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.

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.

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.

A Clinical Rationale for Assessing the Impact of Childhood Sexual Abuse on Adjunctive Subcutaneous Esketamine for Treatment-Resistant Depression.

Background: A history of child sexual abuse (CSA) is related to higher suicide rates and poor treatment outcomes in depressed adult patients. Twenty years after the first study investigating the effects of ketamine/esketamine on depression and suicide, there is a lack of data on the CSA effects on this emerging treatment. Here, we assess the impact of CSA on adjunctive subcutaneous (SC) esketamine for treatment-resistant depression (TRD). Methods: A directed acyclic graphic (DAG) was designed to identify clinical confounders between CSA and esketamine predictors of response. The confounders were applied in a statistical model to predict depression symptom trajectory in a sample of 67 TRD outpatients. Results: The patient sample had a relatively high prevalence rate of CSA (35.82%). Positive family history of first-degree relatives with alcohol use disorder and sex were clinical mediators of the effects of esketamine in a CSA adult population. Overall, the presence of at least one CSA event was unrelated to esketamine symptom reduction. Conclusions: Unlike responses to conventional antidepressants and psychotherapy, CSA does not appear to predict poor response to esketamine.

Repeated subcutaneous esketamine for treatment-resistant depression: Impact of the degree of treatment resistance and anxiety comorbidity.

BACKGROUND: A large number of studies indicate that subanesthetic doses of ketamine induce a fast antidepressant effect. Limited studies have investigated the subcutaneous (SC) route, and it remains unclear for whom this treatment is most suitable. AIMS: The aim of this study was to examine the effect on depressive symptoms of repeated subanesthetic doses of SC esketamine in unipolar and bipolar treatment-resistant depression (TRD) and clinical predictors of response. METHODS: A retrospective analysis of 70 patients who received six SC esketamine doses weekly as an adjunctive treatment was carried out. Doses started at 0.5 mg/kg and it could be titrated up to 1 mg/kg, according to response. The primary outcome was reduction in depressive symptoms. Statistical analysis to investigate clinical predictors of effectiveness included logistic regression analysis using a dependent variable of a 50% reduction in rating scale scores at the end of treatment. Comparisons between groups were made through analysis of variance and treatment effects. RESULTS: At baseline, our sample presented with severe treatment resistance in 65.7%, as assessed by the Maudsley Staging Method (MSM), and 47.1% had anxiety disorder comorbidity. The response rate was 50%. A better outcome was predicted by mild and moderate MSM scores (OR = 3.162, p = 0.041) and anxiety disorder comorbidity (OR = 3.149, p = 0.028). CONCLUSIONS: Our results suggest that higher levels of treatment resistance may be associated with a poor response to SC esketamine. Unlike traditional pharmacotherapies, it might benefit those with poor prognosis such as patients with depression and comorbid anxiety. Therefore, future research could investigate whether esketamine should receive a more prominent place in the treatment algorithm for TRD.

Comparative effectiveness of esketamine in the treatment of anhedonia in bipolar and unipolar depression.

BACKGROUND: Anhedonia is a symptom associated with poorer outcomes in depression treatment, including resistance to treatment, higher functional impact and suicidality. Few drugs are known to adequately treat anhedonia in both unipolar and bipolar depression. The NMDA antagonist ketamine has been demonstrated to be effective in rapidly ameliorating anhedonia in depressive episodes. The main aim of present study is to evaluate the anti-anhedonic effect of esketamine, the S-enantiomer of ketamine recently approved for treatment-resistant depression, in unipolar and bipolar depression. METHODS: 70 patients with unipolar or bipolar depression were treated with 6 weekly subcutaneous esketamine infusions (0.5-1mg/kg). Anhedonia was measured through MADRS item 8 before and 24h after each infusion. RESULTS: A significant reduction in anhedonia severity was observed (p<0.0001) after 6 infusions. The effect was statistically significant 24h after the first infusion (p<0.001) in both unipolar and bipolar groups and increased with repeated infusions. Anti-anhedonic effect of esketamine did not differ between groups. LIMITATIONS: This is an open-label, real-world study. Lack of blinding and of a placebo arm may limit the interpretation of findings. CONCLUSION: Although preliminary, present findings suggest that repeated subcutaneous esketamine infusions are effective for the treatment of anhedonia in both unipolar and bipolar depressed patients. These results need to be confirmed through replication in larger double-blinded controlled trials.

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.

Effects of subcutaneous esketamine on blood pressure and heart rate in treatment-resistant depression.

INTRODUCTION AND OBJECTIVES: The impact of multiple subcutaneous (s.c.) esketamine injections on the blood pressure (BP) and heart rate (HR) of patients with unipolar and bipolar treatment-resistant depression (TRD) is poorly understood. This study aimed to assess the cardiovascular safety of multiple s.c. doses of esketamine in patients with TRD. METHODS: Seventy TRD patients received 394 weekly s.c. esketamine injections in conjunction with oral antidepressant therapy for up to six weeks. Weekly esketamine doses were 0.5, 0.75 or 1.0 mg/kg according to each patient's response to treatment. Participants were monitored before each treatment and every 15 minutes thereafter for 120 minutes. We assessed systolic blood pressure (SBP), diastolic blood pressure (DBP), and HR measurements for the entire treatment course. RESULTS: BP increased after the first s.c. esketamine injection, reaching maximum mean SBP/DBP levels of 4.87/5.54 mmHg within 30-45 minutes. At the end of monitoring, 120 minutes post dose, vital signs returned to pretreatment levels. We did not detect significant differences in BP between doses of 0.5, 0.75, and 1 mg/kg esketamine. Mean HR did not differ significantly between doses or before and after s.c. esketamine injection. CONCLUSIONS: The BP changes observed with repeated s.c. esketamine injections were mild and well tolerated for doses up to 1 mg/kg. The s.c. route is a simple and safe method of esketamine administration, even for patients with clinical comorbidities, including obesity, hypertension, diabetes, and dyslipidemia. However, 14/70 patients experienced treatment-emergent transient hypertension (SBP >180 mmHg and/or a DBP >110 mmHg). Therefore, we strongly recommend monitoring BP for 90 minutes after esketamine dosing. Since s.c. esketamine is cheap, requires less frequent dosing (once a week), and is a simpler procedure compared to intravenous infusions, it might have an impact on public health.

Efficacy and safety of adjunctive therapy using esketamine or racemic ketamine for adult treatment-resistant depression: A randomized, double-blind, non-inferiority study.

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 0.5 mg/kg or esketamine 0.25 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.

Comparative study of esketamine and racemic ketamine in treatment-resistant depression: Protocol for a non-inferiority clinical trial.

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 (0.25 mg/kg) or ketamine (0.5 mg/kg) over 40 minutes. The primary outcome will be the difference in remission rates between the 2 treatment arms at 24 and 72 hours 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.