Prognostic impact of CD200 and CD56 expression in pediatric B-cell acute lymphoblastic leukemia patients.

This study aimed to determine the prognostic impact of CD200 and CD56 expression in pediatric B cell acute lymphoblastic leukemia (B-ALL) patients, both of which have been implicated in immune tolerance and previously suggested as independent risk factors. CD200 has a central role in immune tolerance that protects stem cells and other critical tissues from immune damage. The expression of CD200/CD56 in leukemic blasts were assessed in leukemic blasts before chemotherapy in 43 bone marrow (BM) and/or peripheral blood (PB) samples by flow cytometry. Twenty eight of 43 B-ALL cases (65%) showed CD200 positive expression, 5 of 43 cases (11.6%) showed CD56 expression, and only 2 patients (4.7%) expressed both CD200 and CD56. Patients with CD200+ and CD56+ were significantly associated with lower platelet count; less tendency for induction of remission response as compared to negative ones (p = .01 for both). The overall survival (OS) and DFS were significantly shorter in CD200+ and CD56+ cases as compared to those with CD200- and CD56- expression. In conclusion, CD200 and/or CD56 positive expression in B-ALL at diagnosis suggest a poor prognosis and may be associated with biological aggressiveness.

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.

An investigation of amino-acid neurotransmitters as potential predictors of clinical improvement to ketamine in depression.

Amino-acid neurotransmitter system dysfunction plays a major role in the pathophysiology of major depressive disorder (MDD). We used proton magnetic resonance spectroscopy (¹H-MRS) to investigate whether prefrontal levels of amino-acid neurotransmitters predict antidepressant response to a single intravenous infusion of the N-methyl-D-aspartate (NMDA) antagonist ketamine in MDD patients. Fourteen drug-free patients with MDD were scanned 1-3 d before receiving a single intravenous infusion of ketamine (0.5 mg/kg). We measured gamma aminobutyric acid (GABA), glutamate, and Glx/glutamate ratio (a surrogate marker of glutamine) in the ventromedial prefrontal cortex (VM-PFC) and the dorsomedial/dorsal anterolateral prefrontal cortex (DM/DA-PFC). Correlation analyses were conducted to determine whether pretreatment GABA, glutamate, or Glx/glutamate ratio predicted change in depressive and anxiety symptoms 230 min after ketamine administration. Pretreatment GABA or glutamate did not correlate with improved depressive symptoms in either of the two regions of interest (p>0.1); pretreatment Glx/glutamate ratio in the DM/DA-PFC was negatively correlated with improvement in depressive symptoms [r s(11)=-0.57, p<0.05]. Pretreatment glutamate levels in the VM-PFC were positively correlated with improvement in anxiety symptoms [r s(11)=0.57, p<0.05]. The findings suggest an association between lower Glx/glutamate ratio and greater improvement in response to ketamine treatment. Because glutamine is mainly contained in glia, the decreased Glx/glutamate ratio observed in this study may reflect the reduction in glial cells found in the same regions in post-mortem studies of individuals with MDD, and suggests that the presence of this neuropathological construct may be associated with antidepressant responsiveness to ketamine.

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.

Sensitivity of serum S100B protein as a disease activity marker in Egyptian patients with vitiligo (case-control study).

BACKGROUND: Vitiligo is a depigmented skin disease. S100B is a damage-associated molecular pattern protein proposed as a marker of melanocyte cytotoxicity. AIM: To detect the sensitivity of serum levels of S100B as a disease activity marker in vitiligo patients. METHODS: Four patient groups of both sexes: twenty segmental vitiligo, twenty non-segmental active vitiligo patients, twenty non-segmental stable vitiligo patients and thirty healthy controls age and sex-matched, patients were subjected to vitiligo disease activity score (VIDA score) and Vitiligo Extent Tensity Index (VETI) score. RESULTS: An increased level of S100B was observed in patients with vitiligo compared to control, there was statistically significant increase in its level in non- segmental-active than non-segmental stable and segmental-stable. Roc analysis for S100B to predict cases vs control was confirmed by getting cut off point 80.2 pg/ml, with high sensitivity 96.67 and high specificity 96.67. Roc analysis for S100B to predict non-segmental-active versus segmental and non-segmental was also confirmed by getting cut off point 118.3 pg/ml, with sensitivity 80.0 and specificity 77.50. CONCLUSION: S100B can be used as indicators for disease activity with high sensitivity and specificity in Egyptian vitiligo patients.

New therapeutic targets for mood disorders.

Existing pharmacological treatments for bipolar disorder (BPD) and major depressive disorder (MDD) are often insufficient for many patients. Here we describe a number of targets/compounds that clinical and preclinical studies suggest could result in putative novel treatments for mood disorders. These include: (1) glycogen synthase kinase-3 (GSK-3) and protein kinase C (PKC), (2) the purinergic system, (3) histone deacetylases (HDACs), (4) the melatonergic system, (5) the tachykinin neuropeptides system, (6) the glutamatergic system, and (7) oxidative stress and bioenergetics. The paper reviews data on new compounds that have shown antimanic or antidepressant effects in subjects with mood disorders, or similar effects in preclinical animal models. Overall, an improved understanding of the neurobiological underpinnings of mood disorders is critical in order to develop targeted treatments that are more effective, act more rapidly, and are better tolerated than currently available therapies.

Prognostic impact of CD200 and CD56 expression in adult acute lymphoblastic leukemia patients.

BACKGROUND: The aim of the study is to determine the prognostic relevance of CD200/ CD56 expression in adult acute lymphoblastic leukemia patients. METHODS: The expression of CD200 and CD56 by blast cells was assessed by flow cytometry before the start of chemotherapy in 70 B-ALL patients. RESULTS: Positive expression of CD200 was detected in forty-six patients (66%) and CD56 was detected in 7 patients (10%) out of 70 patients, respectively. Only three patients (4.3%) had co-expression for CD200+ and CD56+. Splenomegaly and thrombocytopenia were frequently observed more in CD200+ patients. Increased frequency of CD34+ was associated with CD200+and CD56+ patients. The CD200+ and CD56+ subgroups of B-ALL patients had inferior OS and disease free survival compared to CD 200- and CD 56- patients. CONCLUSIONS: CD200+ and/or CD56+ positive expression in B-ALL patients at diagnosis is a poor prognostic biomarker. Identification of CD200+ and CD56+ expression at diagnosis is recommended for a better stratification of adult B-ALL patients.

Neural correlates of rapid antidepressant response to ketamine in treatment-resistant unipolar depression: a preliminary positron emission tomography study.

BACKGROUND: Multiple lines of evidence support a role for the glutamatergic system in the pathophysiology of major depressive disorder (MDD). Ketamine, an N-methyl-D-aspartate antagonist, rapidly improves depressive symptoms in individuals with treatment-resistant depression. The neural mechanisms underlying this effect remain unknown. METHODS: In this preliminary study, 20 unmedicated participants with treatment-resistant MDD underwent positron emission tomography to measure regional cerebral glucose metabolism at baseline and following ketamine infusion (single dose of .5mg/kg intravenous over 40minutes). Metabolic data were compared between conditions using a combination of region-of-interest and voxelwise analyses, and differences were correlated with the associated antidepressant response. RESULTS: Whole-brain metabolism did not change significantly following ketamine. Regional metabolism decreased significantly under ketamine in the habenula, insula, and ventrolateral and dorsolateral prefrontal cortices of the right hemisphere. Metabolism increased postketamine in bilateral occipital, right sensorimotor, left parahippocampal, and left inferior parietal cortices. Improvement in depression ratings correlated directly with change in metabolism in right superior and middle temporal gyri. Conversely, clinical improvement correlated inversely with metabolic changes in right parahippocampal gyrus and temporoparietal cortex. CONCLUSIONS: Although preliminary, these results indicate that treatment-resistant MDD subjects showed decreased metabolism in the right habenula and the extended medial and orbital prefrontal networks in association with rapid antidepressant response to ketamine. Conversely, metabolism increased in sensory association cortices, conceivably related to the illusory phenomena sometimes experienced with ketamine. Further studies are needed to elucidate how these functional anatomical changes relate to the molecular mechanisms underlying ketamine's rapid antidepressant effects.

A randomized trial of a low-trapping nonselective N-methyl-D-aspartate channel blocker in major depression.

BACKGROUND: The high-affinity N-methyl-D-aspartate (NMDA) antagonist ketamine exerts rapid antidepressant effects but has psychotomimetic properties. AZD6765 is a low-trapping NMDA channel blocker with low rates of associated psychotomimetic effects. This study investigated whether AZD6765 could produce rapid antidepressant effects in subjects with treatment-resistant major depressive disorder (MDD). METHODS: In this double-blind, randomized, crossover, placebo-controlled study, 22 subjects with DSM-IV treatment-resistant MDD received a single infusion of either AZD6765 (150 mg) or placebo on 2 test days 1 week apart. The primary outcome measure was the Montgomery-Åsberg Depression Rating Scale, which was used to rate overall depressive symptoms at baseline and 60, 80, 110, and 230 min postinfusion and on Days 1, 2, 3, and 7 postinfusion. Several secondary outcome measures were also used, including the Hamilton Depression Rating Scale. RESULTS: Within 80 min, Montgomery-Åsberg Depression Rating Scale scores significantly improved in subjects receiving AZD6765 compared with placebo; this improvement remained significant only through 110 min (d = .40). On the Hamilton Depression Rating Scale, a drug difference was found at 80 and 110 min and at Day 2 (d = .49). Overall, 32% of subjects responded to AZD6765, and 15% responded to placebo at some point during the trial. No difference was observed between the groups with regard to psychotomimetic or dissociative adverse effects. CONCLUSIONS: In patients with treatment-resistant MDD, a single intravenous dose of the low-trapping NMDA channel blocker AZD6765 was associated with rapid but short-lived antidepressant effects; no psychotomimetic effects were observed.

Novel glutamatergic agents for major depressive disorder and bipolar disorder.

Mood disorders such as major depressive disorder (MDD) and bipolar disorder (BPD) are common, chronic, recurrent mental illnesses that affect the lives and functioning of millions of individuals worldwide. Growing evidence suggests that the glutamatergic system is central to the neurobiology and treatment of these disorders. Here, we review data supporting the involvement of the glutamatergic system in the pathophysiology of mood disorders as well as the efficacy of glutamatergic agents as novel therapeutics.

Replication of ketamine's antidepressant efficacy in bipolar depression: a randomized controlled add-on trial.

BACKGROUND: Currently, no pharmacological treatments for bipolar depression exist that exert rapid (within hours) antidepressant or antisuicidal effects. We previously reported that intravenous administration of the N-methyl-D-aspartate antagonist ketamine produced rapid antidepressant effects in patients with treatment-resistant bipolar depression. The present study sought to replicate this finding in an independent sample. METHODS: In this double-blind, randomized, crossover, placebo-controlled study, 15 subjects with DSM-IV bipolar I or II depression maintained on therapeutic levels of lithium or valproate received a single intravenous infusion of either ketamine hydrochloride (.5 mg/kg) or placebo on 2 test days 2 weeks apart. The primary outcome measure was the Montgomery-Asberg Depression Rating Scale, which was used to rate overall depressive symptoms at baseline; at 40, 80, 110, and 230 minutes postinfusion; and on days 1, 2, 3, 7, 10, and 14 postinfusion. RESULTS: Within 40 minutes, depressive symptoms, as well as suicidal ideation, significantly improved in subjects receiving ketamine compared with placebo (d = .89, 95% confidence interval = .61-1.16, and .98, 95% confidence interval = .64-1.33, respectively); this improvement remained significant through day 3. Seventy-nine percent of subjects responded to ketamine and 0% responded to placebo at some point during the trial. The most common side effect was dissociative symptoms, which occurred only at the 40-minute time point. CONCLUSIONS: This study replicated our previous finding that patients with bipolar depression who received a single ketamine infusion experienced a rapid and robust antidepressant response. In addition, we found that ketamine rapidly improved suicidal ideation in these patients.

Course of improvement in depressive symptoms to a single intravenous infusion of ketamine vs add-on riluzole: results from a 4-week, double-blind, placebo-controlled study.

The N-methyl-D-aspartate antagonist ketamine has rapid antidepressant effects in patients with treatment-resistant major depression (TRD); these effects have been reported to last for 1 week in some patients. However, the extent and duration of this antidepressant effect over longer periods has not been well characterized under controlled conditions. Riluzole, a glutamatergic modulator with antidepressant and synaptic plasticity-enhancing effects, could conceivably be used to promote the antidepressant effects of ketamine. This study sought to determine the extent and time course of antidepressant improvement to a single-ketamine infusion over 4 weeks, comparing the addition of riluzole vs placebo after the infusion. Forty-two subjects (18-65) with TRD and a Montgomery-Asberg Depression Rating Scale (MADRS) score of ≥ 22 received a single intravenous infusion of ketamine (0.5 mg/kg). Four to six hours post-infusion, subjects were randomized to double-blind treatment with either riluzole (100-200 mg/day; n=21) or placebo (n=21) for 4 weeks. Depressive symptoms were rated daily. A significant improvement (P<0.001) in MADRS scores from baseline was found. The effect size of improvement with ketamine was initially large and remained moderate throughout the 28-day trial. Overall, 27% of ketamine responders had not relapsed by 4 weeks following a single ketamine infusion. The average time to relapse was 13.2 days (SE=2.2). However, the difference between the riluzole and placebo treatment groups was not significant, suggesting that the combination of riluzole with ketamine treatment did not significantly alter the course of antidepressant response to ketamine alone.

Histone deacetylases and mood disorders: epigenetic programming in gene-environment interactions.

Epigenetics involves molecular mechanisms related to gene expression independent of DNA sequence, mostly mediated by modification of chromatin histones. It has recently been suggested that these transcriptional changes may be implicated in the pathophysiology of mood disorders. In addition, histone deacetylase (HDAC) inhibitors have been shown to control epigenetic programming associated with the regulation of cognition and behavior, and may reverse dysfunctional epigenetic regulation associated with early life events in preclinical models. In this context, the active and continuous adaptation of chromatin, and the access of gene promoters to transcription factor mechanisms may represent a potential therapeutic target in the treatment of mood disorders such as bipolar disorder (BD) and major depressive disorder (MDD). Notably, the standard mood stabilizer valproate (VPA) has been shown to modulate the epigenome by inhibiting HDACs. However, several potential limitations are associated with this class of agents, including lack of selectivity for specific HDAC isoforms as well as risk of potentially serious side effects. Further studies regarding the potential role of chromatin remodeling in the mechanism of action of antidepressants and mood stabilizers are necessary to clarify the potential role of this class of agents as therapeutics for mood disorders.

Rapid antidepressant changes with sleep deprivation in major depressive disorder are associated with changes in vascular endothelial growth factor (VEGF): a pilot study.

While conventional antidepressants benefit many patients with major depressive disorder (MDD), as much as eight to 12 weeks can elapse before significant improvements in depressive symptoms are seen. Treatments that act more rapidly in MDD are urgently needed. Sleep deprivation (SD) has been shown to produce a rapid antidepressant response within one day in 50-60% of patients with MDD; thus, identifying its antidepressant mechanism may contribute to the development of antidepressants that act more rapidly. The present study evaluated the effects of 39 h of SD on mood, as well as on plasma levels of brain derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF) in patients with MDD. After a drug-free period of at least two weeks, 11 patients (6 males, 5 females; ages 25-62) who met DSM-IV criteria for MDD underwent total SD. Plasma samples for BDNF and VEGF assays were collected on Days 1 (baseline) and 2. The six-item Hamilton Rating Scale for Depression (HAMD-6) was the primary outcome measure. HAMD-6 scores decreased significantly after SD (Day 2). SD was negatively correlated with change in HAMD-6 score and change in VEGF levels, indicating that as depression scores decreased following SD, VEGF plasma levels increased. In contrast, SD did not alter plasma BDNF concentrations, nor was an association found between BDNF levels and clinical improvement on the HAMD-6. These results suggest that SD is associated with mood-related changes in plasma VEGF levels, but not plasma BDNF levels. Further studies using larger sample sizes are needed to confirm these preliminary findings.

Rapid decrease in depressive symptoms with an N-methyl-d-aspartate antagonist in ECT-resistant major depression.

BACKGROUND: Ketamine rapidly improves depressive symptoms in patients with treatment-resistant major depressive disorder (MDD) who do not respond to multiple standard antidepressants. However, it remains unknown whether ketamine is equally effective in patients with MDD who previously also did not respond to electroconvulsive therapy (ECT). METHODS: This study compared 17 patients with treatment-resistant MDD who previously did not respond to ECT and 23 patients with treatment-resistant MDD who had not previously received ECT. All subjects received a single open-label infusion of ketamine (0.5 mg/kg). Patients were evaluated using the Montgomery-Asberg Depression Rating Scale (MADRS) at baseline (60 min before the infusion), as well as at 40, 80, 120, and 230 min after infusion. RESULTS: Depressive symptoms were significantly improved in the ECT-resistant group at 230 minutes with a moderate effect size (p < .001, d = 0.50, 95% C.I.: 0.21-0.80). At 230 minutes, the non-ECT exposed group showed significant improvement with a large effect size (p < .001, d=1.00, 95% C.I.: 0.71-1.29). CONCLUSION: Ketamine appears to improve depressive symptoms in patients with MDD who had previously not responded to ECT. These preliminary results encourage further investigation with a larger sample size to determine effectiveness compared to other treatment-resistant patients with MDD.

Glutamatergic modulators: the future of treating mood disorders?

Mood disorders such as bipolar disorder and major depressive disorder are common, chronic, and recurrent conditions affecting millions of individuals worldwide. Existing antidepressants and mood stabilizers used to treat these disorders are insufficient for many. Patients continue to have low remission rates, delayed onset of action, residual subsyndromal symptoms, and relapses. New therapeutic agents able to exert faster and sustained antidepressant or mood-stabilizing effects are urgently needed to treat these disorders. In this context, the glutamatergic system has been implicated in the pathophysiology of mood disorders in unique clinical and neurobiological ways. In addition to evidence confirming the role of the glutamatergic modulators riluzole and ketamine as proof-of-concept agents in this system, trials with diverse glutamatergic modulators are under way. Overall, this system holds considerable promise for developing the next generation of novel therapeutics for the treatment of bipolar disorder and major depressive disorder.

Rapid resolution of suicidal ideation after a single infusion of an N-methyl-D-aspartate antagonist in patients with treatment-resistant major depressive disorder.

OBJECTIVE: Suicidal ideation is a medical emergency, especially when severe. Little research has been done on pharmacologic interventions that could address this problem. Ketamine, an N-methyl-D-asparate antagonist, has been reported to have antidepressant effects within hours. We examined the effects of a single dose of ketamine on suicidal ideation in subjects with treatment-resistant major depressive disorder (MDD). METHOD: Thirty-three subjects with DSM-IV-diagnosed MDD received a single open-label infusion of ketamine (0.5 mg/kg) and were rated at baseline and at 40, 80, 120, and 230 minutes postinfusion with the Scale for Suicide Ideation (SSI), the Montgomery-Åsberg Depression Rating Scale, the Hamilton Depression Rating Scale, and the Beck Depression Inventory. The study was conducted between October 2006 and January 2009. RESULTS: Suicidal ideation scores decreased significantly on the SSI as well as on the suicide subscales of other rating instruments within 40 minutes; these decreases remained significant through the first 4 hours postinfusion (P < .001). Ten subjects (30%) had an SSI score ≥ 4 at baseline; all these scores dropped below 4 (9 dropped by 40 minutes and 1 by 80 minutes). For those patients with a starting score below 4 on the SSI, only 1 reached a score of 4. Depression, anxiety, and hopelessness were significantly improved at all time points (P < .001). CONCLUSIONS: Suicidal ideation in the context of MDD improved within 40 minutes of a ketamine infusion and remained improved for up to 4 hours postinfusion. Future studies with ketamine in suicidal ideation are warranted due to the potential impact on public health. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00088699.

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

CONTEXT: Existing therapies for bipolar depression have a considerable lag of onset of action. Pharmacological strategies that produce rapid antidepressant effects-for instance, within a few hours or days-would have an enormous impact on patient care and public health. OBJECTIVE: To determine whether an N-methyl-D-aspartate-receptor antagonist produces rapid antidepressant effects in subjects with bipolar depression. DESIGN: A randomized, placebo-controlled, double-blind, crossover, add-on study conducted from October 2006 to June 2009. SETTING: Mood Disorders Research Unit at the National Institute of Mental Health, Bethesda, Maryland. Patients Eighteen subjects with DSM-IV bipolar depression (treatment-resistant). INTERVENTIONS: Subjects maintained at therapeutic levels of lithium or valproate received an intravenous infusion of either ketamine hydrochloride (0.5 mg/kg) or placebo on 2 test days 2 weeks apart. The Montgomery-Asberg Depression Rating Scale was used to rate subjects at baseline and at 40, 80, 110, and 230 minutes and on days 1, 2, 3, 7, 10, and 14 postinfusion. MAIN OUTCOME MEASURES: Change in Montgomery-Asberg Depression Rating Scale primary efficacy measure scores. RESULTS: Within 40 minutes, depressive symptoms significantly improved in subjects receiving ketamine compared with placebo (d = 0.52, 95% confidence interval [CI], 0.28-0.76); this improvement remained significant through day 3. The drug difference effect size was largest at day 2 (d = 0.80, 95% CI, 0.55-1.04). Seventy-one percent of subjects responded to ketamine and 6% responded to placebo at some point during the trial. One subject receiving ketamine and 1 receiving placebo developed manic symptoms. Ketamine was generally well tolerated; the most common adverse effect was dissociative symptoms, only at the 40-minute point. CONCLUSION: In patients with treatment-resistant bipolar depression, robust and rapid antidepressant effects resulted from a single intravenous dose of an N-methyl-D-aspartate antagonist.