Ketamine in Bipolar Disorder: A Review

This review (2020) investigates the potential of ketamine for the treatment of bipolar disorder (BD). Although studies with BD and ketamine are limited, studies on (unipolar) depression and neurological effects of ketamine (e.g. BDNF levels) show positive signals.

Abstract

“Bipolar disorder (BD) is a psychiatric illness associated with high morbidity, mortality and suicide rate. It has neuroprogressive course and a high rate of treatment resistance. Hence, there is an unquestionable need for new BD treatment strategies. Ketamine appears to have rapid antidepressive and antisuicidal effects. Since most of the available studies concern unipolar depression, here we present a novel insight arguing that ketamine might be a promising treatment for bipolar disorder.”

Authors: Alina Wilkowska, Łukasz Szałach & Wiesław J. Cubała

Summary

Ketamine might be a promising treatment for bipolar disorder, since it has rapid antidepressive and antisuicidal effects.

Introduction

Bipolar disorder (BD) is a burdensome and recurrent psychiatric condition that affects more than 1% of the population. Ketamine has been shown to have strong antidepressant and antisuicidal effects in treatment-resistant patients, and its unique mechanism of action may point to ketamine as an interesting treatment option for BD.

Ketamine in Bipolar Disorder – Clinical Data Single Administration

Low-dose ketamine intravenous infusion was first reported to have an antidepressant effect in patients with depression and later confirmed in patients with treatment-resistant MDD.

Ketamine was shown to have an antidepressant effect in a randomized, placebo-controlled, double-blind, crossover study with patients with bipolar depression. Similar results were obtained in another study and in a subsequent open-label study with 42 patients with bipolar depression.

Multiple Administration

Multiple administration of ketamine in patients with bipolar depression is scarce, but a very low dose of sublingual ketamine was reported to produce rapid and consistent effects in most patients with unipolar or bipolar depression; mild side effects were observed in 26 patients.

Ketamine infusions may decrease the severity of bipolar depression symptoms, improve quality of life and daily functioning, and reduce agitation, irritability, anxiety, and suicidal ideation.

Rapid Antisuicidal Effect of Ketamine

A single intravenous dose of ketamine was found to significantly reduce suicidal ideation in subjects with treatment-resistant depression. A recent open-label clinical trial found that six intravenous doses of 0.5 mg/kg ketamine three times a week were effective in reducing suicidal ideation in patients with unipolar and bipolar depression.

Ketamine’s antisuicidal mechanism remains speculative, but it may be related to its anti-inflammatory effect on microglia and its antidepressive effect on depression.

Risk of Affective Switch

Due to a lack of data, it is unclear whether ketamine induces an affective switch in treated patients. However, current evidence suggests that patients treated with antidepressants and those with a history of substance abuse are at an increased risk for affective switch.

Antidepressant Effect

Although the precise molecular and cellular mechanisms involved in the antidepressant effect of ketamine are unclear, the blockade of N-methyl-D-aspartate receptors at inhibitory interneurons causes the disinhibition of pyramidal cells and the activation of glutamatergic transmission.

Ketamine activates the BDNF-TrkB cascade in the prefrontal cortex and hippocampus, and increases the levels of BDNF, CREB, PKC, and PKA in brain areas known to be involved in MDD. This may be the reason why ketamine has such a long-lasting antidepressant effect.

Neuroplasticity and BDNF

Neurotrophins are essential for the sprouting of neurites, differentiation of neurons, and synaptogenesis. BDNF plays a role in neuronal maturation, differentiation, and survival, as well as synaptic plasticity, and is associated with a higher risk for early-onset BD, rapid cycling, suicidality, and treatment response.

Synaptogenesis

Ketamine improves spine density in the medial PFC of chronic social defeat stress-susceptible mice 1 week after administration of a single dose. One recent animal study found that ketamine caused the restoration of spines in the PFC lost due to stress. This suggests that maintaining the restored spines is necessary for maintaining behavioral remission and that long term as opposed to acute, antidepressant effects of ketamine.

Epigenetics

Epigenetic changes may play a role in the various phases of bipolar illness, including depression, euthymia, and mania. Ketamine may act via an epigenetic mechanism to treat depression.

Immunological Effects

Bipolar patients have increased levels of several proinflammatory cytokines, including IL-1, IL-4, IL-10, and tumor necrosis factor alpha. They also have a high prevalence of autoimmune diseases.

Ketamine may have immunological effects in bipolar patients by decreasing proinflammatory cytokines, decreasing kynurenine and quinolinic acid levels, and decreasing the level of IL-6 and TNF-.

Ketamine suppresses T-cell differentiation into Th17 cells, which may have an immunomodulatory role in BD patients with a predisposition to autoimmune disease.

Microbiota

The brain-gut-microbiota axis is involved in the pathophysiology of depression through its involvement in the immune system, endocrine system, and vagus nerve. The gut microbiota is altered in patients with bipolar depression.

Ketamine treatment improves gut microbiota composition, and mediates antidepressant effects through this mechanism. Ketamine also decreases stress-induced increases in Clostridium levels, and improves the abnormal composition of gut microbiota in rodents with a depression-like phenotype.

Lithium and Ketamine

Ketamine’s antidepressant effect is due to its NMDA antagonism, which causes activation of mTOR pathway, which increases BDNF synthesis, long-term neuroplasticity and mood stabilization. Lithium can also prolong the activation of mTOR/BDNF-TrkB pathways, which increases the antidepressant-like effects of ketamine in mice.

Ketamine and lithium modulate the glutamatergic system in the brain, and both have an immunomodulatory effect. Lithium treatment increased IL-1 production and decreased IL-6 production in activated monocytes from BD patients.

Staging and Neuroprogression in BD

Manic and depressive episodes are common in bipolar disorder, and there are several staging models that can be used to describe the disorder.

Neuroprogression is a concept that describes the pathological processes in the brain as a consequence of the toxicity-associated mood episodes. It has been suggested that epigenetic modifications appear earlier in life in individuals with bipolar disorder, and that insulin resistance may increase BBB dysfunction.

Ketamine may affect the progression of bipolar disorder by increasing brain-derived neurotrophic factor (BDNF) levels through an epigenetic mechanism effecting histone acetylation and the induction of neuroplasticity. Moreover, ketamine may improve cognitive functions in patients with unipolar and bipolar depression.

Discussion

Ketamine may have beneficial effects on the course of bipolar disorder, including effects on glutamatergic transmission, BDNF levels, and intracellular signal transduction, which are all perturbed in patients with BD. Ketamine may also have favorable effects on gut microbiota, which are disturbed in patients with BD.

Disclosure

Dr Alina Wilkowska, Dr ukasz Szaach, Prof Wiesaw Jerzy Cubaa have received research support from various companies, and they have not reported any potential conflicts of interest for this work.