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Ketamine Alone May Effectively Treat Depression, Study Suggests

By Alexander Beadle

Published: Oct 01, 2021   
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Ketamine alone may be just as effective as ketamine combined with traditional antidepressants for tackling treatment-resistant depression, a new study has found.

The research, published in the Journal of Psychiatric Research, also found that individuals with treatment-resistant depression who received ketamine monotherapy went on to experience a greater reduction in reports of suicidal ideation than those on antidepressants with adjunct ketamine.

The researchers say that this study, which was conducted within a community-based treatment clinic, provides real-world evidence supporting ketamine’s effectiveness as both an adjunct and monotherapy treatment. As a result, they say that more randomized controlled trials (RCT) comparing ketamine monotherapy and adjunct ketamine should be a matter of priority, suggesting that more work should be done to investigate which patients are most likely to benefit from combination treatments versus monotherapy.

Ketamine monotherapy curbs suicidal ideation more effectively

A total of 220 patients receiving ketamine therapy were eligible for inclusion in this retrospective study, with 39 receiving ketamine monotherapy and the remaining 181 being on some combination of ketamine therapy and at least one other traditional antidepressant or mood stabilizer medication.

All of the patients received intravenous (IV) ketamine at the Canadian Rapid Treatment Centre of Excellence for treatment-resistant depression (TRD) over four treatment sessions. All participants started their ketamine treatment regime on a dose equivalent to 0.5 milligrams per kilogram (mg/kg) bodyweight, but patients who saw no clinically meaningful benefits after the first two sessions were permitted to increase their dosage to 0.75 mg/kg for the last two sessions.

Before beginning this treatment, patients were asked to complete a battery of standard self-report assessments designed to quantify and measure overall depressive symptom severity, suicidal ideation, anxiety, and functional impairment. The assessment of depressive symptom severity (which included the subsection of questions on suicidal ideation) was administered at every treatment session, with the assessments for anxiety and functional impairment given at baseline, the midway point, and at a post-treatment follow-up visit.

In both the ketamine monotherapy and adjunctive groups, the researchers saw large reductions in self-reported overall depressive symptom severity and anxiety. Moderate reductions were also observed with respect to suicidal ideation and functional impairment scores.

However, the researchers observed a significantly greater reduction in suicidal ideation scores in the TRD patients receiving ketamine monotherapy, as compared to those using ketamine adjunct to other antidepressants. While the baseline suicidal ideation scores were higher overall in the group prescribed ketamine monotherapy, this trend held in the statistical analysis even after controlling for the higher baseline figures.

Additionally, after the four ketamine infusion sessions it was determined that 39.1 percent of the participants in the ketamine monotherapy group responded to the treatment, with 17.4 percent achieving remission from TRD. In the ketamine adjunct group, these response and remission rates were just 21.9 percent and 6.7 percent, respectively. The researchers believe that more research with larger sample sizes could help to prove the statistical significance of this outcome and to examine whether the specific classes of traditional antidepressant being used with ketamine may have an effect on response and remission rates.

Researching ketamine for treatment-resistant depression

Where most conventional antidepressants target the body’s monoaminergic systems, ketamine makes its effects felt by acting as an N-methyl-D-aspartate receptor (NMDAR) agonist. This unique mechanism of action means that where traditional antidepressants may have failed, as is the case with TRD, ketamine still has the potential to be an effective line of treatment.

Multiple studies have confirmed the safety and efficacy of certain ketamine formulations, culminating in the approval of Spravato – a nasal spray containing the s-enantiomer of ketamine as its active ingredient – by the FDA in 2019 and Health Canada in 2020 for treatment-resistant depression.

However, the majority of the studies that have been done to assess the use of ketamine for depression have focused on patients who were already taking at least one other antidepressant medication. Beyond this new study from the Canadian Rapid Treatment Centre of Excellence, there is very little information in the medical literature focusing on ketamine monotherapy treatments for depression.

“Ketamine has been almost exclusively studied as an antidepressant adjunct to other antidepressants, most commonly monoaminergic agents such as SSRIs,” the researchers wrote. “Due to the dearth of high-quality clinical data on the safety and efficacy of ketamine as an antidepressant monotherapy, the majority of clinicians continue to prescribe ketamine to patients with the condition that they remain on a stable dose of one or more antidepressant drugs for the duration of treatment.”

Given the lack of research into ketamine monotherapy, the researchers are concerned that there is an inadequate evidence base in existence that can guide the decisions of healthcare professionals in choosing to prescribe adjunct ketamine versus ketamine monotherapy.

“An important question remains to be answered regarding the optimal treatment regimen for individuals with TRD: if there is no difference in safety, efficacy, and tolerability between ketamine monotherapy and ketamine adjunct to antidepressant drugs, why would we not ask patients to stop their adjunctive medications to reduce the burden of side effects?” they questioned.

In light of these findings, the researchers believe that there would be merit in conducting larger scale, randomized controlled trials that directly compare the effects of ketamine monotherapy with ketamine as an add-on treatment to traditional antidepressants in TRD. They also anticipate that future research could focus on identifying any factors which may make an individual patient more likely to benefit from one treatment versus the other, or if the specific antidepressants being used in conjunction with ketamine may have a synergistic or detrimental effect on treatment.


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