Ketamine has distinct electrophysiological and behavioral effects in depressed and healthy subjects.

Ketamine's mechanism of action was assessed using gamma power from magnetoencephalography (MEG) as a proxy measure for homeostatic balance in 35 unmedicated subjects with major depressive disorder (MDD) and 25 healthy controls enrolled in a double-blind, placebo-controlled, randomized cross-over trial of 0.5 mg/kg ketamine. MDD subjects showed significant improvements in depressive symptoms, and healthy control subjects exhibited modest but significant increases in depressive symptoms for up to 1 day after ketamine administration. Both groups showed increased resting gamma power following ketamine. In MDD subjects, gamma power was not associated with the magnitude of the antidepressant effect. However, baseline gamma power was found to moderate the relationship between post-ketamine gamma power and antidepressant response; specifically, higher post-ketamine gamma power was associated with better response in MDD subjects with lower baseline gamma, with an inverted relationship in MDD subjects with higher baseline gamma. This relationship was observed in multiple regions involved in networks hypothesized to be involved in the pathophysiology of MDD. This finding suggests biological subtypes based on the direction of homeostatic dysregulation and has important implications for inferring ketamine's mechanism of action from studies of healthy controls alone.

Lithium and Valproate Levels Do Not Correlate with Ketamine's Antidepressant Efficacy in Treatment-Resistant Bipolar Depression.

Ketamine and lithium both inhibit glycogen synthase kinase 3. In addition, lithium and ketamine have synergistic antidepressant-like effects at individually subeffective doses in rodents. We hypothesized that ketamine's antidepressant effects would be improved by therapeutic doses of lithium versus valproate and that serum lithium levels would positively correlate with ketamine's antidepressant efficacy. Thirty-six patients with treatment-resistant bipolar depression maintained on therapeutic-dose lithium (n = 23, 0.79 ± 0.15 mEq/L) or valproate (n = 13, 79.6 ± 12.4 mg/mL) received 0.5 mg/kg ketamine infusion in a randomized, double-blind, placebo-controlled, crossover trial. The primary depression outcome measure-the Montgomery-Åsberg Depression Rating Scale (MADRS)-was assessed before infusion and at numerous postinfusion time points. Both lithium (F 1,118 = 152.08, p < 0.001, and d = 2.27) and valproate (F 1,128 = 20.12, p < 0.001, and d = 0.79) significantly improved depressive symptoms, but no statistically significant difference was observed between mood stabilizer groups (F 1,28 = 2.51, p = 0.12, and d = 0.60). Serum lithium and valproate levels did not correlate with ketamine's antidepressant efficacy. Although the study was potentially underpowered, our results suggest that lithium may not potentiate ketamine's antidepressant efficacy in treatment-resistant bipolar depression.

Ketamine's antidepressant efficacy is extended for at least four weeks in subjects with a family history of an alcohol use disorder.

BACKGROUND: A single subanesthetic infusion of the N-methyl-D-aspartate (NMDA) receptor antagonist ketamine has rapid and potent antidepressant properties in treatment-resistant major depressive disorder (TRD). As a family history of an alcohol use disorder is a positive predictor of ketamine's antidepressant response and the strength of the association increases over time, we hypothesized that depressed subjects with a family history of an alcohol use disorder would have greater antidepressant durability and that riluzole would augment and/or extend ketamine's antidepressant efficacy. METHODS: Fifty-two TRD subjects received an open-label infusion of ketamine (0.5mg/kg over 40 minutes), and, four to six hours post-infusion, were randomized to either flexible-dose (100-200mg/day) riluzole or placebo in the following proportions: Family History Positive (FHP) riluzole (n = 10), FHP placebo (n = 9), Family History Negative (FHN) riluzole (n = 16), and FHN placebo (n = 17). RESULTS: FHP subjects randomized to placebo had a greater antidepressant response than FHN subjects; however, contrary to our initial hypothesis, there was no significant difference in antidepressant efficacy with riluzole. Although potentially underpowered, there was no difference in overall time-to-relapse based on randomization status (riluzole responders: n = 15, placebo responders: n = 17). Yet, time-to-relapse was longer in FHP placebo responders (n = 8) compared to FHN placebo responders (n = 9) with, again, no significant difference in time-to-relapse in FHP riluzole responders (n = 6) compared to FHN riluzole responders (n = 9). CONCLUSIONS: Ketamine's extended antidepressant durability in FHP TRD should be considered in the design and analysis of ketamine depression trials.

Neural correlates of rapid antidepressant response to ketamine in bipolar disorder.

OBJECTIVES: Ketamine, an N-methyl d-aspartate (NMDA) antagonist, has rapid antidepressant effects in depressed subjects with bipolar disorder (BD). Evidence supports a role for the glutamatergic system in the pathophysiology of BD. This double-blind, randomized, cross-over study sought to determine cerebral metabolic correlates of antidepressant response to ketamine. METHODS: Twenty-one subjects with BD currently in a depressed state underwent [(18) F]-fluorodeoxyglucose (FDG) positron emission tomography (PET) imaging after receiving a placebo infusion as well as after receiving a ketamine infusion. Metabolism was compared between ketamine and placebo infusions, and correlated with clinical response. Regional metabolic rate of glucose (rMRGlu) in regions of interest (ROIs) and Montgomery-Åsberg Depression Rating Scale (MADRS) scores were the main outcome measures. RESULTS: The study found that change in metabolism between sessions was significantly correlated with percentage change in MADRS scores in the right ventral striatum; subjects who showed the greatest improvement had the largest metabolic increase after ketamine infusion compared to placebo. In a voxel-wise analysis, subjects with BD had significantly lower glucose metabolism in the left hippocampus following the ketamine infusion than following the placebo infusion. In addition, metabolism in the subgenual anterior cingulate cortex (ACC) following the placebo infusion was positively correlated with percentage improvement in MADRS score following the ketamine infusion. CONCLUSIONS: Taken together, the results suggest that higher activity in the subgenual ACC may predict antidepressant response to ketamine. Ketamine administration altered glucose metabolism in areas known to be involved in mood disorders; these alterations may partially underlie ketamine's mechanism of action.

Concomitant BDNF and sleep slow wave changes indicate ketamine-induced plasticity in major depressive disorder.

The N-methyl-d-aspartate (NMDA) receptor antagonist ketamine has rapid antidepressant effects in treatment-resistant major depressive disorder (MDD). In rats, ketamine selectively increased electroencephalogram (EEG) slow wave activity (SWA) during non-rapid eye movement (REM) sleep and altered central brain-derived neurotrophic factor (BDNF) expression. Taken together, these findings suggest that higher SWA and BDNF levels may respectively represent electrophysiological and molecular correlates of mood improvement following ketamine treatment. This study investigated the acute effects of a single ketamine infusion on depressive symptoms, EEG SWA, individual slow wave parameters (surrogate markers of central synaptic plasticity) and plasma BDNF (a peripheral marker of plasticity) in 30 patients with treatment-resistant MDD. Montgomery-Åsberg Depression Rating Scale scores rapidly decreased following ketamine. Compared to baseline, BDNF levels and early sleep SWA (during the first non-REM episode) increased after ketamine. The occurrence of high amplitude waves increased during early sleep, accompanied by an increase in slow wave slope, consistent with increased synaptic strength. Changes in BDNF levels were proportional to changes in EEG parameters. Intriguingly, this link was present only in patients who responded to ketamine treatment, suggesting that enhanced synaptic plasticity - as reflected by increased SWA, individual slow wave parameters and plasma BDNF - is part of the physiological mechanism underlying the rapid antidepressant effects of NMDA antagonists. Further studies are required to confirm the link found here between behavioural and synaptic changes, as well as to test the reliability of these central and peripheral biomarkers of rapid antidepressant response.

A Randomized, placebo-controlled, crossover pilot trial of the oral selective NR2B antagonist MK-0657 in patients with treatment-resistant major depressive disorder.

Converging lines of evidence suggest that the glutamatergic system may play an increasingly important role in the development of novel therapeutics for major depressive disorder (MDD), particularly agents associated with rapid antidepressant effects. Diverse glutamatergic modulators targeting N-methyl-D-aspartate receptors have shown efficacy in MDD, but their associated psychotomimetic effects presently preclude their use in larger samples. This small, randomized, double-blind, placebo-controlled, crossover pilot study evaluated the potential antidepressant efficacy and tolerability of an oral formulation of the selective N-methyl-D-aspartate NR2B antagonist MK-0657 in patients with treatment-resistant MDD (TRD). The TRD subjects underwent a 1-week drug-free period and were subsequently randomized to receive either MK-0657 monotherapy (4-8 mg/d) or placebo for 12 days. Because of recruitment challenges and the discontinuation of the compound's development by the manufacturer, only 5 of the planned 21 patients completed both periods of the crossover administration of MK-0657 and placebo. Significant antidepressant effects were observed as early as day 5 in patients receiving MK-0657 compared with those receiving placebo, as assessed by the Hamilton Depression Rating Scale and Beck Depression Inventory; however, no improvement was noted when symptoms were assessed with the Montgomery-Asberg Depression Rating Scale, the primary efficacy measure. No serious or dissociative adverse effects were observed in patients receiving this oral formulation of MK-0657. Despite the small sample size, this pilot study suggests that an oral formulation of the NR2B antagonist MK-0657 may have antidepressant properties in TRD patients. Further studies with larger sample sizes are necessary to confirm these preliminary findings.

Family history of alcohol dependence and antidepressant response to an N-methyl-D-aspartate antagonist in bipolar depression.

OBJECTIVES: Both ketamine and ethanol are N-methyl-d-aspartate (NMDA) receptor antagonists. Ketamine has rapid antidepressant properties in major depressive disorder (MDD) as well as bipolar depression. In individuals with MDD, a positive family history of alcohol dependence (FHP) was associated with greater improvement in depressive symptoms after ketamine administration compared to individuals whose family history of alcohol dependence was negative (FHN). This study investigated whether FHP influences ketamine's antidepressant and perceptual effects in individuals with bipolar depression. METHODS: A post hoc analysis was conducted on 33 subjects with DSM-IV bipolar disorder (BD) type I or II depression pooled from two previously published studies. All subjects had undergone a double-blind, randomized, crossover trial of a single intravenous infusion of ketamine (0.5 mg/kg) combined with lithium or valproate therapy. Subjects were rated at baseline; at 40, 80, 120, and 230 min; and at days 1, 2, 3, 7, 10, and 14 post-infusion. The primary outcome measure was Montgomery-Åsberg Depression Rating Scale (MADRS) scores. Patients were categorized as FHP when they reported at least one first-degree relative with alcohol dependence. Measures of psychosis, dissociation, and dysphoria were also collected. RESULTS: After ketamine infusion, subjects with FHP showed significantly greater improvement on MADRS scores than FHN subjects. In addition, patients with FHP had attenuated psychotomimetic and dissociative scores compared to FHN patients. CONCLUSIONS: FHP appears to predict a more sustained antidepressant response to ketamine in individuals with BD. Family history of alcoholism may be an important consideration in the development of glutamatergic-based therapies for depression.

Simultaneous population pharmacokinetic modelling of ketamine and three major metabolites in patients with treatment-resistant bipolar depression.

AIM: To construct a population pharmacokinetic (popPK) model for ketamine (Ket), norketamine (norKet), dehydronorketamine (DHNK), hydroxynorketamine (2S,6S;2R,6R)-HNK) and hydroxyketamine (HK) in patients with treatment-resistant bipolar depression. METHOD: Plasma samples were collected at 40, 80, 110, 230 min on day 1, 2 and 3 in nine patients following a 40 min infusion of (R,S)-Ket (0.5 mg kg⁻¹) and analyzed for Ket, norKet and DHNK enantiomers and (2S,6S;2R,6R)-HNK, (2S,6S;2R,6R)-HK and (2S,6R;2R,6S)-HK. A compartmental popPK model was constructed that included all quantified analytes, and unknown parameters were estimated with an iterative two-stage algorithm in ADAPT5. RESULTS: Ket, norKet, DHNK and (2S,6S;2R,6R)-HNK were present during the first 230 min post infusion and significant concentrations (>5 ng ml⁻¹) were observed on day 1. Plasma concentrations of (2S,6S;2R,6R)-HK and (2S,6R;2R,6S)-HK were below the limit of quantification. The average (S) : (R) plasma concentrations for Ket and DHNK were <1.0 while no significant enantioselectivity was observed for norKet. There were large inter-patient variations in terminal half-lives and relative metabolite concentrations; at 230 min (R,S)-DHNK was the major metabolite in four out of nine patients, (R,S)-norKet in three out of nine patients and (2S,6S;2R,6R)-HNK in two out of nine patients. The final PK model included three compartments for (R,S)-Ket, two compartments for (R,S)-norKet and single compartments for DHNK and HNK. All PK profiles were well described, and parameters for (R,S)-Ket and (R,S)-norKet were in agreement with prior estimates. CONCLUSION: This represents the first PK analysis of (2S,6S;2R,6R)-HNK and (R,S)-DHNK. The results demonstrate that while norKet is the initial metabolite, it is not the main metabolite suggesting that future Ket studies should include the analysis of the major metabolites.

Default Mode Connectivity in Major Depressive Disorder Measured Up to 10 Days After Ketamine Administration.

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

Features of dissociation differentially predict antidepressant response to ketamine in treatment-resistant depression.

BACKGROUND: Ketamine induces rapid and robust antidepressant effects, and many patients also describe dissociation, which is associated with antidepressant response. This follow-up study investigated whether antidepressant efficacy is uniquely related to dissociative symptom clusters. METHODS: Treatment-resistant patients with major depressive disorder (MDD) or bipolar disorder (BD) (n = 126) drawn from three studies received a single subanesthetic (0.5 mg/kg) ketamine infusion. Dissociative effects were measured using the Clinician-Administered Dissociative States Scale (CADSS). Antidepressant response was measured using the 17-item Hamilton Depression Rating Scale (HAM-D). A confirmatory factor analysis established the validity of CADSS subscales (derealization, depersonalization, amnesia), and a general linear model with repeated measures was fitted to test whether subscale scores were associated with antidepressant response. RESULTS: Factor validity was supported, with a root mean square error of approximation of .06, a comparative fit index of .97, and a Tucker-Lewis index of .96. Across all studies and timepoints, the depersonalization subscale was positively related to HAM-D percent change. A significant effect of derealization on HAM-D percent change was observed at one timepoint (Day 7) in one study. The amnesia subscale was unrelated to HAM-D percent change. LIMITATIONS: Possible inadequate blinding; combined MDD/BD datasets might have underrepresented ketamine's antidepressant efficacy; the possibility of Type I errors in secondary analyses. CONCLUSIONS: From a psychometric perspective, researchers may elect to administer only the CADSS depersonalization subscale, given that it was most closely related to antidepressant response. From a neurobiological perspective, mechanistic similarities may exist between ketamine-induced depersonalization and antidepressant response, although off-target effects cannot be excluded.

Are 24-hour motor activity patterns associated with continued rapid response to ketamine?

PURPOSE: This study examined the links between 24-hour activity patterns (specifically, amplitude and timing of wrist activity) and the persisting qualities of clinical antidepressant response to the glutamatergic modulator ketamine. METHODS: Twenty-four-hour activity patterns were compared across 5 days of 24-hour activity rhythms in patients with major depressive disorder who displayed either a brief antidepressant response (24-48 hours), a continued antidepressant response (>72 hours), or no antidepressant response to ketamine. These postinfusion-response profiles were then used retrospectively to examine cohort-specific fitted parameters at baseline, postinfusion day 1 (D1), and postinfusion D3. RESULTS: Relative to the nonresponders, the cohort experiencing a brief antidepressant response had blunted 24-hour amplitude that extended from baseline through D3 and postketamine phase advance of activity on D1 that reverted to baseline on D3. Relative to the nonresponders, the cohort experiencing a continued antidepressant response to ketamine had phase-advanced activity at both baseline and D1, as well as increased amplitude on D1 and D3. CONCLUSION: Taken together, the results suggest that the time course of antidepressant response to ketamine is influenced by underlying biological differences in motor activity timekeeping. These differences may provide clues that link durable mood response with the molecular machinery of the circadian system, thus leading to more effective interventions. In addition, biomarkers of preinfusion motor activity (eg, amplitude, timing) may be useful for recommending future individualized treatment interventions, to the extent that they help identify patients who may relapse quickly after treatment.

A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression.

CONTEXT: Existing therapies for major depression have a lag of onset of action of several weeks, resulting in considerable morbidity. Exploring pharmacological strategies that have rapid onset of antidepressant effects within a few days and that are sustained would have an enormous impact on patient care. Converging lines of evidence suggest the role of the glutamatergic system in the pathophysiology and treatment of mood disorders. OBJECTIVE: To determine whether a rapid antidepressant effect can be achieved with an antagonist at the N-methyl-D-aspartate receptor in subjects with major depression. DESIGN: A randomized, placebo-controlled, double-blind crossover study from November 2004 to September 2005. SETTING: Mood Disorders Research Unit at the National Institute of Mental Health. Patients Eighteen subjects with DSM-IV major depression (treatment resistant). INTERVENTIONS: After a 2-week drug-free period, subjects were given an intravenous infusion of either ketamine hydrochloride (0.5 mg/kg) or placebo on 2 test days, a week apart. Subjects were rated at baseline and at 40, 80, 110, and 230 minutes and 1, 2, 3, and 7 days postinfusion. Main Outcome Measure Changes in scores on the primary efficacy measure, the 21-item Hamilton Depression Rating Scale. RESULTS: Subjects receiving ketamine showed significant improvement in depression compared with subjects receiving placebo within 110 minutes after injection, which remained significant throughout the following week. The effect size for the drug difference was very large (d = 1.46 [95% confidence interval, 0.91-2.01]) after 24 hours and moderate to large (d = 0.68 [95% confidence interval, 0.13-1.23]) after 1 week. Of the 17 subjects treated with ketamine, 71% met response and 29% met remission criteria the day following ketamine infusion. Thirty-five percent of subjects maintained response for at least 1 week. CONCLUSIONS: Robust and rapid antidepressant effects resulted from a single intravenous dose of an N-methyl-D-aspartate antagonist; onset occurred within 2 hours postinfusion and continued to remain significant for 1 week.

Anhedonia as a clinical correlate of suicidal thoughts in clinical ketamine trials.

BACKGROUND: Identifying clinical correlates associated with reduced suicidal ideation may highlight new avenues for the treatment of suicidal thoughts. Anhedonia occurs across psychiatric diagnoses and has been associated with specific neural circuits in response to rapid-acting treatments, such as ketamine. This analysis sought to evaluate whether reductions in suicidal ideation after ketamine administration were related to reduced levels of anhedonia, independent of depressive symptoms. METHODS: This post-hoc analysis included treatment-resistant patients with either major depressive disorder (MDD) or bipolar disorder (BD) from several clinical trials of ketamine. Anhedonia was assessed using a subscale of the Beck Depression Inventory (BDI) and the Snaith-Hamilton Pleasure Scale (SHAPS). The outcome of interest was suicidal ideation, as measured by a subscale of the Scale for Suicide Ideation (SSI5), one day post-ketamine administration. RESULTS: Anhedonia, as measured by the SHAPS, was associated with suicidal thoughts independent of depressive symptoms both before and after ketamine administration. One day post-ketamine administration, improvements on the SHAPS accounted for an additional 13% of the variance in suicidal thought reduction, beyond the influence of depressive symptoms. The BDI anhedonia subscale was not significantly associated with suicidal thoughts after adjusting for depressive symptoms. LIMITATIONS: Data were limited to patients experiencing a major depressive episode and may not be generalizable to patients experiencing an active suicidal crisis. CONCLUSIONS: Suicidal thoughts may be related to symptoms of anhedonia independent of other depressive symptoms. These results have implications for the potential mechanisms of action of ketamine on suicidal thoughts.

Motor-Activity Markers of Circadian Timekeeping Are Related to Ketamine's Rapid Antidepressant Properties.

BACKGROUND: The rapid clinical antidepressant effects of the glutamatergic modulator ketamine may be due to its ability to restore synaptic plasticity and related effects on sleep-wake and circadian systems. Preclinical studies indicate that ketamine alters expression of circadian clock-associated molecules, and clinical studies of ketamine on plasticity-related biomarkers further suggest an association with sleep slow waves and sleep homeostasis. METHODS: Wrist-activity monitors were used to examine the pharmacologic and rapid antidepressant effects of ketamine on markers of circadian timekeeping (amplitude and timing) in mood disorders. Circadian amplitude and timing of activity at baseline, postinfusion day 1 (D1), and day 3 (D3) were measured in 51 patients with major depressive disorder or bipolar disorder. RESULTS: Compared with either placebo or baseline, a mood-independent decrease of the central circadian value (mesor) was present on D1 after ketamine treatment. Mood-associated circadian effects between rapid (D1) responders and nonresponders were found at baseline, D1, and D3. At baseline, a phase-advanced activity pattern and lower mesor distinguished subsequent responders from nonresponders. On D1, ketamine nonresponders had a lower mesor and a blunted 24-hour amplitude relative to baseline. On D3, patients with a persisting clinical response exhibited a higher amplitude and mesor compared with nonresponders. CONCLUSIONS: The findings are the first to demonstrate an association between ketamine's clinical antidepressant effects and circadian timekeeping. The results suggest that traitlike circadian activity patterns indicate rapid mood response to ketamine, and that mediators of continuing ketamine-induced mood changes include altered timing and amplitude of the circadian system.

The antidepressant efficacy of subanesthetic-dose ketamine does not correlate with baseline subcortical volumes in a replication sample with major depressive disorder.

BACKGROUND: This study sought to reproduce, in a larger sample, previous findings of a correlation between smaller raw 3-Tesla (3T) hippocampal volumes and improved antidepressant efficacy of ketamine in individuals with major depressive disorder (MDD). A secondary analysis stratified subjects according to functional BDNF rs6265 (val66met) genotype. METHODS: Unmedicated subjects with treatment-resistant MDD ( n=55) underwent baseline structural 3T MRI. Data processing was conducted with FSL/FIRST and Freesurfer software. The amygdala, hippocampus, and thalamus were selected a priori for analysis. All subjects received a single 0.5mg/kg × 40-minute ketamine infusion. Pearson correlations were performed with subcortical volumes and percent change in MADRS score (from baseline to 230 minutes, 1 day, and 1 week post-infusion). RESULTS: Raw and corrected subcortical volumes did not correlate with antidepressant response at any timepoint. In val/val subjects ( n=23), corrected left and right thalamic volume positively correlated with antidepressant response to ketamine at 230 minutes post-infusion but did not reach statistical significance. In met carriers ( n=14), corrected left and right thalamic volume negatively correlated with antidepressant response to ketamine. CONCLUSION: Baseline subcortical volumes implicated in MDD did not correlate with ketamine's antidepressant efficacy. Baseline thalamic volume and BDNF genotype may be a combinatorial rapid antidepressant response biomarker.

Rating depression over brief time intervals with the Hamilton Depression Rating Scale: standard vs. abbreviated scales.

Although antidepressant trials typically use weekly ratings to examine changes in symptoms over six to 12 weeks, antidepressant treatments may improve symptoms more quickly. Thus, rating scales must be adapted to capture changes over shorter intervals. We examined the use of the 17-item Hamilton Depression Rating Scale (HDRS) to evaluate more rapid changes. Data were examined from 58 patients with major depressive disorder or bipolar disorder enrolled in double-blind, placebo-controlled, crossover studies who received a single infusion of ketamine (0.5 mg/kg) or placebo over 40 min then crossed over to the other condition. HDRS subscales, a single HDRS Depressed mood item, and a visual analogue scale were used at baseline, after a brief interval (230 min), and one week post-infusion. Effect sizes for the ketamine-placebo difference were moderate (d > 0.50), but one and two-item HDRS subscales had the smallest effects. Response rates on active drug were lowest for the complete HDRS (43%); the remaining scales had higher response rates to active drug, but the shortest subscales had higher response rates to placebo. Correlations between the changes from baseline to 230 min post-ketamine across scores were similar for most subscales (r = 0.82-0.97), but correlations using the single items were lower (r < 0.74). Overall, effect sizes for drug-placebo differences and correlations between changes were lower for one- and two-item measures. Response rates were lower with the full HDRS scale. The data suggest that, to best identify rapid antidepressant effects, a scale should have more than two items, but fewer items than a full scale.

Assessing measures of suicidal ideation in clinical trials with a rapid-acting antidepressant.

Rapid reduction of suicidal thoughts is critical for treating suicidal patients. Clinical trials evaluating these treatments require appropriate measurement. Key methodological issues include: 1) the use of single or multi-item assessments, and 2) evaluating whether suicidal ideation measures can track rapid change over time. The current study presents data from two randomized, placebo-controlled, crossover clinical trials evaluating ketamine in individuals with treatment-resistant depression (n = 60). Participants were assessed for suicidal thoughts using the Hamilton Depression Rating Scale (HAM-D), Montgomery-Asberg Depression Rating Scale (MADRS), Beck Depression Inventory (BDI), and Scale for Suicidal Ideation (SSI) at eight time points over three days. Assessments were compared using correlational analyses and effect sizes at 230 min and three days after ketamine infusion. Linear mixed models evaluated change in ideation across all time points. The HAM-D and MADRS suicide items demonstrated correlations of r > .80 with the first five items of the SSI (SSI5). On linear mixed models, an effect for ketamine was found for the HAM-D, MADRS, BDI items, and SSI5 (p < .001), but not for the full SSI (p = .88), which suggests a limited ability to assess change over time in patients with low levels of suicidal thoughts. Taken together, the results suggest that repeated suicidal assessments over minutes to days appear to detect improvement in suicidal thoughts after ketamine infusion compared to placebo. The MADRS suicide item, BDI suicide item, and SSI5 may be particularly sensitive to rapid changes in suicidal thoughts.

D-serine plasma concentration is a potential biomarker of (R,S)-ketamine antidepressant response in subjects with treatment-resistant depression.

RATIONALE: (R,S)-ketamine is a rapid and effective antidepressant drug that produces a response in two thirds of patients with treatment-resistant depression (TRD). The underlying biochemical differences between a (R,S)-ketamine responder (KET-R) and non-responder (KET-NR) have not been definitively identified but may involve serine metabolism. OBJECTIVES: The aim of the study was to examine the relationship between baseline plasma concentrations of D-serine and its precursor L-serine and antidepressant response to (R,S)-ketamine in TRD patients. METHODS: Plasma samples were obtained from 21 TRD patients at baseline, 60 min before initiation of the (R,S)-ketamine infusion. Patients were classified as KET-Rs (n = 8) or KET-NRs (n = 13) based upon the difference in Montgomery-Åsberg Depression Rating Scale (MADRS) scores at baseline and 230 min after infusion, with response defined as a ≥50 % decrease in MADRS score. The plasma concentrations of D-serine and L-serine were determined using liquid chromatography-mass spectrometry. RESULTS: Baseline D-serine plasma concentrations were significantly lower in KET-Rs (3.02 ± 0.21 µM) than in KET-NRs (4.68 ± 0.81 µM), p < 0.001. A significant relationship between baseline D-serine plasma concentrations and percent change in MADRS at 230 min was determined using a Pearson correlation, r = 0.77, p < 0.001, with baseline D-serine explaining 60 % of the variance in (R,S)-ketamine response. The baseline concentrations of L-serine (L-Ser) in KET-Rs were also significantly lower than those measured in KET-NRs (66.2 ± 9.6 µM vs 242.9 ± 5.6 µM, respectively; p < 0.0001). CONCLUSIONS: The results demonstrate that the baseline D-serine plasma concentrations were significantly lower in KET-Rs than in KET-NRs and suggest that this variable can be used to predict an antidepressant response following (R,S)-ketamine administration.

Effect of baseline anxious depression on initial and sustained antidepressant response to ketamine.

OBJECTIVE: Patients with anxious depression are typically more difficult to treat with monoaminergic antidepressants compared to those with nonanxious depression. Although novel research has shown that the N-methyl-D-aspartate (NMDA) receptor antagonist ketamine has rapidly acting, relatively sustained effects in treating depression, we predicted that, consistent with the existent literature on traditional antidepressants, patients with anxious depression would have a poorer antidepressant response. METHOD: Twenty-six inpatients with treatment-resistant major depressive disorder (MDD) (DSM-IV criteria) received a single infusion of ketamine (0.5 mg/kg over 40 minutes) from January 2006-March 2013 and were followed for 28 days. A post hoc analysis compared treatment response and relapse using the Montgomery-Asberg Depression Rating Scale (MADRS) in patients with anxious versus nonanxious depression. Anxious depression was defined as MDD plus a Hamilton Depression Rating Scale anxiety/somatization factor score ≥ 7. RESULTS: Both anxious and nonanxious depressed patients responded positively to ketamine. A linear mixed model controlling for baseline with the MADRS revealed a significant group main effect (P = .03) and group-by-time interaction (P = .01). Post hoc tests indicated that patients with anxious depression had significantly fewer depression symptoms compared to those with nonanxious depression at days 1 through 5, 9 through 12, 15 through 17, and 25, with no significant group differences in dissociative (P = .62) or psychotic (P = .41) side effects. Regarding responders, patients with anxious depression relapsed significantly later than those with nonanxious depression (median ± SE = 19.0 ± 17.9 vs 1.0 ± 0.0 days to relapse, respectively; χ² = 9.30; P = .002). CONCLUSIONS: Unexpectedly, patients with anxious depression responded better to ketamine than those with nonanxious depression, with longer time to relapse and no side effect differences. This finding gives promise for the role of novel glutamatergic medications for the treatment of those with anxious depression, a traditionally difficult-to-treat subgroup of depressed patients. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00088699.

Do the dissociative side effects of ketamine mediate its antidepressant effects?

BACKGROUND: The N-methyl-d-aspartate receptor antagonist ketamine has rapid antidepressant effects in major depression. Psychotomimetic symptoms, dissociation and hemodynamic changes are known side effects of ketamine, but it is unclear if these side effects relate to its antidepressant efficacy. METHODS: Data from 108 treatment-resistant inpatients meeting criteria for major depressive disorder and bipolar disorder who received a single subanesthetic ketamine infusion were analyzed. Pearson correlations were performed to examine potential associations between rapid changes in dissociation and psychotomimesis with the Clinician-Administered Dissociative States Scale (CADSS) and Brief Psychiatric Rating Scale (BPRS), respectively, manic symptoms with Young Mania Rating Scale (YMRS), and vital sign changes, with percent change in the 17-item Hamilton Depression Rating scale (HDRS) at 40 and 230min and Days 1 and 7. RESULTS: Pearson correlations showed significant association between increased CADSS score at 40min and percent improvement with ketamine in HDRS at 230min (r=-0.35, p=0.007) and Day 7 (r=-0.41, p=0.01). Changes in YMRS or BPRS Positive Symptom score at 40min were not significantly correlated with percent HDRS improvement at any time point with ketamine. Changes in systolic blood pressure, diastolic blood pressure, and pulse were also not significantly related to HDRS change. LIMITATIONS: Secondary data analysis, combined diagnostic groups, potential unblinding. CONCLUSIONS: Among the examined mediators of ketamine׳s antidepressant response, only dissociative side effects predicted a more robust and sustained antidepressant. Prospective, mechanistic investigations are critically needed to understand why intra-infusion dissociation correlates with a more robust antidepressant efficacy of ketamine.