Research Update: IV Ketamine versus Intranasal Esketamine for Depression
July 12, 2021
Depression is a major worldwide issue, affecting nearly 300 million people. Traditional treatments include medication and psychotherapy. Unfortunately, about one third of patients will fail to have a meaningful response to standard medications such as SSRIs. Because of ketamine’s unique mechanism of action, many patients who have failed traditional medications will have a rapid and robust response to ketamine.
There are 2 forms of ketamine that have been most researched, intravenous and intranasal. The ketamine molecule exists in two mirror image forms called enantiomers. Think of enantiomers as “right-handed” and “left-handed” mirror image versions of the same ketamine molecule. The intravenous form has been used since the 1970s and is referred to as “racemic” because it contains both of the chemical enantiomers, the R-form and S-form. The intranasal form only contains only the S-form enantiomer and is named esketamine.
Researchers at the National Institute of Mental Health and Queen’s University recently published a study comparing the intravenous and intranasal administration.
The article, entitled “Comparative Efficacy of Racemic Ketamine and Esketamine for Depression; A Systematic Review and Meta-Analysis”, was published in the January 2021 edition of the Journal of Affective Disorders.
The purpose of the study was to compare the effectiveness and tolerability of the intravenous and intranasal forms. The researchers compiled the results of 24 individual trials, which included 1877 patients. The work was funded in part by the National Institute of Mental Health.
The first comparison was response to treatment. Most of the 24 studies defined a response as a 50% reduction of depression symptoms. The symptoms were measured using standard tools such as the Montgomery Asberg Depression Rating Scale. Intravenous ketamine demonstrated a greater response rate than the intranasal form. The intravenous form had a response rate ratio of 3.01, while the intranasal had a response rate ratio of 1.38. “Response ratio” is a measure of proportion of those responding in the treatment group compared to the control group. These results reveal that that IV ketamine group had 3.01 times the response rate compared to control group, while the intranasal group had only 1.38 times the rate of response rate of the control group (less than half the effect of the IV ketamine group).
The second comparison was remission of depression symptoms. Remission is generally defined as improvement to a point where the individual is virtually asymptomatic. In this study remission was defined as a Montgomery Asberg Depression Rating Scale score of less than 12. Intravenous ketamine demonstrated a greater remission rate than the intranasal form. The intravenous infusion had a remission rate ratio of 3.70, while the intranasal form had a remission ratio of 1.47. As with the last comparison, the response ratio suggests that IV ketamine was more than twice as effective as intranasal ketamine in achieving remission.
Exclusion criteria in most studies included psychotic disorders such as schizophrenia. Patients with acute medical problems such as uncontrolled hypertension were also generally excluded. Severe substance use disorders were usually a reason for exclusion in these studies of treatment resistant depression. Finally, pregnancy and breastfeeding were grounds for exclusion in all the trials.
The definition of treatment resistant depression (TRD) varied among the studies that were reviewed. About 20% of the researchers defined TRD as an inadequate response to 1 trial of standard anti depressant medication. About 60% of the researchers defined TRD as an inadequate response to 2 trials of medication. About 15% of time, TRD was defined as a failure of 3 medication trials.
The authors note that the mechanism of ketamine’s rapid and sustained anti depressant effects is still under investigation. The prevailing view is that NMDA receptor blockade appears to play a central role. This causes AMPA receptor activation with multiple pathways involved in the ultimate clinical response.