Clinical characteristics of treatment-resistant depression in adults in Hungary: Real-world evidence from a 7-year-long retrospective data analysis

Abstract

Purpose: Treatment-resistant depression (TRD) is associated with a poor quality of life and high economic burden. This observational retrospective epidemiological study aimed to estimate the proportion of patients with TRD within a cohort of patients with major depressive disorder (MDD) in Hungary and examine the mortality and comorbidities of patients with and without TRD.

Patients and methods: This study included patients with MDD who experienced onset of a new depressive episode between 01 January 2009 and 31 August 2015, using data from a nationwide, longitudinal database.

Results: Overall, 99,531 patients were included in the MDD cohort, of which 8,268 (8.3%) also met the criteria for TRD. The overall survival of non-TRD patients was longer than in TRD patients; the risk of mortality for TRD patients was significantly higher than of non-TRD patients (HR [CI] 1.381 [1.212-1.571]; p<0.001). Patients with TRD had a significantly higher probability of having "Neurotic, stress-related and somatoform disordersˮ, autoimmune conditions, cardio- or cerebrovascular diseases, thyroid gland diseases and self-harming behaviour not resulting in death than non-TRD patients (for all comparisons, p values were less than 0.005).

Discussion: To our best knowledge, this is the first study to assess the frequency of TRD in Hungary. In a cohort of Hungarian MDD patients, we have found that the proportion of TRD (~8.3%) is comparable to those reported in previous studies with similar methodology from other countries. The majority of our other main findings (e.g. more frequent self-harming behaviour, increased risk of "Neurotic, stress-related and somatoform disordersˮ and higher overall mortality in TRD subjects) are also in line with previous results from other countries. Taking the substantial proportion of patients with TRD into consideration, a more comprehensive and targeted treatment strategy would be required for these individuals.

Fig 1. Schematic of patient inclusion and determination of TRD.

The treatment pattern of patients was considered on three different levels. Individual prescriptions were compiled into drug use periods, which were then compiled into PTD episodes. Then, the whole follow-up period for patients was broken down stepwise to determine TRD. Step A–MDD patient identification: Patients are identified based on the inclusion and exclusion criteria. All patients with AD prescriptions in 2007 and 2008 are excluded. Step B–PTD identification: The PTD episodes needed to be identified as treatment failures were only considered within a single PTD episode. Step C–TRD determination: The failure of a treatment (corresponding to a drug use period) was evaluated at the start of the subsequent treatment (regardless of the previous treatment having ended or not). After the second failure was identified (within a PTD episode), the patient was identified to have TRD (up to the end of follow-up). AD, antidepressant; MDD, major depressive disorder; PTD, pharmaceutically treated depression; TRD, treatment-resistant depression.

Fig 2. Algorithm for treatment failure evaluation.

The figure illustrates all the possible scenarios for evaluating of failure of a treatment (A). The evaluation occurs at the start of the next event [initiation of the next treatment (B) or hospitalisation in a psychiatric ward (H)]. The dashed line at the end of treatment A illustrates that the evaluation result was independent of whether treatment A was being received at this time point. X represents the number of days elapsed. The category of treatments (on a scale of 1–3) was determined based on the Hungarian reimbursement guidelines (see S7 Appendix in S3 File).

Fig 3. Number of new MDD and TRD cases by year.

New MDD patients were identified at the patient’s first AD prescription (MDD index date). New patients with TRD were identified at the date of the second treatment failure within the same PTD (TRD index date). The same patient could have the MDD index date and TRD index date in different years. *Data for 2015 only available up to 31 August 2015. AD, antidepressant; PTD, pharmaceutically treated depression; MDD, major depressive disorder; TRD, treatment resistant depression.

Fig 4. Overall survival of TRD and non-TRD patients.

Start: TRD index date for patients with TRD, “matched date” for non-TRD patients; event: death; censoring: at the study end (31 August 2015) or when matched non-TRD patients develop TRD. TRD, treatment-resistant depression.

Fig 5. Distribution of patients by the number of different treatment ingredients used throughout the whole study period.

This analysis includes antidepressant and add-on therapies. Only the number of different treatment ingredients was counted, so a patient using the same treatment multiple times would only count as one treatment. The numbers are counted within the whole study period (and not within a single PTD episode). PTD, pharmaceutically treated depression.

Fig 6. Use of specific drug classes during the whole study period.

Both antidepressant treatments and add-on therapies are included. A patient was considered to use a certain class of treatment if they had at least one prescription filled from the given class of treatment. Lithium is not included in the figure due to very low patient counts. ‘Other’ includes other antidepressant treatments not included in the classes stated. AANTIP, atypical antipsychotics; ANTIE, antiepileptics; BUSP, buspirone; MAOI, monoamine oxidase inhibitors; SNRI, serotonin-norepinephrine reuptake inhibitors; SSRI, selective serotonin reuptake inhibitors; T3/T4, thyroid therapy; TCA, tricyclic antidepressants.

Fig 7. Top 10 most frequently used antidepressant treatments during the whole study period for non-TRD and TRD patients.

Treatments are presented in descending order by the frequency of patients with TRD using them. For patients with TRD, the antidepressants used also include those used prior to identification of TRD. TRD, treatment-resistant depression.