Ketamine therapy research and publications

  

Pharmacology 

Pharmacologically, ketamine is an N-methyl-d-aspartate (NMDA) receptor antagonist. Ketamine has been used for decades as an anesthetic by medical and veterinary communities, medically indicated due to its safety and wide therapeutic range. At subanesthetic doses, ketamine has been shown to increase glutamate levels. This mechanism is relevant, as glutamate regulation and expression are altered in patients with major depressive disorder (MDD) and changes in glutamatergic activities could be specifically linked to suicidality. Ketamine therapy has since been observed in randomized control trials to rapidly reduce depression and most recently, a post hoc analysis of four studies found that ketamine has an impact on suicidal ideation that is independent of improvement in depression and anxiety. 

Depressive Disorders

Major Depressive Disorder (MDD)

Ketamine's efficacy in depressive disorders has been established in several controlled trials. Han et al (2016) performed a meta-analysis to comprehensively and systematically assess the efficacy of ketamine for treating patients with Major Depressive Disorder (MDD). Randomized, double-blind, placebo-controlled studies on ketamine versus placebo for treating MDD were included and three treatment time points (24 hrs and 72 hrs, and day 7) were chosen. Response and remission rates were the main outcomes. Nine high-quality studies that included 368 patients were selected to compare the efficacy of ketamine to placebo. The therapeutic effects of ketamine at 24 hrs and 72 hrs, and day 7 were found to be significantly better than placebo. Response and remission rates in the ketamine group at 24hrs and 72 hrs, and day 7 were 52.2% and 20.6%; 47.9% and 23.8%; and 39.8% and 26.2%, respectively. These results indicated that ketamine could yield a good efficacy in the rapid treatment of MDD.

Fond et al (2014) conducted a meta-analysis which inclduded nine studies (192 patients with major depressive disorder and 34 patients with bipolar depression). Overall, depression scores were significantly decreased in the ketamine groups compared to those in the control groups. Ketamine's efficacy was confirmed in MDD (resistant to previous pharmacological treatments or not), in bipolar depression, and in drug-free patients as well as patients under medication. The duration of ketamine's effects was assessed and seemed to persist for 2-3 days. The meta-analysis confirms ketamine's efficacy in depressive disorders and are encouraging of further studies warranted to detail efficacy in bipolar disorders and other specific depressed populations. 

Treatment Resistant Depression (TRD)

Papadimitropoulou et al (2015) conducted a meta network analysis to compare the efficacy of ketamine with other pharmacological and somatic treatments in adult Treatment Resistant Depression (TRD) patients. Thirty-one randomized controlled trials (RCTs) were included: 19 RCTs investigating 13 pharmacological interventions and 12 RCTs investigating electroconvulsive therapy (ECT) or repetitive transcranial magnetic stimulation (rTMS). Ketamine seemed more efficacious in reducing depressive symptoms at 2 weeks than aripiprazole augmentation, venlafaxine monotherapy, olanzapine/fluoxetine combination, fluoxetine monotherapy, quetiapine augmentation, nortriptyline monotherapy , lamotrigine augmentation, ECT, and rTMS. Based on the evidence synthesis of available RCTs investigating the efficacy of TRD treatments at 2 weeks, ketamine demonstrated superior efficacy compared with other pharmacological and somatic interventions.

Suicidal Ideation (SI)

There is preliminary evidence not only for the antidepressant action of Ketamine, but also for rapid anti-suicidal action. With an estimated prevalence of mood disorders ranging from 3.3 to 21.4 % and the substantially increased risk of suicide among patients with mood disorders, there is an urgent need for faster therapeutics for suicidal ideation and treatment resistant depresion. Reinstalter et al (2015) conducted a systemaic review with a total of nine publication (six studies and three case reports) to investigate the efficacy of Ketamine for SI. Three of these studies were randomized controlled trials, three were open-label non-randomized studies, and three were case reports. Similar to findings of studies examining patients with treatment resistant depression (40 RD), the aforementioned studies examining Ketamine and SI found a reduction in SI is seen as early as 40 minutes and lasted for an average of 3 days.

Obsessive-Compulsive Disorder (OCD)

Rodriguez et al (2013) performed a randomized controlled crossover trial of ketamine in obsessive-compulsive disorder to test whether a single dose of ketamine 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. Unexpectedly, ketamine's effects within the crossover design showed significant carryover effects (lasting longer than 1 week). As a result, only the first-phase data were used in additional analyses. Those receiving ketamine (n=8) reported significant improvement in obsessions during the infusion compared with subjects receiving placebo. One-week post-infusion, 50% of those receiving ketamine (n=8) met criteria for treatment response 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. 

Post Traumatic Stress Disorder (PTSD)

Few pharmacotherapies have demonstrated sufficient efficacy in the treatment of posttraumatic stress disorder (PTSD), a chronic and disabling condition. Feder el al (2014) tested the efficacy and safety of a single intravenous subanesthetic dose of ketamine for the treatment of PTSD and associated depressive symptoms in patients with chronic PTSD. A proof-of-concept, randomized, double-blind, crossover trial comparing ketamine with an active placebo control, midazolam, was conducted and forty-one patients with chronic PTSD related to a range of trauma exposures were recruited. Ketamine infusion was associated with significant and rapid reduction in PTSD symptom severity, compared with midazolam, when assessed 24 hours after infusion. Ketamine was also associated with reduction in comorbid depressive symptoms and with improvement in overall clinical presentation. Ketamine was generally well tolerated without clinically significant persistent dissociative symptoms. This study provides the first evidence for rapid reduction in symptom severity following ketamine infusion in patients with chronic PTSD.

Chronic Pain

Chronic non-cancer pain

Ketamine has been suggested to be efficient in relieving chronic pain. Michelet et al (2017) conducted a meta-analysis of clinical trials comparing ketamine to a placebo during chronic non-cancer pain. The primary endpoint of this study was pain relief 4 weeks after the beginning of treatment. Secondary outcomes were: pain relief 1, 2, 8 and 12 weeks after the beginning of treatment. Six studies were included in this meta-analysis. Overall, 99 patients received ketamine and 96 received placebo. Analysis studies with no high-risk bias found ketamine to decrease pain intensity at 4 weeks. Ketamine also decreased pain intensity at all other evaluated points in time. Results of this meta-analysis found ketamine efficient in alleviating pain up to 12 weeks after the beginning of treatment

Complex Regional Pain Syndrome (CRPS)

Complex regional pain syndrome (CRPS) is a painful debilitating neurological condition that accounts for approximately 1.2% of adult chronic pain population. There is a growing body of clinical evidence to support the use of ketamine in the treatment of neuropathic pain, especially CRPS. Zhao et al (2018) reviewed the current available studies and a meta-analyses was conducted to evaluate the efficacy of ketamine infusion in the treatment of CRPS. Findings suggests that ketamine infusion can provide clinically effective pain relief in short term for less than 3 months. Furthe studies are needed to prove long-term efficacy of ketamine infusion in the treatment of CRPS.

References:

Han, Y., Chen, J., Zou, D., Zheng, P., Li, Q., Wang, H., Li, P., Zhou, X., Zhang, Y., Liu, Y. and Xie, P.  (2016). Efficacy of ketamine in the rapid treatment of major depressive disorder: a  meta-analysis of randomized, double-blind, placebo-controlled studies. Neuropsychiatric  Disease and Treatment, Volume 12, pp.2859-2867

Feder, A., Parides, M. K., Murrough, J. W., Perez, A. M., Morgan, J. E., Saxena, S., . . . Charney, D.  S. (2014). Efficacy of Intravenous Ketamine for Treatment of Chronic Posttraumatic  Stress Disorder. JAMA Psychiatry, 71(6), 681. doi:10.1001/jamapsychiatry.2014.62

Fond, G., Loundou, A., Rabu, C., Macgregor, A., Lançon, C., Brittner, M., Micoulaud-Franchi, J.,  Richieri, R., Courtet, P., Abbar, M., Roger, M., Leboyer, M. and Boyer, L. (2014).  Ketamine administration in depressive disorders: a systematic review and meta- analysis. Psychopharmacology, 231(18), pp.3663-3676.

Michelet, D., Brasher, C., Horlin, A., Bellon, M., Julien-Marsollier, F., Vacher, T., . . . Dahmani, S.  (2017). Ketamine for chronic non-cancer pain: A meta-analysis and trial sequential  analysis of randomized controlled trials. European Journal of Pain, 22(4), 632-646.  doi:10.1002/ejp.1153

Papadimitropoulou, K., Vossen, C., Karabis, A., Donatti, C., & Kubitz, N. (2017). Comparative  efficacy and tolerability of pharmacological and somatic interventions in adult patients  with treatment-resistant depression: A systematic review and network meta-analysis.  Current Medical Research and Opinion, 33(4), 701-711.  doi:10.1080/03007995.2016.1277201

Reinstatler, L., & Youssef, N. A. (2015). Ketamine as a Potential Treatment for Suicidal Ideation:  A Systematic Review of the Literature. Drugs in R&D, 15(1), 37-43.  doi:10.1007/s40268-015-0081-0

Rodriguez, C. I., Kegeles, L. S., Levinson, A., Feng, T., Marcus, S. M., Vermes, D., . . . Simpson, H.  B. (2013). Randomized Controlled Crossover Trial of Ketamine in Obsessive-Compulsive  Disorder: Proof-of-Concept. Neuropsychopharmacology, 38(12), 2475-2483.  doi:10.1038/npp.2013.15

Zhao, J., Wang, Y., & Wang, D. (2018). The Effect of Ketamine Infusion in the Treatment of  Complex Regional Pain Syndrome: A Systemic Review and Meta-analysis. Current Pain  and Headache Reports, 22(2). doi:10.1007/s11916-018-0664-x








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