Does the intensity of dissociation predict antidepressant effects 24 hours after infusion of racemic ketamine and esketamine in treatment-resistant depression? A secondary analysis from a randomized controlled trial.

BACKGROUND: Ketamine and esketamine have both shown significant antidepressant effects in treatment-resistant depression (TRD), and conflicting evidence suggests that induced dissociation by these drugs can be a clinical predictor of esketamine/ketamine's efficacy. METHODS: This study is a secondary analysis from a bi-center, randomized, controlled trial. Participants were randomly assigned 1:1 to receive an IV infusion of esketamine (.25 mg/kg) or racemic ketamine (.50 mg/kg) over 40 minutes. Dissociative symptoms were assessed using the Clinician-Administered Dissociative State Scale (CADSS) 40 minutes following the beginning of the infusion. The variation in depression scores was measured with the Montgomery-Asberg Depression Rating Scale (MADRS), which was administered before the intervention as a baseline measure and 24 hrs, 72 hrs, and 7 days following infusion. RESULTS: Sixty-one patients were included in the analysis. Examining CADSS scores of 15 or below, for every 1-point increment in the CADSS score, there was a mean change of -0.5 (SD = 0.25; p-value 0.04) of predicted MADRS score from baseline to 24 hrs. The results for 72 hrs and 7 days following infusion were not significant. Limitations: This study was not designed to assess the relationship between ketamine or esketamine-induced dissociation and antidepressant effects as the main outcome, therefore confounding variables for this relationship were not controlled. CONCLUSION: We suggest a positive relationship between dissociation intensity, measured by CADSS, and antidepressant effect 24 hours after ketamine and esketamine infusion for a CADSS score of up to 15 points.

Arketamine for bipolar depression: Open-label, dose-escalation, pilot study.

There are significantly fewer options for the treatment of bipolar depression than major depressive disorder, with an urgent need for alternative therapies. In this pilot study, we treated six subjects with bipolar disorder types I and II (according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria) who had been in a current depressive episode for at least four weeks. Four subjects were female (66.66%), and the mean age was 45.33 (±12.32). Subjects received adjunct treatment with two arketamine intravenous infusions one week apart-0.5 mg/kg first and then 1 mg/kg. The mean baseline Montgomery-Åsberg Depression Rating Scale (MADRS) total score was 36.66, which decreased to 27.83 24h after the first infusion of 0.5 mg/kg of arketamine (p = 0.036). In respect of the 1 mg/kg dose, the mean MADRS total score before the second infusion was 32.0, which dropped to 17.66 after 24h (p < 0.001). Arketamine appears to have rapid-acting antidepressant properties, consistent with previous animal studies on major depression. All individuals tolerated both doses, exhibiting nearly absent dissociation, and no manic symptoms. To the best of our knowledge, this pilot trial is the first to test the feasibility and safety of the (R)-enantiomer of ketamine (arketamine) for bipolar depression.

Gravidade da depressão, resposta ao tratamento e PRO (incapacidade e QoL) em pacientes com DRT em um ano de acompanhamento com tratamento padrão: análise do subgrupo brasileiro do estudo observacional multinacional TRAL / Depression severity, treatment response and PRO (disability and QoL) in TRD patients over a 1-year follow-up with standard of care: Analysis of the Brazilian subset of the multicenter, observational TRAL study

Objetivo: A depressão resistente ao tratamento (DRT) é uma preocupação primária no Brasil devido à sua natureza onerosa e complexa, enquanto o diagnóstico e o tratamento geralmente são desafiadores. O presente manuscrito apresenta os resultados clínicos de um ano de acompanhamento em pacientes com DRT em tratamento padrão (SOC) no subgrupo brasileiro do estudo de Depressão Resistente ao Tratamento na América Latina (TRAL). Métodos: Essa fase longitudinal do estudo TRAL tinha como meta caracterizar alterações nos resultados clínicos e outras variáveis de interesse (p. ex., qualidade de vida, incapacidade) em um ano de acompanhamento em pacientes com DRT em 10 centros no Brasil. Os pacientes incluídos tinham diagnóstico clínico de DRT com base nos critérios DSM-5 e confirmado por MINI. A Escala de Depressão de Montgomery-Asberg (MADRS) era usada para avaliar a gravidade da doença e os resultados clínicos. Outras escalas de depressão e instrumentos classificados pelo paciente eram usadas para medir resultados correlacionados. Resultados: Cento e cinquenta e oito pacientes com DRT, na maioria mulheres (84,4%) com idade média de 48,55 anos, foram incluídos na análise. Apenas 31,4% dos pacientes apresentaram uma resposta clinicamente significativa, 10,3% tiveram recidiva e 26,7% alcançaram remissão, conforme medido pela MADRS no final do estudo (EOS). Aproximadamente 55% dos pacientes apresentavam depressão grave/moderadamente grave no EOS. Problemas de mobilidade, cuidados pessoais, problemas nas atividades usuais e dor e desconforto foram relatados pela maioria dos pacientes no EOS, assim como comprometimento marcado/extremo das atividades no trabalho/escola e da vida social/das atividades de lazer no EOS. Conclusões: Os resultados clínicos alcançados atualmente ainda são notavelmente insatisfatórios para DRT. Portanto, o envolvimento de todas as partes interessadas é essencial para implementar protocolos de tratamento mais eficazes no Brasil.

Objective: Treatment-resistant depression (TRD) is a primary concern in Brazil due to its burdensome and complex nature, while diagnosis and treatment is often challenging. The current manuscript presents the clinical outcomes in a one-year follow-up of TRD patients under Standard-of-care (SOC) in the Brazilian subset of the Treatment-Resistant Depression in America Latina (TRAL) study. Methods: This longitudinal phase of TRAL aimed to characterize changes in the clinical outcomes and other variables of interest (e.g. quality of life, disability) in a one-year follow-up of TRD patients in 10 centers in Brazil. Included patients were clinically diagnosed with TRD based on DSM-5 criteria and confirmed by MINI. Montgomery-Asberg Depression Rating Scale (MADRS) was used to assess disease severity and clinical outcomes. Other depression scales and patient rated instruments were used to measure correlated outcomes. Results: One hundred fifty-eight TRD patients, mostly female (84.4%), averaging 48.55 years, were included in the analysis. Only 31.4% of the patients showed a clinically significant response, 10.3% had a relapse and 26.7% achieved remission, as measured through MADRS at end-of-study (EOS). Almost 55% of the patients showed moderately severe/severe depression at EOS. Mobility issues, self-care, problems with usual activities and pain and discomfort were reported by the majority of the patients at EOS, as well as marked/extreme disruption of school/work and social life/leisure activities at EOS. Conclusions: Currently achieved clinical outcomes are still remarkably unsatisfactory for TRD. Therefore, the involvement of all relevant stakeholders is essential to implement more effective treatment protocols in Brazil.

Arketamine as adjunctive therapy for treatment-resistant depression: A placebo-controlled pilot study.

BACKGROUND: Racemic ketamine is a mixture of (R)-ketamine (arketamine) and (S)-ketamine (esketamine), with the latter regarded as the main isomer for antidepressant effects. However, preclinical data and one open-label human trial suggest arketamine might exert a more potent and longer-lasting antidepressant effect with fewer side effects. We aimed to explore the feasibility of a randomized controlled trial of arketamine for treatment-resistant depression (TRD) and to assess its efficacy and safety compared to placebo. METHODS: This is a, randomized, double-blind, crossover, pilot trial (n = 10). All participants received saline and arketamine (0.5 mg/kg) with a one-week interval. Treatment effects were analyzed with a linear mixed effects (LME) model. RESULTS: Our analysis suggested the presence of a carryover effect, so the main efficacy analysis was limited to the first week, which demonstrated a main effect of time (p = 0.038) but not for treatment (p = 0.40) or their interaction (p = 0.95). This indicates that depression improved over time, but without significant difference between arketamine and placebo. Analyzing the two weeks together, findings were the same. Dissociation and other adverse events were minimal. LIMITATIONS: This was a pilot study with a small sample and underpowered. CONCLUSIONS: Arketamine was not superior to placebo for TRD but demonstrated to be extremely safe. Our findings reinforce the importance of continuing studies with this drug, with better powered clinical trials, perhaps considering a parallel design with higher or flexible doses and repeated administrations.

Brain-derived neurotrophic factor serum levels following ketamine and esketamine intervention for treatment-resistant depression: secondary analysis from a randomized trial.

OBJECTIVES: Evidence suggests that ketamine's influence on brain-derived neurotrophic factor (BDNF) might be involved in its mechanism of rapid antidepressant action. We aimed to evaluate the differential impact of ketamine and esketamine on serum BDNF levels and its association with response patterns in treatment-resistant depression (TRD). METHODS: Participants (n = 53) are from a randomized, double-blind clinical trial comparing the efficacy of single-dose ketamine (0.5mg/kg, n = 27) and esketamine (0.25mg/kg, n = 26) in TRD. Depression severity was assessed before and 24 hours, 72 hours, and 7 days after the intervention, using the Montgomery-Åsberg Depression Rating Scale (MADRS). Blood samples were collected before infusion, 24 hours, and 7 days afterwards. RESULTS: There were no significant changes in BDNF levels at post-infusion evaluation points, and no difference in BDNF levels comparing ketamine and esketamine. Both drugs exhibited similar therapeutic effect. There was no association between BDNF levels and response to treatment or severity of depressive symptoms. CONCLUSION: There was no significant treatment impact on BDNF serum levels - neither with ketamine nor esketamine - despite therapeutic response. These results suggest that ketamine or esketamine intervention for TRD has no impact on BDNF levels measured at 24 hours and 7 days after the infusion.

Brain-derived neurotrophic factor serum levels following ketamine and esketamine intervention for treatment-resistant depression: secondary analysis from a randomized trial

Abstract Objectives Evidence suggests that ketamine's influence on brain-derived neurotrophic factor (BDNF) might be involved in its mechanism of rapid antidepressant action. We aimed to evaluate the differential impact of ketamine and esketamine on serum BDNF levels and its association with response patterns in treatment-resistant depression (TRD). Methods Participants (n = 53) are from a randomized, double-blind clinical trial comparing the efficacy of single-dose ketamine (0.5mg/kg, n = 27) and esketamine (0.25mg/kg, n = 26) in TRD. Depression severity was assessed before and 24 hours, 72 hours, and 7 days after the intervention, using the Montgomery-Åsberg Depression Rating Scale (MADRS). Blood samples were collected before infusion, 24 hours, and 7 days afterwards. Results There were no significant changes in BDNF levels at post-infusion evaluation points, and no difference in BDNF levels comparing ketamine and esketamine. Both drugs exhibited similar therapeutic effect. There was no association between BDNF levels and response to treatment or severity of depressive symptoms. Conclusion There was no significant treatment impact on BDNF serum levels - neither with ketamine nor esketamine - despite therapeutic response. These results suggest that ketamine or esketamine intervention for TRD has no impact on BDNF levels measured at 24 hours and 7 days after the infusion. This clinical trial is registered on the Japan Primary Registries Network: UMIN000032355.

Effects of GRIN2B , GRIA1 , and BDNF Polymorphisms on the Therapeutic Action of Ketamine and Esketamine in Treatment-Resistant Depression Patients: Secondary Analysis From a Randomized Clinical Trial.

OBJECTIVE: This study aimed to evaluate the effect of genetic variants in glutamate ionotropic receptor N-methyl- d -aspartate type subunit 2B ( GRIN2B ), glutamate ionotropic receptor α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid type subunit 1 ( GRIA1 ), and brain-derived neurotrophic factor ( BDNF ) genes on therapeutic response, remission, and total Montgomery-Åsberg Depression Rating Scale scores after treatment with ketamine or esketamine in treatment-resistant depression (TRD) patients. METHODS: Participants (N = 60) are from a double-blind, randomized, noninferiority clinical trial comparing single-dose intravenous ketamine (0.5 mg/kg) to esketamine (0.25 mg/kg) for TRD. Montgomery-Åsberg Depression Rating Scale was applied at baseline, 24 hours, 72 hours, and 7 days postinfusion to assess depressive symptoms. Blood samples were collected to evaluate single nucleotide polymorphisms rs1805502 ( GRIN2B ), rs1994862 ( GRIA1 ), and rs6265 ( BDNF ). RESULTS: There was no association between rs1805502, rs1994862, or rs6265 polymorphisms and antidepressant response ( P = 0.909, P = 0.776, and P = 0.482, respectively), remission P = 0.790, P = 0.086, and P = 0.669), or Montgomery-Åsberg Depression Rating Scale scores at each time point ( P = 0.907, P = 0.552, and P = 0.778). CONCLUSIONS: We found no association between the studied single nucleotide polymorphisms (rs6265, rs1805502, and rs1994862) and ketamine's therapeutic action in TRD patients. Further studies with larger samples are needed to clarify the utility of these genes of interest as predictors for antidepressant treatment.

Efficacy and Safety of Subcutaneous Esketamine in the Treatment of Suicidality in Major Depressive Disorder and Bipolar Depression.

BACKGROUND AND OBJECTIVE: Affective disorders account for most cases of suicide. The pharmacological arsenal to treat suicidality is limited and available agents take too long to take effect. A large body of evidence shows optimal results of ketamine for treating depression, but the evidence concerning suicidality has not been fully described. We report the first real-world study of severely depressed patients presenting with suicide ideation who were treated with repeated administration of subcutaneous esketamine. METHODS: We analyzed data from 70 acutely depressed subjects diagnosed with resistant major depressive disorder or bipolar depression. Subjects were administered subcutaneous esketamine once a week for 6 weeks. The primary efficacy endpoint, the change from baseline to 24-h post-administration 6 in the item 10 Montgomery-Åsberg Depression Rating Scale score, was analyzed using a mixed-effects repeated-measures model. RESULTS: There were significant effects for time on item 10 Montgomery-Åsberg Depression Rating Scale scores (p < 0.0001) but not for a time × diagnosis interaction (p = 0.164) from baseline to the end of the study. Efficacy of esketamine did not differ between groups (major depressive disorder vs bipolar depression) at any timepoint. Statistical significance on suicidality scores was observed from 24 h after the first administration (p < 0.001), and a further reduction was observed with repeated administrations. Esketamine was safe and well tolerated. Mean heart rate remained stable during the administrations and the blood pressure increase was self-limited. CONCLUSIONS: Repeated subcutaneous esketamine administration had significant anti-suicidality effects in both major depressive disorder and bipolar groups, with a rapid onset of action and a good tolerability profile. Large randomized controlled trials are warranted to confirm these preliminary findings.

Esketamine for Unipolar Major Depression With Psychotic Features: A Retrospective Chart Review and Comparison With Nonpsychotic Depression.

PURPOSES/BACKGROUND: The aims of the study were to assess subanesthetic esketamine as an antidepressant for major depressive disorder with psychotic features (PMDD) and to compare posttreatment symptoms among those with PMDD to a sample of nonpsychotic depression (major depressive disorder [MDD]). METHODS/PROCEDURES: This study is a retrospective chart review of patients with major depression and current psychotic symptoms, treated with a single parenteral 0.5-mg/kg dose of esketamine. Depression symptoms were assessed at baseline and 24-hour posttreatment with the Montgomery-Åsberg Depression Rating Scale. Individuals with PMDD were matched in a 1:2 ratio to nonpsychotic MDD patients from a randomized, noninferiority clinical trial of esketamine. FINDINGS/RESULTS: A total of 15 individuals with PMDD were included, which had higher baseline depression scores (PMDD = 40.9, MDD = 33.6, P = 0.004). A statistically significant change in depressive symptoms was found for the PMDD sample (ß = -16.20 [95% confidence interval, -23.30 to -9.10], P < 0.001), and no difference between PMDD and MDD groups was observed in the matched-sample analysis (ß = -2.2 [95% confidence interval, -9.32 to 4.58], P = 0.537). Treatment-induced dissociative symptoms were present for both groups, self-contained to within 2 hours after treatment, and no exacerbation of psychotic symptoms was found in clinical assessments. IMPLICATIONS/CONCLUSIONS: Results suggest a single 0.5-mg/kg dose of esketamine may benefit individuals with PMDD, and the symptom reduction may be comparable with esketamine's effects for MDD. Furthermore, esketamine may induce an antidepressant response in those with PMDD without complication of psychotic symptoms. Future research with controlled designs is warranted.

Suicide attempt, impulsivity, and exposure to trauma in college students

Objectives: Past suicide attempt (SA) is one of the most important risk factors for suicide death. An ideation-to-action framework posits that impulsivity, potentially traumatic events, and mental disorders also play a role in increasing suicide risk. This study aimed to assess the association between trait impulsivity, lifetime exposure to trauma, and post-traumatic stress disorder (PTSD) with SA in a sample of Brazilian college students. Methods: A total of 2,137 participants filled self-reported questionnaires consisting of a sociodemographic and clinical questionnaire, Trauma History Questionnaire, Post-Traumatic Stress Disorder Checklist - Civilian version, and Barratt Impulsiveness Scale. Results: Our findings suggest that trait impulsivity may be interpreted as exerting a distal effect on SA, even in the presence of other variables - such as trauma history, psychological neglect, and PTSD - which also increase the odds of SA. High and medium levels of impulsivity, history of trauma, and PTSD increased the likelihood of SA. Conclusions: Intervention strategies to prevent SA may target trait impulsivity and exposure to traumatic experiences.

Allergic reaction induced by subcutaneous administration of ketamine: a case report.

Ketamine can be used for depression and suicidal ideation due to its effectiveness and low complication rates; moreover, allergic reactions are rare. Immediately after subcutaneous (SC) ketamine administration, a 22-year-old man rapidly developed hives on the trunk and face without oxygen desaturation. Symptoms disappeared after treatment with prednisolone. This case presents an allergic reaction to ketamine compatible with mast cell activation and release of preformed mediators, without being able to prove whether the event was mediated by immunoglobulin E. This is the only case reported to date of an allergic reaction to SC ketamine for psychiatric treatment.

Suicide attempt, impulsivity, and exposure to trauma in college students.

OBJECTIVES: Past suicide attempt (SA) is one of the most important risk factors for suicide death. An ideation-to-action framework posits that impulsivity, potentially traumatic events, and mental disorders also play a role in increasing suicide risk. This study aimed to assess the association between trait impulsivity, lifetime exposure to trauma, and post-traumatic stress disorder (PTSD) with SA in a sample of Brazilian college students. METHODS: A total of 2,137 participants filled self-reported questionnaires consisting of a sociodemographic and clinical questionnaire, Trauma History Questionnaire, Post-Traumatic Stress Disorder Checklist - Civilian version, and Barratt Impulsiveness Scale. RESULTS: Our findings suggest that trait impulsivity may be interpreted as exerting a distal effect on SA, even in the presence of other variables - such as trauma history, psychological neglect, and PTSD - which also increase the odds of SA. High and medium levels of impulsivity, history of trauma, and PTSD increased the likelihood of SA. CONCLUSIONS: Intervention strategies to prevent SA may target trait impulsivity and exposure to traumatic experiences.

Clinical predictors of depressive symptom remission and response after racemic ketamine and esketamine infusion in treatment-resistant depression.

BACKGROUND: Major depressive disorder (MDD) is a leading cause of disability worldwide and most people do not achieve symptom remission. Treatment-resistant depression (TRD) is characterized by the failure of at least one adequate trial of a major class of antidepressant, with adequate time and dosage. We aimed to identify clinical predictors of depressive symptom remission and response 24 h and 7 days after racemic ketamine and esketamine infusions. METHODS: A randomized, double-blind, active-controlled, non-inferiority trial using ketamine and esketamine in TRD. Individuals diagnosed with MDD according to Diagnostic and Statistical Manual of Mental Disorders version IV and fulfilling TRD criteria were recruited from March 2017 to June 2018. Participants received a single subanesthetic dose of ketamine (0.5 mg/kg) or esketamine (0.25 mg/kg) for 40 min. Depressive symptoms were assessed using the Montgomery-Åsberg Depression Rating Scale (MADRS) and symptom remission was defined as a MADRS score ≤7 and response defined as ≥50% reduction in depressive symptom severity, 24 h and 7 days after the infusion. Clinical variables were selected based on previous clinical trials. Stepwise backward logistic regression was used, considering a confidence level of 95%. RESULTS: 61 subjects were included: 39 (63.9%) were females with a mean age of 47.2 ± 14.9. Higher number of therapeutic failures (Odds Ratio (OR) = 0.677; 95% confidence interval (CI): 0.47-0.97) and higher severity of illness (OR = 0.912; 95% CI: 0.83-0.99) were associated with fewer remissions of depressive symptoms 7 days after intervention, and with fewer response in 24 h (OR = 0.583; 95% CI: 0,40; 0,84 and OR = 0.909; 95% CI: 0,83; 0,99, respectively). CONCLUSION: Number of treatment failures and severity of illness were predictors of fewer remissions and responses of depressive symptoms in this TRD population. Study of predictors of remission may contribute to better selection patients that may benefit from receiving ketamine.

Impact of Repeated Doses of Subcutaneous Esketamine on Acute Dissociative Symptoms in Treatment-Resistant Depression.

BACKGROUND: Esketamine has been approved by the US Food and Drug Administration (FDA) as an adjunctive treatment for use in conjunction with an oral antidepressant for patients with treatment-resistant depression (TRD), but dissociative symptoms are common adverse effects. METHODS: A retrospective analysis of 394 subcutaneous esketamine injections given to 70 patients with TRD that were administered once a week during a six-week trial in conjunction with oral antidepressant therapy. Doses between 0.5 to 1.0 mg/kg were administered according to the patient's response. Dissociative symptoms were assessed using the Clinician-Administered Dissociative States Scale (CADSS) 30 and 60 min after every weekly treatment (day 1, 8, 15, 22, 29 and 36). RESULTS: Seventy patients received a total of 394 subcutaneous esketamine injections over six weeks. Over time, the evolution of CADSS scores demonstrated a significant mean difference of CADSS at 60 min post-injection (p = 0.010) throughout the six infusions. The mean CADSS scores at 60 min on day 22, 29 and 36 were similar. There were no differences between mean CADSS scores 30 min after the injections, no clinical correlation between response and dissociative symptoms, no correlation between time and demographic and clinical characteristics and no interactions between time and combined medication. CONCLUSIONS: Our results suggest that repeated subcutaneous esketamine doses are safe and well-tolerated regarding their acute dissociative and psychotomimetic symptoms. Symptoms usually peak at 30 min and decrease at 60 min post-injection, returning to their pretreatment levels at 120 min. Dissociative symptoms do not correlate with antidepressant response.

What is the Best Latent Structure of Negative Symptoms in Schizophrenia? A Systematic Review.

BACKGROUND: Determining the best latent structure of negative symptoms in schizophrenia could benefit assessment tools, neurobiological research, and targeted interventions. However, no review systematically evaluated studies that assessed and validated latent models of negative symptoms. OBJECTIVE: To identify and evaluate existing latent structure models in the literature of negative symptoms and to determine the best model. METHOD: Systematic search of MEDLINE, EMBASE, and Scopus on July 19, 2020, for confirmatory factor analysis models of negative symptoms in patients with schizophrenia. The available evidence was assessed through 2 sets of criteria: (1) study design quality-based on negative symptoms assessment and modeling strategy and (2) psychometric quality and model fit-based on fit indices and factor definition quality. RESULTS: In total, 22 studies (n = 17 086) from 9 countries were included. Studies differed greatly regarding symptom scales, setting, and sample size (range = 86-6889). Dimensional models included 2-6 factors (median = 4). Twelve studies evaluated competing models and adopted appropriate instruments to assess the latent structure of negative symptoms. The 5-factor and hierarchical models outperformed unitary, 2-factor, and 3-factor models on all direct comparisons, and most of the analyses derived from the Brief Negative Symptom Scale. Considering the quality criteria proposed, 5-factor and hierarchical models achieved excellent fit in just one study. CONCLUSIONS: Our review points out that the 5-factor and hierarchical models represent the best latent structure of negative symptoms, but the immaturity of the relevant current literature may affect the robustness of this conclusion. Future studies should address current limitations regarding psychometric properties and also address biological and clinical validity to refine available models.

The probability of response after each subcutaneous injection of esketamine in treatment-resistant depression.

INTRODUCTION: The administration of multiple esketamine doses has shown efficacy for unipolar and bipolar treatment-resistant depression (TRD). Nevertheless, the probability of responding or not after each dose in the real-world remains unknown. This study aimed to estimate it throughout four doses of esketamine, administrated via subcutaneous (SC). MATERIAL AND METHODS: We conducted a retrospective analysis of a case series of 70 patients with TRD who received treatment from the esketamine assistance program at Federal University of Sao Paulo, between April 2017 and December 2018. The SC injections were administrated weekly at a dose of 0.5-1.0mg/kg, in conjunction with patients' psychotropic drugs. Response was defined as a decrease of at least 50% in the Montgomery-Åsberg Depression Rating Scale between baseline and 24h after dose. We used hidden Markov modeling in order to estimate de probability of response after each esketamine injection. RESULTS: The probability of a patient that was a "non-responder" to become a "responder" following a SC injection of esketamine was 17.30% and the probability that this patient remains a "non-responder" was 82.70%. The probability of a patient that was a "responder" to remain as a "responder" was 95%. CONCLUSIONS: Patients with TRD who had not responded after the first dose of esketamine, still had a chance of responding after the subsequent dose administrated via SC.