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Background: Fatigue is a multidimensional condition that may overlap with depression. Initial studies found that fatigue responds in only a limited way to standard monoaminergic antidepressants and mood stabilizers but does respond positively to intravenous (IV) racemic (R,S)-ketamine (ketamine). However, IV ketamine's use is limited by cost and access barriers. To date, no study has evaluated intranasal (IN) ketamine in individuals with fatigue. This study sought to evaluate the anti-fatigue effects of a single 50 mg dose of IN ketamine in individuals with major depressive disorder (MDD) or bipolar depression (BDep), both with and without comorbid alcohol use disorder (AUD)., Methods: Twenty-eight individuals with primary diagnoses of MDD or BDep I/II currently experiencing a depressive episode with active suicidality were enrolled; approximately 60 % had comorbid AUD. Changes in the NIH-Brief Fatigue Inventory (NIH-BFI) were assessed at baseline and at 4, 24, and 48 h post-treatment., Results: The group x time interaction for NIH-BFI score was significant (F = 3.44, p = 0.022), favoring IN ketamine over placebo. IN ketamine was well-tolerated with minimal adverse effects., Limitations: Limitations include the limited sample size, short duration, and single, fixed dose., Conclusions: IN ketamine appears to induce rapid anti-fatigue effects in individuals with severe MDD and BDep both with and without comorbid AUD. This suggests that IN ketamine holds potential as an alternative, rapid-acting, anti-fatigue option for different medical conditions., Competing Interests: Declaration of competing interest Dr. Machado-Vieira has received consulting fees from Eurofarma Pharmaceuticals, Abbott, and BioStrategies group; has research contracts with Boerhinger Ingelheim and Janssen Pharmaceuticals; has received speaker fees from Otsuka, EMS, and Cristalia; and is a member of the scientific boards of Symbinas Pharmaceuticals and Allergan. Dr. Machado-Vieira is also the PI for the following grants: NIH (R21HD106779 and R21MH129888), Milken Institute (BD-0000000081), Dr Machado-Vieira was PI for the Janssen 54135419TRD4005 study. Dr. Soares has served on the Advisory Board of Alkermes; as a Consultant for Boehringer, Johnson and Johnson, Livanova, and Sunovian; and received research grants from Compass Pathways, Mind Med, and Relmada. Dr. Zarate is listed as a co-inventor on a patent for the use of ketamine in major depression and suicidal ideation; as a co-inventor on a patent for the use of (2R,6R)-hydroxynorketamine, (S)-dehydronorketamine, and other stereoisomeric dehydroxylated and hydroxylated metabolites of (R,S)-ketamine metabolites in the treatment of depression and neuropathic pain; and as a co-inventor on a patent application for the use of (2R,6R)-hydroxynorketamine and (2S,6S)-hydroxynorketamine in the treatment of depression, anxiety, anhedonia, suicidal ideation, and post-traumatic stress disorder. He has assigned his patent rights to the U.S. government but will share a percentage of any royalties that may be received by the government. All other authors have no conflict of interest to disclose, financial or otherwise., (Copyright © 2024. Published by Elsevier B.V.)

Background: Subanesthetic doses of (R,S)-ketamine (ketamine) have demonstrated rapid and robust antidepressant effects in individuals with depression. However, individual variability in response to ketamine exists, and current biomarkers of ketamine treatment response are not entirely understood. Preclinical evidence suggests a link between hypothalamic-pituitary-adrenal (HPA) axis activation, a determinant of the stress response system, and ketamine's efficacy in stressed mice exhibiting enhanced antidepressant responses. Here, we assessed the relationship between HPA axis, major depression features, and antidepressant response to ketamine in humans., Methods: We investigated 42 participants following medication washout with treatment-resistant depression who participated in a randomized, placebo-controlled, crossover trial receiving intravenous ketamine. Plasma levels of corticotropin-releasing factor (CRF), adrenocorticotropic hormone (ACTH), and cortisol were measured at baseline. Ketamine's antidepressant effects were assessed using the Montgomery-Asberg Depression Rating Scale., Results: We found that baseline HPA axis hormone levels did not significantly moderate the antidepressant effects of ketamine. However, a negative association was observed between ACTH and CRF levels and the overall duration of depressive episodes, suggesting potential biomarker implications. Also, a negative correlation between baseline depressive scores and age of onset was observed, suggesting that the severity of depression might be greater if it develops at a younger age, indicating more enduring stress on the brain and body., Discussion: Although we did not find a moderation effect of the plasma HPA axis hormones on the antidepressant effects of ketamine, moderation effects of the brain HPA axis hormones cannot be precluded and warrants further investigation. Importantly, our results implicate HPA axis components as potential biomarkers for the duration of depressive episodes., Competing Interests: Declaration of competing interest Dr. Zarate is listed as a coinventor on a patent for the use of ketamine in major depression and suicidal ideation. Dr. Zarate is listed as coinventor on a patent for the use of (2R,6R)-hydroxynorketamine, (S)-dehydronorketamine, and other stereoisomeric dehydroxylated and hydroxylated metabolites of (R,S)-ketamine metabolites in the treatment of depression and neuropathic pain. Drs. Zarate, and Gould are listed as co-inventors on a patent application for the crystal forms and methods of synthesis of (2R,6R)-hydroxynorketamine and (2S,6S)-hydroxynorketamine and the use of (2R,6R)-hydroxynorketamine and (2S,6S)-hydroxynorketamine in the treatment of depression, anxiety, anhedonia, suicidal ideation, and post-traumatic stress disorders. Dr. Zarate have assigned their patent rights to the U.S. government but will share a percentage of any royalties that may be received by the government. Dr. Gould has assigned his patent rights to the University of Maryland. All other authors have no conflict of interest to disclose, financial or otherwise., (Copyright © 2024. Published by Elsevier B.V.)

Over 300 million people worldwide suffer from major depressive disorder (MDD). Unfortunately, only 30-40% of patients with MDD achieve complete remission after conventional monoamine antidepressant therapy. In recent years, ketamine has revolutionized the treatment of MDD, with its rapid antidepressant effects manifesting within a few hours as opposed to weeks with conventional antidepressants. Many research endeavors have sought to identify ketamine's mechanism of action in mood disorders; while many studies have focused on ketamine's role in glutamatergic modulation, several studies have implicated its role in regulating neuroinflammation. The complement system is an important component of the innate immune response vital for synaptic plasticity. The complement system has been implicated in the pathophysiology of depression, and studies have shown increases in complement component 3 (C3) expression in the prefrontal cortex of suicidal individuals with depression. Given the role of the complement system in depression, ketamine and the complement system's abilities to modulate glutamatergic transmission, and our current understanding of ketamine's anti-inflammatory properties, there is reason to suspect a common link between the complement system and ketamine's mechanism of action. This review will summarize ketamine's anti- inflammatory roles in the periphery and central nervous system, with an emphasis on complement system regulation., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

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., (© Copyright 2024 Physicians Postgraduate Press, Inc.)

The hippocampus and amygdala have been implicated in the pathophysiology and treatment of major depressive disorder (MDD). Preclinical models suggest that stress-related changes in these regions can be reversed by antidepressants, including ketamine. Clinical studies have identified reduced volumes in MDD that are thought to be potentiated by early life stress and worsened by repeated depressive episodes. This study used 3T and 7T structural magnetic resonance imaging data to examine longitudinal changes in hippocampal and amygdalar subfield volumes associated with ketamine treatment. Data were drawn from a previous double-blind, placebo-controlled, crossover trial of healthy volunteers (HVs) unmedicated individuals with treatment-resistant depression (TRD) (3T: 18 HV, 26 TRD, 7T: 17 HV, 30 TRD) who were scanned at baseline and twice following either a 40 min IV ketamine (0.5 mg/kg) or saline infusion (acute: 1-2 days, interim: 9-10 days post infusion). No baseline differences were noted between the two groups. At 10 days post-infusion, a slight increase was observed between ketamine and placebo scans in whole left amygdalar volume in individuals with TRD. No other differences were found between individuals with TRD and HVs at either field strength. These findings shed light on the timing of ketamine's effects on cortical structures., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Machine learning (ML) techniques have gained popularity in the neuroimaging field due to their potential for classifying neuropsychiatric disorders. However, the diagnostic predictive power of the existing algorithms has been limited by small sample sizes, lack of representativeness, data leakage, and/or overfitting. Here, we overcome these limitations with the largest multi-site sample size to date (N = 5365) to provide a generalizable ML classification benchmark of major depressive disorder (MDD) using shallow linear and non-linear models. Leveraging brain measures from standardized ENIGMA analysis pipelines in FreeSurfer, we were able to classify MDD versus healthy controls (HC) with a balanced accuracy of around 62%. But after harmonizing the data, e.g., using ComBat, the balanced accuracy dropped to approximately 52%. Accuracy results close to random chance levels were also observed in stratified groups according to age of onset, antidepressant use, number of episodes and sex. Future studies incorporating higher dimensional brain imaging/phenotype features, and/or using more advanced machine and deep learning methods may yield more encouraging prospects., (© 2024. The Author(s).)

Background: Approximately one third of individuals with major depressive disorder have treatment-resistant depression (TRD). Glutamatergic modulators such as the N -methyl- d -aspartate receptor antagonist ketamine have rapid and robust antidepressant effects, but their use has been limited by accessibility and route of administration. This open-label pilot study assessed the adjunctive antidepressant efficacy of dextromethorphan/quinidine (DM/Q) in TRD., Methods: Inpatients with TRD (n = 17, 40.8 ± 12.3 years; 9 females/8 males) received adjunctive open-label DM/Q (20 mg/10 mg) up to 3 times daily. The study had no set endpoint; participants were followed until they discontinued DM/Q or were discharged. Montgomery-Asberg Depression Rating Scale (MADRS) scores were obtained at baseline (before DM/Q administration) and regularly during hospitalization. Full response was defined as a ≥50% reduction in baseline MADRS score, partial response as a 25% to 50% decrease in baseline MADRS score, and nonresponse as a <25% reduction or an increase in baseline MADRS score., Results: The 17 inpatients received open-label DM/Q for 5.1 ± 2.7 weeks. Forty-seven percent of participants responded to DM/Q-12% achieved a full response and 35% achieved a partial response. The largest MADRS difference observed at any time point was -6.4 ± 8.4 (-21.0% ± 29.9%), and the MADRS difference observed at time of DM/Q discontinuation or hospital discharge was -4.8 ± 8.4 (-15.9% ± 29.7%). Twenty-four percent of participants experienced a nonserious adverse event; none experienced a serious adverse event., Conclusions: In this open-label pilot study, 47% of participants responded to adjunctive DM/Q, which was well tolerated. Larger placebo-controlled trials are needed to determine the real-world efficacy of DM/Q., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Individuals with major depressive disorder (MDD) are at higher risk for obesity. In turn, weight gain is a predisposing factor for depression. Although clinical data are sparse, suicide risk also appears to be elevated in obese patients. This study used data from the European Group for the Study of Resistant Depression (GSRD) to investigate clinical outcomes associated with body mass index (BMI) in MDD., Methods: Data were drawn from 892 participants with MDD over the age of 18 years (580 female, 50.5 ± 13.6 years). Response and resistance to antidepressant medication, depression rating scale scores, and further clinical and sociodemographic variables were compared using multiple logistic and linear regressions controlled for age, sex, and risk of weight gain due to psychopharmacotherapy., Results: Of the 892 participants, 323 were categorized as treatment-responsive and 569 as treatment-resistant. Within this cohort, 278 (31.1 %) were overweight (BMI = 25-29.9 kg/m 2 ) and 151 (16.9 %) were obese (BMI > 30 kg/m 2 ). Elevated BMI was significantly associated with higher suicidality, longer duration of psychiatric hospitalizations over their lifetimes, earlier age of onset of MDD, and comorbidities. There was a trend-wise association of BMI with treatment resistance., Limitations: Data were analyzed in a retrospective, cross-sectional design. BMI was used as an exclusive measure of overweight and obesity., Conclusions: Participants with comorbid MDD and overweight/obesity were at risk for worse clinical outcomes, suggesting that weight gain should be closely monitored in individuals with MDD in daily clinical practice. Further studies are needed to explore the neurobiological mechanisms linking elevated BMI to impaired brain health., Competing Interests: Declaration of competing interest Not related to this study, C. Kraus received honoraria by Janssen and LivaNova, as well as travel support by Roche Austria and AOP Orphan. B. Kadriu is now a full-time employee and shareholder of Jazz Pharmaceuticals. Within the last three years, L. Bartova has received travel grants and consultant/speaker honoraria from Alpine Market Research, Angelini, Biogen, Diagnosia, Dialectica, Janssen, Lundbeck, Medizin Medien Austria, Novartis, Schwabe and Universimed. C.A. Zarate, Jr. is listed as a co-inventor on a patent for the use of ketamine in major depression and suicidal ideation; as a co-inventor on a patent for the use of (2R,6R)-hydroxynorketamine, (S)-dehydronorketamine, and other stereoisomeric dehydroxylated and hydroxylated metabolites of (R,S)-ketamine metabolites in the treatment of depression and neuropathic pain; and as a co-inventor on a patent application for the use of (2R,6R)-hydroxynorketamine and (2S,6S)-hydroxynorketamine in the treatment of depression, anxiety, anhedonia, suicidal ideation, and post-traumatic stress disorders. He has assigned his patent rights to the U.S. government but will share a percentage of any royalties that may be received by the government. R. Lanzenberger received travel grants and/or conference speaker honoraria from Bruker BioSpin within the last three years and investigator-initiated research funding from Siemens Healthcare regarding clinical research using PET/MR. He is a shareholder of the start-up company BM Health GmbH since 2019. A. Serretti is or has been a consultant/speaker for Abbott, Abbvie, Angelini, AstraZeneca, Clinical Data, Boehringer, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Innovapharma, Italfarmaco, Janssen, Lundbeck, Naurex, Pfizer, Polifarma, Sanofi, Servier, and Taliaz. In the past 3 years S. Kasper has served as a consultant or on advisory boards for Angelini, Biogen, Esai, Janssen, IQVIA, Mylan, Recordati, Sage and Schwabe and has served on speakers bureaus for Angelini, Aspen Farmaceutica S.A., Biogen, Janssen, Recordati, Schwabe, Servier, and Sun Pharma. All other authors have no conflict of interest to declare, financial or otherwise., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Treatment-resistant depression (TRD) is a severe form of major depressive disorder (MDD) with substantial public health impact and poor treatment outcome. Treatment outcome in MDD is significantly heritable, but genome-wide association studies have failed to identify replicable common marker alleles, suggesting a potential role for uncommon variants. Here we investigated the hypothesis that uncommon, putatively functional genetic variants are associated with TRD. Whole-exome sequencing data was obtained from 182 TRD cases and 2021 psychiatrically healthy controls. After quality control, the remaining 149 TRD cases and 1976 controls were analyzed with tests designed to detect excess burdens of uncommon variants. At the gene level, 5 genes, ZNF248, PRKRA, PYHIN1, SLC7A8, and STK19 each carried exome-wide significant excess burdens of variants in TRD cases (q < 0.05). Analysis of 41 pre-selected gene sets suggested an excess of uncommon, functional variants among genes involved in lithium response. Among the genes identified in previous TRD studies, ZDHHC3 was also significant in this sample after multiple test correction. ZNF248 and STK19 are involved in transcriptional regulation, PHYIN1 and PRKRA are involved in immune response, SLC7A8 is associated with thyroid hormone transporter activity, and ZDHHC3 regulates synaptic clustering of GABA and glutamate receptors. These results implicate uncommon, functional alleles in TRD and suggest promising novel targets for future research., (© 2023. The Author(s).)

Objective: A major limitation of current suicide research is the lack of power to identify robust correlates of suicidal thoughts or behavior. Variation in suicide risk assessment instruments used across cohorts may represent a limitation to pooling data in international consortia., Method: Here, we examine this issue through two approaches: (a) an extensive literature search on the reliability and concurrent validity of the most commonly used instruments and (b) by pooling data (N ∼ 6,000 participants) from cohorts from the Enhancing NeuroImaging Genetics Through Meta-Analysis (ENIGMA) Major Depressive Disorder and ENIGMA-Suicidal Thoughts and Behaviour working groups, to assess the concurrent validity of instruments currently used for assessing suicidal thoughts or behavior., Results: We observed moderate-to-high correlations between measures, consistent with the wide range (κ range: 0.15-0.97; r range: 0.21-0.94) reported in the literature. Two common multi-item instruments, the Columbia Suicide Severity Rating Scale and the Beck Scale for Suicidal Ideation were highly correlated with each other (r = 0.83). Sensitivity analyses identified sources of heterogeneity such as the time frame of the instrument and whether it relies on self-report or a clinical interview. Finally, construct-specific analyses suggest that suicide ideation items from common psychiatric questionnaires are most concordant with the suicide ideation construct of multi-item instruments., Conclusions: Our findings suggest that multi-item instruments provide valuable information on different aspects of suicidal thoughts or behavior but share a modest core factor with single suicidal ideation items. Retrospective, multisite collaborations including distinct instruments should be feasible provided they harmonize across instruments or focus on specific constructs of suicidality. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Background: Preclinical evidence indicates that the κ-opioid receptor (KOR)/dynorphin pathway is implicated in depressive-like behaviors. Ketamine is believed to partly exert its antidepressant effects by modulating the opioid system. This post hoc study examined the following research questions: (1) at baseline, were there differences in KOR or dynorphin plasma levels between individuals with major depressive disorder (MDD) and healthy volunteers (HVs) or between men and women? (2) in individuals with MDD, did KOR or dynorphin baseline plasma levels moderate ketamine's therapeutic effects or adverse effects? and (3) in individuals with MDD, were KOR or dynorphin plasma levels affected after treatment with ketamine compared with placebo?, Methods: Thirty-nine unmedicated individuals with MDD (23 women) and 25 HVs (16 women) received intravenous ketamine (0.5 mg/kg) and placebo in a randomized, crossover, double-blind trial. Blood was obtained from all participants at baseline and at 3 postinfusion time points (230 minutes, day 1, day 3). Linear mixed model regressions were used., Results: At baseline, participants with MDD had lower KOR plasma levels than HVs ( F1,60 = 13.16, P < 0.001), and women (MDD and HVs) had higher KOR plasma levels than men ( F1,60 = 4.98, P = 0.03). Diagnosis and sex had no significant effects on baseline dynorphin levels. Baseline KOR and dynorphin levels did not moderate ketamine's therapeutic or adverse effects. Compared with placebo, ketamine was not associated with postinfusion changes in KOR or dynorphin levels., Conclusions: In humans, diagnosis of MDD and biological sex are involved with changes in components of the KOR/dynorphin pathway. Neither KOR nor dynorphin levels consistently moderated ketamine's therapeutic effects or adverse effects, nor were levels altered after ketamine infusion., Trial Registration: NCT00088699 ( ClinicalTrials.gov )., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Clinical trials of intravenous (IV) racemic (R,S)-ketamine (hereafter referred to as IV ketamine) have consistently reported rapid and substantial reductions in overall depressive symptoms compared with saline (inactive placebo) or midazolam (active placebo). The evidence for IV ketamine's specific effects on suicidal ideation is less clear, however. This study sought to examine whether differential placebo (saline or midazolam) response to overall depressive symptoms vs suicidal ideation may help explain these divergent findings., Methods: Data for this participant-level integrative data analysis were drawn from 151 participants across 10 studies, and linear regression was used to examine the relationship between placebo response for suicidal ideation vs other depressive symptoms indexed from standard rating scales-specifically, depressed mood, anhedonia, anxiety, and guilt-over time., Results: For participants receiving saline placebo (n = 46), greater placebo response was observed for suicidal ideation compared with other symptoms indexed from standard depression rating scales, except for anxiety. For those receiving midazolam placebo (n = 105), greater placebo response was observed for suicidal ideation compared with depressed mood or anhedonia, and no significant differences were observed when comparing suicidal ideation with anxiety or guilt., Conclusions: Taken together, the results provide preliminary evidence of a differential placebo response for suicidal ideation vs other depressive symptoms, while anxiety and suicidal ideation appear to produce similar placebo response profiles. These findings may help explain the more modest findings in clinical IV ketamine trials for suicidal ideation than overall depression., (Published by Oxford University Press on behalf of CINP 2022.)

Background: This study examined magnetoencephalographic (MEG) correlates of suicidal ideation (SI) and suicide attempt history in patients with treatment-resistant major depression (TRD) at baseline and following subanesthetic-dose ketamine infusion., Methods: Twenty-nine drug-free TRD patients (12 suicide attempters/17 non-attempters) participated in a crossover randomized trial of ketamine. MEG data were collected during an attentional dot probe task with emotional face stimuli at baseline and several hours post-ketamine infusion. Synthetic aperture magnetometry was used to project source power in the theta, alpha, beta, and gamma frequencies for angry-neutral, happy-neutral, and neutral-neutral face pairings during a one-second peristimulus period. Mixed models were used to test for clinical, behavioral, and electrophysiological effects of group, emotion, session, and SI score., Results: Ketamine significantly reduced SI and depression across the sample. Post-ketamine, attempters had improved accuracy and non-attempters had reduced accuracy on the task. SI was positively associated with gamma power in regions of the frontal and parietal cortices across groups. In an extended amygdala-hippocampal region, attempters differed significantly in their emotional reactivity to angry versus happy faces as indexed by theta power differences, irrespective of drug. Ketamine significantly reduced the association between alpha power and SI for angry compared with happy faces in a fronto-insular/anterior cingulate region important for regulating sensory attentiveness., Limitations: Limitations include a small sample size of attempters., Conclusions: The findings highlight key differences in band-limited power between attempters and non-attempters and reinforce previous findings that ketamine has distinct response properties in patients with a suicide history., (Published by Elsevier B.V.)

Background: Early markers preceding suicide ideation (SI) may provide valuable information for both assessment and treatment. The glutamatergic modulator ketamine has rapid, transient effects on SI, creating an opportunity to observe potential antecedents of the re-emergence of SI. This analysis evaluated whether the interaction between two suicide risk factors-psychological pain and hopelessness-were prospectively associated with SI post-ketamine administration., Methods: Data were drawn from three ketamine clinical trials of participants with treatment-resistant major depressive disorder or bipolar disorder (n = 108) with short- and/or long-term follow-up (three or 11 days). A random intercept cross-lagged panel model evaluated the longitudinal relationship between the correlated concepts, specifically whether the interaction between hopelessness and psychological pain was associated with future SI., Results: Psychological pain and hopelessness were not prospectively associated with SI in short-term or long-term analyses; rather, long-term analyses found that SI was associated with later psychological pain and hopelessness. Similarly, no relationship was observed for other suicide risk factors, including anhedonia, depressed mood, and impaired sleep., Limitations: Secondary analysis of clinical trial data not collected for this purpose; hopelessness and psychological pain were assessed via proxy measures from existing depression rating scales; the small sample size required a restricted statistical model., Conclusions: Psychological pain and hopelessness were not associated with the re-emergence of SI post-ketamine. These results may be due to limited variability in the data. The re-emergence of SI post-ketamine may also not follow patterns typically seen in non-pharmacologic contexts. Individuals with a history of SI warrant careful monitoring post-ketamine administration., (Published by Elsevier B.V.)

Background: Racemic ketamine and esketamine have demonstrated rapid antidepressant effects. We aimed to review the efficacy and safety of racemic and esketamine for depression., Research Design and Methods: We conducted a PRISMA-guided review for relevant randomized controlled trials of racemic or esketamine for unipolar or bipolar major depression from database inception through 2021. We conducted random-effects meta-analyses using pooled rate ratios (RRs) and Cohen's standardized mean differences (d) with their 95% confidence intervals (CI)., Results: We found 36 studies (2903 participants, 57% female, 45.1 +/- 7.0 years). Nine trials used esketamine, while the rest used racemic ketamine. The overall study quality was high. Treatment with any form of ketamine was associated with improved response (RR=2.14; 95% CI, 1.72-2.66; I2=65%), remission (RR=1.64; 95% CI, 1.33-2.02; I2=39%), and depression severity (d=-0.63; 95% CI, -0.80 to -0.45; I2=78%) against placebo. Overall, there was no association between treatment with any form of ketamine and retention in treatment (RR=1.00; 95% CI, 0.99-1.01; I2<1%), dropouts due to adverse events (RR=1.56; 95% CI, 1.00-2.45; I2<1%), or the overall number of adverse events reported per participant (OR=2.14; 95% CI, 0.82-5.60; I2=62%) against placebo., Conclusions: Ketamine and esketamine are effective, safe, and acceptable treatments for individuals living with depression.

Subanesthetic-dose racemic (R,S)-ketamine (ketamine) produces rapid, robust, and sustained antidepressant effects in major depressive disorder (MDD) and bipolar disorder (BD) and has also been shown to effectively treat neuropathic pain, complex regional pain syndrome, and post-traumatic stress disorder (PTSD). However, to date, its mechanism of action remains unclear. Preclinical studies found that (2 R,6 R;2 S,6 S)-hydroxynorketamine (HNK), a major circulating metabolite of ketamine, elicits antidepressant effects similar to those of ketamine. To help determine how (2 R,6 R)-HNK contributes to ketamine's mechanism of action, an exploratory, targeted, metabolomic analysis was carried out on plasma and CSF of nine healthy volunteers receiving a 40-minute ketamine infusion (0.5 mg/kg). A parallel targeted metabolomic analysis in plasma, hippocampus, and hypothalamus was carried out in mice receiving either 10 mg/kg of ketamine, 10 mg/kg of (2 R,6 R)-HNK, or saline. Ketamine and (2 R,6 R)-HNK both affected multiple pathways associated with inflammatory conditions. In addition, several changes were unique to either the healthy human volunteers and/or the mouse arm of the study, indicating that different pathways may be differentially involved in ketamine's effects in mice and humans. Mechanisms of action found to consistently underlie the effects of ketamine and/or (2 R,6 R)-HNK across both the human metabolome in plasma and CSF and the mouse arm of the study included LAT1, IDO1, NAD + , the nitric oxide (NO) signaling pathway, and sphingolipid rheostat., (© 2022. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)

A better understanding of suicidal ideation (SI), including patterns of SI, may help elucidate links between depression, SI, and suicidal behavior. This study sought to identify trajectories of SI in a large, community-based clinical trial of participants with major depressive disorder (MDD) and to investigate the relationships between these trajectories and predictors of interest, including anxiety and anhedonia. A longitudinal latent class analysis was conducted in 3923 participants enrolled in Level 1 of the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study of citalopram for the treatment of MDD. An unconditional latent class analysis was conducted using SI at study weeks 0, 2, 4, 6, and 9 as the indicators. A multinomial regression was then conducted with SI trajectory as the outcome and anhedonia, severity of depressive symptoms, atypical depression, anxiety, history of suicide attempt, history of substance abuse, history of trauma, and other covariates as the predictors. Four SI trajectories were identified: 1) variable SI; 2) little-to-no SI; 3) persistent SI; and 4) improving SI. Compared to the little-to-no SI trajectory, those with more severe anhedonia were more likely to experience persistent SI, while those with more severe anxiety were more likely to experience improving SI. Factors that distinguish SI trajectories, such as anxiety and anhedonia, may be critical targets for intervention or profiles for prognosis., (Copyright © 2022. Published by Elsevier Ltd.)

Background: Neuroimaging studies of suicidal behavior have so far been conducted in small samples, prone to biases and false-positive associations, yielding inconsistent results. The ENIGMA-MDD Working Group aims to address the issues of poor replicability and comparability by coordinating harmonized analyses across neuroimaging studies of major depressive disorder and related phenotypes, including suicidal behavior., Methods: Here, we pooled data from 18 international cohorts with neuroimaging and clinical measurements in 18,925 participants (12,477 healthy control subjects and 6448 people with depression, of whom 694 had attempted suicide). We compared regional cortical thickness and surface area and measures of subcortical, lateral ventricular, and intracranial volumes between suicide attempters, clinical control subjects (nonattempters with depression), and healthy control subjects., Results: We identified 25 regions of interest with statistically significant (false discovery rate < .05) differences between groups. Post hoc examinations identified neuroimaging markers associated with suicide attempt including smaller volumes of the left and right thalamus and the right pallidum and lower surface area of the left inferior parietal lobe., Conclusions: This study addresses the lack of replicability and consistency in several previously published neuroimaging studies of suicide attempt and further demonstrates the need for well-powered samples and collaborative efforts. Our results highlight the potential involvement of the thalamus, a structure viewed historically as a passive gateway in the brain, and the pallidum, a region linked to reward response and positive affect. Future functional and connectivity studies of suicidal behaviors may focus on understanding how these regions relate to the neurobiological mechanisms of suicide attempt risk., (Copyright © 2021 Society of Biological Psychiatry. All rights reserved.)

Ketamine improves motivation-related symptoms in depression but simultaneously elicits similar symptoms in healthy individuals, suggesting that it might have different effects in health and disease. This study examined whether ketamine affects the brain's fronto-striatal system, which is known to drive motivational behavior. The study also assessed whether inflammatory mechanisms-which are known to influence neural and behavioral motivational processes-might underlie some of these changes. These questions were explored in the context of a double-blind, placebo-controlled, crossover trial of ketamine in 33 individuals with treatment-resistant major depressive disorder (TRD) and 25 healthy volunteers (HVs). Resting-state functional magnetic resonance imaging (rsfMRI) was acquired 2 days post-ketamine (final sample: TRD n = 27, HV n = 19) and post-placebo (final sample: TRD n = 25, HV n = 18) infusions and was used to probe fronto-striatal circuitry with striatal seed-based functional connectivity. Ketamine increased fronto-striatal functional connectivity in TRD participants toward levels observed in HVs while shifting the connectivity profile in HVs toward a state similar to TRD participants under placebo. Preliminary findings suggest that these effects were largely observed in the absence of inflammatory (C-reactive protein) changes and were associated with both acute and sustained improvements in symptoms in the TRD group. Ketamine thus normalized fronto-striatal connectivity in TRD participants but disrupted it in HVs independently of inflammatory processes. These findings highlight the potential importance of reward circuitry in ketamine's mechanism of action, which may be particularly relevant for understanding ketamine-induced shifts in motivational symptoms., (© 2020. The Author(s).)

The glutamatergic modulator ketamine has been shown to rapidly reduce depressive symptoms in patients with treatment-resistant major depressive disorder (TRD). Although its mechanisms of action are not fully understood, changes in cortical excitation/inhibition (E/I) following ketamine administration are well documented in animal models and could represent a potential biomarker of treatment response. Here, we analyse neuromagnetic virtual electrode time series collected from the primary somatosensory cortex in 18 unmedicated patients with TRD and in an equal number of age-matched healthy controls during a somatosensory 'airpuff' stimulation task. These two groups were scanned as part of a clinical trial of ketamine efficacy under three conditions: (a) baseline; (b) 6-9 h following subanesthetic ketamine infusion; and (c) 6-9 h following placebo-saline infusion. We obtained estimates of E/I interaction strengths by using dynamic causal modelling (DCM) on the time series, thereby allowing us to pinpoint, under each scanning condition, where each subject's dynamics lie within the Poincaré diagram-as defined in dynamical systems theory. We demonstrate that the Poincaré diagram offers classification capability for TRD patients, in that the further the patients' coordinates were shifted (by virtue of ketamine) toward the stable (top-left) quadrant of the Poincaré diagram, the more their depressive symptoms improved. The same relationship was not observed by virtue of a placebo effect-thereby verifying the drug-specific nature of the results. We show that the shift in neural dynamics required for symptom improvement necessitates an increase in both excitatory and inhibitory coupling. We present accompanying MATLAB code made available in a public repository, thereby allowing for future studies to assess individually tailored treatments of TRD.

Replicated international studies have underscored the human and societal costs associated with major depressive disorder. Despite the proven efficacy of monoamine-based antidepressants in major depression, the majority of treated individuals fail to achieve full syndromal and functional recovery with the index and subsequent pharmacological treatments. Ketamine and esketamine represent pharmacologically novel treatment avenues for adults with treatment-resistant depression. In addition to providing hope to affected persons, these agents represent the first non-monoaminergic agents with proven rapid-onset efficacy in major depressive disorder. Nevertheless, concerns remain about the safety and tolerability of ketamine and esketamine in mood disorders. Moreover, there is uncertainty about the appropriate position of these agents in treatment algorithms, their comparative effectiveness, and the appropriate setting, infrastructure, and personnel required for their competent and safe implementation. In this article, an international group of mood disorder experts provides a synthesis of the literature with respect to the efficacy, safety, and tolerability of ketamine and esketamine in adults with treatment-resistant depression. The authors also provide guidance for the implementation of these agents in clinical practice, with particular attention to practice parameters at point of care. Areas of consensus and future research vistas are discussed.

The prevalence of comorbid psychiatric disorders among patients with eating disorders (ED) is higher than the general population. Individuals diagnosed with eating disorders have changes in their body mass index which could promote severe metabolic disruptions. This study aimed (1) to report the prevalence of comorbid psychiatric disorders among a Mexican adolescent sample diagnosed with eating disorders, (2) to compare our results with the prevalence of psychiatric disorders reported from a national survey of mental health of adolescents, (3) to compare the presence of psychiatric comorbidities between ED diagnoses, and (4) to explore the relationship of these comorbidities with the body mass index. In the study, we included 187 Mexican adolescents diagnosed with eating disorders. The psychiatric comorbidities were evaluated using the Mini International Neuropsychiatric Interview for children/adolescents, and a revised questionnaire on eating and weight patterns. We found that 89% of the Mexican adolescents diagnosed with ED had another psychiatric comorbidity. Major depressive disorder (52.40%) and suicide risk (40%) were the most prevalent comorbidities. Attention and deficit hyperactivity disorder (ADHD) prevalence was different between ED diagnosis, and adolescents with binge-eating disorder and ADHD had the higher body mass index. Our results showed that in this sample of Mexican adolescents, the presence of comorbidities could impact body mass index. This emphasizes the importance that clinicians take into consideration the presence of psychiatric comorbidities to achieve an integrative treatment for adolescents diagnosed with ED.

Background: The glutamatergic modulator ketamine rapidly reduces depressive symptoms in individuals with treatment-resistant major depressive disorder (MDD). However, ketamine's effects on emotional processing biases remain largely unknown, and understanding these processes may help elucidate ketamine's mechanism of action., Methods: Magnetoencephalography (MEG) was used to investigate ketamine's effects on early visual responses to affective stimuli in individuals with MDD (n=31) and healthy volunteers (HVs; n=24). Participants were enrolled in a double-blind, placebo-controlled, crossover clinical trial and were assessed at baseline and after subanesthetic-dose ketamine and placebo-saline infusions. During MEG recording, participants completed an emotional evaluation task in which they indicated the sex or emotional valence (happy-neutral or sad-angry) of facial stimuli. Source-localized event-related field (ERF) M100 and M170 amplitudes and latencies were extracted from regions of interest. Linear fixed effects models examined interactions between diagnosis, stimulus valence, and drug session for behavioral and MEG data., Results: In baseline behavioral analyses, MDD participants exhibited higher accuracy for sad-angry than happy-neutral faces, and HVs responded faster to happy-neutral than sad-angry faces. In the MEG post-infusion analyses, calcarine M100 amplitudes were larger in MDD than HV participants post-placebo but became more similar post-ketamine. Finally, fusiform M170 amplitudes were associated with antidepressant response in MDD participants., Limitations: The modest sample size and the need to collapse across responses to happy and neutral faces to increase statistical power limit the generalizability of the findings., Conclusions: Ketamine rapidly altered emotional stimulus processing in MDD, laying the groundwork for future investigations of biomarkers of antidepressant treatment response., Clinical Trial: Clinicaltrials.gov, NCT#00088699., (Copyright © 2020. Published by Elsevier B.V.)

Background: Ketamine appears to have a therapeutic role in certain mental disorders, most notably depression. However, the comparative performance of different formulations of ketamine is less clear., Objectives: This study aimed to assess the comparative efficacy and tolerability of racemic and esketamine for the treatment of unipolar and bipolar major depression., Design: Systematic review and meta-analysis., Data Sources: We searched PubMed, MEDLINE, Embase, PsycINFO, the Cochrane Central Register of Controlled Clinical Trials, and the Cochrane Database of Systematic Reviews for relevant studies published since database inception and December 17, 2019., Study Eligibility Criteria: We considered randomized controlled trials examining racemic or esketamine for the treatment of unipolar or bipolar major depression., Outcomes: Primary outcomes were response and remission from depression, change in depression severity, suicidality, retention in treatment, drop-outs, and drop-outs due to adverse events., Analysis: Evidence from randomized controlled trials was synthesized as rate ratios (RRs) for treatment response, disorder remission, adverse events, and withdrawals and as standardized mean differences (SMDs) for change in symptoms, via random-effects meta-analyses., Findings: 24 trials representing 1877 participants were pooled. Racemic ketamine relative to esketamine demonstrated greater overall response (RR = 3.01 vs. RR = 1.38) and remission rates (RR = 3.70 vs. RR = 1.47), as well as lower dropouts (RR = 0.76 vs. RR = 1.37)., Conclusions: Intravenous ketamine appears to be more efficacious than intranasal esketamine for the treatment of depression., (Copyright © 2020. Published by Elsevier B.V.)

Ketamine has rapid-acting antidepressant properties but also potentially concerning transient dissociative side effects (SEs). Recent studies noted a positive correlation between treatment response to ketamine and general dissociative SEs, as well as "floating", a depersonalization SE (a subtype of the dissociative SEs). This analysis sought to determine whether floating mediates treatment response to ketamine. Data were pooled from three double-blind, crossover, placebo-controlled ketamine clinical trials across which 82 participants with treatment-resistant depression (TRD) (44 with bipolar depression and 38 with major depressive disorder) received placebo and ketamine (0.5 mg/kg) infusions. SEs were actively solicited in a standardized fashion before and after ketamine infusion. The hypothesis that a post-infusion experience of floating would mediate antidepressant response to ketamine was assessed at 230 min post-infusion and at Day 1. Montgomery-Asberg Depression Rating Scale (MADRS) total score was the dependent variable in a linear mixed effects model. Ketamine significantly decreased MADRS scores (p < 0.0001), but no relationship was detected between floating and MADRS score at either 230 min or Day 1 post-infusion. The hypothesized mediation effect of floating was also not detected at either 230 min or Day 1 post-infusion. Taken together, the findings do not support the hypothesis that ketamine's antidepressant effects are mediated by the dissociative depersonalization subtype SE of floating., (Published by Elsevier Ltd.)

A single, subanesthetic dose of (R,S)-ketamine (ketamine) exerts rapid and robust antidepressant effects. Several groups previously reported that (2S,6S;2R,6R)-hydroxynorketamine (HNK) had antidepressant effects in rodents, and that (2R,6R)-HNK increased cortical electroencephalographic gamma power. This exploratory study examined the relationship between ketamine metabolites, clinical response, psychotomimetic symptoms, and gamma power changes in 34 individuals (ages 18-65) with treatment-resistant depression (TRD) who received a single ketamine infusion (0.5 mg/kg) over 40 min. Plasma concentrations of ketamine, norketamine, and HNKs were measured at 40, 80, 120, and 230 min and at 1, 2, and 3 days post-infusion. Linear mixed models evaluated ketamine metabolites as mediators of antidepressant and psychotomimetic effects and their relationship to resting-state whole-brain magnetoencephalography (MEG) gamma power 6-9 h post-infusion. Three salient findings emerged. First, ketamine concentration positively predicted distal antidepressant response at Day 11 post-infusion, and an inverse relationship was observed between (2S,6S;2R,6R)-HNK concentration and antidepressant response at 3 and 7 days post-infusion. Norketamine concentration was not associated with antidepressant response. Second, ketamine, norketamine, and (2S,6S;2R,6R)-HNK concentrations at 40 min were positively associated with contemporaneous psychotomimetic symptoms; post-hoc analysis revealed that ketamine was the predominant contributor. Third, increased (2S,6S;2R,6R)-HNK maximum observed concentration (C max ) was associated with increased MEG gamma power. While contrary to preclinical observations and our a priori hypotheses, these exploratory results replicate those of a recently published study documenting a relationship between higher (2S,6S;2R,6R)-HNK concentrations and weaker antidepressant response in humans and provide further rationale for studying gamma power changes as potential biomarkers of antidepressant response.

A key objective in the field of translational psychiatry over the past few decades has been to identify the brain correlates of major depressive disorder (MDD). Identifying measurable indicators of brain processes associated with MDD could facilitate the detection of individuals at risk, and the development of novel treatments, the monitoring of treatment effects, and predicting who might benefit most from treatments that target specific brain mechanisms. However, despite intensive neuroimaging research towards this effort, underpowered studies and a lack of reproducible findings have hindered progress. Here, we discuss the work of the ENIGMA Major Depressive Disorder (MDD) Consortium, which was established to address issues of poor replication, unreliable results, and overestimation of effect sizes in previous studies. The ENIGMA MDD Consortium currently includes data from 45 MDD study cohorts from 14 countries across six continents. The primary aim of ENIGMA MDD is to identify structural and functional brain alterations associated with MDD that can be reliably detected and replicated across cohorts worldwide. A secondary goal is to investigate how demographic, genetic, clinical, psychological, and environmental factors affect these associations. In this review, we summarize findings of the ENIGMA MDD disease working group to date and discuss future directions. We also highlight the challenges and benefits of large-scale data sharing for mental health research.

Major depressive disorder (MDD) is associated with altered global brain connectivity (GBC), as assessed via resting-state functional magnetic resonance imaging (rsfMRI). Previous studies found that antidepressant treatment with ketamine normalized aberrant GBC changes in the prefrontal and cingulate cortices, warranting further investigations of GBC as a putative imaging marker. These results were obtained via global signal regression (GSR). This study is an independent replication of that analysis using a separate dataset. GBC was analyzed in 28 individuals with MDD and 22 healthy controls (HCs) at baseline, post-placebo, and post-ketamine. To investigate the effects of preprocessing, three distinct pipelines were used: (1) regression of white matter (WM)/cerebrospinal fluid (CSF) signals only (BASE); (2) WM/CSF + GSR (GSR); and (3) WM/CSF + physiological parameter regression (PHYSIO). Reduced GBC was observed in individuals with MDD only at baseline in the anterior and medial cingulate cortices, as well as in the prefrontal cortex only after regressing the global signal. Ketamine had no effect compared to baseline or placebo in either group in any pipeline. PHYSIO did not resemble GBC preprocessed with GSR. These results concur with several studies that used GSR to study GBC. Further investigations are warranted into disease-specific components of global fMRI signals that may drive these results and of GBCr as a potential imaging marker in MDD.

Background: Defining the neurobiological underpinnings of suicidal ideation (SI) is crucial to improving our understanding of suicide. This study used magnetoencephalographic gamma power as a surrogate marker for population-level excitation-inhibition balance to explore the underlying neurobiology of SI and depression. In addition, effects of pharmacological intervention with ketamine, which has been shown to rapidly reduce SI and depression, were assessed., Methods: Data were obtained from 29 drug-free patients with major depressive disorder who participated in an experiment comparing subanesthetic ketamine (0.5 mg/kg) with a placebo saline infusion. Magnetoencephalographic recordings were collected at baseline and after ketamine and placebo infusions. During scanning, patients rested with their eyes closed. SI and depression were assessed, and a linear mixed-effects model was used to identify brain regions where gamma power and both SI and depression were associated. Two regions of the salience network (anterior insula, anterior cingulate) were then probed using dynamic causal modeling to test for ketamine effects., Results: Clinically, patients showed significantly reduced SI and depression after ketamine administration. In addition, distinct regions in the anterior insula were found to be associated with SI compared with depression. In modeling of insula-anterior cingulate connectivity, ketamine lowered the membrane capacitance for superficial pyramidal cells. Finally, connectivity between the insula and anterior cingulate was associated with improvements in depression symptoms., Conclusions: These findings suggest that the anterior insula plays a key role in SI, perhaps via its role in salience detection. In addition, transient changes in superficial pyramidal cell membrane capacitance and subsequent increases in cortical excitability might be a mechanism through which ketamine improves SI., (Copyright © 2019 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Concerns about ketamine for treating depression include abuse potential and the occurrence of psychotomimetic effects. This study sought to comprehensively assess side effects (SEs) associated with a single subanesthetic-dose intravenous ketamine infusion. A secondary aim was to examine the relationship between Clinician-Administered Dissociative States Scale (CADSS) scores and dissociative symptoms reported on a comprehensive, clinician-administered SE questionnaire., Methods: Data from 188 participants were pooled from four placebo-controlled, crossover ketamine trials and one open-label study (n = 163 with either treatment-resistant major depressive disorder or bipolar disorder and 25 healthy controls). SEs were actively solicited in a standardized fashion and monitored over the time-course of each study. Statistical analyses assessed the effect of drug (ketamine, placebo) on SEs and measured the relationship between CADSS total score and SEs contemporaneously endorsed during structured interviews., Results: Forty-four of 120 SEs occurred in at least 5% of participants over all trials. Thirty-three of these 44 SEs were significantly associated with active drug administration (versus placebo). The most common SE was feeling strange/weird/loopy. Most SEs peaked within an hour of ketamine administration and resolved completely by two hours post-infusion. No serious drug-related adverse events or increased ketamine craving/abuse post-administration were observed. A positive correlation was found between dissociative SEs and total CADSS score., Limitations: The post-hoc nature of the analysis; the limited generalizability of a single subanesthetic-dose ketamine infusion; and the lack of formal measures to assess ketamine's cognitive, urological, or addictive potential., Conclusions: No long-lasting significant SEs occurred over the approximately three-month follow-up period., Competing Interests: Declaration of Competing Interest Dr. Zarate is listed as a co-inventor on a patent for the use of ketamine in major depression and suicidal ideation; as a co-inventor on a patent for the use of (2R,6R)-hydroxynorketamine, (S)-dehydronorketamine, and other stereoisomeric dehydro and hydroxylated metabolites of (R,S)-ketamine metabolites in the treatment of depression and neuropathic pain; and as a co-inventor on a patent application for the use of (2R,6R)-hydroxynorketamine and (2S,6S)-hydroxynorketamine in the treatment of depression, anxiety, anhedonia, suicidal ideation, and post-traumatic stress disorders. He has assigned his patent rights to the U.S. government but will share a percentage of any royalties that may be received by the government. Dr. Kraus received travel support from Roche and AOP Orphan. All other authors have no conflict of interest to disclose, financial or otherwise., (Copyright © 2019. Published by Elsevier B.V.)

Major depressive disorder (MDD) is highly heterogeneous in its clinical presentation. The present exploratory study used magnetoencephalography (MEG) to investigate electrophysiological intrinsic connectivity differences between healthy volunteers and unmedicated participants with treatment-resistant MDD. The study examined canonical frequency bands from delta through gamma. In addition to group comparisons, correlational studies were conducted to determine whether connectivity was related to five symptom factors: depressed mood, tension, negative cognition, suicidal thoughts, and amotivation. The MDD and healthy volunteer groups did not differ significantly at baseline when corrected across all frequencies and clusters, although evidence of generalized slowing in MDD was observed. Notably, however, electrophysiological connectivity was strongly related to suicidal thoughts, particularly as coupling of low frequency power fluctuations (delta and theta) with alpha and beta power. This analysis revealed hub areas underlying this symptom cluster, including left hippocampus, left anterior insula, and bilateral dorsolateral prefrontal cortex. No other symptom cluster demonstrated a relationship with neurophysiological connectivity, suggesting a specificity to these results as markers of suicidal ideation., (Copyright © 2020. Published by Elsevier Inc.)

Major depressive disorder (MDD) is highly prevalent and associated with considerable morbidity, yet its pathophysiology remains only partially understood. While numerous studies have investigated the neurobiological correlates of MDD, most have used only a single neuroimaging modality. In particular, diffusion tensor imaging (DTI) studies have failed to yield uniform results. In this context, examining key tracts and using information from multiple neuroimaging modalities may better characterize potential abnormalities in the MDD brain. This study analyzed data from 30 participants with MDD and 26 healthy participants who underwent DTI, magnetic resonance spectroscopy (MRS), resting-state functional magnetic resonance imaging (fMRI), and magnetoencephalography (MEG). Tracts connecting the subgenual anterior cingulate cortex (sgACC) and the left and right amygdala, as well as connections to the left and right hippocampus and thalamus, were examined as target areas. Reduced fractional anisotropy (FA) was observed in the studied tracts. Significant differences in the correlation between medial prefrontal glutamate concentrations and FA were also observed between MDD and healthy participants along tracts connecting the sgACC and right amygdala; healthy participants exhibited a strong correlation but MDD participants showed no such relationship. In the same tract, a correlation was observed between FA and subsequent antidepressant response to ketamine infusion in MDD participants. Exploratory models also suggested group differences in the relationship between DTI, fMRI, and MEG measures. This study is the first to combine MRS, DTI, fMRI, and MEG data to obtain multimodal indices of MDD and antidepressant response and may lay the foundation for similar future analyses., (Published 2019. This article is a U.S. Government work and is in the public domain in the USA.)

Background: In the search for novel treatments for depression, ketamine has emerged as a unique agent with rapid antidepressant effects. Experimental tasks involving emotional processing can be used during functional magnetic resonance imaging scanning to investigate ketamine's effects on brain function in major depressive disorder (MDD). This study examined ketamine's effects on functional magnetic resonance imaging activity during an emotional processing task., Methods: A total of 33 individuals with treatment-resistant MDD and 24 healthy control participants (HCs) took part in this double-blind, placebo-controlled crossover study. Participants received ketamine and placebo infusions 2 weeks apart, and functional magnetic resonance imaging scans were conducted at baseline and 2 days after each infusion. Blood oxygen level-dependent signal was measured during an emotional processing task, and a linear mixed-effects model was used to analyze differences in activation among group, drug, and task-specific factors., Results: A group-by-drug interaction was observed in several brain regions, including a right frontal cluster extending into the anterior cingulate cortex and insula. Participants with MDD had greater activity than HCs after placebo infusion but showed lower activity after ketamine infusion, which was similar to the activity in HCs after placebo. A group-by-drug-by-task condition interaction was also found, which showed further differences that varied between implicit and explicit emotional conditions., Conclusions: The main results indicate that ketamine had differential effects on brain activity in participants with MDD versus HCs. The pattern of activation in participants with MDD after ketamine infusion resembled the activation in HCs after placebo infusion, suggesting a normalization of function during emotional processing. The findings contribute to a better understanding of ketamine's actions in the brain., (Published by Elsevier Inc.)

The goal of this study was to infer the effectiveness of midazolam as a comparator in preserving the blind in ketamine studies for mood disorders through patient-level analyses of efficacy trial outcomes. In this integrative data analysis (k = 9, N = 367 patients with mood disorders), clinical outcomes were compared across four groups: ketamine (midazolam-controlled), ketamine (saline-controlled), midazolam, and saline. Ketamine doses ranged from 0.5 to 0.54 mg/kg and midazolam doses ranged from 0.02 to 0.045 mg/kg. The baseline-to-Day 1 effect size was d = 0.7 (95% CI: 0.4-0.9) for ketamine (midazolam) versus midazolam and d = 1.8 (95% CI: 1.4-2.2) for ketamine (saline) versus saline. The effect of ketamine relative to control was larger in saline-controlled studies than in midazolam-controlled studies (t(276) = 2.32, p = 0.02). This was driven by a comparatively larger effect under midazolam than saline (t(111) = 5.40, p < 0.0001), whereas there was no difference between ketamine (midazolam) versus ketamine (saline) (t(177) = 0.65, p = 0.51). Model-estimated rates of response (with 95% CI) yielded similar results: ketamine (midazolam), 45% (34-56%); ketamine (saline), 46% (34-58%); midazolam, 18% (6-30%); saline, 1% (0-11%). The response rate for ketamine was higher than the control condition for both saline (t(353) = 7.41, p < 0.0001) and midazolam (t(353) = 4.59, p < 0.0001). Studies that used midazolam as a comparator yielded smaller effects of ketamine than those which used saline, which was accounted for by greater improvement following midazolam compared to saline.

Treatment outcomes for major depressive disorder (MDD) need to be improved. Presently, no clinically relevant tools have been established for stratifying subgroups or predicting outcomes. This literature review sought to investigate factors closely linked to outcome and summarize existing and novel strategies for improvement. The results show that early recognition and treatment are crucial, as duration of untreated depression correlates with worse outcomes. Early improvement is associated with response and remission, while comorbidities prolong course of illness. Potential biomarkers have been explored, including hippocampal volumes, neuronal activity of the anterior cingulate cortex, and levels of brain-derived neurotrophic factor (BDNF) and central and peripheral inflammatory markers (e.g., translocator protein (TSPO), interleukin-6 (IL-6), C-reactive protein (CRP), tumor necrosis factor alpha (TNFα)). However, their integration into routine clinical care has not yet been fully elucidated, and more research is needed in this regard. Genetic findings suggest that testing for CYP450 isoenzyme activity may improve treatment outcomes. Strategies such as managing risk factors, improving clinical trial methodology, and designing structured step-by-step treatments are also beneficial. Finally, drawing on existing guidelines, we outline a sequential treatment optimization paradigm for selecting first-, second-, and third-line treatments for acute and chronically ill patients. Well-established treatments such as electroconvulsive therapy (ECT) are clinically relevant for treatment-resistant populations, and novel transcranial stimulation methods such as theta-burst stimulation (TBS) and magnetic seizure therapy (MST) have shown promising results. Novel rapid-acting antidepressants, such as ketamine, may also constitute a paradigm shift in treatment optimization for MDD.

Background: Fatigue and depression are closely associated. The purpose of this secondary analysis was to understand the relationships between depression and improvements in specific depression domains on the anti-fatigue effects of ketamine, which we previously reported., Methods: This secondary analysis re-evaluated data collected longitudinally from 39 patients with treatment-resistant Major Depressive Disorder (MDD) enrolled in a double-blind, randomized, placebo-controlled, crossover trial using a single intravenous infusion of ketamine hydrochloride (0.5 mg/kg over 40 minutes) or placebo. A mediation model assessed the effect of depression on the anti-fatigue effects of a single dose of intravenous ketamine versus placebo at Day 1 post-infusion. Fatigue was measured using the National Institutes of Health-Brief Fatigue Inventory (NIH-BFI), and depression was assessed by the Montgomery-Ǻsberg Depression Rating Scale (MADRS)., Results: Compared to placebo, ketamine significantly improved fatigue (p = .0003) as measured by the NIH-BFI, but the anti-fatigue effects of ketamine disappeared (p = .47) when controlling for depression as measured by MADRS total score. In this study sample, the anti-fatigue effects of ketamine were mostly accounted for by the changes in amotivation and depressed mood scores., Conclusions: In this study, ketamine did not have a unique effect on fatigue outside of its general antidepressant effects in patients with treatment-resistant depression. Specifically, the anti-fatigue effects of ketamine observed in this study seem to be explained by the effects of ketamine on two symptom domains of depression: amotivation and depressed mood. The study findings suggest that the anti-fatigue effects of ketamine should be assessed by fatigue-specific measures other than the NIH-BFI or future studies should enroll fatigued patients without depression., (Published by Elsevier B.V.)

Preclinical and clinical evidence has demonstrated that ketamine has rapid antidepressant effects. Studies using pre-treatment with an AMPA inhibitor suggest that enhancing AMPA throughput is crucial to ketamine's effects, including increases in both basal and evoked gamma power. This study sought to replicate previous findings of increased gamma response to a somatosensory stimulus at 230 min and Day 1 in ketamine responders versus non-responders in 31 depressed subjects and 25 healthy controls. A significant difference in peak gamma power was seen in the depressed ketamine responders versus non-responders. These results implicate AMPA throughput in ketamine's mechanism of antidepressant action., (Copyright © 2018. Published by Elsevier B.V.)

Background: This randomized, placebo-controlled, crossover trial examined the antidepressant efficacy of the muscarinic antagonist scopolamine in major depressive disorder subjects with more severe and refractory forms of major depressive disorder relative to previous reports., Methods: Participants included 23 medication-free major depressive disorder subjects (12 F/11 M, 20-55 years) currently experiencing a major depressive episode. Subjects had scored ≥20 on the Montgomery-Asberg Depression Rating Scale. Following a single-blind, placebo lead-in, participants were randomized to receive 2 counterbalanced blocks of 3 i.v. infusions of scopolamine (4 μg/kg) and placebo in a double-blind manner. The primary and secondary outcomes were the Montgomery-Asberg Depression Rating Scale and the Hamilton Anxiety Rating Scale, respectively. Magnetoencephalography and plasma brain-derived neurotrophic factor concentrations were obtained prior to and after each treatment phase., Results: As assessed by both the Montgomery-Asberg Depression Rating Scale and Hamilton Anxiety Rating Scale, scopolamine had no significant antidepressant or anxiolytic effects relative to placebo. No significant drug vs placebo effects were seen in magnetoencephalography gamma power or brain-derived neurotrophic factor plasma concentrations, and brain-derived neurotrophic factor changes did not correlate with change in Montgomery-Asberg Depression Rating Scale score in response to scopolamine., Conclusions: These results do not support the efficacy of scopolamine for more severe or refractory forms of depression. No pre- to post-infusion changes in plasma brain-derived neurotrophic factor were detected, and magnetoencephalography gamma power changed only in the placebo lead-in, suggesting that these biomarker measures were not affected by scopolamine in this cohort. While difficult to interpret given the lack of antidepressant response, the findings suggest that the neurobiological effects of ketamine and scopolamine are at least partly distinct.

Ketamine, a drug with rapid antidepressant effects and well-described effects on slow wave sleep (SWS), is a useful intervention for investigating sleep-wake mechanisms involved in novel therapeutics. The drug rapidly (within minutes to hours) reduces depressive symptoms in individuals with major depressive disorder (MDD) or bipolar disorder (BD), including those with treatment-resistant depression. Ketamine treatment elevates extracellular glutamate in the prefrontal cortex. Glutamate, in turn, plays a critical role as a proximal element in a ketamine-initiated molecular cascade that increases synaptic strength and plasticity, which ultimately results in rapidly improved mood. In MDD, rapid antidepressant response to ketamine is related to decreased waking as well as increased total sleep, SWS, slow wave activity (SWA), and rapid eye movement (REM) sleep. Ketamine also increases brain-derived neurotrophic factor (BDNF) levels. In individuals with MDD, clinical response to ketamine is predicted by low baseline delta sleep ratio, a measure of deficient early night production of SWS. Notably, there are important differences between MDD and BD that may be related to the effects of diagnosis or of mood stabilizers. Consistent with its effects on clock-associated molecules, ketamine alters the timing and amplitude of circadian activity patterns in rapid responders versus non-responders with MDD, suggesting that it affects mood-dependent central neural circuits. Molecular interactions between sleep homeostasis and clock genes may mediate the rapid and durable elements of clinical response to ketamine and its active metabolite.

Growing evidence suggests that the glutamatergic modulator ketamine has rapid antidepressant effects in treatment-resistant depressed subjects. The anticholinergic agent scopolamine has also shown promise as a rapid-acting antidepressant. This study applied genome-wide markers to investigate the role of genetic variants in predicting acute antidepressant response to both agents. The ketamine-treated sample included 157 unrelated European subjects with major depressive disorder (MDD) or bipolar disorder (BD). The scopolamine-treated sample comprised 37 unrelated European subjects diagnosed with either MDD or BD who had a current Major Depressive Episode (MDE), and had failed at least two adequate treatment trials for depression. Change in Montgomery-Asberg Depression Rating Scale (MADRS) or the 17-item Hamilton Depression Rating Scale (HAM-D) scale scores at day 1 (24 h post-treatment) was considered the primary outcome. Here, we conduct pilot genome-wide association study (GWAS) analyses to identify potential markers of ketamine response and dissociative side effects. Polygenic risk score analysis of SNPs ranked by the strength of their association with ketamine response was then calculated in order to assess whether common genetic markers from the ketamine study could predict response to scopolamine. Findings require replication in larger samples in light of low power of analyses of these small samples. Neverthless, these data provide a promising illustration of our future potential to identify genetic variants underlying rapid treatment response in mood disorders and may ultimately guide individual patient treatment selection in the future.

Background: No pharmacological treatments exist for active suicidal ideation (SI), but the glutamatergic modulator ketamine elicits rapid changes in SI. We developed data-driven subgroups of SI trajectories after ketamine administration, then evaluated clinical, demographic, and neurobiological factors that might predict SI response to ketamine., Methods: Data were pooled from five clinical ketamine trials. Treatment-resistant inpatients (n = 128) with DSM-IV-TR-diagnosed major depressive disorder (MDD) or bipolar depression received one subanesthetic (0.5 mg/kg) ketamine infusion over 40 min. Composite SI variable scores were analyzed using growth mixture modeling to generate SI response classes, and class membership predictors were evaluated using multinomial logistic regressions. Putative predictors included demographic variables and various peripheral plasma markers., Results: The best-fitting growth mixture model comprised three classes: Non-Responders (29%), Responders (44%), and Remitters (27%). For Responders and Remitters, maximal improvements were achieved by Day 1. Improvements in SI occurred independently of improvements in a composite Depressed Mood variable for Responders, and partially independently for Remitters. Indicators of chronic SI and self-injury were associated with belonging to the Non-Responder group. Higher levels of baseline plasma interleukin-5 (IL-5) were linked to Remitters rather than Responders., Limitations: Subjects were not selected for active suicidal thoughts; findings only extend to Day 3; and plasma, rather than CSF, markers were used., Conclusion: The results underscore the heterogeneity of SI response to ketamine and its potential independence from changes in Depressed Mood. Individuals reporting symptoms suggesting a longstanding history of chronic SI were less likely to respond or remit post-ketamine., (Published by Elsevier B.V.)

Background: Ketamine is known to rapidly reduce depressive symptoms and suicidal ideation (SI) in patients with major depressive disorder (MDD), but evidence is limited for its acceptability and effectiveness in "real-world" settings. This case series examines serial ketamine infusions in reducing SI and depression scores in adults with MDD admitted to a tertiary care hospital., Methods: Five inpatients with MDD and SI admitted to hospital in Toronto, Canada received six infusions of 0.5 mg/kg intravenous (IV) ketamine (n = 5) over approximately 12 days, in addition to treatment-as-usual. Suicide and depression rating scores (Scale for Suicidal Ideation, SSI; Montgomery-Åsberg Depression Rating Scale, MADRS) were obtained at baseline, on treatment days, on days 14 and 42 (primary endpoint)., Results: All patients experienced benefit with ketamine. SSI scores diminished by 84% from 14.0 ± 4.5 at baseline to 2.2 ± 2.5 at study endpoint. MADRS scores diminished by 47% from 42.2 ± 5.3 at baseline to 22.4 ± 8.0. Two patients withdrew from the study, one to initiate electroconvulsive therapy and one due to an adverse event (dissociative effects) during the ketamine infusion., Limitations: The major limitation of this study is the small sample size., Discussion: These preliminary pilot data are promising with a greater than two-fold reduction in SI following ketamine infusions. They demonstrate that six serial ketamine infusions may be safe and feasible. These findings support the need for large scale randomized controlled trials to confirm the efficacy of serial ketamine for treatment of SI in "real-world" settings., (Copyright © 2018. Published by Elsevier B.V.)

Learning Objective: After participating in this activity, learners should be better able to evaluate the evidence supporting the antidepressant effects of glutamatergic modulators.Both preclinical and clinical studies have implicated glutamatergic system dysfunction in the pathophysiology of mood disorders such as bipolar depression and major depressive disorder. In particular, rapid reductions in depressive symptoms have been noted in response to subanesthetic doses of the glutamatergic modulator ketamine in subjects with major depressive disorder or bipolar depression. These results have prompted the repurposing or development of other glutamatergic modulators, both as monotherapy or adjunctive to other therapies. Here, we highlight the evidence supporting the antidepressant effects of various glutamatergic modulators, including (1) broad glutamatergic modulators (ketamine, esketamine, dextromethorphan, dextromethorphan-quinidine [Nuedexta], AVP-786, nitrous oxide [N2O], AZD6765), (2) subunit (NR2B)-specific N-methyl-D-aspartate (NMDA) receptor antagonists (CP-101,606/traxoprodil, MK-0657 [CERC-301]), (3) glycine-site partial agonists (D-cycloserine, GLYX-13, sarcosine, AV-101), and (4) metabotropic glutamate receptor modulators (AZD2066, RO4917523/basimglurant, JNJ40411813/ADX71149, R04995819 [RG1578]).

Background: The symptoms of major depressive disorder (MDD) are rapidly alleviated by administration of a single dose of the glutamatergic modulator ketamine. However, few studies have investigated the potential sustained neural effects of this agent beyond immediate infusion. This study used functional magnetic resonance imaging to examine the effect of a single ketamine infusion on the resting state default mode network (DMN) at 2 and 10 days after a single ketamine infusion in unmedicated subjects with MDD as well as healthy control subjects (HCs)., Methods: Data were drawn from a double-blind, placebo-controlled crossover study of 58 participants (33 with MDD and 25 HCs) who received an intravenous infusion of either ketamine hydrochloride (0.5 mg/kg) or placebo on 2 separate test days spaced 2 weeks apart. Eight minutes of functional magnetic resonance imaging resting state data was acquired at baseline and at about 2 and 10 days after both infusions. The DMN was defined using seed-based correlation and was compared across groups and scans., Results: In subjects with MDD, connectivity between the insula and the DMN was normalized compared with HCs 2 days postketamine infusion. This change was reversed after 10 days and did not appear in either of the placebo scans. Group-specific connectivity differences in drug response were observed, most notably in the insula in subjects with MDD and in the thalamus in HCs., Conclusions: Connectivity changes in the insula in subjects with MDD suggest that ketamine may normalize the interaction between the DMN and salience networks, supporting the triple network dysfunction model of MDD., (Published by Elsevier Inc.)

(R,S)-Ketamine produces rapid, robust, and sustained antidepressant effects in major depressive disorder. Specifically, its pharmacological efficacy in treatment refractory depression is considered a major breakthrough in the field. However, the mechanism of action of ketamine's rapid effect remains to be determined. In order to identify pathways that are responsible for ketamine's effect, a targeted metabolomic approach was carried out using a double-blind, placebo-controlled crossover design, with infusion order randomized with medication-free patients with treatment-resistant major depressive disorder (29 subjects) and healthy controls (25 subjects). The metabolomic profile of these subjects was characterized at multiple time points, and a comprehensive analysis was investigated between the following: MDD and healthy controls, treatment and placebo in both groups and the corresponding response to ketamine treatment. Ketamine treatment resulted in a general increase in circulating sphingomyelins, levels which were not correlated with response. Ketamine response resulted in more pronounced effects in the kynurenine pathway and the arginine pathway at 4 h post-infusion, where a larger decrease in circulating kynurenine levels and a larger increase in the bioavailability of arginine were observed in responders to ketamine treatment, suggesting possible mechanisms for response to ketamine treatment.

The glutamatergic modulator ketamine has striking and rapid antidepressant effects in major depressive disorder (MDD), but its mechanism of action remains unknown. Proton magnetic resonance spectroscopy (1H-MRS) is the only non-invasive method able to directly measure glutamate levels in vivo; in particular, glutamate and glutamine metabolite concentrations are separable by 1H-MRS at 7T. This double-blind, placebo-controlled, crossover study that included 1 H-MRS scans at baseline and at 24 h post ketamine and post-placebo infusions sought to determine glutamate levels in the pregenual anterior cingulate (pgACC) of 20 medication-free MDD subjects and 17 healthy volunteers (HVs) 24 h post ketamine administration, and to evaluate any other measured metabolite changes, correlates, or predictors of antidepressant response. Metabolite levels were compared at three scan times (baseline, post-ketamine, and post-placebo) in HVs and MDD subjects at 7T using a 1 H-MRS sequence specifically optimized for glutamate. No significant between-group differences in 1 H-MRS-measured metabolites were observed at baseline. Antidepressant response was not predicted by baseline glutamate levels. Our results suggest that any infusion-induced increases in glutamate at the 24-h post ketamine time point were below the sensitivity of the current technique; that these increases may occur in different brain regions than the pgACC; or that subgroups of MDD subjects may exist that have a differential glutamate response to ketamine.

Background: The glutamatergic modulator ketamine has rapid antidepressant effects in individuals with major depressive disorder and bipolar depression. Thus, modulating glutamatergic transmission may be critical to effectively treating depression, though the mechanisms by which this occurs are not fully understood., Methods: This double-blind, crossover, placebo-controlled study analyzed data from 18 drug-free major depressive disorder subjects and 18 heathy controls who received a single i.v. infusion of ketamine hydrochloride (0.5 mg/kg) as well as an i.v. saline placebo. Magnetoencephalographic recordings were collected prior to the first infusion and 6 to 9 hours after both ketamine and placebo infusions. During scanning, participants passively received tactile stimulation to the right index finger. Antidepressant response was assessed across timepoints using the Montgomery-Asberg Depression Rating Scale. Dynamic causal modeling was used to measure changes in α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)- and N-methyl-D-aspartate (NMDA)-mediated connectivity estimates in major depressive disorder subjects and controls using a simple model of somatosensory evoked responses., Results: Both major depressive disorder and healthy subjects showed ketamine-mediated NMDA-blockade sensitization, with major depressive disorder subjects showing enhanced NMDA connectivity estimates in backward connections and controls showing enhanced NMDA connectivity estimates in forward connections in our model. Within our major depressive disorder subject group, ketamine efficacy, as measured by improved mood ratings, correlated with reduced NMDA and AMPA connectivity estimates in discrete extrinsic connections within the somatosensory cortical network., Conclusions: These findings suggest that AMPA- and NMDA-mediated glutamatergic signaling play a key role in antidepressant response to ketamine and, further, that dynamic causal modeling is a powerful tool for modeling AMPA- and NMDA-mediated connectivity in vivo., Clinicaltrials.gov: NCT#00088699., (Published by Oxford University Press on behalf of CINP 2018. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Background: An urgent need exists for faster-acting pharmacological treatments in major depressive disorder (MDD). The glutamatergic modulator ketamine has been shown to have rapid antidepressant effects, but much remains unknown about its mechanism of action. Functional MRI (fMRI) can be used to investigate how ketamine impacts brain activity during cognitive and emotional processing., Methods: This double-blind, placebo-controlled, crossover study of 33 unmedicated participants with MDD and 26 healthy controls (HCs) examined how ketamine affected fMRI activation during an attentional bias dot probe task with emotional face stimuli across multiple time points. A whole brain analysis was conducted to find regions with differential activation associated with group, drug session, or dot probe task-specific factors (emotional valence and congruency of stimuli)., Results: A drug session by group interaction was observed in several brain regions, such that ketamine had opposite effects on brain activation in MDD versus HC participants. Additionally, there was a similar finding related to emotional valence (a drug session by group by emotion interaction) in a large cluster in the anterior cingulate and medial frontal cortex., Conclusions: The findings show a pattern of brain activity in MDD participants following ketamine infusion that is similar to activity observed in HCs after placebo. This suggests that ketamine may act as an antidepressant by normalizing brain function during emotionally valenced attentional processing., Clinical Trial: NCT#00088699: https://www.clinicaltrials.gov/ct2/show/NCT00088699.

Background: Some glutamatergic modulators have demonstrated rapid and relatively sustained antidepressant properties in patients with major depressive disorder. Because the potassium channel activator diazoxide increases glutamate uptake via potassium channel activation, we hypothesized that it might exert antidepressant effects by increasing the removal of glutamate from the synaptic cleft, thereby reducing excessive glutamate transmission., Methods: This randomized, double-blind, placebo-controlled, crossover, single-site inpatient clinical study was conducted at the National Institute of Mental Health to assess the efficacy and safety of a 3-week course of diazoxide (200-400 mg daily, twice a day) versus a 3-week course of placebo in 6 participants with treatment-refractory major depressive disorder. The primary clinical outcome measure was change in Montgomery-Asberg Depression Rating Scale score from baseline to posttreatment. Quantitative insulin sensitivity check index, as well as concomitant imaging measures (electroencephalography, proton magnetic resonance spectroscopy, magnetoencephalography), were used as potential surrogate markers of target (KATP channel) engagement., Results: The study was halted due to severe adverse effects. Given the small sample size, statistical evaluation of the effect of diazoxide on Montgomery-Asberg Depression Rating Scale scores or the imaging measures was not pursued. Visual inspection of the quantitative insulin sensitivity check index test revealed no evidence of target engagement., Conclusions: Although the results are negative, they are an important addition to the literature in this rapidly changing field.