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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.
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Transtorno Depressivo Maior , Transtorno Depressivo Resistente a Tratamento , Administração Intranasal , Antidepressivos/uso terapêutico , Depressão , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Resistente a Tratamento/tratamento farmacológico , Humanos , Ketamina , Estudos RetrospectivosRESUMO
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.
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Transtorno Depressivo Maior , Transtorno Depressivo Resistente a Tratamento , Ketamina , Adulto , Depressão , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Resistente a Tratamento/diagnóstico , Transtorno Depressivo Resistente a Tratamento/tratamento farmacológico , Método Duplo-Cego , Feminino , Humanos , Ketamina/uso terapêutico , Masculino , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
We aimed to analyze the efficacy and safety of arketamine, the R(-)-enantiomer of ketamine, for treatment-resistant depression (TRD) in humans. Open-label pilot trial, seven subjects with TRD received a single intravenous infusion of arketamine (0.5 mg/kg); primary outcome was change in Montgomery-Åsberg Depression Rating Scale (MADRS) 24 h after. Mean MADRS dropped from 30.7 before infusion to 10.4 after one day, a mean difference of 20.3 points [CI 95% 13.6-27.0; p < 0.001]; dissociation was nearly absent. Arketamine might produce fast-onset and sustained antidepressant effects in humans with favorable safety profile, like previously reported with animals; further controlled-trials are needed.
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Antidepressivos/farmacologia , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Resistente a Tratamento/tratamento farmacológico , Ketamina/farmacologia , Avaliação de Resultados em Cuidados de Saúde , Adulto , Idoso , Antidepressivos/administração & dosagem , Antidepressivos/efeitos adversos , Feminino , Humanos , Infusões Intravenosas , Ketamina/administração & dosagem , Ketamina/efeitos adversos , Pessoa de Meia-Idade , Projetos Piloto , Escalas de Graduação Psiquiátrica , Indução de Remissão , Índice de Gravidade de DoençaRESUMO
INTRODUCTION: Catatonia, documented since the 19th century, remains a significant challenge in terms of recognition and treatment. Over the last two decades, ketamine has brought new perspectives to psychiatry, sparking widespread interest. Concurrently, catatonia has attracted heightened scientific attention. Preliminary evidence suggests the therapeutic potential of ketamine for catatonia. METHODS: We systematically searched Medline/PubMed, Embase, PsycINFO, Lilacs, and Cochrane Library databases, as well as Google Scholar, for studies with ketamine or its enantiomers as intervention for catatonia, with no restrictions to underlying diagnosis, date, language, or study design. RESULTS: Twenty articles were included, encompassing a total of 25 catatonic patients receiving ketamine or esketamine. Predominantly female (61.9 %), with a mean age of 44.4 years, patients mostly exhibited manifestations compatible with the retarded subtype of catatonia. Mood disorders were the most prevalent underlying diagnoses. Ketamine was primarily administered intravenously over a 40-minute period and in multiple-dosing schemes. Mean response and remission rates of catatonic manifestations for the whole sample were 80 % and 44 %, respectively, with no reports of worsening catatonic features or psychotic symptoms. Only one patient discontinued treatment due to intolerable dissociative effects. CONCLUSION: Challenging the conventional contraindication of ketamine in psychotic disorders, current evidence highlights its potential efficacy, particularly in treating catatonia. Pending further research, we advocate reevaluating this contraindication, as it may offer a promising therapeutic option, especially for challenging cases. Preliminary evidence suggests potentially greater benefits for catatonic patients with underlying mood disorders compared to primary psychotic disorders.
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OBJECTIVE: Converging evidence supports the role of the glutamate, an excitatory amino acid neurotransmitter, in the pathophysiology of obsessive-compulsive disorder (OCD). Ketamine and esketamine, both noncompetitive N -methyl- d -aspartate antagonists, have emerged as a promising medication for this psychiatric disorder, given its possible efficacy with faster onset and good tolerability. The purpose of this retrospective chart review is to evaluate whether unbiased clinical documentation supports formal clinical trials of esketamine for an OCD indication. METHODS: A retrospective chart review of patients with treatment-resistant OCD receiving a single dose of esketamine (0.5mg/kg) added to standard therapy was conducted. The Yale-Brown Obsessive-Compulsive Scale and the Montgomery-Åsberg Depression Rating Scale were used to evaluate OCD and depressive symptoms respectively at baseline, 24 hours, and 7 days after esketamine administration. Descriptive statistics were used to analyze the data. RESULTS: Eight subjects were identified in this retrospective chart review: esketamine was administered subcutaneously in 7 and intravenously in 1. One week after infusion, 25% of the sample met criteria for treatment response and 50% for partial response. Major depressive disorder was a comorbid diagnosis in 75% of the sample and 2 of these subjects showed a positive antidepressant response. CONCLUSIONS: Our findings provide preliminary evidence that esketamine may reduce obsessive-compulsive symptoms in a subset of treatment-resistant OCD patients.
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Transtorno Depressivo Maior , Ketamina , Transtorno Obsessivo-Compulsivo , Humanos , Ketamina/uso terapêutico , Transtorno Depressivo Maior/tratamento farmacológico , Estudos Retrospectivos , Resultado do Tratamento , Transtorno Obsessivo-Compulsivo/tratamento farmacológico , Transtorno Obsessivo-Compulsivo/diagnósticoRESUMO
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.
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Transtorno Bipolar , Transtorno Depressivo Maior , Ketamina , Feminino , Humanos , Masculino , Antidepressivos/uso terapêutico , Transtorno Bipolar/tratamento farmacológico , Transtorno Bipolar/diagnóstico , Depressão , Transtorno Depressivo Maior/tratamento farmacológico , Método Duplo-Cego , Projetos Piloto , Resultado do TratamentoRESUMO
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.
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Transtorno Depressivo Resistente a Tratamento , Ketamina , Humanos , Fator Neurotrófico Derivado do Encéfalo , Ketamina/uso terapêutico , Depressão , Transtorno Depressivo Resistente a Tratamento/tratamento farmacológicoRESUMO
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.
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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.
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Depressão , Transtorno Depressivo Resistente a Tratamento , Humanos , Projetos Piloto , Depressão/tratamento farmacológico , Antidepressivos/efeitos adversos , Quimioterapia Combinada , Transtorno Depressivo Resistente a Tratamento/tratamento farmacológico , Método Duplo-Cego , Resultado do TratamentoRESUMO
Dissociative symptoms are common, possibly severe, side effects associated with the use of ketamine and esketamine in depression. We investigated the relationship between trait dissociation and dissociation induced by ketamine and esketamine used as augmentation therapy in treatment-resistant depression (TRD). Adults with TRD were randomly assigned to receive a single intravenous infusion, with a duration of 40 min, of either esketamine 0.25 mg/kg or ketamine 0.5 mg/kg. We assessed trait dissociation with the Dissociative Experience Scale (DES) and, to evaluate induced dissociation, the Clinician-Administered Dissociative States Scale (CADSS) was used. Thirty-two subjects received esketamine and 29 received ketamine. The groups had similar median DES scores (p = 0.26). More than 30% of the patients in both groups had DES scores ≥30 points. The median CADSS score in the esketamine group was equivalent to that in the ketamine group (p = 0.40). Every 5 points increment in the DES was associated with a 10.9% (95% CI 4.5-17.8%) increase in the CADSS, in an exponential fashion when the two groups were pooled together. Subjects with high trait dissociation had a higher risk of induced dissociation state (relative risk [RR] 1.41, 95% CI 1.11-1.78) and very high induced dissociation (RR 3.05, 95% CI 1.14-8.15). Induced dissociation was not a serious adverse effect. The findings suggest that trait dissociation is a predictor of induced dissociation by Ketamine or Esketamine in TRD subjects. Screening for trait dissociation and counseling patients with high trait dissociation on the risks of dissociation by these drugs are recommended.
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Transtorno Depressivo Resistente a Tratamento , Ketamina , Adulto , Antidepressivos/efeitos adversos , Depressão , Transtorno Depressivo Resistente a Tratamento/tratamento farmacológico , Humanos , Ketamina/efeitos adversosRESUMO
The objective of this study is to evaluate cognition in patients using either ketamine or esketamine to treat TRD. We also evaluate if both ketamine and esketamine as one group influence cognition in patients with TRD. Fifty-four patients with TRD were infused with either ketamine or esketamine and were assessed at three time points: baseline, 24 h, and 7 days after infusion. We applied neuropsychological tests to evaluate executive functions, processing speed, short term memory, and auditory-verbal episodic memory. There is no cognitive difference between ketamine and esketamine, with the exception of one variable. When considered as one group, ketamine and esketamine do not impair cognition; on the contrary, they improve some neuropsychological functions such as visuospatial short-term memory, executive functions, processing speed, and several measures related to episodic verbal memory. Ketamine and esketamine do not present differing cognitive effects when used in antidepressant doses to treat TRD. Furthermore, they rapidly improve many cognitive aspects of patients with TRD at 24 h after the infusion and maintain these effects for at least 7 days.
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Transtorno Depressivo Resistente a Tratamento , Ketamina , Depressão , Transtorno Depressivo Resistente a Tratamento/tratamento farmacológico , Método Duplo-Cego , HumanosRESUMO
BACKGROUND: Ketamine and its enantiomers have recently been highlighted as one of the most effective therapeutic options in refractory depression. However, racemic ketamine and esketamine have not been directly compared. The aim of this study is to assess the efficacy and safety of esketamine compared to ketamine in patients with treatment-resistant depression (TRD). METHODS: This is a randomized, double-blind, active-controlled, bicentre, non-inferiority clinical trial, with two parallel groups. Participants were randomly assigned to a 40-min single intravenous infusion of ketamine 0.5â¯mg/kg or esketamine 0.25â¯mg/kg. The primary outcome was the difference in remission rates for depression 24 h following intervention using the Montgomery-Åsberg Depression Rating Scale (MADRS), with a non-inferiority margin of 20%. RESULTS: 63 subjects were included and randomly assigned (29 to receive ketamine and 34 to receive esketamine). At 24 h, 24.1% of participants in the ketamine group and 29.4% of participants in the esketamine group showed remission, with a difference of 5.3% (95% CILB -13.6%), confirming non-inferiority. MADRS scores improved from 33 (SD 9.3) to 16.2 (SD 10.7) in the ketamine group and from 33 (SD 5.3) to 17.5 (SD 12.2) in the esketamine one, with a difference of -5.27% (95% CILB, -13.6). Both groups presented similar mild side effects. CONCLUSIONS: Esketamine was non-inferior to ketamine for TRD 24 h following infusion. Both treatments were effective, safe, and well tolerated. TRIAL REGISTRATION: Registered in Japan Primary Registries Network: UMIN000032355.
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Transtorno Depressivo Resistente a Tratamento , Ketamina , Adulto , Antidepressivos/efeitos adversos , Depressão , Transtorno Depressivo Resistente a Tratamento/tratamento farmacológico , Método Duplo-Cego , Humanos , Japão , Ketamina/efeitos adversos , Resultado do TratamentoRESUMO
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.
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INTRODUCTION: The use of ketamine as an option in the treatment of depressive disorder is growing rapidly, supported by numerous clinical trials attesting its efficacy and safety. Esketamine, the S (+) enantiomer of ketamine, is the most widely used form in the anesthetic environment in some countries, and new studies have shown that it may also be effective in depression and with better tolerability. However, no study so far has directly compared esketamine with racemic ketamine. Here we propose a protocol of a clinical trial to evaluate esketamine as a noninferior medication when compared to ketamine in the treatment of patients with treatment-resistant depression. METHODS/DESIGN: This study protocol is for a randomized, controlled, double-blind noninferiority clinical trial. Subjects will be 18 years or older, with major depression characterized as treatment-resistant. Participants will receive a single infusion of either esketamine (0.25âmg/kg) or ketamine (0.5âmg/kg) over 40 minutes. The primary outcome will be the difference in remission rates between the 2 treatment arms at 24 and 72âhours after drug infusion. Secondary outcomes will include other timepoints, measurements of cognition, dissociation, and blood biomarkers. DISCUSSION: A head-to-head study is the best way to evaluate whether the esketamine is in fact comparable to the racemic ketamine in terms of both efficacy and safety, and, if positive, it would be an initial step to increase the access to that type of treatment worldwide. ETHICS AND DISSEMINATION: The study was approved by the local Institutional Review Board (University Hospital Professor Edgard Santos-Federal University of Bahia-Number: 46657415.0.0000.0049). Subjects will only participate after voluntarily agreeing and signing the Informed Consent Form. The study findings will be published in peer-reviewed journals and presented at national and international conferences. TRIAL REGISTRATION: This trial has been registered in the Japan Primary Registries Network (JPRN): UMIN000032355, which is affiliated with the World Health Organization.