Ketamine for Treatment-Resistant Depression: What Current Evidence Tells Us

Introduction

In recent years, ketamine has gained significant attention as a promising treatment for treatment-resistant depression (TRD). Unlike conventional antidepressants, which often take weeks to show benefits, ketamine appears to offer rapid relief from depressive symptoms. This unique characteristic has made it a focus of extensive clinical research, particularly for individuals who have not responded to traditional therapies. An impressive, growing body of high-quality studies supports the benefits of ketamine for TRD. This article is intended to summarize the current medical literature (scientific evidence) on ketamine for TRD, for individuals considering ketamine therapy.

Ketamine differs from traditional antidepressants in its mechanism of action by targeting the brain's glutamatergic system, specifically as an NMDA receptor antagonist. This unique pathway enhances synaptic plasticity and rapidly restores neural connectivity, leading to almost immediate antidepressant effects. In contrast, most conventional antidepressants modulate serotonin, norepinephrine, or dopamine levels and typically take weeks to show efficacy.

Current Evidence on Ketamine for TRD

Rapid Antidepressant Effects

Ketamine’s most notable feature is its ability to provide rapid antidepressant effects. Clinical studies reveal that a single infusion of intravenous ketamine can produce noticeable improvements in depressive symptoms within hours, with peak effects typically observed at 24 hours post-infusion (Bahji et al., 2020; Daly et al., 2019; Kishimoto et al., 2019). However, a single infusion appears to be generally short-lived in benefit, generally persisting for one to two weeks (Kishimoto et al., 2019; Newport et al., 2015). This has led clinicians to adopt a multiple-dose approach, which appears to improve its durability.

Repeated and Maintenance Dosing

Repeated doses of ketamine have shown promise in prolonging its therapeutic benefits. For example, Murrough et al. (2013) demonstrated that multiple infusions over a two-week period yielded cumulative benefits, with sustained improvement in depressive symptoms. Additionally, weekly maintenance infusions have been effective in preserving the antidepressant effects for responders (Singh et al., 2016).

Ketamine can be given to patients in different ways: By mouth, intramuscular injection, intravenously (IV), and intranasally (by spray in the nose). Expanding research explored how ketamine's effects might be enhanced or diminished by 'how it was administered' (called mode of administration). The mode of administration indeed appears to impact outcomes. Intravenous ketamine appears more effective than intranasal esketamine, suggesting that the route and formulation of ketamine might affect its benefits (Bahji et al., 2020).

Comparisons and Safety

Esketamine, a derivative of ketamine, has been approved as an adjunctive treatment for TRD. Studies indicate that esketamine is similarly effective and well-tolerated compared to racemic ketamine (Popova et al., 2019; Bahji et al., 2020). Both treatments are associated with mild, transient side effects such as dissociation, headache, and nausea, in some individuals. However, because most trials have been conducted in a relatively short-timeframe, questions still remain as to the safety of long-term use or higher doses of ketamine, with further research needed to address these concerns (Singh et al., 2016; Daly et al., 2019). This limitation of evidence generally leads clinicians to recommend ketamine only over limited periods of time - not as an ongoing treatment agent.

Summary of Limitations and Future Directions

While ketamine offers a groundbreaking approach to managing TRD, with uniquely impressive results in the short-term, it is not without limitations and more research is needed to optimize this therapy. Current questions and limitations in knowledge include:

1. Long-term Efficacy: More studies are needed to determine the longest extent of ketamine's effects and the potential for dependence or tolerance with prolonged use (Newport et al., 2015; Kishimoto et al., 2019). In other words, while ketamine does not appear to hold high risk for addiction, the question of whether it can lead to addiction remains to be answered with certainty. Also, it is not known for certain whether ketamine benefits are reduced when it is used for a long-period of time.

2. Optimal Dosing Strategies: Researchers are still exploring the best dosing regimens and administration routes to maximize benefits and minimize side effects (Daly et al., 2019; Murrough et al., 2013). While current evidence has provided some good grounding for dosing for the treatment of TRD, determining the optimal dose for the individual in each case, is evolving all the time, informed by newer studies and clinical experience, as ketamine is used by more clinicians and their patients.

3. Broader Applicability: The nature of clinical research is that it typically begins in adults with similar profiles. This means that because ketamine is still a relatively new therapy in mental health, limited data exist for its use in certain populations, such as adolescents and individuals with chronic suicidal ideation (i.e., suicidal ideation that has occured for a long time, rather than in a short period of time) (Grunebaum et al., 2018).

Summary of the evidence

Ketamine appears to represent an promising, impactful and transformative option for individuals with TRD, offering rapid and significant relief where traditional treatments have failed. Its short-term efficacy is well-documented, and repeated dosing regimens show potential for sustained benefits. However, as a relatively new therapeutic approach, ketamine still requires further study to address questions surrounding its long-term safety and optimization. Fortunately, ketamine therapy is now accessible to those in need, providing hope for individuals with TRD as research continues to refine this innovative treatment.

About the Author

Dr. David George currently maintains an active, clinical practice at Neuregen, a Scottsdale, Arizona-based, Integrative Psychiatry and Neurologic Health clinic. Neuregen offers full spectrum ketamine therapy as part of a comprehensive, brain-based approach to mental health and brain rehabilitation. Neuregen is dedicated to transforming lives and offering an alternative to conventional, mental health approaches, through an integrative, evidence-informed, and compassionate approach to care.

References

Bahji, A., Vázquez, G., & Zarate, C. (2020). Comparative efficacy of racemic ketamine and esketamine for depression: A systematic review and meta-analysis. Journal of Affective Disorders, 278, 542–555. https://doi.org/10.1016/j.jad.2020.09.071

Daly, E. J., Trivedi, M. H., Janik, A., Li, H., Zhang, Y., Li, X., ... & Singh, J. B. (2019). Efficacy and safety of a 4-week course of repeated subcutaneous ketamine injections for treatment-resistant depression. Journal of Clinical Psychiatry, 80(2).

Grunebaum, M. F., Ellis, S. P., Keilp, J. G., Moitra, V. K., Cooper, T. B., Marver, J. E., ... & Mann, J. J. (2018). Ketamine for rapid reduction of suicidal thoughts in major depression: A midazolam-controlled randomized clinical trial. American Journal of Psychiatry, 175(4), 327-335.

Kishimoto, T., Chawla, J. M., Hagi, K., Zarate, C. A., Kane, J. M., Bauer, M., & Correll, C. U. (2019). Single-dose infusion ketamine and non-ketamine NMDA receptor antagonists for unipolar and bipolar depression: A meta-analysis of efficacy, safety and time trajectories. Psychological Medicine, 50(1), 1–13.

Murrough, J. W., Perez, A. M., Pillemer, S., Stern, J., Parides, M. K., Aan Het Rot, M., ... & Charney, D. S. (2013). Rapid and longer-term antidepressant effects of repeated ketamine infusions in treatment-resistant depression. Biological Psychiatry, 74(4), 250–256.

Newport, D. J., Carpenter, L. L., McDonald, W., Potash, J. B., Tohen, M., & Nemeroff, C. B. (2015). Ketamine and other NMDA antagonists: Early promise, clinical issues, and future directions. Journal of Clinical Psychiatry, 76(4), 0–0.

Popova, V., Daly, E. J., Trivedi, M., Cooper, K., Lane, R., Lim, P., ... & Drevets, W. C. (2019). Efficacy and safety of flexibly dosed esketamine nasal spray combined with a newly initiated oral antidepressant in treatment-resistant depression: Results of a randomized, double-blind, active-controlled study (TRANSFORM-2). American Journal of Psychiatry, 176(6), 428–438.

Singh, J. B., Fedgchin, M., Daly, E., Xiang, J., Melman, C., DeBrady, L., ... & Manji, H. (2016). Intravenous esketamine in adult treatment-resistant depression: A double-blind, double-randomization, placebo-controlled study. Biological Psychiatry, 80(6), 424–431.