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Ketamine

Ketamine-A Narrative Review of Its Uses in Medicine

April 24, 2015 / Anxiety Disorders / PTSD, Ketamine, Neuroscience, Papers, Pharmacology & Chemistry, Psychiatry & Medicine, Psychology, Publications / By / , , , ,

Abstract

One of the most fascinating drugs in the anesthesiologist’s armament is ketamine, an N-methyl-D-aspartate receptor antagonist with a myriad of uses. The drug is a dissociative anesthetic and has been used more often as an analgesic in numerous hospital units, outpatient pain clinics, and in the prehospital realm. It has been used to treat postoperative pain, chronic pain, complex regional pain syndrome, phantom limb pain, and other neuropathic conditions requiring analgesia. Research has also demonstrated its efficacy as an adjunct in psychotherapy, as a treatment for both depression and posttraumatic stress disorder, as a procedural sedative, and as a treatment for respiratory and neurologic conditions. Ketamine is not without its adverse effects, some of which can be mitigated with certain efforts. Such effects make it necessary for the clinician to use the drug only in situations where it will provide the greatest benefit with the fewest adverse effects. To the best of our knowledge, none of the reviews regarding ketamine have taken a comprehensive look at the drug’s uses in all territories of medicine. This review will serve to touch on its chemical data, pharmacokinetics and pharmacodynamics, medical uses, and adverse effects while focusing specifically on the drugs usage in anesthesia and analgesia.

Radvansky, B. M., Puri, S., Sifonios, A. N., Eloy, J. D., & Le, V. (2015). Ketamine-A Narrative Review of Its Uses in Medicine. American journal of therapeutics. https://dx.doi.org/10.1097/MJT.0000000000000257
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Ketamine-induced modulation of the thalamo-cortical network in healthy volunteers as a model for schizophrenia

April 20, 2015 / Ketamine, Neuroscience, Papers, Psychology, Psychotic Disorders, Publications / By / , , , , , ,

Abstract

BACKGROUND:

Schizophrenia has been associated with disturbances of thalamic functioning. In the light of recent evidence suggesting a significant impact of the glutamatergic system on key symptoms of schizophrenia, we assessed whether the modulation of the glutamatergic system via blockage of the NMDA-receptor might lead to changes of thalamic functional connectivity.

METHODS:

Based on the “ketamine-model” of psychosis we investigated changes in cortico-thalamic functional connectivity by intravenous ketamine challenge during a 55 minutes resting-state scan. 30 healthy volunteers were measured with pharmacological functional magnetic resonance imaging (fMRI) using a double-blind, randomized, placebo-controlled, crossover design.

RESULTS:

Functional connectivity analysis revealed significant ketamine-specific changes within the “thalamus hub network”, more precisely an increase of cortico-thalamic connectivity of the somatosensory and temporal cortex.

CONCLUSIONS:

Our results indicate that changes of thalamic functioning as described for schizophrenia can be partly mimicked by NMDA-receptor blockage. This adds substantial knowledge about the neurobiological mechanisms underlying the profound changes of perception and behaviour during the application of NMDA-receptor antagonists.

Höflich, A., Hahn, A., Küblböck, M., Kranz, G. S., Vanicek, T., Windischberger, C., … & Guertel, W. (2015). Ketamine-induced modulation of the thalamo-cortical network in healthy volunteers as a model for schizophrenia. The international journal of neuropsychopharmacology. http://dx.doi.org/10.1093/ijnp/pyv040
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Ketamine and other N-methyl-D-aspartate receptor antagonists in the treatment of depression: a perspective review

April 13, 2015 / Depressive Disorders, Ketamine, Papers, Psychology, Publications / By / , , , , , ,

Abstract

Current pharmacotherapies for major depressive disorder (MDD) and bipolar depression (BDep) have a distinct lag of onset that can generate great distress and impairment in patients. Furthermore, as demonstrated by several real-world effectiveness trials, their efficacy is limited. All approved antidepressant medications for MDD primarily act through monoaminergic mechanisms, agonists or antagonists with varying affinities for serotonin, norepinephrine and dopamine. The glutamate system has received much attention in recent years as an avenue for developing novel therapeutics. A single subanesthetic dose infusion of the noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist ketamine has been shown to have rapid and potent antidepressant effects in treatment-resistant MDD and BDep. In a reverse translational framework, ketamine’s clinical efficacy has inspired many preclinical studies to explore glutamatergic mechanisms of antidepressant action. These studies have revealed enhanced synaptic plasticity/synaptogenesis via numerous molecular and cellular mechanisms: release of local translational inhibition of brain-derived neurotrophic factor and secretion from dendritic spines, mammalian target of rapamycin activation and glycogen synthase kinase-3 inhibition. Current efforts are focused on extending ketamine’s antidepressant efficacy, uncovering the neurobiological mechanisms responsible for ketamine’s antidepressant activity in biologically enriched subgroups, and identifying treatment response biomarkers to personalize antidepressant selection. Other NMDA receptor antagonists have been studied both preclinically and clinically, which have revealed relatively modest antidepressant effects compared with ketamine but potentially other favorable characteristics, for example, decreased dissociative or psychotomimetic effects; therefore, there is great interest in developing novel glutamatergic antidepressants with greater target specificity and/or decreased adverse effects.

Iadarola, N. D., Niciu, M. J., Richards, E. M., Voort, J. L. V., Ballard, E. D., Lundin, N. B., … & Zarate, C. A. (2015). Ketamine and other N-methyl-D-aspartate receptor antagonists in the treatment of depression: a perspective review. Therapeutic Advances in Chronic Disease. https://dx.doi.org/10.1177/2040622315579059
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The use of ketamine as an antidepressant: a systematic review and meta-analysis

April 7, 2015 / Depressive Disorders, Ketamine, Papers, Psychology, Publications / By / ,

Abstract

Objective

The current meta-analysis examines the effects of ketamine infusion on depressive symptoms over time in major depressive disorder (MDD) and bipolar disorder (BD).

Methods

Following a systematic review of the literature, data were extracted from 21 studies (n  = 437 receiving ketamine) and analysed at four post-infusion time points (4 h, 24 h, 7 days and 12–14 days). The moderating effects of several factors were assessed including: repeat/single infusion, diagnosis, open-label/participant-blind infusion, pre–post/placebo-controlled design and the sex of patients.

Results

Effect sizes were significantly larger for repeat than single infusion at 4 h, 24 h and 7 days. For single infusion studies, effect sizes were large and significant at 4 h, 24 h and 7 days. The percentage of males was a predictor of antidepressant response at 7 days. Effect sizes for open-label and participant-blind infusions were not significantly different at any time point.

Conclusions

Single ketamine infusions elicit a significant antidepressant effect from 4 h to 7 days; the small number of studies at 12–14 days post infusion failed to reach significance. Results suggest a discrepancy in peak response time depending upon primary diagnosis — 24 h for MDD and 7 days for BD. The majority of published studies have used pre–post comparison; further placebo-controlled studies would help to clarify the effect of ketamine over time.

Coyle, C. M., & Laws, K. R. (2015). The use of ketamine as an antidepressant: a systematic review and meta‐analysis. Human Psychopharmacology: Clinical and Experimental, 30(3), 152-163. https://dx.doi.org/10.1002/hup.2475
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Ketamine Users Have High Rates of Psychosis and/or Depression

March 1, 2015 / Depressive Disorders, Ketamine, Papers, Psychology, Psychotic Disorders, Publications, Substance Use Disorder / By / , , , ,

Abstract

Ketamine has been linked to psychosis and used in the treatment of depression. However, no study has examined the prevalence of psychotic and depressive disorders in dependent ketamine users. This study aimed to examine the frequency of various psychopathologies among a series of patients seeking treatment for ketamine use in Hong Kong, China. The case records of 129 patients with a history of ketamine use receiving treatment at three substance use clinics between January 2008 and August 2012 were retrieved for data collection. Patients’ demographic data, patterns of substance misuse, and comorbid psychiatric diagnoses were recorded and entered into analyses. The mean age of onset and length of ketamine use were 17.7 ± 4.4 and 8.7 ± 5.7 years, respectively. All patients were dependent on ketamine at the time of data collection. Multiple substance misuse was common. Eighty-four of the 129 (65.1%) patients were found to have comorbid psychiatric disorders, most commonly substance-induced psychotic disorder (31.8%) followed by depressive disorder (27.9%). Psychosis and/or depression were common in ketamine-dependent patients referred to a psychiatric substance use clinic. The findings provide evidence of an association between chronic ketamine use and the presence of psychosis and/or depression. The results raise the issue of safety when using ketamine in the long-term treatment of depression.

Liang, H. J., Tang, K. L., Chan, F., Ungvari, G. S., & Tang, W. K. (2015). Ketamine Users Have High Rates of Psychosis and/or Depression. Journal of addictions nursing, 26(1), 8-13. https://dx.doi.org/10.1097/JAN.0000000000000060
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Ketamine as a promising prototype for a new generation of rapid-acting antidepressants

February 27, 2015 / Depressive Disorders, Ketamine, Neuroscience, Papers, Psychology, Publications / By / , ,

Abstract

The discovery of ketamine’s rapid and robust antidepressant effects opened a window into a new generation of antidepressants. Multiple controlled trials and open-label studies have demonstrated these effects across a variety of patient populations known to often achieve little to no response from traditional antidepressants. Ketamine has been generally well tolerated across patient groups, with transient mild-to-moderate adverse effects during infusion. However, the optimal dosing and route of administration and the safety of chronic treatment are not fully known. This review summarizes the clinical effects of ketamine and its neurobiological underpinnings and mechanisms of action, which may provide insight into the neurobiology of depression, relevant biomarkers, and treatment targets. Moreover, we offer suggestions for future research that may continue to advance the field forward and ultimately improve the psychopharmacologic interventions available for those individuals struggling with depressive and trauma-related disorders.

Abdallah, C. G., Averill, L. A. and Krystal, J. H. (2015), Ketamine as a promising prototype for a new generation of rapid-acting antidepressants. Annals of the New York Academy of Sciences, 1344: 66–77. doi: 10.1111/nyas.12718

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What Can Neuroscience Tell Us About the Potential of Psychedelics in Healthcare?

February 23, 2015 / Ayahuasca, DMT, Iboga / Ibogaine, Ketamine, LSD, MDMA, Mescaline / Cacti, Mushrooms / Psilocybin, Neuroscience, Papers, Psychology, Publications / By /

Abstract

Health-related psychedelic research should focus on helping us flourish, not just remedying ill-health or addiction. We don’t know enough about how psychedelics could enhance human flourishing. Factors promoting health-through-flourishing include finding meaning in life, spiritual practices, comfortable levels of social bonds, emotionally/physically satisfying sex in a long-term monogamous relationship and control over one’s daily life. Psychedelic research could find more.Neuroscience anchors psychedelic research into disease and disorder, e.g. addiction, PSTD, migraine, anxiety, pain etc. Neurophenomenological psychedelics research could illuminate relationships between health, ASC/NOSCs and cognitive liberty to promote human flourishing. If we accept the self as an epiphenomenon of subsystems within the brain, we ‘know’ ‘unconsciously’, but are not aware of, many things which affect our lives profoundly. These include control over identifying, remembering and forgetting our states of mind and how to move between them. A prerequisite for integrated investigations into ASC/NOSCs is the establishment of a taxonomic knowledge base which lists, categorises and characterises ASC/NOSCs to enable us to choose specific states of mind and move securely among them. Or, in other words, to enable us to exercise our cognitive liberty safely.

I believe that human health and flourishing would be enhanced were we able to direct our states of being by consciously choosing them. Given the promise of mindfulness techniques to enhance our health, happiness and spiritual growth, constructing both personal and generic classifications of salient ASC/NOSCs makes sense. Laws need to change. The neuroscience of pleasure, love, spirituality, decision-making, pattern recognition and location of meaning should inform health-enhancing psychedelic research while promoting flourishing through cognitive liberty.

As part of cognitive liberty, our end-of-life choices should include how we die. In other words, our idea of the good death should include access to psychedelics. Dying high is increasingly likely to become a popular choice as baby boomers age and place their economic clout behind the reform of end-of-life laws as well as drug laws. Achieving such crucial legal changes depends partly on the ability to produce research to anchor evidence based law and policy. Research into psychedelics, ASC/NOSCs and the neurobiology of the dying process is essential.

Mackenzie, R. (2015). What can neuroscience tell us about the potential of psychedelics in healthcare? How the Neurophenomenology of Psychedelics Research Could Help us to Flourish Throughout Our Lives, as Well as to Enhance Our Dying. Current Drug Abuse Reviews, 7(3), 136-144. http://dx.doi.org/10.2174/1874473708666150107114927
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Regulation of neural responses to emotion perception by ketamine in individuals with treatment-resistant major depressive disorder

February 17, 2015 / Depressive Disorders, Ketamine, Neuroscience, Papers, Psychology, Publications / By / , , , , , ,

Abstract

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.

Murrough, J. W., Collins, K. A., Fields, J., DeWilde, K. E., Phillips, M. L., Mathew, S. J., … & Iosifescu, D. V. (2015). Regulation of neural responses to emotion perception by ketamine in individuals with treatment-resistant major depressive disorder. Translational psychiatry, 5(2). https://dx.doi.org/10.1038/tp.2015.10
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Neural correlates of change in major depressive disorder anhedonia following open-label ketamine

February 17, 2015 / Depressive Disorders, Ketamine, Neuroscience, Papers, Psychology, Publications / By / , , , , ,

Abstract

Anhedonia is a cardinal symptom of major depression and is often refractory to standard treatment, yet no approved medication for this specific symptom exists. In this exploratory re-analysis, we assessed whether administration of rapid-acting antidepressant ketamine was associated specifically with reduced anhedonia in medication-free treatment-refractory patients with major depressive disorder in an open-label investigation. Additionally, participants received either oral riluzole or placebo daily beginning 4 hours post-infusion. A subgroup of patients underwent fluorodeoxyglucose positron emission tomography scans at baseline (1–3 days pre-infusion) and 2 hours post-ketamine infusion. Anhedonia rapidly decreased following a single ketamine infusion; this was sustained for up to three days, but was not altered by riluzole. Reduced anhedonia correlated with increased glucose metabolism in the hippocampus and dorsal anterior cingulate cortex (dACC) and decreased metabolism in the inferior frontal gyrus and orbitofrontal cortex (OFC). The tentative relationship between change in anhedonia and glucose metabolism remained significant in dACC and OFC, and at trend level in the hippocampus, a result not anticipated, when controlling for change in total depression score. Results, however, remain tenuous due to the lack of a placebo control for ketamine. In addition to alleviating overall depressive symptoms, ketamine could possess anti-anhedonic potential in major depressive disorder, which speculatively, may be mediated by alterations in metabolic activity in the hippocampus, dACC and OFC.

Lally, N., Nugent, A. C., Luckenbaugh, D. A., Niciu, M. J., Roiser, J. P., & Zarate, C. A. (2015). Neural correlates of change in major depressive disorder anhedonia following open-label ketamine. Journal of Psychopharmacology. https://dx.doi.org/10.1177/0269881114568041
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Peak experiences and the afterglow phenomenon: When and how do therapeutic effects of hallucinogens depend on psychedelic experiences?

February 9, 2015 / Anxiety Disorders / PTSD, Depressive Disorders, Headache Pain and Neurological Disorders, Ketamine, LSD, Mescaline / Cacti, Mushrooms / Psilocybin, Neuroscience, Papers, Psychology, Publications, Substance Use Disorder / By / , ,

Abstract

Interest in the therapeutic potential of psychedelic substances has recently resumed. During an early phase of human psychedelic research, their therapeutic application in different pathologies had been suggested, and the first evidence for efficacy was provided. The range of recent clinical applications of psychedelics spans from cluster headaches and obsessive-compulsive disorder to addiction and the treatment of fear and anxiety in patients suffering from terminal illness, indicating potentially different therapeutic mechanisms. A variety of approaches in psychotherapy emphasize subjective experiences, such as so-called peak experiences or afterglow phenomena, as differentially mediating therapeutic action. This review aims to re-evaluate earlier and recent concepts of how psychedelic substances may exert beneficial effects. After a short outline of neurophenomenological aspects, we discuss different approaches to how psychedelics are used in psychotherapy. Finally, we summarize evidence for the relationship between subjective experiences and therapeutic success. While the distinction between pharmacological and psychological action obviously cannot be clear-cut, they do appear to contribute differently from each other when their effects are compared with regard to pathologies.

Majić, T., Schmidt, T. T., & Gallinat, J. (2015). Peak experiences and the afterglow phenomenon: When and how do therapeutic effects of hallucinogens depend on psychedelic experiences? Journal of Psychopharmacology. https://dx.doi.org/10.1177/0269881114568040
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