Esketamine For the Treatment of Depression in a Patient With Multiple Sclerosis

The central nervous system consists of myelinated and unmyelinated axons. Myelination insulates axons and increases the speed of nerve conduction.¹ Multiple sclerosis (MS) is an autoimmune disorder that attacks myelinated axons in the central nervous system. This disorder causes inflammation, neuronal loss, and demyelination,² which manifest in a variety of ways: all caused by neuronal impairment. Patients can have anything from numbness and tingling to vision impairment from optic neuritis to bladder and bowel dysfunction.³

Depression is a common comorbidity in patients with MS. It is imperative to screen for depression in MS patients, as it is shown to be a strong determinant of quality of life.⁴ Depression can occur in up to 50% of MS patients and is 2–3 times more prevalent compared to the general population.⁵ The reason for this prevalence is multifaceted. Living with MS can cause pain and fatigue and can decrease quality of life due to progression of the disease and lack of a cure. Biologic mechanisms in MS such as hippocampal microglial activation, lesion burden, and regional atrophy can also predispose patients to depression.⁶

Esketamine is a drug derived from an anesthetic, ketamine. It causes an increase in glutamate, which enhances neural communication and helps regulate and boost mood.⁷ It is an N-methyl-D-aspartate glutamate receptor antagonist and is used intranasally for treatment-resistant depression. Esketamine was approved by the US Food and Drug Administration for treatment-resistant depression and suicidality associated with major depressive disorder (MDD).

Case Report

A 42-year-old white man with MS presented to the psychiatric clinic with depression and anxiety. His MS was diagnosed in 2019 and had been stable since diagnosis. Approximately 6 months after his MS diagnosis, he developed depressive symptoms including low mood, sleep disturbances, poor motivation and drive, and decreased interest and lack of pleasure, along with suicidal thoughts and episodes of rage. The clinical history also documented substantial functional impairment. He had required medical leave and subsequently went on disability, stopped driving because of anger and road-rage episodes, and experienced weight loss. The exact amount of weight loss and more detailed measures of occupational and daily functional impairment were not available in the clinical records. His neurologist initiated escitalopram at a dose of 20 mg/d. He was on this dose for a year before he stopped it due to nonresponse. Bupropion was initiated in 2021, and he was on it at a dose of 450 mg/d for over a year.

His medications at presentation included glatiramer acetate injection 40 mg 3 times a week for MS, amphetamine/dextroamphetamine 10 mg twice/d, and bupropion 450 mg/d. When he presented to the clinic, he was started on oxcarbazepine 450 mg twice/d for anger outbursts and aripiprazole 5 mg once/d. Oxcarbazepine was not tolerated and was discontinued. Intranasal esketamine was initiated at the end of 2022.

At initiation of esketamine, standardized symptom measures demonstrated substantial depressive and anxiety symptom burden, with a Patient Health Questionnaire-9 (PHQ-9)⁸ score of 23, Generalized Anxiety Disorder-7 (GAD-7)⁹ score of 20, and Beck Depression Inventory (BDI)¹⁰ score of 59. These instruments were used to quantify severity and longitudinal treatment response and were not used as substitutes for the clinical history or as the sole basis for diagnosis. After 1 week of esketamine, his PHQ-9 score decreased to 15, GAD-7 score to 13, and BDI score to 29. At completion of the 8-session induction period, scores were PHQ-9 of 8, GAD-7 of 5, and BDI of 18. After 2 esketamine sessions, the patient also reported fewer episodes of rage and suicidal thoughts. He subsequently received more than 70 treatment visits. His most recently documented scores were PHQ-9 of 8, GAD-7 of 11, and BDI of 18, representing reductions from baseline of approximately 65%, 45%, and 69%, respectively. Formal longitudinal quality-of-life measures were not collected; therefore, sustained benefit is characterized here as maintenance of reduced symptom scores rather than comprehensive functional recovery.

Discussion

This is the first case, to our knowledge, of a patient with MS whose depression was successfully treated with esketamine. Treatment response was assessed longitudinally using the PHQ-9, BDI, and GAD-7, together with the clinical history. These scales quantified symptom severity and change over time but were not considered sufficient by themselves to establish the diagnosis of MDD. Response to treatment is commonly defined as a 50% reduction in symptom burden; remission of depression is defined as a PHQ-9 score <5 or a BDI score <10. Although the patient did not achieve the stated remission thresholds, a rapid reduction in measured symptoms was observed. By the first week, the BDI score had decreased by approximately 50%. At the end of induction, all 3 questionnaire scores were substantially below baseline. The early reduction in rage episodes and suicidal thoughts after 2 sessions provides additional clinical context to the changes in rating scales, although these symptoms cannot be attributed exclusively to depression.

This case introduces intranasal esketamine as a potentially useful treatment option for depressive symptoms in a patient with MS. The observed reduction in standardized symptom scores occurred early in treatment and remained substantially below baseline during continued treatment. This case, therefore, supports further study of esketamine in patients with MS and significant depressive symptoms, when not responsive to other medications.

Conclusion

This case demonstrates the use of esketamine for patients with MS who have depression. The use of intranasal esketamine can be effective for patients who have failed previous attempts with oral antidepressants.

Article Information

Published Online: September 22, 2026. https://doi.org/10.4088/PCC.26cr04246
© 2026 Physicians Postgraduate Press, Inc.
Prim Care Companion CNS Disord 2026;28(5):26cr04246
Submitted: April 3, 2026; accepted September 2, 2026.
To Cite: Mathews M, Aickareth G, Abraham A, et al. Esketamine for the treatment of depression in a patient with multiple sclerosis. Prim Care Companion CNS Disord 2026;28(5):26cr04246.
Author Affiliations: Allegheny Health Network, Pittsburgh, Pennsylvania (M. Mathews); University of Texas at Houston, Texas (Aickareth); Synapse Behavioral Health, Marlton, New Jersey (Abraham, Pontelandofo, R Mathews, S. Mathews, Golden); Lake Erie College of Osteopathic Medicine, Erie, Pennsylvania (Kamat).
Corresponding Author: Meghna Mathews, MD, Allegheny Health Network, Pittsburgh, Pennsylvania ([email protected]).
Financial Disclosure: None.
Funding/Support: None.
Patient Consent: Consent was received from the patient to publish the case report, and information, including dates, has been de-identified to protect patient anonymity.