Sample
The sample for this retrospective observational study was taken from the 2017 National Health and Wellness Survey (NHWS; Kantar Health, New York, USA) that was conducted in five European countries: France, Germany, Italy, Spain, and the United Kingdom (UK). The NHWS, which is part of the Kantar patient-centered research program (PaCeR) and is not publicly available, is self-administered general health survey of the adult population (aged ≥18 years) administered via the Internet and designed to reflect the health in the general population of each country. The European NHWS was reviewed and granted exemption status by the Pearl Institutional Review Board (Indianapolis, IN; 17-KANT-141). All respondents provided informed consent.
Patients with MDD were classified as those who experienced depression in the past 12 months, received a diagnosis for depression, and indicated that they were currently treated with ≥1 medication for depression. Excluded were patients with a co-existing condition of bipolar disease based on self-reported diagnosis or a positive screen on the Mood Disorder Questionnaire [26] or a self-reported diagnosis of schizophrenia. Potential patients with TRD were identified as patients fulfilling at least one of the following three criteria: (1) currently prescribed ≥2 medications for depression for ≥3 months, (2) currently prescribed monotherapy with a Monoamine Oxidase Inhibitor (MAOI) or Reversible Inhibitor of Monoamine Oxidase (RIMA) (prescribed only in France, Germany and the UK), and (3) a depression symptom score of ≥10 using the Patient Health Questionnaire (PHQ-9). The PHQ-9 is a validated scale used to screen for depression and assess severity with scores ranging from 0 to 27 with scores at or above 10 indicating symptoms of moderate to severe depression [27]. The study sample compared MDD patients with TRD to (a) MDD patients without treatment resistance (nTRD) and to (b) the general population who did not experience depression in the past 12 months nor have a diagnosis of depression (Fig. 1).
Measures
Depression-specific measures
Depression-specific variables examined included family history of depression (yes vs. no), length of diagnosis (calculated by year of diagnosis, relative to year of the survey; < 1 year vs. 1–3 years vs. 3–5 years vs. > 5 years), participation in talk therapy (yes vs. no), anxiety, suicide ideation and current classes of MDD medications. The presence of suicide ideation was assessed using the PHQ-9 question, “Over the past 2 weeks, how often have you been bothered by thoughts that you would be better off dead or of hurting yourself in some way?”
Demographics and health characteristics
The demographic variables examined included age, sex, marital status (married/living with a partner vs. not married), education (university degree vs. less than a university degree), and annual household income (low < 20,000 € or £, medium 20,000–39,000 € or £, high 40,000+ € or £, or decline to answer). For health characteristics, NHWS respondents provided data on BMI, smoking status, alcohol use, and exercise behavior. All information was collected according to country residence.
Comorbidities
The burden of comorbidities was measured using the Charlson Comorbidity Index (CCI) [28]. Additionally, specific physical comorbidities were assessed, which included a self-reported diagnosis of anemia, arrhythmia, cancer, chronic heart failure, chronic kidney disease, diabetes (type 1 or 2), hepatitis (A, B, or C), hypertension, and rheumatoid arthritis.
Health-related quality of life
The EuroQol-5 Dimensions 5-levels (EQ-5D-5 L) was used to assess HRQoL. The EQ-5D-5 L is a self-reported measure of health for clinical and economic appraisal [29] consisting of five questions regarding mobility, self-care, usual activities, pain/discomfort, and anxiety/depression and a visual analogue scale (EQ-VAS). The EQ-VAS asks respondents to indicate on a line their self-rated health, with the endpoints being “Best imaginable health state” and “Worst imaginable health state”.
The Medical Outcomes Study 12-Item Short Form Survey Instrument version 2 (SF-12v2), which is a multipurpose, generic health status instrument consisting of 12 questions was also used to measure HRQoL [30]. Eight health domains, physical functioning, physical role limitations, bodily pain, general health, vitality, social functioning, emotional role limitations, and mental health, were calculated as well as two summary scores, the physical component summary (PCS) and mental component summary (MCS), each normalized to a mean of 50 and a standard deviation (SD) of 10 for the general population of the US. Higher scores indicate better health status.
Work productivity loss and activity impairment
Work productivity loss among employed respondents and activity impairment among all respondents in the past week was assessed using the six-item Work Productivity and Activity Impairment-General Health (WPAI-GH) questionnaire [31]. The WPAI-GH assesses presenteeism (reduced productivity while at work), absenteeism (time absent from work), overall work productivity impairment (a combination of presenteeism and absenteeism), and activity impairment. Scores on the WPAI-GH represent the percentage of time impaired in the past week.
Healthcare resource utilization
Participants were asked to provide the number of each type of HRU (healthcare professional [HCP] visits, ER visits, hospitalizations, other types of visits, psychiatrist visits, and psychologist/therapist visits). These responses were then converted into a categorical variable representing the percentage who reported ≥1 event and those who reported none, for each type of event.
Statistical analysis
Demographic and patient characteristics were examined for TRD patients compared to respondents with nTRD and to the general population using chi-square tests or one-way analysis of variance for categorical or continuous variables, respectively. All socio-demographic and health status variables were included in models. Generalized linear models were performed to examine group differences after adjusting these estimates for confounders. For normally distributed outcome variables, a normal distribution and identity function were specified, whereas a negative binomial distribution and log-link function were specified for positively skewed outcome variables. For the generalized linear models, two-sided p-values < 0.05 were considered to be statistically significant. Estimated marginal means and 95% confidence intervals (CI) were calculated for each group on all outcomes as well as adjusted difference, relative risks (RR), or odds ratios (OR) and 95% CI for TRD and nTRD versus the general population.