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Ketamine

Ketamine decreases sensitivity of male rats to misleading negative feedback in a probabilistic reversal-learning task

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

Abstract

RATIONALE: Depression is characterized by an excessive attribution of value to negative feedback. This imbalance in feedback sensitivity can be measured using the probabilistic reversal-learning (PRL) task. This task was initially designed for clinical research, but introduction of its rodent version provides a new and much needed translational paradigm to evaluate potential novel antidepressants.

OBJECTIVES: In the present study, we aimed at evaluating the effects of a compound showing clear antidepressant properties-ketamine (KET)-on the sensitivity of rats to positive and negative feedback in the PRL paradigm.

METHODS: We trained healthy rats in an operant version of the PRL task. For successful completion of the task, subjects had to learn to ignore infrequent and misleading feedback, arising from the probabilistic (80:20) nature of the discrimination. Subsequently, we evaluated the effect of KET (5, 10, and 20 mg/kg) on feedback sensitivity 1, 24, and 48 h after administration.

RESULTS: We report that acute administration of the highest dose of KET (20 mg/kg) rapidly and persistently decreases the proportion of lose-shift responses made by rats after receiving negative feedback.

CONCLUSION: Present results suggest that KET decreases negative feedback sensitivity and that changes in this basic neurocognitive function might be one of the factors responsible for its antidepressant action.

Rychlik, M., Bollen, E., & Rygula, R. (2016). Ketamine decreases sensitivity of male rats to misleading negative feedback in a probabilistic reversal-learning task. Psychopharmacology, 1-8. 10.1007/s00213-016-4497-1
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“Being with a Buddha”: A Case Report of Methoxetamine Use in a United States Veteran with PTSD

January 29, 2017 / Anxiety Disorders / PTSD, Ketamine, Papers, Psychology / By / , ,

Abstract

Methoxetamine (MXE) is a ketamine analogue with a high affinity for the N-methyl-D-aspartate (NMDA) receptor. MXE is a newly emerging designer drug of abuse and is widely available through on-line sources and is not detected by routine urine drug screens. In this report, we describe a United States (US) veteran with posttraumatic stress disorder (PTSD) and heavy polysubstance use, who injected high dose MXE for its calming effect. Given MXE’s structural similarities to ketamine and recent work showing that ketamine reduces PTSD symptoms, we hypothesize that MXE alleviated this veteran’s PTSD symptoms through action at the NMDA receptor and via influences on brain-derived neurotrophic factor (BDNF). To our knowledge, this is the first case report of self-reported use of MXE in the US veteran population. More awareness of designer drugs, such as MXE, is an important first step in engaging patients in the treatment of designer drug addiction in both military/veteran settings and civilian settings.
Striebel, J. M., Nelson, E. E., & Kalapatapu, R. K. (2017). “Being with a Buddha”: A Case Report of Methoxetamine Use in a United States Veteran with PTSD. Case reports in psychiatry, 2017. 10.1155/2017/2319094
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"Being with a Buddha": A Case Report of Methoxetamine Use in a United States Veteran with PTSD

January 29, 2017 / Anxiety Disorders / PTSD, Ketamine, Papers, Psychology / By / , ,

Abstract

Methoxetamine (MXE) is a ketamine analogue with a high affinity for the N-methyl-D-aspartate (NMDA) receptor. MXE is a newly emerging designer drug of abuse and is widely available through on-line sources and is not detected by routine urine drug screens. In this report, we describe a United States (US) veteran with posttraumatic stress disorder (PTSD) and heavy polysubstance use, who injected high dose MXE for its calming effect. Given MXE’s structural similarities to ketamine and recent work showing that ketamine reduces PTSD symptoms, we hypothesize that MXE alleviated this veteran’s PTSD symptoms through action at the NMDA receptor and via influences on brain-derived neurotrophic factor (BDNF). To our knowledge, this is the first case report of self-reported use of MXE in the US veteran population. More awareness of designer drugs, such as MXE, is an important first step in engaging patients in the treatment of designer drug addiction in both military/veteran settings and civilian settings.
Striebel, J. M., Nelson, E. E., & Kalapatapu, R. K. (2017). “Being with a Buddha”: A Case Report of Methoxetamine Use in a United States Veteran with PTSD. Case reports in psychiatry, 2017. 10.1155/2017/2319094
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Prophylactic Ketamine Attenuates Learned Fear

January 27, 2017 / Anxiety Disorders / PTSD, Depressive Disorders, Ketamine, Neuroscience, Papers, Psychology, Publications / By / , , , , , ,

Abstract

Ketamine has been reported to be an efficacious antidepressant for major depressive disorder (MDD) and posttraumatic stress disorder (PTSD). Most recently, ketamine has also been shown to be prophylactic against stress-induced depressive-like behavior in mice. It remains unknown, however, when ketamine should be administered relative to a stressor in order to maximize its antidepressant and/or prophylactic effects. Moreover, it is unknown if ketamine can be prophylactic against subsequent stressors. We systematically administered ketamine at different time points relative to a fear experience in order to determine when ketamine is most effective at reducing fear expression or preventing fear reactivation. Using a contextual fear conditioning (CFC) paradigm, mice were administered a single dose of saline or ketamine (30 mg kg−1) at varying time points before or after CFC. Mice administered prophylactic ketamine 1 week, but not 1 month or 1 h before CFC, exhibited reduced freezing behavior when compared with mice administered saline. In contrast, ketamine administration following CFC or during extinction did not alter subsequent fear expression. However, ketamine administered before reinstatement increased the number of rearing bouts in an open field, possibly suggesting an increase in attentiveness. These data indicate that ketamine can buffer a fear response when given a week before as prophylactic, but not when given immediately before or after a stress-inducing episode. Thus, ketamine may be most useful in the clinic if administered in a prophylactic fashion 1 week before a stressor in order to protect against heightened fear responses to aversive stimuli.

McGowan, J. C., LaGamma, C. T., Lim, S. C., Tsitsiklis, M., Neria, Y., Brachman, R. A., & Denny, C. A. (2017). Prophylactic Ketamine Attenuates Learned Fear. Neuropsychopharmacology. 10.1038/npp.2017.19
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Reply to: Ketamine and Psychosis History: Antidepressant Efficacy and Psychotomimetic Effects Postinfusion

January 23, 2017 / Depressive Disorders, Ketamine, Papers, Psychology, Psychotic Disorders, Publications / By / , ,

Abstract

New and encouraging findings regarding the use of ketamine for depression in the context of psychotic symptoms have been published by Pennybaker et al. (1). In their analysis, patients with bipolar disorder without a history of psychosis had a more robust response to ketamine, and patients with a history of psychosis had a significant response compared with placebo as well. Concerning dissociative symptoms, even though patients with a history of psychosis endorsed more symptoms, these were not maintained after a 40-minute period, and no full psychosis was induced in their sample.

da Frota Ribeiro, C. M., Sanacora, G., & Ostroff, R. (2017). Reply to: Ketamine and Psychosis History: Antidepressant Efficacy and Psychotomimetic Effects Postinfusion. Biological Psychiatry. 10.1016/j.biopsych.2017.01.012
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Administration of ketamine for unipolar and bipolar depression

January 18, 2017 / Depressive Disorders, Ketamine, Papers, Psychology, Publications / By / , , , , , ,

Abstract

OBJECTIVE: Clinical trials demonstrated that ketamine exhibits rapid antidepressant efficacy when administered in subanaesthetic dosages. We reviewed currently available literature investigating efficacy, response rates and safety profile.

METHODS: Twelve studies investigating unipolar, seven on bipolar depression were included after search in medline, scopus and web of science.

RESULTS: Randomized, placebo-controlled or open-label trials reported antidepressant response rates after 24 h on primary outcome measures at 61%. The average reduction of Hamilton Depression Rating Scale (HAM-D) was 10.9 points, Beck Depression Inventory (BDI) 15.7 points and Montgomery-Asberg Depression Rating Scale (MADRS) 20.8 points. Ketamine was always superior to placebo. Most common side effects were dizziness, blurred vision, restlessness, nausea/vomiting and headache, which were all reversible. Relapse rates ranged between 60% and 92%. To provide best practice-based information to patients, a consent-form for application and modification in local language is included.

CONCLUSIONS: Ketamine constitutes a novel, rapid and efficacious treatment option for patients suffering from treatment resistant depression and exhibits rapid and significant anti-suicidal effects. New administration routes might serve as alternative to intravenous regimes for potential usage in outpatient settings. However, long-term side effects are not known and short duration of antidepressant response need ways to prolong ketamine’s efficacy.

Kraus, C., Rabl, U., Vanicek, T., Carlberg, L., Popovic, A., Spies, M., … & Willeit, M. (2017). Administration of ketamine for unipolar and bipolar depression. International Journal of Psychiatry in Clinical Practice, 21(1), 2-12. 10.1080/13651501.2016.1254802
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Ketamine for the treatment of major depressive disorder and bipolar depression: A review of the literature

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

Abstract

Introduction: Over the past decade, ketamine has been studied for major depressive disorder and bipolar depression. Ketamine is believed to exert its antidepressant properties through N-methyl-D-aspartate receptor antagonism.

Methods: Study authors completed a literature review of seven randomized controlled trials of ketamine usage in major depressive disorder and bipolar depression.

Results: Ketamine demonstrated a statistically significant improvement over placebo or midazolam in major depressive disorder. Ketamine also exhibited a statistically significant improvement over placebo in bipolar depression.

Discussion: Ketamine has shown promise in quickly reducing symptoms in patients with treatment resistant depression and bipolar depression. Using ketamine may be helpful for patients that have exhausted other therapeutic options.

Grady, S. E., Marsh, T. A., Tenhouse, A., & Klein, K. (2017). Ketamine for the treatment of major depressive disorder and bipolar depression: A review of the literature. Mental Health Clinician, 7(1), 16-23. 10.9740/mhc.2017.01.016

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Ketamine Mechanism of Action: Separating the Wheat from the Chaff

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

Abstract

(R,S)-ketamine (ketamine) exerts rapid (within hours) and robust (>60% response) antidepressant effects in severely ill-depressed patients who have failed conventional treatments (Zarate et al, 2006). This clinical finding has been paradigm-shifting as there is now tremendous hope that very ill-depressed patients can be treated in a matter of hours, rather than many weeks or months required for standard therapies to take effect (if they do at all).

Gould, T. D., Zanos, P., & Zarate, C. A. (2017). Ketamine Mechanism of Action: Separating the Wheat from the Chaff. Neuropsychopharmacology, 42(1), 368-369. 10.1038/npp.2016.210
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Ketamine accelerates fear extinction via mTORC1 signaling

December 30, 2016 / Anxiety Disorders / PTSD, Ketamine, Neuroscience, Papers, Psychology, Publications / By / , , , ,

Abstract

Impaired fear extinction contributes to the persistence of post-traumatic stress disorder (PTSD), and can be utilized for the study of novel therapeutic agents. Glutamate plays an important role in the formation of traumatic memories, and in the pathophysiology and treatment of PTSD, highlighting several possible drug targets. Recent clinical studies demonstrate that infusion of ketamine, a glutamate NMDA receptor antagonist, rapidly and significantly reduces symptom severity in PTSD patients. In the present study, we examine the mechanisms underlying the actions of ketamine in a rodent model of fear conditioning, extinction, and renewal. Rats received ketamine or saline 24 h after fear conditioning and were then subjected to extinction-training on each of the following three days. Ketamine administration enhanced extinction on the second day of training (i.e., reduced freezing behavior to cue) and produced a long-lasting reduction in freezing on exposure to cue plus context 8 days later. Additionally, ketamine and extinction exposure increased levels of mTORC1 in the medial prefrontal cortex (mPFC), a region involved in the acquisition and retrieval of extinction, and infusion of the selective mTORC1 inhibitor rapamycin into the mPFC blocked the effects of ketamine on extinction. Ketamine plus extinction also increased cFos in the mPFC and administration of a glutamate-AMPA receptor antagonist blocked the effects of ketamine. These results support the hypothesis that ketamine produces long-lasting mTORC1/protein synthesis and activity dependent effects on neuronal circuits that enhance the expression of extinction and could represent a novel approach for the treatment of PTSD.

Girgenti, M. J., Ghosal, S., LoPresto, D., Taylor, J. R., & Duman, R. S. (2017). Ketamine accelerates fear extinction via mTORC1 signaling. Neurobiology of Disease, 100, 1-8. 10.1016/j.nbd.2016.12.026
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Antisuicidal Response Following Ketamine Infusion Is Associated With Decreased Nighttime Wakefulness in Major Depressive Disorder and Bipolar Disorder

December 6, 2016 / Depressive Disorders, Ketamine, Papers, Psychology, Publications / By / , , , , , ,

Abstract

OBJECTIVE: Insomnia and disrupted sleep are associated with increased risk of suicide. The N-methyl-D-aspartate antagonist ketamine has been associated with reduced suicidal thoughts, but the mechanism of action is unknown. This study sought to evaluate differences in nocturnal wakefulness in depressed individuals who did and did not have an antisuicidal response to ketamine.

METHODS: Thirty-four participants with baseline suicidal ideation diagnosed with either DSM-IV major depressive disorder (n = 23) or bipolar depression (n = 11) between 2006 and 2013 completed nighttime electroencephalography (EEG) the night before and the night after a single ketamine infusion (0.5 mg/kg over 40 minutes). Suicidal ideation was assessed at baseline and the morning after ketamine infusion via several measures, including the Hamilton Depression Rating Scale suicide item, the suicide item of the Montgomery-Asberg Depression Rating Scale, and the first 5 items of the Scale for Suicide Ideation. A generalized linear mixed model evaluated differences in nocturnal wakefulness, as verified by EEG, between those who had an antisuicidal response to ketamine and those who did not, controlling for baseline nocturnal wakefulness. Results were also compared to the sleep of healthy controls (n = 22).

RESULTS: After analyses adjusted for baseline sleep, participants with an antisuicidal response to ketamine showed significantly reduced nocturnal wakefulness the night after ketamine infusion compared to those without an antisuicidal response (F₁,₂₂ = 5.04, P = .04). Level of nocturnal wakefulness after antisuicidal response to ketamine did not differ significantly from nocturnal wakefulness in the control sample but did differ at a trend level (F₁,₄₀ = 3.15, P = .08).

CONCLUSIONS: Reductions in wakefulness following ketamine may point to a biological mechanism underlying the effect of ketamine on suicidal ideation.

Vande Voort, J. L., Ballard, E. D., Luckenbaugh, D. A., Bernert, R. A., Richards, E. M., Niciu, M. J., … & Zarate, C. A. (2016). Antisuicidal response following ketamine infusion is associated with decreased nighttime wakefulness in major depressive disorder and bipolar disorder. Journal of clinical psychiatry. 10.4088/JCP.15m10440
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