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Ketamine

Ketamine for Depression, 3: Does Chirality Matter?

June 22, 2017 / Depressive Disorders, Ketamine, Papers, Psychology, Publications / By /

Abstract

Ketamine is a racemic mixture of the enantiomers R-ketamine and S-ketamine (esketamine). S-ketamine has greater analgesic and anesthetic effects than R-ketamine and is less likely to cause psychotomimetic and other adverse effects. There is therefore an emerging interest favoring the use of S-ketamine over racemic ketamine when the drug is used for analgesia or anesthesia. This article examines preclinical and clinical literature on the antidepressant properties of S-ketamine. Animal data suggest potential advantages for R-ketamine over S-ketamine. Case reports, case series, and some small randomized controlled trials suggest that single or repeated intravenous infusions (0.2-0.4 mg/kg) or intranasal administrations (28-84 mg) of S-ketamine have antidepressant action in patients with medication-refractory depression and that the observed benefits are similar in magnitude to the antidepressant benefits reported with racemic ketamine. However, there are no direct comparisons between S-ketamine and either R-ketamine or racemic ketamine in depressed patients; therefore, it is not possible to make an informed choice when considering the enantiomers and the racemate for the indication of depression.
Andrade, C. (2017). Ketamine for Depression, 3: Does Chirality Matter?. The Journal of clinical psychiatry, 78(6), e674-e677. 0.4088/JCP.17f11681
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Rapid infusion of esketamine for unipolar and bipolar depression: a retrospective chart review

June 21, 2017 / Depressive Disorders, Ketamine, Papers, Psychology, Publications / By / , , , , , ,

Abstract

BACKGROUND:
This study evaluated efficacy and safety of intravenous subanesthetic doses of esketamine using an administration time of 10 minutes in patients with treatment-resistant depression and bipolar depression.
METHODS:
A retrospective chart review was conducted to identify patients who met the inclusion criteria for treatment-resistant depression and bipolar depression according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision criteria, and these patients received rapid infusion of esketamine between June 2012 and December 2015. The Montgomery-Åsberg Depression Rating Scale (MADRS) was administered to measure and score depressive symptom severity before infusion and at 24 hours, 72 hours, and 7 days after infusion. In addition, Clinical Global Impression scale was administered before and 7 days after esketamine infusion.
RESULTS:
Esketamine was administered to 30 patients. A total of 27 patients met the inclusion criteria and had MADRS evaluation data, which showed that 23 had unipolar and 4 had bipolar depression. Thirteen patients (48.1%) showed therapeutic response (MADRS reduction ≥50%) within 1 week (7 days) of intervention. Remission (MADRS <7) was observed in 10 patients (37.0%) in the same period. Therapeutic response and remission frequencies were seen in 16 (59.3%) and 11 (40.7%) patients, respectively, within 24 hours following drug infusion. The most relevant side effect observed during the esketamine infusion was dissociative symptoms ranging from mild to severe, which was reported by 11.1% of patients as a very disturbing experience.
LIMITATIONS:
This study was done retrospectively, had a small sample size, and there was no comparative group.
CONCLUSION:
The present study demonstrates that rapid infusion of esketamine is possibly not the optimal choice to administer this drug for treatment-resistant depression due to tolerability reasons. Further controlled studies are required to investigate efficacy, safety, and tolerability profiles among the different types of ketamines and methods of using this drug in depressed patients.
Correia-Melo, F. S., Argolo, F. C., Araújo-de-Freitas, L., Leal, G. C., Kapczinski, F., Lacerda, A. L., & Quarantini, L. C. (2017). rapid infusion of esketamine for unipolar and bipolar depression: a retrospective chart review. Neuropsychiatric disease and treatment, 13, 1627. 10.2147/NDT.S135623
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Low-dose ketamine for treatment resistant depression in an academic clinical practice setting

June 20, 2017 / Depressive Disorders, Ketamine, Papers, Psychology, Publications / By / , , ,

Abstract

BACKGROUND:
Recent studies demonstrating a rapid, robust improvement in treatment resistant depression (TRD) following a single sub-anesthetic infusion of ketamine have generated much excitement. However, these studies are limited in their generalizability to the broader TRD population due to their subject exclusion criteria which typically limit psychiatric comorbidity, concurrent medication, and level of suicide risk. This paper describes the safety and efficacy of sub-anesthetic ketamine infusions in a naturalistic TRD patient sample participating in a real-world TRD treatment program within a major university health system.
METHODS:
The effects of a sub-anesthetic dose (0.5mg/kg) of ketamine infused IV over forty minutes on TRD patients participating in a treatment program at the University of California, San Diego was investigated by retrospectively analyzing the medical charts of 41 adult TRD patients with a diagnosis of Major Depressive Disorder (MDD) or Bipolar Disorder (BD).
RESULTS:
Subjects were aged 48.6, 78% white, 36.6% female, and 82.9% had MDD. Significant psychiatric comorbidity existed in 73%. Average pre-infusion BDI score was 32.6 ± 8.4 (S.D) and dropped to 16.8 ± 3.1 at 24-h post-infusion (p < 0.001). The 24-h response (≥ 50% reduction from pre-infusion) and remission (BDI <13) rates were 53.7% and 41.5%, respectively. Three quarters of responders maintained responder status at 7-days. Ketamine infusions were well tolerated with occasional nausea or anxiety and mild hemodynamic effects during the infusion.
LIMITATIONS:
Retrospective nature of this study, lack of control group and use of self-report depression ratings scales.
CONCLUSIONS:
This is the first published study of sub-anesthetic ketamine infusions in a real-world TRD population. The results suggest that this treatment is effective and well tolerated in this population.
Feifel, D., Malcolm, B., Boggie, D., & Lee, K. (2017). Low-dose ketamine for treatment resistant depression in an academic clinical practice setting. Journal of affective disorders, 221, 283-288. 10.1016/j.jad.2017.06.043
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Associations between Specific Dissociative Symptoms and Symptom Subsets and Anti-Depressant Response to Ketamine

May 15, 2017 / Depressive Disorders, Ketamine, Papers, Psychology, Publications / By / , , , , ,

Abstract

Ketamine has been shown to produce rapid antidepressant effects in major depression and bipolar disorder. Due to ketamine’s glutamatergic properties, many patients report dissociative effects, which recent studies have shown to be associated with increased anti-depressant response. Thus we investigated the connection between distinct subscales of dissociation and differing treatment response.

Shovestul, B., Jaso, B., Luckenbaugh, D., Park, L., Niciu, M., & Zarate, C. (2017). 199-Associations between Specific Dissociative Symptoms and Symptom Subsets and Anti-Depressant Response to Ketamine. Biological Psychiatry, 81(10), S82-S83. 10.1016/j.biopsych.2017.02.212
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Ketamine as a Treatment for Adolescent Major Depressive Disorder

May 15, 2017 / Depressive Disorders, Ketamine, Papers, Psychology, Publications / By / , ,

Abstract

Nearly 1 in 4 adolescents will experience major depressive disorder (MDD). Suicide is the 3rd leading cause of death in this age group. 40% of adolescents with MDD fail to respond to initial treatment with selective serotonin reuptake inhibitors (SSRIs). Of that SSRI-resistant population, nearly half remain depressed despite alternate medication and psychotherapy. Thus, better treatments for adolescent depression are urgently needed. Subanesthetic doses of ketamine, an NMDA antagonist, produce rapid antidepressant and anti-suicidal effects in depressed adults. There are few case reports and no prospective controlled trials of ketamine for the treatment of adolescent MDD.

Dwyer, J., Sanacora, G., & Bloch, M. (2017). 1002-Ketamine as a Treatment for Adolescent Major Depressive Disorder. Biological Psychiatry, 81(10), S405. 10.1016/j.biopsych.2017.02.729
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Clinical Predictors of an Antisuicidal Response to Ketamine

May 15, 2017 / Depressive Disorders, Ketamine, Papers, Psychology, Publications / By / , , , , , ,

Abstract

Suicide is one of the leading causes of death in the United States. Despite treatment efforts, the national suicide rate has increased in recent years. Currently, there are no pharmacological treatments for suicidal ideation (SI). For individuals experiencing a suicidal crisis, rapid acting medications may save lives. Recent studies suggest ketamine, a glutamate modulator, elicits rapid antisuicidal responses. We examined clinical factors that might predict ketamine’s antisuicidal response as a step towards understanding ketamine’s mechanism of action on suicidal thoughts.

Yarrington, J., Ballard, E., Luckenbaugh, D., Niciu, M., Lener, M., Kadriu, B., … & Zarate, C. (2017). 1004-Clinical Predictors of an Antisuicidal Response to Ketamine. Biological Psychiatry, 81(10), S406. 10.1016/j.biopsych.2017.02.731
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Mood Dependent Effects of Ketamine on REM Eye Movements in Patients with Treatment Resistant Depression (TRD)

May 15, 2017 / Depressive Disorders, Ketamine, Papers, Psychology, Publications / By / , , , ,

Abstract

Both REM and NREM sleep are dysregulated in depression. REM dysregulation in MDD is thought to be partially linked to a deficient inhibitory influence of Process-S, leading to increased REM density (RD) and short REM latency (RL). Consistent with its effects on enhanced synaptic plasticity, ketamine increases SWS and early night slow-wave activity (SWA) in patients with TRD. Here we extend the examination of ketamine effects on rapid mood improvement to RD, an important marker of REM sleep in depression.

Hejazi, N., Yu, K., Park, L., Duncan, W., & Zarate, C. (2017). 861-Mood Dependent Effects of Ketamine on REM Eye Movements in Patients with Treatment Resistant Depression (TRD). Biological Psychiatry, 81(10), S348-S349. 10.1016/j.biopsych.2017.02.586
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Dose-Related Effects of Adjunctive Ketamine in Taiwanese Patients with Treatment-Resistant Depression

May 11, 2017 / Depressive Disorders, Ketamine, Papers, Psychology, Publications / By / , , , , , ,

Abstract

The antidepressant effects of ketamine are thought to depend on brain-derived neurotrophic factor (BDNF) genotype and dose. The purpose of this study was to characterize the dose-related antidepressant effects of ketamine in patients with treatment-resistant depression drawn from a Chinese population predominately possessing lower activity BDNF genotypes (Val/Met, Met/Met). We conducted a double-blind, randomized, parallel-group, placebo-controlled trial of a single ketamine infusion (saline, 0.2 mg/kg, 0.5 mg/kg). Patients (N=71; BDNF genotype: Val/Val (N=12, 17%), Val/Met (N=40, 56.3%), and Met/Met (N=19, 26.8%)) received mood ratings before infusion, after infusion, and for the subsequent 14 days. Plasma ketamine levels and BDNF genotypes were assessed. This study found a significant dose-related ketamine effect on scores on the Hamilton Depression Rating Scale (HAMD). The responder analysis (>50% reduction from baseline HAMD on at least 2 days between days 2 and 5) also revealed a significant dose-related effect (saline: 12.5%, 0.2 mg/kg: 39.1%; 0.5 mg/kg: 45.8%). This is the first report to our knowledge to demonstrate the dose-related efficacy of R/S-ketamine for treatment-resistant depression and the first to characterize ketamine effects in a genotyped Chinese population in which most (83%) patients possessed at least one copy of the lower functioning Met allele of the BDNF gene.
Su, T. P., Chen, M. H., Li, C. T., Lin, W. C., Hong, C. J., Gueorguieva, R., … & Krystal, J. H. (2017). Dose-Related Effects of Adjunctive Ketamine in Taiwanese Patients with Treatment-Resistant Depression. Neuropsychopharmacology. 10.1038/npp.2017.94
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Cognitive Behavior Therapy May Sustain Antidepressant Effects of Intravenous Ketamine in Treatment-Resistant Depression

May 11, 2017 / Depressive Disorders, Ketamine, Papers, Psychology, Publications / By / , , , , , ,

Abstract

INTRODUCTION:
Ketamine has shown rapid though short-lived antidepressant effects. The possibility of concerning neurobiological changes following repeated exposure to the drug motivates the development of strategies that obviate or minimize the need for longer-term treatment with ketamine. In this open-label trial, we investigated whether cognitive behavioral therapy (CBT) can sustain or extend ketamine’s antidepressant effects.
METHODS:
Patients who were pursuing ketamine infusion therapy for treatment-resistant depression were invited to participate in the study. If enrolled, the subjects initiated a 12-session, 10-week course of CBT concurrently with a short 4-treatment, 2-week course of intravenous ketamine (0.5 mg/kg infused over 40 min) provided under a standardized clinical protocol.
RESULTS:
Sixteen participants initiated the protocol, with 8 (50%) attaining a response to the ketamine and 7 (43.8%) achieving remission during the first 2 weeks of protocol. Among ketamine responders, the relapse rate at the end of the CBT course (8 weeks following the last ketamine exposure) was 25% (2/8). On longer-term follow-up, 5 of 8 subjects eventually relapsed, the median time to relapse being 12 weeks following ketamine exposure. Among ketamine remitters, 3 of 7 retained remission until at least 4 weeks following the last ketamine exposure, with 2 retaining remission through 8 weeks following ketamine exposure. Ketamine nonresponders did not appear to benefit from CBT.
CONCLUSIONS:
CBT may sustain the antidepressant effects of ketamine in treatment-resistant depression. Well-powered randomized controlled trials are warranted to further investigate this treatment combination as a way to sustain ketamine’s antidepressant effects.
Wilkinson, S. T., Wright, D., Fasula, M. K., Fenton, L., Griepp, M., Ostroff, R. B., & Sanacora, G. (2017). Cognitive Behavior Therapy May Sustain Antidepressant Effects of Intravenous Ketamine in Treatment-Resistant Depression. Psychotherapy and Psychosomatics, 86(3), 162-167. 10.1159/000457960
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Population scale data reveals the antidepressant effects of ketamine and other therapeutics approved for non-psychiatric indications.

May 3, 2017 / Depressive Disorders, Ketamine, Papers, Psychiatry & Medicine, Psychology, Publications / By / , , ,

Abstract

Current therapeutic approaches to depression fail for millions of patients due to lag in clinical response and non-adherence. Here we provide new support for the antidepressant effect of an anesthetic drug, ketamine, by Inverse-Frequency Analysis of eight million reports from the FDA Adverse Effect Reporting System. The results of the examination of population scale data revealed that patients who received ketamine had significantly lower frequency of reports of depression than patients who took any other combination of drugs for pain. The analysis also revealed that patients who took ketamine had significantly lower frequency of reports of pain and opioid induced side effects, implying ketamine’s potential to act as a beneficial adjunct agent in pain management pharmacotherapy. Further, the Inverse-Frequency Analysis methodology provides robust statistical support for the antidepressant action of other currently approved therapeutics including diclofenac and minocycline.
Cohen, I. V., Makunts, T., Atayee, R., & Abagyan, R. (2017). Population scale data reveals the antidepressant effects of ketamine and other therapeutics approved for non-psychiatric indications. Scientific Reports, 7. 10.1038/s41598-017-01590-x
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