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Background
According to the World Health Organization (WHO),1 major depressive disorder (MDD) is the most disabling disease worldwide, with an estimated global prevalence of 6%, affecting multiple dimensions and limiting patients in their instrumental activities of daily living (IADLs).2,3 In Latina America (LatAm), MDD prevalence varies between 23.0% to 35% in certain contexts.4
Between 20% and 33.3% of MDD patients develop treatmentresistant depression (TRD),5-7 which is defined as a failure to respond to two or more antidepressants at therapeutic doses over an appropriate period, within the current depressive episode,8 even when novel therapies are considered.9,10 TRD represents an additional burden to MDD, impacting social, economic, educational and occupational dimensions. In a context of limited healthcare resources, the significant economic burden11 and the influence of MDD/TRD on Quality of Life (QoL), disability, and work-productivity5,12,13 are major concerns.
The Treatment Resistant Depression in America Latina (TRAL) study aims to address the gap in MDD/TRD epidemiological data14 in LatAm, while doing clinical and burden of the disease characterization of MDD/TRD patients. A descriptive comparison between TRD and non-TRD patients was also included. This paper presents the subset of Mexico, with the inclusion of some global results from LatAm for contextual framing.
Objectives
This study has two main objectives:
Methods
Study design and population
TRAL was a multicenter, multinational observational study conducted from October 2017 to December 2018 in Argentina, Brazil, Colombia and Mexico. The study comprised two components: one cross-sectional, and 1-year follow-up of TRD patients. The present results pertain to 14 psychiatric centers in Mexico, where cross-sectional data were collected on socio-demographic factors, clinical and psychiatric variables, medication, QoL, work-impairment, and healthcare resource utilization.
Patient were enrolled during routine medical appointments based on MDD screening with the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-V) criteria, and confirmed by the MINI International Neuropsychiatric Interview (MINI), 7.02 version.15 For more information, please refer to previous TRAL publications.14
Data and assessments
All patients were evaluated for depression severity using the Montgomery-Åsberg Depression Rating Scale (MADRS),16 which was also used to diagnose TRD. TRD diagnosis was established for patients who were under follow-up and had been treated with ≥2 antidepressants during the current episode, with no complete response to treatment based on MADRS scores.8
Sociodemographic information, clinical characterization, current and past psychiatric treatments, and healthcare resource utilization in the previous year were collected by the physicians. Patients self-reported on their QoL (EuroQol-5 Dimension [EQ-5D-5L]), work impairment (Work Productivity and Activity Impairment Questionnaire - WPAI), and disability (Sheehan Disability Scale - SDS).
Written informed consent was obtained from all participants. The study was approved by the local Independent Ethics Committee / Institutional Review Board.
Statistical Analysis
TRAL sample size was calculated to be representative of the entire region, although not specifically for each country. Quantitative variables were summarized as mean, median, standard deviation, minimum, and maximum values. Qualitative variables were presented as absolute frequency and percentage, both for overall sample and subgroups based on TRD/non-TRD categorization.
Epidemiology was reported as absolute frequency, percentages, and 95% confidence interval (95% CI). Inferential analysis was conducted for group comparisons. Statistical significance was set at 5%, and all analyses were performed using SAS® (version 9.4, SAS Institute Inc., Cary).
Results
Sociodemographic and clinical characteristics in Mexico MDD patients had an average age of 43.9 (±15.4) years and were predominantly female (79.1%), as shown in Table 1. Most patients were married or in a consensual union (48.9%), and had more than 10 years of formal education (68%). TRD patients were significantly older than non-TRD patients (47.6 versus 42.9; p = .0004).
Table 1 Socio-demographic characteristics, overall, and by TRD (TRD vs. non-TRD patients)
| MDD (n=697) | Non-TRD (n=553) | TRD (n=144) | p-value | |
|---|---|---|---|---|
| Age (years), mean±SD | 43.9 ± 15.4 | 42.9 ± 15.8 | 47.6 ± 12.9 | .0004* |
| Female, n (%) | 551 (79.1%) | 432 (78.1%) | 119 (82.6%) | .2352† |
| Marital status Single | 266 (38.3%) | 219 (39.6%) | 47 (33.1%) | |
| Married/Consensual union | 340 (48.9%) | 268 (48.5%) | 72 (50.7%) | |
| Divorced/Separated | 59 (8.5%) | 43 (7.8%) | 16 (11.3%) | .3701† |
| Widower | 30 (4.3%) | 23 (4.2%) | 7 (4.9%) | |
| Missing | 2 | 0 | 2 | |
| Years of formal education 0 | 2 (0.3%) | 2 (0.4%) | 0.0 | |
| 1-4 years | 14 (2.0%) | 14 (2.5%) | 0.0 | |
| 5-9 years | 204 (29.4%) | 162 (29.3%) | 42 (29.6%) | .2341¥ |
| 10-12 years | 227 (32.7%) | 184 (33.3%) | 43 (30.3%) | |
| ≥ 13 years | 247 (35.6%) | 190 (34.4%) | 57 (40.1%) | |
| Missing | 3 | 1 | 2 |
Sample and TRD prevalence
The Mexican subset included 697 (47.3%) out of 1475 MDD patients. Most patients (86.2%, n = 601) were under treatment. TRD was identified in 144 patients from the Mexican sample (20.7%, 95%CI: 17.7%; 23.7%) (Supplemental Table 1).
MDD patients received care in both private (50.2%) and public (49.8%) healthcare settings, with a higher prevalence of TRD in the private setting (22.3%, 95%CI: 17.9%; 26.6%) (Supplemental Table 1). More detailed results can be found in a previous publication.14
Clinical characterization of MDD and TRD Overall, MDD patients had a mean score of 26.72 ± 9.78 for MADRS, with 25.4% of them categorized as severely depressed (MADRS ≥ 35). TRD patients (30.17 ±8.63) had higher MADRS scores compared to non-TRD patients (25.82 ± 9.87), and a higher proportion were rated as severely depressed (TRD - 31.9% vs Non-TRD - 23.7%) (see Table 2). Based on the MINI assessment, 13.6% of the sample met the criteria for suicidality, with 11.3% reporting lifetime attempt. Additionally, 4.2% of the sample met the criteria for current suicide behavior disorder, and 2.9% for current posttraumatic stress disorder (PTSD). TRD patients were more likely to
Table 2 Depression and anxiety assessment (MADRS and MINI) among participants with MDD, based on TRD status
| MDD (n=697) | Non-TRD (n=553) | TRD (n=144) | |
|---|---|---|---|
| Montgomery-Asberg Depression Scale (MADRS) Mean score ± SD | 26.7 ± 9.8 | 25.8 ± 9.9 | 30.2 ± 8.6 |
| Cut-off scores, n (%) Symptom absent (0-6) | 27 (3.9%) | 27 (4.9%) | 0 (0.0%) |
| Mild depression (7-19) | 119 (17.1%) | 98 (17.7%) | 21 (14.6%) |
| Moderate (20-34) | 374 (53.7%) | 297 (53.7%) | 77 (53.5%) |
| Severe depression (35-60) | 177 (25.4%) | 131 (23.7%) | 46 (31.9%) |
| Mini-International Neuropsychiatric Interview (MINI): Suicidality, n (%) Current (past month) | 95 (13.6%) | 65 (11.8%) | 30 (20.8%) |
| Lifetime attempt | 79 (11.3%) | 40 (7.2%) | 39 (27.1%) |
| Low | 57 (8.2%) | 39 (7.1%) | 18 (12.5%) |
| Moderate | 30 (4.3%) | 20 (3.6%) | 10 (6.9%) |
| High | 56 (8.0%) | 32 (5.8%) | 24 (16.7%) |
| Primary diagnosis of suicidality, n (%) Current (past month) | 17 (2.4%) | 9 (1.6%) | 8 (5.6%) |
| Lifetime attempt | 28 (4.0%) | 12 (2.2%) | 16 (11.1%) |
| Suicide behaviour disorder, n (%) Current | 29 (4.2%) | 19 (3.4%) | 10 (6.9%) |
| In early remission | 31 (4.4%) | 13 (2.4%) | 18 (12.5%) |
| Primary diagnosis of suicide behaviour disorder, n (%) Current | 15 (2.2%) | 9 (1.6%) | 6 (4.2%) |
| In early remission | 14 (2.0%) | 6 (1.1%) | 8 (5.6%) |
| Post-traumatic stress disorder Meets criteria, n (%) Current (past month) | 20 (2.9%) | 12 (2.2%) | 8 (5.6%) |
| Primary diagnosis, n (%) Current (past month) | 6 (0.9%) | 2 (0.4%) | 4 (2.8%) |
Unless otherwise noted, data are expressed as numbers and percentages. a) Range: 0 to 60, with higher values indicating a higher level of depression. MDD: major depressive disorder, TRD: treatment-resistant depression, non-TRD: MDD patient without TRD.
Unless otherwise noted, data are expressed as numbers and percentages. P-values indicate TRD vs non-TRD comparisons. MDD: major depressive disorder, TRD: treatment-resistant depression, non-TRD: MDD patient without TRDX experience current suicidality (20.8% vs 11.8%) or lifetime attempt (27.1% vs 7.2%) than non-TRD. As for suicide behavior disorder, TRD patients had a higher proportion in early remission (12.5% vs 2.4%), with a similar pattern observed for current PTSD, where TRD patients had a rate of 5.6% and non-TRD of 2.2% (Table 2).
MDD treatment schemes - overall TRAL sample
Concerning previous medication, 46.5% of MDD patients received psychiatric medication (TRD - 98.6%, non-TRD - 32.9%), versus 86.2% for current medication (TRD - 97.9%, non-TRD - 83.2%). Other current relevant therapy (non-TRD - 33%, TRD - 48%) is present in 29.3% of the participants. Selective-serotonin reuptake inhibitors (SSRIs) were the most used class, accounting for 67.6% of the sample, followed by serotonin and noradrenaline reuptake inhibitors (SNRIs) (22.9%) and antipsychotics (14.6%).
The use of SSRIs was more frequent in non-TRD patients, while for SNRIs, antipsychotics, antiepileptics, psychotherapy, and previous or current use of lithium, TRD patients showed higher frequency of use (Table 3).
Table 3 Previous and current medication for MDD
| MDD (n=697) | Non-TRD (n=553) | TRD (n=144) | |
|---|---|---|---|
| Previous psychiatric medication | 324 (46.5%) | 182 (32.9%) | 142 (98.6%) |
| Other previous relevant medication | 43 (6.2%) | 30 (5.4%) | 13 (9.0%) |
| Current relevant psychiatric therapy | 601 (86.2%) | 460 (83.2%) | 141 (97.9%) |
| Current other relevant therapy | 204 (29.3%) | 150 (27.1%) | 54 (37.5%) |
| Current medication per treatment class: Tricyclic antidepressants | 2 (0.3%) | 2 (0.4%) | 0 (0.0%) |
| SSRIs | 416 (67.6%) | 340 (71.7%) | 76 (53.9%) |
| SNRIs | 141 (22.9%) | 78 (16.5%) | 63 (44.7%) |
| SDRIs | 4 (0.7%) | 2 (0.4%) | 2 (1.4%) |
| Multimodal | 8 (1.3%) | 7 (1.5%) | 1 (0.7%) |
| Antipsychotics | 90 (14.6%) | 43 (9.1%) | 47 (33.3%) |
| Antiepileptics | 55 (8.9%) | 34 (7.2%) | 21 (14.9%) |
| Brain stimulation techniques | 2 (0.3%) | 0 (0.0%) | 2 (1.4%) |
| Psychotherapy | 5 (0.8%) | 1 (0.2%) | 4 (2.8%) |
| Others* | 8 (1.3%) | 4 (0.8%) | 4 (2.8%) |
| Current use of ketamine/esketamine | 0 | - | - |
| Previous use of ketamine/esketamine | 5 (1.5%) | 0 (0.0%) | 5 (3.5%) |
| Current use of lithium | 4 (0.7%) | 0 (0.0%) | 4 (2.8%) |
| Previous use of lithium | 5 (1.5%) | 0 (0.0%) | 5 (3.5%) |
Unless otherwise noted, data are expressed as numbers and percentages. MDD: major depressive disorder, TRD: treatment-resistant depression, non-TRD: MDD patient without TRD. *Modafinil, armodafinil, riluzole.
Quality of life (EQ-5D-5L) and Work productivity impairment due to depression (WPAI:D) and disability (SDS) The majority of MDD patients reported having no problems walking (60.4%) or washing/dressing themselves (54.9%) (Supplementary Table 2). Nearly 39% of patients reported having moderate or severe problems doing their usual activities. Severe or extreme pain was reported by 10.3% of patients, while 26.3% reported being severely or extremely depressed or anxious. The median current health score in EQ-5D was 65.0. Also, 65.8% of the sample reported being moderately to extremely affected by anxiety/depression. Non-TRD patients (64.52 ± 17.17) had a better subjective assessment of their overall health status than TRD patients (52.90 ± 19.56). TRD patients yielded significantly lower QoL scores compared to non-TRD patients.
The median percentage of work time missed due to depression was 15.0%, and the median percentage of impairment while working was 50.0% (Supplementary Table 2). The median percentage of overall work impairment due to depression was 58.3%, and the percentage of activity impairment was 60.0%. Activity impairment due to depression suggested higher impairment in TRD (62.92 ± 25.08) compared to non-TRD (51.41 ± 25.54) patients.
According to the SDS, patients reported that their symptoms markedly (31.8%) or extremely (37.0%) disrupted the school/ work and their social life/leisure activities. The median overall SDS score was 17.0. On average, patients missed school/ work or were unable to carry out daily activities for 1.1 days in the previous week due to their symptoms. TRD patients reported significantly higher disability (SDS) in every dimension analyzed, indicating a significant disruption in IADLs compared to non-TRD patients.
Healthcare resource utilization among MDD patients The proportion of days in ambulatory care is higher for TRD patients, with 36.4% of TRD patients having at least 60 days of ambulatory care compared to only 15.0% of non-TRD patients. Interestingly, both the number of psychiatrist and psychologist consultations were higher in TRD patients (psychiatrist: 10.04 ± 8.92, psychologist: 2.11 ± 5.42) compared to non-TRD patients (psychiatrist - 3.62 ± 3.69, psychologist - 0.80 ± 2.82). The mean number of emergency visits was 0.8 in the previous year. The same trend is observed for the number of consultations with other specialists, with higher values for TRD patients (1.01 ± 3.44) versus non-TRD patients (0.13 ± 0.61). Accordingly, non-pharmaceutical consultations were reportedly higher in TRD patients (0.30 ± 1.72) versus non-TRD patients (0.02 ± 0.19) (Supplemental Table 3).
Discussion
In the TRAL study, Mexico exhibited the lowest prevalence of TRD, including all patients (20.7%) and among treated patients (23.5%),14 contrasting the highest prevalence observed in Brazil (all patients: 40.4, treated patients: 43.1%). This is consistent with previous research indicating that Mexico has a lower prevalence of depressive disorders.4,17 Limited access to mental health services in Mexico and challenges in the diagnosis of MDD/TRD or other mental conditions may partially explain this. Nonetheless, TRAL suggests a high prevalence of TRD among MDD individuals receiving attention in healthcare facilities in LatAm,14 which affects patients, caregivers and society across various dimensions, highlighting the importance of earlier diagnosis and better therapeutic approaches.
TRD patients exhibited poorer outcomes in terms of QoL (EQ-5D), disability (SDS) and work-productivity (WPAI) when compared to non-TRD patients, reiterating previous research findings.5,12,13 The severe symptomatology observed in TRD patients (MADRS), may partially account for these worse outcomes, underlined by some symptoms, such as suicidality and PTSD. Additionally, TRD patients’ age was higher, which might be linked to the chronic neurological changes associated with MDD.
Comorbidities were more frequent among TRD patients, adding to the significant economic burden of TRD.18,19 The burden extends beyond the toll on patients and caregivers, affecting physicians as well.20 A study in Brazil showed that health costs and resource utilization are significantly higher in TRD patients when compared to non-TRD.12
TRAL14 is a landmark real-world evidence study in the region where available evidence on TRD was scarce. These findings are relevant to all stakeholders and healthcare decision makers. The sample size, covering four important countries in the region, constitutes a strength of TRAL’s methodology.
The sample size of the Mexican study provides an interesting analysis of TRD prevalence and patients characterization. However, the sample size was not calculated considering country-level comparisons or to be representative of the Mexican population. Additionally, only patients under followup at local healthcare facilities were included in the study.
The Mexican sample was almost evenly distributed between private and public settings, providing a depiction of the impact of TRD regardless of patient income. However, fewer therapeutic options and longer time to treatment initiation were found in the public setting.
In Mexico, measures have been implemented to improve mental health resources, but the treatment gap remains relevant, particularly among the elderly21 and adolescents.22 Three areas emerge as priorities: prevention, hospitalization and social reintegration.23 Mexico has one of the highest prevalence of mental disorders in the Americas (42.6%).24 Fighting social stigma is essential since untreated mental health conditions lead to severe problems. Population should seek help when the first symptoms are identified. Availability of treatment is still insufficient, and the distribution of care services is inadequate, especially in primary care units,25 but significant efforts are in place.
Conclusions
The data from TRAL provides further evidence on the medical needs for TRD. The prevalence of TRD in LatAm was 29.1, while in the Mexican MDD population, it was 20.7. The results demonstrate that TRD severely impacts mental health, quality of life, as well as significant healthcare resources utilization. Public policies should focus on improving early diagnosis and the availability of therapies for TRD.
Conflict of interest
JLVH and JIB have no conflicts of interest to disclose. LDAS serves as a researcher for Avalon Salud, where he holds the positions of principal investigator and sub-investigator for several original epidemiological research protocols conducted by the institution. He has received professional fees for conducting subject interviews in the present study by Janssen Research & Development, as approved by the Independent Research Ethics Committee. Dr. Alviso has also served as a speaker, participated in advisory boards, or received scientific fees from the following organizations: Janssen, Pfizer, Sanofi Aventis, Schwabe-Pharma, Novartis, Lundbeck, Roche, Lilly, Asofarma, Psicofarma, Ferrer, Servier, and Shire. CC received support from Janssen Cilag. CBP received support from the National Institute of Psychiatry. GK and PC are currently employed at Janssen Pharmaceutical.
