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The rewards that we get from our choices and actions can have a major influence on our future behavior. Understanding how reward biasing of behavior is implemented in the brain is important for many reasons, including the fact that diminution in reward biasing is a hallmark of clinical depression. We hypothesized that reward biasing is mediated by the anterior cingulate cortex (ACC), a cortical hub region associated with the integration of reward and executive control and with the etiology of depression. To test this hypothesis, we recorded neural activity during a biased judgment task in patients undergoing intracranial monitoring for either epilepsy or major depressive disorder. We found that beta (12-30 Hz) oscillations in the ACC predicted both associated reward and the size of the choice bias, and also tracked reward receipt, thereby predicting bias on future trials. We found reduced magnitude of bias in depressed patients, in whom the beta-specific effects were correspondingly reduced. Our findings suggest that ACC beta oscillations may orchestrate the learning of reward information to guide adaptive choice, and, more broadly, suggest a potential biomarker for anhedonia and point to future development of interventions to enhance reward impact for therapeutic benefit., (© 2024. The Author(s).)

Major depressive disorder (MDD) is a mental health disorder that can cause disability and functional impairment that standard-of-care (SOC) antidepressant therapies (ADTs) can take weeks to treat. Zuranolone is a neuroactive steroid and positive allosteric modulator of synaptic and extrasynaptic γ-aminobutyric acid (GABA) type A receptors approved as an oral, once-daily, 14-day treatment course in adults with postpartum depression and under investigation in adults with MDD. The phase 3 CORAL Study (NCT04476030) evaluated the efficacy and safety of zuranolone 50 mg co-initiated with SOC ADT (zuranolone+ADT) vs placebo co-initiated with SOC ADT (placebo+ADT) in adults with MDD. Patients were randomized 1:1 to once-daily, blinded zuranolone+ADT or placebo+ADT for 14 days, then continued open-label SOC ADT for 28 more days. The primary endpoint was change from baseline (CFB) in the 17-item Hamilton Rating Scale for Depression (HAMD-17) total score at Day 3. Among 425 patients in the full analysis set, CFB in HAMD-17 total score at Day 3 was significantly improved with zuranolone+ADT vs placebo+ADT (least squares mean [standard error], -8.9 [0.39] vs -7.0 [0.38]; p = 0.0004). The majority of patients receiving zuranolone+ADT that experienced treatment-emergent adverse events (TEAEs) reported mild or moderate events. The most common TEAEs present in ≥10% of patients in either zuranolone+ADT or placebo+ADT groups were somnolence, dizziness, headache, and nausea. These results demonstrate that zuranolone+ADT provided more rapid improvement in depressive symptoms compared with placebo+ADT in patients with MDD, with a safety profile consistent with previous studies. Clinical trial registration: ClinicalTrials.gov identifier: NCT04476030., (© 2023. The Author(s).)

Treatment-resistant depression (TRD) affects one in three patients with major depressive disorder and is associated with increased risk of all-cause mortality. Studies of real-world practices suggest that antidepressant monotherapy continues to be the most widely used treatment after inadequate response to a first-line treatment. However, rates of remission with antidepressants in TRD are suboptimal. Atypical antipsychotics are the most widely studied augmentation agent and aripiprazole, brexpiprazole, cariprazine, quetiapine extended-release, and olanzapine-fluoxetine combination are approved for depression. Benefits of using atypical antipsychotics for TRD has to be weighted against their potential adverse events, such as weight gain, akathisia, and tardive dyskinesia., Competing Interests: Disclosure Dr C. Vas, A. Jain, and M. Trivedi have no conflicts to disclose. Dr M.K. Jha has received contract research grants from Acadia Pharmaceuticals, Neurocrine Bioscience, Navitor/Supernus and Janssen Research & Development; educational grant to serve as Section Editor of the Psychiatry & Behavioral Health Learning Network; consultant fees from Eleusis Therapeutics US, Inc, Janssen Global Services, Janssen Scientific Affairs, Worldwide Clinical Trials/Eliem and Inversargo, Boehringer Ingelheim, and Guidepoint Global; and honoraria from North American Center for Continuing Medical Education, Medscape/WebMD, Clinical Care Options, and Global Medical Education. Dr S.J. Mathew has served as a consultant to Allergan, Alkermes, Almatica Pharma, Axsome Therapeutics, Biohaven, BioXcel Therapeutics, Clexio Biosciences, COMPASS Pathways, Delix Therapeutics, Eleusis, EMA Wellness, Engrail Therapeutics, Greenwich Biosciences, Intra-Cellular Therapies, Janssen, Levo Therapeutics, Perception Neurosciences, Praxis Precision Medicines, Neumora, Neurocrine, Relmada Therapeutics, Sage Therapeutics, Seelos Therapeutics, Signant Health, and Sunovion; and received research support from Biohaven Pharmaceuticals, Boehringer Ingelheim, Janssen, Merck, Neurocrine, Sage Therapeutics, and Vistagen Therapeutics., (Copyright © 2023 Elsevier Inc. All rights reserved.)

One in three adults with major depressive disorder (MDD) do not experience clinically significant improvement after multiple sequential courses of antidepressants and have treatment-resistant depression (TRD). The presence of TRD contributes to the morbidity and excess mortality associated with MDD and has been linked to significantly increased health care expenses. In the absence of a consensus definition of TRD, this report takes a broad approach by considering inadequate response to one or more courses of antidepressants and focuses on atypical antipsychotics that are approved by the U.S. Food and Drug Administration for treatment of depression (aripiprazole, brexpiprazole, cariprazine, extended-release quetiapine, and olanzapine-fluoxetine combination). While multiple acute-phase studies have demonstrated the efficacy of these medications in improving depressive symptoms, clinically meaningful improvement (i.e., remission) remains limited, with significant concerns about side effects (including weight gain, metabolic dysfunction, extrapyramidal symptoms, and tardive dyskinesia), especially with long-term use. With the rapidly evolving landscape of antidepressant treatments over the past few years, which has witnessed approval of rapid-acting antidepressants (e.g., esketamine nasal spray and dextromethorphan-bupropion combination) and several more in the late-stage pipeline (e.g., zuranolone and psilocybin), it remains to be seen whether the use of atypical antipsychotics will go the way of the older and rarely prescribed antidepressants (such as tricyclics and monoamine oxidase inhibitors). Pragmatic clinical trials are needed to compare the effectiveness of atypical antipsychotics with TRD-specific pharmacotherapies and neuromodulation treatments and to identify the optimal sequencing of these varied approaches for patients with MDD. When using atypical antipsychotics, clinicians and patients are encouraged to use a shared decision-making approach by personalizing treatment selection based on anticipated side effects, tolerability, cost, and feasibility.

Background: The goal of this study was to replicate previous findings of three distinct treatment response pathways associated with repeated intravenous (IV) ketamine infusions among patients with major depressive disorder (MDD)., Methods: We conducted growth mixture modeling to estimate latent classes of change in depression (Quick Inventory of Depressive Symptomatology-Self Report, QIDS-SR) across six treatment visits in 298 patients with MDD treated with IV ketamine in an outpatient community clinic. Mean age was 40.36 and patients were primarily male (58.4 %). The sample had relatively severe depression (QIDS-SR = 16.61) at pre-treatment and the majority had not responded to at least two prior medications., Results: Best-fit indices indicated three trajectory groups to optimally demonstrate non-linear, quadratic changes in depressive symptoms during ketamine treatment. Two groups had severe depression at baseline but diverged into a group of modest improvement over the treatment course (n = 78) and a group of patients with rapid improvement (n = 103). A third group had moderate depression at baseline with moderate improvement during the treatment course (n = 117). Additional planned trajectory comparisons showed that suicidality at entry was higher in the high depression groups and that change in suicidality severity followed that of depression., Limitations: This was a retrospective analysis of a naturalistic sample. Patients were unblinded and more heterogenous than those included in most controlled clinical trial samples., Conclusions: This replication study in an independent community-based ketamine clinic sample revealed similar response trajectories, with only about a third of depressed patients benefitting substantially from an acute induction course of ketamine infusions., Competing Interests: Conflict of Interest Drs. Averill, Lijffijt, Mathew, O'Brien, Swann and Tamman are supported through the use of resources and facilities at the Michael E. Debakey VA Medical Center, Houston, Texas. Dr. Averill has served as a consultant, speaker and/or advisory board member for Guidepoint, Transcend Terapeutics, Source Research Foundation, Reason for Hope, Beond, and Ampelis. Dr. Lijffijt receives support from BrainsWay and Ceruvia Lifesciences. Dr. Mathew has served as a consultant to Allergan, Alkermes, Axsome Therapeutics, BioXcel Therapeutics, Clexio Biosciences, COMPASS Pathways, Eleusis, EMA Wellness, Engrail Therapeutics, Greenwich Biosciences, Intra-Cellular Therapies, Janssen, Levo Therapeutics, Perception Neurosciences, Praxis Precision Medicines, Neumora, Neurocrine, Relmada Therapeutics, Sage Therapeutics, Seelos Therapeutics, Signant Health, Sunovion and Worldwide Clinical Trials. Dr. Mathew has received research support from Biohaven Pharmaceuticals, Boehringer-Ingelheim, Janssen, Merck, Sage Therapeutics, and VistaGen Therapeutics. Drs. Mathew, Lee, and Murphy receive support from The Menninger Clinic. All other authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier B.V.)

Objective: Rapid-acting treatment options are needed for major depressive disorder (MDD). The objective of this systematic review and meta-analysis was to estimate the magnitude of the treatment effect for intranasal esketamine over placebo at 24 hours after the first dose and at endpoint., Data Sources: PubMed, abstracts of major psychiatric meetings, and ClinicalTrials.gov were searched up to November 2020 with no language constraints, cross-referencing the term intranasal with esketamine and randomized ., Study Selection: Of 27 studies reviewed, 8 articles, with a total of 1,437 patients with MDD, met study criteria and were included in the meta-analysis., Data Extraction: Randomized, double-blind clinical trials comparing adjunctive treatment of standard antidepressants with intranasal esketamine for MDD, using intranasal placebo augmentation as a comparator, were selected., Results: Estimates of the standardized mean difference (SMD) in change scores were pooled after examining for homogeneity using the test statistic proposed by DerSimonian and Laird. Findings of the random effects model were presented. Augmentation of standard antidepressants with intranasal esketamine resulted in greater Montgomery-Asberg Depression Rating Scale (MADRS) score reduction than adjunctive intranasal placebo at 24 hours. Across the trials, the SMD was 0.34 (95% CI = 0.11 to 0.46, P  < .0001) with a 2.9-point greater mean MADRS score reduction following intranasal esketamine versus active control plus intranasal saline. A similar finding was evident at endpoint., Conclusions: This updated systematic review and meta-analysis found that augmentation of antidepressants with intranasal esketamine was statistically and clinically more effective in reducing depression severity than augmentation with placebo, at both 24 hours and study endpoint. Future studies are needed to evaluate dose-response relationship for esketamine., (© Copyright 2022 Physicians Postgraduate Press, Inc.)

Objective: Ketamine is a novel and rapidly acting treatment for major depressive disorder (MDD). Benzodiazepines are commonly coprescribed with antidepressants in MDD. This study sought to examine data from a randomized clinical trial that compared a single infusion of intravenous (IV) ketamine to midazolam placebo in treatment-resistant depression ( DSM-IV-TR MDD) and to assess whether the use of concomitant oral benzodiazepines differentially affected treatment response to ketamine versus midazolam., Methods: This trial ran from December 2015 to December 2016. Subjects who were taking oral benzodiazepines (n = 44) were compared to those who were not (n = 55). A significant treatment-by-benzodiazepine effect could be interpreted as a possible moderator of differential treatment response to ketamine versus midazolam. Benzodiazepine use was examined as both a binary and a continuous predictor, to assess the impact of dosage., Results: Benzodiazepine users did not differ from non-users on the original study's primary outcome measure, score on the 6-item Hamilton Depression Rating Scale (HDRS-6), at baseline, but the former had more severe anxiety. When oral benzodiazepine use was modeled as a binary predictor, benzodiazepine use did not impact differential treatment response. However, when benzodiazepine dosage was considered, there was a significant impact of benzodiazepine use on differential treatment response. Oral benzodiazepines significantly impacted HDRS-6 ( P  = .018) and Clinical Global Impressions-Severity of Illness scale (CGI-S; P  = .008) scores at day 1 (24 hours post treatment); effects were nonsignificant for all day 3 outcomes. Among ketamine subjects, higher doses of benzodiazepines were associated with less improvement in depression scores at day 1., Conclusions: Concomitant oral benzodiazepines at higher doses may attenuate the antidepressant effects of IV ketamine at day 1 but not day 3 post-infusion., Trial Registration: ClinicalTrials.gov identifier: NCT01920555., (© Copyright 2022 Physicians Postgraduate Press, Inc.)

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: Mood disorders are a leading cause of morbidity. Many patients experience treatment-resistant depression (TRD), and suicide rates are rising. Faster-acting and more effective antidepressant medications are needed. Four decades of research has transformed the use of ketamine from an anesthetic to an outpatient treatment for major depressive disorder (MDD). Ketamine is a N-methyl-d-aspartate (NMDA) receptor antagonist and has been shown to rapidly improve mood symptoms and suicidal ideation by targeting the glutamate system directly., Methods: We used the PubMed database to identify relevant articles published until September 1, 2020. We focused on meta-analyses, randomized controlled trials, and original observational studies. We included relevant studies for depression, MDD, TRD, bipolar disorder, anxiety, posttraumatic stress disorder (PTSD), suicide, ketamine, and esketamine., Results: Both racemic ketamine and esketamine have been shown to rapidly treat depression and suicidality. There is evidence that ketamine can be helpful for anxiety and PTSD; however, more research is needed. Intranasal esketamine has been FDA approved to treat depression., Conclusions: This narrative review describes the evolution of ketamine to treat mood disorders and suicidality. We provide the evidence supporting recent developments using esketamine as well as unresolved issues in the field, such as dosing and safety.

Clinical Trial Registration: Rapid antidepressant effects associated with ketamine have shifted the landscape for the development of therapeutics to treat major depressive disorder (MDD) from a monoaminergic to glutamatergic model. Treatment with ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, may be effective, but has many non-glutamatergic targets, and clinical and logistical problems are potential challenges. These factors underscore the importance of manipulations of binding mechanics to produce antidepressant effects without concomitant clinical side effects. This will require identification of efficient biomarkers to monitor target engagement. The mismatch negativity (MMN) is a widely used electrophysiological signature linked to the activity of NMDA receptors (NMDAR) in humans and animals and validated in pre-clinical and clinical studies of ketamine. In this review, we explore the flexibility of the MMN and its capabilities for reliable use in drug development for NMDAR antagonists in MDD. We supplement this with findings from our own research with three distinct NMDAR antagonists. The research described illustrates that there are important distinctions between the mechanisms of NMDAR antagonism, which are further crystallized when considering the paradigm used to study the MMN. We conclude that the lack of standardized methodology currently prevents MMN from being ready for common use in drug discovery. This manuscript describes data collected from the following National Institutes of Health (NIH) and Veterans Affairs (VA) studies: AV-101, NCT03583554; lanicemine, NCT03166501; ketamine, NCT02556606.

Objective: To conduct a meta-analysis of studies of vortioxetine in adults with major depressive disorder (MDD)., Data Sources: Abstracts were identified using PubMed by cross-referencing vortioxetine with placebo and randomize d. No language or publication year restrictions were used., Study Selection: Randomized, double-blind, placebo-controlled clinical trials comparing oral vortioxetine monotherapy with placebo for acute treatment of MDD., Data Extraction: Data were extracted with a pre-coded form, as follows: number of patients randomized, treatment group, Montgomery-Asberg Depression Rating Scale (MADRS) response and remission rates, and mean change in scores from baseline and standard errors for the MADRS, Hamilton Anxiety Rating Scale (HARS), and Digit Symbol Substitution Test (DSST)., Results: 7,269 subjects randomized to vortioxetine (n = 3,630) or placebo (n = 3,639) from 17 studies were included. The probability of receiving placebo did not predict difference in change in MADRS scores between vortioxetine and placebo (estimate = 4.1, P  = .54). The standardized mean difference (SMD) (95% CI) for change in MADRS score for vortioxetine overall versus placebo was 0.33 (0.24 to 0.41) and was 0.24 (0.08 to 0.39), 0.33 (0.19 to 0.47), 0.26 (-0.06 to 0.58), and 0.44 (0.27 to 0.62) for 5-mg, 10-mg, 15-mg, and 20-mg doses, respectively. Greater difference in efficacy between drug and placebo was observed in studies with a low rather than a high placebo response rate., Conclusions: Vortioxetine is more effective than placebo in improving depression, anxiety, and cognition. Less informative or uninformative studies obscured the true treatment effect., (© Copyright 2021 Physicians Postgraduate Press, Inc.)

Background: Ketamine's potent and rapid antidepressant properties have shown great promise to treat severe forms of major depressive disorder (MDD). A recently hypothesized antidepressant mechanism of action of ketamine is the inhibition of N-methyl-D-aspartate receptor-dependent bursting activity of the habenula (Hb), a small brain structure that modulates reward and affective states., Methods: Resting-state functional magnetic resonance imaging was conducted in 35 patients with MDD at baseline and 24 hours following treatment with i.v. ketamine. A seed-to-voxel functional connectivity (FC) analysis was performed with the Hb as a seed-of-interest. Pre-post changes in FC and the associations between changes in FC of the Hb and depressive symptom severity were examined., Results: A reduction in Montgomery-Åsberg Depression Rating Scale scores from baseline to 24 hours after ketamine infusion was associated with increased FC between the right Hb and a cluster in the right frontal pole (t = 4.65, P = .03, false discovery rate [FDR]-corrected). A reduction in Quick Inventory of Depressive Symptomatology-Self Report score following ketamine was associated with increased FC between the right Hb and clusters in the right occipital pole (t = 5.18, P < .0001, FDR-corrected), right temporal pole (t = 4.97, P < .0001, FDR-corrected), right parahippocampal gyrus (t = 5.80, P = .001, FDR-corrected), and left lateral occipital cortex (t = 4.73, P = .03, FDR-corrected). Given the small size of the Hb, it is possible that peri-habenular regions contributed to the results., Conclusions: These preliminary results suggest that the Hb might be involved in ketamine's antidepressant action in patients with MDD, although these findings are limited by the lack of a control group., (© The Author(s) 2020. Published by Oxford University Press on behalf of CINP.)

Background: The N-methyl-D-aspartate receptor antagonist ketamine is potentially effective in treatment resistant depression. However, its antidepressant efficacy is highly variable, and there is little information about predictors of response., Methods: We employed growth mixture modeling (GMM) analysis to examine specific response trajectories to intravenous (IV) ketamine (three infusions; mean dose 0.63 mg/kg, SD 0.28, range 0.30 - 2.98 mg/kg over 40 min) in 328 depressed adult outpatients referred to a community clinic. The Quick Inventory of Depressive Symptomatology-Self-Report (QIDS-SR) assessed depression severity at baseline and before each infusion, up to three infusions for four total observations., Results: GMM revealed three QIDS-SR response trajectories. There were two groups of severely depressed patients, with contrasting responses to ketamine. One group (n=135, baseline QIDS-SR=18.8) had a robust antidepressant response (final QIDS-SR=7.3); the other group (n=97, QIDS-SR=19.8) was less responsive (final QIDS-SR=15.6). A third group (n=96) was less severely depressed at baseline (QIDS-SR=11.7), with intermediate antidepressant response (final QIDS-SR=6.6). Comparisons of demographic and clinical characteristics between groups with severe baseline depression revealed higher childhood physical abuse in the group with robust ketamine response (p=0.01)., Limitations: This was a retrospective analysis on a naturalistic sample. Patients were unblinded and more heterogenous than those included in most controlled clinical trial samples. Information pertaining to traumatic events occurring after childhood and pre-existing or concurrent medical conditions that may have affected outcomes was not available., Conclusions: Overall, ketamine's effect in patients with severe baseline depression and history of childhood maltreatment may be consistent with ketamine-induced blockade of behavioral sensitization., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objective: Preclinical studies point to the KCNQ2/3 potassium channel as a novel target for the treatment of depression and anhedonia, a reduced ability to experience pleasure. The authors conducted the first randomized placebo-controlled trial testing the effect of the KCNQ2/3 positive modulator ezogabine on reward circuit activity and clinical outcomes in patients with depression., Methods: Depressed individuals (N=45) with elevated levels of anhedonia were assigned to a 5-week treatment period with ezogabine (900 mg/day; N=21) or placebo (N=24). Participants underwent functional MRI during a reward flanker task at baseline and following treatment. Clinical measures of depression and anhedonia were collected at weekly visits. The primary endpoint was the change from baseline to week 5 in ventral striatum activation during reward anticipation. Secondary endpoints included depression and anhedonia severity as measured using the Montgomery-Åsberg Depression Rating Scale (MADRS) and the Snaith-Hamilton Pleasure Scale (SHAPS), respectively., Results: The study did not meet its primary neuroimaging endpoint. Participants in the ezogabine group showed a numerical increase in ventral striatum response to reward anticipation following treatment compared with participants in the placebo group from baseline to week 5. Compared with placebo, ezogabine was associated with a significantly larger improvement in MADRS and SHAPS scores and other clinical endpoints. Ezogabine was well tolerated, and no serious adverse events occurred., Conclusions: The study did not meet its primary neuroimaging endpoint, although the effect of treatment was significant on several secondary clinical endpoints. In aggregate, the findings may suggest that future studies of the KCNQ2/3 channel as a novel treatment target for depression and anhedonia are warranted.

Objective: Esketamine, the S-enantiomer of ketamine, was recently approved as a rapid-acting intranasal therapy for depression and is currently under development for suicidality. The authors sought to determine the efficacy of adjunctive intranasal esketamine in major depressive disorder (MDD)., Data Sources: A systematic search of PubMed/MEDLINE was conducted up to January 2019, in addition to abstracts of major psychiatric meetings held since 2010. Searches were conducted by cross-referencing the term intranasal with the term esketamine. Where necessary, authors and/or study sponsors were contacted in order to obtain a copy of the presentation as well as any pertinent study details., Study Selection: 241 study abstracts were initially identified and reviewed. Selected studies were randomized, double-blind clinical trials comparing adjunctive intranasal esketamine to adjunctive placebo for MDD., Data Extraction: Data were extracted independently by two of the authors. A random effects model was used to calculate the standardized mean difference (SMD) between esketamine and placebo (intranasal saline) in the Montgomery-Asberg Depression Rating Scale (MADRS) score change from baseline to endpoint, serving as the primary outcome of the study., Results: Five trials with 774 patients were pooled. Adjunctive esketamine was significantly more effective than placebo for MADRS score change, response, and remission (N = 774, SMD = 0.36, 95% CI = 0.24-0.49, P < .0001; response: risk ratio [RR] = 1.40, 95% CI = 1.22-1.61, P < .0001; remission: RR = 1.45, 95% CI = 1.20-1.75, P < .0001). Results remained statistically significant regardless of differences in the study sample, fixed vs new/optimized baseline antidepressants., Conclusions: Adjunctive intranasal esketamine for patients with MDD who are either treatment-resistant or acutely suicidal appears to be an effective treatment strategy., (© Copyright 2020 Physicians Postgraduate Press, Inc.)

Purpose/background: Major depressive disorder (MDD) and obesity commonly co-occur. We sought to assess the impact of body mass index (BMI) on the acute antidepressant effects of ketamine in patients with treatment-resistant depression., Methods/procedures: Post hoc analyses were conducted from a multisite, randomized, double-blind, placebo-controlled trial designed to assess the rapid-onset effects of intravenous ketamine. Patients (n = 99) were randomized to a single dose administration of ketamine 0.1 mg/kg (n = 18), ketamine 0.2 mg/kg (n = 20), ketamine 0.5 mg/kg (n = 22), ketamine 1.0 mg/kg (n = 20), or active placebo, midazolam 0.045 mg/kg (n = 19). Patients were stratified for BMI. For patients randomized to ketamine (n = 80), BMI was assessed as a continuous variable and also categorically (obese, overweight, not obese/overweight [reference]). The primary outcome measure was the change on the 6-item Hamilton Depression Rating Scale 24 hours after treatment. Outcomes at day 3 were also assessed., Findings/results: The 6-item Hamilton Depression Rating Scale change scores at 24 hours were inversely associated with BMI (-0.28 ± 0.12, P = 0.02). With BMI operationalized categorically, both obese (-4.15 ± 1.41, P = 0.004) and overweight (-1.99 ± 1.14, P = 0.08) categories were inversely related to the 6-item Hamilton Depression Rating Scale change score at 24 hours, statistically significant for the obese category, as compared with the reference group. Similar but weaker findings were observed at 72 hours after infusion., Implications/conclusions: Higher BMI and obesity were associated with a more robust acute antidepressant response to ketamine. This may have clinical relevance for a great number of patients who have both MDD and obesity., Clinical Trial Registration: NCT01920555.

Treatment guidelines for mixed states of depression or (hypo)mania focus almost exclusively on psychopharmacologic intervention without tapping into the benefits of psychotherapy. The authors highlight the complex clinical picture and illness course of mixed states, and discuss the benefit of taking a patient-centered approach to treatment incorporating techniques from a variety of evidence-based psychotherapies. A careful assessment of suicide risk as well as interventions designed specifically for anxiety are also recommended., Competing Interests: Disclosure The authors have nothing to disclose related to this work. Drs B. O’Brien, A.C. Swann, S.J. Mathew and M. Lijffijt are supported by the use of resources and facilities at the Michael E. Debakey VA Medical Center, Houston, Texas., (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.

Background: As there has been a demonstrated link between sleep disturbance and suicide, the present study investigated the relationship between self-reported sleep disturbance during inpatient psychiatric treatment and clinical outcomes at discharge and six months post-discharge., Methods: Participants were 2,970 adults receiving care in a long-term inpatient psychiatric hospital. Greater than 90% of inpatients reported at least mild sleep disturbance throughout treatment. Group-based trajectory modeling was used to determine patterns of sleep disturbance changes over time., Results: Participants fit into distinct categories based on their trajectories of sleep problems across treatment: No Sleep Problems (10.3% of participants, no sleep problems endorsed over the course of inpatient psychiatric treatment), Resolvers (sleep problems completely resolved over the course of inpatient psychiatric treatment; 10.6%), Non-Responders (did not respond to inpatient psychiatric treatment; 35.7%) and Responders (sleep problems decreased but did not fully resolve over the course of inpatient psychiatric treatment; 43.4%). Individuals with comorbid major depressive disorder and generalized anxiety disorder were significantly more likely to demonstrate higher rates of sleep disturbance throughout inpatient psychiatric treatment and their sleep problems did not respond to treatment as usual (Non-Responders). Further, patients in the Non-Responder group had significantly more suicidal ideation and worse clinical outcomes (higher anxiety, more disability, and lower well-being) at discharge and six months post-discharge, as well as were on more medication including hypnotics throughout treatment., Conclusions: Findings indicate the urgent need to design and implement inpatient psychiatry sleep protocols to not only improve sleep and clinical outcomes, but also reduce the risk for suicide post-discharge., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Serum brain-derived neurotrophic factor (BDNF) is decreased in individuals with major depressive disorder (MDD). Pre-clinical and clinical reports suggest that the glutamate release inhibitor riluzole increases BDNF and may have antidepressant properties. Here we report serum (sBDNF) and plasma (pBDNF) levels from a randomized controlled, adjunctive, sequential parallel comparison design trial of riluzole in MDD., Methods: Serum and plasma BDNF samples were drawn at baseline and weeks 6 and 8 from 55 subjects randomized to adjunctive treatment with riluzole or placebo for 8 weeks., Results: Riluzole responders had lower baseline serum (19.08 ng/ml [SD 9.22] v. 28.80 ng/ml [9.63], p = 0.08) and plasma (2.72 ng/ml [1.07] v. 4.60 ng/ml [1.69], p = 0.06) BDNF compared to non-responders at a trend level. This pattern was nominally seen in placebo responders for baseline pBDNF to some degree (1.21 ng/ml [SD 1.29] v. 3.58 ng/ml [SD 1.67], p = 0.12) but not in baseline sBDNF., Limitations: A number of limitations warrant comment, including the small sample size of viable BDNF samples and the small number of riluzole responders., Conclusions: Preliminary evidence reported here suggests that lower baseline BDNF may be associated with better clinical response to riluzole., (Copyright © 2018. Published by Elsevier B.V.)

Objective: Suicide is a public health crisis with limited treatment options. The authors conducted a systematic review and individual participant data meta-analysis examining the effects of a single dose of ketamine on suicidal ideation., Method: Individual participant data were obtained from 10 of 11 identified comparison intervention studies that used either saline or midazolam as a control treatment. The analysis included only participants who had suicidal ideation at baseline (N=167). A one-stage, individual participant data, meta-analytic procedure was employed using a mixed-effects, multilevel, general linear model. The primary outcome measures were the suicide items from clinician-administered (the Montgomery-Åsberg Depression Rating Scale [MADRS] or the Hamilton Depression Rating Scale [HAM-D]) and self-report scales (the Quick Inventory of Depressive Symptomatology-Self Report [QIDS-SR] or the Beck Depression Inventory [BDI]), obtained for up to 1 week after ketamine administration., Results: Ketamine rapidly (within 1 day) reduced suicidal ideation significantly on both the clinician-administered and self-report outcome measures. Effect sizes were moderate to large (Cohen's d=0.48-0.85) at all time points after dosing. A sensitivity analysis demonstrated that compared with control treatments, ketamine had significant benefits on the individual suicide items of the MADRS, the HAM-D, and the QIDS-SR but not the BDI. Ketamine's effect on suicidal ideation remained significant after adjusting for concurrent changes in severity of depressive symptoms., Conclusions: Ketamine rapidly reduced suicidal thoughts, within 1 day and for up to 1 week in depressed patients with suicidal ideation. Ketamine's effects on suicidal ideation were partially independent of its effects on mood, although subsequent trials in transdiagnostic samples are required to confirm that ketamine exerts a specific effect on suicidal ideation. Additional research on ketamine's long-term safety and its efficacy in reducing suicide risk is needed before clinical implementation.

Riluzole is a glutamate-modulating agent with neuroprotective properties approved for use in amyotrophic lateral sclerosis. The efficacy and safety of riluzole vs placebo as an adjunct to antidepressant medication in outpatients with major depressive disorder (MDD) was examined in a 3-site, 8-week, randomized, double-blind, placebo-controlled, fixed-dose trial using a sequential parallel comparison design comprised of two phases of 4 weeks. Patients with MDD in a current major depressive episode (N=104) with an inadequate response to either a prospective or a historical trial of an antidepressant medication were randomized in a 2 : 3 : 3 ratio to the treatment sequences of riluzole/riluzole, placebo/placebo, and placebo/riluzole, respectively. The primary outcome was change in depression severity, as assessed by the Montgomery-Åsberg Depression Rating Scale (MADRS). Secondary efficacy outcomes included the response rate, defined as at least a 50% improvement in MADRS, Clinical Global Impressions severity and improvement subscales, and patient-reported measures of depression and cognitive function. Eighty-five patients completed the randomized treatment phases. Treatment groups did not differ in mean change in MADRS scores, response rate, or in any secondary efficacy outcomes. Riluzole was generally well tolerated, with a side effect profile consistent with its clinical use. In conclusion, a fixed dose of riluzole (100 mg/day) did not show adjunctive antidepressant efficacy compared to placebo. The trial was adequately powered to detect a moderate riluzole effect, and the risk for exaggerated placebo responses was mitigated. The lack of efficacy suggests that mechanisms underlying riluzole's neuroprotective effects are insufficient for clinical response in treatment-resistant depression.

Animal models of depression repeatedly showed stress-induced nucleus accumbens (NAc) hypertrophy. Recently, ketamine was found to normalize this stress-induced NAc structural growth. Here, we investigated NAc structural abnormalities in major depressive disorder (MDD) in two cohorts. Cohort A included a cross-sectional sample of 34 MDD and 26 healthy control (HC) subjects, with high-resolution magnetic resonance imaging (MRI) to estimate NAc volumes. Proton MR spectroscopy ( 1 H MRS) was used to divide MDD subjects into two subgroups: glutamate-based depression (GBD) and non-GBD. A separate longitudinal sample (cohort B) included 16 MDD patients who underwent MRI at baseline then 24 h following intravenous infusion of ketamine (0.5 mg/kg). In cohort A, we found larger left NAc volume in MDD compared to controls (Cohen's d=1.05), but no significant enlargement in the right NAc (d=0.44). Follow-up analyses revealed significant subgrouping effects on the left (d⩾1.48) and right NAc (d⩾0.95) with larger bilateral NAc in non-GBD compared to GBD and HC. NAc volumes were not different between GBD and HC. In cohort B, ketamine treatment reduced left NAc, but increased left hippocampal, volumes in patients achieving remission. The cross-sectional data provided the first evidence of enlarged NAc in patients with MDD. These NAc abnormalities were limited to patients with non-GBD. The pilot longitudinal data revealed a pattern of normalization of left NAc and hippocampal volumes particularly in patients who achieved remission following ketamine treatment, an intriguing preliminary finding that awaits replication.

Major depressive disorder (MDD) is severely disabling, and current treatments have limited efficacy. The glutamate N-methyl-D-aspartate receptor (NMDAR) antagonist ketamine was recently repurposed as a rapidly acting antidepressant, catalysing the vigorous investigation of glutamate-signalling modulators as novel therapeutic agents for depressive disorders. In this Review, we discuss the progress made in the development of such modulators for the treatment of depression, and examine recent preclinical and translational studies that have investigated the mechanisms of action of glutamate-targeting antidepressants. Fundamental questions remain regarding the future prospects of this line of drug development, including questions concerning safety and tolerability, efficacy, dose-response relationships and therapeutic mechanisms.

The objective of this study was to investigate the efficacy and safety of adjunctive lanicemine (NMDA channel blocker) in the treatment of major depressive disorder (MDD) over 12 weeks. This phase IIb, randomized, parallel-arm, double-blind, placebo-controlled study was conducted at 49 centers in four countries between December 2011 and August 2013 in 302 patients aged 18-70 years, meeting criteria for single episode or recurrent MDD and with a history of inadequate treatment response. Patients were required to be taking an allowed antidepressant for at least four weeks prior to screening. Patients were randomized equally to receive 15 double-blind intravenous infusions of adjunctive lanicemine 50 mg, lanicemine 100 mg, or saline over a 12-week course, in addition to ongoing antidepressant. The primary efficacy end point was change in Montgomery-Åsberg Depression Rating Scale (MADRS) total score from baseline to week 6. Secondary efficacy outcome variables included change in MADRS score from baseline to week 12, response and remission rates, and changes in Clinical Global Impression scale, Quick Inventory of Depressive Symptomology Self-Report score, and Sheehan Disability Scale score. Of 302 randomized patients, 240 (79.5%) completed treatment. Although lanicemine was generally well tolerated, neither dose was superior to placebo in reducing depressive symptoms on the primary end point or any secondary measures. There was no significant difference between lanicemine and placebo treatment on any outcome measures related to MDD. Post hoc analyses were performed to explore the possible effects of trial design and patient characteristics in accounting for the contrasting results with a previously reported trial.

Two phase 2B, randomized, double-blind studies assessed the efficacy and safety of fixed or flexible dose of triple monoamine uptake inhibitor BMS-820836 in patients with treatment-resistant depression to demonstrate whether switching to BMS-820836 was superior to the continuation of standard antidepressant treatment. Patients with a history of inadequate response to 1 to 3 adequate trials of antidepressant therapies were prospectively treated with duloxetine 60 mg/d for 8 weeks (CN162-006) or duloxetine 60 mg/d or escitalopram 20 mg/d for 7 weeks (CN162-007). Inadequate responders were randomized to continue their prospective phase treatment or switch to flexible-dose (0.5-2 mg/d; CN162-006) or fixed-dose (0.25, 0.5, 1, or 2 mg/d; CN162-007) BMS-820836 for 6 weeks. The primary end point in both studies was mean change in Montgomery-Åsberg Depression Rating Scale (MADRS) total score from randomization to study end point. BMS-820836 flexible (0.5-2 mg/d) or fixed dose of 1 mg/d or greater showed efficacy similar to the continuation of antidepressant treatment, with no statistically significant or clinically meaningful differences. In the CN162-006 study, the adjusted mean (SE) change in MADRS total score was -8.7 (0.661) and -8.1 (0.656) for BMS-820836 and duloxetine, respectively (P = 0.526). In the CN162-007 study, the adjusted mean (SE) change in MADRS total score was -7.3 (0.830) and -6.6 (0.842) for BMS-820836 of 1 and 2 mg, respectively, and -6.9 (0.602) for the continuation group (P = 0.910). Thus, BMS-820836 was well tolerated, with no evidence of dose-dependent discontinuations due to adverse events, but it failed to demonstrate superiority to the continuation of an existing antidepressant in patients with treatment-resistant depression.

Hippocampal volume reduction has been related to treatment-resistant depression (TRD) and is hypothesized to reflect impaired amino-acid neurotransmission. To better understand the role of amino acid neurotransmission in hippocampal volume deficits, and subsequent resistance to treatment, this study investigated the relationship between hippocampal volumes and GABA levels in the anterior cingulate cortex (ACC), previously associated with TRD. Thirty-three medication-free major depressive disorder (MDD; 14 TRD and 19 non-TRD) and 26 healthy controls (HC) subjects were studied. Participants underwent high-resolution magnetic resonance imaging (MRI) to estimate hippocampal volume and proton MR spectroscopy ((1)H MRS) to measure ACC GABA levels. MDD patients, with known ACC GABA levels, were divided into two groups: MDD Low GABA and MDD High GABA. We found a significant reduction in hippocampal volume in the MDD Low GABA group compared to MDD High GABA (p<0.001) and HC (p=0.01). The relationship between hippocampal volume and cortical GABA was population (i.e. MDD group) and region specific (i.e. prefrontal cortex). Comparing TRD, non-TRD and HC groups, there was a main effect of group on hippocampal volume (p=0.04), which post hoc analysis revealed as smaller hippocampal volume in TRD subjects than in non-TRD (p=0.05) and HC groups (p=0.03). No hippocampal volume differences between non-TRD and HC groups. The data provides insight into the role of prefrontal neurochemical deficits in the limbic structural abnormalities observed in MDD. In addition, it replicates the relationship between TRD and smaller hippocampal volumes., (Published by Elsevier B.V.)

Major depressive disorder (MDD) is one of the most disabling diseases worldwide and is becoming a significant public health threat. Current treatments for MDD primarily consist of monoamine-targeting agents and have limited efficacy. However, the glutamate neurotransmitter system has recently come into focus as a promising alternative for novel antidepressant treatments. We review the current data on the glutamate NMDA receptor antagonist ketamine, which has been shown in clinical trials to act as a rapid antidepressant in MDD. We also examine ketamine efficacy on dimensions of psychopathology, including anhedonia, cognition, and suicidality, consistent with the NIMH Research Domain Criteria initiative. Other aspects of ketamine reviewed in this paper include safety and efficacy, different administration methods, and the risks of misuse of ketamine outside of medical settings. Finally, we conclude with a discussion of glutamatergic agents other than ketamine currently being tested as novel antidepressants., (© 2015 New York Academy of Sciences.)

Accumulating evidence underscores the utility of ketamine in treating severely treatment-resistant depressed patients. We investigated the relationship between the rapid antidepressant effects of ketamine and hippocampal volume, a biomarker of antidepressant treatment outcome. We gave 16 medication-free, major depressive disorder (MDD) patients a single, sub-anesthetic dose infusion of ketamine (0.5 mg/kg, over 40 min). We assessed depression severity pre-treatment, and at 24 h post-treatment, with the Montgomery-Åsberg Depression Rating Scale (MADRS). Prior to treatment, patients underwent magnetic resonance imaging (MRI) to estimate their hippocampal volume: We obtained viable MRI data in 13 patients. Delta MADRS (post- minus pre-treatment) was significantly correlated with the pre-treatment volumes of the left hippocampus (r = 0.66; p = 0.01), but not the right hippocampus (r = 0.49; p = 0.09). The correlation between delta MADRS and the left hippocampus remained high (r > 0.6; p = 0.13), after controlling for several demographic and clinical variables, although the p value increased due to the reduced degree of freedom (df = 5). Ketamine exerts enhanced antidepressant effects in patients with a relatively smaller hippocampus, a patient population that has been repeatedly shown to be refractory to traditional antidepressants., (© The Author(s) 2014.)

The glutamate N-methyl-D-aspartate (NMDA) receptor antagonist ketamine displays rapid antidepressant effects in patients with treatment-resistant depression (TRD); however, the potential for adverse neurocognitive effects in this population has not received adequate study. The current study was designed to investigate the delayed neurocognitive impact of ketamine in TRD and examine baseline antidepressant response predictors in the context of a randomized controlled trial. In the current study, 62 patients (mean age = 46.2 ± 12.2) with TRD free of concomitant antidepressant medication underwent neurocognitive assessments using components of the MATRICS Consensus Cognitive Battery (MCCB) before and after a single intravenous infusion of ketamine (0.5 mg/kg) or midazolam (0.045 mg/kg). Participants were randomized to ketamine or midazolam in a 2:1 fashion under double-blind conditions and underwent depression symptom assessments at 24, 48, 72 h, and 7 days post treatment using the Montgomery-Asberg Depression Rating Scale (MADRS). Post-treatment neurocognitive assessment was conducted once at 7 days. Neurocognitive performance improved following the treatment regardless of treatment condition. There was no differential effect of treatment on neurocognitive performance and no association with antidepressant response. Slower processing speed at baseline uniquely predicted greater improvement in depression at 24 h following ketamine (t = 2.3, p = 0.027), while controlling for age, depression severity, and performance on other neurocognitive domains. In the current study, we found that ketamine was devoid of adverse neurocognitive effects at 7 days post treatment and that slower baseline processing speed was associated with greater antidepressant response. Future studies are required to further define the neurocognitive profile of ketamine in clinical samples and to identify clinically useful response moderators.

Objective: Ketamine has demonstrated rapid antidepressant effects in patients with treatment-resistant depression (TRD); however, the safety and tolerability of ketamine in this population have not been fully described. Herein we report the largest study to date of the safety, tolerability, and acceptability of ketamine in TRD., Method: Data from 205 intravenous (IV) ketamine infusions (0.5 mg/kg over 40 minutes) in 97 participants with DSM-IV-defined major depressive disorder (MDD) were pooled from 3 clinical trials conducted between 2006 and 2012 at 2 academic medical centers. Safety and tolerability measures included attrition, adverse events (AEs), hemodynamic changes, and assessments of psychosis and dissociation., Results: The overall antidepressant response rate, defined as a ≥ 50% improvement in Montgomery-Asberg Depression Rating Scale score, was 67% (65 of 97 participants). Four of 205 infusions (1.95%) were discontinued due to AEs. The overall attrition rate was 3.1% (3 of 97). In the first 4 hours after the infusion, the most common general AEs were drowsiness, dizziness, poor coordination, blurred vision, and feeling strange or unreal. Approximately one third of individuals experienced protocol-defined hemodynamic changes. Ketamine resulted in small but significant increases in psychotomimetic and dissociative symptoms (all P < .05). There were no cases of persistent psychotomimetic effects, adverse medical effects, or increased substance use in a subgroup of patients with available long-term follow-up information., Conclusions: In this relatively large group of patients with TRD, ketamine was safe and well tolerated. Further research investigating the safety of ketamine in severe and refractory depression is warranted., Trial Registration: ClinicalTrials.gov identifiers: NCT00419003, NCT00548964, and NCT00768430., (© Copyright 2015 Physicians Postgraduate Press, Inc.)

The glutamate N-methyl-D-aspartate receptor antagonist ketamine has demonstrated antidepressant effects in individuals with treatment-resistant major depressive disorder (TRD) within 24 h of a single dose. The current study utilized functional magnetic resonance imaging (fMRI) and two separate emotion perception tasks to examine the neural effects of ketamine in patients with TRD. One task used happy and neutral facial expressions; the other used sad and neutral facial expressions. Twenty patients with TRD free of concomitant antidepressant medication underwent fMRI at baseline and 24 h following administration of a single intravenous dose of ketamine (0.5 mg kg(-1)). Adequate data were available for 18 patients for each task. Twenty age- and sex-matched healthy volunteers were scanned at one time point for baseline comparison. Whole-brain, voxel-wise analyses were conducted controlling for a family-wise error rate (FWE) of P<0.05. Compared with healthy volunteers, TRD patients showed reduced neural responses to positive faces within the right caudate. Following ketamine, neural responses to positive faces were selectively increased within a similar region of right caudate. Connectivity analyses showed that greater connectivity of the right caudate during positive emotion perception was associated with improvement in depression severity following ketamine. No main effect of group was observed for the sad faces task. Our results indicate that ketamine specifically enhances neural responses to positive emotion within the right caudate in depressed individuals in a pattern that appears to reverse baseline deficits and that connectivity of this region may be important for the antidepressant effects of ketamine.

Inflammation and oxidative stress are important mechanisms that have been implicated in the pathophysiology of major depressive disorder (MDD). Glutathione (GSH) is the most abundant antioxidant in human tissue, and a key index of antioxidant capacity and, hence, of oxidative stress. The aims of this investigation were to examine possible relationships between occipital GSH and dimensional measures of depressive symptom severity, including anhedonia - the reduced capacity to experience pleasure - and fatigue. We hypothesized that the magnitude of anhedonia and fatigue will be negatively correlated with occipital GSH levels in subjects with MDD and healthy controls (HC). Data for eleven adults with MDD and ten age- and sex-matched HC subjects were included in this secondary analysis of data from a previously published study. In vivo levels of GSH in a 3cm×3cm×2cm voxel of occipital cortex were obtained by proton magnetic resonance spectroscopy ((1)H MRS) on a 3T MR system, using the standard J-edited spin-echo difference technique. Anhedonia was assessed by combining interest items from depression and fatigue rating scales, and fatigue by use of the multidimensional fatigue inventory. Across the full sample of participants, anhedonia severity and occipital GSH levels were negatively correlated (r=-0.55, p=0.01). No associations were found between fatigue severity and GSH in this sample. These preliminary findings are potentially consistent with a pathophysiological role for GSH and oxidative stress in anhedonia and MDD. Larger studies in anhedonic depressed patients are indicated., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Objective: Ketamine, a glutamate N-methyl-d-aspartate (NMDA) receptor antagonist, has shown rapid antidepressant effects, but small study groups and inadequate control conditions in prior studies have precluded a definitive conclusion. The authors evaluated the rapid antidepressant efficacy of ketamine in a large group of patients with treatment-resistant major depression., Method: This was a two-site, parallel-arm, randomized controlled trial of a single infusion of ketamine compared to an active placebo control condition, the anesthetic midazolam. Patients with treatment-resistant major depression experiencing a major depressive episode were randomly assigned under double-blind conditions to receive a single intravenous infusion of ketamine or midazolam in a 2:1 ratio (N=73). The primary outcome was change in depression severity 24 hours after drug administration, as assessed by the Montgomery-Åsberg Depression Rating Scale (MADRS)., Results: The ketamine group had greater improvement in the MADRS score than the midazolam group 24 hours after treatment. After adjustment for baseline scores and site, the MADRS score was lower in the ketamine group than in the midazolam group by 7.95 points (95% confidence interval [CI], 3.20 to 12.71). The likelihood of response at 24 hours was greater with ketamine than with midazolam (odds ratio, 2.18; 95% CI, 1.21 to 4.14), with response rates of 64% and 28%, respectively., Conclusions: Ketamine demonstrated rapid antidepressant effects in an optimized study design, further supporting NMDA receptor modulation as a novel mechanism for accelerated improvement in severe and chronic forms of depression. More information on response durability and safety is required before implementation in clinical practice.

Chronic fatigue syndrome (CFS), a complex illness characterized by fatigue, impaired concentration, and musculoskeletal pain, is often misdiagnosed as a psychiatric illness due to the overlap of its symptoms with mood and anxiety disorders. Using proton magnetic resonance spectroscopic imaging ((1)H MRSI), we previously measured levels of the major brain metabolites in CFS, in generalized anxiety disorder (GAD), and in healthy control subjects, and found significantly higher levels of ventricular cerebrospinal fluid (CSF) lactate in CFS compared to the other two groups. In the present study, we sought to assess the specificity of this observation for CFS by comparing ventricular lactate levels in a new cohort of 17 CFS subjects with those in 19 healthy volunteers and in 21 subjects with major depressive disorder (MDD), which, like GAD, is a neuropsychiatric disorder that has significant symptom overlap with CFS. Ventricular CSF lactate was significantly elevated in CFS compared to healthy volunteers, replicating the major result of our previous study. Ventricular lactate measures in MDD did not differ from those in either CFS or healthy volunteers. We found a significant correlation between ventricular CSF lactate and severity of mental fatigue that was specific to the CFS group. In an exploratory analysis, we did not find evidence for altered levels of the amino acid neurotransmitters, gamma-aminobutyric acid (GABA) and glutamate + glutamine ('Glx'), in CFS compared to MDD or healthy controls. Future (1)H MRS studies with larger sample sizes and well-characterized populations will be necessary to further clarify the sensitivity and specificity of neurometabolic abnormalities in CFS and MDD.

Background: A single subanesthetic (intravenous) IV dose of ketamine might have rapid but transient antidepressant effects in patients with treatment-resistant depression (TRD). Here we tested the tolerability, safety, and efficacy of repeated-dose open-label IV ketamine (six infusions over 12 days) in 10 medication-free symptomatic patients with TRD who had previously shown a meaningful antidepressant response to a single dose., Methods: On day 1, patients received a 40-min IV infusion of ketamine (.5 mg/kg) in an inpatient setting with continuous vital-sign monitoring. Psychotomimetic effects and adverse events were recorded repeatedly. The primary efficacy measure was change from baseline in the Montgomery-Asberg Depression Rating Scale (MADRS) score. If patients showed a > or =50% reduction in MADRS scores on day 2, they received five additional infusions on an outpatient basis (days 3, 5, 8, 10, and 12). Follow-up visits were conducted twice-weekly for > or =4 weeks or until relapse., Results: Ketamine elicited minimal positive psychotic symptoms. Three patients experienced significant but transient dissociative symptoms. Side effects during and after each ketamine infusion were generally mild. The response criterion was met by nine patients after the first infusion as well as after the sixth infusion. The mean (SD) reduction in MADRS scores after the sixth infusion was 85% (12%). Postketamine, eight of nine patients relapsed, on average, 19 days after the sixth infusion (range 6 days-45 days). One patient remained antidepressant-free with minimal depressive symptoms for >3 months., Conclusions: These pilot findings suggest feasibility of repeated-dose IV ketamine for the acute treatment of TRD.

Background: Significant alterations in gamma-aminobutyric acid (GABA) and glutamate levels have been previously reported in major depressive disorder (MDD); however, no studies to date have investigated associations between these amino acid neurotransmitters and treatment resistance., Methods: The objective of this study was to compare occipital cortex (OCC) and anterior cingulate cortex (ACC) GABA and glutamate+glutamine (Glx) levels measured by proton magnetic resonance spectroscopy ((1)H MRS) in 15 medication-free treatment-resistant depression (TRD) patients with those in 18 nontreatment-resistant MDD (nTRD) patients and 24 healthy volunteers (HVs)., Results: Levels of OCC GABA relative to voxel tissue water (W) were decreased in TRD patients compared with both HV (20.2% mean reduction; p = .001; Cohen's d = 1.3) and nTRD subjects (16.4% mean reduction; p = .007; Cohen's d = 1.4). There was a similar main effect of diagnosis for ACC GABA/W levels (p = .047; Cohen's d = .76) with TRD patients exhibiting reduced GABA in comparison with the other two groups (22.4% to 24.5% mean reductions). Group differences in Glx/W were not significant in either brain region. Only GABA results in OCC survived correction for multiple comparisons., Conclusions: Our findings corroborate previous reports of decreased GABA in MDD and provide initial evidence for a distinct neuronal amino acid profile in patients who have failed to respond to several standard antidepressants, possibly indicative of abnormal glutamate/glutamine/GABA cycling. Given interest in novel antidepressant mechanisms in TRD that selectively target amino acid neurotransmitter function, the translational relevance of these findings awaits further study.

Treatment-resistant depression continues to pose a major medical challenge, as up to one-third of patients with major depressive disorder fail to have an adequate response to standard pharmacotherapies. An improved understanding of the complex circuitry underlying depressive disorders has fostered an explosion in the development of new, nonpharmacological approaches. Each of these treatments seeks to restore normal brain activity via electrical or magnetic stimulation. In this article, the authors discuss the ongoing evolution of neurostimulatory treatments for treatment-resistant depression, reviewing the methods, efficacy, and current research on electroconvulsive therapy, repetitive transcranial magnetic stimulation, magnetic seizure therapy, focal electrically administered stimulated seizure therapy, transcranial direct current stimulation, chronic epidural cortical stimulation, and vagus nerve stimulation. Special attention is given to deep brain stimulation, the most focally targeted approach. The history, purported mechanisms of action, and current research are outlined in detail. Although deep brain stimulation is the most invasive of the neurostimulatory treatments developed to date, it may hold significant promise in alleviating symptoms and improving the quality of life for patients with the most severe and disabling mood disorders.

A clinical follow-up study was performed of adolescent major depressives and normal control subjects approximately 10 years after the subjects had undergone serial cortisol measurements over a 24-h period. In light of their young adulthood clinical status, our objective was to ascertain whether there were any premorbid cortisol abnormalities associated with depressive course of illness. In all, 77 young adults who had received a diagnosis of adolescent major depressive disorder, or were determined to be normal volunteers free of psychiatric diagnosis at index period and during follow-up, were studied. When subjects were adolescents, blood samples were collected for cortisol at 20-min intervals during the 24-h period coinciding with the third consecutive night of sleep EEG. The subjects, in young adulthood at the time of follow-up, were reinterviewed regarding longitudinal course of illness, and the original adolescent cortisol data were analyzed in the light of information obtained. Of the subjects who had experienced at least one lifetime major depressive episode during the follow-up period, the subgroup who would go on to make suicide attempts during the follow-up period secreted significantly greater levels of cortisol in the 4, 6, and 12 h prior to sleep onset. Conversely, this same subgroup exhibited reduced cortisol levels 2-4 h following sleep onset. Adolescents who are at risk to make suicide attempts appear to display significant elevations of cortisol prior to sleep onset, a time when the hypothalamic-pituitary-adrenal (HPA) axis is normally most quiescent. Dysregulation of the HPA axis, combined with dysfunction of sleep-onset mechanisms previously reported in this same cohort, might serve as premorbid biological substrates that predict suicide attempts during follow-up.