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Ketamine infusion well-tolerated in small sample with mood disorders

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.

Ketamine treatments were given in an electroconvulsive therapy suite. In late 2014, Yale began providing ketamine as an off-label therapy on a case-by-case basis for patients who could not participate in research protocols. In the current article, the authors assessed the participants’ experience over 29 months of providing ketamine as a clinical treatment for severe and treatment-resistant mood disorders.

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.

“There remains an urgent need for more powerful and comprehensive long-term safety data on ketamine from much larger samples,” Wilkinson and colleagues wrote.

“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.”

Acute and Longer-Term Outcomes Using Ketamine as a Clinical Treatment at the Yale Psychiatric Hospital

Objective: Ketamine has emerged as a rapid-acting antidepressant, though controversy remains whether sufficient data exist to justify its use outside of research protocols. In October 2014, the authors’ institution began providing ketamine as an off-label therapy on a case-by-case basis for patients unable to participate in research protocols. Here, the participant experience during 29 months of providing ketamine as a clinical treatment for severe and treatment-resistant mood disorders through February 2017 is described.

Methods: Patients were initially treated with a single- or double-infusion protocol (0.5 mg/kg for 40 minutes intravenously) and were later transitioned to a 4-infusion protocol over 2 weeks.

Results: Fifty-four patients received ketamine, with 518 total infusions performed. A subset of 44 patients with mood disorders initiated the 4-infusion protocol, of whom 45.5% responded and 27.3% remitted by the fourth infusion. A subsample (n = 14) received ketamine on a long-term basis, ranging from 12 to 45 total treatments, over a course of 14 to 126 weeks. No evidence was found of cognitive decline, increased proclivity to delusions, or emergence of symptoms consistent with cystitis in this subsample.

Conclusions: In general, ketamine infusions were tolerated well. The response and remission rates in this clinical sample were lower than those observed in some research protocols. The small number of patients who were treated on a maintenance schedule limits the conclusions that can be drawn regarding the long-term safety of ketamine; however, no long-term adverse effects were observed in this sample.