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Ketamine

Ketamine for Depression, 1: Clinical Summary of Issues Related to Efficacy, Adverse Effects, and Mechanism of Action

April 1, 2017 / Depressive Disorders, Ketamine, Papers, Psychology / By /

Abstract

Ketamine is an anesthetic drug that is also used for off-label indications such as the mediation of analgesia and sedation in various settings. It is additionally recognized as an agent with antidepressant potential. For depression, it is most commonly administered as a slow intravenous infusion in subanesthetic doses (usually 0.5 mg/kg). As an antidepressant, is strikingly different from conventional antidepressant drugs in that it brings about rapid and marked attenuation of depressive symptoms even in patients with refractory depression. The benefits are observed within hours of administration, peak after about a day, and are lost 3-12 days later. Patients who do not benefit after the initial dose may benefit with serial dosing or at higher doses. Benefits can be maintained for weeks to months by the continuation of ketamine sessions at 2- to 4-day intervals. Adverse effects include dissociative and psychotomimetic changes that are almost always mild and transient, if present; transient elevation of heart rate and blood pressure often occur. These changes are usually well tolerated and are very seldom responsible for treatment discontinuation. Whereas ketamine is an N-methyl-d-aspartate receptor antagonist, and whereas much is known about its different biological effects, its actions that mediate the antidepressant response are presently not known for certain. Although big data on ketamine are presently unavailable, the drug holds promise in the treatment of depression, especially refractory depression.
Andrade, C. (2017). Ketamine for Depression, 1: Clinical Summary of Issues Related to Efficacy, Adverse Effects, and Mechanism of Action. The Journal of clinical psychiatry, 78(4), e415. 10.4088/JCP.17f11567
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A Consensus Statement on the Use of Ketamine in the Treatment of Mood Disorders

April 1, 2017 / Depressive Disorders, Ketamine, Papers, Psychology / By / , , , , , ,

Abstract

IMPORTANCE:
Several studies now provide evidence of ketamine hydrochloride’s ability to produce rapid and robust antidepressant effects in patients with mood and anxiety disorders that were previously resistant to treatment. Despite the relatively small sample sizes, lack of longer-term data on efficacy, and limited data on safety provided by these studies, they have led to increased use of ketamine as an off-label treatment for mood and other psychiatric disorders.
OBSERVATIONS:
This review and consensus statement provides a general overview of the data on the use of ketamine for the treatment of mood disorders and highlights the limitations of the existing knowledge. While ketamine may be beneficial to some patients with mood disorders, it is important to consider the limitations of the available data and the potential risk associated with the drug when considering the treatment option.
CONCLUSIONS AND RELEVANCE:
The suggestions provided are intended to facilitate clinical decision making and encourage an evidence-based approach to using ketamine in the treatment of psychiatric disorders considering the limited information that is currently available. This article provides information on potentially important issues related to the off-label treatment approach that should be considered to help ensure patient safety.

Sanacora, G., Frye, M. A., McDonald, W., Mathew, S. J., Turner, M. S., Schatzberg, A. F., … & Nemeroff, C. B. (2017). A consensus statement on the use of ketamine in the treatment of mood disorders. Jama psychiatry, 74(4), 399-405. 10.1001/jamapsychiatry.2017.0080
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Use of Ketamine in Clinical PracticeA Time for Optimism and Caution

April 1, 2017 / Depressive Disorders, Ketamine, Papers, Psychology / By / ,

Abstract

Increasing evidence, primarily from small studies, supports the idea that the dissociative anesthetic ketamine has rapid antidepressant effects in patients with treatment-refractory major depression.1 The beneficial effects of ketamine are observed within hours of administration and can last approximately 1 week. Given that up to one-third of patients with major depression fail current treatments,2 there is a clear need for novel and more effective treatments. Results to date have led to increasing off-label use of ketamine in clinical practices, with little guidance about clinical administration. In this issue of the JAMA Psychiatry, Sanacora and colleagues3 provide a much-needed consensus statement to help guide clinical use of ketamine.
Zorumski, C. F., & Conway, C. R. (2017). Use of ketamine in clinical practice: a time for optimism and caution. Jama psychiatry, 74(4), 405-406. 10.1001/jamapsychiatry.2017.0078
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Altered peripheral immune profiles in treatment-resistant depression: response to ketamine and prediction of treatment outcome

March 21, 2017 / Depressive Disorders, Ketamine, Papers, Psychiatry & Medicine, Psychology / By / , , , , , ,

Abstract

A subset of patients with depression have elevated levels of inflammatory cytokines, and some studies demonstrate interaction between inflammatory factors and treatment outcome. However, most studies focus on only a narrow subset of factors in a patient sample. In the current study, we analyzed broad immune profiles in blood from patients with treatment-resistant depression (TRD) at baseline and following treatment with the glutamate modulator ketamine. Serum was analyzed from 26 healthy control and 33 actively depressed TRD patients free of antidepressant medication, and matched for age, sex and body mass index. All subjects provided baseline blood samples, and TRD subjects had additional blood draw at 4 and 24 h following intravenous infusion of ketamine (0.5 mg kg−1). Samples underwent multiplex analysis of 41 cytokines, chemokines and growth factors using quantitative immunoassay technology. Our a priori hypothesis was that TRD patients would show elevations in canonical pro-inflammatory cytokines; analyses demonstrated significant elevation of the pro-inflammatory cytokine interleukin-6. Further exploratory analyses revealed significant regulation of four additional soluble factors in patients with TRD. Several cytokines showed transient changes in level after ketamine, but none correlated with treatment response. Low pretreatment levels of fibroblast growth factor 2 were associated with ketamine treatment response. In sum, we found that patients with TRD demonstrate a unique pattern of increased inflammatory mediators, chemokines and colony-stimulating factors, providing support for the immune hypothesis of TRD. These patterns suggest novel treatment targets for the subset of patients with TRD who evidence dysregulated immune functioning.
Kiraly, D. D., Horn, S. R., Van Dam, N. T., Costi, S., Schwartz, J., Kim-Schulze, S., … & Iosifescu, D. V. (2017). Altered peripheral immune profiles in treatment-resistant depression: response to ketamine and prediction of treatment outcome. Translational psychiatry, 7(3), e1065. 10.1038/tp.2017.31
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The Nucleus Accumbens and Ketamine Treatment in Major Depressive Disorder

March 8, 2017 / Depressive Disorders, Ketamine, Neuroscience, Papers / By / , , , , , ,

Abstract

Animal models of depression repeatedly showed stress-induced nucleus accumbens (NAc) hypertrophy. Recently, ketamine was found to normalize this stress-induced NAc structural growth. Here, we investigated NAc structural abnormalities in major depressive disorder (MDD) in two cohorts. Cohort A included a cross-sectional sample of 34 MDD and 26 healthy control (HC) subjects, with high-resolution magnetic resonance imaging (MRI) to estimate NAc volumes. Proton MR spectroscopy (1H MRS) was used to divide MDD subjects into two subgroups: glutamate-based depression (GBD) and non-GBD. A separate longitudinal sample (cohort B) included 16 MDD patients who underwent MRI at baseline then 24 h following intravenous infusion of ketamine (0.5 mg/kg). In cohort A, we found larger left NAc volume in MDD compared to controls (Cohen’s d=1.05), but no significant enlargement in the right NAc (d=0.44). Follow-up analyses revealed significant subgrouping effects on the left (d⩾1.48) and right NAc (d⩾0.95) with larger bilateral NAc in non-GBD compared to GBD and HC. NAc volumes were not different between GBD and HC. In cohort B, ketamine treatment reduced left NAc, but increased left hippocampal, volumes in patients achieving remission. The cross-sectional data provided the first evidence of enlarged NAc in patients with MDD. These NAc abnormalities were limited to patients with non-GBD. The pilot longitudinal data revealed a pattern of normalization of left NAc and hippocampal volumes particularly in patients who achieved remission following ketamine treatment, an intriguing preliminary finding that awaits replication.
Abdallah, C. G., Jackowski, A., Salas, R., Gupta, S., Sato, J. R., Mao, X., … & Mathew, S. J. (2017). The nucleus accumbens and ketamine treatment in major depressive disorder. Neuropsychopharmacology, 1, 8. 10.1038/npp.2017.49
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Ketamine as a Rapid-Acting Antidepressant: Promising Clinical and Basic Research

March 8, 2017 / Depressive Disorders, Ketamine, Neuroscience, Papers, Psychology / By / ,

Abstract

Suicidal ideation and attempts are a common medical emergency, accounting for about 650,000 adult evaluations per year in emergency settings (1). Depressive disorders are a major driving force behind this, but first-line antidepressants, such as selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), can take months to work, making them of limited use in acutely suicidal patients. Potentially safe and fast-acting interventions would be invaluable in acute situations until standard antidepressants have time to take effect.
Ketamine, best known as an N-methyl-d-aspartate receptor (NMDAR) antagonist commonly used as an anesthetic, has recently drawn attention for possibly filling the role. At lower doses it exhibits strong antidepressant effects in many patients, and it acts on the order of minutes. Despite these promising effects, its use as an antidepressant has been controversial, as ketamine is also a Schedule III controlled substance that is used recreationally for its dissociative and hallucinogenic effects. Furthermore, the full mechanism of action regarding its antidepressant effects has long remained unclear.
In the present article, we review research surrounding ketamine’s potential as a fast-acting antidepressant from a “two-pronged” approach: first, summarizing established and new knowledge on its mechanism of action and second, reviewing clinical research addressing its potential to quickly reduce depression and suicidality.
Tuck, A. N., & Ghazali, D. H. (2017). Ketamine as a Rapid-Acting Antidepressant: Promising Clinical and Basic Research. American Journal of Psychiatry Residents’ Journal, 12(3), 3-5. 10.1176/appi.ajp-rj.2017.120302
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Intranasal Ketamine and Cognitive-Behavioral Therapy for Treatment-Refractory Obsessive-Compulsive Disorder

March 1, 2017 / Ketamine, Papers, Psychology, Publications / By / , ,

Adams, T. G., Bloch, M. H., & Pittenger, C. (2017). Intranasal Ketamine and Cognitive-Behavioral Therapy for Treatment-Refractory Obsessive-Compulsive Disorder. Journal of clinical psychopharmacology, 37(2), 269-271. 10.1097/JCP.0000000000000659
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Rapid antidepressant effect of ketamine correlates with astroglial plasticity in the hippocampus

February 8, 2017 / Depressive Disorders, Ketamine, Neuroscience, Papers, Psychology, Publications / By / , , ,

Abstract

BACKGROUND AND PURPOSE: Astroglia contribute to the pathophysiology of major depression and antidepressant drugs act by modulating synaptic plasticity; therefore, the present study investigated whether the fast antidepressant action of ketamine is reflected in a rapid alteration of the astrocytes’ morphology in a genetic animal model of depression.

EXPERIMENTAL APPROACH: S-Ketamine (15 mg·kg-1 ) or saline was administered as a single injection to Flinders Line (FSL/ FRL) rats. Twenty-four hours after the treatment, perfusion fixation was carried out and the morphology of glial fibrillary acid protein (GFAP)-positive astrocytes in the CA1 stratum radiatum (CA1.SR) and the molecular layer of the dentate gyrus (GCL) of the hippocampus was investigated by applying stereological techniques and analysis with Imaris software. The depressive-like behaviour of animals was also evaluated using forced swim test.

KEY RESULTS: FSL rats treated with ketamine exhibited a significant reduction in immobility time in comparison with the FSL-vehicle group. The volumes of the hippocampal CA1.SR and GCL regions were significantly increased 1 day after ketamine treatment in the FSL rats. The size of astrocytes in the ketamine-treated FSL rats was larger than those in the FSL-vehicle group. Additionally, the number and length of the astrocytic processes in the CA1.SR region were significantly increased 1 day following ketamine treatment.

CONCLUSIONS AND IMPLICATIONS: Our results support the hypothesis that astroglial atrophy contributes to the pathophysiology of depression and a morphological modification of astrocytes could be one mechanism by which ketamine rapidly improves depressive behaviour.

Ardalan, M., Rafati, A. H., Nyengaard, J. R., & Wegener, G. (2017). Rapid antidepressant effect of ketamine correlates with astroglial plasticity in the hippocampus. British Journal of Pharmacology, 174(6), 483-492. 10.1111/bph.13714
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Sub-anesthetic doses of ketamine exert antidepressant-like effects and upregulate the expression of glutamate transporters in the hippocampus of rats

February 3, 2017 / Depressive Disorders, Ketamine, Neuroscience, Papers, Psychology, Publications / By / , , ,

Abstract

Clinical studies on the role of the glutamatergic system in the pathogenesis of depression found that ketamine induces an antidepressant response, but the molecular mechanisms remain unclear. The present study investigated the effects of sub-anesthetic doses of ketamine on the glutamate reuptake function in the rat hippocampus. Chronic unpredictable mild stress (CUMS) was applied to construct animal models of depression. Sixty adult male Sprague-Dawley rats were randomly assigned to 5 groups and received a different regimen of CUMS and ketamine (10, 25, and 50 mg/kg) treatment. The sucrose preference test and open-field test were used to assess behavioral changes. The expression levels of excitatory amino acid transporters (EAATs) were measured by western blot. Microdialysis and high-performance liquid chromatography (HPLC) were used to detect hippocampal glutamate concentrations. We found that the expression of EAAT2 and EAAT3 were obviously downregulated, and extracellular concentrations of glutamate were significantly increased in the hippocampi of depressive-like rats. Ketamine (10, 25, and 50 mg/kg) upregulated the expression of EAAT2 and EAAT3, decreased the hippocampal concentration of extracellular glutamate, and alleviated the rats’ depressive-like behavior. The antidepressant effect of ketamine may be linked to the regulation of EAAT expression and the enhancement of glutamate uptake in the hippocampus of depressive-like rats.

Zhu, X., Ye, G., Wang, Z., Luo, J., & Hao, X. (2017). Sub-anesthetic doses of ketamine exert antidepressant-like effects and upregulate the expression of glutamate transporters in the hippocampus of rats. Neuroscience Letters, 639, 132-137. 10.1016/j.neulet.2016.12.070
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Ketamine Therapy for Treatment-resistant Depression in a Patient with Multiple Sclerosis: A Case Report

February 1, 2017 / Depressive Disorders, Ketamine, Papers, Psychology, Publications / By / ,

Abstract

Objective: Depression is a common condition among patients with multiple sclerosis and often becomes resistant to oral antidepressants. We report a patient with multiple sclerosis who developed severe treatment-resistant depression and who was successfully treated with intravenous ketamine over the period of two years.
Methods: Ketamine treatment protocol included an initial series of six treatments administered every other day, followed by a maintenance schedule. Ketamine was administered intravenously at 0.5mg/kg of ideal body weight over 40 minutes. Depression symptoms were measured using Beck Depression Index.
Results: The patient’s Beck Depression Index score prior to initiating ketamine treatment was 38, corresponding to severe depression. Response to treatment, defined as 50-percent reduction in Beck Depression Index score, was observed after five treatments. For this patient, the maintenance schedule ranged from a weekly treatment to one treatment every three weeks. During the two-year observation period, this patient was able to maintain a stable non-depressed mood and had no worsening of her MS symptoms.
Conclusion: Ketamine may be an alternative treatment for resistant depression and may have a special use in patients with multiple sclerosis.
Messer, M. M., & Haller, I. V. (2017). Ketamine Therapy for Treatment-resistant Depression in a Patient with Multiple Sclerosis: A Case Report. Innovations in clinical neuroscience, 14(1-2), 56.
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