Effects of esketamine on patient-reported outcomes in major depressive disorder with active suicidal ideation and intent: a pooled analysis of two randomized phase 3 trials (ASPIRE I and ASPIRE II).

PURPOSE: To assess the effect of esketamine nasal spray on patient-reported outcomes (PROs) in patients with major depressive disorder having active suicidal ideation with intent (MDSI). METHODS: Patient-level data from two phase 3 studies (ASPIRE I; ASPIRE II) of esketamine + standard of care (SOC) in patients (aged 18-64 years) with MDSI, were pooled. PROs were evaluated from baseline through end of the double-blind treatment phase (day 25). Outcome assessments included: Beck Hopelessness Scale (BHS), Quality of Life (QoL) in Depression Scale (QLDS), European QoL Group-5-Dimension-5-Level (EQ-5D-5L), and 9-item Treatment Satisfaction Questionnaire for Medication (TSQM-9). Changes in BHS and QLDS scores (baseline to day 25) were analyzed using a mixed-effects model for repeated measures (MMRM). RESULTS: Pooled data for esketamine + SOC (n = 226; mean age: 40.5 years, 59.3% females) and placebo + SOC (n = 225; mean age: 39.6 years, 62.2% females) were analyzed. Mean ± SD change from baseline to day 25, esketamine + SOC vs placebo + SOC (least-square mean difference [95% CI] based on MMRM): BHS total score, - 7.4 ± 6.7 vs - 6.8 ± 6.5 [- 1.0 (- 2.23, 0.21)]; QLDS score, - 14.4 ± 11.5 vs - 12.2 ± 10.8 [- 3.1 (- 5.21, - 1.02)]. Relative risk (95% CI) of reporting perceived problems (slight to extreme) in EQ-5D-5L dimensions (day 25) in esketamine + SOC vs placebo + SOC: mobility [0.78 (0.50, 1.20)], self-care [0.83 (0.55, 1.27)], usual activities [0.87 (0.72, 1.05)], pain/discomfort [0.85 (0.69, 1.04)], and anxiety/depression [0.90 (0.80, 1.00)]. Mean ± SD changes from baseline in esketamine + SOC vs placebo + SOC for health status index: 0.23 ± 0.21 vs 0.19 ± 0.22; and for EQ-Visual Analogue Scale: 24.0 ± 27.2 vs 19.3 ± 24.4. At day 25, mean ± SD in domains of TSQM-9 scores in esketamine + SOC vs placebo + SOC were: effectiveness, 67.2 ± 25.3 vs 56.2 ± 26.8; global satisfaction, 69.9 ± 25.2 vs 56.3 ± 27.8; and convenience, 74.0 ± 19.4 vs 75.4 ± 18.7. CONCLUSION: These PRO data support the patient perspective of the effect associated with esketamine + SOC in improving health-related QoL in patients with MDSI. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: ASPIRE I, NCT03039192 (Registration date: February 1, 2017); ASPIRE II, NCT03097133 (Registration date: March 31, 2017).

Effect of Concomitant Benzodiazepines on the Antidepressant Effects of Ketamine: Findings From the RAPID Intravenous Ketamine Study.

Objective: Ketamine is a novel and rapidly acting treatment for major depressive disorder (MDD). Benzodiazepines are commonly coprescribed with antidepressants in MDD. This study sought to examine data from a randomized clinical trial that compared a single infusion of intravenous (IV) ketamine to midazolam placebo in treatment-resistant depression (DSM-IV-TR MDD) and to assess whether the use of concomitant oral benzodiazepines differentially affected treatment response to ketamine versus midazolam.Methods: This trial ran from December 2015 to December 2016. Subjects who were taking oral benzodiazepines (n = 44) were compared to those who were not (n = 55). A significant treatment-by-benzodiazepine effect could be interpreted as a possible moderator of differential treatment response to ketamine versus midazolam. Benzodiazepine use was examined as both a binary and a continuous predictor, to assess the impact of dosage.Results: Benzodiazepine users did not differ from non-users on the original study's primary outcome measure, score on the 6-item Hamilton Depression Rating Scale (HDRS-6), at baseline, but the former had more severe anxiety. When oral benzodiazepine use was modeled as a binary predictor, benzodiazepine use did not impact differential treatment response. However, when benzodiazepine dosage was considered, there was a significant impact of benzodiazepine use on differential treatment response. Oral benzodiazepines significantly impacted HDRS-6 (P = .018) and Clinical Global Impressions-Severity of Illness scale (CGI-S; P = .008) scores at day 1 (24 hours post treatment); effects were nonsignificant for all day 3 outcomes. Among ketamine subjects, higher doses of benzodiazepines were associated with less improvement in depression scores at day 1.Conclusions: Concomitant oral benzodiazepines at higher doses may attenuate the antidepressant effects of IV ketamine at day 1 but not day 3 post-infusion.Trial Registration: ClinicalTrials.gov identifier: NCT01920555.

Esketamine Nasal Spray for the Rapid Reduction of Depressive Symptoms in Major Depressive Disorder With Acute Suicidal Ideation or Behavior.

PURPOSE/BACKGROUND: Numerous health authority approvals of esketamine nasal spray, combined with oral antidepressant, to treat depressive symptoms in adults with major depressive disorder and acute suicidal ideation or behavior were based on 2 identically designed, double-blind, phase 3 studies. METHODS/PROCEDURES: Across both ASPIRE studies (NCT03039192, NCT03097133), patients (N = 456) were randomized to esketamine 84 mg or placebo nasal spray twice weekly for 4 weeks plus comprehensive standard of care, including hospitalization and newly initiated or optimized antidepressant(s). In post hoc analyses of pooled data, changes from baseline at 24 hours after the first dose in Montgomery-Åsberg Depression Rating Scale total score and Clinical Global Impression-Severity of Suicidality-Revised, in the full cohort and in subgroups, were analyzed using analysis of covariance. FINDINGS/RESULTS: Esketamine plus standard of care demonstrated significantly greater improvement in Montgomery-Åsberg Depression Rating Scale total score versus placebo plus standard of care at 24 hours (least square mean difference [95% confidence interval], -3.8 [-5.75 to -1.89]) and at earlier (4 hours: -3.4 [-5.05 to -1.71]) and later time points (day 25: -3.4 [-5.36 to -1.36]). The between-group difference (95% confidence interval) for change in Clinical Global Impression-Severity of Suicidality-Revised at 24 hours was -0.20 (-0.43 to 0.04) for all patients and -0.31 (-0.61 to -0.01) for those with a history of suicide attempt. Common adverse events (≥20%) during esketamine treatment were dizziness, dissociation, nausea, somnolence, and headache. IMPLICATIONS/CONCLUSIONS: Esketamine plus comprehensive standard of care rapidly reduces depressive symptoms in patients with major depressive disorder who have acute suicidal ideation or behavior, especially in those with a history of suicide attempt, providing a new treatment option for this particularly ill and vulnerable population.

The effect of esketamine in patients with treatment-resistant depression with and without comorbid anxiety symptoms or disorder.

BACKGROUND: Comorbid anxiety is generally associated with poorer response to antidepressant treatment. This post hoc analysis explored the efficacy of esketamine plus an antidepressant in patients with treatment-resistant depression (TRD) with or without comorbid anxiety. METHODS: TRANSFORM-2, a double-blind, flexible-dose, 4-week study (NCT02418585), randomized adults with TRD to placebo or esketamine nasal spray, each with a newly-initiated oral antidepressant. Comorbid anxiety was defined as clinically noteworthy anxiety symptoms (7-item Generalized Anxiety Disorder scale [GAD-7] score ≥10) at screening and baseline or comorbid anxiety disorder diagnosis at screening. Treatment effect based on change in Montgomery-Åsberg Depression Rating Scale (MADRS) total score, and response and remission were examined by presence/absence of comorbid anxiety using analysis of covariance and logistic regression models. RESULTS: Approximately 72% (162/223) of patients had baseline comorbid anxiety. Esketamine-treated patients with and without anxiety demonstrated significant reductions in MADRS (mean [SD] change from baseline at day 28: -21.0 [12.51] and -22.7 [11.98], respectively). Higher rates of response and remission, and a significantly greater decrease in MADRS score at day 28 were observed compared to antidepressant/placebo, regardless of comorbid anxiety (with anxiety: difference in LS means [95% CI] -4.2 [-8.1, -0.3]; without anxiety: -7.5 [-13.7, -1.3]). There was no significant interaction of treatment and comorbid anxiety (p = .371). Notably, in the antidepressant/placebo group improvement was similar in those with and without comorbid anxiety. CONCLUSION: Post hoc data support efficacy of esketamine plus an oral antidepressant in patients with TRD, regardless of comorbid anxiety.

The effect of single administration of intravenous ketamine augmentation on suicidal ideation in treatment-resistant unipolar depression: Results from a randomized double-blind study.

This study aimed to assess the effect of a single infusion of intravenous (IV) ketamine on suicidal ideation in patients with treatment-resistant depression (TRD). Patients with TRD were randomized in a double-blind fashion to a single infusion of IV ketamine or IV midazolam placebo. Suicidal ideation was measured using the Montgomery-Asberg Depression Rating Scale (MADRS) suicide item at 3, 5, 7, 14 and 30 days post infusion. Clinically significant suicidal ideation was defined as a MADRS suicide item score ≥2. Forty patients who received IV ketamine and 16 who received IV midazolam had suicide item scores of ≥2 at baseline (IV ketamine group mean 2.90±0.74; IV midazolam group 2.69±0.70). The mean suicide scores of these groups differed significantly from each other on day 30; the IV ketamine group had a lower mean score than controls (2.03±1.59 vs. 3.00±1.41, t-test p = 0.049; Hedges' g 0.71). Among patients with a suicide score of ≥2 at baseline and <2 at day 3, the two groups did not differ significantly on mean scores changes at days 3, 5, 7, 14 or 30. Recurrence of suicidal ideation was extensive in both treatment groups. A single infusion of IV ketamine may reduce suicidal ideation in TRD out to 30 days post infusion, but early anti-suicidal effects appear to diminish rapidly. This post-hoc analysis was not powered to compare different doses of ketamine. A single infusion of IV ketamine might have a role as an adjunct to standard treatments in patients with TRD and suicidal ideation. Trial registration: NCT01920555.

Perinatal depressive symptoms often start in the prenatal rather than postpartum period: results from a longitudinal study.

Depressive symptoms during and after pregnancy confer risks for adverse outcomes in both the mother and child. Postpartum depression is traditionally diagnosed after birth of the child. Perinatal depression is a serious, prevalent heterogeneous syndrome that can occur during the period from conception through several months after childbirth. Onset and course are not well understood. There is a paucity of longitudinal studies of the disorder that include the antenatal period in population-based samples. We used an Internet panel of pregnant women recruited in 2 cohorts; 858 ascertained in the first and 322 ascertained in the third trimesters of pregnancy. We recruited the second cohort in order to assure sufficient sample to examine depressive symptoms later in pregnancy and in the postpartum period. Assessments included standard psychometric measures, health history, and pregnancy experience. The Edinburgh Postnatal Depression Scale was used for the assessment of depressive symptoms. Nearly 10% of women entered the pregnancy with depressive symptoms. Prevalence was about the same at 4 weeks and 3 months postpartum. During pregnancy, prevalence increased to 16% in the third trimester. Among incident cases, 80% occurred during pregnancy, with 1/3 occurring in the first trimester. We describe predictors of incident depressive symptoms and covariates associated with time-to-onset which include health history (psychiatric and medical) and social support covariates. The majority of incident depressive symptoms occur during pregnancy rather than afterward. This finding underscores the mandate for mental health screening early in pregnancy and throughout gestation. It will be important to find safe and effective interventions that prevent, mitigate, or delay the onset of depressive symptoms that can be implemented during pregnancy.

Esketamine Nasal Spray for Rapid Reduction of Depressive Symptoms in Patients With Major Depressive Disorder Who Have Active Suicide Ideation With Intent: Results of a Phase 3, Double-Blind, Randomized Study (ASPIRE II).

BACKGROUND: Patients with major depressive disorder (MDD) having active suicidal ideation with intent require immediate treatment. METHODS: This double-blind study (ASPIRE II) randomized adults (aged 18-64 years) with MDD having active suicidal ideation with intent to esketamine 84 mg or placebo nasal spray twice weekly for 4 weeks, given with comprehensive standard of care (hospitalization ≥5 days and newly initiated or optimized oral antidepressant[s]). Change from baseline to 24 hours post-first dose in Montgomery-Asberg Depression Rating Scale total score (primary efficacy endpoint) was analyzed using ANCOVA. Clinical Global Impression-Severity of Suicidality-revised (key secondary endpoint) was analyzed using ANCOVA on ranks of change. RESULTS: Of 230 patients who were randomized (115 per arm), 227 received study drug and were included in efficacy/safety analyses; 184 (80.0%) completed double-blind treatment. Greater improvement in Montgomery-Asberg Depression Rating Scale total score was observed with esketamine (mean [SD]: -15.7 [11.56]) vs placebo (-12.4 [10.43]), each with standard of care, at 24 hours (least-squares mean difference [SE]: -3.9 [1.39], 95% CI: -6.60, -1.11; 2-sided P = .006). This was also noted at the earlier (4-hour) timepoint (least-squares mean difference -4.2, 95% CI: -6.38, -1.94). Patients in both treatment groups experienced rapid reduction in Clinical Global Impression-Severity of Suicidality-revised score; the between-group difference was not statistically significant. The most common adverse events among esketamine-treated patients were dizziness, dissociation, nausea, dysgeusia, somnolence, headache, and paresthesia. CONCLUSION: This study confirmed rapid and robust reduction of depressive symptoms with esketamine nasal spray in severely ill patients with MDD who have active suicidal ideation with intent. Trial Registration: Clinical Trials.gov identifier: NCT03097133.

Studying pre-treatment and ketamine-induced changes in white matter microstructure in the context of ketamine's antidepressant effects.

Ketamine is increasingly being used as a therapeutic for treatment-resistant depression (TRD), yet the effects of ketamine on the human brain remain largely unknown. This pilot study employed diffusion magnetic resonance imaging (dMRI) to examine relationships between ketamine treatment and white matter (WM) microstructure, with the aim of increasing the current understanding of ketamine's neural mechanisms of action in humans. Longitudinal dMRI data were acquired from 13 individuals with TRD two hours prior to (pre-infusion), and four hours following (post-infusion), an intravenous ketamine infusion. Free-water imaging was employed to quantify cerebrospinal fluid-corrected mean fractional anisotropy (FA) in 15 WM bundles pre- and post-infusion. Analyses revealed that higher pre-infusion FA in the left cingulum bundle and the left superior longitudinal fasciculus was associated with greater depression symptom improvement 24 h post-ketamine. Moreover, four hours after intravenous administration of ketamine, FA rapidly increased in numerous WM bundles in the brain; this increase was significantly associated with 24 h symptom improvement in select bundles. Overall, the results of this preliminary study suggest that WM properties, as measured by dMRI, may have a potential impact on clinical improvement following ketamine. Ketamine administration additionally appears to be associated with rapid WM diffusivity changes, suggestive of rapid changes in WM microstructure. This study thus points to pre-treatment WM structure as a potential factor associated with ketamine's clinical efficacy, and to post-treatment microstructural changes as a candidate neuroimaging marker of ketamine's cellular mechanisms.

Esketamine Nasal Spray for Rapid Reduction of Major Depressive Disorder Symptoms in Patients Who Have Active Suicidal Ideation With Intent: Double-Blind, Randomized Study (ASPIRE I).

OBJECTIVE: To compare esketamine to placebo, each in addition to standard-of-care treatment, for rapidly reducing major depressive disorder symptoms, including suicidal ideation. METHODS: This phase 3, double-blind, multicenter study (ASPIRE I), conducted between June 2017 and December 2018, enrolled 226 adults having major depressive disorder based on Diagnostic and Statistical Manual of Mental Disorders fifth edition (DSM-5) criteria, active suicidal ideation with intent, and need for psychiatric hospitalization. Patients were randomized 1:1 to esketamine 84 mg or placebo nasal spray twice-weekly for 4 weeks, each with comprehensive standard-of-care treatment (initial psychiatric hospitalization and newly initiated or optimized oral antidepressant[s] therapy). Change from baseline to 24 hours post-first dose in Montgomery-Asberg Depression Rating Scale (MADRS) total score (primary endpoint) was analyzed using analysis of covariance (ANCOVA), and change in Clinical Global Impression of Severity of Suicidality Revised version (CGI-SS-r; key secondary endpoint) score was analyzed using ANCOVA on ranks with treatment difference estimated using the Hodges-Lehmann estimate. RESULTS: Greater improvement in MADRS total score was observed with esketamine + standard-of-care versus placebo + standard-of-care at 24 hours (least-squares mean difference [SE]: -3.8 [1.39]; 95% CI, -6.56 to -1.09; 2-sided P = .006), as well as at earlier (4 hours) and later time points during 4-week double-blind treatment. The difference between groups in the severity of suicidality was not statistically significant (median of treatment difference [95% CI]: 0.0 [-1.00 to 0.00]; 2-sided P = .107). The most common adverse events among esketamine-treated patients were dizziness, dissociation, headache, nausea, and somnolence. CONCLUSIONS: These findings demonstrate rapid and robust efficacy of esketamine nasal spray in reducing depressive symptoms in severely ill patients with major depressive disorder who have active suicidal ideation with intent. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03039192.

Monitoring Changes in Depression Severity Using Wearable and Mobile Sensors.

Background: While preliminary evidence suggests that sensors may be employed to detect presence of low mood it is still unclear whether they can be leveraged for measuring depression symptom severity. This study evaluates the feasibility and performance of assessing depressive symptom severity by using behavioral and physiological features obtained from wristband and smartphone sensors. Method: Participants were thirty-one individuals with Major Depressive Disorder (MDD). The protocol included 8 weeks of behavioral and physiological monitoring through smartphone and wristband sensors and six in-person clinical interviews during which depression was assessed with the 17-item Hamilton Depression Rating Scale (HDRS-17). Results: Participants wore the right and left wrist sensors 92 and 94% of the time respectively. Three machine-learning models estimating depressive symptom severity were developed-one combining features from smartphone and wearable sensors, one including only features from the smartphones, and one including features from wrist sensors-and evaluated in two different scenarios. Correlations between the models' estimate of HDRS scores and clinician-rated HDRS ranged from moderate to high (0.46 [CI: 0.42, 0.74] to 0.7 [CI: 0.66, 0.74]) and had moderate accuracy with Mean Absolute Error ranging between 3.88 ± 0.18 and 4.74 ± 1.24. The time-split scenario of the model including only features from the smartphones performed the best. The ten most predictive features in the model combining physiological and mobile features were related to mobile phone engagement, activity level, skin conductance, and heart rate variability. Conclusion: Monitoring of MDD patients through smartphones and wrist sensors following a clinician-rated HDRS assessment is feasible and may provide an estimate of changes in depressive symptom severity. Future studies should further examine the best features to estimate depressive symptoms and strategies to further enhance accuracy.

Time to relapse after a single administration of intravenous ketamine augmentation in unipolar treatment-resistant depression.

OBJECTIVE: To examine the rate and time to relapse for remitters and responders to ketamine in treatment-resistant depression (TRD). METHODS: Subjects with TRD were randomized to a single infusion of one of several doses of intravenous ketamine, or midazolam. Using Kaplan-Meier survival function, the current report examines the rate and time to relapse, defined as MADRS ≥ 22, over a period of 30 days, in subjects who achieved remission (MADRS ≤ 10) or response (≥ 50% reduction in MADRS) on day three post-infusion of intravenous ketamine 0.1, 0.5, or 1.0 mg/kg. RESULTS: Of the 60 randomized participants who received a single ketamine (0.1, 0.5, or 1.0 mg/kg) infusion, 19 (34%) met criteria for remission and 27 (48%) for response, on day 3 post-infusion. A numerical dose-response relationship was observed, with remitters/responders on ketamine 1.0 mg/kg having the lowest relapse rate, followed by ketamine 0.5 mg/kg and 0.1 mg/kg, respectively (% of remitters who relapsed by day 14: 38% with 1.0 mg/kg, 50% with 0.5 mg/kg, 100% with 0.1 mg/kg;% of responders who relapsed by day 14: 30% with 1.0 mg/kg, 50% with 0.5 mg/kg, 80% with 0.1 mg/kg). LIMITATIONS: The sample size was small. No MADRS measurements at day one post-infusion. The study was not powered to assess differences in relapse prevention between different doses of ketamine. CONCLUSION: Time to relapse after successful treatment with a single infusion of ketamine appears to follow a dose-response relationship, where higher dosage leads to increased time to relapse.

Correction: Double-blind, placebo-controlled, dose-ranging trial of intravenous ketamine as adjunctive therapy in treatment-resistant depression (TRD).

Supplementary Figure 1 and Supplementary Tables 1-4 have been re-uploaded so as to reflect the versions supplied during proofs stage. The publisher apologizes for the error in versioning. The HTML version of the paper has been updated.

Double-blind, placebo-controlled, dose-ranging trial of intravenous ketamine as adjunctive therapy in treatment-resistant depression (TRD).

Numerous placebo-controlled studies have demonstrated the ability of ketamine, an NMDA receptor antagonist, to induce rapid (within hours), transient antidepressant effects when administered intravenously (IV) at subanesthetic doses (0.5 mg/kg over 40 min). However, the optimal antidepressant dose remains unknown. We aimed to compare to active placebo the rapid acting antidepressant properties of a broad range of subanesthetic doses of IV ketamine among outpatients with treatment-resistant depression (TRD). A range of IV ketamine doses were compared to active placebo in the treatment of adult TRD over a 3-day period following a single infusion over 40 min. This was an outpatient study conducted across six US academic sites. Outpatients were 18-70 years old with TRD, defined as failure to achieve a satisfactory response (e.g., less than 50% improvement of depression symptoms) to at least two adequate treatment courses during the current depressive episode. Following a washout period, 99 eligible subjects were randomly assigned to one of the five arms in a 1:1:1:1:1 fashion: a single intravenous dose of ketamine 0.1 mg/kg (n = 18), a single dose of ketamine 0.2 mg/kg (n = 20), a single dose of ketamine 0.5 mg/kg (n = 22), a single dose of ketamine 1.0 mg/kg (n = 20), and a single dose of midazolam 0.045 mg/kg (active placebo) (n = 19). The study assessments (HAM-D-6, MADRS, SDQ, PAS, CGI-S, and CGI-I) were performed at days 0, 1, 3 (endpoint), 5, 7, 14, and 30 to assess the safety and efficacy. The overall group × time interaction effect was significant for the primary outcome measure, the HAM-D-6. In post hoc pairwise comparisons controlling for multiple comparisons, standard dose (0.5 mg/kg) and high dose (1 mg/kg) of intravenous ketamine were superior to active placebo; a low dose (0.1 mg/kg) was significant only prior to adjustment (p = 0.02, p-adj = 0.14, d = -0.82 at day 1). Most of the interaction effect was due to differences at day 1, with no significant adjusted pairwise differences at day 3. This pattern generally held for secondary outcomes. The infusions of ketamine were relatively well tolerated compared to active placebo, except for greater dissociative symptoms and transient blood pressure elevations with the higher doses. Our results suggest that there is evidence for the efficacy of the 0.5 mg/kg and 1.0 mg/kg subanesthetic doses of IV ketamine and no clear or consistent evidence for clinically meaningful efficacy of lower doses of IV ketamine. Trial Registration: NCT01920555.

Efficacy of intravenous ketamine treatment in anxious versus nonanxious unipolar treatment-resistant depression.

OBJECTIVE: To examine the effect of high baseline anxiety on response to ketamine versus midazolam (active placebo) in treatment-resistant depression (TRD). METHODS: In a multisite, double-blind, placebo-controlled trial, 99 subjects with TRD were randomized to one of five arms: a single dose of intravenous ketamine 0.1, 0.2, 0.5, 1.0 mg/kg, or midazolam 0.045 mg/kg. The primary outcome measure was change in the six-item Hamilton Rating Scale for Depression (HAMD6). A linear mixed effects model was used to examine the effect of anxious depression baseline status (defined by a Hamilton Depression Rating Scale Anxiety-Somatization score ≥7) on response to ketamine versus midazolam at 1 and 3 days postinfusion. RESULTS: N = 45 subjects had anxious TRD, compared to N = 54 subjects without high anxiety at baseline. No statistically significant interaction effect was found between treatment group assignment (combined ketamine treatment groups versus midazolam) and anxious/nonanxious status on HAMD6 score at either days 1 or 3 postinfusion (Day 1: F(1, 84) = 0.02, P = 0.88; Day 3: F(1, 82) = 0.12, P = 0.73). CONCLUSION: In contrast with what is observed with traditional antidepressants, response to ketamine may be similar in both anxious and nonanxious TRD subjects. These pilot results suggest the potential utility of ketamine in the treatment of anxious TRD.

Repeat-dose ketamine augmentation for treatment-resistant depression with chronic suicidal ideation: A randomized, double blind, placebo controlled trial.

BACKGROUND: Several studies indicate that ketamine has rapid antidepressant effects in patients with treatment-resistant depression (TRD). The extent to which repeated doses of ketamine (versus placebo) reduce depression in the short and long term among outpatients with TRD and chronic, current suicidal ideation remains unknown. METHODS: Twenty-six medicated outpatients with severe major depressive disorder with current, chronic suicidal ideation were randomized in a double-blind fashion to six ketamine infusions (0.5 mg/kg over 45 minutes) or saline placebo over three weeks. Depression and suicidal ideation were assessed at baseline, 240 min post-infusion, and during a three-month follow-up phase. RESULTS: During the infusion phase, there was no differences in depression severity or suicidal ideation between placebo and ketamine (p = 0.47 and p = 0.32, respectively). At the end of the infusion phase, two patients in the ketamine group and one in the placebo group met criteria for remission of depression. At three-month follow-up, two patients in each group met criteria for remission from depression. LIMITATIONS: Limitations include the small sample size, uncontrolled outpatient medication regimens, and restriction to outpatients, which may have resulted in lower levels of suicidal ideation than would be seen in emergency or inpatient settings. CONCLUSIONS: Repeated, non-escalating doses of ketamine did not outperform placebo in this double-blind, placebo controlled study of patients with severe TRD and current, chronic suicidal ideation. This result may support our previously published open-label data that, in this severely and chronically ill outpatient population, the commonly used dose of 0.5 mg/kg is not sufficient.

Ketamine-Associated Brain Changes: A Review of the Neuroimaging Literature.

Major depressive disorder (MDD) is one of the most prevalent conditions in psychiatry. Patients who do not respond to traditional monoaminergic antidepressant treatments have an especially difficult-to-treat type of MDD termed treatment-resistant depression. Subanesthetic doses of ketamine-a glutamatergic modulator-have shown great promise for rapidly treating patients with the most severe forms of depression. As such, ketamine represents a promising probe for understanding the pathophysiology of depression and treatment response. Through neuroimaging, ketamine's mechanism may be elucidated in humans. Here, we review 47 articles of ketamine's effects as revealed by neuroimaging studies. Some important brain areas emerge, especially the subgenual anterior cingulate cortex. Furthermore, ketamine may decrease the ability to self-monitor, may increase emotional blunting, and may increase activity in reward processing. Further studies are needed, however, to elucidate ketamine's mechanism of antidepressant action.

The antidepressant efficacy of subanesthetic-dose ketamine does not correlate with baseline subcortical volumes in a replication sample with major depressive disorder.

BACKGROUND: This study sought to reproduce, in a larger sample, previous findings of a correlation between smaller raw 3-Tesla (3T) hippocampal volumes and improved antidepressant efficacy of ketamine in individuals with major depressive disorder (MDD). A secondary analysis stratified subjects according to functional BDNF rs6265 (val66met) genotype. METHODS: Unmedicated subjects with treatment-resistant MDD ( n=55) underwent baseline structural 3T MRI. Data processing was conducted with FSL/FIRST and Freesurfer software. The amygdala, hippocampus, and thalamus were selected a priori for analysis. All subjects received a single 0.5mg/kg × 40-minute ketamine infusion. Pearson correlations were performed with subcortical volumes and percent change in MADRS score (from baseline to 230 minutes, 1 day, and 1 week post-infusion). RESULTS: Raw and corrected subcortical volumes did not correlate with antidepressant response at any timepoint. In val/val subjects ( n=23), corrected left and right thalamic volume positively correlated with antidepressant response to ketamine at 230 minutes post-infusion but did not reach statistical significance. In met carriers ( n=14), corrected left and right thalamic volume negatively correlated with antidepressant response to ketamine. CONCLUSION: Baseline subcortical volumes implicated in MDD did not correlate with ketamine's antidepressant efficacy. Baseline thalamic volume and BDNF genotype may be a combinatorial rapid antidepressant response biomarker.

Classics in Chemical Neuroscience: Ketamine.

Ketamine, a molecule of many faces, has contributed immeasurably to numerous realms of clinical practice and scientific inquiry. From anesthesia and analgesia to depression and schizophrenia, it continues to shed light on the molecular underpinnings of pain, consciousness, and the pathophysiology of neuropsychiatric disorders. In particular, research on ketamine's mechanism of action is providing new hope in the search for therapies for treatment-resistant depression and affords insights into disorders of glutamatergic dysfunction. In this Review, we will cover aspects of ketamine's synthesis, manufacturing, metabolism, pharmacology, approved and off-label indications, and adverse effects. We will also discuss the captivating history of this molecule, its influence on neuropsychiatry, and its potential to advance the fields of chemical neuroscience and neuropharmacology.

The Role of Chronic Stress in Anxious Depression.

Depression is a heterogeneous disease with many different subtypes. Patients with the anxious depression-a common subtype of major depression-are at an increased risk for treatment-resistance to standard antidepressants, with resultant increases in morbidity. However, the underlying pathophysiology of anxious depression remains unknown. Without such knowledge, the development of targeted treatments towards this specific depression subtype will likely remain elusive. One method by which research into the neurobiology of anxious depression may prove fruitful is with the research domain criteria (RDoC). RDoC provides a framework for investigation into the underlying pathophysiology of mental illness. By studying disorders in terms of RDoC constructs-such as the sustained threat construct of the negative valence system-new insights may be gained into neurobiological mechanisms of disease. These mechanisms may be useful for the development of novel antidepressants that are based on specific brain targets. Specifically, we review the impact that sustained threat-or chronic stress-has on the eventual development of depression (especially anxious depression) through pathological changes to molecules, cells, neurocircuitry, physiology, and behavior.