Interactions between ketamine and prescription antidepressants

From 2015 to 2018 alone, the number of ketamine clinics in the US has quintupled - from roughly 60 to 300[1]. Given the high disease burden of depression and other psychiatric disorders, many are flocking to the infusion clinics in hopes of a quantum change. But what is at stake, particularly when it comes to ketamine’s safety and efficacy together with other more traditional antidepressants?

Ketamine is a dissociative anesthetic with a rapid onset of activity, a unique property not seen in many other prescription antidepressants that take weeks to exert their effects. It primarily acts on the NMDA receptor as an antagonist at the GABA-releasing interneurons, inducing a downstream elevation in glutamate stimulation of the AMPA receptors, which is implicated in its antidepressant properties. It also secondarily binds to opioid receptors and modulates the monoamine systems (dopamine, serotonin, norepinephrine)[2]. Ketamine’s binding profile, therefore, gives rise to the sensible concerns regarding its possible interactions with other pharmaceuticals, with antidepressants being the most commonly prescribed for patients potentially benefiting from off-label ketamine therapy.

Broadly, there seems to be no significant adverse interactions between ketamine and regularly prescribed antidepressants, with the exception of a few. In fact, many patients receiving ketamine infusion therapy are advised to stay on their longitudinal medication regimen whilst receiving ketamine. The possible interactions for each class of antidepressants are detailed below.

Selective serotonin reuptake inhibitors (SSRIs)

No concerning interactions exist - clinical trials have shown ketamine’s safety and efficacy in patient populations concurrently using escitalopram and sertraline[3][4]. Combination treatment may confer synergistic effects, as demonstrated by a clinical trial comparing escitalopram + ketamine v. escitalopram + placebo for major depressive disorder (MDD), in which ketamine was found to augment the therapeutic efficacy of the SSRI with improvement in suicidality[5]. Another trial on sertraline also suggests that ketamine may be used as adjuvant therapy[6]. However, it’s important to note that ketamine is metabolized by the liver enzymes P450 CYP2B6 and CYP3A4 primarily, so any inhibitors and inducers of these enzymes could alter the metabolism of ketamine. Paroxetine, sertraline, fluoxetine, and fluvoxamine are all CYP3A4 inhibitors, so concurrent use of ketamine can possibly elevate the bioavailability of ketamine. However, this slight elevation may not be clinically significant[7][8].

Serotonin-norepinephrine reuptake inhibitors (SNRIs)

The safety profile of the SNRI-ketamine combination shares similarities with that of SSRIs + ketamine, with clinical trials again demonstrating the safety of the former combination[3][4]. A possible adverse event involves elevations in blood pressure. Both SNRIs and ketamine are individually known to induce sympathetic activation, so theoretically the combination could pose hemodynamic risks. In practice, however, there may only be a transient and self-limiting elevation[9]. Additionally, venlafaxine is also a CYP3A4 inhibitor, possibly increasing the bioavailability of ketamine[8].

Tricyclic antidepressants (TCAs)

Generally safe[2]. However, similar to SNRIs, the combination could confer cardiovascular changes, including high blood pressure, as well as overwhelming sedation, as both TCAs and ketamine individually induce sedation[10]. A case report of fibromyalgia and another of melancholic depression illustrate the safety and efficacy of nortriptyline + ketamine[11][12].

Monoamine oxidase inhibitors (MAOIs)

Due to the high risk of serotonin syndrome when MAOIs are combined with serotonergic medications (including SSRIs), MAOIs are cautiously used in conjunction with ketamine. Two studies on tranylcypromine, an MAOI, did not observe any signs of serotonin syndrome nor cardiovascular changes in patients with MDD and treatment-resistant depression, however[2]. In particular, tranylcypromine and selegiline are both CYP3A4 inhibitors, but the interaction is again of arguable clinical significance[7][8].

Bupropion

No clinically significant adverse effects noted[2]. Mild increases in blood pressure can occur when used in conjunction with ketamine[9]. Combination is well-tolerated in anecdotal reports.

Mirtazapine

Possibly safe[2]. However, it should be noted that optimal doses (read: low) should be achieved for both mirtazapine and ketamine; otherwise, due to the sedating properties of mirtazapine, the combination can cause overwhelming sedation, dizziness, cognitive impairment, and even respiratory depression, especially in the elderly[13]. Anecdotal reports suggest that responsible use should minimize adverse effects.

Lithium

Lithium and ketamine pose minimal risks when taken together, but combination use has not been found to enhance therapeutic efficacy than ketamine alone for MDD[2].

Lamotrigine

No adverse effects are noted per se, but lamotrigine has been reported to have an antagonistic action against ketamine, dampening some of the consciousness-altering effects of ketamine and conferring more “lucidity” to the user[2][7]. Interestingly, pretreatment with lamotrigine prior to ketamine administration in healthy individuals can negate some of the undesired side effects of ketamine, as well as boost ketamine-induced euphoria. Lamotrigine may also have utility in protecting against ketamine-induced psychosis[7].

Benzodiazepines

The safety of this combination is largely dependent on the dose of each substance and the tolerance of the user. High-dose use relative to tolerance can incur risks of overwhelming sedation, confusion, and even respiratory depression. Clinical trials, however, have looked at the efficacy of ketamine for depression in patients concurrently taking benzodiazepines, with no serious adverse effects reported[2][7]. But there is a twist: benzodiazepines significantly attenuate the antidepressant effects of ketamine. Above a certain threshold, the antidepressant response is abolished altogether. Several benzodiazepines, such as diazepam and midazolam, are also CYP3A4 inhibitors[8].

As a disclaimer, the combinatorial space involving multiple compounds, set and setting, and individualized factors is still challenging to model, so one must still proceed with caution when using any of these compounds with ketamine. Isolated case reports do exist of patients who have been inflicted with derealization, disorientation, mania, emotional incontinence, and other symptoms mimicking psychosis following ketamine administration on top of their regular polydrug regimen[14][15][16][17]. However, one can hardly overemphasize that these adverse effects can occur with the use of ketamine alone, and it is the set of the user’s neurobiology, psychology, physical health, and the environments that determines the likelihood of these risks - “there are as many paths as there are travelers”. The overall risks at a population level for ketamine + antidepressants are still low enough to warrant concurrent use in clinical trials and for therapeutic purposes. Further, it is also unclear which medications (or set of medications) negatively interacted with ketamine in the above studies/reports - the more compounds are used, the higher the risks are. As with all therapeutic modalities, preferably consult medical professionals prior to use, and if possible, start with low doses and slowly up-titrate.

References:

[1] Bricken, H., & Hilary Bricken Since joining Harris Bricken in 2010. (2020, March 4). The ketamine clinic craze: Legalities and possibilities. Harris Bricken Sliwoski LLP. Retrieved from https://harrisbricken.com/cannalawblog/the-ketamine-clinic-craze-legalities-and-possibilities/

[2] Veraart, J. K., Smith-Apeldoorn, S. Y., Bakker, I. M., Visser, B. A., Kamphuis, J., Schoevers, R. A., & Touw, D. J. (2021). Pharmacodynamic interactions between ketamine and psychiatric medications used in the treatment of depression: A systematic review. International Journal of Neuropsychopharmacology, 24(10), 808–831. https://doi.org/10.1093/ijnp/pyab039

[3] Kryst, J., Kawalec, P., & Pilc, A. (2019). Efficacy and safety of intranasal esketamine for the treatment of major depressive disorder. Expert Opinion on Pharmacotherapy, 21(1), 9–20. https://doi.org/10.1080/14656566.2019.1683161

[4] Fedgchin, M., Trivedi, M., Daly, E. J., Melkote, R., Lane, R., Lim, P., Vitagliano, D., Blier, P., Fava, M., Liebowitz, M., Ravindran, A., Gaillard, R., Ameele, H. V., Preskorn, S., Manji, H., Hough, D., Drevets, W. C., & Singh, J. B. (2019). Efficacy and safety of fixed-dose esketamine nasal spray combined with a new oral antidepressant in treatment-resistant depression: Results of a randomized, double-blind, active-controlled study (transform-1). International Journal of Neuropsychopharmacology, 22(10), 616–630. https://doi.org/10.1093/ijnp/pyz039

[5] Hu, Y.-D., Xiang, Y.-T., Fang, J.-X., Zu, S., Sha, S., Shi, H., Ungvari, G. S., Correll, C. U., Chiu, H. F., Xue, Y., Tian, T.-F., Wu, A.-S., Ma, X., & Wang, G. (2015). Single I.V. ketamine augmentation of newly initiated escitalopram for major depression: Results from a randomized, placebo-controlled 4-week study. Psychological Medicine, 46(3), 623–635. https://doi.org/10.1017/s0033291715002159

[6] Arabzadeh, S., Hakkikazazi, E., Shahmansouri, N., Tafakhori, A., Ghajar, A., Jafarinia, M., & Akhondzadeh, S. (2018). Does oral administration of ketamine accelerate response to treatment in major depressive disorder? results of a double-blind controlled trial. Journal of Affective Disorders, 235, 236–241. https://doi.org/10.1016/j.jad.2018.02.056

[7] Andrade, C. (2017). Ketamine for depression, 5: Potential pharmacokinetic and pharmacodynamic drug interactions. The Journal of Clinical Psychiatry, 78(7). https://doi.org/10.4088/jcp.17f11802

[8] Lacy, C. F., Armstrong, L. L., Goldman, M. P., & Lance, L. L. (2017). Cytochrome P450 Enzymes: Substrates, Inhibitors, and Inducers. Drug Information Handbook (15th ed.). Lexi-Comp. 1899-1912.

[9] Lev, E. (2021, June 9). Combining ketamine treatment with other psychiatric medications: What to know. Mindbloom . Retrieved from https://www.mindbloom.com/blog/ketamine-treatment-other-medications-ssri-snri-maoi-wellbutrin-adderall

[10] Drug interaction report. Drugs.com. (n.d.). Retrieved from https://www.drugs.com/interactions-check.php?drug_list=1411-0%2C168-0%2C1734-0

[11] Sidhye, U., & Munot, P. (2019). Case report of fibromyalgia. Journal on Recent Advances in Pain, 5(2), 70–72. https://doi.org/10.5005/jp-journals-10046-0144

[12] Gálvez, V., O’Keefe, E., Cotiga, L., Leyden, J., Harper, S., Glue, P., Mitchell, P. B., Somogyi, A. A., DeLory, A., & Loo, C. K. (2014). Long-lasting effects of a single subcutaneous dose of ketamine for treating melancholic depression: A case report. Biological Psychiatry, 76(3). https://doi.org/10.1016/j.biopsych.2013.12.010

[13] Drug interaction report. Drugs.com. (n.d.). Retrieved April 12, 2022, from https://www.drugs.com/interactions-check.php?drug_list=1411-0%2C1640-0

[14] Paul, R., Schaaff, N., Padberg, F., Möller, H.-J., & Frodl, T. (2009). Comparison of racemic ketamine ands-ketamine in treatment-resistant major depression: Report of two cases. The World Journal of Biological Psychiatry, 10(3), 241–244. https://doi.org/10.1080/15622970701714370

[15] Correia-Melo, F. S., Silva, S. S., Araújo-de-Freitas, L., & Quarantini, L. C. (2017). S-(+)-    ketamine-induced dissociative symptoms as a traumatic experience in patients with treatment-resistant depression. Revista Brasileira De Psiquiatria, 39(2), 188–189. https://doi.org/10.1590/1516-4446-2016-2070

[16] Szymkowicz, S. M., Finnegan, N., & Dale, R. M. (2013). A 12-month naturalistic observation of three patients receiving repeat intravenous ketamine infusions for their treatment-resistant depression. Journal of Affective Disorders, 147(1-3), 416–420. https://doi.org/10.1016/j.jad.2012.10.015

[17] &NA; (2013). Duloxetine/ketamine interaction. Reactions Weekly, (1368). https://doi.org/10.2165/00128415-201113680-00061

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