Ketamine for Depression

Ketamine was approved as an anesthetic in 1970. It is generally considered an "off-label" drug for the treatment of depression. Its main mechanism of action is blocking one of the receptors that a neurotransmitter, glutamate blinds to. It is know to have a dose dependent effect. With a low dose, it causes analgesic effect while with a high dose it produces anesthetic effects. Ketamine’s antidepressant is currently widely researched. The mechanism of how it works as an antidepressant is not clearly understood yet. Ketamine is a regulated scheduled substance and only licensed healthcare professionals can prescribe this medication to treat depression. It is often combined with psychotherapy as it seems to make the treatment more effective. Its effectiveness has been studied in people with major depression, post-traumatic stress disorder (PTSD), obsessive compulsive disorder, bipolar disease, anxiety disorders, and eating disorders. Although it is generally a safe medication under proper supervision, certain patients such as patients with schizophrenia or psychosis, pregnancy, or unstable medical conditions are not good candidates for ketamine therapy.

Ketamine is available in several routs of administration such as intravenous, intramuscular, intranasal, oral, sublingual, subcutaneous, and perrectal. Intranasal esketamine was approved by FDA for TRD in 2019. They have different bioavailability and produce various effects from the metabolites of ketamine. Many of the earlier studies about ketamine has been with intravenous ketamine. Now more and more researches are conducted using oral and sublingual ketamine showing its efficacy for depression, anxiety and other indications. This form of ketamine makes the treatment more accessible and affordable.

Berman et al. studied the effect of intravenous ketamine in patients with major depressive disorder in 2000. Seven patients were involved in this study. It was noticed that mood symptoms improved rapidly within 4 hours of administration of ketamine. Ketamine infusion was given at the dosage of 0.5mg/kg for 40 minutes. Reduction in symptoms was measured on the Hemilton depression rating scale. This score was reduced by 13 points on average. These patients had failed to show any improvement with two traditional antidepressants. Ketamine showed an antidepressant effect and reduced the severity of the major depressive disorder. A restrospective study published in the Journal of Affective disorders closely observed the effect of ketamine intravenous therapy (KIT) in patients with depression. In this retrospective analysis, 9016 patients who received ketamine intravenous therapy (KIT) were studied. They received 4-8 infusions over 7-28 days. Symptoms of depression were analyzed using Patient Health Questionnaire-9 (PHQ-9). As a result, 53.6% of patients showed more than a 50% reduction in symptoms of depression in a PHQ-9 score and 73% of patients showed a reduction in suicidal ideation. It indicated a robust response to ketamine in patients with depression.

A randomized control study involved 41 patients with treatment-resistant depression. A single infusion of ketamine decreased depression scores by 22.3 in 27% of the patients. Each infusion of ketamine decreased the depression score by 2 points. Only 5% of patients had remission. A case series evaluated the effectiveness of oral ketamine in patients with depression. Twenty-two patients were observed. They took three different types of antidepressants, but there was no improvement. There was a significant improvement in symptoms of depression after the administration of ketamine.  18% of patients showed more than 50% improvement in depression in the Beck Depression Inventory 2 score. 14% of patients had partial improvement in mood stability, and 45% showed no response.After many researches such as the ones above, a meta analysis by Marcontoni et al(2020) analyzed 28 studies and concluded that a single ketamine infusion was effective in reducing depression scores in TRD patients. The effect was observed as early as 4 hour post infusio, and peaked at 24 hours thereby providing evidence of the rapid impact of ketamine on mood. Its effect was reduced at 7 days infusion.

We have three randomized control studies at the time of this writing and many more opent label studies. Recently, two retrospective chart reviews with over 1000 patients each showed oral ketamine’s efficacy for depression and anxiety(Hull et al, Hassan et al). In these studies, the patients and providers interacted via telemedicine platform rather that with in-person visits.