1. Weijian, Liu, et al. “Neurocognitive Performance and Repeated-Dose Intravenous Ketamine in Major Depressive Disorder” Journal of Affective Disorders. 2019 Mar 1; 246: 241-247.
SUMMARY: In this study 64 patients with Major Depressive Disorder (MDD) were given 6 low-dose ketamine infusions over a 12-day period followed by a 2-week observational period. Neurocognitive assessments were performed at days 0, 13 and 26. Significant improvements in speed of processing (F=20.7, p<0.001) and verbal learning (F=11.1, p<0.001) were found which were mediated by significant improvements in depressive symptoms.
2. Murrough, Perez, et al. “Rapid and Longer-Term Antidepressant Effects of Repeated Ketamine Infusions in Treatment-Resistant Major Depression” Biological Psychiatry. 2013 Aug 15; 74(4): 250–256.
SUMMARY: In this article, there were 24 patients treated with six IV infusions of ketamine (.5mg/kg) over 12 days. The overall response rate was 71% as defined as a reduction in the MADRS scale by greater than 50%. The median time to relapse after the last ketamine infusion was 18 days. 25% were symptom-free at 90 days, 75% of patients had symptom-free days between 11-27 days. Side effects were reported to be a mild significant increase in dissociative symptoms. One patient had to discontinue therapy due to an increase in blood pressure that did not respond to medications (highest BP 180/115).
3. Shiroma, Johns, et al. “Augmentation of response and remission to serial intravenous subanesthetic ketamine in treatment resistant depression” Journal of Affective Disorders. 2014 Feb; 155: 123-9.
SUMMARY: In this article, there were 14 patients treated with six IV infusions during a 12-day period. 12 subjects finished all six infusions with 92% response rate and 66% went into remission. 5 out of 11 responders remained in “response status” during the next 28 days. For the 6 out of 11 responders that relapsed, the mean time was 16 days. Response was defined as ≥50% improvement in baseline MADRS score and remission was defined as MADRS score ≤9. No subject experienced severe dissociative symptoms or hemodynamic changes that required stopping the infusions.
4. Sanacora, Frye, McDonald, et al. “A Consensus Statement on the Use of Ketamine in the Treatment of Mood Disorders” JAMA Psychiatry. April 2017; 74(4): 399-405.
SUMMARY: 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. 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.
5. Diazgranados, Nancy, et al. “A Randomized Add-on Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Bipolar Depression” Arch Gen Psychiatry. 2010 August; 67(8): 793–802.
SUMMARY: This is a randomized, placebo-controlled, double-blind, crossover, add-on study conducted from October 2006 to June 2009. Eighteen subjects with DSM-IV bipolar depression (treatment-resistant) maintained at therapeutic levels of either lithium or valproate received an intravenous infusion of either ketamine hydrochloride (0.5 mg/kg) or placebo on 2 test days 2 weeks apart. The MADRS was used to rate subjects at baseline and at 40, 80, 110, and 230 minutes and on days 1, 2, 3, 7, 10, and 14 post-infusion. Within 40 minutes, depressive symptoms significantly improved in subjects receiving ketamine compared with placebo; this improvement remained significant through day 3. The drug difference effect size was largest at day 2. 71% of subjects responded to ketamine and 6% responded to placebo at some point during the trial. One subject receiving ketamine and 1 receiving placebo developed manic symptoms. Ketamine was generally well tolerated; the most common adverse effect was dissociative symptoms.
6. Murrough, James, et al. “Antidepressant Efficacy of Ketamine in Treatment-Resistant Major Depression: A Two-Site Randomized Controlled Trial” American Journal of Psychiatry. October 2013; 170: 1134–1142.
SUMMARY: In this trial 72 patients were randomly assigned to receive low-dose ketamine infusion therapy or low-dose midazolam infusion therapy for treatment of treatment-resistant major depression currently experiencing a major depressive episode. The ketamine group had greater improvement in the MADRS score than the midazolam group 24 hours after treatment. The MADRS score was lower in the ketamine group than in the midazolam group by 7.95 points. The likelihood of response at 24 hours was greater with ketamine than with midazolam, with response rates of 64% and 28%, respectively.
7. Murrough, James, et al. “Rapid and Longer-Term Antidepressant Effects of Repeated Ketamine Infusions in Treatment-Resistant Major Depression” Biol Psychiatry. 2013 August 15; 74(4): 250–256.
SUMMARY: In this study, 24 patients with treatment resistant depression underwent a washout of antidepressant medication followed by a series of up to six intravenous infusions of ketamine (0.5 mg/kg) administered open-label three times weekly over a 12-day period. Participants meeting response criteria were monitored for relapse for up to 83 days from the last infusion. The overall response rate at study end was 70.8%. There was a large mean decrease in the MADRS score at two hours following the first ketamine infusion and this decrease was largely sustained for the duration of the infusion period. Response at study end was strongly predicted by response at four hours (94% sensitive, 71% specific). Among responders, median time to relapse following the last ketamine infusion was 18 days.
8. Marije aan het Rot, et al. “Safety and Efficacy of Repeated-Dose Intravenous Ketamine for Treatment-Resistant Depression” Biol Psychiatry. 2010; 67: 139–145.
SUMMARY: In this study 10 medication-free, symptomatic patients with treatment resistant depression who had previously shown a meaningful antidepressant response to a single dose of ketamine were given 6 ketamine infusions over 12 days to assess the tolerability, safety, and efficacy of repeated-dose ketamine infusions. Ketamine elicited minimal positive psychotic symptoms. Three patients experienced significant but transient dissociative symptoms. Side effects during and after each ketamine infusion were generally mild. The response criterion, a >50% reduction in MADRS, was met by nine patients after the first infusion as well as after the sixth infusion. The mean (SD) reduction in MADRS scores after the sixth infusion was 85%. Post-ketamine, eight of nine patients relapsed, on average, 19 days after the sixth infusion (range 6 days–45 days). One patient remained antidepressant-free with minimal depressive symptoms for >3 months.
9. Abdallah CG, et al. “Hippocampal volume and the rapid antidepressant effect of ketamine” Journal of Psychopharmacology. 2015 May; 29(5): 591-5.
SUMMARY: This study investigated the relationship between the rapid antidepressant effects of ketamine and hippocampal volume, a biomarker of antidepressant treatment outcome. 16 medication-free, major depressive disorder patients were given a single, sub-anesthetic dose infusion of ketamine (0.5 mg/kg, over 40 min). Depression severity pre-treatment and at 24 hours post-treatment were assessed with the Montgomery-Åsberg Depression Rating Scale (MADRS). Prior to treatment, patients underwent magnetic resonance imaging to estimate their hippocampal volume. The change in MADRS score was significantly correlated with the pre-treatment volumes of the left hippocampus. In summary, ketamine exerts enhanced antidepressant effects in patients with a relatively smaller hippocampus, a patient population that has been repeatedly shown to be refractory to traditional antidepressants.