Rapid and sustained antidepressant effects of intravenous ketamine in treatment-resistant major depressive disorder and suicidal ideation: a randomized clinical trial.

BACKGROUND: Major depressive disorder (MDD) is the most disabling and burdensome mental disorder, negatively affecting an individual's quality of life and daily functioning. the current study was conducted with the aim of investigating the clinical effects of intravenous ketamine on symptoms of MDD and suicidal ideation. METHODS: The current randomized clinical trial was carried out on 64 patients diagnosed with treatment-resistant major depressive disorder between April and August 2022. The participants were randomly assigned to two groups: the intervention group received a dose of 0.5 mg/kg of ketamine, while the control group received normal saline. The Montgomery-Asberg Depression Scale and Beck's Suicidal Ideation Scale were utilized to assess depression and suicidal ideation, respectively. RESULTS: One hour after the administration of ketamine treatment, there was a notable and significant improvement in both depression symptoms (35.16 ± 8.13 vs. 14.90 ± 10.09) and suicidal ideation (6.74 ± 6.67 vs. 0.42 ± 1.52). Moreover, there were statistically significant differences in depression scores between the two groups at one hour, four hours, one day, three days, one week, one month, and two months after the administration of ketamine (p-value < 0.001). However, ketamine recipients frequently experienced side effects such as increased heart rate, headache, dizziness, and dissociative syndrome symptoms. CONCLUSION: The observed rapid onset of action and sustained effect demonstrate the potential of ketamine to provide relief from depressive symptoms in a shorter timeframe compared to traditional treatment approaches. These findings contribute to the growing body of evidence supporting the use of ketamine as a valuable therapeutic option for patients with treatment-resistant depression. IRCT REGISTRATION: IRCT registration number: IRCT20210806052096N1; IRCT URL: https://www.irct.ir/trial/62243 ; Ethical code: IR.ZUMS.REC.1400.150; Registration date: 2022-04-09.

Therapeutic doses of ketamine acutely attenuate the aversive effect of losses during decision-making.

The discovery of rapid-acting antidepressant, ketamine has opened a pathway to a new generation of treatments for depression, and inspired neuroscientific investigation based on a new perspective that non-adaptive changes in the intrinsic excitatory and inhibitory circuitry might underlie the pathophysiology of depression. Nevertheless, it still remains largely unknown how the hypothesized molecular and synaptic levels of changes in the circuitry might mediate behavioral and neuropsychological changes underlying depression, and how ketamine might restore adaptive behavior. Here, we used computational models to analyze behavioral changes induced by therapeutic doses of ketamine, while rhesus macaques were iteratively making decisions based on gains and losses of tokens. When administered intramuscularly or intranasally, ketamine reduced the aversiveness of undesirable outcomes such as losses of tokens without significantly affecting the evaluation of gains, behavioral perseveration, motivation, and other cognitive aspects of learning such as temporal credit assignment and time scales of choice and outcome memory. Ketamine's potentially antidepressant effect was separable from other side effects such as fixation errors, which unlike outcome evaluation, was readily countered with strong motivation to avoid errors. We discuss how the acute effect of ketamine to reduce the initial impact of negative events could potentially mediate longer-term antidepressant effects through mitigating the cumulative effect of those events produced by slowly decaying memory, and how the disruption-resistant affective memory might pose challenges in treating depression. Our study also invites future investigations on ketamine's antidepressant action over diverse mood states and with affective events exerting their impacts at diverse time scales.

Barriers to Esketamine Nasal Spray Treatment Among Adults With Treatment-Resistant Depression.

Background: Under a risk evaluation and mitigation strategy program, esketamine nasal spray CIII requires self administration at a certified treatment center. Our objective was to identify factors associated with esketamine initiation and continuation.Methods: A retrospective observational cohort study was conducted among US adults who met treatment-resistant depression (TRD) criteria. Cases (n = 966) initiated esketamine between October 11, 2019, and February 28, 2022, and were compared to controls (n = 39,219) with TRD but no esketamine use. Outcomes included initiation, induction (8 administrations within 45 days), and interruptions (30-day treatment gap). Comorbid psychiatric conditions were identified using International Classification of Diseases, Tenth Revision, Clinical Modification, codes.Results: Cases resided significantly closer to treatment centers (8.9 vs 20.3 miles). Compared to 0-9 miles, initiation rate decreased by 11.9%, 50.8%, 68.1%, 75.9%, and 92.8% for individuals residing 10-19, 20-29, 30-39, 40-49, and 50+ miles from a center. After adjustment, factors associated with increased likelihood of initiation were posttraumatic stress disorder, major depressive disorder with suicidal ideation, and male sex, while increasing distance, substance use disorder, Medicaid, Charlson Comorbidity Index (CCI), and older age were associated with lower likelihood. Factors associated with lower likelihood of completing induction were Medicaid, low socioeconomic status (SES), CCI, and Hispanic communities. Factors associated with increased likelihood of interruption were alcohol use disorder, distance, and minority communities, while generalized anxiety disorder and Medicaid were associated with lower likelihood.Conclusions: Travel distance, insurance, low SES, and minority communities are potential barriers to treatment. Alternative care models may be needed to ensure adequate access to care.J Clin Psychiatry 2024;85(2):23m15102.

A Randomized, Double-Blind, Placebo-Controlled Pilot Trial of the Acute Antisuicidal and Antidepressant Effects of Intranasal (R,S)-Ketamine in Severe Unipolar and Bipolar Depression With and Without Comorbid Alcohol Use Disorder.

Objective: Although individuals with a family history of alcohol use disorder (AUD) have a superior antidepressant response to ketamine, outcomes in patients with current AUD remain unclear. This study sought to investigate whether intranasal (IN) racemic (R,S)-ketamine had antisuicidal and antidepressant effects in unipolar and bipolar depression and whether comorbid AUD conferred superior antisuicidal outcomes for patients.Methods: This was a double-blind, randomized, placebo-controlled trial (May 2018 to January 2022) of single administration, fixed-dose (50 mg) IN (R,S)-ketamine (or saline comparator) in unmedicated inpatients meeting Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision, criteria for a current major depressive episode (bipolar or unipolar), with current suicidal ideation (SI) and past attempt. Patients with and without comorbid AUD were enrolled. Change in Scale for Suicide Ideation score was the primary outcome measure, and change in Montgomery-Åsberg Depression Rating Scale score was the secondary outcome measure.Results: No significant group × time effect was noted for SI (F = 1.1, P = .36). A statistical trend toward superior improvement in suicidality was observed in participants with comorbid AUD. The group × time interaction was significant for improvements in depression (F = 3.06, P = .03) and largely unaffected by comorbid AUD or primary mood disorder type. Within the ketamine group, a significant correlation was observed between improvement in depressive symptoms and SI for patients without comorbid AUD (r =0.927, P = .023) that was absent in patients with AUD (r = 0.39, P = .44).Conclusion: IN ketamine induced rapid antidepressant effects compared to placebo but did not significantly alter SI scores. The treatment was well tolerated. Continued investigation with IN ketamine as a practical alternative to current formulations is warranted.Trial Registration: ClinicalTrials.gov identifier: NCT03539887.

Irritable bowel syndrome: low dose antidepressant improves symptoms.

The studyFord AC, Wright-Hughes A, Alderson SL, et al. Amitriptyline at low-dose and titrated for irritable bowel syndrome as second-line treatment in primary care (ATLANTIS): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 2023;402:1773-85.To read the full NIHR Alert, go to: https://evidence.nihr.ac.uk/alert/irritable-bowel-syndrome-low-dose-antidepressant-improves-symptoms/.

Acute Dissociation and Ketamine's Antidepressant and Anti-Suicidal Ideation Effects in a Midazolam-Controlled Trial.

OBJECTIVE: We sought to explore relationships of acute dissociative effects of intravenous ketamine with change in depression and suicidal ideation and with plasma metabolite levels in a randomized, midazolam-controlled trial. METHODS: Data from a completed trial in suicidal, depressed participants (n = 40) randomly assigned to ketamine was used to examine relationships between ketamine treatment-emergent dissociative and psychotomimetic symptoms with pre/post-infusion changes in suicidal ideation and depression severity. Nonparametric correlational statistics were used. These methods were also used to explore associations between dissociative or psychotomimetic symptoms and blood levels of ketamine and metabolites in a subset of participants (n = 28) who provided blood samples immediately post-infusion. RESULTS: Neither acute dissociative nor psychotomimetic effects of ketamine were associated with changes in suicidal ideation or depressive symptoms from pre- to post-infusion. Norketamine had a trend-level, moderate inverse correlation with dissociative symptoms on Day 1 post-injection (P = .064; P =.013 removing 1 outlier). Dehydronorketamine correlated with Clinician-Administered Dissociative States Scale scores at 40 minutes (P = .034), 230 minutes (P = .014), and Day 1 (P = .012). CONCLUSION: We did not find evidence that ketamine's acute, transient dissociative, or psychotomimetic effects are associated with its antidepressant or anti-suicidal ideation actions. The correlation of higher plasma norketamine with lower dissociative symptoms on Day 1 post-treatment suggests dissociation may be more an effect of the parent drug.

Discovering the Potential Value of Coenzyme Q10 as an Adjuvant Treatment in Patients With Depression.

PURPOSE/BACKGROUND: Depressive disorder or mental cold is the most common mental disorder, and depression exists all over the world and in all countries and cultures. The results of several studies have shown that using compounds with antioxidant properties has been fruitful in patients with depression. Coenzyme Q10 (CoQ10) is a fat-soluble antioxidant and exerts its antioxidant effect by directly neutralizing free radicals or reducing tocopherol and preventing the inhibition of mitochondrial activity because of oxidative stress. This study aimed to investigate the effects of oral CoQ10 in patients with depression as an adjunctive treatment. METHODS/PROCEDURES: Sixty-nine patients with moderate and severe depression were randomly divided into 2 CoQ10 groups (36) and placebo (33). The first group of patients received CoQ10 supplements at a dose of 200 mg daily for 8 weeks along with standard interventions and treatments for depression, and the second group received standard treatments for depression along with a placebo. The change in the score of Montgomery-Åsberg Depression Rating Scale depression scale was evaluated 4 and 8 weeks after the intervention. Also, at baseline and 8 weeks later at the end of the study, serum levels of total antioxidant capacity, total thiol groups, nitric oxide, malondialdehyde, and interleukin 6 were assessed. FINDINGS/RESULTS: The changes in the depression score at the end of the study showed that, in the group receiving the CoQ10 supplement after 8 weeks, there was a reduction in depression symptoms, which was statistically significant compared with before the start of the study Meanwhile, no significant changes were observed in the patients of the placebo group in terms of symptom reduction. Compared with baseline and the placebo condition, serum levels of nitric oxide and total thiol groups significantly decreased and increased, respectively. Also, no statistically significant changes were observed for interleukin 6, malondialdehyde, and total antioxidant capacity. IMPLICATIONS/CONCLUSIONS: A dose of 200 mg of CoQ10 supplement daily for 8 weeks can reduce depression and fatigue, as well as improve the quality of life of patients with depression. In addition, CoQ10 can significantly improve inflammation and oxidative stress status in patients with depression.

Effects of a single subanesthetic dose of esketamine on postoperative subthreshold depressive symptoms in patients undergoing unilateral modified radical mastectomy: a randomised, controlled, double-blind trial.

BACKGROUND: Breast cancer is the most common malignant tumor in females worldwide. During disease development, breast cancer patients suffer anxious and depressed, which may lead to worse quality of life or even higher mortality. Esketamine has been regarded as an antidepressant in breast cancer patients with mild or moderate depression. Here, we wonder whether the administration of esketamine could reduce the postoperative depressive symptom score of breast cancer patients who have no preoperative depression. METHODS: A total of 64 patients treated with unilateral modified radical mastectomy were randomly divided into an experimental group (esketamine group, Group E) and a control group (Group C), with 32 cases in each one. After anesthesia induction, Group C received 0.2 ml/kg of normal saline intravenously and Group E was administered 0.2 mg/kg intravenous esketamine. The primary outcome was the Patient Health Questionnaire-9 (PHQ-9) scores. The secondary outcomes included the Visual Analogue Scale (VAS) scores for pain, inflammatory markers, perioperative-related indicators, and the incidence of postoperative delirium, nausea and vomiting. RESULTS: The PHQ-9 score on postoperative day (POD) 1 in Group E declined from the preoperative level, while the score in Group C was higher than before, and the former was far lower than the latter (P = 0.047). There is no statistically significant difference in PHQ-9 scores between Group E and Group C on POD 3, 7, and 30. Moreover, the postoperative leukocyte level of Group E was higher than that of Group C, and the difference was statistically significant (P = 0.030). CONCLUSIONS: A single subanesthetic dose of esketamine can result in lower postoperative score on subthreshold depressive symptoms compared to the Group C on POD 1, without increasing the occurrence of postoperative adverse reactions. TRIAL REGISTRATION: Registration number: Chinese Clinical Trial Registry ChiCTR2200057028. Date of registration: 26/02/2022.

Suicide ideation and male-female differences in major depressive disorder.

OBJECTIVE: This study aimed to explore male-female differences in suicide ideation (SI) and suicide risk factors in major depressive disorder (MDD). METHODS: We analysed 482 adults (sample 1) and 438 elderly outpatients (sample 2) with MDD. Sample 1 was treated with different antidepressant combinations (escitalopram; bupropion plus escitalopram; venlafaxine plus mirtazapine) and assessed by means of the Concise Health Risk Tracking (SI), Quick Inventory of Depressive Symptomatology, Altman Mania Rating Scale and Psychiatric Diagnostic Screening Questionnaire. Sample 2 was treated with venlafaxine and assessed using the Hamilton scale for depression, Anxiety Sensitivity Index and Penn State Worry Questionnaire for anxiety, Beck Scale for Suicide Ideation and Repeatable Battery for the Assessment of Neuropsychological Status. RESULTS: In sample 1, females had greater depression severity (O.R 0.961 99%CI: 0.929 - 0.995), males reported more alcohol abuse (O.R 1.299 99%CI: 1.118 - 1.509) and active SI (O.R 1.109 99%CI: 1.005 - 1.255). In sample 2 men showed more severe SI (O.R 1.067; 99%CI: 1.014 - 1.122) and weight loss (OR = 5.89 99%CI: 1.01 - 34.19), women more gastrointestinal symptoms. CONCLUSIONS: In these selected samples, although women had more severe depression, men had more suicide risk factors. Such differences might contribute to men's increased suicide risk.

In major depressive disorder sex differences affect the clinical expression of depressive episodes. In comparison to men, women endorse higher levels of overall depression in adult MDD and more somatic anxiety and gastrointestinal symptoms in late-life MDD.After controlling for confounding variables, males have more severe SI and a larger number of suicide risk factors (eg. alcohol abuse; weight loss). The association between male sex and SI is detectable in both adults and elderly patients with MDD.Further studies are necessary to elucidate how sex differences in suicide ideation and suicide risk factors are related to men's increased suicide risk.

20(S)-Protopanaxadiol Exerts Antidepressive Effects in Chronic Corticosterone-Induced Rodent Animal Models as an Activator of Brain-Type Creatine Kinase.

20(S)-Protopanaxadiol (PPD) is one of the bioactive ingredients in ginseng and possesses neuroprotective properties. Brain-type creatine kinase (CK-BB) is an enzyme involved in brain energy homeostasis via the phosphocreatine-creatine kinase system. We previously identified PPD as directly bound to CK-BB and activated its activity in vitro. In this study, we explored the antidepressive effects of PPD that target CK-BB. First, we conducted time course studies on brain CK-BB, behaviors, and hippocampal structural plasticity responses to corticosterone (CORT) administration. Five weeks of CORT injection reduced CK-BB activity and protein levels and induced depression-like behaviors and hippocampal structural plasticity impairment. Next, a CK inhibitor and an adeno-associated virus-targeting CKB were used to diminish CK-BB activity or its expression in the brain. The loss of CK-BB in the brain led to depressive behaviors and morphological damage to spines in the hippocampus. Then, a polyclonal antibody against PPD was used to determine the distribution of PPD in the brain tissues. PPD was detected in the hippocampus and cortex and observed in astrocytes, neurons, and vascular endotheliocytes. Finally, different PPD doses were used in the chronic CORT-induced depression model. Treatment with a high dose of PPD significantly increased the activity and expression of CK-BB after long-term CORT injection. In addition, PPD alleviated the damage to depressive-like behaviors and structural plasticity induced by repeated CORT injection. Overall, our study revealed the critical role of CK-BB in mediating structural plasticity in CORT-induced depression and identified CK-BB as a therapeutic target for PPD, allowing us to treat stress-related mood disorders.

Functional connectivity of the amygdala subregions and the antidepressant effects of repeated ketamine infusions in major depressive disorder.

BACKGROUND: Amygdala subregion-based network dysfunction has been determined to be centrally implicated in major depressive disorder (MDD). Little is known about whether ketamine modulates amygdala subarea-related networks. We aimed to investigate the relationships between changes in the resting-state functional connectivity (RSFC) of amygdala subregions and ketamine treatment and to identify important neuroimaging predictors of treatment outcomes. METHODS: Thirty-nine MDD patients received six doses of ketamine (0.5 mg/kg). Depressive symptoms were assessed, and magnetic resonance imaging (MRI) scans were performed before and after treatment. Forty-five healthy controls underwent one MRI scan. Seed-to-voxel RSFC analyses were performed on the amygdala subregions, including the centromedial amygdala (CMA), laterobasal amygdala (LBA), and superficial amygdala subregions. RESULTS: Abnormal RSFC between the left LBA and the left precuneus in MDD patients is related to the therapeutic efficacy of ketamine. There were significant differences in changes in bilateral CMA RSFC with the left orbital part superior frontal gyrus and in changes in the left LBA with the right middle frontal gyrus between responders and nonresponders following ketamine treatment. Moreover, there was a difference in the RSFC of left LBA and the right superior temporal gyrus/middle temporal gyrus (STG/MTG) between responders and nonresponders at baseline, which could predict the antidepressant effect of ketamine on Day 13. CONCLUSIONS: The mechanism by which ketamine improves depressive symptoms may be related to its regulation of RSFC in the amygdala subregion. The RSFC between the left LBA and right STG/MTG may predict the response to the antidepressant effect of ketamine.

Role of adjunctive cariprazine for treatment-resistant depression in patients with major depressive disorder: A systematic review and meta-analysis of randomized controlled trials.

INTRODUCTION: Cariprazine is an orally active dopamine D3-preferring D3/D2 receptor and serotonin 5-HT1A receptor partial agonist, being considered as a treatment for refractory MDD. Therefore, we aim to perform the first meta-analysis of current literature, to collate changes in depression from baseline and assess tolerability of adjunctive cariprazine in MDD populace. METHODS: PubMed, Embase, Google Scholar, ClinicalTrials.Gov, and Cochrane Library were searched from inception till 1st September 2023. RCTs of adult patients with refractory MDD under adjunctive cariprazine vs. placebo were included. Primary outcomes included improvement in MADRS, CGI-S, and HAM-D 17 scores. Secondary outcomes included treatment-emergent adverse events. The statistical analysis was performed using generic inverse variance with random-effects model. The overall risk ratios (RR) were calculated for dichotomous outcomes. RESULTS: A total of five RCTs were analysed, enrolling 2013 participants (cariprazine: 959 participants, Placebo: 1054). Supplementation of ADT with cariprazine demonstrated a significant improvement in MADRAS, CGI-S and HAMD-17 scores from baseline (LSMD: -1.88, 95% CI [-2.94, -0.83], p=0.0005), (LSMD: -0.18, 95% CI [-0.29, -0.07], p=0.002), and (LSMD: -0.96, 95% CI [-1.70, -0.21], p=0.01) respectively. Treatment with adjunctive cariprazine therapy demonstrated significantly increased incidence of akathisia, nausea, dizziness, fatigue, restlessness, somnolence, and tremors when compared with placebo. CONCLUSION: Our meta-analysis provides evidence supporting the efficacy of adjunctive cariprazine in patients with refractory MDD. However, it is essential to consider the safety profile of cariprazine, particularly the increased risk of adverse events. The vigilant monitoring and management of these side effects should be integrated into clinical practice to minimize discontinuation rates and optimize patient outcomes.

Perspectives on the impact of vortioxetine on the treatment armamentarium of major depressive disorder.

INTRODUCTION: Major Depressive Disorder (MDD) is a mental health issue that significantly affects patients' quality of life and functioning. Despite available treatments, many patients continue to suffer due to incomplete symptom resolution and side effects. AREAS COVERED: This manuscript examines Vortioxetine's role in Major Depressive Disorder (MDD) treatment, highlighting its potential to reshape therapeutic strategies due to its unique Multimodal action and proven broad-spectrum efficacy in multiple depressive domains. A detailed examination of Vortioxetine's pharmacological aspects, including indications, dosage, pharmacodynamics, and pharmacokinetics, is provided, emphasizing its safety and effectiveness. The discussion extends to Vortioxetine's role in acute-phase treatment and maintenance of MDD and its profound impact on specialized depression domains. EXPERT OPINION: Vortioxetine is distinguished for its novel multimodal serotonin modulation mechanism, showcasing significant promise as an innovative treatment for MDD. Its efficacy, which is dose-dependent, along with a commendable tolerability profile, positions it as a potential leading option for initial treatment strategies. The discourse on dosage titration, particularly the strategy of initiating treatment at lower doses followed by gradual escalation, underscores the approach toward minimizing initial adverse effects while optimizing therapeutic outcomes, aligning with the principles of personalized medicine in psychiatric care.

Efficacy of intravenous ketamine and intranasal esketamine with dose escalation for Major depression: A systematic review and meta-analysis.

OBJECTIVE: Intravenous (IV) racemic ketamine and intranasal (IN) esketamine have demonstrated rapid antidepressant effects in treatment-resistant depression (TRD). This systematic review aims to evaluate the efficacy and safety of ketamine and esketamine at various dosages for depression. METHODS: We included randomized controlled trials (RCTs) with parallel group dose comparison of ketamine and esketamine for depression/TRD. Ovid Medline, Embase, PsycINFO, Scopus and Cochrane databases were searched. Standardized mean differences were calculated using Hedges'-g to complete random effects meta-analysis. The efficacy outcomes were changes in depression outcomes for IV ketamine and IN esketamine respectively. Safety was assessed by reported adverse effects. RESULTS: A random effects meta-analysis of studies (n = 12) showed efficacy in reducing depression symptoms with IV ketamine (Hedges'g = 1.52 [0.98-2.22], Z = 4.23, p < 0.001) and IN esketamine (Hedges' g = 0.31 [0.18-0.44], Z = 4.53, P < 0.001) compared to control/placebo. Treatment response was observed at IV ketamine doses ≤0.2 mg/kg, >0.2-0.5 mg/kg and > 0.5 mg/kg. Higher IV ketamine doses (>0.5 mg/kg) did not lead to greater treatment response. Esketamine doses of 56-84 mg were superior to 28 mg dose. LIMITATIONS: Overall quality of evidence was low and limited by small number of studies. Publication bias was high. CONCLUSIONS: This meta-analysis suggests that IV ketamine may be efficacious at doses as low as 0.2 mg/kg, with increasing dose response at 0.5 mg/kg, without demonstrable increased benefit at 1 mg/kg, based on a small number of studies. Efficacy for IN esketamine increases with doses above 28 mg with best response being found between 56 and 84 mg for reducing depressive symptoms.

New pharmacotherapies to tackle the unmet needs in bipolar disorder: a focus on acute suicidality.

INTRODUCTION: Suicidal behavior is relatively frequent in patients with bipolar disorder (BD) and constitutes their most frequent cause of death. Suicide rates remain high in patients with BD despite adherence to guidelines recommending lithium as first line, and/or antidepressants, antipsychotics, psychotherapy, psychosocial interventions, and electroconvulsive therapy. Hence the need to identify more effective and rapid anti-suicide interventions. AREAS COVERED: To tackle the unmet needs of pharmacotherapy, we investigated the PubMed database on 24-25 January 2024 using strategies like ('acute suicid*'[ti] OR 'suicide crisis syndrome' OR 'acute suicidal affective disturbance') AND (lithium[ti] OR clozapine[ti]), which obtained 3 results, and ('acute suicid*'[ti] OR 'suicide crisis syndrome' OR 'acute suicidal affective disturbance') AND (ketamine[ti] OR esketamine[ti] OR NMDA[ti] OR glutamat*[ti]), which yielded 14 results. We explored glutamatergic abnormalities in BD and suicide and found alterations in both. The noncompetitive NMDS antagonist ketamine and its S-enantiomer esketamine reportedly decrease acute suicidality. EXPERT OPINION: Intranasal esketamine or subcutaneous ketamine, single-bolus or intravenous, and possibly other glutamate receptor modulators may improve suicidal behavior in patients with unipolar and bipolar depression. This may be achieved through prompt remodulation of glutamate activity. The correct use of glutamatergic modulators could reduce acute suicidality and mortality in patients with BD.

GM-1020: a novel, orally bioavailable NMDA receptor antagonist with rapid and robust antidepressant-like effects at well-tolerated doses in rodents.

The NMDA receptor (NMDAR) antagonist ketamine has shown great potential as a rapid-acting antidepressant; however, its use is limited by poor oral bioavailability and a side effect profile that necessitates in-clinic dosing. GM-1020 is a novel NMDAR antagonist that was developed to address these limitations of ketamine as a treatment for depression. Here, we present the preclinical characterization of GM-1020 alongside ketamine, for comparison. In vitro, we profiled GM-1020 for binding to NMDAR and functional inhibition using patch-clamp electrophysiology. In vivo, GM-1020 was assessed for antidepressant-like efficacy using the Forced Swim Test (FST) and Chronic Mild Stress (CMS), while motor side effects were assessed in spontaneous locomotor activity and on the rotarod. The pharmacokinetic properties of GM-1020 were profiled across multiple preclinical species. Electroencephalography (EEG) was performed to determine indirect target engagement and provide a potentially translational biomarker. These results demonstrate that GM-1020 is an orally bioavailable NMDAR antagonist with antidepressant-like efficacy at exposures that do not produce unwanted motor effects.

Sustained antidepressant effect of ketamine through NMDAR trapping in the LHb.

Ketamine, an N-methyl-D-aspartate receptor (NMDAR) antagonist1, has revolutionized the treatment of depression because of its potent, rapid and sustained antidepressant effects2-4. Although the elimination half-life of ketamine is only 13 min in mice5, its antidepressant activities can last for at least 24 h6-9. This large discrepancy poses an interesting basic biological question and has strong clinical implications. Here we demonstrate that after a single systemic injection, ketamine continues to suppress burst firing and block NMDARs in the lateral habenula (LHb) for up to 24 h. This long inhibition of NMDARs is not due to endocytosis but depends on the use-dependent trapping of ketamine in NMDARs. The rate of untrapping is regulated by neural activity. Harnessing the dynamic equilibrium of ketamine-NMDAR interactions by activating the LHb and opening local NMDARs at different plasma ketamine concentrations, we were able to either shorten or prolong the antidepressant effects of ketamine in vivo. These results provide new insights into the causal mechanisms of the sustained antidepressant effects of ketamine. The ability to modulate the duration of ketamine action based on the biophysical properties of ketamine-NMDAR interactions opens up new opportunities for the therapeutic use of ketamine.

Esketamine Nasal Spray versus Quetiapine for Treatment-Resistant Depression.

BACKGROUND: In treatment-resistant depression, commonly defined as a lack of response to two or more consecutive treatments during the current depressive episode, the percentage of patients with remission is low and the percentage with relapse is high. The efficacy and safety of esketamine nasal spray as compared with extended-release quetiapine augmentation therapy, both in combination with ongoing treatment with a selective serotonin reuptake inhibitor (SSRI) or a serotonin-norepinephrine reuptake inhibitor (SNRI), in patients with treatment-resistant depression are unknown. METHODS: In an open-label, single-blind (with raters unaware of group assignments), multicenter, phase 3b, randomized, active-controlled trial, we assigned patients, in a 1:1 ratio, to receive flexible doses (according to the summary of product characteristics) of esketamine nasal spray (esketamine group) or extended-release quetiapine (quetiapine group), both in combination with an SSRI or SNRI. The primary end point was remission, defined as a score of 10 or less on the Montgomery-Åsberg Depression Rating Scale (MADRS), at week 8 (scores range from 0 to 60, with higher scores indicating more severe depression). The key secondary end point was no relapse through week 32 after remission at week 8. All patients were included in the analysis; patients who discontinued the trial treatment were considered as having had an unfavorable outcome (i.e., they were grouped with patients who did not have remission or who had a relapse). Analyses of the primary and key secondary end points were adjusted for age and number of treatment failures. RESULTS: Overall, 336 patients were assigned to the esketamine group and 340 to the quetiapine group. More patients in the esketamine group than in the quetiapine group had remission at week 8 (91 of 336 patients [27.1%] vs. 60 of 340 patients [17.6%]; P = 0.003) and had no relapse through week 32 after remission at week 8 (73 of 336 patients [21.7%] vs. 48 of 340 patients [14.1%]). Over 32 weeks of follow-up, the percentage of patients with remission, the percentage of patients with a treatment response, and the change in the MADRS score from baseline favored esketamine nasal spray. The adverse events were consistent with the established safety profiles of the trial treatments. CONCLUSIONS: In patients with treatment-resistant depression, esketamine nasal spray plus an SSRI or SNRI was superior to extended-release quetiapine plus an SSRI or SNRI with respect to remission at week 8. (Funded by Janssen EMEA; ESCAPE-TRD ClinicalTrials.gov number, NCT04338321.).