Treatment pathway and mortality-causing mechanism of treatment-resistant depression: A six-year population-based retrospective cohort study

Abstract

<p>Background: Treatment-resistant depression (TRD) necessitates distinct treatment practice relative to treatment-responsive depression, but the treatment pathway from incidence to resistance remains under-reported. As we evaluate the survival consequences of TRD, few studies also investigated its mechanism leading to the worsened survival outcome. <br></p><p>Objectives: We aimed to illustrate the antidepressant treatment pathway from incident depression to TRD, and examine the association between TRD and all-cause mortality and its mediating mechanism. <br></p><p>Methods: This was a population-based retrospective cohort study using territory-wide electronic medical records in the public healthcare setting of Hong Kong. Incident depression patients diagnosed in 2014 were followed up from the first diagnosis to death or December 2019 for TRD identification, which was defined as having taken at least two regimens of antidepressants for a defined duration and a third regimen to confirm previous treatment failures. We matched the TRD cohort 1:4 to the non-TRD cohort on propensity scores estimated by age, sex, history of physical disorders, and history of psychiatric conditions before depression diagnoses. Index dates were the prescription dates of the third regimen for TRD group, whilst the same index dates were assigned for the matched non-TRD control. Study outcomes included a prescription trajectory, all-cause mortality, and the preceding mediators. <br></p><p>Results: 18% of incident patients developed TRD within six years of follow-up. Selective serotonin reuptake inhibitors were the most common as first-line antidepressant therapy and treatment options varied greatly thereafter. Cox model showed that patients with TRD had 1.52-fold (95% CI: 1.14–2.02) greater risk of all-cause mortality, compared with non-TRD patients. Path analysis using structural equation modeling suggested that psychiatric conditions onset after TRD significantly mediated 41.6% of the mortality in patients with TRD (p = 0.003). <br></p><p>Conclusions: Our study demonstrates the hard-to-treat nature of managing TRD from its complex treatment pathway. Identifying patients with TRD and subsequent monitoring for post-TRD psychiatric diagnoses, particularly self-harm, psychosis and schizophrenia, could be a way to improve survivorship.<br></p>