A patient with treatment-resistant depression and suicidality achieving remission with an intranasal NMDA receptor antagonist

Presentation and history
A 25-year-old female school teacher with treatment-resistant depression (TRD), who was otherwise healthy with a strong family history of depression, was referred to our clinic in April 2023 by a general practitioner (GP) due to suicidal ideation – a psychiatric emergency.

The patient was diagnosed by the GP to have major depressive disorder (MDD) in March 2022. As a result of workrelated stress, she developed depressive symptoms, including unprovoked crying, reduced appetite, insomnia, withdrawal from parents, and loss of motivation and interest in exercise and hobbies. (Table) She was initially treated with flupenthixol plus melitracen and escitalopram, but was switched to mirtazapine and vortioxetine due to poor response. Despite gradual uptitration of antidepressant doses over 1 year, response remained poor. The GP then switched vortioxetine to desvenlafaxine. However, little improvement was seen despite uptitration of desvenlafaxine to the maximum dose. 

In April 2023, the patient developed suicidal ideation and wrote a suicide note after a minor conflict with her father. Immediately, she was suspended from work and referred to our clinic. She presented with depressive symptoms and active suicidal ideation. While she and her family were considering our advice on esketamine for urgent relief of symptoms, her oral medications were adjusted, with mirtazapine uptitrated, aripiprazole added as augmentation for TRD, and pregabalin given for anxiety. (Table)

Treatment with esketamine nasal spray and response
The patient started her first dose of esketamine at our clinic in April 2023. After dosing, she rested for 2 hours in a private room, in which she was closely monitored by our nurses and had blood pressure (BP) checked regularly. She experienced no adverse effects (AEs) before leaving the clinic. Treatment response was rapid, with suicidal thoughts reportedly subsiding after the first dose and Beck Depression Inventory (BDI) score substantially dropping after the first two doses. (Table)

As esketamine treatment continued, the patient experienced substantial improvement in sleep, appetite and daily functioning. She resumed work 7 days after her first dose, showing good performance and an ability to manage work relationships. Subsequently, she took sick leave only on days of esketamine administration. After 2–3 weeks of treatment, her condition stabilized, and her oral medications were downtitrated. Gradually, she became motivated, resumed exercise and hobbies, and enjoyed chatting with her parents again. Her life returned to the premorbid state. (Table)

The patient tolerated esketamine well and did not experience any AEs, including dissocation or BP elevation. Nevertheless, she decided to stop treatment after 2 months due to financial concerns.

Discussion
A patient is considered to have TRD when symptoms of MDD do not improve after ≥2 lines of antidepressants. TRD patients have decreased quality of life and increased risks of unemployment and suicide.^1-3

Esketamine nasal spray is a fast-acting glutamatergic N-methyl-D-aspartate (NMDA) receptor antagonist indicated, in combination with oral antidepressant therapy, in adults with moderate-to-severe TRD and as acute short-term treatment for rapid reduction of depressive symptoms, which, according to clinical judgment, constitute a psychiatric emergency.⁴

In the phase III, randomized, double-blind TRANSFORM-2 study (n=227), patients with TRD who received esketamine plus an antidepressant had greater improvement in depressive symptoms in terms of mean Montgomery-Åsberg Depression Rating Scale (MADRS) score than those receiving antidepressants only (least-square [LS] mean difference, 4.0; 95 percent confidence interval [CI], -7.31 to -0.64; p=0.020). Response to esketamine was rapid, with onset as early as 24 hours postdose, and increased over time during repeated dosing. Remission rate on day 28 was significantly higher in esketamine-treated patients vs those receiving antidepressants only (69.3 percent vs 52.0 percent; odds ratio, 2.4; 95 percent CI, 1.30–4.54).⁵

Esketamine also demonstrated rapid and robust efficacy in severely ill MDD patients with suicidal ideation and intent. In the phase III, randomized, short-term ASPIRE I (n=226) and ASPIRE II (n=230) studies, the efficacy and safety of 4-week esketamine treatment plus comprehensive standard-of-care (SoC; initial psychiatric hospitalization and newly initiated or optimized oral antidepressant therapy) were compared with placebo plus SoC. Across both studies, esketamine demonstrated statistically significant and clinically meaningful reduction in depressive symptoms in terms of MADRS score at 24 hours after the first dose vs placebo (LS mean difference, -3.8; 95 percent CI, -5.75 to -1.89). Symptom improvement was documented as early as 4 hours after the first dose (LS mean difference, -3.4; 95 percent CI, -5.05 to -1.71).^6-8

Esketamine was well tolerated in a 16-week study. The most common AEs were transient dysgeusia, vertigo, dissociation, somnolence, and dizziness. BP increases were also observed on treatment days, but most of the events were mild and transient and resolved by 1.5 hours after dosing.⁹ A designated room with suitable setting for esketamine administration, including a comfortable couch and a quiet environment for rest, will help clinicians to manage and patients to recover from transient AEs after dosing. (Figure)

Our TRD patient was in a psychiatric emergency due to her suicidal ideation. Although her suicidal thoughts were fading, she was still at risk. Esketamine treatment led to prompt resolution of her suicidal ideation after the first dose. She also experienced rapid improvements in mood and functioning within 1 week of commencing esketamine treatment, which allowed her to resume work. After 2 months of treatment, her BDI score decreased from 39/63 to 4/63, suggesting clinical remission that was not achieved with multiple previous lines of oral antidepressants. (Table)

Notably, the patient tolerated esketamine well with no AEs, even during the initial 2-hour in-clinic observation period. The quiet and comfortable environment in the room designated for esketamine adminstration, together with prior education on possible AEs and nurses’ reassurance, helped her feel safe and relaxed during treatment.

Early treatment with esketamine is beneficial to TRD patients, especially professionals who want to minimize sick leave. This case illustrates good tolerability and efficacy of esketamine in providing rapid and significant relief of symptoms in a young professional with TRD and suicidality, whose life returned to premorbid state shortly after commencing esketamine for psychiatric emergency.