Building a database for brain 18 kDa translocator protein imaged using [11C]PBR28 in healthy subjects.

Translocator protein 18 kDa (TSPO) has been widely imaged as a marker of neuroinflammation using several radioligands, including [11C]PBR28. In order to study the effects of age, sex, and obesity on TSPO binding and to determine whether this binding can be accurately assessed using fewer radio high-performance liquid chromatography (radio-HPLC) measurements of arterial blood samples, we created a database of 48 healthy subjects who had undergone [11C]PBR28 scans (23 high-affinity binders (HABs) and 25 mixed-affinity binders (MABs), 20 F/28 M, age: 40.6 ± 16.8 years). After analysis by Logan plot using 23 metabolite-corrected arterial samples, total distribution volume ( VT) was found to be 1.2-fold higher in HABs across all brain regions. Additionally, the polymorphism plot estimated nondisplaceable uptake ( VND) as 1.40 mL · cm-3, which generated a specific-to-nondisplaceable ratio ( BPND) of 1.6 ± 0.6 in HABs and 1.1 ± 0.6 in MABs. VT increased significantly with age in nearly all regions and was well estimated with radio-HPLC measurements from six arterial samples. However, VT did not correlate with body mass index and was not affected by sex. These results underscore which patient characteristics should be accounted for during [11C]PBR28 studies and suggest ways to perform such studies more easily and with fewer blood samples.

PET radioligand binding to translocator protein (TSPO) is increased in unmedicated depressed subjects.

BACKGROUND: Inflammation is associated with major depressive disorder (MDD). Translocator protein 18 kDa (TSPO), a putative biomarker of neuroinflammation, is quantified using positron emission tomography (PET) and 11C-PBR28, a TSPO tracer. We sought to (1) investigate TSPO binding in MDD subjects currently experiencing a major depressive episode, (2) investigate the effects of antidepressants on TSPO binding, and (3) determine the relationship of peripheral and central inflammatory markers to cerebral TSPO binding. Twenty-eight depressed MDD subjects (unmedicated (n = 12) or medicated (n = 16)) and 20 healthy controls (HC) underwent PET imaging using 11C-PBR28. Total distribution volume (VT, proportional to Bmax/Kd) was measured and corrected with the free fraction in plasma (fp). The subgenual prefrontal cortex (sgPFC) and anterior cingulate cortex (ACC) were the primary regions of interest. Peripheral blood samples and cerebrospinal fluid were analyzed to investigate the relationship between TSPO binding and peripheral and central inflammatory markers, including interleukins and neurotrophic factors previously linked to depression. RESULTS: TSPO binding was higher in MDD versus HC in the sgPFC (Cohen's d = 0.64, p = .038, 95% CI 0.04-1.24) and ACC (d = 0.60, p = .049, 95% CI 0.001-1.21), though these comparisons missed the corrected threshold for statistical significance (α = .025). Exploratory analyses demonstrated that unmedicated MDD subjects had the highest level of TSPO binding, followed by medicated MDD subjects, who did not differ from HC. TSPO binding correlated with interleukin-5 in cerebrospinal fluid but with no other central inflammatory markers. CONCLUSIONS: This study found a trend towards increased TSPO binding in the brains of MDD subjects, and post hoc analysis extended these findings by demonstrating that this abnormality is significant in unmedicated (but not medicated) MDD subjects.

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.

Therapeutic Modulation of Glutamate Receptors in Major Depressive Disorder.

Current pharmacotherapies for major depressive disorder (MDD) have a distinct lag of onset that can prolong distress and impairment for patients, and realworld effectiveness trials further suggest that antidepressant efficacy is limited in many patients. All currently approved antidepressant medications for MDD act primarily through monoaminergic mechanisms, e.g., receptor/reuptake agonists or antagonists with varying affinities for serotonin, norepinephrine, or dopamine. Glutamate is the major excitatory neurotransmitter in the central nervous system, and glutamate and its cognate receptors are implicated in the pathophysiology of MDD, as well as in the development of novel therapeutics for this disorder. Since the rapid and robust antidepressant effects of the N-methyl-D-aspartate (NMDA) antagonist ketamine were first observed in 2000, other NMDA receptor antagonists have been studied in MDD. These have been associated with relatively modest antidepressant effects compared to ketamine, but some have shown more favorable characteristics with increased potential in clinical practice (for instance, oral administration, decreased dissociative and/or psychotomimetic effects, and reduced abuse/diversion liability). This article reviews the clinical evidence supporting the use of glutamate receptor modulators with direct affinity for cognate receptors: 1) non-competitive NMDA receptor antagonists (ketamine, memantine, dextromethorphan, AZD6765); 2) subunit (NR2B)-specific NMDA receptor antagonists (CP- 101,606/traxoprodil, MK-0657); 3) NMDA receptor glycine-site partial agonists (D-cycloserine, GLYX- 13); and 4) metabotropic glutamate receptor (mGluR) modulators (AZD2066, RO4917523/basimglurant). Several other theoretical glutamate receptor targets with preclinical antidepressant-like efficacy, but that have yet to be studied clinically, are also briefly discussed; these include α-amino-3-hydroxyl-5-methyl-4- isoxazoleproprionic acid (AMPA) agonists, mGluR2/3 negative allosteric modulators, and mGluR7 agonists.

Antisuicidal Response Following Ketamine Infusion Is Associated With Decreased Nighttime Wakefulness in Major Depressive Disorder and Bipolar Disorder.

OBJECTIVE: Insomnia and disrupted sleep are associated with increased risk of suicide. The N-methyl-d-aspartate antagonist ketamine has been associated with reduced suicidal thoughts, but the mechanism of action is unknown. This study sought to evaluate differences in nocturnal wakefulness in depressed individuals who did and did not have an antisuicidal response to ketamine. METHODS: Thirty-four participants with baseline suicidal ideation diagnosed with either DSM-IV major depressive disorder (n = 23) or bipolar depression (n = 11) between 2006 and 2013 completed nighttime electroencephalography (EEG) the night before and the night after a single ketamine infusion (0.5 mg/kg over 40 minutes). Suicidal ideation was assessed at baseline and the morning after ketamine infusion via several measures, including the Hamilton Depression Rating Scale suicide item, the suicide item of the Montgomery-Asberg Depression Rating Scale, and the first 5 items of the Scale for Suicide Ideation. A generalized linear mixed model evaluated differences in nocturnal wakefulness, as verified by EEG, between those who had an antisuicidal response to ketamine and those who did not, controlling for baseline nocturnal wakefulness. Results were also compared to the sleep of healthy controls (n = 22). RESULTS: After analyses adjusted for baseline sleep, participants with an antisuicidal response to ketamine showed significantly reduced nocturnal wakefulness the night after ketamine infusion compared to those without an antisuicidal response (F1,22 = 5.04, P = .04). Level of nocturnal wakefulness after antisuicidal response to ketamine did not differ significantly from nocturnal wakefulness in the control sample but did differ at a trend level (F1,40 = 3.15, P = .08). CONCLUSIONS: Reductions in wakefulness following ketamine may point to a biological mechanism underlying the effect of ketamine on suicidal ideation. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00088699.

Nocturnal Wakefulness Is Associated With Next-Day Suicidal Ideation in Major Depressive Disorder and Bipolar Disorder.

OBJECTIVE: Self-reported sleep disturbances may confer elevated risk for suicidal ideation, suicide attempts, and death. However, limited research has evaluated polysomnographically determined sleep disturbance as an acute physiologic risk factor for suicidal thoughts. This study sought to investigate the relationship between nocturnal wakefulness in association with next-day suicidal ideation using overnight polysomnography assessment from data collected between 2006 and 2013. METHODS: Sixty-five participants with DSM-IV-diagnosed major depressive disorder or bipolar depression underwent overnight polysomnography monitoring in a sleep laboratory. The Hamilton Depression Rating Scale (HDRS) was administered the morning after polysomnography recording to assess next-day suicidal ideation, severity of depressive symptoms, and subjective sleep disturbances. RESULTS: Using a generalized linear mixed model, a significant time-by-ideation interaction was found indicating greater nocturnal wakefulness at 4:00 am among participants with suicidal ideation (F4,136 = 3.65, P = .007). Increased time awake during the 4:00 am hour (4:00 to 4:59) was significantly associated with elevated suicidal thoughts the next day (standardized ß = 0.31, P = .008). This relationship persisted after controlling for age, gender, diagnosis, and severity of depressive symptoms. CONCLUSIONS: Greater nocturnal wakefulness, particularly in the early morning hours, was significantly associated with next-day suicidal thoughts. Polysomnographically documented sleep disruption at specific times of night may represent an acute risk factor of suicidal ideation that warrants additional research. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00024635.

A randomized, placebo-controlled pilot trial of the delta opioid receptor agonist AZD2327 in anxious depression.

RATIONALE: Patients with anxious major depressive disorder (AMDD) have more severe symptoms and poorer treatment response than patients with non-AMDD. Increasing evidence implicates the endogenous opioid system in the pathophysiology of depression. AZD2327 is a selective delta opioid receptor (DOR) agonist with anxiolytic and antidepressant activity in animal models. OBJECTIVE: This double-blind, parallel group design, placebo-controlled pilot study evaluated the safety and efficacy of AZD2327 in a preclinical model and in patients with AMDD. METHODS: We initially tested the effects of AZD2327 in an animal model of AMDD. Subsequently, 22 subjects with AMDD were randomized to receive AZD2327 (3 mg BID) or placebo for 4 weeks. Primary outcome measures included the Hamilton Depression Rating Scale (HAM-D) and the Hamilton Anxiety Rating Scale (HAM-A). We also evaluated neurobiological markers implicated in mood and anxiety disorders, including vascular endothelial growth factor (VEGF) and electroencephalogram (EEG). RESULTS: Seven (54 %) patients responded to active drug and three (33 %) responded to placebo. No significant main drug effect was found on either the HAM-D (p = 0.39) or the HAM-A (p = 0.15), but the HAM-A had a larger effect size. Levels of AZ12311418, a major metabolite of AZD2327, were higher in patients with an anti-anxiety response to treatment compared to nonresponders (p = 0.03). AZD2327 treatment decreased VEGF levels (p = 0.02). There was a trend (p < 0.06) for those with an anti-anxiety response to have higher EEG gamma power than nonresponders. CONCLUSION: These results suggest that AZD2327 has larger potential anxiolytic than antidepressant efficacy. Additional research with DOR agonists should be considered.

Reliability of 7T (1) H-MRS measured human prefrontal cortex glutamate, glutamine, and glutathione signals using an adapted echo time optimized PRESS sequence: A between- and within-sessions investigation.

PURPOSE: To ascertain the mechanisms of neuropsychiatric illnesses and their treatment, accurate and reliable imaging techniques are required; proton magnetic resonance spectroscopy ((1) H-MRS) can noninvasively measure glutamatergic function. Evidence suggests that aberrant glutamatergic signaling plays a role in numerous psychopathologies. Until recently, overlapping glutamatergic signals (glutamate, glutamine, and glutathione) could not easily be separated. However, the advent of novel pulse sequences and higher field magnetic resonance imaging (MRI) allows more precise resolution of overlapping glutamatergic signals, although the question of signal reliability remains undetermined. MATERIALS AND METHODS: At 7T MR, we acquired (1) H-MRS data from the medial pregenual anterior cingulate cortex of healthy volunteers (n = 26) twice on two separate days. An adapted echo time optimized point-resolved spectroscopy sequence, modified with the addition of a J-suppression pulse to attenuate N-acetyl-aspartate multiplet signals at 2.49 ppm, was used to excite and acquire the spectra. In-house software was used to model glutamate, glutamine, and glutathione, among other metabolites, referenced to creatine. Intraclass correlation coefficients (ICCs) were computed for within- and between-session measurements. RESULTS: Within-session measurements of glutamate, glutamine, and glutathione were on average reliable (ICCs ≥0.7). As anticipated, ICCs for between-session values of glutamate, glutamine, and glutathione were slightly lower but nevertheless reliable (ICC >0.62). A negative correlation was observed between glutathione concentration and age (r(24) = -0.37; P < 0.05), and a gender effect was noted on glutamine and glutathione. CONCLUSION: The adapted sequence provides good reliability to measure glutamate, glutamine, and glutathione signals.

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.

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 and other N-methyl-D-aspartate receptor antagonists in the treatment of depression: a perspective review.

Current pharmacotherapies for major depressive disorder (MDD) and bipolar depression (BDep) have a distinct lag of onset that can generate great distress and impairment in patients. Furthermore, as demonstrated by several real-world effectiveness trials, their efficacy is limited. All approved antidepressant medications for MDD primarily act through monoaminergic mechanisms, agonists or antagonists with varying affinities for serotonin, norepinephrine and dopamine. The glutamate system has received much attention in recent years as an avenue for developing novel therapeutics. A single subanesthetic dose infusion of the noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist ketamine has been shown to have rapid and potent antidepressant effects in treatment-resistant MDD and BDep. In a reverse translational framework, ketamine's clinical efficacy has inspired many preclinical studies to explore glutamatergic mechanisms of antidepressant action. These studies have revealed enhanced synaptic plasticity/synaptogenesis via numerous molecular and cellular mechanisms: release of local translational inhibition of brain-derived neurotrophic factor and secretion from dendritic spines, mammalian target of rapamycin activation and glycogen synthase kinase-3 inhibition. Current efforts are focused on extending ketamine's antidepressant efficacy, uncovering the neurobiological mechanisms responsible for ketamine's antidepressant activity in biologically enriched subgroups, and identifying treatment response biomarkers to personalize antidepressant selection. Other NMDA receptor antagonists have been studied both preclinically and clinically, which have revealed relatively modest antidepressant effects compared with ketamine but potentially other favorable characteristics, for example, decreased dissociative or psychotomimetic effects; therefore, there is great interest in developing novel glutamatergic antidepressants with greater target specificity and/or decreased adverse effects.

Baseline working memory activation deficits in dimensional anxious depression as detected by magnetoencephalography.

OBJECTIVE: Anxiety often co-occurs with major depressive disorder (MDD). This preliminary study sought to ascertain the extent to which anxious depression drives group neurobiological differences between patients with MDD and healthy volunteers (HVs). METHODS: Magnetoencephalography beta-band frequency was used to compare differences in brain response during the N-back working memory task between 30 medication-free patients with treatment-resistant MDD (anxious depression=18; nonanxious depression=12) and 28 HVs. RESULTS: Compared to HVs, patients with anxious depression had significantly reduced desynchronisation (less activation) in the left precuneus, right cuneus, and left insula extending into the inferior and middle frontal cortex during the 2-back condition compared with the 1-back condition of the N-back working memory task--indicating less activation of these neural networks in patients with anxious depression during the condition with the highest level of task demands. No other significant group differences were found during the working memory conditions. CONCLUSION: This preliminary study suggests that a subset of patients--those with anxious depression--may be driving observed group differences between patients with MDD and HVs. Further neurobiological studies and replication experiments are necessary to determine the extent to which this subgroup has preferentially influenced our understanding of the underlying neurobiology of depression.

A single infusion of ketamine improves depression scores in patients with anxious bipolar depression.

OBJECTIVE: Patents with anxious bipolar disorder have worse clinical outcomes and are harder to treat with traditional medication regimens compared to those with non-anxious bipolar disorder. Ketamine has been shown to rapidly and robustly decrease symptoms of depression in depressed patients with bipolar disorder. We sought to determine whether baseline anxiety status reduced ketamine's ability to decrease symptoms of depression. METHODS: Thirty-six patients with anxious (n = 21) and non-anxious (n = 15) treatment-resistant bipolar depression (types I and II; concurrently treated with either lithium or valproate) received a single infusion of ketamine (0.5 mg/kg) over 40 min. Post-hoc analyses compared changes in the Montgomery-Åsberg Depression Rating Scale (MADRS) and Hamilton Depression Rating Scale (HDRS) in anxious versus non-anxious depressed patients with bipolar disorder through 14 days post-infusion. Anxious bipolar depression was defined as DSM-IV bipolar depression plus a HDRS Anxiety/Somatization Factor score of ≥ 7. RESULTS: A linear mixed model revealed a significant effect of anxiety group on the MADRS (p = 0.04) and HDRS (p = 0.04). Significant drug effects (all p < 0.001) suggested that both anxious and non-anxious groups had an antidepressant response to ketamine. The drug-by-anxiety interactions were not significant (all p > 0.28). CONCLUSIONS: Both anxious and non-anxious patients with bipolar depression had significant antidepressant responses to ketamine, although the anxious depressed group did not show a clear antidepressant response disadvantage over the non-anxious group. Given that anxiety has been shown to be a predictor of poor treatment response in bipolar depression when traditional treatments are used, our findings suggest a need for further investigations into ketamine's novel role in the treatment of anxious 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.

Pharmacologic treatment of dimensional anxious depression: a review.

OBJECTIVE: To review the pharmacologic treatment of dimensionally defined anxious depression. DATA SOURCES: English-language, adult human research articles published between 1949 and February 2013 were identified via PUBMED and EMBASE. The search term was treatment of anxious depression. STUDY SELECTION: We identified and reviewed 304 original articles. Of these, 31 studies of patients with anxious depression, who were treated with an antidepressant or antipsychotic, are included in this review. DATA EXTRACTION: All studies explicitly used a dimensional definition of anxious depression. All patients were treated with either antidepressants or antipsychotic medications. RESULTS: Of the 31 relevant psychopharmacologic studies identified, 7 examined patients receiving only 1 medication, 2 studied cotherapeutic strategies, 1 examined antipsychotic augmentation, and 21 compared multiple medications. Eleven were pooled analyses from several studies. All studies were of adults (18-92 years old). The Hamilton Depression Rating Scale Anxiety/Somatization Factor Score was used to define anxious depression in 71% of the studies, and 77.4% were post hoc analyses of previous datasets. Seventeen studies found selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and/or tricyclic antidepressants (TCAs) to be useful for successfully treating anxious depression. However, patients with anxious depression were less likely to experience sustained response or remission. Furthermore, baseline anxious depression puts patients at greater risk for side effect burden. CONCLUSIONS: Despite achieving response with SSRIs, SNRIs, and TCAs, patients with dimensionally defined anxious depression do not maintain response or remission and often report a larger burden of side effects compared to nonanxious depressive patients, suggesting that it is a harder-to-treat subtype of major depressive disorder.

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.

Improvement in suicidal ideation after ketamine infusion: relationship to reductions in depression and anxiety.

OBJECTIVE: Suicide is a psychiatric emergency. Currently, there are no approved pharmacologic treatments for suicidal ideation. Ketamine is an N-methyl-D-aspartate (NMDA) receptor antagonist that rapidly reduces suicidal ideation as well as depression and anxiety, but the dynamic between these symptoms is not known. The aim of this analysis was to evaluate whether ketamine has an impact on suicidal thoughts, independent of depressive and anxiety symptoms. METHODS: 133 patients with treatment-resistant depression (major depressive disorder or bipolar I/II disorder) received a single subanesthetic infusion of ketamine (0.5 mg/kg over 40 min). Post-hoc correlations and linear mixed models evaluated the relationship between suicidal ideation and depression and anxiety symptoms using the Hamilton Depression Rating Scale (HAMD), Scale for Suicidal Ideation (SSI), Beck Depression Inventory (BDI), and Hamilton Anxiety Rating Scale (HAMA) focusing on 230 min post-infusion. RESULTS: At 230 min post-infusion, correlations between changes in suicidal ideation and depression ranged from 0.23 to 0.44 (p < .05), accounting for up to 19% in the variance of ideation change. Correlations with anxiety ranged from 0.23 to 0.40 (p < .05), accounting for similar levels of variance. Ketamine infusion was associated with significant reductions in suicidal ideation compared to placebo, when controlling for the effects of ketamine on depression (F1,587 = 10.31, p = .001) and anxiety (F1,567 = 8.54, p = .004). CONCLUSIONS: Improvements in suicidal ideation after ketamine infusion are related to, but not completely driven by, improvements in depression and anxiety. Investigation of the specific effects of ketamine on suicidal thoughts is warranted.

Clinical predictors of ketamine response in treatment-resistant major depression.

OBJECTIVE: The N-methyl-D-aspartate receptor antagonist ketamine has rapid antidepressant effects in treatment-resistant major depressive disorder (MDD) and bipolar depression. Clinical predictors may identify those more likely to benefit from ketamine within clinically heterogeneous populations. METHOD: Data were analyzed from 4 studies of treatment-resistant inpatients with DSM-IV-TR-diagnosed MDD or bipolar I or II depression. Patients who were currently experiencing a moderate-to-severe major depressive episode were enrolled between November 2004 and March 2013. All subjects received a single subanesthetic (0.5 mg/kg) ketamine infusion over 40 minutes. Patients were analyzed at the 230-minute postinfusion time point (n = 108), at day 1 (n = 82), and at day 7 (n = 71). Univariate Pearson correlations were performed for each variable with percent change from baseline in the 17-item Hamilton Depression Rating Scale (HDRS). Multivariate linear regression was then conducted for statistically significant predictors (P ≤ .05, 2-tailed). RESULTS: Higher body mass index correlated with greater HDRS improvement at 230 minutes (standardized ß = -0.30, P = .004) and at day 1 (standardized ß = -0.37, P = .001), but not at day 7 (standardized ß = -0.18, P = .10). Family history of an alcohol use disorder in a first-degree relative was associated with greater HDRS improvement at day 1 (standardized ß = -0.27, P = .014) and day 7 (standardized ß = -0.41, P < .001). No prior history of suicide attempt(s) was associated with greater improvement only at day 7 (standardized ß = 0.28, P = .01). The overall statistical model explained 13%, 23%, and 36% of HDRS percent change variance at 230 minutes, day 1, and day 7, respectively. CONCLUSIONS: Despite its post hoc nature, this study identified several clinical correlates of ketamine's rapid and durable antidepressant effects. Further investigation of these relationships is critical for individualized treatment of depression.

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.