Effect of Repeated Intravenous Esketamine on Adolescents With Major Depressive Disorder and Suicidal Ideation: A Randomized Active-Placebo-Controlled Trial.

OBJECTIVE: Suicide is a major cause of death in adolescents with limited treatment options. Ketamine and its enantiomers have shown rapid anti-suicidal effects in adults with major depressive disorder (MDD), but their efficacy in adolescents is unknown. We conducted an active, placebo-controlled trial to determine the safety and efficacy of intravenous esketamine in this population. METHOD: A total of 54 adolescents (aged 13-18 years) with MDD and suicidal ideation were included from an inpatient setting and randomly assigned (1:1) to receive 3 infusions of esketamine (0.25 mg/kg) or midazolam (0.02mg/kg) over 5 days, with routine inpatient care and treatment. Changes from baseline to 24 hours after the final infusion (day 6) in the scores of the Columbia Suicide Severity Rating Scale (C-SSRS) Ideation and Intensity (primary outcome) and the Montgomery-Åsberg Depression Rating Scale (MADRS, key secondary outcome) were analyzed using linear mixed models. In addition, the 4-week clinical treatment response was a key secondary outcome. RESULTS: The mean changes in C-SSRS Ideation and Intensity scores from baseline to day 6 were significantly greater in the esketamine group than in the midazolam group (Ideation, -2.6 [SD = 2.0] vs -1.7 [SD = 2.2], p = .007; Intensity, -10.6 [SD = 8.4] vs -5.0 [SD = 7.4], p = .002), and the changes in MADRS scores from baseline to day 6 were significantly greater in the esketamine group than in the midazolam group (-15.3 [SD = 11.2] vs -8.8 [SD = 9.4], p = .004). The rates of anti-suicidal and antidepressant responses at 4 weeks posttreatment were 69.2% and 61.5% after esketamine, and were 52.5% and 52.5% after midazolam, respectively. The most common adverse events in the esketamine group were nausea, dissociation, dry mouth, sedation, headache, and dizziness. CONCLUSION: These preliminary findings indicate that 3-dose intravenous esketamine, added to routine inpatient care and treatment, was an effective and well-tolerated therapy for treating adolescents with MDD and suicidal ideation. CLINICAL TRIAL REGISTRATION INFORMATION: The efficacy and safety of esketamine combined with oral antidepressants in the treatment of major depressive disorder with suicidal ideation. http://www.chictr.org.cn. Chinese Clinical Trial Registry: ChiCTR2000041232. DIVERSITY & INCLUSION STATEMENT: We worked to ensure that the study questionnaires were prepared in an inclusive way. The author list of this paper includes contributors from the location and/or community where the research was conducted who participated in the data collection, design, analysis, and/or interpretation of the work. We actively worked to promote sex and gender balance in our author group.

The efficacy and safety of esketamine in the treatment of major depressive disorder with suicidal ideation: study protocol for a randomized controlled trial.

BACKGROUND: Major depressive disorder (MDD) is a high risk factor for suicide, with up to 20% of MDD patients attempting suicide during their lifetime. Current treatments for MDD are slow onset of action, low efficiency, and the inability to control suicidal behaviors quickly and effectively. Intravenous ketamine has been shown to have a rapid but transient antidepressant effect, but there is still lack evidence on the efficacy and safety of intravenous esketamine in reducing suicidal ideation and depressive symptoms in MDD patients with suicidal ideation. We designed a study to investigate the effect of short-term repeated intravenous infusion of esketamine three times in MDD patients with suicidal ideation. METHODS: This study features a randomized, double-blind, placebo-controlled trial (RCT) comparing short-term repeated intravenous infusions of esketamine with placebo as a supplement to conventional antidepressants with an intervention period of 6 days and one infusion every other day, followed by 4 weeks of follow-up. These methods support the examination of the efficacy, safety, tolerability, and mechanism of action of short-term repeated intravenous infusions of esketamine in MDD patients with suicidal ideation. DISCUSSION: This is the first RCT to explore the efficacy and safety of short-term repeated infusion of esketamine on suicidal ideation and depressive symptoms in MDD patients with suicidal ideation. If proven effective and tolerated, it will provide evidence for rapid and effective treatment of suicidal ideation and depressive symptoms in MDD individuals with suicidal ideation. TRIAL REGISTRATION: Chinese Clinical Trial Register, ChiCTR2000041232 . Registered 22 December 2020.

The association between overweight/obesity and poor cognitive function is mediated by inflammation in patients with major depressive disorder.

BACKGROUND: Cognitive dysfunction is a common and core feature of major depressive disorder (MDD). Evidences exerted a potentially harmful role of obesity and higher peripheral levels of inflammation in cognitive function, but few studies have explored whether markers of peripheral inflammation might mediate the association between overweight/obesity and deficits in cognitive function. Our study aimed to examine the cognitive function in MDD patients and clarify the effects of overweight/obesity and inflammatory cytokines on cognitive dysfunction in this population. METHOD: We used a cross-sectional design in this study. A total of 265 patients with MDD were enrolled and divided into underweight, normal weight and overweight/obese groups. The MATRICS Consensus Cognitive Battery (MCCB) was administered to measure the cognition. Plasma levels of nineteen cytokines were measured using high sensitivity multiplex bead-based assays. RESULTS: We found overweight/obese MDD patients associated with higher plasma levels of tumor necrosis factor (TNF)-α, interleukin (IL)-8, and macrophage inflammatory protein (MIP)-1ß and worse performance in speed of processing and working memory. The mediation analysis found higher levels of IL-8 (direct: ß = -0.591 (95 % Confidence Interval (CI): -1.0 to -0.2), P = 0.002; indirect: ß = 0.060 (95 % CI.: 0.0-0.2), P = 0.032) and TNF-α (direct: ß = -0.589 (95 % CI.: -1.0 to -0.2), P = 0.002; indirect: ß = 0.059 (95 % CI.: 0.1-0.2), P = 0.037) were associated with more deficits in speed of processing, and partially mediated the relationship between body mass index and speed of processing. CONCLUSION: Our results suggest that elevated inflammation might be one biological mechanism underlying the link between higher body mass and deficits in processing speed in patients with MDD.

Cognitive Function Mediates the Anti-suicide Effect of Repeated Intravenous Ketamine in Adult Patients With Suicidal Ideation.

Objective: Prior research has shown that ketamine has anti-suicide effects. Additional evidence also suggests that ketamine may offer pro-cognitive effects. Herein, we propose that the anti-suicide effects of ketamine are partially mediated via pro-cognitive effects. We aimed to determine whether improvement in cognitive function mediated change in suicidal ideation was associated with ketamine treatment. Methods: Unipolar or bipolar depressive patients (n = 86) with suicidal ideation received six infusions of ketamine (0.5 mg/kg) over 2 weeks. The current severity of suicidal ideation and depression symptoms were assessed with the Beck Scale for Suicide Ideation (SSI) and the Montgomery-Asberg Depression Rating Scale (MADRS), respectively, at baseline, days 13 and 26. Cognitive domains, including processing speed, working memory, visual learning, and verbal learning were measured with the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery at the same time points. Results: Mediation analysis showed a significant total effect of ketamine treatment on SSI score (coef = -1.853, 95%CI [-2.2, -1.5]). The direct and total indirect (MADRS total score and any of cognitive domains) effects of ketamine on suicidal ideation both were statistically significant (direct: coef = -1.064 to -1.352; total indirect: coef = -0.501 to -0.788). MADRS total score and processing speed (but not other cognitive domains) were significant partial mediators of the association between ketamine treatment and improvements in suicidal ideation. Conclusion: Depressive symptoms severity and processing speed performance partially mediated improvements in suicidal ideation after repeated ketamine infusions in persons with unipolar or bipolar depressive disorder.

The effectiveness of repeated intravenous ketamine on subjective and objective psychosocial function in patients with treatment-resistant depression and suicidal ideation.

BACKGROUND: Ketamine has rapid and robust antidepressant effects in adults with treatment-resistant depression (TRD), while its effects on functional outcomes have not been sufficiently evaluated. The aim was to evaluate the efficacy of ketamine treatment on both subjective and objective functioning, and to explore whether improvements in depressive symptom and cognition mediated changes in functioning. METHODS: Adults (n=111) with TRD and/or suicidality received six infusions of ketamine (0.5mg/kg, thrice-weekly). Depression symptoms were assessed with the Montgomery-Asberg Depression Rating Scale (MADRS) at baseline, day 13 and day 26. Cognitive domains, including processing speed, working memory, visual learning and verbal learning were measured with the MATRICS Consensus Cognitive Battery, and subjective and objective functioning were measured with the Sheehan Disability Scale (SDS) and the Global Assessment of Functioning (GAF) at the same time-points. RESULTS: Significant improvement was observed in SDS total score (effect size [ES]=-1.563) and GAF score (ES=1.700) during the 26-day observation. Results from path analysis indicated that reductions of the total MADRS score and improvements in processing speed aggregately significantly mediated the reductions of SDS total score (total indirect effect coef=-3.993, 95%CI [-4.9, -3.2], direct effect coef=-1.374, 95%CI [-2.4, -0.4]) as well as the increases of GAF score (total indirect effect coef=6.022, 95%CI [4.5, 7.8], direct effect coef=3.987, 95%CI [2.1, 5.8]). CONCLUSION: Six infusions of ketamine was associated with improvements in functional outcomes in adults with TRD and/or suicidality. Depressive symptoms severity and processing speed performance were significant partial mediators of objective and subjective functioning improvements.

The potential pro-cognitive effects with intravenous subanesthetic ketamine in adults with treatment-resistant major depressive or bipolar disorders and suicidality.

BACKGROUND: Ketamine has rapid and robust antidepressant effects in depression, while its effects on cognitive measures are less clearly understood. This aim of the study herein is to determine whether ketamine has direct pro-cognitive effects in real-world treatment depression and/or suicidality. METHODS: Subjects with unipolar (n = 84) and bipolar (n = 27) depression suffering treatment resistance or suicidality received six infusions of ketamine (0.5 mg/kg) during a 12-day period. Depression symptoms were assessed using the Montgomery-Asberg Depression Rating Scale at baseline, day 13 and day 26. Cognitive domains, including processing speed, working memory, visual learning and verbal learning were also measured using the MATRICS Consensus Cognitive Battery at the same time-points. RESULTS: Significant improvement was observed in processing speed at day 13 (effect size [ES] = 0.501) and day 26 (ES = 0.654), and verbal learning at day 13 (ES = 0.362). Path analysis showed significant direct (ß = 2.444, P = 0.017) and indirect (ß = 1.220, P = 0.048) effect of ketamine on processing speed, indicating its improvement was partly independent of improvement in depressive symptoms. The direct effect (ß = -1.963, P = 0.052) of ketamine on verbal learning was not significant, whereas the indirect effect (ß = 1.386, P = 0.024) was significant, indicating treatment with ketamine indirectly improved verbal learning performance, via changes in depressive symptom. CONCLUSION: Six infusions of ketamine have a potential mood independent pro-cognitive effect on processing speed in adults with treatment depression and/or suicidality. The potential pro-cognitive effects of ketamine provide the basis for hypothesizing that other clinical outcomes (e.g., suicidality, functional impairment) reported with ketamine treatment may be in part mediated by improvement in cognition.

Plasma inflammatory cytokines and treatment-resistant depression with comorbid pain: improvement by ketamine.

BACKGROUND: Treatment-resistant depression (TRD) and pain frequently coexist clinically. Ketamine has analgesic and antidepressant effects, but few studies have evaluated individual differences in antidepressant outcomes to repeated ketamine in TRD patients with comorbid pain. Our aims were to determine the difference in ketamine's antidepressant effects in TRD patients with or without pain and then to examine whether inflammatory cytokines might contribute to ketamine's effect. METHODS: Sixty-six patients with TRD received six infusions of ketamine. Plasma levels of 19 inflammatory cytokines were assessed at baseline and post-infusion (day 13 and day 26) using the Luminex assay. Plasma inflammatory cytokines of sixty healthy controls (HCs) were also examined. RESULTS: TRD patients with pain had a higher antidepressant response rate (χ2 = 4.062, P = 0.044) and remission rate (χ2 = 4.062, P = 0.044) than patients without pain. Before ketamine treatment, GM-CSF and IL-6 levels were higher in the pain group than in the non-pain and HC groups. In the pain group, levels of TNF-α and IL-6 at day 13 and GM-CSF, fractalkine, IFN-γ, IL-10, MIP-3α, IL-12P70, IL-17α, IL-1ß, IL-2, IL-4, IL-23, IL-5, IL-6, IL-7, MIP-1ß, and TNF-α at day 26 were lower than those at baseline; in the non-pain group, TNF-α levels at day 13 and day 26 were lower than those at baseline. In the pain group, the changes of IL-6 were associated with improvement in pain intensity (ß = 0.333, P = 0.001) and depressive symptoms (ß = 0.478, P = 0.005) at day 13. Path analysis showed the direct (ß = 2.995, P = 0.028) and indirect (ß = 0.867, P = 0.042) effects of changes of IL-6 on improvement in depressive symptoms both were statistically significant. CONCLUSION: This study suggested that an elevated inflammatory response plays a critical role in individual differences in TRD patients with or without pain. Ketamine showed great antidepressant and analgesic effects in TRD patients with pain, which may be related to its effects on modulating inflammation. TRIAL REGISTRATION: ChiCTR , ChiCTR-OOC-17012239. Registered on 26 May 2017.