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Ketamine for Delirium Tremens
This study suggests that ketamine can safely be used to avoid intubation and may decrease length of intensive care unit stay.
Severe alcohol withdrawal, or delirium tremens (DT), is a life-threatening condition that can require massive doses of benzodiazepines or barbiturates (GABA agonists), which can require intubation and prolonged intensive care unit (ICU) care. These authors studied a retrospective sample of adult patients admitted to a single ICU with DT to determine whether adjunctive therapy with ketamine improved outcomes.
They compared outcomes in 29 patients who received symptom-triggered therapy with GABA agonists with outcomes in 34 patients who were treated after initiation of a guideline that added an intravenous ketamine infusion (0.15–0.3 mg/kg/hour) to GABA agonist therapy. Using multivariable modeling that accounted for initial ethanol level and the total amount of GABA agonist required for treatment, patients who received ketamine had significantly lower rates of intubation (29% vs. 76% for patients who did not receive ketamine) and shorter ICU stay (5.7 days vs. 11.2 for patients who did not receive ketamine). There were no reported adverse events.
BackgroundKetamine has been demonstrated to improve depressive symptoms.
AimsEvaluation of efficacy, safety and feasibility of repeated oral ketamine for out-patients with treatment-resistant depression (TRD).
MethodIn a randomised, double-blind, placebo-controlled, proof-of-concept trial, 41 participants received either 1 mg/kg oral ketamine or placebo thrice weekly for 21 days (ClinicalTrials.gov Identifier: NCT02037503). Evaluation was performed at baseline, 40 and 240 min post administration and on days 3, 7, 14 and 21. The main outcome measure was change in Montgomery–Åsberg Depression Rating Scale (MADRS).
ResultsTwenty-two participants were randomised to the ketamine group, and 19 to the control, with 82.5% (n = 33) completing the study. In the ketamine group, a decrease in depressive symptoms was evident at all time points, whereas in the control group a decrease was evident only 40 min post administration. The reduction in MADRS score on day 21 was 12.75 in the ketamine group versus 2.49 points with placebo (P < 0.001). Six participants in the ketamine group (27.3%) achieved remission compared with none of the controls (P < 0.05). The number needed to treat for remission was 3.7. Side-effects were mild and transient.
ConclusionsRepeated oral ketamine produced rapid and persistent amelioration of depressive symptoms in out-patients with TRD, and was well tolerated. These results suggest that add-on oral ketamine may hold significant promise in the care of patients suffering from TRD in the community.
Repeated oral ketamine produced rapid and persistent improvement of depressive symptoms in a small sample of outpatients with treatment-resistant depression who continued their usual treatment, according to a proof-of-concept study published in The British Journal of Psychiatry.
“Intravenous ketamine … has been demonstrated to act as a novel antidepressant, with an extended effect following repeated infusions while maintaining a good safety profile,” Yoav Domany, MD, from Tel Aviv Sourasky Medical Center and Sackler School of Medicine, and postdoctoral research fellow, department of psychiatry and behavioral neuroscience, University of Cincinnati, and colleagues wrote. “However, intravenous administration presents major obstacles to clinical applicability, especially in community setting.”
Though previous study has examined IV and intranasal ketamine for treatment-resistant depression, research on oral ketamine is lacking. Therefore, the investigators conducted a randomized, placebo-controlled, proof-of-concept trial to determine the efficacy, safety and feasibility of add-on repeated oral ketamine for outpatients with treatment-resistant depression.
The researchers randomly allocated 41 participants to receive either 1 mg/kg oral ketamine or placebo three times a week for 21 days. All participants were instructed to continue taking their usual prescribed care. Patients were assessed at baseline, 40 minutes and 240 minutes after administration and on days 3, 7, 14 and 21 to measure change in Montgomery–Åsberg Depression Rating Scale (MADRS) scores.
Of 22 participants who received treatment with ketamine and 19 who received placebo (control group), 33 patients completed the study. Among those receiving ketamine, Domany and colleagues observed a reduction in depressive symptoms between baseline and all other time points (P < .005), including day 21. In the control group, there was also a decrease in symptoms, but only at 40 minutes after initial administration (P < .05).
At the endpoint (day 21), the reduction in MADRS score was 12.75 among those receiving ketamine compared with 2.49 points among those receiving placebo (P < .001). The researchers reported that 27.3% of the ketamine group (n = 6) achieved remission as opposed to none in the control group (P < .05) at day 21.
Adverse effects were mild and transient, according to the safety analysis. Common adverse effects included increased systolic blood pressure, euphoria, dizziness and drowsiness after initial administration, all of which resolved within 1 hour. Follow-up safety evaluation at day 28 showed a maintained effect on MADRS scores in the ketamine group.
“Our results, although promising, cannot yet be applied to clinical practice without larger, randomized studies,” Domany and colleagues wrote. “Such studies are needed to address questions such as optimal dosing regimens, patient selection and treatment duration to properly assess the safety of long-term ketamine usage, the risk of misuse and the restricted means appropriate for at-home prescription.”
Researchers observed no long-term adverse effects in a small sample of patients with severe and treatment-resistant mood disorders who received ketamine infusions as clinical treatment.
Although the response and remission rates after a four-infusion protocol were lower than those reported in most clinical trials, the small size and racial homogeneity of the study population limit the generalizability of these findings, according to data published in Journal of Clinical Psychiatry.
“Ketamine is being used as an off-label treatment for depression by an increasing number of providers, yet there is very little long-term data on patients who have received ketamine for more than just a few weeks,” Samuel T. Wilkinson, MD, from the department of psychiatry, Yale School of Medicine and Yale Psychiatric Hospital, told Healio Psychiatry.
“Controversy remains about whether ketamine should be used outside of research protocols due to concerns regarding potential negative clinical outcomes for repeated use, including impaired cognition, delusions and interstitial cystitis,” Wilkinson and colleagues wrote in their article.
At first, patients received a single- or double-infusion protocol (0.5 mg/kg over 40 minutes IV); but in early 2015, the researchers transitioned to a four-dose protocol over 2 weeks based on emerging evidence supporting the safety of a multiple-infusion protocol. They tracked symptom severity and set cognitive assessments at baseline and after every 6 to 12 treatments.
From October 2014 through February 2017, 54 patients received ketamine, with 518 total infusions performed. Ketamine infusions given at 0.5 mg/kg over 40 minutes were well-tolerated. Two patients discontinued treatment prematurely: one for intolerable dissociative effects and one for transient hypertension.
In the subset of 44 patients with mood disorders who began the four-infusion protocol, 45.5% responded and 27.3% remitted by the fourth infusion, which were lower rates than those reported in most previous clinical trials, according to the authors. Patients showed a significant reduction in symptoms over time. The overall mean score, as measured by the Quick Inventory of Depressive Symptomatology (Self-Report), dropped by 37.9% and the overall mean depression score dropped by 37.8%.
“While our paper has a number of limitations, one of its strengths is the long-term follow-up of a small cohort of patients who have received ketamine for depression, some for over a year,” Wilkinson told Healio Psychiatry. “Though we were not able to follow patients with the same level of rigor as a sponsored clinical trial, we observed no obvious adverse long-term effects on cognition, development of psychosis, or new-onset cases of ketamine abuse.”
In a subsample of 14 patients who received long-term ketamine infusions ranging from 12 to 45 total treatments over a course of 14 to 126 weeks, there was no evidence of cognitive decline, increased inclination for delusions or emerging symptoms consistent with cystitis.
“Given that racemic ketamine hydrochloride no longer has patent protections, it is unlikely that large and long-term clinical trials will be conducted to provide such long-term safety data,” they continued. “The formation of a registry combining data from community and academic sites is therefore the most realistic way of capturing long-term data on the effectiveness and safety of ketamine as a treatment for mood disorders.” –