Efficacy and safety of ketamine in bipolar depression: A systematic review

This review (2017) compared the safety and efficacy of ketamine for bipolar depression across scientific studies (1 clinical trial, 4 case studies, 5 cohort studies), which showed that symptoms are reduced swiftly and effectively in response to treatment, but they reappear relatively quickly within 3-14 days depending on the scale used to measure symptoms. Ketamine may be considered safe and effective for treating some cases of bipolar depression, although it has a short duration of action, in the absence of confirming studies designed specifically for bipolar depression.

Abstract

“The depression is the most prevalent state throughout the life of the bipolar patient. Ketamine has been shown to be an effective and rapid treatment for depression. The objective of the present work is to perform a systematic review on the efficacy and safety of ketamine as treatment of bipolar depression, as well as its different patterns of administration. The search found 10 relevant manuscripts that met the inclusion criteria: one clinical trial, 5 cohort studies, and 4 case reports. Intravenous infusion was used in 60% of the studies. According to data, ketamine seems to be an effective and safe treatment for bipolar depression, although the length of its effect is short. Adverse effects observed generally occurred at the time of infusion, and tended to completely disappear within 1–2 h. Therefore, more studies are necessary to explore new patterns of administration, as well as on its safety and adverse effects.”

Authors: Susana Albrich, Mónica Martínez-Cengotitabengoa, Purificación López, Iñaki Zorrilla, Nuria Núñez, Eduard Vieta & Ana González-Pinto

Summary

Bipolar depression is one of the most prevalent medical diseases and is also one of the most costly for the healthcare system. Ketamine is a phencyclidine derivate and NMDA receptor antagonist that has been shown to have a swift and potent effect against depressive episodes at sub-anaesthetic doses.

A literature search was performed on PubMed and Embase databases between January 2012 and October 2015 to find studies that evaluated the use of ketamine in cases of depression.

This review was conducted using PRISMA19 methodology and included 1 clinical trial, 5 cohort studies and 4 case series. Ketamine was administered by intravenous infusion and intramuscular injection, and sublingual administration.

A double blind, randomised, crossed and controlled study was performed to determine the degree to which ketamine has an antidepressant effect in patients with bipolar depression. The results showed that ketamine has a swift and continuous anti-suicide effect.

In a post hoc analysis of 2 double-blind, crossed and controlled studies, individuals with a family history of alcohol dependency showed better and longer lasting improvements to their depressive symptoms compared to those without a FHAP. They also displayed less perceptive distortion due to ketamine.

The authors describe a clinical case of severe depression within ECT-resistant BD I, treated with TMS or stimulation of the vagus nerve.

After different strategies, the subject accepted combined treatment of TMS and ketamine administered weekly for 3 years. One year after the start of treatment, remission of the symptoms occurred, with partial improvement in functioning. Rybakowski et al.27 found that ketamine had an effect on 25 patients with a bipolar depressive episode, while Permoda-Osip et al.28 found that 10 patients had responded to the treatment and that their B12 vitamin levels had increased in comparison with the subjects who had not responded.

Treatment with i.m. ketamine was effective for the treatment of phobic mania and depressive symptoms in the majority of patients. The treatment was well tolerated and the effects lasted for 3 — 7 days without side effects.

The patients experienced dizziness, somnolence, cognitive deterioration, anxiety, nausea, blurred vision or headache during the infusion phase, but these effects disappeared after 1 hour. The dissociative effects experienced were mild moderate in intensity and always lasted for less than min after administration.

Ketamine has been shown to be swiftly effective in reducing depres- sive symptoms and attempted suicides in depressed subjects with bipolar depression, although this effect has not been shown to last over time. Ketamine has been suggested to increase the efficacy of ECT in treating depression, but this has not been proven. In addition, the neuroprotector effect and efficacy of ketamine complementary to thiopental during ECT anaesthesia was evaluated for patients with severe depressive disorder. Low levels of vitamin B12 and folic acid, as well as high levels of homocysteine, have been found to be associated with depression. Additionally, vitamin B12 has been found to influence the mechanism of action of ketamine, and it would be highly interesting to have biomarkers that predict which patients will respond to ketamine.

Patients with genetic alcoholism heritability showed higher levels of the inflammatory biomarker IL-6 than patients who did not respond to ketamine. This suggests that a genetic variation in gene NR2A may be involved in the susceptibility to alcohol dependency. Ketamine is usually administered by i.v. infusion, but new formats have been studied recently such as oral, i.n., i.m. or s.l. Ketamine undergoes a metabolic transformation in the liver that converts it into norketamine, which has a longer half-life. With oral ketamine oral we found cases in which it did not seem to be effective, while in other studies it did bring about a reduction in symptoms. Injectable ketamine has also proven effective in different diagnoses.

Ketamine should be administered i.m. after an initial i.v. dose, but the oral preparation may increase the risk of abuse. Ketamine may cause side effects, such as headache, nausea, feeling slightly dazed, sleepiness and dizziness. These effects tend to disappear completely after 60 min. Ketamine stimulates the mammalian target of rapacymin receptor (mTOR), and may increase cardiac effort and frequency, as well as arterial pressure. Ketamine must be administered with caution to patients with cardiovascular diseases, and should not be used in depressed bipolar patients with a current or past history of neoplasia.

Ketamine may be considered a safe treatment for bipolar depression, although it has a short duration of action. More studies are needed to confirm its efficacy.