The role of ketamine as an antidepressant agent : Bali Journal of Anesthesiology

Secondary Logo

Journal Logo


The role of ketamine as an antidepressant agent

Widnyana, Made Gede1; Senapathi, Tjokorda Gde Agung1,; Aryani, Luh Nyoman Alit2; Ryalino, Christopher3

Author Information
Bali Journal of Anesthesiology 7(2):p 57-59, April-June 2023. | DOI: 10.4103/bjoa.bjoa_81_23
  • Open

Depression is a common mental health condition that affects millions of people worldwide.[1,2] Whereas traditional antidepressant medications have been effective for many individuals, a significant number of patients continue to struggle with depression even after trying multiple treatments. It is estimated that up to one-third of individuals with depression do not respond to traditional treatments such as antidepressant medication and psychotherapy,[3,4] which has led researchers to investigate alternative treatments.

Ketamine, a dissociative anesthetic and a popular recreational drug, has gained significant attention in recent years as a potential treatment for depression.[5,6] Whereas traditional antidepressants such as selective serotonin reuptake inhibitors (SSRIs) have been the first line of treatment for depression for decades, ketamine offers a new approach to managing the condition. This article will explore how ketamine works as a treatment for depression, along with its potential benefits and drawbacks.

How ketamine works as a treatment for depression

The exact mechanism by which ketamine works as an antidepressant is not fully understood.[7,8] However, it is thought to work by increasing the levels of certain neurotransmitters in the brain, such as glutamate[9] and serotonin.[8] Glutamate is an excitatory neurotransmitter that plays a role in learning and memory. Studies have shown that individuals with depression have reduced levels of glutamate in certain areas of the brain, such as the prefrontal cortex. Ketamine has been shown to increase glutamate levels in the brain,[9,10] which may help to improve mood. Serotonin is another neurotransmitter that is involved in regulating mood. SSRIs are commonly used to treat depression by increasing the availability of serotonin in the brain. Ketamine has also been shown to increase serotonin levels,[11] which may contribute to its antidepressant effects.

In addition to its effects on neurotransmitters, ketamine may also have a direct effect on the brain’s neural pathways.[12] It has been shown to increase the growth of new connections between neurons, which may help to improve mood[13] and maintain cognitive function.[14,15]

Ketamine works differently from traditional antidepressants by targeting the glutamate system in the brain.[9] Specifically, it blocks N-methyl-D-aspartate receptors, which are involved in learning and memory processes. This blockade results in an increase in the production of brain-derived neurotrophic factor (BDNF),[16] a protein that helps promote the growth and survival of neurons in the brain. BDNF is thought to play a crucial role in the development and maintenance of neural circuits that are involved in mood regulation, which may explain how ketamine can produce rapid and long-lasting antidepressant effects.

Potential benefits of ketamine for depression

One of the most significant benefits of ketamine for depression is its rapid onset of action.[17] Traditional antidepressants can take weeks or even months to produce noticeable improvements in mood. This quick response time can be particularly beneficial for patients who are experiencing severe depressive symptoms and require immediate relief.

In addition to its rapid onset of action, ketamine has been found to be highly effective in treating depression, particularly in cases of treatment-resistant depression.[6] Studies have shown that ketamine can improve depressive symptoms in patients who have not responded to traditional antidepressant medications.[17-19] This high efficacy rate is particularly promising for patients who have struggled with depression for an extended period and have not found relief from other treatments.

Another potential benefit of ketamine for depression is its long-lasting effects.[18,20,21] Whereas the initial effects of ketamine may be short-lived, research has shown that repeated treatments can produce more sustained improvements in mood. In one study, patients who received six ketamine infusions over a 2-week period reported significant improvements in mood that lasted for several weeks after treatment.[18]

Ketamine has also been found to improve suicidal ideation in patients with depression. Suicidal ideation is a significant concern for individuals with depression, and finding effective treatments to reduce suicidal thoughts and behaviors is critical. Studies have shown that ketamine can reduce suicidal ideation in patients with depression, even in cases where traditional antidepressant medications have been ineffective.[22,23]

One of the advantages of ketamine for depression is its safety and tolerability profile.[24,25] When administered by a trained healthcare provider in a clinical setting, ketamine is generally safe and well-tolerated. However, like any medication, ketamine can produce side effects, including nausea, dizziness, and dissociation. These side effects are typically mild and short-lived, but it is essential to monitor patients closely during treatment.

Finally, ketamine has the potential to target different neurotransmitter systems, including glutamate, GABA, and dopamine.[8,26] These neurotransmitters play a crucial role in mood regulation, and modulating these systems may contribute to ketamine’s antidepressant effects. The ability to target multiple neurotransmitter systems may make ketamine a particularly effective treatment for depression in patients who have not responded to traditional antidepressant medications.

Drawbacks of ketamine for depression

One of the most significant drawbacks of ketamine use in treating depression is its short-term effectiveness. Ketamine has been found to produce a rapid antidepressant effect, often within hours or days of administration. However, this effect is usually short-lived, and patients may need to undergo repeated treatments to maintain the positive effects. In some cases, patients may only experience relief for a few days to a few weeks before the depressive symptoms return. This can be frustrating for patients who are seeking long-term relief from their symptoms.

Another major concern with ketamine use is the potential for abuse and addiction. Ketamine is classified as a Schedule III controlled substance by the U.S. Drug Enforcement Administration.[27] While it is less addictive than some other drugs, it still has the potential for abuse and addiction. Regular use of ketamine can lead to tolerance, dependence, and addiction, which can have significant negative consequences for the user.

To address these concerns, researchers are continuing to investigate the use of ketamine for depression and are exploring alternative delivery methods and dosing strategies to minimize the risk of abuse and maximize the benefits. For example, some studies investigated the use of intranasal ketamine, which can be self-administered at home and may have a lower risk of abuse than intravenous ketamine.[28-30] Other studies investigated the use of lower doses of ketamine, which may have fewer side effects and be more tolerable for patients.[17,31]

In addition to the potential for abuse, ketamine use can also cause side effects. Common side effects of ketamine use include dissociation, hallucinations, and changes in perception, which can be unsettling for some patients. There may also be other side effects such as dizziness, nausea, and vomiting. Whereas these side effects are usually temporary and subside once the drug wears off, they can be distressing and may make some patients reluctant to continue with ketamine treatment.

Another drawback of ketamine use is the lack of long-term data on its safety and efficacy. Whereas the drug has been studied in several clinical trials, there is still limited research on its long-term effects, particularly in terms of its safety and efficacy over longer periods.[32,33] This lack of data makes it difficult to assess the risks and benefits of ketamine treatment accurately.

Finally, the cost of ketamine treatment for depression can be a significant drawback. Ketamine treatment is still considered an off-label use, meaning that insurance coverage may be limited or not available. This can make it difficult for some patients to access this treatment, particularly those who cannot afford to pay for it out of pocket.


Ketamine represents a new approach to treating depression that offers several potential benefits over traditional antidepressants, including rapid onset and long-lasting effects. However, concerns about abuse potential, dissociative effects, and long-term safety data still need to be addressed. Overall, ketamine is an exciting development in the treatment of depression, and ongoing research is needed to fully understand its potential benefits and drawbacks.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.


1. World Health Organization. Depression and Other Common Mental Disorders: Global Health Estimates. Geneva: World Health Organization; 2017
2. Santomauro DF, Mantilla Herrera AM, Shadid J, Zheng P, Ashbaugh C, et al. Global prevalence and burden of depressive and anxiety disorders in 204 countries and territories in 2020 due to the COVID-19 pandemic. Lancet 2021;398:1700-12
3. Al-Harbi KS. Treatment-resistant depression: Therapeutic trends, challenges, and future directions. Patient Prefer Adherence 2012;6:369-88
4. Jaffe DH, Rive B, Denee TR. The humanistic and economic burden of treatment-resistant depression in Europe: A cross-sectional study. BMC Psychiatry 2019;19:1-11
5. Bottemanne H, Morlaas O, Claret A, Sharot T, Fossati P, Schmidt L. Evaluation of early ketamine effects on belief-updating biases in patients with treatment-resistant depression. JAMA Psychiatry 2022;79:1124-32
6. Dai D, Miller C, Valdivia V, Boyle B, Bolton P, Li S, et al. Neurocognitive effects of repeated ketamine infusion treatments in patients with treatment resistant depression: A retrospective chart review. BMC Psychiatry 2022;22:1-8
7. Zanos P, Gould TD. Mechanisms of ketamine action as an antidepressant. Mol Psychiatry 2018;23:801-11
8. Matveychuk D, Thomas RK, Swainson J, Khullar A, MacKay M-A, Baker GB, et al. Ketamine as an antidepressant: Overview of its mechanisms of action and potential predictive biomarkers. Ther Adv Psychopharmacol 2020;10:204512532091665
9. Lazarevic V, Yang Y, Flais I, Svenningsson P. Ketamine decreases neuronally released glutamate via retrograde stimulation of presynaptic adenosine A1 receptors. Mol Psychiatry 2021;26:7425-35
10. Abdallah CG, De Feyter HM, Averill LA, Jiang L, Averill CL, Chowdhury GMI, et al. The effects of ketamine on prefrontal glutamate neurotransmission in healthy and depressed subjects. Neuropsychopharmacology 2018;43:2154-60
11. Tiger M, Veldman ER, Ekman CJ, Halldin C, Svenningsson P, Lundberg J. A randomized placebo-controlled PET study of ketamine’s effect on serotonin 1B receptor binding in patients with SSRI-resistant depression. Transl Psychiatry 2020;10:159
12. Wu H, Savalia NK, Kwan AC. Ketamine for a boost of neural plasticity: How, but also when?. Biol Psychiatry 2021;89:1030-2
13. Park LT, Falodun TB, Zarate CA. Ketamine for treatment-resistant mood disorders. Focus (Madison) 2019;17:8-12
14. Davis MT, DellaGiogia N, Maruff P, Pietrzak RH, Esterlis I. Acute cognitive effects of single-dose intravenous ketamine in major depressive and posttraumatic stress disorder. Transl Psychiatry 2021;11:205
15. Gill H, Gill B, Rodrigues NB, Lipsitz O, Rosenblat JD, El-Halabi S, et al. The effects of ketamine on cognition in treatment-resistant depression: A systematic review and priority avenues for future research. Neurosci Biobehav Rev 2021;120:78-85
16. Woelfer M, Li M, Colic L, Liebe T, Di X, Biswal B, et al. Ketamine-induced changes in plasma brain-derived neurotrophic factor (BDNF) levels are associated with the resting-state functional connectivity of the prefrontal cortex. World J Biol Psychiatry 2020;21:696-710
17. Mandal S, Sinha VK, Goyal N. Efficacy of ketamine therapy in the treatment of depression. Indian J Psychiatry 2019;61:480-5
18. Zheng W, Zhou YL, Liu WJ, Wang CY, Zhan YN, Li HQ, et al. Rapid and longer-term antidepressant effects of repeated-dose intravenous ketamine for patients with unipolar and bipolar depression. J Psychiatr Res 2018;106:61-8
19. Lan X, Zhou Y, Wang C, Li W, Zhang F, Liu H, et al. Pre-treatment pain symptoms influence antidepressant response to ketamine in depressive patients. Front Psychiatry 2022;13:1-8
20. Zhou Y, Zheng W, Liu W, Wang C, Zhan Y, Li H, et al. Antidepressant effect of repeated ketamine administration on kynurenine pathway metabolites in patients with unipolar and bipolar depression. Brain Behav Immun 2018;74:205-12
21. Vasavada MM, Loureiro J, Kubicki A, Sahib A, Wade B, Hellemann G, et al. Effects of serial ketamine infusions on corticolimbic functional connectivity in major depression. Biol Psychiatry Cogn Neurosci Neuroimaging 2021;6:735-44
22. Abbar M, Demattei C, El-Hage W, Llorca PM, Samalin L, Demaricourt P, et al. Ketamine for the acute treatment of severe suicidal ideation: Double blind, randomised placebo controlled trial. BMJ 2022;376:1-9
23. Sinyor M, Williams M, Belod S, Orserd B, Vincenth M, Mahi L, et al. Ketamine augmentation for major depressive disorder and suicidal ideation: Preliminary experience in an inpatient psychiatry setting. J Affect Disord 2018;241:103-9
24. Kirby T. Ketamine for depression: The highs and lows. The Lancet Psychiatry 2015;2:783-4
25. Yavi M, Lee H, Henter ID, Park LT, Zarate CA. Ketamine treatment for depression: A review. Discov Ment Heal 2022;2:9
26. Muscat SA, Hartelius G, Crouch CR, Morin KW. An integrative approach to ketamine therapy may enhance multiple dimensions of efficacy: Improving therapeutic outcomes with treatment resistant depression. Front Psychiatry 2021;12:1-20
27. Lopez MJ, Tadi PDrug Enforcement. Drug Enforcement Administration Drug Scheduling. StatPearls. Treasure Island, FL: StatPearls Publishing; 2023 Available on:
28. An D, Wei C, Wang J, Wu A. Intranasal ketamine for depression in adults: A systematic review and meta-analysis of randomized, double-blind, placebo-controlled trials. Front Psychol 2021;12:1-9
29. Shrestha R, Pant S, Shrestha A, Batajoo KH, Thapa R, Vaidya S. Intranasal ketamine for the treatment of patients with acute pain in the emergency department. World J Emerg Med 2016;7:19-24
30. Shimonovich S, Gigi R, Shapira A, Sarig-Meth T, Nadav D, Rozenek M, et al. Intranasal ketamine for acute traumatic pain in the emergency department: A prospective, randomized clinical trial of efficacy and safety. BMC Emerg Med 2016;16:1-9
31. Can AT, Hermens DF, Dutton M, Gallay CC, Jensen E, Jones M, et al. Low dose oral ketamine treatment in chronic suicidality: An open-label pilot study. Transl Psychiatry 2021;11:101
32. Gass N, Becker R, Reinwald J, Cosa-Linan A, Sack M, Weber-Fahr W, et al. Differences between ketamine’s short-term and long-term effects on brain circuitry in depression. Transl Psychiatry 2019;9:172
33. Strous JFM, Weeland CJ, van der Draai FA, Daams JG, Denys D, Lok A, et al. Brain changes associated with long-term ketamine abuse, A systematic review. Front Neuroanat 2022;16:795231
© 2023 Bali Journal of Anesthesiology