When it comes to advancing the practice of the mental health field, few developments are as controversial and interesting as treating depressive disorders with nonconventional methods. Globally, depression is a leading cause of disability and most traditional anti-depressants require several weeks before a patient starts to feel any improvement, which can be particularly difficult for them. For decades, treatment options for those suffering from major depressive disorders, particularly treatment-resistant ones, have been underwhelming and unsatisfactory. However, what if this suffering could be alleviated in a matter of hours? This article summarises the recent publications that consider efficacy for the treatment of Depressive Disorders.
Originally considered as an anesthetic, Ketamine is now emerging as a potential game-changer in the fight against depression. But how useful is it, and what does current evidence say about its effectiveness, safety, mechanisms, and overall clinical utility? Let’s expand on the recently published findings and consider implications for the future of depression treatment.
Ketamine and Depressive Disorders: History
The discovery of the antidepressant effects of ketamine is arguably the most important advance in mental health in decades (Chen et al., 2024). Ketamine has been an anesthetic in use for both medical and veterinary purposes for decades now. Its first use was in the sixties when it was used as a substitute for Phencyclidine (PCP) due to its capacity to induce sedation and relieve pain. Today, ketamine is widely used in surgical, emergency, and pain management practices. Since the 2000s, there has been an increasing interest in ketamine because of its potent, rapid anti-depressant effects for treatment-resistant depression (TRD). More recent studies have highlighted ketamine’s astonishing ability to reduce depressive and anxiety symptoms in hours instead of the days or weeks needed with traditional medication (Bahji et al., 2022; Johnston et al., 2023).
Ketamine and Depressive Disorders: Mode of Action
What is the underlying mechanism of ketamine’s effect on depression? Recent research suggests that ketamine works by modulating glutamate; which is the foremost excitatory neurotransmitter in the brain. This, in turn, results in higher synaptic pliability and enhanced neural connectivity. When an N-methyl-D-aspartate (NMDA) receptor is blocked, there is a starting point for a cascade process of neuroplastic activity, mostly within the prefrontal cortex and hippocampus, which are crucial areas for mood control (Chen et al., 2024).
Studies also have explored how ketamine works in the brain by examining biological markers (Kadriu et al., 2020). In 2018, Shadli et al. tried to understand how ketamine affects brain activity in people with generalized anxiety disorder and social anxiety disorder using EEG scans. Their research found that ketamine reduced theta wave activity in the right frontal area, which is linked to a decrease in fear-related symptoms in patients with social anxiety disorder.
A double-blind, active-controlled cross-over study conducted by Glue et al. (2024) featured ketamine’s rapid onset of action, where patients reported a reduction in both, depression and anxiety symptoms, within one hour of its administration. These effects lasted for up to seven days in some patients, with 56% of participants showing a clinically meaningful response. The study also explored a less common route of intramuscular ketamine administration and confirmed its antidepressant and anxiolytic efficacy. This aligns with earlier findings from multiple research groups, which have consistently reported ketamine’s rapid-onset activity in TRD patients.
The overall findings suggest that ketamine’s antidepressant action is not merely pharmacological but also involves the activation of cellular and synaptic plasticity mechanisms. Ketamine’s effects extend beyond neurons to include glial cells, such as astrocytes and microglia, which play supportive roles in brain function (Lewis et al. (2024), but the casual involvement of these cell types has not been definitively tested.
As ketamine is quickly metabolized in the liver, it produces several psychoactive metabolites. Some preclinical studies suggest that at least two of these metabolites may play a role in the ketamine antidepressant effect. An important esketamine metabolite, (S)-norketamine [(S)-NK], is effective in counteracting the depressogenic effects of inflammation and chronic social defeat in mice (Lewis et al. (2024). Nonetheless, these results still need further substantiation as well as a clarification of the mode of action involved.
Ketamine and Depressive Disorders: Challenges
Although promising, ketamine comes with its own set of challenges. Its dissociative side effects and variable patient responses remain significant concerns. Li et al. (2024) conducted a meta-analysis on ketamine’s use in preventing postpartum depression (PPD) after cesarean delivery. With thirteen randomized controlled trials and one retrospective study that included 2,916 patients, including six using ketamine and eight using esketamine, the risk ratios and EPDS scores of postpartum depression were significantly reduced among the ketamine/esketamine group relative to the control group at one week and four weeks postoperative periods. However, while ketamine and esketamine significantly reduced PPD incidence and Edinburgh Postnatal Depression Scale (EPDS) scores, they also increased short-term adverse effects like dizziness, diplopia, and hallucinations. These side effects, though transient, highlight the need for careful patient selection and monitoring.
Notwithstanding that initial reports suggest that ketamine can be both safe and effective in depressive disorders, its use in psychiatric treatment raises important factors to consider. Studies suggest that ketamine may be particularly effective for individuals with treatment-resistant depression or those in need of rapid symptom relief. However, careful screening is necessary to assess contraindications, such as a history of psychosis or cardiovascular instability. In treatments of psychotic depression, available data is limited and very recent, and the majority of clinical trials do not enroll patients with psychosis (Medeiros et al.,2024). In the presence of psychotic and depersonalization symptoms, other antidepressant treatments are generally the first line of choice. Overall, combined therapy with oral antipsychotic medication is usually preferred.
Ketamine and Depressive Disorders: Conclusion
The variability in individual responses to ketamine underscores the importance of a personalised approach. Clinical predictors, such as a family history of alcohol abuse or childhood trauma, may influence ketamine’s efficacy (Medeiros et al.,2024). Brain-based biomarkers, particularly electroencephalogram (EEG) changes in gamma power, have shown promise in predicting treatment response. A comprehensive evaluation of psychiatric and medical history is essential to ensure appropriate use.
Given that the use of ketamine in mental health care raises important ethical and legal questions; thus, practitioners should remain up to date on local legislation and regulatory guidance. At the time of publication, Ketamine can be prescribed in Australia for depression however treatment should be delivered by an experienced professional and supervised by a psychiatrist with whom the patient has an ongoing therapeutic relationship. Given the risks, prescribing ketamine is a complex treatment that requires very close monitoring during and after the treatment period. As research progresses, ongoing clinical trials and longitudinal studies will provide deeper insights into its long-term efficacy, safety, and best practices for integration into mental health care.
References:
- Bahji, A., Vazquez, G. H., & Zarate, C. A. (2022). Comparative efficacy of racemic ketamine and esketamine for depression: A systematic review and meta-analysis. Journal of Affective Disorders, 300, 1-9. https://doi.org/10.1016/j.jad.2021.12.038
- Chen, M., Ma, S., Liu, H., Dong, Y., Tang, J., Ni, Z., Tan, Y., Duan, C., Li, H., Huang, H., Li, Y., Cao, X., Lingle, C. J., Yang, Y., & Hu, H. (2024). Brain region-specific action of ketamine as a rapid antidepressant. Science, 385(6709), eado7010. https://doi.org/10.1126/science.ado7010
- Glue, P., Neehoff, S., Beaglehole, B., Shadli, S., McNaughton, N., & Hughes-Medlicott, N. J. (2024). Ketamine for treatment-resistant major depressive disorder: Double-blind active control crossover study. Journal of Psychopharmacology, 38(2), 162-167. https://doi.org/10.1177/02698811241227026
- Johnston, J. N., Kadriu, B., Allen, J., Gilbert, J. R., & Zarate, C. A. (2023). Ketamine’s mechanisms of rapid antidepressant efficacy: Evidence from neuroimaging studies. Neuropsychopharmacology, 48(1), 1-12. https://doi.org/10.1038/s41386-022-01460-9
- Kadriu, B., Musazzi, L., Henter, I. D., Graves, M., Popoli, M., & Zarate, C. A. (2020). Glutamatergic neurotransmission: Pathway to developing novel rapid-acting antidepressant treatments. International Journal of Neuropsychopharmacology, 23(1), 1-12. https://doi.org/10.1093/ijnp/pyz068
- Lewis, V., Rurak, G., Salmaso, N., & Aguilar-Valles, A. (2024). An integrative view on the cell-type-specific mechanisms of ketamine’s antidepressant actions. Trends in Neurosciences, 47(3), 195-208. https://doi.org/10.1016/j.tins.2023.12.004
- Li, S., Zhou, W., Li, P., & Lin, R. (2024). Effects of ketamine and esketamine on preventing postpartum depression after cesarean delivery: A meta-analysis. Journal of Affective Disorders, 351, 720-728. https://doi.org/10.1016/j.jad.2024.01.202
- Medeiros, G. C., Demo, I., Goes, F. S., Zarate, C. A. Jr., & Gould, T. D. (2024). Personalized use of ketamine and esketamine for treatment-resistant depression. Translational Psychiatry, 14(1), 481. https://doi.org/10.1038/s41398-024-03180-8
- Shadli, S. M., Glue, P., McIntosh, J., McNaughton, N., & Martin, D. (2018). EEG changes associated with ketamine treatment in generalized anxiety disorder and social anxiety disorder. Clinical Neurophysiology, 129(1), 1-8. https://doi.org/10.1016/j.clinph.2017.10.015
