The patient, a 62-year-old businessman, experienced his first major depressive episode in 2004, presenting with depressed mood, anhedonia, insomnia, low energy, thoughts of worthlessness, and suicidal ideation. In 2005, he had a hypomanic episode characterized by elevated mood, grandiosity, impulsive spending, and a diminished need for sleep lasting more than 4 days but less than a week. This was followed by a low mood for an extended period, which resulted in his retirement in 2012. He had second and third major depressive episodes in 2017 and 2019, both accompanied by suicide attempts (Figure 1). Due to poor response to multiple psychotropic medications at adequate doses and durations, including but not limited to venlafaxine, mirtazapine, lithium, olanzapine, and quetiapine, his response remained poor. In 2019, electroconvulsive therapy (ECT) combined with intravenous ketamine was attempted, leading to partial improvement and discharge after 12 sessions of treatment. After that, repetitive Transcranial Magnetic Stimulation (rTMS) was administered for 2 years and only with partial response. The fourth major depressive episode was noted in 2022. Due to personal preference, ECT and rTMS were refused. Thus, we started the esketamine nasal spray (ESK-NS) treatment course in October 2022 (Figure 1).

Given his history of hypertension, computed tomography angiography (CTA) was performed before initiating ESK-NS treatment to rule out contraindications such as aneurysmal vascular disease or arteriovenous malformations. The induction phase involved esketamine administration twice weekly for 4 weeks, combined with venlafaxine, mirtazapine, lithium, and quetiapine, with only minor dosage adjustments throughout treatment. Depression severity was assessed using the Patient Health Questionnaire-9 (PHQ-9), a self-administered instrument for evaluating depressive symptoms [1]. The PHQ-9 cutoff scores categorize the severity of depression as follows: none (0-4), mild (5-9), moderate (10-14), moderately severe (15-19), and severe (20-27). As shown in Figure 2, his initial PHQ-9 score was 25, which dropped to 15 by the end of the induction phase in November 2022. Although this still indicated moderately severe depression, the patient reported subjective improvement and opted to continue with a maintenance phase of weekly or biweekly dosing (Maintenance Phase 1.1 in Figure 2). By March 2023, his PHQ-9 score decreased to 7 (mild depression), prompting him to request a shift to monthly dosing based on personal preference (Maintenance Phase 1.2 in Figure 2). We agreed to his requirements based on clinical improvement and individualized treatment strategy. By July 2023, his PHQ-9 score further decreased to 5. However, during this period of monthly dosing, he experienced a buying spree, though no other manic symptoms were present at the time. In July 2023, the patient requested to extend the dosing interval to once every 2 months (Maintenance Phase 1.3 in Figure 2). Considering his sustained improvement and the recent buying spree, we agreed to this adjustment while increasing his lithium dosage from 300 mg every other day to 300 mg daily. However, his depression recurred in December 2023, with his PHQ-9 score rising to 23. A second induction phase was initiated for 1 month, resulting in symptom improvement and a PHQ-9 score reduction to 12. By April 2024, after several months of maintenance treatment, his PHQ-9 score decreased to 8. In July 2024, further improvement was observed, with a PHQ-9 score of 6 (Maintenance Phases 2.1 & 2.2 in Figure 2).

Throughout the treatment, the patient experienced common side effects, including dissociation, dizziness, and transient hypertension. He was on regular medication with nebivolol and valsartan, maintaining a usual blood pressure (BP) below 130 mm Hg. Elevated BP was noted after each administration but subsided quickly. The patient’s systolic blood pressure (SBP) exceeded 160 mm Hg on three occasions, accompanied by dizziness and headaches. During these instances, nifedipine was administered. No other associated complications were noted. At all other times, his SBP remained below 160 mm Hg, with no related symptoms.

The Institutional Review Board of Kaohsiung Veterans General Hospital approved the publication of this case report (protocol number KSVGH24-CT8-09, date of approval August 6, 2024) with a waiver for written patient consent.

Esketamine was approved in 2019 by the US FDA for treatment-resistant depression (TRD) and in 2020 for major depression with suicidal ideation (MDSI) [2]. In Taiwan, esketamine was approved for MDSI in January 2022. Effective treatment options for treatment-resistant bipolar depression (B-TRD) remain limited, presenting a significant clinical challenge [3]. Previous studies have demonstrated the efficacy of esketamine in patients with B-TRD [3]. In this case report, a patient diagnosed with bipolar MDSI (B-MDSI) and B-TRD achieved near-remission (PHQ-9 score=7 in March and 5 in July 2023) during the maintenance phase of ESK-NS treatment [1], with minimal adjustments to other medication. The patient’s mood was maintained well with weekly, biweekly, and monthly dosing regimens. Still, his depression recurred when the interval was prolonged to 2 months, indicating that the dosing frequency should be adjusted cautiously. Although US guidelines for ESK-NS allow individualized dosing in the maintenance phase, most studies support a fortnightly regimen [2], and a clinical trial has demonstrated the effectiveness of dosing once every 4 weeks [4]. Based on this evidence, we will recommend that the patient maintain a dosing frequency of at least once every 4 weeks to ensure sustained efficacy.

The patient experienced a buying spree in July 2023 without any other manic symptoms. To prevent any potentially unrecognized hypomania, we agreed to the patient’s request to reduce the esketamine frequency (PHQ-9 score of 5 in July 2023) while temporarily increasing the lithium dosage. To the best of our knowledge, mood switching is rare in patients with B-TRD undergoing ESK-NS treatment [3]. However, careful evaluation for potential manic or hypomanic symptoms during ESK-NS treatment for B-TRD is still essential.

Transient hypertension was a notable side effect of esketamine, peaking within 40 minutes after administration. Careful monitoring is essential, particularly in patients with hypertension, to avoid severe complications, such as aneurysm rupture. Most recommendations advise monitoring unless SBP exceeds 180 mm Hg or is accompanied by symptoms [5]. Further studies and guidelines for transient hypertension during esketamine treatment are needed to establish. Regular BP control is also crucial. Additionally, CTA might be considered for high-risk patients in whom contraindications cannot be confidently excluded based on clinical evaluation alone.

While this case provides insight into treating B-TRD and B-MDSI with esketamine, its findings are limited by the single-patient design. Randomized controlled trials are necessary to establish its efficacy and safety. Further research into the cardiovascular effects of esketamine is also essential for optimizing treatment protocols.