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Ketamine For The Treatment of Bipolar Disorder

Bipolar disorder is a common mental health illness, affecting over 2% of people worldwide. It is the psychiatric disorder with the highest risk of suicide (approximately 6-7% of persons with bipolar disorders commit suicide). There is increasing evidence that the current treatment methods for bipolar disorder, which may include pharmacotherapy alone do not fully alleviate symptoms, prevent recurrence, or improve function following bipolar episodes.1 In the medical community, it is generally understood that the combination of medicine and psychotherapy is more effective that one modality alone. However, finding the most efficacious and safest treatment approach for bipolar disorder is still up for debate, with ketamine showing promise as option or adjuvant to conventional therapy.

Much like my stance on Obsessive-Compulsive Disorder (OCD) and other mental disorders, it is my opinion that people may be on a spectrum of bipolar-type symptoms. Although you may not clinically meet criteria for the diagnosis of dipolar disorder, that does exclude you from benefiting from ketamine or other forms of therapy. And after interacting with hundreds of patients at our ketamine infusion clinic in San Luis Obispo, some reoccurring themes have become apparent.

Oftentimes, patients will state that they have periods of lows, with depressive symptoms, while other times they are functioning quite well. I can certainly relate to this; I personally struggle with alternating days or weeks of highs and lows. Some days I feel “on” and can focus on my work, while other times, everything feels like a burden. The thought of getting out of my cocoon and engaging in social interactions feels downright painful, sometimes impossible. A more ideal mental state involves balance, tranquility, and control. A reoccurring theme after an IV ketamine infusion is the ability to control emotions, thinking clearly before taking action, and an overwhelming sense of calmness.

Today we will review bipolar disorder. I will discuss the various types, epidemiology, risk factors, symptoms, and current treatment options. Lastly, I will show that ketamine therapy may have a role for individuals suffering from bipolar disorder.

What is bipolar disorder?

Bipolar disorder types I and II are among a class of affective disorders which are characterized by severe and persistent mood swings resulting in behavioral impairment and significant psychological distress. The main features that separate the types of bipolar disorder include the presence of manic or hypomanic episodes that may alternate with depressive episodes. According to the DSM-5, symptoms must be present for at least one week for a diagnosis of a manic episode to be made, or two weeks for diagnosis of a depressive episode.

Bipolar type I disorder is defined by presence of manic episodes which includes a range of manifestations (eg, elevated mood, increased energy levels and decreased need for sleep, overconfidence, talkativeness, grandiosity, irritability). Delusions and hallucinations occur in up to 75% of manic episodes.2 Individuals with bipolar type II disorder will have depressive episodes which alternate with hypomania rather than mania. Cyclothymic disorder is characterized by recurring depressive and hypomanic states, lasting for at least 2 years, that do not meet the diagnostic threshold for a major affective episode.3

How common is bipolar disorder?

Bipolar disorder is a leading source of disability, with rate of lifetime prevalence estimated at 2.4%.4 Suicide is alarming common in this patient population. Suicide rates among people with bipolar disorder are 20-30 times as high as the rate in the general population.5 Bipolar type II disorder is more common among females, while the prevalence of bipolar type I disorder is similar among males and females. Bipolar disorders typically arise at a young age which may be associated with a worse prognosis rather than late adult onset.

Risk factors for bipolar disorder


Bipolar disorder is one of the most heritable mental illnesses, with estimates of heritability ranging from 70-90%.6

Environmental stressors

One risk factor for the development of bipolar disorder appears to be exposure to a stressor (eg, divorce, death of loved one, trauma). Substance abuse, especially at a young age, may be associated with bipolar disorder, and certainly is a common trigger along with comorbid disorder. It is estimated that 60% of individuals with bipolar disorder abuse drugs which includes alcohol.

Brain structure

Brain imaging including MRI and PET scans have shown structural differences in persons with bipolar disorder. Additionally, a long duration of bipolar disorder illness has been associated with reduced brain volumes in areas such as the prefrontal cortex, which plays a role in stress regulation.

Hormonal, epigenetic mechanisms, deregulation of cell (mitochondria) function, inflammation, and pathways that disrupt neuroplasticity have all been proposed mechanisms that promote development and progression of bipolar disorder.7

Symptoms of bipolar disorder

Patients with bipolar disorder commonly have coexisting mental disorders including anxiety (71%), substance abuse (56%), personality disorders (36%) and ADHD (10-20%).8 Additionally, there appears to be an association between bipolar disorder and medical conditions such as obesity, diabetes mellitus type II, migraines, and irritable bowel syndrome.

venn diagram of mania and depression for bipolar disorder

Current treatments for bipolar disorder

Lithium,9 mood-stabilizing anticonvulsants (eg, carbamazepine, lamotrigine, and valproate),10 and second-generation antipsychotics (eg, aripiprazole, asenapine, cariprazine, lurasidone, olanzapine, paliperidone, quetiapine, risperidone, ziprasidone, etc.)11 have been considered cornerstone pharmacological agents used as prophylactic treatment along with preventing bipolar disorder recurrences. The use of antidepressants for bipolar disorder remains controversial given their potential side effects and lack of efficacy.12 The combination of psychotherapy like Cognitive Behavioral Therapy or CBT with medicine intervention adds more benefit than either modality alone.

Ketamine for the treatment of bipolar disorder

Studies have demonstrated that the antidepressant and anti-suicidal effects of ketamine may be beneficial for patients who suffer from bipolar disorder.13 Ketamine therapy carries a low risk profile, which is unlike many of the side effects and adverse reactions associated with various bipolar disorder medications such as lithium (thyroid and kidney toxicity), quetiapine (weight gain), risperidone (hormonal imbalance), valproate (liver toxicity). Even a single administration of ketamine has been shown to have rapid antidepressant effects when used at low dose for patient who suffer from bipolar depression and treatment resistance.14 Other studies have shown that multiple doses of ketamine administration improved mood, cognition, and sleep in most (77%) of patients.15 A recent study of 16 bipolar patients who underwent a series of six low-dose ketamine infusions, which is the standard protocol at our clinic, experienced response and remission rate 73.7% and 63.2%, respectively, at 24 hours after their last infusion.16

There are a handful of case reports (eight at the time of this writing) of ketamine-induced manic episodes, thus patients with bipolar type I disorder and schizophrenia are typically excluded from consideration of undergoing ketamine therapy.17 It is the author’s opinion from a publication in Frontiers in Psychiatry that the exclusion of patients with bipolar type I disorder is “unfortunate and unwarranted”, especially in patients with refractory disease.18 Perhaps instead, ketamine should be used as an adjuvant rather than replacement when mood stabilization is achieved with other medications.


With bipolar disorder being common and associated with a high rate of suicidality despite current methods of treatment, clearly, we need to look at other modes of therapy. There are currently no pharmacological interventions approved for suicidality in bipolar disorder, however, one of the FDA-approved indications for one form of ketamine is depressive symptoms in adults with major depressive disorder (MDD) with acute suicidal ideation or behavior.

I envision a future where IV ketamine infusions are offered in acute care settings, such as the emergency department, for when patients with bipolar disorder are in a time of crisis. But why do we let patients spiral so deeply? I strongly feel that the focus of mental health in this day of age should be on prevention. It is my hope that ketamine will be sought out as an option to prevent these dangerous mental health rollercoasters.

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The information provided on this blog and website is for general informational purposes only. It should not be considered a substitute for professional medical advice, diagnosis, or treatment. Use the information at your own risk. Consult a qualified healthcare professional for personalized guidance on your medical concerns. We make no guarantees regarding the accuracy or completeness of the information, and we assume no liability for its use.


  1. Goodwin GM, Haddad PM, Ferrier IN, Aronson JK, Barnes T, Cipriani A, Coghill DR, Fazel S, Geddes JR, Grunze H, Holmes EA, Howes O, Hudson S, Hunt N, Jones I, Macmillan IC, McAllister-Williams H, Miklowitz DR, Morriss R, Munafò M, Paton C, Saharkian BJ, Saunders K, Sinclair J, Taylor D, Vieta E, Young AH. Evidence-based guidelines for treating bipolar disorder: Revised third edition recommendations from the British Association for Psychopharmacology. J Psychopharmacol. 2016 Jun;30(6):495-553. doi: 10.1177/0269881116636545. Epub 2016 Mar 15. PMID: 26979387; PMCID: PMC4922419.
  2. Chakrabarti S, Singh N. Psychotic symptoms in bipolar disorder and their impact on the illness: A systematic review. World J Psychiatry. 2022 Sep 19;12(9):1204-1232. doi: 10.5498/wjp.v12.i9.1204. PMID: 36186500; PMCID: PMC9521535.
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  4. Merikangas KR, Jin R, He JP, Kessler RC, Lee S, Sampson NA, Viana MC, Andrade LH, Hu C, Karam EG, Ladea M, Medina-Mora ME, Ono Y, Posada-Villa J, Sagar R, Wells JE, Zarkov Z. Prevalence and correlates of bipolar spectrum disorder in the world mental health survey initiative. Arch Gen Psychiatry. 2011 Mar;68(3):241-51. doi: 10.1001/archgenpsychiatry.2011.12. PMID: 21383262; PMCID: PMC3486639.
  5. Plans L, Barrot C, Nieto E, Rios J, Schulze TG, Papiol S, Mitjans M, Vieta E, Benabarre A. Association between completed suicide and bipolar disorder: A systematic review of the literature. J Affect Disord. 2019 Jan 1;242:111-122. doi: 10.1016/j.jad.2018.08.054. Epub 2018 Aug 23. PMID: 30173059.
  6. Gordovez FJA, McMahon FJ. The genetics of bipolar disorder. Mol Psychiatry. 2020 Mar;25(3):544-559. doi: 10.1038/s41380-019-0634-7. Epub 2020 Jan 6. PMID: 31907381.
  7. Carvalho, Andre F. and Firth, Joseph and Vieta, Eduard. Bipolar Disorder. New England Journal of Medicine. 383. 1. 58:66. 2020. doi: 10.1056/NEJMra1906193
  8. Krishnan KR. Psychiatric and medical comorbidities of bipolar disorder. Psychosom Med. 2005 Jan-Feb;67(1):1-8. doi: 10.1097/01.psy.0000151489.36347.18. PMID: 15673617.
  9. Nestsiarovich A, Gaudiot CES, Baldessarini RJ, Vieta E, Zhu Y, Tohen M. Preventing new episodes of bipolar disorder in adults: Systematic review and meta-analysis of randomized controlled trials. Eur Neuropsychopharmacol. 2022 Jan;54:75-89. doi: 10.1016/j.euroneuro.2021.08.264. Epub 2021 Sep 3. PMID: 34489127.
  10. Peselow ED, Clevenger S, IsHak WW. Prophylactic efficacy of lithium, valproic acid, and carbamazepine in the maintenance phase of bipolar disorder: a naturalistic study. Int Clin Psychopharmacol. 2016 Jul;31(4):218-23. doi: 10.1097/YIC.0000000000000097. PMID: 26523730.
  11. Lindström L, Lindström E, Nilsson M, Höistad M. Maintenance therapy with second generation antipsychotics for bipolar disorder - A systematic review and meta-analysis. J Affect Disord. 2017 Apr 15;213:138-150. doi: 10.1016/j.jad.2017.02.012. Epub 2017 Feb 14. PMID: 28222360.
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  14. Diazgranados N, Ibrahim L, Brutsche NE, Newberg A, Kronstein P, Khalife S, Kammerer WA, Quezado Z, Luckenbaugh DA, Salvadore G, Machado-Vieira R, Manji HK, Zarate CA Jr. A randomized add-on trial of an N-methyl-D-aspartate antagonist in treatment-resistant bipolar depression. Arch Gen Psychiatry. 2010 Aug;67(8):793-802. doi: 10.1001/archgenpsychiatry.2010.90. PMID: 20679587; PMCID: PMC3000408.
  15. Lara DR, Bisol LW, Munari LR. Antidepressant, mood stabilizing and procognitive effects of very low dose sublingual ketamine in refractory unipolar and bipolar depression. Int J Neuropsychopharmacol. 2013 Oct;16(9):2111-7. doi: 10.1017/S1461145713000485. Epub 2013 May 20. PMID: 23683309.
  16. Zheng W, Zhou YL, Liu WJ, Wang CY, Zhan YN, Lan XF, Zhang B, Ning YP. A preliminary study of adjunctive ketamine for treatment-resistant bipolar depression. J Affect Disord. 2020 Oct 1;275:38-43. doi: 10.1016/j.jad.2020.06.020. Epub 2020 Jun 25. PMID: 32658821.
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  18. Bennett Raquel, Yavorsky Christian, Bravo Gary. Ketamine for Bipolar Depression: Biochemical, Psychotherapeutic, and Psychedelic Approaches. Frontiers in Psychiatry. 13. 2022. doi: 10.3389/fpsyt.2022.867484

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