Single Intravenous Dose Of Ketamine Research Articles

Intravenous ketamine for emergency department treatment of suicidal ideation in a paediatric population: protocol for a double-blind, randomised, placebo-controlled, parallel-arm pilot trial (KSI study)

IntroductionSuicidal ideation (SI) is a common and severe cause of morbidity in adolescents. Patients frequently present to the emergency department (ED) for care, yet there is no acute therapeutic intervention...

Randomized trial of ketamine masked by surgical anesthesia in patients with depression.

Ketamine may have antidepressant properties, but its acute psychoactive effects complicate successful masking in placebo-controlled trials. We present a single-center, parallel-arm, triple-masked, randomized, placebo-controlled trial assessing the antidepressant efficacy of intravenous ketamine masked by surgical anesthesia (ClinicalTrials.gov, NCT03861988). Forty adult patients with major depressive disorder who were scheduled for routine surgery were randomized to a single infusion of ketamine (0.5 mg/kg) or placebo (saline) during usual anesthesia. All participants, investigators, and direct patient care staff were masked to treatment allocation. The primary outcome was depression severity measured by the Montgomery-Åsberg Depression Rating Scale (MADRS) at 1, 2, and 3 days post-infusion. After all follow-up visits, participants were asked to guess which intervention they received. A mixed-effects model showed no evidence of effect of treatment assignment on the primary outcome (-5.82, 95% CI -13.3 to 1.64, p=0.13). 36.8% of participants guessed their treatment assignment correctly; both groups allocated their guesses in similar proportions. In conclusion, a single dose of intravenous ketamine delivered during surgical anesthesia had no greater effect than placebo in acutely reducing the severity of depressive symptoms in adults with major depressive disorder. This trial successfully masked treatment allocation in moderate-to-severely depressed patients using surgical anesthesia. Although this masking strategy is impractical for most placebo-controlled trials, future studies of novel antidepressants with acute psychoactive effects should make efforts to fully mask treatment assignment in order to minimize subject-expectancy bias.

A Pilot Study of Ketamine Infusion after Suicide Attempt: New Frontiers in Treating Acute Suicidality in a Real-World Medical Setting.

Ketamine, in research settings, rapidly reduces suicidal thoughts 2-24 h after a single infusion in patients with high suicidal ideation. In this study, the authors investigate ketamine's effects on suicidality in a real-world sample of recent suicide attempters on a tertiary-care Consultation-Liaison (CL) psychiatry service. Using an open-label design, 16 transdiagnostic CL patients were recruited, 18-65 years old, to receive a single dose of intravenous ketamine (0.5 mg/kg) in the acute medical setting. All were psychiatrically hospitalized post-infusion. Baseline suicidality and depression measures were compared to ratings taken at 24 h, 5 days, 12 days, and 1, 3 and 6 months post-infusion using paired t-tests. Across all measures, rapid, statistically significant decreases (p's < 0.001) were observed with large to very large effect sizes (Cohen's d's: 1.7-8.8) at acute timepoints (24 h; 5 days). These gains were uniformly maintained to 6 months post-infusion. Open-label ketamine appeared to rapidly and robustly reduced suicidal symptoms in an ultra-high-risk, heterogeneous, real-world sample. Ketamine infusion may therefore be a safe, feasible, viable method to rapidly reduce suicidality among medically hospitalized patients after a suicide attempt, with potentially enduring benefits. The current pilot findings suggest ketamine could be readily integrated into the settings where high-risk CL patients already receive healthcare, with the potential to become an important and novel tool in the treatment of suicidality.

Ketamine and other glutamate receptor modulators for depression in adults with bipolar disorder.

Ketamine and other glutamate receptor modulators for depression in adults with bipolar disorder.

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

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

The effects of ketamine on typical and atypical depressive symptoms.

Ketamine's effects on different dimensions of depressive symptomatology, including typical/melancholic and atypical depression, remain largely unknown. This study examined the effects of a single intravenous dose of ketamine on general depressive symptoms (measured using the Montgomery-Asberg Depression Rating Scale (MADRS), typical/melancholic symptoms (measured using the MADRS5), and atypical symptoms (measured using the Scale for Atypical Symptoms (SAS)). Data from 68 participants with treatment-resistant major depressive disorder (MDD) or bipolar depression were pooled from three separate, double-blind, placebo-controlled, crossover studies investigating ketamine's efficacy in depression. MDD participants were unmedicated; bipolar participants received therapeutic-dose lithium or valproate. Clinical symptoms were collected preinfusion and up to 14days postinfusion. Effect sizes were calculated for days 1 and 3 postinfusion. The primary measures of interest for this exploratory analysis were total MADRS, MADRS5, and SAS scores. Individual symptoms were also analyzed in an exploratory manner. Scores improved significantly at Day 1 postinfusion (MADRS: Cohen's d=0.64; MADRS5: Cohen's d=0.61; SAS: Cohen's d=0.41) and continued to be significantly improved over placebo at Day 3 (MADRS: Cohen's d=0.49; MADRS5: Cohen's d=0.43; SAS: Cohen's d=0.39). Effect sizes were greater for typical/melancholic than atypical symptoms at Day 1 postinfusion. Ketamine appears to effectively treat both the typical/melancholic and atypical symptoms of depression, but may have early preferential effects for the former.

Concurrent benzodiazepines undermine the antidepressant effect of ketamine

Fatigue and depression are closely associated. The purpose of this secondary analysis was to understand the relationships between depression and improvements in specific depression domains on the anti-fatigue effects of ketamine, which we previously reported.This secondary analysis re-evaluated data collected longitudinally from 39 patients with treatment-resistant Major Depressive Disorder (MDD) enrolled in a double-blind, randomized, placebo-controlled, crossover trial using a single intravenous infusion of ketamine hydrochloride (0.5 mg/kg over 40 minutes) or placebo. A mediation model assessed the effect of depression on the anti-fatigue effects of a single dose of intravenous ketamine versus placebo at Day 1 post-infusion. Fatigue was measured using the National Institutes of Health–Brief Fatigue Inventory (NIH-BFI), and depression was assessed by the Montgomery–Ǻsberg Depression Rating Scale (MADRS).Compared to placebo, ketamine significantly improved fatigue (p = .0003) as measured by the NIH-BFI, but the anti-fatigue effects of ketamine disappeared (p = .47) when controlling for depression as measured by MADRS total score. In this study sample, the anti-fatigue effects of ketamine were mostly accounted for by the changes in amotivation and depressed mood scores.In this study, ketamine did not have a unique effect on fatigue outside of its general antidepressant effects in patients with treatment-resistant depression. Specifically, the anti-fatigue effects of ketamine observed in this study seem to be explained by the effects of ketamine on two symptom domains of depression: amotivation and depressed mood. The study findings suggest that the anti-fatigue effects of ketamine should be assessed by fatigue-specific measures other than the NIH-BFI or future studies should enroll fatigued patients without depression.

Efficacy of intravenous ketamine treatment in anxious versus nonanxious unipolar treatment-resistant depression.

To examine the effect of high baseline anxiety on response to ketamine versus midazolam (active placebo) in treatment-resistant depression (TRD). In a multisite, double-blind, placebo-controlled trial, 99 subjects with TRD were randomized to one of five arms: a single dose of intravenous ketamine 0.1, 0.2, 0.5, 1.0mg/kg, or midazolam 0.045mg/kg. The primary outcome measure was change in the six-item Hamilton Rating Scale for Depression (HAMD6). A linear mixed effects model was used to examine the effect of anxious depression baseline status (defined by a Hamilton Depression Rating Scale Anxiety-Somatization score ≥7) on response to ketamine versus midazolam at 1 and 3 days postinfusion. N=45 subjects had anxious TRD, compared to N=54 subjects without high anxiety at baseline. No statistically significant interaction effect was found between treatment group assignment (combined ketamine treatment groups versus midazolam) and anxious/nonanxious status on HAMD6 score at either days 1 or 3 postinfusion (Day 1: F(1, 84)=0.02, P=0.88; Day 3: F(1, 82)=0.12, P=0.73). In contrast with what is observed with traditional antidepressants, response to ketamine may be similar in both anxious and nonanxious TRD subjects. These pilot results suggest the potential utility of ketamine in the treatment of anxious TRD.

Disentangling the association of depression on the anti-fatigue effects of ketamine

BackgroundFatigue and depression are closely associated. The purpose of this secondary analysis was to understand the relationships between depression and improvements in specific depression domains on the anti-fatigue effects of ketamine, which we previously reported. MethodsThis secondary analysis re-evaluated data collected longitudinally from 39 patients with treatment-resistant Major Depressive Disorder (MDD) enrolled in a double-blind, randomized, placebo-controlled, crossover trial using a single intravenous infusion of ketamine hydrochloride (0.5 mg/kg over 40 minutes) or placebo. A mediation model assessed the effect of depression on the anti-fatigue effects of a single dose of intravenous ketamine versus placebo at Day 1 post-infusion. Fatigue was measured using the National Institutes of Health–Brief Fatigue Inventory (NIH-BFI), and depression was assessed by the Montgomery–Ǻsberg Depression Rating Scale (MADRS). ResultsCompared to placebo, ketamine significantly improved fatigue (p = .0003) as measured by the NIH-BFI, but the anti-fatigue effects of ketamine disappeared (p = .47) when controlling for depression as measured by MADRS total score. In this study sample, the anti-fatigue effects of ketamine were mostly accounted for by the changes in amotivation and depressed mood scores. ConclusionsIn this study, ketamine did not have a unique effect on fatigue outside of its general antidepressant effects in patients with treatment-resistant depression. Specifically, the anti-fatigue effects of ketamine observed in this study seem to be explained by the effects of ketamine on two symptom domains of depression: amotivation and depressed mood. The study findings suggest that the anti-fatigue effects of ketamine should be assessed by fatigue-specific measures other than the NIH-BFI or future studies should enroll fatigued patients without depression.

Double-blind, placebo-controlled, dose-ranging trial of intravenous ketamine as adjunctive therapy in treatment-resistant depression (TRD)

Numerous placebo-controlled studies have demonstrated the ability of ketamine, an NMDA receptor antagonist, to induce rapid (within hours), transient antidepressant effects when administered intravenously (IV) at subanesthetic doses (0.5 mg/kg over 40 min). However, the optimal antidepressant dose remains unknown. We aimed to compare to active placebo the rapid acting antidepressant properties of a broad range of subanesthetic doses of IV ketamine among outpatients with treatment-resistant depression (TRD). A range of IV ketamine doses were compared to active placebo in the treatment of adult TRD over a 3-day period following a single infusion over 40 min. This was an outpatient study conducted across six US academic sites. Outpatients were 18–70 years old with TRD, defined as failure to achieve a satisfactory response (e.g., less than 50% improvement of depression symptoms) to at least two adequate treatment courses during the current depressive episode. Following a washout period, 99 eligible subjects were randomly assigned to one of the five arms in a 1:1:1:1:1 fashion: a single intravenous dose of ketamine 0.1 mg/kg (n = 18), a single dose of ketamine 0.2 mg/kg (n = 20), a single dose of ketamine 0.5 mg/kg (n = 22), a single dose of ketamine 1.0 mg/kg (n = 20), and a single dose of midazolam 0.045 mg/kg (active placebo) (n = 19). The study assessments (HAM-D-6, MADRS, SDQ, PAS, CGI-S, and CGI-I) were performed at days 0, 1, 3 (endpoint), 5, 7, 14, and 30 to assess the safety and efficacy. The overall group × time interaction effect was significant for the primary outcome measure, the HAM-D-6. In post hoc pairwise comparisons controlling for multiple comparisons, standard dose (0.5 mg/kg) and high dose (1 mg/kg) of intravenous ketamine were superior to active placebo; a low dose (0.1 mg/kg) was significant only prior to adjustment (p = 0.02, p-adj = 0.14, d = −0.82 at day 1). Most of the interaction effect was due to differences at day 1, with no significant adjusted pairwise differences at day 3. This pattern generally held for secondary outcomes. The infusions of ketamine were relatively well tolerated compared to active placebo, except for greater dissociative symptoms and transient blood pressure elevations with the higher doses. Our results suggest that there is evidence for the efficacy of the 0.5 mg/kg and 1.0 mg/kg subanesthetic doses of IV ketamine and no clear or consistent evidence for clinically meaningful efficacy of lower doses of IV ketamine. Trial Registration: NCT01920555.

Ketamine Shown to Reduce Suicidal Ideation in Severely Depressed Patients

Back to table of contents Previous article Next article Clinical and Research NewsFull AccessKetamine Shown to Reduce Suicidal Ideation in Severely Depressed PatientsRebecca GreenbergRebecca GreenbergSearch for more papers by this authorPublished Online:22 Jan 2018https://doi.org/10.1176/appi.pn.2018.1b3AbstractKetamine is showing promise as a treatment for suicidal ideation.A single adjunctive infusion of ketamine reduces suicidal thoughts in severely depressed patients within 24 hours and remains effective for up to six weeks, according to a preliminary study published last month in AJP in Advance. The findings build on a meta-analysis showing that ketamine relieved suicidal symptoms for up to one week after infusion. For the study, Michael F. Grunebaum, M.D., and colleagues at Columbia University Medical Center and the New York State Psychiatric Institute randomly assigned 80 adults with major depressive disorder and suicidal ideation to receive ketamine or midazolam infusions. Of the sample, 54 percent were taking antidepressant medication. After infusions, patients received additional medications for six months, individually tailored to what researchers thought would work best for each patient.The researchers assessed participants’ suicidal ideation using the clinician-rated Scale for Suicidal Ideation (SSI) at baseline. The SSI is scaled from 0 (least severe) to 2 (most severe) and consists of 19 items that probe the patient’s wish to die, passive and active suicide attempt thoughts, duration and frequency of ideation, sense of control, deterrents, and preparatory behavior for an attempt. This assessment was repeated 24 hours before infusion with ketamine or midazolam, 230 minutes after infusion, 24 hours after infusion, and at weeks one to six after infusion. Patients were also asked about symptoms of depression and anxiety before and after the infusion, as well as adverse effects following the infusion and again at six-week follow-up.Within 24 hours of patients’ having received intravenous ketamine (0.5 mg/kg in 100 mL saline) or midazolam (0.02 mg/kg in 100 mL saline) infused over 40 minutes, patients in the ketamine group experienced a greater reduction in SSI score than that of the midazolam group. The proportion of patients whose scores improved by 50 percent or greater 24 hours after receiving an infusion was 55 percent for the ketamine group and 30 percent for the midazolam group. Compared with the midazolam group, the ketamine group also experienced greater reductions in overall mood disturbance, depression, and fatigue within 24 hours as measured by the Profile of Mood States.“Longitudinal analysis of the uncontrolled six-week follow-up showed that clinical improvement after randomized and open ketamine treatment was generally maintained through six weeks of open, optimized clinical follow-up treatment with respect to SSI score and depression ratings,” Grunebaum and colleagues wrote. Patients in the ketamine group experienced an increase in blood pressure and dissociative symptoms compared with patients in the midazolam group, but these adverse effects typically resolved within minutes to hours following the infusion.Further testing could elicit more about the drug’s potential to relieve depression and suicide risk, Grunebaum told Psychiatric News. It could even provide the basis for a new generation of antidepressants that work by a different mechanism, he added.“The next questions we would like to answer about ketamine as an adjunctive or mono therapy relate to strategies and safety of long-term treatment, for example, over months or years,” Grunebaum said. “With its mechanism of action, we hope to facilitate the development of new medications that work faster and help more people with fewer side effects than currently available drugs.“For most people, serious depression is a chronic relapsing, remitting, often lifelong illness. Given the promising shorter-term results for ketamine, it would be clinically important to study strategies [for administering it] and safety for longer-term treatment.” ■“Ketamine for Rapid Reduction of Suicidal Thoughts in Major Depression: A Midazolam-Controlled Randomized Clinical Trial” can be accessed here. “The Effect of a Single Dose of Intravenous Ketamine on Suicidal Ideation: A Systematic Review and Individual Participant Data Meta-Analysis” is available here. ISSUES NewArchived

Meta‐analysis: Dose of ketamine reduces symptoms of suicidal ideation rapidly

A systematic review of 10 studies has found that a single intravenous dose of ketamine reduced suicidal thoughts within a day in patients with a psychiatric disorder, with the effects of the dose lasting up to one week. The researchers stated that although these results should be considered preliminary, they suggest that ketamine appears promising as a rapid‐acting treatment for patients at acute risk of suicide. Results were published online Oct. 3 in the American Journal of Psychiatry.

The Effect of a Single Dose of Intravenous Ketamine on Suicidal Ideation: A Systematic Review and Individual Participant Data Meta-Analysis.

Suicide is a public health crisis with limited treatment options. The authors conducted a systematic review and individual participant data meta-analysis examining the effects of a single dose of ketamine on suicidal ideation. Individual participant data were obtained from 10 of 11 identified comparison intervention studies that used either saline or midazolam as a control treatment. The analysis included only participants who had suicidal ideation at baseline (N=167). A one-stage, individual participant data, meta-analytic procedure was employed using a mixed-effects, multilevel, general linear model. The primary outcome measures were the suicide items from clinician-administered (the Montgomery-Åsberg Depression Rating Scale [MADRS] or the Hamilton Depression Rating Scale [HAM-D]) and self-report scales (the Quick Inventory of Depressive Symptomatology-Self Report [QIDS-SR] or the Beck Depression Inventory [BDI]), obtained for up to 1 week after ketamine administration. Ketamine rapidly (within 1 day) reduced suicidal ideation significantly on both the clinician-administered and self-report outcome measures. Effect sizes were moderate to large (Cohen's d=0.48-0.85) at all time points after dosing. A sensitivity analysis demonstrated that compared with control treatments, ketamine had significant benefits on the individual suicide items of the MADRS, the HAM-D, and the QIDS-SR but not the BDI. Ketamine's effect on suicidal ideation remained significant after adjusting for concurrent changes in severity of depressive symptoms. Ketamine rapidly reduced suicidal thoughts, within 1 day and for up to 1 week in depressed patients with suicidal ideation. Ketamine's effects on suicidal ideation were partially independent of its effects on mood, although subsequent trials in transdiagnostic samples are required to confirm that ketamine exerts a specific effect on suicidal ideation. Additional research on ketamine's long-term safety and its efficacy in reducing suicide risk is needed before clinical implementation.

Efficacy of Ketamine in Bipolar Depression: Systematic Review and Meta-analysis.

To consolidate the evidence from the literature to evaluate the role of ketamine in the treatment of bipolar depression. Major databases, including MEDLINE, EMBASE, Cochrane, and Scopus, were searched through October 2014, for studies reporting the role of ketamine in the treatment of bipolar depression. Only randomized controlled trials were included in the meta-analysis. We calculated standardized mean differences (SMDs) with SE for each study included in the meta-analysis. A random effect model was used to calculate the pooled SMDs. Heterogeneity was assessed using the Cochran Q test and I statistic. Of the 721 articles that were screened, 5 studies that enrolled a total of 125 subjects with bipolar depression (mean age, 44.6±4.3 y and 65.6% females) were included in the systematic review; 3 randomized controlled trials (69 subjects) were included in the meta-analysis. The meta-analysis showed significant improvement in depression among patients receiving a single dose of intravenous ketamine compared with those who received placebo (SMD=-1.01; 95% confidence interval, -1.37, -0.66; P<0.0001). The maximum improvement was observed 40 minutes after the ketamine infusion. No heterogeneity was observed between the studies (Cochran Q test P=0.38, I=0%). The 2 studies that were excluded from the meta-analysis also showed significant improvement in depression after ketamine therapy. Individual studies also reported improvement in anhedonia and suicidal ideation after ketamine therapy. None of the subjects had serious side effects, and the side effects were similar between the ketamine and placebo groups. This study suggests that ketamine is effective in treatment-resistant bipolar depression and may reduce suicidal ideation and anhedonia.

Ketamine and other glutamate receptor modulators for depression in bipolar disorder in adults.

There is emerging evidence that glutamatergic system dysfunction might play an important role in the pathophysiology of bipolar depression. This review focuses on the use of glutamate receptor modulators for depression in bipolar disorder. 1. To assess the effects of ketamine and other glutamate

Regulation of neural responses to emotion perception by ketamine in individuals with treatment-resistant major depressive disorder.

The glutamate N-methyl-D-aspartate receptor antagonist ketamine has demonstrated antidepressant effects in individuals with treatment-resistant major depressive disorder (TRD) within 24 h of a single dose. The current study utilized functional magnetic resonance imaging (fMRI) and two separate emotion perception tasks to examine the neural effects of ketamine in patients with TRD. One task used happy and neutral facial expressions; the other used sad and neutral facial expressions. Twenty patients with TRD free of concomitant antidepressant medication underwent fMRI at baseline and 24 h following administration of a single intravenous dose of ketamine (0.5 mg kg−1). Adequate data were available for 18 patients for each task. Twenty age- and sex-matched healthy volunteers were scanned at one time point for baseline comparison. Whole-brain, voxel-wise analyses were conducted controlling for a family-wise error rate (FWE) of P<0.05. Compared with healthy volunteers, TRD patients showed reduced neural responses to positive faces within the right caudate. Following ketamine, neural responses to positive faces were selectively increased within a similar region of right caudate. Connectivity analyses showed that greater connectivity of the right caudate during positive emotion perception was associated with improvement in depression severity following ketamine. No main effect of group was observed for the sad faces task. Our results indicate that ketamine specifically enhances neural responses to positive emotion within the right caudate in depressed individuals in a pattern that appears to reverse baseline deficits and that connectivity of this region may be important for the antidepressant effects of ketamine.

Randomized Controlled Crossover Trial of Ketamine in Obsessive-Compulsive Disorder: Proof-of-Concept

Serotonin reuptake inhibitors (SRIs), the first-line pharmacological treatment for obsessive-compulsive disorder (OCD), have two limitations: incomplete symptom relief and 2-3 months lag time before clinically meaningful improvement. New medications with faster onset are needed. As converging evidence suggests a role for the glutamate system in the pathophysiology of OCD, we tested whether a single dose of ketamine, a non-competitive N-methyl-D-aspartate (NMDA) glutamate receptor antagonist, could achieve rapid anti-obsessional effects. In a randomized, double-blind, placebo-controlled, crossover design, drug-free OCD adults (n=15) with near-constant obsessions received two 40-min intravenous infusions, one of saline and one of ketamine (0.5 mg/kg), spaced at least 1-week apart. The OCD visual analog scale (OCD-VAS) and the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) were used to assess OCD symptoms. Unexpectedly, ketamine's effects within the crossover design showed significant (p<0.005) carryover effects (ie, lasting longer than 1 week). As a result, only the first-phase data were used in additional analyses. Specifically, those receiving ketamine (n=8) reported significant improvement in obsessions (measured by OCD-VAS) during the infusion compared with subjects receiving placebo (n=7). One-week post-infusion, 50% of those receiving ketamine (n=8) met criteria for treatment response (≥35% Y-BOCS reduction) vs 0% of those receiving placebo (n=7). Rapid anti-OCD effects from a single intravenous dose of ketamine can persist for at least 1 week in some OCD patients with constant intrusive thoughts. This is the first randomized, controlled trial to demonstrate that a drug affecting glutamate neurotransmission can reduce OCD symptoms without the presence of an SRI and is consistent with a glutamatergic hypothesis of OCD.

The antidepressant-like effects of glutamatergic drugs ketamine and AMPA receptor potentiator LY 451646 are preserved in bdnf+/− heterozygous null mice

Accumulating evidence suggests that biogenic amine-based antidepressants act, at least in part, via regulation of brain-derived neurotrophic factor (BDNF) signaling. Biogenic amine-based antidepressants increase BDNF synthesis and activate its signaling pathway through TrkB receptors. Moreover, the antidepressant-like effects of these molecules are abolished in BDNF deficient mice. Glutamate-based drugs, including the NMDA antagonist ketamine, and the AMPA receptor potentiator LY 451646, mimic the effects of antidepressants in preclinical tests with high predictive validity. In humans, a single intravenous dose of ketamine produces an antidepressant effect that is rapid, robust and persistent. In this study, we examined the role of BDNF in expression of the antidepressant-like effects of ketamine and an AMPA receptor potentiator (LY 451646) in the forced swim test (FST). Ketamine and LY 451646 produced antidepressant-like effects in the FST in mice at 45 min after a single injection, but no effects were observed one week after a single ketamine injection. As previously reported, the effects of imipramine in the forced swim test were blunted in heterozygous BDNF knockout (bdnf+/−) mice. However ketamine and LY 451646 produced similar antidepressant-like responses in wildtype and bdnf+/− mice. Neither ketamine nor LY 451646 significantly influenced the levels BDNF or TrkB phosphorylation in the hippocampus when assessed at 45 min or 7 days after the drug administration. These data demonstrate that under the conditions tested, neither ketamine nor the AMPA-potentiator LY 451656 activate BDNF signaling, but produce a characteristic antidepressant-like response in heterozygous bdnf+/− mice. These data indicate that unlike biogenic amine-based agents, BDNF signaling does not play a pivotal role in the antidepressant effects of glutamate-based compounds.This article is part of a Special Issue entitled ‘Anxiety and Depression’.

An Intraoperative Pre-incision Single Dose of Intravenous Ketamine does not have an Effect on Postoperative Analgesic Requirements under Clinical Conditions

Evidence about the effectiveness of the N-methyl-D-aspartate antagonist ketamine to reduce postoperative acute and long-lasting pain is inconclusive. The aim of this study was to investigate effects of adding an intraoperative, pre-incision single intravenous dose of ketamine to a routine anaesthesia regimen on postoperative analgesic requirements, side-effects and persisting pain up to three months. After obtaining Ethical Committee approval and written informed patient consent, 120 patients were included in this prospective, randomised, double-blinded, placebo-controlled study. Patients were randomised into three groups, receiving 0.15 mg/kg ketamine intravenously, 0.5 mg/kg ketamine intravenously or normal saline in groups low-dose ketamine, moderate-dose ketamine and placebo, respectively. Anaesthesia maintenance, intraoperative pain management and postoperative pain therapy were standardised. The primary study endpoint was consumption of morphine during the first 24 hours after surgery. Three months after surgery, pain scores were assessed. Data were compared by t-test and Kruskall-Wallis test with alpha = 0.05. There was no difference between the groups in the assessed variables. These findings indicate that with the anaesthesia regimen described, and in the doses used, a single intravenous dose of ketamine does not reduce postoperative analgesic requirement or postoperative pain at three months.