Ketamine for Bipolar Disorder

In this article, we will closely examine Ketamine, a versatile anaesthetic agent used in both human and veterinary medicine. Recent psychiatric research has indicated ketamine as an effective treatment for depression. What about ketamine for bipolar disorder? In this article, we will explore how ketamine works and the use of ketamine for bipolar disorder.
Klara Hatinova

Klara Hatinova

Klara is postgraduate researcher in experimental psychology at the
University of Oxford.

A blue image with text saying "Ketamine for Bipolar Disorder"

Can you treat Bipolar Disorder with Ketamine?

Ketamine is an FDA-approved treatment for bipolar disorder when administered as esketamine.

Ketamine can reduce suicidality without increasing the risks of mood switches, making it safe when administered in a controlled medical environment. Emphasis must be placed on controlled administration of ketamine, particularly in bipolar disorder, as incorrect dosing and setting during ketamine infusion could have detrimental effects on well-being.

Interestingly, ketamine has also been suggested as treatment for OCD. However, ketamine for ocd does not have FDA approval.

What is Ketamine?

Ketamine, first synthesized in the 1960s, has been used as an anaesthetic and analgesic in human and veterinary medicine for over 60 years [1]. It is a dissociative anaesthetic, meaning it can create feelings of detachment or dissociation from the environment and oneself [2].

Ketamine has a unique profile of effects through its action at the NMDA glutamate receptor, which has led to its use for various purposes beyond anaesthesia and pain relief. For example, ketamine has rapid-acting and long-lasting antidepressant effects [1]. Ketamine is also a popular recreational drug due to its ability to produce hallucinogenic effects and a state known as "K-hole" or "K-holing" [3]. Recreational use of ketamine is forbidden, as it is an addictive substance, and uncontrolled dosing and formulation increases the risk of adverse events [4]. Importantly, ketamine is not an opioid.

How does Ketamine work?

Ketamine works primarily by binding to the N-methyl-D-aspartate (NMDA) receptor throughout the brain, blocking the neurotransmitter glutamate. Glutamate plays a critical role in day-to-day brain function, and this activity is believed to help with ketamine's uses in anaesthesia, pain management, and depression treatment [2]. Blocking the NMDA receptor reduces the activity of brain circuits, leading to sedation [5].

Ketamine also has more subtle effects on other brain receptors, including those for opioids, serotonin, gamma aminobutyric acid (GABA), and dopamine. These effects are likely also important for ketamine’s beneficial impact on pain, depression, and anaesthesia, but precisely how these works is being actively investigated [2].

Furthermore, ketamine inhibits the voltage-gated Na and K channels and prevents serotonin and dopamine reuptake. This is an activity that resembles the neuropharmacological effects of (SSRIs), Tricyclic antidepressants or stimulants. It also affects receptors such as α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, kainate, and aminobutyric acid A receptors [6].

As demonstrated from the spectrum of receptors ketamine binds to, exactly how ketamine works is still a topic of active investigation. In the following section, we will cover the use of ketamine for bipolar, focusing on more specific therapeutic mechanisms.

Ketamine and Bipolar Disorder

Bipolar disorder is a chronic psychiatric illness that is difficult to treat, with many patients experiencing persisting depression [7]. Ketamine has shown benefits in treating bipolar disorder, particularly in addressing depressive symptoms, in several studies [8, 7, 9, 10, 11, 12, 13, 14, 15].

Esketamine in bipolar disorder

Esketamine, a specific chemical isolate of ketamine, has been approved for the treatment of bipolar disorder in 2019 [16]. This means that ketamine can be prescribed by psychiatrists if individuals with bipolar disorder experience high suicidality or do not get better after trying conventional treatments for bipolar disorder.

Ketamine is a mixture of two chemical compounds – S-ketamine and R-ketamine. S-ketamine, also called esketamine, has demonstrated lower dissociative effects and lower risk of overdose, making it a safe and more tolerated treatment than the mixture of R and S ketamine.

Suicidality reduction by ketamine in bipolar disorder

Suicidality is a major challenge in bipolar disorder, where many of the conventionally used drugs are ineffective [17].

Research agrees that ketamine can have rapid antidepressant and anti-suicidal effects [13]. Most of these studies have primarily focused on major depression patients, which lack the manic and switching characteristic of bipolar disorder. This study from the National Institute of Mental Health, however, recruited participants with major depression and bipolar disorder. They demonstrated that suicidality dramatically reduced 40 min post-injection and remained lower than the placebo group for the 3 days follow-up [15]. Furthermore, this study in the New England Journal of Medicine, a prestigious medical journal, reported that ketamine was more effective at reducing suicide risk in bipolar disorder than in major depression [16].

How does ketamine reduce suicidality?

The specific mechanism of how ketamine reduces suicidality is still being researched. Improvements in depression and anxiety symptoms are likely a psychological mechanism through which ketamine reduces suicidal thoughts [15].

At the neurobiological level, ketamine increases levels of glutamate, particularly in the prefrontal cortex and midbrain [18]. This increase in glutamate facilitates neuroplasticity, which is the re-wiring of neural connections. Re-wiring neural connections can improve decision-making clarity and elevate mood [18, [19].

Considerations when using Ketamine for Bipolar Disorder

It is critical to remember that bipolar disorder is characterized by mood switching. Increasing the activity of glutamate in the brain can disrupt the balance of mood regulation, increasing the risk of mood switching towards a manic state [19]. This finding has been primarily demonstrated in mice models. lithium, a mood-stabilizer commonly used for bipolar treatment, reversed mania induced by ketamine [19]. On the other hand, a clinical systematic review found only one patient with ketamine transitioned into a manic phase within the 6-week study, the same number of patients as in the placebo condition [16]. These results were replicated by a larger study encompassing patients with major depression [9].

Importantly, not everyone is a good candidate for ketamine therapy.

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Klara Hatinova

Klara Hatinova

Klara is a postgraduate researcher in experimental psychology at the University of Oxford. She has worked across a spectrum of hot topics in neuroscience, including her current project measuring reinforcement learning strategies in Parkinson’s disease. Previously, she studied the efficacy of psilocybin as a therapy for critical mental health conditions and examined molecular circadian rhythms of migraine disorders. She completed her undergraduate degree in Neuroscience at the University of Glasgow and participated in a year abroad at the University of California, where she worked on a clinical trial for spinal cord injury.