OBJECTIVE:Ketamine rapidly reduces suicidal ideation in major depressive disorder (MDD), but its effects are transient. Preclinical and clinical studies suggest that ketamine's antidepressant and antisuicidal effects may be partly mediated by mu-opioid receptor (MOR) modulation. The authors investigated the efficacy and safety of low-dose sublingual buprenorphine, a partial MOR agonist, as a follow-on treatment to prolong the effects of intravenous ketamine. METHODS:This was a randomized, double-blind, placebo-controlled trial conducted at a single outpatient center in the United States. Adults with MDD and a total score ≥6 on the Scale for Suicide Ideation (SSI) were randomly assigned in a 1:1 ratio to receive either sublingual buprenorphine (0.2 to 0.8 mg/day) or a matched placebo for 4 weeks, beginning 48 hours after a single open-label intravenous ketamine infusion (0.5 mg/kg over 40 minutes). The primary outcome was the change in SSI total score, assessed weekly from day 1 through day 31. RESULTS:From November 2020 to March 2025, 50 participants (68% female) received ketamine, of whom 45 completed at least 1 week of follow-on treatment. Both groups showed significant reductions in SSI total scores, with greater improvement in the buprenorphine group (mean change, -11.6, SD=5.8; N=23) than the placebo group (mean change, -6.3, SD=7; N=22) (Glass delta=0.76, 95% CI=0.11, 1.39). Mixed-effects modeling showed a significant time-by-treatment interaction (p<0.001). Depression scores did not differ significantly between groups. No serious treatment-related adverse events occurred. CONCLUSIONS:This randomized controlled trial provides the first evidence that a pharmacological intervention, buprenorphine, significantly sustains and enhances the antisuicidal effects of ketamine in MDD. These findings offer a potentially scalable and safe therapeutic option for a population at risk of suicide.

Importance:Ketamine has well-known dissociative, analgesic, and antidepressant properties, but it is unknown whether the neurophysiologic effects that are associated with these properties can be modulated separately from one another. Considering that specific cortical oscillations have been associated with specific therapeutic effects, modulating selective aspects of ketamine neurophysiology could inform efforts to develop more targeted therapies. Objective:To determine whether the neurophysiologic signatures of ketamine are associated with removal of conscious awareness using general anesthesia (GA). Design, Setting, and Participants:This cohort study was a secondary analysis of participant-level data from 3 prospective studies conducted between 2017 and 2023. The primary analysis included data from 2 study cohorts (University of Michigan and Stanford University), and the supplementary analysis included data from a third cohort (University of Auckland). The study cohorts included healthy volunteers, patients undergoing elective surgery, and patients with a diagnosis of depression (all aged ≥18 years). Exposure:Participants received a subanesthetic infusion of ketamine (0.5 mg/kg body weight) over 40 minutes or placebo with or without GA. Main Outcomes and Measures:The primary outcome was change in electroencephalographic (EEG) band power during medication infusion. Changes were computed using nonparametric paired statistical text (Wilcoxon signed-rank test). Results:This study included 52 participants in the primary analysis (mean [SD] age, 43.4 [18.3] years; 34 females [65.4%]) and 27 additional participants in the supplementary analysis (mean [SD] age, 30.2 [8.2] years; 15 females [55.6%]). GA differentially altered EEG features commonly associated with ketamine in all 52 participants (100%) in the primary analysis. Compared with awake administration, ketamine administered during GA preserved its βγ power modulation (mean [SEM] increase from 6.3 [11.3] to 11.6 [2.2] dB for awake administration; increase from 8.5 [2.9] to 11.2 [3.8] dB for administration during GA) but lacked its characteristic θ augmentation (increase from 17.3 [10.5] to 22.9 [3.1] dB during awake administration; nonsignificant decrease from 29.0 [3.0] to 27.8 [3.5] dB for administration during GA). Conclusions and Relevance:In this cohort study, coadministration of ketamine with GA selectively modulated the θ but not the βγ neurophysiologic correlates of ketamine. These findings suggest a potential method to explore the role of these components in the behavioral effects of ketamine.

Stanford neuromodulation therapy (SNT) is a rapid-acting, high-dose, intermittent theta-burst stimulation protocol. Although it has previously demonstrated efficacy for treatment-resistant depression (TRD) in a randomized controlled trial (RCT), replication in a larger sample is needed. Additionally, the electrophysiological effects of SNT remain unknown. Here we report results from a new double-blind, sham-controlled RCT along with electroencephalography (EEG) findings from the initial and current trials. In the current RCT, 53 participants with TRD were enrolled, and 48 who continued to meet entry criteria were randomized to receive active (N=24) or sham (N=24) SNT. At 1-month, remission (primary outcome) was achieved in 50.0% of active vs. 20.8% of sham participants (χ2 1,48=4.5, p=0.035), and response (secondary outcome) similarly favored active treatment (54.2% vs. 25.0%; χ2 1,48=4.3, p=0.039). Beta band EEG findings converged across trials: frontal beta power decreased significantly following active but not sham SNT in both the initial pilot study and the current trial. Additionally, beta baseline activity and post-SNT changes related to treatment efficacy in the current study. Specifically, greater post-SNT reduction in left anterior cingulate cortex (L-ACC) beta power correlated with greater clinical improvement immediately (rho=0.48, p=0.019) and 1-month after (rho=0.51, p=0.012) active SNT. Moreover, higher pre-treatment L-ACC beta power predicted greater subsequent clinical benefit from active SNT (immediate-post: β=-10.26, p=0.0042; 1-month after: β=-9.00, p=0.024). Neither of these L-ACC beta power findings was observed with sham stimulation. In sum, this study replicates SNT's therapeutic efficacy, identifies left frontal beta suppression as a potential mechanism of action, and highlights baseline L-ACC beta power as a candidate scalable pre-treatment biomarker of efficacy.

Cognitive impairments contribute significantly to psychosocial dysfunction in major depressive disorder (MDD), yet mechanistically selective treatments targeted to these impairments are lacking. We evaluated guanfacine immediate release (GIR), an alpha 2A receptor agonist, as a novel treatment for selectively improving cognitive control circuit function and behavioral performance in a subtype of depression, the cognitive biotype. Seventeen MDD participants of this biotype completed 6-8 weeks of GIR treatment (target dose: 2mg/night), meeting our per protocol criteria. GIR significantly increased activation and connectivity within the cognitive control circuit. The clinical response rate was 76.5% (defined by ≥ 50% improvement on the 17-item Hamilton Rating Scale for Depression (HRSD-17), exceeding conventional antidepressant rates, and 64.7% achieved remission (HRSD-17 score of ≤ 7). GIR significantly improved cognitive control performance, quality of life, and global life satisfaction. This study is the first to demonstrate both efficacy and target engagement of GIR as a mechanistically selective treatment specifically for the cognitive biotype of depression.

Schizophrenia (SZ) and bipolar disorder (BP) patients share overlapping neurocognitive deficits of varied magnitude. Neuroimaging in patients and postmortem gene expression analyses suggest that compromised cingulate gyrus GABA-ergic interneurons may contribute to cognitive impairments in SZ and BP. To address this, we used radioactive in situ hybridization to investigate potential gene expression signatures for SZ and BP using interneuron cell-type specific markers including glutamic acid decarboxylase (GAD67), parvalbumin (PV), somatostatin (SST), and vasoactive intestinal peptide (VIP) within specific Brodmann's areas (BA) of the cingulate gyrus. We report reduced GAD67 mRNA in anterior midcingulate cortex (aMCC) of BP subjects within BA24c', the most dysregulated subregion across disorders that also demonstrated reduced PV and VIP mRNA in the SZ group. In the retrosplenial (RSC) and ectosplenial (ESC) cortices, decreases in PV expression were shared by both SZ and BP subjects. Our results show unique and shared transcription signatures of two disorders in specific cingulate gyrus regions and cell types. SZ and BP displayed divergent aMCC gene expression reductions suggesting transcriptional changes are associated with disease-specific gene/subregion signatures, potentially underlying differential subregional dysregulation within areas associated with error detection/action monitoring and the salience network. In RSC/ESC, transcriptional changes are associated with more common expression patterns, possibly related to overlapping effects on visuospatial memory processing and allocation of attentional resources involving the default mode network.

Certain medications carry a risk by providing therapeutic benefits at the expense of misuse potential. Ketamine is increasingly being used for the treatment of depression, and studies indicate that it may also have utility for substance use disorder (SUD) treatment. However, it has recreational appeal and known misuse potential. Driven by the ongoing expansion of its use in clinical settings, concerns for misuse of ketamine are escalating. In this review, we summarize neurochemical, molecular, and brain circuit mechanisms associated with ketamine reinforcement and misuse potential and discuss their relevance toward its potential for SUD treatment. We focus on ketamine's direct actions on opioid and glutamatergic systems, highlighting recent discoveries on its interactions with mu opioid receptors (MORs) and NMDA receptors (NMDARs) in addiction-relevant brain circuits. We propose that ketamine's reinforcing properties and misuse potential stem from its bifunctional engagement with these receptors, with its (S)-ketamine enantiomer, compared with (R)-ketamine, being ketamine's primary risk driver. We contextualize this bifunctional NMDAR/MOR mechanism within ketamine's known efficacy for treatment of depression and other mental health conditions, including its potential for SUD treatment. We conclude that the brain mechanisms contributing to ketamine reinforcement, its recreational appeal, and its misuse potential are intertwined with its antidepressant properties and potential for SUD treatment.

Background The endogenous opioid system is thought to play a role in the placebo antidepressant response. A recent trial comparing the rapid antidepressant effects of ketamine versus placebo in surgical patients, some of whom were on chronic opioid therapy, revealed a substantial placebo effect. This finding provided an opportunity to test the hypothesis that opioid agonist exposure interacts with placebo antidepressant responses. Methods This post hoc analysis utilized data from a previously reported randomized, anesthesia-blinded, placebo-controlled trial of intravenous ketamine in depressed patients undergoing routine surgery. Mixed-effects models were used to determine whether baseline opioid use influenced antidepressant responses to the trial interventions, as measured by the Montgomery-Åsberg Depression Rating Scale (MADRS) over 1 to 14 days post-treatment. Results The analysis showed that baseline opioid use significantly reduced post-treatment depression severity in patients who received placebo, but not in those who received ketamine. This reduction was independent of baseline depression severity, baseline pain intensity, and ethnicity. Additionally, there was negligible correlation between postoperative pain intensity and depression severity. Limitations This post hoc analysis was conducted on a small sample, and the findings need to be confirmed by prospective controlled studies. Conclusions Opioid use at baseline attenuated the placebo antidepressant response independently of pain in depressed patients who received the study treatment under general anesthesia for routine surgery. The antidepressant response was preserved in opioid users who received intravenous ketamine.

Cognitive impairments are a major contributor to psychosocial dysfunction in major depressive disorder, yet mechanistically selective treatments targeting these impairments are lacking. Here, in line with a precision medicine approach, we evaluated guanfacine immediate release (GIR), an α2A receptor agonist, as a novel treatment aimed at enhancing cognitive control circuit function and behavioral performance in a neurobiologically defined subtype of depression, the cognitive biotype NCT04181736 . This biotype was prospectively identified based on impairments in both cognitive control circuitry and associated behavioral performance. Seventeen participants with major depressive disorder meeting these prospective criteria completed 6−8 weeks of GIR treatment (target dose of 2 mg per night), consistent with our preregistered per-protocol analysis plan. GIR significantly increased activation and connectivity within the cognitive control circuit. The clinical response (defined as a ≥50

Ketamine and esketamine have been approved as an adjunctive therapy for treatment-resistant major depressive disorder with acute suicidal ideation and behavior in adults. The current paper aimed to systematically review the available data on their efficacy in children and adolescents. The MEDLINE was searched with the keyword ‘esketamine’ on July 5th, 2024 (by following the PRISMA statement). The review has been registered in PROSPERO for ketamine and esketamine separately (CRD42024552011 and CRD42024516053). Out of 5131 articles originally identified, 29 were included for analysis and discussion. There is only one double-blind RCT with ketamine and another one with esketamine. The ketamine trial tested the effects at 24 h of a single dose with a crossover design and reported that the therapeutic effect lasted for at least two weeks. No effect on suicidality was reported. The esketamine trial reported that mood and suicidality improved after the three infusions were completed. The improvement in depressive symptoms persisted until the end of the study, but the improvement in suicidality did not. ketamine attenuated the negativity bias and reduced depressive cognitive style. Esketamine did not harm cognition, but instead, it improved processing speed. The current systematic review found only positive reports in the literature, but the scarcity of data suggests there is no definitively convincing evidence concerning the usefulness of ketamine and esketamine in the treatment of paediatric resistant depression. More research is needed, both in light of the problematic data in adults as well as in the light of the problems this kind of substance could cause in brain development and maturation.

Suicide has emerged as a public health emergency, but selective treatments remain scarce and unacceptable to those high in need. Perceived stigma represents a central barrier to treatment and thus prevention, but has yet to be evaluated in association with sleep, anti-suicidal treatment response, and other resiliency outcomes. Comprehensive screening (n=310 participants screened, n=59 completed a full-battery eligibility assessment) for current suicide risk (CSSRS>1), DSM-V-defined MDD, and clinically-significant insomnia (ISI>10, PSQI>5) supported inclusion in an open-label suicide prevention clinical trial (iSleep: Insomnia Treatment for Improved Well-Being). A multi-component, non-pharmacological (5-week) treatment (integrating CBTi, IRT, and SRT interventions) was manualized according to session-by-session powerpoints, handouts, and therapist guide sheets. Measures: The Columbia Suicide Severity Rating Scale (CSSRS), Beck Scale for Suicide (BSS), Quick Inventory of Depressive Symptomatology (QIDS-SR), Insomnia Severity Index (ISI), Pittsburgh Sleep Quality Index (PSQI), Disturbing Dream and Nightmare Severity Index (DDNSI), Perceived Stigma Scale (PSS), and Rudd Hope Scale (RHS). Assessments occurred at Baseline, Treatment, and Posttreatment (2 weeks, 1,3 mos). Data and safety monitoring procedures supported risk assessment, triage, and outpatient safety planning. Thirty-five participants (aged 20-70; M=41 years) were allocated treatment. Perceived Stigma: Significant mean differences were observed in PSS scores at pretreatment among participants, indicating lower perceived stigma ratings toward sleep treatment (PSS-SLP) relative to mental health treatment (PSS-MH) [M=10.0, SD=4.4; M=13.3, SD=6.35, respectively]: t(34)=3.94, p<.001; CI=1.60-5.02. Hope Measures: Paired t-tests revealed significant improvements in RHS scores from pre- to posttreatment phases [M=13.23, SD=4.03; M=16.03, SD=4.4, respectively]: t(30)=-3.03, p<.01; CI=-4.69—0.91. This paralleled large, posttreatment reductions (87%) in suicidal ideation, alongside depression, insomnia, sleep-quality, and nightmare improvements (p<.001). Lower perceived stigma was associated with sleep treatment compared to psychological treatment, further supporting the utility of sleep as a modifiable, non-stigmatizing therapeutic target for suicidal behaviors. In addition, use of a rapid-action insomnia intervention (iSleep Treatment) resulted in significant posttreatment improvements in hope and overall well-being. This is the first known report testing perceived stigma in the context of a suicide prevention clinical trial, while demonstrating therapeutic impact to hope and resiliency measures underlying anti-suicidal response. This work was supported by NIH funding (K23MH093490; Bernert).

Background: Psychotic major depression (PMD) differs from non-psychotic MD (NPMD) in psychopathology and is linked to changes in brain volumetry and hypothalamic-pituitary-adrenal (HPA) axis function that can be reflected by its principal output - the glucocorticoid cortisol. NPMD patients exhibit smaller hippocampi than healthy controls (HC), purportedly representing exposure to chronic stress. However, the relationship between the individual clinical phenotype, hippocampal volume and diurnal cortisol signaling remains unclear. Methods: Since understanding the interplay among symptoms, neuroimaging and HPA function is crucial for discerning biological differences between PMD and NPMD, this study explored the link between clinical phenotype, hippocampal structural MRI and circadian plasma cortisol levels in 32 HC, 27 NPMD and 26 PMD patients. Results: PMD patients showed significantly elevated evening (6 p.m. - 1 a.m.) cortisol levels compared to NPMD and HC, while NPMD and HC did not differ. No group differences in hippocampal volume were observed, but a significant interaction effect emerged between overnight (1 a.m. - 9 a.m.) cortisol levels, hippocampal volume, and clinical phenotype. NPMD patients displayed a negative correlation between overnight cortisol levels and hippocampal volume, which was specific to the ascending cortisol curve (2 a.m. - 5 a.m.) and absent in PMD and HC. The hippocampus-cortisol interaction was associated with depressive symptom severity in NPMD but not PMD, where cortisol alone predicted greater severity. Conclusions: These findings imply a time-dependent relationship between hippocampal volume and overnight cortisol in NPMD, which is absent in PMD and HC. In contrast, PMD patients exhibited increased evening cortisol levels. In an exploratory analysis, these effects were also related to symptom severity at similar timepoints. While correlational, these results point to distinct neurobiological mechanisms underlying NPMD and PMD, which are potentially related to the heterogeneous clinical manifestations.

Background The subgenual cingulate cortex (SGC) has been identified as a key structure within multiple neural circuits whose dysfunction is implicated in the neurobiology of depression. Deep brain stimulation in the SGC is thought to reduce and normalize local metabolism, causing normalization of circuit behavior and an improvement in depressive symptoms. We hypothesized that nonablative stereotactic radiosurgery (SRS) to the SGC would reduce local metabolism and reduce the severity of depression in patients with treatment-resistant bipolar depression. Methods Under the FDA's Humanitarian Device Exemption program, patients were screened for inclusion and exclusion criteria. Three volunteers meeting the criteria provided informed consent. Bilateral SGC targets were irradiated to a maximum dose of 75 Gy in one fraction. Subjects were followed for one year following the procedure with mood assessments (Hamilton Depression Rating Scale (HDRS), Clinical Global Impression-Improvement, Clinical Global Impression-Severity, and Young Mania Rating Scale), neurocognitive testing (Delis-Kaplan Executive Function System, Wechsler Adult Intelligence Scale III digit span, and California Verbal Learning Test II), and imaging. Further imaging was completed approximately two years after the procedure. Clinical improvement was defined as a ≥50% reduction in HDRS. Results Two of the three subjects showed clinical improvement in depressive symptoms during the follow-up period, while one subject showed no change in symptom severity. One of three subjects was hospitalized for the emergence of an episode of psychotic mania after discontinuing antipsychotic medications against medical advice but promptly recovered with the reinstitution of an antipsychotic. Sequential assessments did not reveal impairment in any cognitive domain assessed. For one of the three subjects, MRI imaging showed evidence of edema at 12 months post-SRS, which resolved at 22 months post-procedure. In a second of three patients, there was evidence of local edema at the target site at long-term follow-up. All imaging changes were asymptomatic. Conclusion Radiosurgical targeting of the SGC may be a noninvasive strategy for the reduction of severe depression in treatment-resistant bipolar disorder. Two out of three patients showed clinical improvement. While these results are promising, further study, including improvements in target selection and dosing considerations, is needed.

Objective: Major depressive disorder (MDD) is a common psychiatric disorder for which pharmacologic standard-of-care treatments have limited efficacy, particularly among individuals with cognitive dysfunction. Cognitive dysfunction is observed in approximately 25%-50% of those with MDD, wherein response to standard-of-care medications is reduced. Vortioxetine is an approved antidepressant that has shown evidence of procognitive effects in patients. It is not known if it has greater clinical efficacy in MDD patients with cognitive dysfunction, a more difficult to treat population, than other antidepressants. Methods: This study was a reanalysis of 1,812 subjects with MDD across 4 placebo- controlled trials. Baseline cognition was measured bythe Digit Symbol Substitution Test (DSST), the primary measure used to demonstrate vortioxetine's procognitive effects in clinical studies. Analyses examined whether baseline cognitive function was associated with differences in treatment outcomes. Results: Baseline DSST did not predict placebo-adjusted treatment effects of vortioxetine on depressive symptoms (pooled Cohen d=-0.02, 95% CI =-0.12 to 0.07). Analyses of additional cognitive measures similarly did not predict placebo-adjusted treatment effects on depression (all 95% CI contained zero). Finally, analyses of trials with selective serotonin reuptake inhibitors (SSRIs)/serotonin and norepinephrine reuptake inhibitors (SNRIs) as active comparators also revealed no prediction of SSRI/SNRIadjusted treatment effects of vortioxetine on depression. Conclusions: These findings, taken together, suggest that cognitive function does not moderate depression outcomes in vortioxetine, with results comparable to other antidepressants. J Clin Psychiatry 2024;85(4):24m15295