This post hoc analysis of two Phase III double-blind studies assessed the effects of baseline irritability on clinical outcomes in participants with treatment-resistant depression (TRD) (n=560) treated with intranasal ketamine (esketamine) plus an oral antidepressant (ESK + AD). ESK + AD improved symptoms of depression regardless of baseline irritability level and increased odds of achieving a response in all participants.
Objective
To evaluate the impact of baseline irritability on clinical outcomes in adults with treatment-resistant depression (TRD) treated with fixed or flexible doses of esketamine nasal spray plus a newly initiated oral antidepressant (ESK + AD), and to explore whether treatment with ESK affects irritability symptoms over time.
Methods
This was a post hoc analysis of pooled data from two 4-week, double-blind, phase 3 studies: TRANSFORM-1 (NCT02417064) and TRANSFORM-2 (NCT02418585). Adults with TRD (n = 560) were randomly assigned to ESK + AD or placebo nasal spray plus oral (AD+PBO). Irritability was assessed with Item 6 of the 7-item Generalized Anxiety Disorder scale at screening and baseline. Changes in depression severity (Montgomery-Åsberg Depression Rating Scale [MADRS] total score) were evaluated by analysis of covariance (ANCOVA) models. Rates of MADRS response (≥50 % decrease from baseline total score) and remission (total score ≤ 12) were examined using multiple logistic regression models.
Results
Of 560 participants with TRD, 52.9 %, 23.2 %, and 23.9 % had high, low, and varying levels of irritability, respectively. No significant interaction between baseline irritability and treatment group was observed for change in MADRS total score, treatment response, or remission at day 28; numerically greater improvement was observed on all outcomes with ESK + AD versus AD+PBO at day 28 regardless of baseline irritability level. Percentages of patients reporting adverse events were similar across the three baseline irritability groups.
Limitations
TRANSFORM-1 and TRANSFORM-2 were not designed to prospectively evaluate predetermined irritability outcomes.
Conclusions
These post hoc results support efficacy of ESK + AD in patients with TRD, regardless of baseline irritability
Irritability—an elevated tendency to anger or aggression in response to frustration or perceived threat—is a frequent but often under-recognised feature of major depressive disorder (MDD). The extracted text notes that persistent irritability is reported by roughly 30%–50% of adults with MDD, is linked to earlier illness onset and comorbid anxiety, and is associated with worse outcomes including longer and more severe episodes, reduced functioning, and greater suicidal ideation. Despite these associations, the relationship between irritability and treatment outcomes in treatment-resistant depression (TRD) has not been well characterised. Jha and colleagues used pooled data from two Phase III trials of intranasal esketamine (ESK) plus a newly initiated oral antidepressant (ESK+AD) versus placebo nasal spray plus a newly initiated oral antidepressant (AD+PBO) to examine whether baseline irritability influenced antidepressant response in adults with TRD. The investigators also explored change in irritability symptoms over the 28-day double‑blind treatment period as a secondary interest.
This report is a post hoc analysis of pooled data from two similarly designed, multinational, randomised, double-blind, active-controlled Phase III trials, TRANSFORM-1 and TRANSFORM-2. Eligible participants had moderate-to-severe depression (MADRS total score ≥28) and documentation of nonresponse to 1–5 oral antidepressants in the current episode at screening; at randomisation all participants met a TRD definition of nonresponse to ≥2 adequate oral antidepressant trials in the current major depressive episode. Key exclusions included recent suicidal intent or behaviour, psychotic or bipolar disorders, recent moderate-to-severe substance use disorder, and positive drug screens for specified substances. The primary clinician-rated outcome was the Montgomery–Åsberg Depression Rating Scale (MADRS), administered at baseline and on days 2, 8, 15, 22 and 28 by independent blinded raters using a structured interview guide. Irritability was operationalised using item 6 of the GAD-7 ("Becoming easily annoyed or irritated"); patients were classified as high (item score ≥2 at both screening and baseline), varying (item score ≥2 at either visit), or low (item score <2 at both visits). Safety was assessed through treatment-emergent adverse events (TEAEs) coded with MedDRA v20.0. Efficacy and safety analyses used the full analysis set (all randomised patients who received ≥1 dose of study nasal medication and ≥1 dose of oral antidepressant during the 4-week induction). Changes in MADRS total score at day 28 were analysed with ANCOVA models including fixed effects for treatment, irritability level, study identifier, class of oral antidepressant (SSRI or SNRI) and baseline value as covariate; logistic regression models examined response (≥50% MADRS reduction) and remission (MADRS ≤12) with treatment, irritability level and study identifier as predictors and with a treatment-by-irritability interaction term tested. Number needed to treat (NNT) was estimated from response and remission rates. Changes in irritability (GAD-7 item 6) were analysed with Wilcoxon signed-rank and rank-sum tests. The extracted text states no multiplicity adjustment was applied.
The pooled full analysis set included 560 patients (ESK+AD n = 339; AD+PBO n = 221). At baseline, 296 patients (52.9%) met criteria for high irritability, 134 (23.9%) for varying irritability, and 130 (23.2%) for low irritability. Patients with high irritability were reported to be younger at MDD diagnosis, to have higher BMI, longer current episode duration, more prior oral antidepressant nonresponses in the current episode, greater lifetime suicidal ideation/behaviour, higher anxiety symptoms and more comorbid anxiety disorders than those with low irritability; baseline MADRS scores were similar across irritability subgroups. A total of 518 patients (ESK+AD n = 310; AD+PBO n = 208) had MADRS recorded at day 28 and were included in the post hoc endpoint analyses. In the pooled population, ESK+AD produced a greater mean improvement in MADRS total score at day 28 than AD+PBO (least squares mean change −19.9 vs −15.6, P < 0.001). This superiority reached statistical significance within the low (P = 0.011) and varying (P = 0.008) irritability subgroups; the high irritability subgroup showed a numerically greater improvement with ESK+AD but did not meet significance (P = 0.122). There was no statistically significant interaction between baseline irritability and treatment effect on MADRS change (interaction P = 0.267). Response and remission rates also favoured ESK+AD overall. At day 28, response occurred in 58.7% of ESK+AD patients versus 45.2% of AD+PBO patients (P < 0.001), and remission in 42.3% versus 30.8% (P = 0.004). NNTs for response or remission were <10 for most subgroup comparisons, although the NNT to achieve remission in the high irritability group was reported as 16, higher than in the low and varying groups (both <10). Logistic regression estimated that ESK+AD nearly doubled the odds of response overall (OR 1.92, 95% CI 1.33–2.76). Subgroup ORs for response ranged from 1.79 (95% CI 1.09–2.93) in the high irritability group to 2.21 (95% CI 1.03–4.73) in the low irritability group; some subgroup CIs crossed 1. For remission the overall OR was 1.75 (95% CI 1.20–2.56), with subgroup ORs reported as 1.39 (95% CI 0.84–2.32) for high irritability, 2.35 (95% CI 1.01–5.47) for varying irritability, and 2.31 (95% CI 1.07–4.97) for low irritability. Irritability measured by GAD-7 item 6 improved significantly from baseline to day 28 within all treatment subgroups (within-group P ≤ 0.005). Between‑group differences in change were not statistically significant, though trends favouring greater improvement with ESK+AD were noted in the high and varying irritability groups (P = 0.087 and P = 0.084, respectively); the largest median improvement (2 points) occurred in ESK+AD patients with high baseline irritability. Safety findings were described as consistent with prior reports and generally tolerable across irritability subgroups. The extracted text indicates four patients experienced at least one serious adverse event (SAE) distributed across treatment arms, but the extraction is fragmented and does not clearly report denominators for all events. The most common TEAEs in ESK+AD recipients during the double-blind phase included nausea (range 16.7%–33.9%), dissociation (25.6%–30.9%), dizziness (18.0%–28.9%), dysgeusia/bitter taste (11.1%–26.9%) and vertigo (16.7%–35.9%).
Jha and colleagues interpret these post hoc pooled-trial analyses to indicate that intranasal esketamine, when added to a newly initiated oral antidepressant, is associated with greater improvement in depressive symptoms and higher response and remission rates than oral antidepressant plus placebo in adults with TRD, irrespective of baseline irritability. The investigators highlight that more than half of the sampled TRD patients reported high irritability and that high irritability was associated with earlier age at MDD diagnosis, greater anxiety, higher BMI, more prior antidepressant nonresponses and more frequent lifetime suicidal ideation/behaviour; baseline MADRS scores did not differ by irritability level, suggesting that MADRS alone may not capture the broader syndromic burden of irritability. The authors note that although MADRS improvements were numerically larger with ESK+AD across irritability strata, statistically significant differences in MADRS change were clearer in the low and varying irritability groups than in the high irritability group, whereas response rates showed a statistically significant advantage for ESK+AD even in the high irritability subgroup. They further discuss NNT findings, pointing out that NNTs <10 for response across groups support potential clinical benefit, while the higher NNT for remission in the high irritability group suggests remitting these patients may be more challenging. Several limitations are acknowledged. The analysis was post hoc and the trials were not prospectively designed to test irritability-specific hypotheses. Subgroup sample sizes were limited, no adjustment for multiplicity was made, and irritability was assessed using a single GAD-7 item that likely does not capture the full construct or provide informant perspectives. The authors also recognise potential confounding because irritability was associated with other clinical features (for example, prior nonresponse and comorbid anxiety), and they note the sample was predominantly White, which limits generalisability. Finally, the investigators call for prospective studies that use more comprehensive irritability measures and include more diverse samples to replicate and extend these findings. They conclude that the current analyses provide supportive evidence of esketamine's efficacy in TRD regardless of baseline irritability and offer preliminary indications that esketamine may reduce irritability symptoms, while emphasising the need for further targeted research.
Irritability, commonly characterized as an elevated proneness to anger and/or aggression in response to frustration or threat, is a common but underrecognized symptom in adults with major depressive disorder (MDD). A persistently irritable mood (occurring >50% of the time) is reported by approximately 30%-50% of individuals with MDD. Concurrent irritability may be more common in women and is associated with earlier age of MDD onset and presence of comorbid anxiety disorder. Irritability has also been linked to poorer prognosis in MDD, including a more chronic and severe course of illness, greater psychosocial functional impairment, longer major depressive episodes (MDEs), and reduced quality of life due to greater prevalence of residual symptoms between MDEs. Recent reports further suggest that irritability and its associated features, including anger attacks and aggressive behavior, are strongly associated with current and future suicidal ideation. In those analyses, treatment-related improvements in irritability predicted lower levels of future suicidal ideation. Nevertheless, the association of irritability with clinical features and treatment outcomes in adults with treatment-resistant major depression (TRD) remains poorly J o u r n a l P r e -p r o o f Journal Pre-proof understood. TRD is commonly defined as MDD with inadequate response to at least two antidepressant (AD) trials of adequate dose and duration given to achieve remission in the current MDE. Esketamine nasal spray (ESK), the (S)-enantiomer of ketamine, is a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist indicated for use in conjunction with an oral AD for the treatment of TRD in adults and for the treatment of depressive symptoms in adults with MDD with acute suicidal ideation or behavior (Janssen Pharmaceuticals, 03/2019 and 07/2020). In two similarly designed, active-controlled, phase 3 trials of ESK plus a newly initiated oral AD (ESK+AD) in adults with TRD (TRANSFORM-1 and TRANSFORM-2), 4 weeks of treatment with twice-weekly fixed or flexibly dosed ESK (56 mg or 84 mg) resulted in clinically meaningful improvement (TRANSFORM-1) and statistically significant improvement (TRANSFORM-2) in depressive symptoms versus placebo nasal spray plus an antidepressant (AD+PBO) as measured by the Montgomery-Åsberg Depression Rating Scale (MADRS), and with response observed in ESK-treated patients as early as 24 hours after the first dose. Additionally, intravenous infusion of ketamine was recently shown to rapidly reduce depressive symptoms, irritability, and suicidality in adults with TRD or treatment-resistant bipolar disorder with anxiety, irritability, and agitation at baseline. These findings suggest that ESK may have the potential to mitigate depression and irritability symptoms in adults with TRD and irritability at baseline. In this post-hoc analysis of pooled data from TRANSFORM-1 and TRANSFORM-2, we aimed to evaluate the impact of irritability at baseline on clinical outcomes in adults J o u r n a l P r e -p r o o f with TRD treated with ESK plus a newly initiated oral AD. We also sought to explore whether treatment with ESK affects irritability symptoms over time.
This study was a post hoc analysis of pooled data from TRANSFORM-1 (ClinicalTrials.gov identifier: NCT02417064) and TRANSFORM-2 (ClinicalTrials.gov identifier: NCT02418585), two similarly designed, phase 3, randomized, double-blind, active-controlled, multinational studies. Full trial methods have been previously reported. Briefly, the studies were conducted in. Patients had moderate-to-severe depression (i.e., MADRStotal score of ≥28 and Inventory of Depressive Symptomatology) score ≥34). At the start of the screening/observational phase, patients were required to have had nonresponse to 1-5 oral ADs in the current depressive episode based on the Massachusetts General Hospital Antidepressant Treatment Response Questionnaire and confirmed by documented records. At randomization, all patients were required to have TRD, defined as nonresponse to an adequate trial (dose, duration, and adherence) of ≥2 oral ADs in the current MDE, with nonresponse to the current ongoing AD in the screening/observational phase defined as ≤25% improvement in the MADRS total score from week 1 to week 4 and a MADRS total score ≥28 at weeks 2 and 4. Key exclusion criteria included suicidal ideation with intent to act within the prior 6 months or suicidal behavior within the prior year; diagnosis of psychotic disorder, bipolar disorder or related disorders; moderate or severe substance use disorder within the prior 6 months; and positive test result(s) for specified drugs of abuse.
The MADRS, a 10-item clinician-rated scale designed to measure depression severity and detect changes due to antidepressant treatment, was administered at baseline and on days 2, 8, 15, 22, and 28 of the double-blind treatment phase by offsite, independent blinded raters, using the Structured Interview Guide for the MADRS. The Generalized Anxiety Disorder 7-item (GAD-7) scale, a patient-reported assessment, was completed at screening and pre-dose on day 1 and day 28. The GAD-7 is a brief, validated measure of overall anxiety that asks, "Over the last 2 weeks, how often have you been bothered by the following problems?" Item 6 specifically focuses on "Becoming easily annoyed or irritated," with responses scored as 0 (not at all), 1 (several days), 2 (more than half the
Journal Pre-proof days), and 3 (nearly every day), and the item has been used as a brief screener for irritability in previous studies. Efficacy and safety endpoints were evaluated according to patients' level of irritability at screening and baseline, as assessed by GAD-7 item 6, and defined as high (item score ≥2 at both screening and baseline visits), varying (item score ≥2 at either of the two visits), or low (item score <2 at both visits) (Supplementary Table). Safety evaluations included incidence of reported treatment-emergent adverse events (TEAEs), which were assessed throughout the studies and coded in accordance with the Medical Dictionary for Regulatory Activities (MedDRA) Version 20.0.
Efficacy and safety analyses were performed on the full analysis set, which included all randomly assigned patients who received ≥1 dose of intranasal study medication and 1 dose of oral AD during the 4-week double-blind induction phase. Between-group differences in demographics and baseline characteristics were evaluated using t-tests for continuous variables or Chi-square tests for categorical variables. The extent to which baseline irritability and treatment impacted changes in mean depression severity (measured using MADRS total score) at day 28 was evaluated by analysis of covariance (ANCOVA) models, with fixed effects for treatment, level of irritability (high, varying, and low), study identification, and class of AD (selective serotonin reuptake inhibitor [SSRI] or serotonin norepinephrine reuptake inhibitor [SNRI]), and baseline value as a covariate. Rates of treatment response (≥50%
Journal Pre-proof decrease from baseline in MADRS total score) and remission (MADRS total score ≤12) at day 28 were examined using logistic regression models, including treatment, level of irritability, and study identification. The interaction term between treatment and irritability level was also examined within ANCOVA and logistic regression models. The number needed to treat (NNT) was estimated using both response and remission rates at Day 28. TEAEs were summarized descriptively. Withingroup and between-group differences in change in irritability scores from baseline to day 28 were evaluated using the Wilcoxon signed rank test and Wilcoxon rank sum test, respectively. There was no adjustment made for multiplicity.
The data sharing policy of Janssen Pharmaceutical Companies of Johnson & Johnson is available at. As noted on this site, requests for access to the study data can be submitted through Yale Open Data Access (YODA) Project site at.
The full analysis set comprised 560 patients (ESK+AD, n = 339; AD+PBO, n = 221). At baseline, 296 (52.9%) patients had high irritability, 130 (23.2%) had low irritability, and 134 (23.9%) had varying irritability. Demographics and baseline characteristics are shown in Table. Patients with high irritability at baseline were significantly younger at J o u r n a l P r e -p r o o f Journal Pre-proof the time of MDD diagnosis with higher body mass index (BMI) compared with patients in the low irritability group (all P < 0.05). They also had longer duration of the current MDE, more prior oral AD nonresponses in the current MDE, more frequent lifetime suicidal ideation/behavior, greater levels of anxiety symptoms, and a greater number of comorbid anxiety disorders than those in the low irritability group (all P < 0.05). MADRS scores were similar across all irritability groups at baseline. A total of 518 patients (ESK+AD, n = 310; AD+PBO, n = 208) had MADRS total score recorded at day 28 and were included in the post hoc analysis.
In the overall study population, a significantly greater improvement from baseline in MADRS total score at day 28 was observed among patients treated with ESK+AD compared with AD+PBO (least squares mean [LSM] change in MADRS score -19.9 vs -15.6, P < 0.001; Fig.). This pattern was statistically significant in both the low (P = 0.011) and varying (P = 0.008) irritability groups. The pattern failed to reach statistical significance in the high irritability group (P = 0.122), though numerically greater improvements in MADRS scores were observed in the ESK+AD group. There was no significant interaction between baseline irritability and treatment group (P = 0.267).
With the exception of remission among patients who had high irritability at baseline, NNTs to achieve response or remission were <10 for all comparisons, denoting that J o u r n a l P r e -p r o o f Journal Pre-proof ESK+AD is a potentially efficacious intervention for TRD regardless of baseline irritability (Fig.). In the overall study population, a significantly greater proportion of patients treated with ESK+AD compared with AD+PBO met the criteria for response (58.7% vs 45.2%, P < 0.001; Fig.) and remission (42.3% vs 30.8%, P = 0.004; Fig.) at day 28. At each level of baseline irritability, response and remission rates were numerically higher in the ESK+AD than the AD+PBO group, with no interaction observed between baseline irritability and response (P = 0.898) or remission (P = 0.411). For response, this differential improvement was statistically significant in the high irritability group (P = 0.049) but not in the varying and low groups (P = 0.198 and P = 0.128, respectively); for remission, a trend was evident for the varying and low irritability groups (P = 0.073 and P = 0.061, respectively) but not for the high irritability group (P = 0.308).
Patients treated with ESK+AD had almost two-fold (92%) increased odds of achieving treatment response at day 28 than those receiving AD+PBO in the overall study population (odds ratio [OR] 1.92, 95% CI 1.33-2.76; Fig.). An increased odds of achieving response with ESK+AD treatment was observed across all irritability groups and ranged from 79% to 121% (high baseline irritability: OR 1.79, 95% CI 1.09-2.93; varying baseline irritability: OR 1.85, 95% CI 0.88-3.88; low baseline irritability: OR 2.21, 95% CI 1.03-4.73).
Journal Pre-proof Patients treated with ESK+AD also had 75% increased odds of achieving treatment remission at day 28 than those receiving AD+PBO (OR 1.75, 95% CI 1.20-2.56; Fig.). This trend was evident across all irritability groups (high baseline irritability: OR 1.39, 95% CI 0.84-2.32; varying baseline irritability: OR 2.35, 95% CI 1.01-5.47; low baseline irritability: OR 2.31, 95% CI 1.07-4.97).
A significant within-group improvement from baseline in mean GAD-7 item 6 irritability score at day 28 was observed in all treatment groups, irrespective of baseline irritability (P ≤ 0.005) (Supplementary Table). No significant differences were observed between treatments, although a trend for a greater improvement from baseline with ESK+AD versus AD+PBO was evident in the high and varying irritability groups at day 28 (P = 0.087 and P = 0.084, respectively). The greatest median change from baseline (2-point improvement) was observed in the ESK+AD group with high baseline irritability.
Overall, ESK was generally well tolerated (Table). Adverse events (AEs) were similarly distributed across all irritability subgroups and were consistent with those reported for the overall population. Only 4 patients experienced ≥1 serious adverse event (SAE) (2 [1.11%] patients in the ESK+AD arm [road traffic accident/multiple injuries and depression] and 1 [0.86%,
Journal Pre-proof positional vertigo] in the AD+PBO arm of the high irritability group; 1 [1.in the ESK+AD arm of the low irritability group). During the double-blind treatment phase, the most common TEAEs observed in patients receiving ESK+AD treatment were nausea (16.7%-33.9%), dissociation (25.6%-30.9%), dizziness (18.0%-28.9%), dysgeusia/bitter taste (11.1%-26.9%), and vertigo (16.7%-35.9%).
In this post hoc analysis of pooled data from the TRANSFORM-1 and TRANSFORM-2 trials of ESK+AD versus AD+PBO in patients with TRD, high levels of irritability were reported by more than 50% of patients. Presence of irritability, in turn, was associated with younger age at MDD diagnosis, more lifetime suicidal ideation/behavior, higher levels of anxiety, and higher BMI. Overall, ESK+AD treatment was associated with greater improvement in depressive symptoms and higher rates of response and remission than AD+PBO in patients with TRD. ESK also demonstrated an acceptable safety profile across irritability subgroups, consistent with the overall study population and previous reports. Regardless of the level of baseline irritability, the general pattern of results did not differ; response and remission rates based on the MADRS total score were numerically higher in the ESK+AD group than in the AD+PBO group. Analyses of MADRS improvement across the pooled 28-day trials suggest a greater advantage for ESK+AD in the low and varying irritability groups. However, closer inspection of the NNT to achieve response or remission may provide more insight. The NNT to achieve response J o u r n a l P r e -p r o o f is consistent between irritability groups and in line with the NNT across the ESK development program. In contrast, the NNT to achieve remission in the high irritability group is noticeably higher (N = 16) than that seen in the low and varying irritability groups (N <10). Among patients with depressive disorders, a generally accepted rule of thumb is that NNTs <10 for efficacy measures suggest that the intervention is potentially beneficialand NNTs <5 suggest that the intervention is likely to be clinically important. Thus, reaching a clinically meaningful level of improvement (as quantified by response) was consistent regardless of baseline level of irritability; however, treating to remission may be a greater challenge among those with high irritability at baseline. Prospective studies are needed to replicate these findings. Baseline characteristics of patients with TRD and high versus low irritability aligned with findings reported in prior publications for patients with MDD and irritability. Compared with the low baseline irritability group, high baseline irritability was associated with younger age at time of MDD diagnosis, longer duration of the current MDE, more prior oral AD nonresponses in the current MDE, more frequent lifetime suicidal ideation/behavior, greater levels of anxiety, and a greater number of comorbid anxiety disorders. Notably, the overall depressive symptom severity at baseline did not differ among the three groups, suggesting that a commonly used measure of depression in adults (the MADRS) does not fully capture the syndromic burden associated with irritability. These observations add to the existing literature base, suggesting a more chronic and severe course of illness in individuals with MDD or TRD and concurrent irritability.
The biological mechanisms responsible for the association between irritability and more severe illness course remain poorly understood, especially in adults with MDD, given that most neuroimaging research to date has focused on irritability in pediatric patients. Aberrant response to threat is one of the possible mechanisms that links irritability to anxiety in previous studies of youths with irritability. Aberrant response to frustration in response to an anticipated reward may link irritability to the anger and aggression, which are in turn associated with features such as suicidality and impaired long-term quality of life and social functioning. Future studies are needed to comprehensively assess irritability in adults with MDD, including those with TRD, to evaluate its impact on the syndromic presentation, longer-term course, and response to antidepressant treatments. Irrespective of treatment arm, irritability symptoms improved across all subgroups in the current analysis, with patients with high baseline irritability in the ESK+AD group showing the greatest improvement in irritability scores. Further studies will be needed to fully evaluate the effect of ESK on irritability in patients with TRD, ideally using a more comprehensive measure of irritability that provides a larger range of patient responses and in a sample that is enriched for individuals who have high levels of irritability. Several limitations should be considered when interpreting the findings of the current study. This post hoc analysis was based on pooled data from two randomized controlled trials that were not designed to prospectively evaluate predetermined irritability outcomes. Additionally, the small number of patients in each subgroup limits statistical power for subgroup analyses and there was no adjustment made for J o u r n a l P r e -p r o o f multiplicity. Though there is precedent for using a single item of the GAD-7 to assess irritability, it is unlikely to represent the full range of irritability as a construct and provides no insight into the perspectives of care partners or other knowledgeable informants. Further exploration of these effects with a more comprehensive measure of irritability, both via self-and informant-reporting, would likely provide valuable insights and a greater range of potential patient/informant responses that are more amenable to statistical analysis. Given that irritability was associated with other characteristics (such as number of prior ADs that resulted in nonresponse, comorbid anxiety, and higher BMI), findings of this report, such as an association between irritability and suicidality, may be confounded by those characteristics. A further limitation of this study is that the participants included in this report were predominantly White. Future studies in more diverse groups of participants are needed to replicate and extend these findings to improve generalizability. In conclusion, this post hoc analysis supports the efficacy of esketamine nasal spray in patients with TRD, regardless of irritability at baseline, and provides preliminary evidence that esketamine nasal spray may reduce irritability symptoms in patients with TRD. J o u r n a l P r e -p r o o f Logistic regression models included study identification, treatment, irritability (high, varying vs low) and interaction of treatment and irritability (high, varying vs low) as predictors.
J o u r n a l P r e -p r o o f
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The purpose of this study is to compare the efficacy and safety of switching treatment-resistant depression (TRD) subjects from a prior antidepressant treatment (to which they have not responded) to either intranasal esketamine plus a new oral antidepressant or switching to a new oral antidepressant plus intranasal placebo.
Papers in Blossom that reference this study
Reif, A., Bitter, I., Buyze, J. et al. · New England Journal of Medicine (2023)