Ketamine for Bipolar Disorder Treatment

sad woman sitting alone in her house

William Chua/iStock/Getty Images

Table of Contents
View All
Table of Contents

You may have heard about ketamine treatment for depression, but did you know ketamine can also be used to treat bipolar disorder? Specifically, it is used to treat the depression “pole” of bipolar.

Ketamine is lauded because it can lift a depressed mood quickly—often within hours. Because bipolar disorder has such a high rate of treatment resistance and suicidality, this is significant, compared to other medications that may take weeks before the full effect is reached.

How Does Ketamine for Bipolar Treatment Work?

Ketamine exists in two different forms chemically—r-ketamine and s-ketamine. They are enantiomers, meaning they have the same chemical formula but arranged differently structurally.

R-ketamine, which is what is generally used for IV infusions, shows more long-lasting effects than s-ketamine (typically used in Spravato nose spray). Additionally, r-ketamine may have a better safety profile than s-ketamine, as it seems to be less prone to abuse and have fewer side effects.

Ketamine is thought to be so effective because it works on so many different systems in the brain. One of the biggest systems it works on is the glutamate system—which helps neurons communicate. In fact, it is present in upwards of 90% of all synapses in the brain. 

When someone has been dealing with chronic stress or chronic depression often they may start to lose some of those connections due to increased release of glutamate, leaving one glutamate-deficient, but ketamine induces glutamate production—and quickly.

Ketamine is a N-methyl-D-asparate (NMDA) antagonist, which means that it selectively blocks glutamate from overachieving the NMDA receptor—it acts like a gate to let in precisely the amount of glutamate needed. Learning, memory and neuroplasticity processes all depend on the activities of the NMDA receptors.

First, ketamine induces changes in brain circuitry functioning, which improves behaviors in hours (hence the rapid decrease in suicidality). It then stimulates regrowth of synapses, which help neurons in the brain connect with each other.

The addition or strengthening of synapses helps our brains be able to store more, as the neurons are better able to communicate with each other. Decreased neuronal synapses are often observed in depression, but ketamine increases the formation of new synapses in the brain, which help builds neural plasticity.

In bipolar, specifically in mania, thinning gray matter has been shown to be linked with manic symptoms such as decreased impulse control and decreased control over senses. It has been shown that ketamine increased gray matter activity.

Gray Matter

Gray matter is the outermost layer of the brain and is responsible for controlling movement, memory and emotions.

How Effective Is Ketamine for Bipolar Disorder Treatment?


One of the most powerful arguments for using ketamine for bipolar treatment is its high rate of response. People with bipolar disorder face a standardized mortality rate of 20 times more than the general population due to death by suicide.

Additionally, upwards of 25% of those with bipolar disorder are treatment-resistant, meaning at least two or more types of treatment (medication, psychotherapy, electroconvulsive therapy) have failed.

Because of these statistics, finding an effective treatment that works rapidly is key. In randomized controlled trials, more than 75% of patients responded to ketamine, while 0% responded to treatment as usual—and most responded within an hour and typically enjoyed up to three days of relief from suicidal ideation.

While three days of relief from suicidal ideation is significant, this is compared to up to seven days for those with unipolar depression as well as some relief from anxiety.

However, Lamictal (lamotrigine) is a common mood stabilizer that many people with bipolar disorder take, and it affects ketamine’s efficacy, so this may contribute to potentially lower efficacy rates. Another study of people with bipolar found that those who were on lithium responded slightly better to ketamine than those who were on the mood stabilizer valproate.

Benefits of Ketamine for Bipolar Disorder

There are three major schools of thought on how ketamine works on bipolar disorder: biochemically, psychotherapeutically and psychedelically. It is possible to see benefits in all three of these areas:

  • Biochemical Paradigm: At the very core of ketamine treatment is the fact that it is a medical treatment with a chemical substance with proven results in treating mental illness. In the biochemical model, someone will receive sub-psychedelic dosages of ketamine and receive psychotherapy separately. In this paradigm, it is strictly treated as just a medication. This model may be best used for those in acute conditions and/or who are hospitalized.
  • Psychotherapeutic Paradigm: The psychotherapeutic paradigm considers ketamine as somewhat of a lubricant, and therapy is conducted while the person is under the influence of ketamine. The thought behind this is that it deepens the insights one might otherwise get from psychotherapy alone and opens one up to make new(/novel) connections. In one qualitative study, a participant reported the ketamine-assisted therapy sessions to feel like an “amplifcation” of the content of his regular talk therapy. This approach is really well-suited for those who are interested in going deeper on their self-discovery.
  • Psychedelic Paradigm: The final school of thought approaches ketamine the way others approach more “traditional” psychedelics such as psilocybin or LSD. Whereas biochemical and psychotherapeutic applications of ketamine treatment deliberately keep the dosages sub-dissociative, the psychedelic model purposely uses the medicine to create an altered consciousness that usually leads to vivid visions. Some research shows that the level of dissociation may actually be correlated with higher levels of antidepressant effects. Those who have expressed curiosity about existential concerns are well-suited for this type of ketamine treatment.

Things to Consider

Although ketamine is generally safe and well-tolerated in medical settings, it is still a powerful treatment that can be expensive and have some side effects you will want to know about.

Cost

Ketamine treatment can be very expensive, with infusions running upwards of several hundred dollars and not always covered by insurance. Spravato (esketamine) is the only form of ketamine technically covered by insurance as it is FDA-approved, but depending on insurance, it still may be costly.

Time

Because ketamine, in most of its formats, will cause some dissociative effects, and/or dizziness/fogginess, you will be recommended not to drive anywhere from six to 24 hours, so you may need to depend on others to drive you.

Additionally, you will want to factor in time to prepare yourself mentally for treatment by relaxing or meditating, as well as time after for recovery—so, in addition to the financial commitment, it is also a time commitment.

Mania

Although current evidence of a depressive state switching to a manic state because of ketamine is limited, the potential for danger does exist. Several reports show instances of people switching to manic states following ketamine administration—especially in those who are on SSRIs. Lithium or another mood stabilizer may help with this.

Substance Use 

Although one might worry about risk of substance use/seeking ketamine illegally after treatment, the risks are relatively low (but not zero). In fact, ketamine treatment has even been found to help those dealing with substance use. That said, there have been reported cases of people becoming addicted to ketamine following treatment.

Physical Side Effects

Because ketamine was originally developed as an anesthetic (though it is given at a dosage lower than anesthesia for bipolar treatment), many of the side effects are similar to those you might deal with if you were under anesthesia, though they are all temporary and should subside within a few hours.

Temporary side effects may include nausea, mild sedation and/or dizziness. Also, it should not be combined with medications that cause hypertension, sedation or that slow down breathing.

A Word From Verywell

Ketamine has some incredibly promising research behind it for treating bipolar and other mood disorders, but, like any medical treatment, you should consult with your doctor before moving forward with any new treatments for your condition.

13 Sources
Verywell Mind uses only high-quality sources, including peer-reviewed studies, to support the facts within our articles. Read our editorial process to learn more about how we fact-check and keep our content accurate, reliable, and trustworthy.
  1. Jelen LA, Young AH, Stone JM. Ketamine: A tale of two enantiomers. J Psychopharmacol. 2021;35(2):109-123. doi:10.1177/0269881120959644

  2. Onaolapo AY, Onaolapo OJ. Glutamate and depression: Reflecting a deepening knowledge of the gut and brain effects of a ubiquitous molecule. World J Psychiatry. 2021;11(7):297-315. doi:10.5498/wjp.v11.i7.297

  3. for the ENIGMA Bipolar Disorder Working Group, Hibar DP, Westlye LT, et al. Cortical abnormalities in bipolar disorder: an MRI analysis of 6503 individuals from the ENIGMA Bipolar Disorder Working Group. Mol Psychiatry. 2018;23(4):932-942. doi:10.1038/mp.2017.73

  4. Onaolapo AY, Onaolapo OJ. Glutamate and depression: Reflecting a deepening knowledge of the gut and brain effects of a ubiquitous molecule. World J Psychiatry. 2021;11(7):297-315. doi:10.5498/wjp.v11.i7.297

  5. Baldessarini RJ, Vázquez GH, Tondo L. Bipolar depression: a major unsolved challenge. Int J Bipolar Disord. 2020;8:1. doi:10.1186/s40345-019-0160-1

  6. Zarate CA, Brutsche NE, Ibrahim L, et al. Replication of ketamine’s antidepressant efficacy in bipolar depression: a randomized controlled add-on trial. Biol Psychiatry. 2012;71(11):939-946. doi:10.1016/j.biopsych.2011.12.010

  7. Dean RL, Marquardt T, Hurducas C, et al. Ketamine and other glutamate receptor modulators for depression in adults with bipolar disorder. Cochrane Database of Systematic Reviews. 2021;(10). doi:10.1002/14651858.CD011611.pub3

  8. Xu AJ, Niciu MJ, Lundin NB, et al. Lithium and valproate levels do not correlate with ketamine’s antidepressant efficacy in treatment-resistant bipolar depression. Neural Plast. 2015;2015:858251. doi:10.1155/2015/858251

  9. Bennett R, Yavorsky C, Bravo G. Ketamine for bipolar depression: biochemical, psychotherapeutic, and psychedelic approaches. Front Psychiatry. 2022;0. doi:10.3389/fpsyt.2022.867484

  10. Do the dissociative side effects of ketamine mediate its antidepressant effects? Journal of Affective Disorders. 2014;159:56-61. doi:10.1016/j.jad.2014.02.017

  11. Wilkowska A, Szałach Ł, Słupski J, et al. Affective switch associated with oral, low dose ketamine treatment in a patient with treatment resistant bipolar i depression. Case report and literature review. Front Psychiatry. 2020;0. doi:10.3389/fpsyt.2020.00516

  12. Schak KM, Vande Voort JL, Johnson EK, et al. Potential risks of poorly monitored ketamine use in depression treatment. AJP. 2016;173(3):215-218. doi:10.1176/appi.ajp.2015.15081082

  13. Walsh Z, Mollaahmetoglu OM, Rootman J, et al. Ketamine for the treatment of mental health and substance use disorders: comprehensive systematic review. BJPsych open. 2022;8(1):e19. doi:10.1192/bjo.2021.1061

By Theodora Blanchfield, AMFT
Theodora Blanchfield is an Associate Marriage and Family Therapist and mental health writer.