress, sleep disorder, and substance-use disorder. Intentional self-harm occurred four times more commonly in TRD episodes.

The all-cause mortality rate for patients with MDD with TRD episodes was reported as 10.7/1,000 person-years at risk, compared with 8.7/1,000 person-years at risk for patients with MDD without TRD episodes (hazard ratio, 1.23; 95% CI, 1.07-1.41).

The average time from the beginning of the first antidepressant treatment to the initiation of the second and from the beginning of the second antidepressant treatment to the start of the third was 165 and 197 days, respectively.

According to the researchers, the severity of MDD defined utilizing the self-rating Montgomery-Åsberg Depression Rating Scale at the time of MDD diagnosis was observed to be the most significant prognostic factor for TRD (C index = .69).

The authors indicated that their findings demonstrate TRD was correlated with a more significant disease burden with regard to utilization of healthcare resources, absences from work, intentional self-harm, and mortality and that these results are not explained by MDD duration. The authors also noted that the long duration from MDD diagnosis until TRD indicates that clinicians could enhance their alignment to recommendations of judicious follow-up of patient symptoms.

The authors concluded, “Our finding that the risk of subsequent TRD can be assessed by severity could help clinicians identify at first MDD diagnosis the patients in need of closer follow-up.”

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