Electroconvulsive Therapy Combined with the Treatments of Clozapine and Aripiprazole in a Patient with Treatment-resistant Mania: A Case Report

Treatment-resistant mania (TRM) represents a critical challenge in psychiatric care. TRM is defined as a condition where patients with bipolar disorder, particularly those in the manic phase, fail to respond adequately to standard treatments [1]. But a clear consensus on the definition of TRM is conspicuously absent, which poses significant hurdles for research and clinical management [1,2]. Electroconvulsive therapy (ECT), a powerful tool in psychiatry, has established efficacy for bipolar disorder, particularly in improving manic symptoms [3,4]. In many studies, ECT has shown a response rate of about 80% in bipolar mania, and its use in TRM has also been suggested [3]. Clozapine, a second-generation (atypical) antipsychotic, has earned its place in the management of treatment-resistant conditions. Its use in treatment-resistant bipolar depression and mania has been shown in many studies, with some suggesting a response rate up to 60%–70% [5,6]. The combination of clozapine and ECT has further been recognized for its enhanced therapeutic potential, particularly in refractory schizophrenia, showing greater improvement rates than either therapy alone [7,8]. Our case report is distinctive as it involved the use of bitemporal ECT and clozapine, along with the use of aripiprazole long-acting injectable (LAI), a combination largely underexplored in the existing literature. In this case report, we intended to shed light on this combination approach for TRM, defined TRM according to the CINP guideline, to further elucidate the potential of clozapine, aripiprazole LAI, and ECT in treating TRM. Case Report The patient, a 47-year-old divorced woman, previously studied Japanese at a university and was unemployed. The onset of her bipolar I disorder occurred at the age of 21 years following an abortion, precipitating her first major depressive episode. Her presenting symptoms included suicidality, self-harm, and severe depressive ideation, necessitating two withdrawals from university. The patient had no family history of psychiatric disorders, no history of substance abuse, and denied any physical illnesses. The patient's first contact with our medical facility was at the age of 23 years, due to a manic episode characterized by increased talkativeness, elevated mood, and overspending which was compatible with a manic episode. Subsequent 17 hospitalizations were primarily due to persistent elevated mood, pressured speech, and delusions of love involving celebrities. She had poor medical compliance, but she agreed to a home-based treatment. The patient experienced a period of remission from ages 36 to 42 years when she worked at a relative's company. Since the age of 43 years, she had experienced about two manic episodes per year, requiring hospitalizations ranging from 1 to 4 months each time. The patient's previous hospitalization occurred eight months previously, at the age of 46 years, due to a manic episode. She was treated with monthly long-acting injectable aripiprazole 400 mg, as well as daily oral aripiprazole 20 mg, carbamazepine 1,200 mg, and valproic acid 1,000 mg for four months. But serum levels of carbamazepine (4.28 mmol) and valproic acid (61.33 µg/mL) were subtherapeutic for the acute manic state. This led to severe hyponatremia (Na: 119 mEq/L) and hypokalemia (K: 2 mmol/L) and subsequent admission to a general hospital. Right after one month, the patient was discharged from the general hospital, and because of an unresolved manic episode, she returned to our hospital for help. She reported poor medication compliance, persistent manic symptoms, and limited sleep. Her mental state showed excessive speech, elevated mood, delusions of romantic relationships with celebrities, and expansive mood. Therefore, she was arranged admission for further management. The results of the physical examination showed the height of 157 cm and weight of 47 kg, with normal laboratory and electrocardiographic findings, except for an abnormal EEG showing intermittent delta wave activities. Initially, the patient received carbamazepine, which was discontinued due to persist subtherapeutic level despite using therapeutic dosage, and the patient was placed on monthly LAI aripiprazole 400 mg, daily oral valproic acid 1,500 mg, and zotepine 150 mg. Due to a lack of response after one month, the regimen was adjusted to monthly LAI aripiprazole 400 mg and daily oral clozapine 300 mg. But valproic acid and zotepine were discontinued. These regimens had been continued for two months, but the patient had no improvement in the manic symptoms. Thus, we decided to start a course of bitemporal ECT. Before ECT, the patient's baseline Young Mania Rating Scale (YMRS) score was 35/60. Giving bitemporal ECT twice weekly for a total of 12 sessions, we maintained her concurrent medication management. After every third ECT session, a day apart, we used the YMRS to assess the severity of manic symptoms (Figure 1). Anesthesia was induced with propofol (50–58 mg) and succinylcholine (50–58 mg) before each ECT session.Figure 1: The evolution of Young Mania Rating Scale scores over electroconvulsive therapy (ECT) sessions. The timeline included the score before to ECT, scores at the 3rd, 6th, 9th, and 12th ECT sessions, and scores at the follow-ups at the 1st and 2nd month after the last ECT session.The initial ECT session resulted in generalized tonic–clonic seizures lasting for 30 seconds and postictal delirium. After nine sessions, the patient's YMRS score was remarkably decreased to 13. The mean seizure duration across all sessions was 32.91 seconds. After the 12th session, the YMRS score was further reduced to 9, indicating symptom remission. After discharge, the patient continued to receive monthly LAI aripiprazole 400 mg and daily oral clozapine 300 mg as maintenance therapy. She was followed up for two additional months. The YMRS scores in the first and second months were 8 and 7, respectively, with no signs of mania relapse. Discussion Assessing treatment-resistant mania: applying the CINP definition to the clinical case Based on the available evidence and existing literature, despite various treatments, the patient's manic episodes continued. Specifically, treatments exceeded the six-week minimum needed to consider mania treatment resistant, according to Sachs (1996) [9]. Later, the treatment was simplified to monthly long-acting injectable (LAI) aripiprazole 400 mg and daily clozapine 300 mg due to unimproved manic symptoms. This change meets the TRM criteria, which include poor response to at least two medications [2]. The CINP guidelines define TRM as a lack of significant reduction in YMRS or MRS scores or a significant increase in MADRS or HDRS scores after a treatment duration of 8–10 weeks, despite adequate doses of medication [1]. In this case, the patient's baseline YMRS score remained elevated at 35/60 before receiving ECT, showing no substantial improvement despite numerous treatment trials for over four months. Her clinical picture clearly fulfills the CINP definition of TRM. Electroconvulsive therapy in the management of severe mania unresponsive to aripiprazole and clozapine: a Young Mania Rating Scale score analysis Our patient was suffering from severe TRM, as shown with a baseline YMRS score of 35. Traditional pharmacological interventions comprising clozapine and aripiprazole LAI were ineffective in symptom control. Lithium, a commonly used mood stabilizer, was not considered before ECT due to the patient's adverse reactions, including tremors and weight gain, noted in her past medical history, leading to noncompliance and a preference against its use. Therefore, we decided to give bitemporal ECT as an adjunct treatment. A significant response to bitemporal ECT was first observed after the 9th session, when the YMRS score was reduced to 13, indicating a decrease of over 50% from the baseline [10]. Remission, defined as a YMRS score of 12 or less, was accomplished after the 12th ECT session, with the YMRS score reported as 9. Remarkably, remission was achieved while maintaining the preexisting medication regimens, highlighting ECT's rôle as an effective adjunctive therapy for TRM. The patient's consistently low YMRS scores during 1-month and 2-month follow-ups underscore the treatment's prolonged efficacy, with no evidence of manic relapse. Given the patient's history of poor medication compliance, aripiprazole LAI was used to improve treatment adherence. The absence of relapse after two months following bitemporal ECT further showed the sustained therapeutic impact of ECT in our patient. Summary The case offered compelling evidence supporting the combination of aripiprazole LAI and oral clozapine with bitemporal ECT in TRM. This combined therapy not only achieved symptom remission but also showed a favorable safety profile. Our patient continued to remain in remission after discontinuing ECT, relying solely on aripiprazole LAI and clozapine as maintenance therapy. Based on the observations on this patient, we suggest that the combination of clozapine and aripiprazole LAI, particularly when supplemented with ECT, can be a potential alternative treatment for TRM patients. If future observations reveal elevated YMRS scores or indications of manic episodes, we further suggest that the use of maintenance ECT at bimonthly intervals is a feasible therapeutic option (The publication of this case report was approved by an institutional review board in Kaohsiung Municipal Kai-Syuan Psychiatric Hospital [IRB protocol number = KSPH-2023-08, and date of approval = August 1, 2023] with the need of collecting a signed consent from the patient). Data Availability Statement Data sharing is not available to this article because no datasets were generated or analyzed during the writing this case report. Financial Support and Sponsorship All authors deny receiving any financial assistance or endorsements in writing this case report. Conflicts of Interest All authors declare that they have no conflicts of interest in writing this article.