Treatment-Resistant Depression in Real-World Clinical Practice: A Systematic Literature Review of Data from 2012 to 2022.

OBJECTIVE: Real-world evidence in treatment-resistant depression (TRD; commonly defined as non-response to ≥ 2 consecutive treatments at adequate dosage and duration) is lacking. A systematic literature review was conducted to understand disease burden and treatment outcomes for patients with TRD, studied in a real-world setting over the last decade. DATA SOURCES: A literature search was conducted in May 2022 in MEDLINE, Embase, The Cochrane Libraries and PsycINFO, comprising studies published from 2012 to 2022. Bibliographies of all relevant identified systematic reviews and relevant conference proceedings from 2020 to 2022 were manually hand-searched. STUDY SELECTION: Real-world studies, including cohort, cross-sectional, case-control, chart review and registry studies, published in English and reporting outcomes in adults with TRD, were included. DATA EXTRACTION: Extracted data included study and baseline disease characteristics, treatment type, treatment response, clinical outcomes and health-related quality of life. RESULTS: Twenty studies were included. Criteria for TRD varied, but patients typically experienced long-lasting depression (range 1.4 to 16.5 years). Across studies, mean disease severity scores demonstrated moderate to severe depression, reflecting a high burden of disease at baseline. Remission rates were typically low but generally increased with longer follow-up durations. However, the heterogeneity of interventions, follow-up durations (range 2 weeks to 9.4 years) and assessment tools precluded their quantitative synthesis. Studies were frequently limited by low sample size (range 14 to 411 patients) and health-related quality of life was infrequently assessed. CONCLUSIONS: There is a lack of clinical consensus regarding the definition, assessment and monitoring of TRD in real-world practice. Nevertheless, TRD carries a high burden of illness and there is an unmet need for faster and more effective treatments. To better understand the personal burden of affected patients, future studies would benefit from standardisation of severity assessment and measures of treatment effectiveness, as well as greater consideration of health-related quality of life.

Many people continue to experience depression even after trying two or more medications. This is called treatment-resistant depression (TRD). Most of the information we have on TRD comes from clinical trials, which take place under tightly-controlled conditions. It is important to understand the effects of TRD and TRD treatments on people in their day-to-day lives. Researchers studying people's day-to-day lives call this researching in a "real-world setting". We searched for studies carried out in real-world settings in the last 10 years. We found 20 relevant studies. As these studies were in real-world settings, there were many differences between them, including differences in how TRD was diagnosed, the treatments used, how long people were monitored and how results were measured. This made it difficult to compare how successful different treatments were. Most studies included a small number of people and monitored them for a relatively short time. We found people with TRD had usually lived with it for many years and their symptoms were moderate or severe. Only two studies asked people how TRD affected their lives. These two studies found health-related quality of life and work productivity was low. Most studies found lots of people still had symptoms of depression after treatment. However, symptoms typically improved more when studies monitored people for a longer time. To improve our knowledge of TRD, future studies should monitor more people for longer and use the same ways of measuring results. They should also ask how TRD affects people's daily lives.

Indirect adjusted comparison of 6-month clinical outcomes between esketamine nasal spray and other real-world polypharmacy treatment strategies for treatment resistant depression: results from the ICEBERG study.

Background: The efficacy of esketamine nasal spray (NS) as a rapid-acting agent for treatment resistant depression (TRD) was demonstrated in comparisons with placebo, when both were given in addition to a newly initiated selective serotonin reuptake inhibitor (SSRI)/serotonin norepinephrine reuptake inhibitor (SNRI). How esketamine NS compares with commonly used real-world (RW) polypharmacy treatment strategies is not known. Method: ICEBERG was an adjusted indirect treatment comparison that analysed data from SUSTAIN-2 (NCT02497287; clinicaltrials.gov), a long-term, open-label study of esketamine NS plus SSRI/SNRI, and the European Observational TRD Cohort (EOTC; NCT03373253; clinicaltrials.gov), an observational study of routine clinical practice. Data were compared between patients receiving esketamine NS (SUSTAIN-2) and those from the EOTC treated with polypharmacy treatment strategies, either combination or augmentation. Analyses were adjusted for potential confounders, using rescaled average treatment effect among treated estimates. Threshold analyses were conducted to assess potential impact of unmeasured confounders on the robustness of analyses where esketamine NS was found to be significantly superior. Sensitivity analyses were used to understand the impact of analysis method selection and data handling. Results: Esketamine NS treatment resulted in a higher probability of 6-month response (49.7% [95% confidence interval (CI) 45.6-53.9]) and remission (33.6% [95% CI 29.7-37.6]) versus RW polypharmacy (26.8% [95% CI 21.0-32.5] and 19.4%, [95% CI 14.2-24.6], respectively). Relative risk calculations showed esketamine NS was 1.859 (95% CI 1.474-2.345; p < 0.0001) times as likely to result in response and 1.735 (1.297-2.322; p = 0.0002) times as likely to result in remission versus RW polypharmacy at 6 months. Threshold and extensive sensitivity analyses supported that analyses of esketamine NS superiority were robust. Conclusion: ICEBERG supports esketamine NS being superior to current RW individualized polypharmacy strategies, including augmentation, with benefits extending beyond acute use, to improved chance of 6-month response and remission. While unobserved confounding factors may certainly impact results of an indirect comparison, threshold analysis supported a low likelihood of this affecting the conclusions.To view an animated summary of this publication, please click on the Supplementary video.

ICEBERG study: an indirect adjusted comparison estimating the long-term benefit of esketamine nasal spray when compared with routine treatment of treatment resistant depression in general psychiatry.

Background: Treatment resistant depression (TRD) affects 10-30% of patients with major depressive disorder. In 4-week trials, esketamine nasal spray (NS) was efficacious vs. placebo when both were initiated in addition to a new selective serotonin or serotonin norepinephrine reuptake inhibitor. However, comparison with an extended range of real-world treatments (RWT) is lacking. Methods: ICEBERG was an adjusted indirect treatment comparison using propensity score-based inverse probability weighting, performed on 6-month response and remission data from patients receiving esketamine NS plus oral antidepressant from the SUSTAIN-2 (NCT02497287; clinicaltrials.gov) study, compared with patients receiving other RWT from the European Observational TRD Cohort (EOTC; NCT03373253; clinicaltrials.gov) study. SUSTAIN-2 was a long-term open-label study of esketamine NS, while the EOTC was conducted at a time when esketamine NS was not available as RWT. Threshold and sensitivity analyses were conducted to assess how robust the primary analyses were. Results: Patients receiving esketamine NS had a higher probability of 6-month response (49.7% [95% confidence interval (CI) 45.6-53.9]) and remission (33.6% [95% CI 29.7-37.6]) vs. patients receiving RWT (26.4% [95% CI 21.5-31.4] and 18.2% [95% CI 13.9-22.5], respectively), according to rescaled average treatment effect among treated estimates. Resulting adjusted odds ratios (OR) and relative risk (RR) favoured esketamine NS over RWT for 6-month response (OR 2.756 [95% CI 2.034-3.733], p < 0.0001; RR 1.882 [95% CI 1.534-2.310], p < 0.0001) and remission (OR 2.276 [95% CI 1.621-3.196], p < 0.0001; RR 1.847 [95% CI 1.418-2.406], p < 0.0001). Threshold analyses suggested that differences between the two studies were robust, and results were consistent across extensive sensitivity analyses. Conclusion: ICEBERG supports that, at 6 months, esketamine NS has a substantial and significant benefit over RWT for patients with TRD. While results may be affected by unobserved confounding factors, threshold analyses suggested these were unlikely to impact the study conclusions.To view an animated summary of this publication, please click on the Supplementary video.

Esketamine Nasal Spray versus Quetiapine for Treatment-Resistant Depression.

BACKGROUND: In treatment-resistant depression, commonly defined as a lack of response to two or more consecutive treatments during the current depressive episode, the percentage of patients with remission is low and the percentage with relapse is high. The efficacy and safety of esketamine nasal spray as compared with extended-release quetiapine augmentation therapy, both in combination with ongoing treatment with a selective serotonin reuptake inhibitor (SSRI) or a serotonin-norepinephrine reuptake inhibitor (SNRI), in patients with treatment-resistant depression are unknown. METHODS: In an open-label, single-blind (with raters unaware of group assignments), multicenter, phase 3b, randomized, active-controlled trial, we assigned patients, in a 1:1 ratio, to receive flexible doses (according to the summary of product characteristics) of esketamine nasal spray (esketamine group) or extended-release quetiapine (quetiapine group), both in combination with an SSRI or SNRI. The primary end point was remission, defined as a score of 10 or less on the Montgomery-Åsberg Depression Rating Scale (MADRS), at week 8 (scores range from 0 to 60, with higher scores indicating more severe depression). The key secondary end point was no relapse through week 32 after remission at week 8. All patients were included in the analysis; patients who discontinued the trial treatment were considered as having had an unfavorable outcome (i.e., they were grouped with patients who did not have remission or who had a relapse). Analyses of the primary and key secondary end points were adjusted for age and number of treatment failures. RESULTS: Overall, 336 patients were assigned to the esketamine group and 340 to the quetiapine group. More patients in the esketamine group than in the quetiapine group had remission at week 8 (91 of 336 patients [27.1%] vs. 60 of 340 patients [17.6%]; P = 0.003) and had no relapse through week 32 after remission at week 8 (73 of 336 patients [21.7%] vs. 48 of 340 patients [14.1%]). Over 32 weeks of follow-up, the percentage of patients with remission, the percentage of patients with a treatment response, and the change in the MADRS score from baseline favored esketamine nasal spray. The adverse events were consistent with the established safety profiles of the trial treatments. CONCLUSIONS: In patients with treatment-resistant depression, esketamine nasal spray plus an SSRI or SNRI was superior to extended-release quetiapine plus an SSRI or SNRI with respect to remission at week 8. (Funded by Janssen EMEA; ESCAPE-TRD ClinicalTrials.gov number, NCT04338321.).

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

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 disordersË®, 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 disordersË® 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.

Regulation of the hypoxic response in Candida albicans.

The regulation of the response of Candida albicans to hypoxic (low-oxygen) conditions is poorly understood. We used microarray and other transcriptional analyses to investigate the role of the Upc2 and Bcr1 transcription factors in controlling expression of genes involved in cell wall metabolism, ergosterol synthesis, and glycolysis during adaptation to hypoxia. Hypoxic induction of the ergosterol pathway is mimicked by treatment with sterol-lowering drugs (ketoconazole) and requires UPC2. Expression of three members of the family CFEM (common in several fungal extracellular membranes) of cell wall genes (RBT5, PGA7, and PGA10) is also induced by hypoxia and ketoconazole and requires both UPC2 and BCR1. Expression of glycolytic genes is induced by hypoxia but not by treatment with sterol-lowering drugs, whereas expression of respiratory pathway genes is repressed. However, Upc2 does not play a major role in regulating expression of genes required for central carbon metabolism. Our results indicate that regulation of gene expression in response to hypoxia in C. albicans is complex and is signaled both via lowered sterol levels and other unstudied mechanisms. We also show that induction of filamentation under hypoxic conditions requires the Ras1- and Cdc35-dependent pathway.