Intranasal Ketamine as a Potential Novel Treatment for Treatment Resistant Depression & Suicidal Ideation
Treating mental health issues in the United States is a difficult business. The stigma surrounding mental health disorders, the lack of mental health providers and the lack of resources have been an issue for years. Covid-19 has likely not done any favors to the mental health of the country. According to the World Health Organization approximately 16 million people per year attempt suicide (Xiong et al., 2020). Based on this statistic, and the likelihood that the COVID-19 has severely impacted the mental and psychological health in the United States it is imperative that new ways to rapidly address the suffering of those with depression and suicidal thoughts be investigated and implemented (Xiong et al., 2020). When a patient presents for treatment either with treatment resistant depression or with active suicidal ideation they are often considered at imminent risk for self-harm and require hospitalization to keep them safe. This period of imminent risk is a time of significant stress and hopelessness for both the patients and families involved. Standard antidepressants often require 4-6 weeks for optimal effect and hospital bed availability is a problem in many areas of the country (Canuso et al., 2018). The use of intranasal ketamine has shown promise in rapidly improving depressive symptoms, including suicidal ideation among some people who are at imminent risk for suicide (Canuso et al., 2018). Though additional research is needed and continues, intranasal ketamine may offer providers and option to help patients who have not experienced an improvement in depressive symptoms through traditional medications as well as those that are experiencing suicidal thoughts.
Operational Definition & Practice Implications
The discussion here will be limited to the use of intranasal ketamine (commonly sold under the trade name Spravato). The medication can be administered intravenously, intramuscularly, and orally as well. Spravato is esketamine, one of the 2 isomers of ketamine and is the only NMDA antagonist FDA approved for those with treatment resistant depression or major depressive disorder with suicidal ideation (Titusville, 2020). We will operationally define the patient population of interest as those with treatment resistant depression or major depressive disorder at imminent risk of suicide, presenting to the emergency department or psychiatric provider with active thoughts of suicide and some intent or plan to carry that out. According to Hubers et al., (2018) this presentation is a significant predictor if death by suicide.
If ongoing research continues to provide evidence that intranasal ketamine can provide some substantial relief in a short period of time, this medication could provide a novel approach for providers and patients alike. One could argue that there are 2 distinct areas where intranasal ketamine could be of benefit.
1. This medication could provide quick relief to a patient experiencing hopelessness and active suicidal thoughts. A 2018 study found a significant reduction in scores using the Montgomery-Asberg Depression Scale (MADRS) at 4 hours post administration of intranasal ketamine and continuing at 25 days. (Canuso et al., 2018). Ketamine has a half-life of 7-12 hours, with a more rapid decline noted in plasma concentrations in the initial 2-4 hours. In the Canuso et al. (2018) study used 84mg of intranasal ketamine and dosed it twice weekly for 4 weeks. While intranasal ketamine should not be considered a miracle drug, it could provide a quick and much needed improvement in depressive symptoms including suicidal ideation. This reprieve could have the effect of allowing a patient who has lost hope, to again believe that they can feel better.
2. This medication could be administered over a short duration to afford providers an opportunity to start an SSRI or SNRI that will take some time to get up to speed and provide symptom relief. Intranasal ketamine can be administered on an emergency basis but also for longer duration giving symptom relief while allowing more traditional treatment medications to get up to speed. It would also afford providers the opportunity to arrange treatment with other members of the treatment team such as therapists, primary care, and family to assure the patient has an integrated approach to care and support from multiple avenues.
Current State of the Science/Evidence
Research and discussion on the use of psychedelic medication in psychiatric medicine and therapy has exploded in recent years, and many would argue that the use of psychedelics will grow in popularity and acceptance in the very near future. There will likely be increasing requests for the use of these medications as the public becomes more aware of the availability and research through media outlets.
Intranasal ketamine has shown promise in several studies in treating depressive symptoms, including suicidality. A systematic review from 2021, reviewed the outcomes of 15 studies or case reports where IV or intranasal ketamine were administered and found support for improvement of depressive symptoms in multiple cases (Siegel et al., 2021). But perhaps the greatest support came from the FDA approval in 2019 of intranasal ketamine for treatment resistant depression, and then in 2020 for major depressive disorder with acute suicidality. The 2020 approval came following 2 phase 3 clinical trials using intranasal ketamine on patients with suicidal thoughts (Popova et al., 2019). Patients experiencing suicidal thoughts had previously been excluded from research. These studies did not specifically demonstrate a reduction in SI but did demonstrate a rapid improvement in depressive symptoms, sometimes in as little as 4 hours (Popova et al., 2019). Research on the use of intranasal ketamine has demonstrated short term safety (Iqbal & Mathew, 2020). The most common side effects included dissociation, dizziness, sedation, increased blood pressure, hypoesthesia, vomiting, euphoric mood, and vertigo (Titusville, 2020). The medication can cause a transient increase in blood pressure for approximately 4 hours following the administration so it must be used with caution in those with hypertension (Titusville, 2020). It is also contraindicated in patients who are known to have an aneurysm or with a history of a brain bleed (Titusville, 2020). The FDA does continue to collect information about adverse reactions to intranasal ketamine through the Risk Evaluation & Mitigation Strategy (REMS) program which will be discussed below. Providers should continue to monitor research findings as additional data is collected and reported to be aware of the most recent information available. Because of the explosion of research related to psychedelic medicine it is likely that indications, research findings and best practices will continue to evolve in the coming years.
S.W.O.T Analysis
Strengths
The strength of intranasal ketamine has already been mentioned. This is the ability to offer an alternative therapy to those with treatment resistant depression and immediate treatment to those at imminent risk for suicide. This combined with the safety profile discussed above support the use of intranasal in specific subset of patients under the guidance of professionals specifically certified in the administration and follow up necessary. Until now psychiatric providers have offered medications that take weeks to work to patients who are in crisis. The patient may see medication side effects before seeing a relief and they may not have the patience and fortitude to wait out the process. Offering a faster improvement in symptomatology could shorten (but not eliminate) inpatient hospital stays and lower the risk of suicide in a more immediate timeframe. Pompili (2018) states, “Clinical environments will encounter unprecedented opportunities to assess and manage suicide risk.”
Weaknesses
The use of intranasal ketamine is not, however, without its barriers or weaknesses. The most troubling weakness being that intranasal ketamine has not yet completely demonstrated its effectiveness in preventing suicide or reducing suicidal ideation despite its approval by the FDA. While the available research does support a reduction in depressive symptoms as discussed above, additional research and investigation is clearly necessary to further make the case for the use of this medication. However, it does seem reasonable that a quick improvement in depressive symptoms may also allow some relief of suicidal ideation or at the very least some additional time for other treatment modalities to take effect, whether that be a medication, working with a therapist or even considering another method such as ECT or TMS. One of the reasons that reduction of SI has not fully been demonstrated is that investigators often exclude participants with suicidal ideation from their study because of ethical concerns (Siegel et al., 2021). Providers using intranasal ketamine must be aware that the medication does not mean a patient with suicidal ideation should not be hospitalized and should be certain to use clinical judgement and consider patient safety the utmost priority.
An additional barrier or hurdle to using this medication in practice is that only a certified center or provider can offer intranasal ketamine. To administer intranasal ketamine a provider must be certified with the Risk Evaluation & Mitigation Strategy (REMS) program for intranasal ketamine. The purpose of the REMS program is to ensure that the medication is only administered by qualified professionals, to ensure that patients are educated about the risk of sedation and dissociation and to collect data to further support the safe use of the medication (Titusville, 2020). This means that when a provider identifies a patient who may benefit from intranasal ketamine there may be a delay while a certified provider is identified, and the requirements are completed. If additional research supports, the use of intranasal ketamine it is possible that more emergency rooms and providers will become certified resulting in the treatment becoming more readily available. In addition, to being a certified provider the patient must be observed for 2 hours following the administration of the medication and is unable to drive following the appointment leading to time and transportation constraints for some patients. Going to a certified center could also be a barrier for someone whose depression or anxiety are so severe they have trouble leaving their home.
Opportunities
The barrier or weakness above does however provide an opportunity for providers working in the mental health arena and with an interest in psychedelic medicine, to become a certified as intranasal ketamine providers or clinics offering this novel treatment to patients in their area. A brief search reveals information about the use of ketamine for depression in The New York Times, USA today, Fox News and CBS. As media coverage about ketamine continues the public demand for information and providers will increase. Patients will start to ask their providers about ketamine and providers will be looking for trusted colleagues as referrals. While some could see this as a moneymaking opportunity, quality providers can grow their practice while providing education to both patients and other providers.
Threats
Perhaps the biggest threat to intranasal ketamine becoming more widely used is the abuse potential of ketamine. Ketamine can be abused as a street drug, causing relaxation at low doses and a dream like state at higher doses (Gautam et. al, 2020). The medication needs to be carefully regulated with regard to dispensation and used very selectively in patients with a known history of a substance use disorder. Some providers view the use of ketamine in a negative light because of the use of ketamine as a street drug. With additional research this threat may eventually be decreased. It should be noted that some research supports the use of ketamine in the treatment of substance use disorders with ketamine showing promising treatment results by decreasing relapse events, increasing abstinence, and diminishing cravings (Sepulveda et al., 2022).
Safety in the PMHNP Practice
Providers who are interested in suggesting treatment with intranasal ketamine should carefully screen and pre-select patients, develop relationships with providers they refer to so they can trust patients are being cared for safely and appropriately and actively engage in keeping up on ongoing research.
Psychiatric Mental Health Nurse Practitioners (PMHNP) who are interested in offering selective patients, ketamine as a treatment option, either in their own practice or through referral to another provider should exercise caution in patient selection and carefully screen candidates prior to proceeding with the therapy. As a prescriber it important to screen perspective ketamine patients for any previous substance use, including alcohol, opiates, or prescription drugs (Titusville, 2020). In addition, to screening prior to administration the PMHNP should also monitor for any signs of physical or psychological dependence during treatment. One argument for why the administration of intranasal ketamine requires provider or clinic certification is that it helps to limit the risk of abuse or misuse because the medication can only be administered in limited settings (Pompili, 2020). If the PMHNP is referring to another provider for intranasal ketamine screening should still be conducted prior to the referral and the PMHNP should refer to a trusted provider who is willing to collaborate during the treatment process. Prior to referring to another provider it should also be confirmed that the administering provider is using FDA approved intranasal ketamine. In 2022 the FDA issued a warning to providers and patients indicating that intranasal ketamine compounded or dispensed from a compounding pharmacy is not FDA approved and has been associated with increased risk of adverse events (Food & Drug Administration 2022).
In addition, to screening patients for prior or current substance use disorders all patients being considered for intranasal ketamine should have a complete medical history taken. The medication is contraindicated in patients with history aneurysm, AV malformation, or history of bleeding on the brain. It should be used with caution in those with hypertension, cardiac problems, history of stroke or heart attack and those with liver disease (Titusville, 2020). As an additional safety it may be prudent to check in with the patient’s primary care provider or specialist if there are any concerns or uncertainties about co-morbid medical conditions. This collaborative relationship can benefit the patient and allows all members of the care team an opportunity to weigh on how intranasal ketamine can impact other medical conditions.
Perhaps the most important safety mechanism to have in place before either administering intranasal ketamine (if certified) or referring a patient for intranasal ketamine is constant and thorough following of the most current research. The research is quickly unfolding as evidenced by the FDA approving intranasal ketamine in 2019 for treatment resistant depression and then introducing a new indication in 2020 (Titusville, 2020). Having a new treatment for patients that have previously not found relief from current regimens and for those at risk for suicide is offers mental health providers a new era of treatment, but it will require constant updates and continuous education (Pompili, 2020).
Conclusion
Psychiatric providers have many tools available to them and intranasal ketamine is beginning to be added as another available option. Research and FDA indications support the use of intranasal ketamine for patients with treatment resistant depression and major depressive disorder with suicidal ideation (Titusville, 2020). Intranasal ketamine may be an option to address the needs of patients either with treatment resistant depression or who are suicidal. This treatment has the benefit of being fast acting, offering patients relief that has been previously unavailable. It seems to be well tolerated and though there are some restrictions on who can prescribe and administer the medication and it does require a time commitment on the part of the patient the relief it offers may be well worth the hurdles in this subset of patients. Additional research is underway and as more longitudinal studies take place intranasal ketamine has the potential to become more of a mainstay of treatment.
References
Canuso, C. M., Singh, J. B., Fedgchin, M., Alphs, L., Lane, R., Lim, P., Pinter, C., Hough, D., Sanacora, G., Manji, H. & Drevets, W.C. (2018). Efficacy and Safety of Intranasal Esketamine for the Rapid Reduction of Symptoms of Depression and Suicidality in Patients at Imminent Risk for Suicide: Results of a Double Blind Randomized, Placebo-Controlled Study. The Journal of Psychiatry, 175(7), 620-630. https://doi.org/10.1176/appi.ajp.2018.170-60720.
Food & Drug Administration (2022) FDA alerts health care professionals of potential risks associated with compounded ketamine nasal spray. https://www.fda.gov/drugs/human-drug compounding/fda-alerts-health-care-professionals-potential-risks-associated-compounded-ketamine-nasal-spray. Gautam, C. S., Mahajan, S. S., Sharma, J., Singh, H., & Singh, J. (2020). Repurposing Potential of Ketamine: Opportunities and Challenges. Indian journal of psychological medicine, 42(1), 22–29 https://doi.org/10.4103/IJPSYM.IJPSYM_228_1
Hubers, A., Moaddine, S., Peersmann, S., Stijnen, T., van Duijn, E., van der Mast, R. C., Dekkers, O. M., & Giltay, E. J. (2018). Suicidal ideation and subsequent completed suicide in both psychiatric and non-psychiatric populations: a meta-analysis. Epidemiology and psychiatric sciences, 27(2), 186–198. https://doi.org/10.1017/S2045796016001049
Pompili M. (2020). Intranasal Esketamine and Current Suicidal Ideation With Intent in Major Depression Disorder: Beat the Clock, Save a Life, Start a Strategy. Frontiers in psychiatry, 11, 325 https://doi.org/10.3389/fpsyt.2020.00325
Popova, V., Daly, E. J., Trivedi, M., Cooper, K., Lane, R., Lim, P., Mazzucco, C., Hough, D., Thase, M.E.,Shelton, R. C., Molero, P., Vieta, E., Bajbouj, M., Manji, H., Drevets, W. C., & Singh, J. B. (2019). Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Combined With a Newly Initiated Oral Antidepressant in Treatment-Resistant Depression: A Randomized Double-Blind Active-Controlled Study. The American journal of psychiatry, 176(6), 428–438. https://doi.org/10.1176/appi.ajp.2019.19020172
Sepulveda Ramos C, Thornburg M, Long K, et al. (March 30, 2022) The Therapeutic Effects of Ketamine in Mental Health Disorders: A Narrative Review. Cureus 14(3): e23647. doi:10.7759/cureus.23647
Siegel, A. N., Di Vincenzo, J. D., Brietzke, E., Gill, H., Rodrigues, N. B., Lui, L., Teopiz, K. M., Ng, J., Ho, R., McIntyre, R. S., & Rosenblat, J. D. (2021). Antisuicidal and antidepressant effects of ketamine and esketamine in patients with baseline suicidality: A systematic review. Journal of psychiatric research, 137, 426–436. https://doi.org/10.1016/j.jpsychires.2021.03.009
SPRAVATO® [Prescribing Information]. Titusville, N.J., Janssen Pharmaceuticals, Inc. July 2020.
Xiong, J., Lipsitz, O., Chen-Li, D., Rosenblat, J. D., Rodrigues, N. B., Carvalho, I., Lui, L., Gill, H., Narsi, F., Mansur, R. B., Lee, Y., & McIntyre, R. S. (2021). The acute antisuicidal effects of single-dose intravenous ketamine and intranasal esketamine in individuals with major depression and bipolar disorders: A systematic review and meta-analysis. Journal of psychiatric research, 134,57–68. https://doi.org/10.1016/j.jpsychires.2020.12.038