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

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

Blood-based biomarkers of antidepressant response to ketamine and esketamine: A systematic review and meta-analysis.

(R,S)-ketamine (ketamine) and its enantiomer (S)-ketamine (esketamine) can produce rapid and substantial antidepressant effects. However, individual response to ketamine/esketamine is variable, and there are no well-accepted methods to differentiate persons who are more likely to benefit. Numerous potential peripheral biomarkers have been reported, but their current utility is unclear. We conducted a systematic review/meta-analysis examining the association between baseline levels and longitudinal changes in blood-based biomarkers, and response to ketamine/esketamine. Of the 5611 citations identified, 56 manuscripts were included (N = 2801 participants), and 26 were compatible with meta-analytical calculations. Random-effect models were used, and effect sizes were reported as standardized mean differences (SMD). Our assessments revealed that more than 460 individual biomarkers were examined. Frequently studied groups included neurotrophic factors (n = 15), levels of ketamine and ketamine metabolites (n = 13), and inflammatory markers (n = 12). There were no consistent associations between baseline levels of blood-based biomarkers, and response to ketamine. However, in a longitudinal analysis, ketamine responders had statistically significant increases in brain-derived neurotrophic factor (BDNF) when compared to pre-treatment levels (SMD [95% CI] = 0.26 [0.03, 0.48], p = 0.02), whereas non-responders showed no significant changes in BDNF levels (SMD [95% CI] = 0.05 [-0.19, 0.28], p = 0.70). There was no consistent evidence to support any additional longitudinal biomarkers. Findings were inconclusive for esketamine due to the small number of studies (n = 2). Despite a diverse and substantial literature, there is limited evidence that blood-based biomarkers are associated with response to ketamine, and no current evidence of clinical utility.

International pooled patient-level meta-analysis of ketamine infusion for depression: In search of clinical moderators.

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; ß*(95% CI) = 0.58 (0.44, 0.72); p < 0.0001] and post-acute [~7 days; ß*(95% CI) = 0.38 (0.23, 0.54); p < 0.0001] depression severity were observed. Two study-level moderators emerged as significant: ketamine effects (relative to placebo) were larger in studies that required a higher degree of previous treatment resistance to federal regulatory agency-approved antidepressant medications (≥2 failed trials) for study entry; and in studies that used a crossover design. A comprehensive data-driven search for combined moderators identified statistically significant, but modest and clinically uninformative, effects (effect size 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.

A Participant-Level Integrative Data Analysis of Differential Placebo Response for Suicidal Ideation and Nonsuicidal Depressive Symptoms in Clinical Trials of Intravenous Racemic Ketamine.

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.

The rapid anti-suicidal ideation effect of ketamine: A systematic review.

In many countries suicide rates have been trending upwards for close to twenty years-presenting a public health crisis. Most suicide attempts and deaths are associated with psychiatric illness, usually a depressive disorder. Subanesthetic ketamine is the only FDA-approved antidepressant that works in hours not weeks-thus potentially transforming treatment of suicidal patients. We reviewed all randomized controlled trials of the effect of ketamine on suicidal ideation to determine if ketamine rapidly reduces suicidal ideation [SI] in depressed patients and how long the benefit persists after one dose and if the route of administration or dose affects the outcome. A systematic review was conducted as per PRISMA [preferred reporting items for systematic reviews and meta-analyses] criteria. PubMed search inclusive of "ketamine" and "suicide" yielded 358 results. Papers (N = 354) were then read by at least two authors, identifying 12 meeting eligibility requirements and eleven RCTs examining whether ketamine treatment ameliorated SI. Four of five RCTs examined racemic ketamine (0.5 mg/kg) given intravenously and found an advantage for ketamine over control for rapid reduction in SI in acutely depressed patients. Two studies examined intranasal esketamine in depressed suicidal patients and found no advantage over saline. One study examined outcome six weeks after a single intravenous dose of ketamine and found benefit for SI sustained relative to 24 h post-dose. Further research is warranted into: optimal dosing strategy, including number and frequency; and long-term efficacy and safety. Ultimately, it remains to be shown that ketamine's benefit for SI translates into prevention of suicidal behavior.

Ketamine for suicidal ideation in adults with psychiatric disorders: A systematic review and meta-analysis of treatment trials.

OBJECTIVE: Ketamine may reduce suicidal ideation in treatment-resistant depression. But it is not known how quickly this occurs and how long it persists. We undertook a systematic review and meta-analysis to determine the short- and long-term effectiveness of ketamine for suicidality. METHOD: CENTRAL, EMBASE, Medline, and PsycINFO were searched until 12 December 2018. Randomised controlled trials of ketamine or esketamine reporting data on suicidal ideation, self-harm, attempted or completed suicide in adults diagnosed with any psychiatric disorder were included. Two reviewers independently extracted data, and certainty of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation tool. Standardised mean difference was used for continuous outcomes. RESULTS: Twenty-five reports from 15 independent trials, with a total of 572 participants diagnosed with predominately affective disorders, were included. The evidence was rated moderate to low. In most trials, ketamine was administered at 0.5 mg/kg via a single intravenous infusion over a 30- to 45-minute period. Only a single trial of intranasal esketamine was identified. At 4 hours post-infusion, treatment with ketamine was associated with a significant reduction in suicidal ideation scores (standardised mean difference = -0.51, 95% confidence interval = [-1.00, -0.03]), which persisted until 72 hours post-infusion (time points between 12 and 24 hours: standardised mean difference = -0.63, 95% confidence interval = [-0.99, -0.26]; between 24 and 72 hours: standardised mean difference = -0.57, 95% confidence interval = [-0.99, -0.14]), but not thereafter. However, there was marked heterogeneity of results. In a single trial of esketamine, marginal effects on suicidal ideation were observed. In terms of actual suicidal behaviour, there were virtually no data on effects of ketamine or esketamine. CONCLUSION: A single infusion of ketamine may have a short-term (up to 72 hours) beneficial impact on suicidal thoughts. While confirmation of these results in further trials is needed, they suggest possible use of ketamine to treat acute suicidality. Means of sustaining any anti-suicidal effect need to be found.

Revising Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, criteria for the bipolar disorders: Phase I of the AREDOC project.

OBJECTIVE: To derive new criteria sets for defining manic and hypomanic episodes (and thus for defining the bipolar I and II disorders), an international Task Force was assembled and termed AREDOC reflecting its role of Assessment, Revision and Evaluation of DSM and other Operational Criteria. This paper reports on the first phase of its deliberations and interim criteria recommendations. METHOD: The first stage of the process consisted of reviewing Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, and recent International Classification of Diseases criteria, identifying their limitations and generating modified criteria sets for further in-depth consideration. Task Force members responded to recommendations for modifying criteria and from these the most problematic issues were identified. RESULTS: Principal issues focussed on by Task Force members were how best to differentiate mania and hypomania, how to judge 'impairment' (both in and of itself and allowing that functioning may sometimes improve during hypomanic episodes) and concern that rejecting some criteria (e.g. an imposed duration period) might risk false-positive diagnoses of the bipolar disorders. CONCLUSION: This first-stage report summarises the clinical opinions of international experts in the diagnosis and management of the bipolar disorders, allowing readers to contemplate diagnostic parameters that may influence their clinical decisions. The findings meaningfully inform subsequent Task Force stages (involving a further commentary stage followed by an empirical study) that are expected to generate improved symptom criteria for diagnosing the bipolar I and II disorders with greater precision and to clarify whether they differ dimensionally or categorically.

Ketamine versus midazolam in bipolar depression with suicidal thoughts: A pilot midazolam-controlled randomized clinical trial.

OBJECTIVES: To evaluate feasibility and effects of a sub-anesthetic infusion dose of ketamine versus midazolam on suicidal ideation in bipolar depression. Neurocognitive, blood and saliva biomarkers were explored. METHODS: Sixteen participants with bipolar depression and a Scale for Suicidal Ideation (SSI) score of ≥4 were randomized to ketamine (0.5 mg/kg) or midazolam (0.02 mg/kg). Current pharmacotherapy was maintained excluding benzodiazepines within 24 hours. The primary clinical outcome was SSI score on day 1 post-infusion. RESULTS: Results supported feasibility. Mean reduction of SSI after ketamine infusion was almost 6 points greater than after midazolam, although this was not statistically significant (estimate=5.84, SE=3.01, t=1.94, P=.074, 95% confidence interval ([CI)]=-0.65 to 12.31). The number needed to treat for response (SSI <4 and at least 50% below baseline) was 2.2, and for remission (SSI=0) was 3.2. The strongest neurocognitive correlation was between memory improvement on the Selective Reminding Test (SRT) and reduction in SSI score on day 1 after ketamine (ρ=-.89, P=.007). Pre- to post-infusion decrease in serum brain derived neurotrophic factor (BDNF) correlated with reduction in SSI from baseline to day 1 after ketamine (n=5, ρ=0.90, P=.037) but not midazolam (P=.087). CONCLUSIONS: The study demonstrated feasibility. Suicidal thoughts were lower after ketamine than after midazolam at a trend level of significance, likely due to the small pilot sample. Memory improvement and BDNF are promising biomarkers. Replication is needed in an adequately powered full-scale trial.

Religion as a Risk Factor for Suicide Attempt and Suicide Ideation Among Depressed Patients.

We aimed to examine the relationship between religion and suicide attempt and ideation. Three hundred twenty-one depressed patients were recruited from mood-disorder research studies at the New York State Psychiatric Institute. Participants were interviewed using the Structured Clinical Interview for DSM Disorders, Columbia University Suicide History form, Scale for Suicide Ideation, and Reasons for Living Inventory. Participants were asked about their religious affiliation, importance of religion, and religious service attendance. We found that past suicide attempts were more common among depressed patients with a religious affiliation (odds ratio, 2.25; p = 0.007). Suicide ideation was greater among depressed patients who considered religion more important (coefficient, 1.18; p = 0.026) and those who attended services more frequently (coefficient, 1.99; p = 0.001). We conclude that the relationship between religion and suicide risk factors is complex and can vary among different patient populations. Physicians should seek deeper understanding of the role of religion in an individual patient's life in order to understand the person's suicide risk factors more fully.

Intramuscular ketamine vs. midazolam for rapid risk-reduction in suicidal, depressed emergency patients: Clinical trial design and rationale.

Emergency department (ED) visits for suicidal ideation or behavior have been increasing in all age groups, particularly younger adults. A rapid-acting treatment to reduce suicidal thinking, adapted for ED use, is needed. Previous studies have shown a single dose of ketamine can improve depression and suicidal ideation within hours. However, most studies used 40 min intravenous infusions which can be impractical in a psychiatric ED. The ER-Ketamine study we describe here is a randomized midazolam-controlled clinical trial (RCT; NCT04640636) testing intramuscular (IM) ketamine's feasibility, safety, and effectiveness to rapidly reduce suicidal ideation and depression in a psychiatric ED. A pre-injection phase involves screening, informed consent, eligibility confirmation, and baseline assessment of suicidal ideation, depression, and comorbidities. The randomized double-blind IM injection is administered in the ED under research staff supervision, vital sign monitoring, pharmacokinetic blood sampling, and clinical assessments. The post-injection phase occurs on a psychiatric inpatient unit with follow-up research assessments through four weeks post-discharge. Outcome measures are feasibility, safety, and effects on suicidal ideation and depression at 24 h post-injection, and through follow-up. The target sample is N = 90 adults in a major depressive episode, assessed by ED clinicians as warranting hospitalization for suicide risk. Here we report design, rationale, and preliminary feasibility and safety for this ongoing study. Demographics of the 53 participants (ages 18 to 65 years) randomized to date suggest a diverse sample tending towards younger adults.

Racial and ethnic disparities in time to first antidepressant medication or psychotherapy.

Time from first DSM4 major depressive episode (MDE) until treatment in the community was compared across racial/ethnic groups. This secondary analysis used structured baseline data from a depression research clinic (N = 260). Chi-square and survival analyses compared rates and delays to antidepressant medication and psychotherapy. Non-Hispanic Black and Hispanic (any race) participants had lower rates of both antidepressant medication and psychotherapy and longer delays to antidepressant medication compared with non-Hispanic White participants. The results underscore the need to reduce these disparities.

Avoidant attachment transmission to offspring in families with a depressed parent.

BACKGROUND: Insecure attachment is associated with mental health morbidity. We explored associations between parent and offspring attachment style in a longitudinal study of families with a depressed parent. METHODS: Parents (N = 169) with a DSM-IV mood disorder and their adult offspring (N = 267), completed the Adult Attachment Questionnaire at one or more time points during up to 9.7 years of follow-up. Linear mixed effects models explored associations between parent and offspring anxious and avoidant attachment scores. Residualized models accounted for parent and offspring depression severity. RESULTS: Avoidant attachment scores were associated between parents and offspring with (p = .034) and without (p = .012) adjustment for baseline age and sex of parent and offspring. Depressed father-offspring relationships showed more avoidant attachment in offspring compared to depressed mother-offspring pairs (p = .010). After accounting for depression severity, parent average residualized avoidant attachment scores did not significantly correlate with those of offspring (unadjusted p = .052; adjusted p = .085), though the effect sizes did not change substantially, and 75 % of the correlation was retained. Parent-son relationships exhibited stronger avoidant attachment correlations compared to parent-daughter pairs (p = .048). LIMITATIONS: Small sub-sample of fathers, parent and offspring assessments not always completed at the same time, and use of a self-report attachment style instrument. CONCLUSIONS: Familial transmission of insecure avoidant attachment, a risk factor for negative mental health outcomes, merits research as a potential treatment target. In this preliminary study, its transmission to offspring seemed mostly independent of depression. Depressed fathers and their sons may deserve focus to reduce insecure avoidant attachment and improve clinical course.

Decreased suicidal ideation in depressed patients with or without comorbid posttraumatic stress disorder treated with selective serotonin reuptake inhibitors: an open study.

Comorbidity of posttraumatic stress disorder (PTSD) and major depressive disorder (MDD) is associated with higher morbidity including suicidal ideation and behavior. Selective serotonin reuptake inhibitors (SSRIs) are a known treatment for PTSD, MDD and comorbid PTSD and MDD. Since the patients with comorbid MDD and PTSD (PTSD-MDD) are sicker, we hypothesize a poorer response to treatment compared to patients with MDD only. Ninety-six MDD patients were included in the study: 76 with MDD only and 20 with PTSD-MDD. Demographic and clinical parameters at baseline were assessed. We examined clinical parameters before and after 3 months of open SSRI treatment in subjects with PTSD-MDD and compared this group to individuals with MDD only. At baseline, PTSD-MDD patients had higher Hamilton Depression Rating Scale and Buss-Durkee Hostility Scale scores compared with MDD only subjects. There was a significant decrease in scores on the Hamilton Depression Rating Scale, Beck Depression Inventory, Beck Hopelessness Scale, and Beck Scale for Suicidal Ideation after 3 months of treatment with SSRIs in both groups. The magnitude of improvement in Beck Scale for Suicidal Ideation scores was greater in the PTSD-MDD group compared to the MDD only subjects. Symptoms of depression including suicidal ideation improved in MDD patients with or without comorbid PTSD after 3 months of treatment with SSRIs but improvement in suicidal ideation was greater in the PTSD-MDD group. Our finding has not supported the hypothesis that a response to treatment is poorer in the PTSD-MDD group which may indicate that sicker patients benefit more from the treatment.

Ketamine vs midazolam: Mood improvement reduces suicidal ideation in depression.

OBJECTIVE: Studies demonstrate rapid antidepressant and anti-suicidal ideation effects of subanesthetic ketamine. The specific subcomponents of depression that are most closely tied to reduction of suicidal ideation with ketamine treatment are less explored. METHODS: Exploratory, post hoc analysis of data from a randomized clinical trial of ketamine vs midazolam in patients with major depressive disorder (MDD) and clinically significant suicidal ideation examined changes in factor analysis-derived symptom clusters from standard measures of depression (Hamilton Depression Rating Scale, HDRS; Beck Depression Inventory, BDI) and mood disturbance (Profile of Mood States, POMS), and their relationship to severity of suicidal ideation (Beck Scale for Suicidal Ideation; SSI). Ratings obtained before and one day after blinded intravenous infusion were decomposed into component factors or published subscales. Treatment effects on factors/subscales were compared between drugs, correlations with changes in suicidal ideation were tested, and stepwise regression was used to derive predictors of change in SSI. RESULTS: Factor scores for HDRS Psychic Depression, HDRS Anxiety, BDI Subjective Depression, POMS Depression and POMS Fatigue improved more with ketamine than midazolam. Stepwise regression showed across both drugs that improvement in HDRS Psychic Depression, POMS Depression, and HDRS Anxiety predicted 51.6% of the variance in reduction of suicidal ideation. LIMITATIONS: Secondary analysis of clinical trial data. CONCLUSIONS: Ketamine's rapid effects on suicidal ideation appear to be mostly a function of its effects on core mood and anxiety symptoms of MDD, with comparatively little contribution from neurovegetative symptoms with the potential exception of vigor/fatigue. TRIAL REGISTRATION: Data used in this secondary analysis came from ClinicalTrials.gov identifier: NCT01700829.

Plasma kynurenine levels are elevated in suicide attempters with major depressive disorder.

BACKGROUND: Inflammation has been linked to depression and suicide risk. One inflammatory process that has been minimally investigated in this regard is cytokine-stimulated production of kynurenine (KYN) from tryptophan (TRP). Recent data suggest that KYN increases in cerebrospinal fluid (CSF) are associated with depressive symptoms secondary to immune activation. KYN may alter dopaminergic and glutamatergic tone, thereby contributing to increased arousal, agitation and impulsivity - important risk factors in suicide. We hypothesized that patients with major depressive disorder (MDD) and a history of suicide attempt would have higher levels of KYN than depressed nonattempters, who in turn would have higher levels than healthy volunteers. METHODS: Plasma KYN, TRP, and neopterin were assayed by high performance liquid chromatography in three groups: healthy volunteers (n=31) and patients with MDD with (n=14) and without (n=16) history of suicide attempt. Analysis of variance tested for group differences in KYN levels. RESULTS: KYN levels differed across groups (F=4.03, df=(2,58), and p=0.023): a priori planned contrasts showed that KYN was higher in the MDD suicide attempter subgroup compared with MDD non-attempters (t=2.105, df=58, and p=0.040), who did not differ from healthy volunteers (t=0.418, df=58, and p=0.677). In post hoc testing, KYN but not TRP was associated with attempt status, and only suicide attempters exhibited a positive correlation of the cytokine activation marker neopterin with the KYN:TRP ratio, suggesting that KYN production may be influenced by inflammatory processes among suicide attempters. CONCLUSION: These preliminary results suggest that KYN and related molecular pathways may be implicated in the pathophysiology of suicidal behavior.

Computerized-Adaptive vs. Traditional Ratings of Depression and Suicidal Thoughts: An Assay Sensitivity Pilot Study in a Ketamine Clinical Trial.

There is a public health need for improved suicide risk assessment tools. This pilot methodology study compared the assay sensitivity of computerized adaptive tests (CAT) of depression and suicidal ideation vs. traditional ratings in a randomized trial subgroup. The last 20 persons to enroll in a published ketamine trial in suicidal depression were studied. This subgroup received traditional and CAT ratings at baseline, 24 h post-infusion and follow-up week 2, 4, and 6: Hamilton Depression Rating Scale, Beck Depression Inventory, and Beck Scale for Suicidal Ideation vs. the CAT-Depression Inventory and CAT-Suicide Scale. Results showed larger effect sizes (ES) for CAT compared with traditional clinician-rated and self-report scales. Coefficients of variation for baseline measurements were lower for CAT compared with traditional scales. This is the first study to show that CAT may have greater assay sensitivity for treatment effects, particularly for suicidal ideation, compared with traditional clinician-rated and non-adaptive self-rated scales in a randomized trial. The findings suggest CAT can enable quick long-term follow-up assessments via cellphone, tablet, or computer while minimizing response bias due to repeated measurement of the same symptom items. Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT01700829.

Relationship of Brain Glutamate Response to D-Cycloserine and Lurasidone to Antidepressant Response in Bipolar Depression: A Pilot Study.

N-methyl-D-aspartate glutamate-receptor (NMDAR) antagonists such as ketamine have demonstrated efficacy in both major depressive disorder (MDD) and bipolar disorder depression (BP-D). We have previously reported that reduction in Glx (glutamate + glutamine) in the ventromedial prefrontal cortex/anterior cingulate cortex (vmPFC/ACC), measured by proton magnetic resonance spectroscopy (1H MRS) at 3T during a ketamine infusion, mediates the relationship of ketamine dose and blood level to improvement in depression. In the present study, we assessed the impact of D-cycloserine (DCS), an oral NMDAR antagonist combined with lurasidone in BP-D on both glutamate and Glx. Subjects with DSM-V BP-D-I/II and a Montgomery-Asberg Depression Rating Scale (MADRS) score>17, underwent up to three 1H MRS scans. During Scan 1, subjects were randomized to receive double-blind lurasidone 66 mg or placebo. During Scan 2, all subjects received single-blind DCS 950 mg + lurasidone 66 mg, followed by 4 weeks of open label phase of DCS+lurasidone and an optional Scan 3. Five subjects received lurasidone alone and three subjects received placebo for Scan 1. Six subjects received DCS+lurasidone during Scan 2. There was no significant baseline or between treatment-group differences in acute depression improvement or glutamate response. In Scan 2, after a dose of DCS+lurasidone, peak change in glutamate correlated negatively with improvement from baseline MADRS (r = -0.83, p = 0.04). There were no unexpected adverse events. These preliminary pilot results require replication but provide further support for a link between antidepressant effect and a decrease in glutamate by the NMDAR antagonist class of antidepressants.