Prescription Ketamine Therapy for Treatment-Resistant Depression

Depression impacts millions of Americans every year. According to the National Institute of Mental Health, more than 21 million U.S. adults, about 1 in 12, experience at least one major depressive episode annually, and alarmingly, 1 in 7 adolescents are also affected [1]. 

For some patients, standard antidepressant therapy can provide satisfactory relief, but studies indicate that depression may still not be well controlled for as many as 55% of patients who are using two or more traditional therapies [2]. When a patient fails to respond to two or more traditional antidepressant therapies, they may be diagnosed with a condition known as Treatment-Resistant Depression (TRD). This condition can severely impact quality of life—at home, at work, and in relationships. Tragically, up to 30% of individuals with TRD attempt suicide at least once [3]. These patients are desperate for life-saving alternative therapy options. 

Prescription ketamine therapy offers a promising and innovative approach to TRD when conventional therapies fall short. It is quickly gaining recognition for its rapid-acting antidepressant effects. Unlike traditional antidepressants, which can take weeks to experience any noticeable effect, ketamine acts quickly in the brain, sometimes providing symptom relief within hours or days [4]. Most treatment protocols involve repeat sessions for sustained benefit. 

Typical Ketamine Protocol:
Patients may begin with 2–3 treatments per week for 2–4 weeks. This is often followed by weekly or biweekly sessions for 1–3 months, then tapering to occasional “as-needed” maintenance treatments. Sessions generally last 1–1.5 hours, including recovery time.

What Research Shows [5]:

• 70% of patients report improved mood after the first treatment
• 60% experience a significant drop in suicidal thoughts
• 40% achieve lasting improvement with continued therapy

Neuro Effects of Ketamine [6]:

• Restores glutamate levels, improving communication between neurons
• Promotes neurogenesis – growth of new neurons and brain connections (especially in mood-regulating regions)
• Activates receptors associated with well-being and resilience
• Reduces inflammation in the brain

Intravenous ketamine infusions under medical supervision in a clinical setting are growing quickly in popularity. Various compounded ketamine options also exist, including customized, patient-friendly alternatives like nasal sprays or sublingual formulations. Compounded ketamine formulations can also provide access during periods of drug shortages.

Compounded ketamine formulations are customized for individual patient needs based on a patient-specific order from a licensed provider, and the decision to use compounded ketamine therapy requires collaboration and ongoing discussion between the prescriber, the patient, and the compounding pharmacist. Like all custom-compounded preparations, there is no established safety or efficacy data like FDA-approved ketamine or esketamine products have.

While the benefits of prescription ketamine therapy show remarkable potential, it is not recommended as a first-line treatment for depression. If your provider determines that prescription ketamine therapy is appropriate for you, it should always be administered under the direct, on-site supervision of a trained medical professional. This is essential, as ketamine can cause dissociative or psychological effects, and proper monitoring helps prevent complications. Patients should never stop current antidepressant treatments without consulting with their practitioner first. Patients should also speak with their healthcare provider and compounding pharmacist to determine which other medications are safe to use during ketamine therapy. 

If you or a loved one is struggling to find relief from depression, speak with your provider and compounding pharmacist to explore whether prescription ketamine therapy may be the right choice for you.

By Jonathan Head, PharmD, Las Colinas Pharmacy

1. National Institute of Mental Health. Major Depression. U.S. Department of Health and Human Services; 2021. Available from: https://www.nimh.nih.gov/health/statistics/major-depression
2. Amos TB, Tandon N, Lefebvre P, Pilon D, Kamstra RL, Pivneva I, et al. Direct and indirect cost burden and change of employment status in treatment-resistant depression: A matched-cohort study using a US commercial claims database. J Clin Psychiatry. 2018;79(2):17m11725. doi:10.4088/JCP.17m11725
3. Rivera M, Shao S, Liu C, Zhao Y, Wang J. Treatment-resistant depression in adolescents: Challenges and future directions. Front Psychiatry. 2024;15:1417977. doi:10.3389/fpsyt.2024.1417977
4. Zarate CA, Brutsche N, Laje G, Luckenbaugh DA, Venkata SLV, Ramamoorthy A, et al. Ketamine treatment for depression: A systematic review and meta-analysis. Am J Psychiatry. 2017;174(8):746–758. doi:10.1176/appi.ajp.2017.16101203
5. Murrough JW, Perez AM, Pillemer S, Stern J, Parides MK, Aan Het Rot M, et al. Rapid and longer-term antidepressant effects of repeated ketamine infusions in treatment-resistant major depression. J Clin Psychiatry. 2018;79(6):17m11725. doi:10.4088/JCP.16m11117
6. Luckenbaugh DA, Niciu MJ, Ionescu DF, Gueorguieva R, Machado-Vieira R, Yuan P, et al. Do the dissociative side effects of ketamine mediate its antidepressant effects? J Affect Disord. 2013;149(1-3):56–61. doi:10.1016/j.jad.2013.01.010