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Jul 28, 2021
7 min read

Ketamine for depression: how it works, benefits, risks

Ketamine, an anesthetic drug with psychoactive properties, is now used off-label to treat depression and suicidal ideation. This breakthrough treatment seems to be a promising option for people who struggle with these mood disorders. Here’s how ketamine works to relieve the symptoms of depression, the benefits and risks of using ketamine, and what’s new in depression treatment.

Disclaimer

If you have any medical questions or concerns, please talk to your healthcare provider. The articles on Health Guide are underpinned by peer-reviewed research and information drawn from medical societies and governmental agencies. However, they are not a substitute for professional medical advice, diagnosis, or treatment.

You’ve tried different antidepressants and psychotherapists to manage your severe depressive symptoms, but you may have found little relief. Your healthcare provider may have even tried putting you on several antidepressants at once. You’re feeling frustrated and like you may never find a solution. 

If that sounds familiar, it may be time to consider more out-of-the-box options. Ketamine for depression is an effective treatment for many people with treatment-resistant depression. Learn more about how ketamine works and what to expect if you and your healthcare provider decide this is a good option for you. 

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What is ketamine?

Ketamine is a type of anesthetic that has been used for over 50 years.

Ketamine was approved in 1970 by the U.S. Food and Drug Administration (FDA) for general anesthesia, either by itself or other anesthetic medication in patients undergoing medical procedures and surgery. This anesthetic was heavily used on the battlefield in the Vietnam War (WHO, 2016). 

The World Health Organization listed it as an “Essential Medicine” in 1985 due to its good safety profile during surgery. Ketamine does not lower blood pressure or slow down breathing during a procedure like some other anesthetics do (WHO, 2016).

Ketamine has been used for both human and veterinary surgeries, which is why the street drug is sometimes called a “horse tranquilizer” or “cat Valium.”

Sure enough, ketamine has been a popular street drug for decades, known for its mind-altering, trance-like effects. The ketamine you might get in anesthesia or what’s used for depression may have similar effects, but it can be quite dangerous and addictive as a street drug. When ketamine is administered in a medical setting, it’s regulated carefully. 

Research shows that ketamine may have the potential to treat anxiety, chronic and severe pain, post-traumatic stress disorder (PTSD), and treatment-resistant depression. 

What is treatment-resistant depression? 

Depression is one of the most common mental health disorders, affecting about 7% of adults in the U.S. (NIMH, 2019).

The gold standard for treating depression is a combination of antidepressants and psychotherapy. Typically, a healthcare provider will prescribe a selective serotonin reuptake inhibitor (SSRIs) that you take every day. Many people only start to feel their depressive symptoms lift after six weeks or more of antidepressant treatment (Bains, 2021).

Although the standard treatments work for many people, some people continue to have trouble with depressive symptoms even after trying multiple medications and giving them enough time to work. Treatment-resistant depression is when a person doesn’t get better despite taking at least two different types of antidepressant medications with proper dosing for at least six weeks. Up to 30% of people with major depressive disorder (MDD) experience treatment-resistant depression (Jaffe, 2019

Researchers recognized the problem and began examining how ketamine might be able to help treatment-resistant depression.

How does ketamine work to relieve depression?

It’s not clear how ketamine works. We know that ketamine likely doesn’t work on serotonin as many antidepressants do, or at least not in the same way. Ketamine affects the brain in novel ways that exert an antidepressant effect.

Ketamine affects neurotransmitters in the brain 

Ketamine acts on several different receptors in the brain. The result is that it influences the levels of multiple neurotransmitters, chemical messengers that affect activity in the brain. Among the neurotransmitters ketamine may influence are glutamate and GABA (gamma-aminobutyric acid). People with low levels of GABA and high levels of glutamate may feel anxious. Low levels of both GABA and glutamate may result in depression. Ketamine may help with these two neurotransmitters by affecting both glutamate and GABA levels (Carboni, 2021).

Ketamine may help restructure your brain

Inflammation and stress may affect your brain structure. Ketamine spurs new connections to grow in areas of the brain affected by depression, like the prefrontal cortex and the hippocampus. These parts of the brain are responsible for regulating your mood, memory, behavior, and personality (Carboni, 2021). 

Your brain has a “disappointment center” called the lateral habenula, which processes your emotions. A study in both animals and humans showed that depression causes the lateral habenula to “over-fire” negative thoughts, which may cause depression (Yang, 2017). Ketamine directly affects this part of the brain, and it may “reset” the disappointment center, helping to improve symptoms of depression (Carboni, 2021)

Researchers continue to study the different ways ketamine affects the brain.

How is ketamine given?

Ketamine has been used off-label for treatment-resistant depression, pain management, and palliative care for years. Off-label use is a common occurrence and means using an FDA-approved medication for an unapproved use when the healthcare provider sees a clear need for the treatment. 

Two types of ketamine are used to treat major depressive disorder symptoms in treatment-resistant depression (Thase, 2020)

  • IV infusion: Since 2000, ketamine has been administered by IV infusions after researchers reported it significantly improved depressive symptoms within 72 hours of receiving the medication. In some cases, more than half of the study participants showed a decrease in their depressive symptoms after 24 hours. Multiple additional studies confirmed this rapid improvement (Carboni, 2021).
  • Nasal spray—In 2019, the FDA approved a nasal spray for adults with treatment-resistant depression. The spray is called esketamine (brand name Spravato) (Carboni, 2021).

If you would like to be approved for ketamine treatment, you must meet the criteria for treatment-resistant depression and be currently taking an antidepressant.

If you receive ketamine through an IV, the infusion takes about 40 minutes. The medication is given at a slow and controlled rate with the dose calculated to your weight. Your healthcare provider may adjust your dose depending on how your body reacts to the medicine. Ketamine infusions are typically given twice a week over three or four weeks (six to eight treatments) (Thase, 2020).

Side effects of ketamine 

All medications have side effects, and ketamine is no exception. It’s generally considered safe, but there is a chance it may cause the following adverse effects (Thase, 2020): 

  • Nausea and vomiting
  • High blood pressure
  • Increased heart rate
  • Confusion
  • Hallucinations
  • Drowsiness
  • Dissociation or having an out-of-body experience
  • Perception distortions where your vision is blurry and time seems to be slower or faster

Many people notice dissociation and perception changes with the first infusion. These side effects don’t last long; most resolve within 90 minutes of finishing the infusion. More research is needed to examine the impact of long-term or frequent ketamine infusions.

What are the benefits of ketamine?

Ketamine offers some powerful benefits for treatment-resistant depression. 

Can relieve symptoms of depression quickly

IV ketamine works pretty quickly—for many people, just 1–3 infusions is all it takes to start seeing an improvement in depressive symptoms. In comparison, typical antidepressant therapy may take six weeks or more to work (Carboni, 2021).

May kick-start your antidepressant 

Studies show that ketamine can speed up the effects of your antidepressant when you’re in that six-week waiting period at the start of a new medication (Thase, 2020).

May help even if electroconvulsive therapy (ECT) didn’t

Electroconvulsive therapy (ECT) is a proven technique that works rapidly in many people with treatment-resistant depression. Still, some people may not tolerate this treatment well or may be unwilling to try it because of the risk of cognitive side effects (NIMH, nd). For those people, ketamine may be a good option. One study found that ketamine helped relieve depressive symptoms in people who did not find relief from ECT (Thase, 2020). 

Generally safe and well-tolerated

Studies show that short-term and low-dose ketamine treatments are well-tolerated. Adverse effects of ketamine usually happen with very high doses for more extended periods (Corriger, 2019).

What are the risks of ketamine?

For people with treatment-resistant depression or other conditions, ketamine can be a great option, but it certainly has its downsides. It’s essential that you work with your healthcare provider on finding the right treatment for you. 

Ketamine can be addictive 

If you have a personal history of a substance use disorder, your healthcare provider may need to consider if ketamine is the right treatment for you. 

Ketamine is expensive

Currently, many insurance plans do not cover ketamine infusions for treatment-resistant depression. You may need to pay out of pocket, and it can be quite pricey.  

Ketamine is given under medical supervision 

Currently, ketamine treatment, whether IV or nasal spray (as esketamine), is only given under medical supervision. This means you cannot receive ketamine treatment at home, making it a lot less accessible to many.

Ketamine is not for everyone with treatment-resistant depression 

You may not be able to receive ketamine treatment if you have any of the following conditions (Rosenbaum, 2021):

  • Are currently pregnant
  • Have a history of psychosis
  • Increased intracranial pressure
  • Uncontrolled high blood pressure
  • Acute or unstable heart disease
  • An active substance use disorder to non-prescription, prescription, recreational drugs, cannabis, or alcohol

Getting better

Ketamine has shown promising results for depression, treatment-resistant depression, and suicidal ideation. Depression is best treated with an interdisciplinary approach with antidepressant medication, psychotherapy like cognitive behavioral therapy (CBT), lifestyle modifications, and, if appropriate for you, ketamine. Speak to your healthcare provider to see if ketamine is right for you.

References

  1. Bains, N., & Abdijadid, S. (2021). Major depressive disorder. StatPearls [Internet]. Retrieved from https://www.statpearls.com/ArticleLibrary/viewarticle/24655
  2. Carboni, E., Carta, A. R., Carboni, E., & Novelli, A. (2021). Repurposing ketamine in depression and related disorders: can this enigmatic drug achieve success? Frontiers in Neuroscience, 15. Retrieved from https://www.frontiersin.org/articles/10.3389/fnins.2021.657714/full
  3. Corriger, A., & Pickering, G. (2019). Ketamine and depression: a narrative review. Drug Design, Development and Therapy, 13, 3051–3067. doi: 10.2147/DDDT.S221437. Retrieved from https://pubmed.ncbi.nlm.nih.gov/31695324/
  4. Drug Enforcement Administration (DEA). (2020). Ketamine fact sheet. Retrieved from https://www.dea.gov/sites/default/files/2020-06/Ketamine-2020_1.pdf
  5. Jaffe, D. H., Rive, B., & Denee, T. R. (2019). The humanistic and economic burden of treatment-resistant depression in Europe: a cross-sectional study. BMC Psychiatry, 19(1), 1-11. doi: 10.1186/s12888-019-2222-4. Retrieved from https://bmcpsychiatry.biomedcentral.com/articles/10.1186/s12888-019-2222-4
  6. National Institute of Mental Health (NIMH). (2019). Major depression. National Institute of Health. Retrieved from https://www.nimh.nih.gov/health/statistics/major-depression
  7. National Institute of Mental Health (NIMH). (nd). Rapidly-acting treatments for treatment-resistant depression (RAPID). National Institute of Health. Retrieved from https://www.nimh.nih.gov/research/research-funded-by-nimh/research-initiatives/rapidly-acting-treatments-for-treatment-resistant-depression-rapid
  8. Rosenbaum, S. (2021). Ketamine. StatPearls [Internet]. Retrieved from https://www.statpearls.com/ArticleLibrary/viewarticle/23876
  9. Sanacora G, Frye MA, McDonald W, et al.(2017). A consensus statement on the use of ketamine in the treatment of mood disorders. JAMA Psychiatry. 74(4):399–405. doi: 10.1001/jamapsychiatry.2017.0080. Retrieved from https://pubmed.ncbi.nlm.nih.gov/28249076/
  10. Thase, M., Connolly, KR. (2020). Ketamine and esketamine for treating unipolar depression in adults: Administration, efficacy, and adverse effects. UpToDate. Retrieved from https://www.uptodate.com/contents/ketamine-and-esketamine-for-treating-unipolar-depression-in-adults-administration-efficacy-and-adverse-effects
  11. Wilkowska, A., Szałach, Ł., & Cubała, W. J. (2020). Ketamine in bipolar disorder: a review. Neuropsychiatric Disease and Treatment, 16, 2707–2717. doi: 10.2147/NDT.S282208. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7670087/
  12. World Health Organization (WHO). (2016). Fact files on ketamine. Retrieved from https://www.who.int/medicines/news/20160309_FactFile_Ketamine.pdf
  13. Yang, Y., Wang, H., Hu, J., & Hu, H. (2018). Lateral habenula in the pathophysiology of depression. Current Opinion in Neurobiology, 48, 90-96. doi: 10.1016/j.conb.2017.10.024. Retrieved from https://pubmed.ncbi.nlm.nih.gov/29175713/