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IV Ketamine for Treatment-Resistant Depression

A systematic review examines the benefits of IV ketamine for depression.

Source: PublicDomainPictures/Pixabay

A new meta-analysis, by Marcantoni and collaborators, reviews the efficacy of intravenous ketamine for the management of treatment-resistant depression. The paper was published in the December 2020 issue of the Journal of Affective Disorders. Before I summarize the findings of this paper, let me provide some background information about ketamine and treatment-resistant depression.

Ketamine for treatment-resistant depression

Many people with depression do not respond well (or at all) to one or more commonly prescribed antidepressants, like the selective serotonin reuptake inhibitor (SSRIs) or serotonin and norepinephrine reuptake inhibitors (SNRIs).

Some common SSRIs are sertraline (Zoloft), fluoxetine (Prozac), citalopram (Celexa), escitalopram (Lexapro), and paroxetine (Paxil). Common SNRIs include venlafaxine (Effexor), desvenlafaxine (Pristiq), duloxetine (Cymbalta), and levomilnacipran (Fetzima).

Individuals who do not respond to antidepressant medications might meet the criteria for treatment-resistant depression, which is commonly defined as not responding to two or more antidepressants or psychotherapies.

A drug called ketamine has shown promise in helping people with treatment-resistant depression. Ketamine may help individuals who did not benefit from SSRI or SNRI medications or individuals who have severe depression with suicidal tendencies.

Though ketamine is administered in a variety of ways (e.g., oral, intranasal, intravenous), the only form of ketamine approved by the FDA for use in depression is in the form of a nasal spray (esketamine; brand name Spravato).

However, ketamine administered intravenously—sometimes called intravenous ketamine (IV ketamine) or ketamine infusion—has yet to receive FDA approval for use in treatment-resistant depression. But what does the research say? Is IV ketamine helpful in treatment-resistant depression? And if so, how long will its antidepressant effects last? To answer these questions, let us review the research by Marcantoni and colleagues.

Ketamine for treatment-resistant depression: Methods and results

To identify all published research reports on the effectiveness of ketamine infusion in individuals with treatment-resistant depression, the authors conducted a search of various databases (e.g., PubMed, PsycINFO) for investigations “evaluating intravenous sub-anaesthetic dose of ketamine administration in adults (≥18 years) diagnosed with major depressive or bipolar disorder and presenting [treatment-resistant depression].”

The final sample consisted of 28 studies (35 publications): Most (19) of these investigations took place in the US. The rest took place in Taiwan, Poland, Czech, Canada, Iran, India, and China. The total number of participants was 1000 (ranging from one to 99, in different trials).

Of the 28 investigations, 19 (7 randomized controlled trials and 12 open-label trials; 818 participants) were included in the meta-analysis as well.

The findings showed the following:

Ketamine infusion (even a single dose of 0.5 mg/kg) was effective in reducing depressive symptoms in individuals with treatment-resistant depression.

Furthermore, “This effect was observed as early as 4 hours post-infusion, and peaked at 24 hours thereby providing evidence of the rapid impact of ketamine on mood.”

However, the effects of ketamine were reduced after seven days, suggesting the antidepressant benefits of ketamine are short-lived.

The meta-analysis of randomized controlled trials showed the following:

One day after the IV ketamine treatment, patients were seven times more likely to have a positive clinical reaction when compared with the placebo group. The clinical benefits of ketamine were reduced a week after the infusion—the positive clinical reactions were now five times, instead of seven times, more likely.

Clinical remission rates showed a similar pattern. Patients in the ketamine treatment group were six times more likely to show remission after a day, but only four times more likely to show remission after a week when compared to the control condition.

And according to the systematic review, “clinical relapse occurred between 7 and 30 days in approximately a quarter of the participants following a single ketamine infusion.”

Sustaining the benefits of ketamine

Based on the results from the systematic review, “multiple ketamine infusions (0.5 mg/kg, 3 times/week over 2 weeks) not only enhanced its effectiveness compared to a single infusion, but it also delayed clinical relapse.”

To sustain the benefits of ketamine, “higher-frequency course of treatments” should be “followed by longer-term, lower-frequency maintenance doses.”

These lower maintenance doses could continue as long as necessary (e.g., several weeks), such as until the suicidal tendencies decrease significantly or the patient begins to experience the benefits of a new antidepressant medication (e.g., SSRIs) or psychotherapy (e.g., cognitive-behavioral therapy).

Source: LeNislavAx/Pixabay

Though this seems like a promising approach, we should keep in mind the potential risks of long-term administration of ketamine. For one, long-term use of ketamine increases the risk of addiction and drug abuse. Furthermore, though some side effects of ketamine (e.g., increased blood pressure, dissociation) are already known, long-term side effects of ketamine infusion are not well understood.

In short, though the results are encouraging, more research is necessary before long-term use of IV ketamine for depression receives a strong recommendation.

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