Mortality-causing mechanisms and healthcare resource utilisation of treatment-resistant depression: A six-year population-based cohort study

Abstract

Background: Few studies investigated the mechanisms of treatment-resistant depression (TRD) leading to the worsened survival outcome, and economic evidence was mostly restricted to short follow-ups. We aimed to examine the association and potential mediators between TRD and all-cause mortality, and estimate a longer-term associated health resource utilisation pattern.

Methods: This was a population-based cohort study using territory-wide electronic medical records in Hong Kong. Incident depression patients diagnosed in 2014 were followed up from the first diagnosis to death or December 2019 for TRD identification. 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.

Findings: 18% of incident patients developed TRD within six years of follow-up. 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 suggested that post-TRD psychiatric conditions significantly mediated 41⋅6% of mortality in patients with TRD (p=0.003). TRD was associated with 1⋅8-fold (95%CI: 1⋅63-2⋅00) higher healthcare costs compared to non-TRD patients over six years in negative binomial regression, with higher costs for both psychiatric and non-psychiatric services utilisation in all settings.

Interpretation: Identifying patients with TRD and subsequent monitoring for post-TRD psychiatric diagnoses could be a way to reduce premature mortality. Multidisciplinary care involving both psychiatric and general medical professionals is also warranted to relieve the multifaceted impacts on healthcare resources and overall cost.

Funding: Unconditional educational grant from Janssen.

Keywords: Death-causing mechanism; Health Economics; Mediation analysis; Population-based electronic medical records; Restrospective cohort study; Treatment-resistant depression.

Figure 1

Schematic presentation of study design for survival and mediation analyses *For TRD patients, index dates were the dates on which they received the third prescription before the study end date. Same index dates were assigned to the matched non-TRD patients in the same matching stratum, who did not have a date of the third prescription by definition. The matching was performed using propensity score based on age, gender, history of physical comorbidities, psychiatric and suicidal attempts as of 2014. The follow-up of both groups started on the index dates until death or the end of study. Index dates, censoring and covariates adjustment used were the same throughout survival, mediation and healthcare resource utilisation analyses.

Figure 2

Flowchart of incident cohort and 1:4 matched cohorts identification ^a Patients were excluded if their dates of death were earlier than their first dates in 2014 with depression-related diagnosis. ^b Prescription records of antidepressant between 2014 and 2019 were extracted to define patients’ TRD status. Antidepressants treatment regimens could be monotherapy or combination treatments with antipsychotics or mood stabilisers. Abbreviation: MDD – Major depressive disorder; TRD – Treatment-resistant depression.

Figure 3

Treatment trajectory and resistance evolvement among incident patients with depression (N= 5,834)^{a a} 5,834 out of the 8,223 patients in the 2014 incident depression cohort were eligible for inclusion in this diagram as they had antidepressant monotherapy of adequate duration as their first treatment after incident diagnosis. The size of the colored nodes represents the number of patients taking different treatment regimens at each treatment step while the connecting grey bars represent the patient flow between the steps. ‘Stopped first/second-line treatment’ represents those with prescriptions from the previous step that ended before death or the study end date. ‘Continued first/second-line treatment’ represents those with prescription durations from the previous step that continued up until death or the study end date. Abbreviation: SSRI – Selective serotonin reuptake inhibitor, SNRI – Selective norepinephrine reuptake inhibitor, TCA – Tricyclic antidepressant, MAOI – Monoamine oxidase inhibitor, AD - Antidepressant. The ‘Atypical’ group includes other antidepressants with mechanisms of action that are different from the major antidepressant classes.

Figure 4

Mediating effect of TRD status on all-cause mortality^{a-c a} The values are binary probit estimates illustrating the total, direct and mediated effects of TRD on mortality event through the post-index acquisition of new physical disorders and psychiatric conditions among matched incident patients in 2014. Total effect was the sum of direct effect and indirect effects via two mediators, whilst the indirect effect was the product of β values in the association between TRD and mediator and, between mediator and mortality. ^b Path model adjusted for post-matching acquisition of new physical disorders before the index date as confounder control. ^c Physical disorders include myocardial infarction, congestive heart failure, peripheral vascular siease, cerebrovascular disease, dementia, chronic pulmonary disease, connective tissue disease, ulcer disease, liver disease, diabetes, hemiplegia or paraplegia, moderate-to-severe renal disease, tumours, leukaemia, lymphoma and acquired immunodeficiency syndrome. Mental health conditions include attention-deficit-hyperactivity disorder, autism, psychosis, schizophrenia, epilepsy, anxiety disorder and personality disorder. Abbreviations = CFI – Comparative fit index, RMSEA – Root-mean-square error of approximation, TLI – Tucker-Lewis index.

Figure 5

Healthcare resource utilisation comparison between treatment-resistant and treatment responsive patients All-cause healthcare resource utilisation refers to all recorded episodes or hospitalisation days per patient-year from index date to death or December 2019. *Significant at 0.05 between TRD and non-TRD patients using negative binomial regression with log link function, adjusting for post-matching acquisition of physical disorders and that of psychiatric conditions. Abbreviation: OR – Odds ratio, PY – Patient-year, SD – Standard deviation, TRD – Treatment-resistant depression.