Ketamine for Bipolar Depression and What the Research Shows

A physician's look at what studies show about IV ketamine for bipolar depression, the question of mania, and who may be a candidate. From HILLMED in Plano, Texas.

By Jerron C. Hill, M.D., Anesthesiologist and Founder of HILLMED

For many people with bipolar disorder, the depressive episodes are the hardest part. They tend to last longer than the highs, and they often respond slowly to treatment. Some people try several medications over months or years and still don't feel like themselves.

That's why researchers have spent more than 15 years studying whether ketamine, a medication that works very differently from standard antidepressants, can help. Here is what that research shows, what it doesn't, and how I think about it as a physician.

What bipolar depression is

Bipolar I disorder involves at least one manic episode; depressive episodes are common but are not required for the diagnosis. Bipolar II involves hypomanic episodes and major depressive episodes, without a history of mania. Depression can cause low mood, loss of interest, sleep changes, low energy, and thoughts of death or suicide.

Treatment differs from treatment for unipolar depression. Antidepressants alone are generally avoided in bipolar I disorder because of the risk of mood destabilization. Care may include lithium, lamotrigine, or certain antipsychotic medications, selected for the person’s current symptoms and longer-term needs.

Why it's so hard to treat

Even with good care, many people with bipolar depression don't improve enough. Approved treatments can take weeks to work, and each medication change means another wait. During that time, the risk of suicide is real. That long gap is a big reason researchers have looked for faster-acting options.

How ketamine is different

Ketamine blocks NMDA receptors involved in glutamate signaling. Researchers are studying how downstream changes in brain signaling and neuroplasticity contribute to its antidepressant effects; the mechanism is not fully understood. Some patients experience mood improvement within hours, although others respond later or do not respond.

At HILLMED, we use low-dose IV ketamine, given slowly under physician supervision after a medical and psychiatric evaluation.

What the research shows

Evidence for ketamine in bipolar depression is promising, but remains more limited than the evidence for major depressive disorder. Results vary across studies and patients.

• Early controlled trials in 2010 and 2012 studied ketamine added to lithium or valproate. In these small trials, 71% and 79% responded at some point after ketamine, respectively, versus 6% and 0% after placebo. Improvement began within 40 minutes, with group-level benefits lasting approximately three days. These findings do not mean every patient will improve or that benefit always lasts the same amount of time. [1, 2]

• A 2023 systematic review included eight studies with 235 participants. It reported an overall response rate of approximately 48% with ketamine and 5% in placebo comparison groups. Because the review combined different study designs and populations, these figures are not equivalent to results from one large randomized trial. Evidence for sustained benefit with repeated treatment remains limited. [3]

• A 2026 randomized trial published in JAMA Psychiatry compared four ketamine infusions over two weeks with midazolam in 68 adults with treatment-resistant bipolar I or II depression. Treatment was added to a stable mood stabilizer or antipsychotic. Depression scores improved more with ketamine at day 14. This supports short-term benefit but does not establish long-term effectiveness. [4]

These results are encouraging, but they have limits. Most studies were small, and few followed people for more than a few weeks. We still don't know the best number of infusions or how long benefits last.

What about the risk of mania?

This is the first question many patients and families ask, and it's the right one. Any treatment that lifts mood in bipolar disorder could, in theory, tip someone into mania or hypomania.

Mania and hypomania were uncommon but did occur in studies summarized in the 2023 review. The 2026 trial reported no full episodes of mania, hypomania, psychosis, or suicide attempts, although one participant in each group developed mixed features with subthreshold hypomanic symptoms. Small samples and brief follow-up cannot establish the true long-term risk. [3, 4]

Most studies evaluated ketamine added to ongoing mood-stabilizing treatment. This is also how I approach treatment. Continuing these medications is important, but does not eliminate the possibility of mood switching. Patients should promptly report reduced need for sleep, racing thoughts, unusual energy, irritability, or impulsive behavior.

Who may be a candidate

An IV ketamine evaluation may make sense if you:

• Have a confirmed diagnosis of bipolar I or II disorder, currently in a depressive episode

• Have tried at least two evidence-based treatments without enough relief

• Are on a stable mood stabilizer or antipsychotic, and have a psychiatrist or other mental health provider involved in your care

Current mania, mixed features, active psychosis, uncontrolled hypertension, or cardiovascular disease that makes a rise in blood pressure hazardous may make treatment inappropriate. Substance-use history requires individualized assessment rather than an automatic exclusion. Pregnancy or breastfeeding requires specialist discussion because safety evidence is limited.

What treatment looks like at HILLMED

Every patient starts with a consultation and a review of their medical and psychiatric history. We work alongside your mental health provider, so your mood stabilizer and other care stay in place. If ketamine is a good fit, treatment usually begins with a series of infusions at our Plano clinic, with your blood pressure, heart rate and oxygen monitored throughout.

We also discuss follow-up, changes in mood or sleep between treatments, and whether additional infusions are appropriate. The plan depends on your response and tolerability.

Safety and medical supervision

IV ketamine for bipolar depression is an off-label use. Neither IV ketamine nor esketamine (Spravato) is FDA-approved for bipolar depression. Treatment requires informed consent, appropriate medical supervision, and coordination with ongoing psychiatric care.

Common acute effects include dissociation, temporary blood pressure increases, nausea, dizziness, and sedation. These often resolve during recovery, but monitoring continues until discharge criteria are met. Less common serious risks include breathing problems and significant cardiovascular reactions. Repeated exposure also warrants attention to misuse, urinary symptoms, and liver problems. Arrange a driver and follow the clinic’s instructions about driving and other activities. [5]

A physician's perspective

My experience administering ketamine as an anesthesiologist informs our approach to evaluation, dosing, and monitoring. We individualize treatment for each patient and review their response throughout care.

Ketamine is not a cure for bipolar disorder and does not replace ongoing psychiatric treatment. For carefully selected patients, it may offer relief while mood-stabilizing treatment, therapy, regular sleep, and follow-up remain part of the plan.

When to seek help right away

If you are having thoughts of suicide, call or text 988 for the Suicide & Crisis Lifeline. If you are in immediate danger or cannot stay safe, call 911 or go to the nearest emergency department. Do not wait for an outpatient ketamine appointment.

Frequently asked questions

Can ketamine trigger mania in bipolar disorder?

Yes. Mania or hypomania has occurred in some studies, even though reported rates have generally been low. The short 2026 trial found no full manic or hypomanic episodes, but did report one case of subthreshold mixed features in each group. Continued psychiatric care and monitoring are essential. [3, 4]

Do I need to stop my bipolar medication to have ketamine?

No. In the research, and at HILLMED, ketamine is added to your existing mood stabilizer or antipsychotic, not used in place of it. Don't change any medication without talking to your prescriber.

How quickly does ketamine work for bipolar depression?

Some patients improve within hours; early trials detected improvement within 40 minutes. Others need more time or do not benefit. A single infusion’s effects may fade within days, and the need for further treatment is individualized. [1, 2]

How many infusions will I need?

It varies. The 2026 Ket-BD trial used four infusions over two weeks. Your plan is based on your history and how you respond, and we review it with you as treatment goes on.

Is ketamine FDA-approved for bipolar depression?

No. Using IV ketamine for bipolar depression is off-label, which is common in medicine. Esketamine (Spravato) is also not approved for bipolar depression.

Does insurance cover ketamine for bipolar depression?

Coverage varies by plan, and IV ketamine for bipolar depression is often not covered. Contact HILLMED for current pricing and payment information, and check coverage directly with your insurer.

Learning more about treatment

IV ketamine may help some people with treatment-resistant bipolar depression when added to ongoing psychiatric treatment. The research supports potential short-term improvement, while long-term benefit and safety remain areas of study.

Dr. Hill has successfully treated many patients with bipolar depression over the past nine years. To learn more and schedule a complimentary teleconference consultation, please call HILLMED at 972.212.4341. We serve patients in Plano and throughout Dallas–Fort Worth, including Dallas, Frisco, Richardson, and McKinney.

About the author

Jerron C. Hill, M.D., is an anesthesiologist and the founder of HILLMED in Plano, Texas. He brings decades of anesthesia experience and nine years of clinical experience treating patients with IV ketamine to individualized, physician-supervised care.

Selected references

1. Diazgranados N, et al. A randomized add-on trial of an N-methyl-D-aspartate antagonist in treatment-resistant bipolar depression. Arch Gen Psychiatry. 2010;67(8):793–802. doi:10.1001/archgenpsychiatry.2010.90. https://pmc.ncbi.nlm.nih.gov/articles/PMC3000408/

2. Zarate CA Jr, et al. Replication of ketamine’s antidepressant efficacy in bipolar depression: a randomized controlled add-on trial. Biol Psychiatry. 2012;71(11):939–946. https://pmc.ncbi.nlm.nih.gov/articles/PMC3343177/

3. Fancy F, et al. Ketamine for bipolar depression: an updated systematic review. Ther Adv Psychopharmacol. 2023;13. doi:10.1177/20451253231202723. https://pmc.ncbi.nlm.nih.gov/articles/PMC10524067/

4. Orsini DK, et al. Serial Ketamine Infusions for Treatment-Resistant Bipolar Depression: A Randomized Clinical Trial. JAMA Psychiatry. Published September 2, 2026. doi:10.1001/jamapsychiatry.2026.2658. https://pubmed.ncbi.nlm.nih.gov/42684694/

5. Pfizer. Ketamine Hydrochloride Injection prescribing information. https://labeling.pfizer.com/ShowLabeling.aspx?id=4485

This article is for education only and is not medical advice. Talk with your physician before starting or changing any treatment.