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Intravenous ketamine, which displays rapid antidepressant properties, is posited to reverse depression by rapidly enhancing neuroplasticity. The authors tested whether an automated, computer-based approach could efficiently leverage enhanced neuroplasticity to extend the durability of rapid clinical response.A total of 154 adults (ages 18-60) with treatment-resistant unipolar depression were randomized in a double-blind, parallel-arm design to receive an active/active treatment combination (ketamine plus active "automated self-association training" [ASAT]; N=53) or one of two control arms that lacked either the active drug component (saline plus active ASAT; N=51) or the active behavioral component (ketamine plus sham ASAT; N=50). One day after a single infusion of intravenous ketamine (0.5 mg/kg over 40 minutes) or inert placebo (saline), active ASAT-targeting self-worth through automated "evaluative conditioning" training delivered by computer-or sham ASAT (consisting of identical computer tasks that included no positive or self-referential stimuli) was given, delivered twice daily over 4 consecutive days (eight sessions, ≤20 minutes per session). The prespecified primary outcome measure throughout the main (30-day) study period was score on the Montgomery-Åsberg Depression Rating Scale (MADRS).Ketamine rapidly and significantly reduced depression scores at 24 hours postinfusion (group-by-time interaction: standardized beta [β]=-1.30, 95% CI=-1.89, -0.70; t=-4.29, df=150). In intent-to-treat linear mixed models, depression scores in the ketamine+ASAT group remained significantly and stably low over the 30-day study period relative to those of the saline+ASAT group (β=-0.61, 95% CI=-0.95, -0.28; t=-3.62, df=148). By contrast, depression scores following ketamine+sham treatment followed a significant, increasing linear trajectory from 24 hours to 30 days, approaching the levels observed in the saline+ASAT group (group-by-time interaction relative to the saline+ASAT group: β=0.015, 95% CI=0.003, 0.03; t=2.35, df=568).After priming the brain with ketamine, training positive self-associations could provide an efficient, low-cost, portable, noninvasive, and highly dissemination-ready strategy for leveraging and extending ketamine's rapid antidepressant effects.

Depression is disabling and highly prevalent. Intravenous (IV) ketamine displays rapid-onset antidepressant properties, but little is known regarding which patients are most likely to benefit, limiting personalized prescriptions. We identified randomized controlled trials of IV ketamine that recruited individuals with a relevant psychiatric diagnosis (e.g., unipolar or bipolar depression; post-traumatic stress disorder), included one or more control arms, did not provide any other study-administered treatment in conjunction with ketamine (although clinically prescribed concurrent treatments were allowable), and assessed outcome using either the Montgomery-Åsberg Depression Rating Scale or the Hamilton Rating Scale for Depression (HRSD-17). Individual patient-level data for at least one outcome was obtained from 17 of 25 eligible trials [pooled n = 809]. Rates of participant-level data availability across 33 moderators that were solicited from these 17 studies ranged from 10.8% to 100% (median = 55.6%). After data harmonization, moderators available in at least 40% of the dataset were tested sequentially, as well as with a data-driven, combined moderator approach. Robust main effects of ketamine on acute [~24-hours; β*(95% CI) = 0.58 (0.44, 0.72); p β*(95% CI) = 0.38 (0.23, 0.54); p r ≤ 0.29, a small-medium effect). Ketamine robustly reduces depressive symptoms in a heterogeneous range of patients, with benefit relative to placebo even greater in patients more resistant to prior medications. In this largest effort to date to apply precision medicine approaches to ketamine treatment, no clinical or demographic patient-level features were detected that could be used to guide ketamine treatment decisions.Review Registration: PROSPERO Identifier: CRD42021235630

As sleep problems have been identified as an important, yet understudied, predictor of suicide risk, the present study analyzed the relationship between daytime sleepiness and nighttime sleep disturbance in a high-risk population of adults admitted to an inpatient psychiatric hospital. Objectives were to (1) examine the time course of subjective daytime sleepiness, nighttime sleep disturbance, and suicide risk throughout inpatient psychiatric treatment, (2) examine pre- to post-treatment changes in sleep disturbance with treatment as usual in an inpatient psychiatric setting, and (3) investigate whether daytime sleepiness and nighttime sleep disturbance predicted suicide risk above and beyond anxiety and depression. Participants were 500 consecutively admitted adults admitted to an intermediate length of stay (4-6 weeks) inpatient psychiatric hospital (47% female; 18-87 years of age). Measures of sleep, suicide risk, depression, and anxiety were completed at admission, weeks 1 through 4, and at discharge. Latent growth curve modeling (LGM) and hierarchal linear modeling (HLM) were conducted. The LGM analysis demonstrated that daytime sleepiness, nighttime sleep disturbance, and suicide risk all improved throughout inpatient treatment. Further, HLM showed that daytime sleepiness predicted suicide risk above and beyond symptoms of anxiety, depression, major sleep medications, and prior suicidal ideation and attempts, while nighttime sleep disturbance predicted suicide risk above and beyond symptoms of anxiety, major sleep medications, and prior suicidal ideation and attempts. Findings indicate the need to reevaluate safety protocols that may impact sleep, particularly that may increase daytime sleepiness, and to develop evidence-based sleep interventions for individuals admitted to inpatient psychiatric hospitals.

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. Clinical trial registration: 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.

Disorders of mood and cognition are prevalent, disabling, and notoriously difficult to treat. Fueling this challenge in treatment is a significant gap in our understanding of their neurophysiological basis. Here, we used intracranial neural recordings in three patients with severe depression to investigate the neural substrates of this disorder. Across prefrontal regions, we found that reduced depression severity is associated with decreased low-frequency neural activity and increased high-frequency activity. When constraining our model to decode using a single region, spectral changes in the anterior cingulate cortex best predicted depression severity in all three subjects. Relaxing this constraint revealed unique, individual-specific sets of spatio-spectral features predictive of symptom severity, reflecting the heterogeneous nature of depression. The ability to decode depression severity from neural activity increases our fundamental understanding of how depression manifests in the human brain and provides a target neural signature for personalized neuromodulation therapies.

BackgroundPrefrontal circuits in the human brain play an important role in cognitive and affective processing. Neuromodulation therapies delivered to certain key hubs within these circuits are being used with increasing frequency to treat a host of neuropsychiatric disorders. However, the detailed neurophysiological effects of stimulation to these hubs are largely unknown.MethodsHere, we performed intracranial recordings across prefrontal networks while delivering electrical stimulation to two well-established white matter hubs involved in cognitive regulation and depression: the subcallosal cingulate (SCC) and ventral capsule/ventral striatum (VC/VS).ResultsWe demonstrate a shared frontotemporal circuit consisting of the ventromedial PFC, amygdala, and lateral orbitofrontal cortex where gamma oscillations are differentially modulated by stimulation target. Additionally, we found subject-specific responses to stimulation in the dorsal anterior cingulate cortex and demonstrate the capacity for further tuning of neural activity using current-steered stimulation.ConclusionsOur findings indicate a potential neurophysiological mechanism for the dissociable therapeutic effects seen across the SCC and VC/VS DBS targets for psychiatric neuromodulation and our results lay the groundwork for personalized, network-guided neurostimulation therapy.

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).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.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.This was a retrospective analysis of a naturalistic sample. Patients were unblinded and more heterogenous than those included in most controlled clinical trial samples.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.

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.

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.

This secondary analysis of a randomized clinical trial examines whether automated self-association training can prolong the antidepressant effect of a single infusion of ketamine beyond 1 month in patients with treatment-resistant depression.

The kynurenine pathway (KP) is a strategic metabolic system that combines regulation of neuronal excitability via glutamate receptor function and neuroinflammation via other KP metabolites. This pathway has great promise in treatment of depression and suicidality. The KP modulator AV-101 (4-chlorokynurenine, 4-Cl-KYN), an oral prodrug of 7-chlorokynurenic acid (7-Cl-KYNA), an N-methyl-d-aspartate receptor (NMDAR) glycine site antagonist, and of 4-chloro-3-hydroxyanthranilic acid (4-Cl-3-HAA), a suppressor of NMDAR agonist quinolinic acid (QUIN), is a promising potential antidepressant that targets glutamate functioning via the KP. However, a recent placebo-controlled clinical trial of AV-101 in depression found negative results. This raises the question of whether AV-101 can penetrate the brain and engage the NMDAR and KP effectively. To address this problem, ten healthy US military veterans (mean age = 32.6 years ± 6.11; 1 female) completed a phase-1 randomized, double-blind, placebo-controlled, crossover study to examine dose-related effects of AV-101 (720 and 1440 mg) on NMDAR engagement measured by γ-frequency band auditory steady-state response (40 Hz ASSR) and resting EEG. Linear mixed models revealed that 1440 mg AV-101, but not 720 mg, increased 40 Hz ASSR and 40 Hz ASSR γ-inter-trial phase coherence relative to placebo. AV-101 also increased 4-Cl-KYN, 7-Cl-KYNA, 4-Cl-3-HAA, 3-HAA, and KYNA in a dose-dependent manner, without affecting KYN and QUIN. AV-101 was safe and well tolerated. These results corroborate brain target engagement of 1440 mg AV-101 in humans, consistent with blockade of interneuronal NMDAR blockade. Future studies should test higher doses of AV-101 in depression. Suicidal behavior, which has been associated with high QUIN and low KYNA, is also a potential target for AV-101.

BackgroundKetamine’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.MethodsResting-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.ResultsA 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 ConclusionsThese 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.

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.

Treatment-resistant depression (TRD) is a problematic and prevalent public health and societal concern. Although electroconvulsive therapy (ECT) is the gold standard TRD intervention, the treatment evokes apprehension due to public perceptions, feasibility, and tolerability. Despite significant medical advancements, few medications have been approved by the U.S. Food and Drug Administration for TRD. In 2019, intranasal esketamine, the S-isomer of racemic ketamine, was approved for TRD, garnering significant excitement about the potential for the drug to act as an alternative treatment to ECT. The goal of this narrative review is to compare the safety, efficacy, and tolerability of ketamine and ECT; clarify whether ketamine is a reasonable alternative to ECT; and to facilitate improved treatment assignment for TRD. Empirical quantitative and qualitative studies and national and international guidelines for these treatments are reviewed. The field awaits the results of two ongoing large comparative effectiveness trials of ECT and IV ketamine for TRD, which should help guide clinicians and patients as to the relative risk and benefit of these interventions. Over the next five years we anticipate further innovations in neuromodulation and in drug development which broadly aim to develop more tolerable versions of ECT and ketamine, respectively.

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.

Despite the growing off-label use of ketamine for depression and other psychiatric indications, its long-term safety profile and abuse potential remain unclear. We present a case of a patient who presented with paranoia and personality changes attributed to ketamine misuse, which illustrates the need for more robust screening and systematic monitoring with this medication. Continued evaluation of the abuse potential of ketamine in long-term treatment as well as restricted access and in-office administration are important, to develop a better understanding of the risk-benefit profile of this drug.

Background Brain imaging and genetics are fields acquiring data at increasing speed, but more information does not always result in a better understanding of the underlying biology. We developed the ProcessGeneLists (PGL) approach to use genetics and mRNA gene expression data to generate regions of interest for imaging studies. Methods We applied PGL to past suicide attempt (ATT): We averaged the mRNA expression levels of genes (n = 130) possibly associated with ATT (p ≤ 10−3 in a published genome-wide association study, GWAS) in each brain region studied in the Human Allen Brain Atlas (6 ex-vivo brains, 158 to 946 regions/brain have mRNA expression data) and compared that to the averaged mRNA expression levels of all other genes in each region in each brain in the atlas. Results PGL revealed 8 regions where “attempt-related genes” were differentially expressed (Wilcoxon test with Bonferroni correction 8.88−11 = −6) and dorsolateral prefrontal cortex (dlPFC pFWE Conclusion PGL uncovered a brain function/genotype interaction in ATT by using published GWAS data to inform imaging studies. This could inform individualized therapies in the future.

The success of deep brain stimulation (DBS) for treating Parkinson's disease has led to its application to several other disorders, including treatment-resistant depression. Results with DBS for treatment-resistant depression have been heterogeneous, with inconsistencies largely driven by incomplete understanding of the brain networks regulating mood, especially on an individual basis. We report results from the first subject treated with DBS for treatment-resistant depression using an approach that incorporates intracranial recordings to personalize understanding of network behavior and its response to stimulation. These recordings enabled calculation of individually optimized DBS stimulation parameters using a novel inverse solution approach. In the ensuing double-blind, randomized phase incorporating these bespoke parameter sets, DBS led to remission of symptoms and dramatic improvement in quality of life. Results from this initial case demonstrate the feasibility of this personalized platform, which may be used to improve surgical neuromodulation for a vast array of neurologic and psychiatric disorders.

Evidence supporting specific therapies for late-life treatment-resistant depression (LL-TRD) is necessary. This study used Bayesian adaptive randomization to determine the optimal dose for the probability of treatment response (≥50% improvement from baseline on the Montgomery-Asberg Depression Rating Scale) 7 days after a 40 min intravenous (IV) infusion of ketamine 0.1 mg/kg (KET 0.1), 0.25 mg/kg (KET 0.25), or 0.5 mg/kg (KET 0.5), compared to midazolam 0.03 mg/kg (MID) as an active placebo. The goal of this study was to identify the best dose to carry forward into a larger clinical trial. Response durability at day 28, safety and tolerability, and effects on cortical excitation/inhibition (E/I) ratio using resting electroencephalography gamma and alpha power, were also determined. Thirty-three medication-free US military veterans (mean age 62; range: 55-72; 10 female) with LL-TRD were randomized double-blind. The trial was terminated when dose superiority was established. All interventions were safe and well-tolerated. Pre-specified decision rules terminated KET 0.1 (N = 4) and KET 0.25 (N = 5) for inferiority. Posterior probability was 0.89 that day-seven treatment response was superior for KET 0.5 (N = 11; response rate = 70%) compared to MID (N = 13; response rate = 46%). Persistent treatment response at day 28 was superior for KET 0.5 (response rate = 82%) compared to MID (response rate = 37%). KET 0.5 had high posterior probability of increased frontal gamma power (posterior probability = 0.99) and decreased posterior alpha power (0.89) during infusion, suggesting an acute increase in E/I ratio. These results suggest that 0.5 mg/kg is an effective initial IV ketamine dose in LL-TRD, although further studies in individuals older than 75 are required.

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

Background While riluzole has been investigated for the treatment of depression, little is known about its longer-term efficacy and optimal treatment duration in treatment-resistant depression (TRD). The objective of this study is to characterize the longer-term outcome of adjunctive riluzole therapy for TRD in an open-label extension of an 8-week acute treatment trial. Methods The data from 66 patients with TRD who received adjunctive riluzole in a 12-week open-label extension phase were analyzed. Response rates (⩾50% reduction in the Mongomery-Asberg Depression Rating Scale [MADRS] score), relapse rates (a MADRS score of ⩾22 in patients who had previously achieved response), and adverse events were examined in patients who had achieved response at the end of the acute phase and those who had not. Results Among acute phase responders, the maintained response rate was 66.7% (8/12) and the relapse rate was 8.3% (1/12). In acute phase non-responders, the response rate was 24.1% (13/54). The most commonly reported adverse event was fatigue (9.1%). Three cases were considered serious adverse events; vomiting (n = 1), shortness of breath (n = 1), and aborted suicide attempt (n = 1). Limitations This longer-term study was open-label and uncontrolled. The sample size was relatively small. Conclusions Longer-term adjunctive riluzole appears relatively well tolerated and beneficial for maintaining previous response. Additionally, approximately one fourth of patients who did not respond to 8-week antidepressant treatment might respond if treated with riluzole for 12 weeks. Those findings warrant further investigation because adjunctive riluzole could represent an option for treatment of depression when standard antidepressants have failed.

Objective: To conduct a meta-analysis of studies of vortioxetine in adults with major depressive disorder (MDD). DataSources: Abstracts were identified using PubMed by cross-referencing vortioxetine with placebo and randomized. 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.