Combination therapy of modified electroconvulsive therapy and long-acting injectable aripiprazole for dopamine supersensitivity psychosis: a case report

ABSTRACT

In the treatment of schizophrenia, long-term pharmacotherapy with D2-receptor antagonists can induce dopamine supersensitivity psychosis (DSP). We report a male patient with schizophrenia with suspected DSP due to excessive polypharmacy. He was hospitalized for several years. Most psychotropic drugs were reduced and subsequently stopped without the exacerbation of symptoms by administering modified electroconvulsive therapy (mECT). Aripiprazole was then selected as the main drug for treatment, which was subsequently changed to the long-acting injection formulation. He was eventually discharged and returned home. Combination therapy with mECT and aripiprazole, especially the long-acting injectable formulation, may help improve and prevent DSP.

KEYWORDS:

• Aripiprazole
• dopamine supersensitivity psychosis
• modified electroconvulsive therapy
• polypharmacy
• schizophrenia

Background

Schizophrenia is a chronic and severe psychiatric disease that is characterized by various symptoms and poor prognoses (Marder et al., 2019). Typically, the onset of schizophrenia occurs in young people during their 20s, and patients remit and recur repeatedly. During the chronic period, patients’ abilities for daily life become impaired, and life expectancy is reduced (Nielsen et al., 2013). The leading and original etiological theory for schizophrenia is the dopamine hypothesis, (Howes et al., 2017), (McCutcheon et al., 2019) which led to the development of antipsychotics that antagonize the dopamine D2 receptor for the treatment of schizophrenia. Since then, antipsychotics have been repeatedly updated, and various antipsychotics are now used for a wide range of conditions (Huhn et al., 2019; Leucht et al., 2013)

However, some patients relapse even under appropriate continuous pharmacotherapy. Moreover, the more relapses that occur, the poorer the medical condition and the greater the decline in functioning. Consequently, excessive polypharmacy and long-term hospitalization have become significant problems, especially in Japan. Long-term treatment with D2-receptor antagonists can induce dopamine supersensitivity psychosis (DSP), which results in frequent relapses and progressive exacerbation of schizophrenia (Chouinard et al., 2017). Intermittent antipsychotic dosing regimens, long-acting injectable antipsychotics (LAI), and modified electroconvulsive therapy are proposed as treatment option for DSP (Chouinard et al., 2017; Potkin et al., 2020). However, there is limited evidence for effective treatments for DSP. Here, we report a patient with suspected DSP due to excessive polypharmacy, who improved after undergoing mECT and LAI formulation of aripiprazole.

Case presentation

The patient was a man in his 40s at the time of admission to our hospital. He graduated from both elementary school and junior high school in his community. Subsequently, he stayed at home without attending high school or working. There was no trouble during his pregnancy and perinatal period. He had no abnormality in his childhood and he could go to elementary school without any problems. His family members did not have any psychiatric or neurological diseases. At the age of 11, he began presenting with silly smiling. The patient began exhibiting loosening of association and abnormal behavior at age 13. In his early 20s, he visited a psychiatrist at a local general hospital and was diagnosed with schizophrenia, and pharmacotherapy was started. When he was in his early 30s, he was admitted to the psychiatry ward of the local general hospital for approximately 2 months. Following discharge, he continued to visit the outpatient clinic and received welfare. Medication contents were not clear in this period.

When he was aged around 40 years, he became unable to continue taking medication regularly, and his mental condition worsened. He became confused and exhibited mild suicidal ideation. Therefore, he was admitted to the psychiatry ward of the local general hospital. Suicidal ideation improved after admission; however, loosening association and abnormal behavior continued to worsen. At times, he spontaneously engaged in running and praying, and communicating with him was impossible. The dosage and type of antipsychotics and other psychotropic drugs were gradually increased, yet his symptoms showed no improvement. There are no hospitals in his living area that can prescribe clozapine, including this hospital. He was taken more than 3460 mg of antipsychotics in chlorpromazine conversion. He was hospitalized for several years and was then transferred to our hospital to undergo mECT.

When he was admitted to our hospital, he was unable to engage in meaningful conversations because of his severe loosening association. He also presented with auditory hallucinations and would suddenly begin praying as though he was being manipulated by another person. He did not present movement symptoms like tardive dyskinesia, parkinsonism, or catatonia. Positive and Negative Syndrome Scale (PANSS) total score was 116 at the time of admission. His vital signs were stable. Neuro- and physical examination showed no abnormality. A blood test showed no leukocytosis, lymphocytosis, or elevation of creatine kinase. Electroencephalography showed no slow waves or spike waves. Electrocardiography showed no long-QT. Chest X-ray showed no significant abnormalities. Brain computed tomography showed low density in a small area in the subcortical region of the left parietal lobe. However, this was attributed to an old infarction and thus was unrelated to his treatments or medical condition. Our hospital did not have MRI.

Figure 1 shows the patient’s treatment course following admission to our hospital. Initially, psychotropic drugs were gradually reduced to avoid adverse events, such as severe arrhythmia during the mECT session due to excessive pharmacotherapy. After drugs had been adequately reduced, mECT sessions were initiated. A total of 10 mECT sessions were performed, during which drugs were continuously reduced and eventually stopped. Aripiprazole was started for maintenance pharmacotherapy following mECT and was subsequently changed to a LAI formulation. Olanzapine was retained as a key treatment drug. Total dosage of antipsychotics was reduced to 1200 mg in chlorpromazine conversion. His loosening association improved, and he was able to engage in some conversation. His auditory hallucinations disappeared, and he no longer spontaneously prayed. PANSS total score has improved to 84. He was discharged soon after the mECT sessions and returned home to live with his family for the first time in several years. He resumed his visits to his original psychiatry outpatient clinic of the local general hospital.

Figure 1. Clinical time course of the patient from admission to discharge at our hospital. Psychotropic drugs were reduced gradually initially. Subsequently, mECT was initiated. Aripiprazole was then started and changed to the LAI formulation.

Discussion

The patient remained unstable despite treatment with numerous antipsychotics, which led to long-term hospitalization. Unnecessary drugs were successfully reduced and stopped without exacerbating the patient’s medical condition by applying mECT. In addition, LAI formulation of aripiprazole was shown to be appropriate for maintenance pharmacotherapy following the mECT course.

Several factors have been suggested that are associated with the development of DSP. One is metabolism of antipsychotics. Lower activity of drug metabolizing enzyme is assumed to lead higher concentration of antipsychotics, and increase the risk of DSP (Kanahara et al., 2019). Genetic rare variants are suggested to be associated with early onset schizophrenia and treatment resistance (Lencz et al., 2021). Child onset schizophrenia tends to present severe negative symptoms, bizarre and impulsive behaviors. They may have higher risk to progress worse disease course, make long-term excessive polypharmacy, and induce DSP (Cheng et al., 2021). This case was included in child onset that have higher risk of DSP, while genetic or biochemical risk factors were not detected.

Dopamine supersensitivity is caused by the upregulation of dopamine D2 receptors owing to long-term treatment with antipsychotics (Iyo et al., 2013). Once DSP occurs, psychotic symptoms become easily exacerbated by a small reduction in antipsychotics (Carpenter et al., 1977). Therefore, recovering from excessive polypharmacy is extremely difficult for patients in a state of DSP. Some animal studies suggest the efficacy of mECT for DSP; Lerer et al. demonstrated that electroconvulsive shock can prevent antipsychotic-induced dopamine hypersensitivity based on estimates of DRD2 density and locomotor activity in haloperidol-treated rats (Lerer et al., 1982). However, evidence for mECT treatment for DSP in humans is very limited (Kanahara et al., 2018). Therefore, whether mECT would improve the pathological condition of DSP in this patient was unclear. Nevertheless, mECT made a contribution to the reduction of antipsychotics without the exacerbation of psychotic symptoms. Subsequently, aripiprazole was selected as the main treatment drug for this patient.

Aripiprazole is one of the atypical antipsychotics that have unique dopamine D2-receptor partial agonist properties, and is called a dopamine system stabilizer because of its characteristic pharmacological mechanism of action. Partial agonists bind to dopamine receptors and block stimulation caused by excessive dopamine in the synaptic gap. However, they do not completely block neurotransmission; rather, they moderately stimulate the postsynaptic cell. In clinical practice, some DSP patients experience exacerbation of symptoms during the process of switching to aripiprazole (Takase et al., 2015). D2 ligands with agonist properties, such as aripiprazole, can increase DSP by binding to the D2 receptor in its unblocked state and producing a greater agonist effect (Di Lorenzo et al., 2007; Takase et al., 2015). Therefore, aripiprazole should be used with caution in DSP patients and in patients being treated with high-dose antipsychotics. On the other hand, animal studies have demonstrated that that aripiprazole both prevents and improves dopamine supersensitivity (Tadokoro et al., 2012). It has also been suggested that aripiprazole as either monotherapy or combination therapy may prevent DSP and reduce idiopathic psychosis and drug resistance (Chouinard et al., 2017). High doses of antipsychotics with short half-lives are more likely to result in DSP than antipsychotics with longer half-lives (Iyo et al., 2013). The use of LAI, with a long half-life but without an acute increase in drug concentration, may prevent patients from developing DSP (Kimura et al., 2021). LAI formulation of aripiprazole showed good efficacy in maintenance therapy after mECT in this patient. In addition, particularly during the chronic period, LAI formulations are useful for maintaining patients’ quality of life and promoting social participation (Correll et al., 2016). Moreover, LAI aripiprazole is effective in preventing relapse in patients with schizophrenia (Wang et al., 2014)

Overall, this case suggests that combination therapy with mECT and LAI formulation of dopamine system stabilizers may safely reduce antipsychotic doses and achieve favorable therapeutic effects in DSP patients with polypharmacy. It was previously reported that the combination therapy with mECT and aripiprazole produced a favorable therapeutic effect (Iyo et al., 2013). However, the evidence for the efficacy and safety of this combination therapy for DSP is still very limited, and it is important to accumulate more cases in the future. Finally, preventing DSP is the most important in long-term medication of schizophrenia. LAI formulation of dopamine system stabilizers may also be effective to minimize risk of DSP. Long-term careful medication is needed to avoid DSP.

Conclusion

We reported a patient with suspected DSP due to excessive polypharmacy. The patient successfully reduced and switched drugs without experiencing an exacerbation of symptoms by simultaneously undergoing mECT. Aripiprazole was selected as the main treatment drug, which we expect will prevent relapses and rehospitalizations in the future.

Author contributions

Yu.M., M.N., and S.K. treated the patient and drafted the manuscript. Yo.M. and H.O. critically reviewed and revised the manuscript. All authors made substantial contributions, drafted the manuscript, and approved the final manuscript.

Patient consent statement

Written consent was obtained from the patient.

Acknowledgments

We thank the patient for participating in this study. We thank Sarina Iwabuchi, PhD, from Edanz (https://jp.edanz.com/ac) for editing a draft of this manuscript.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

Data sharing is not applicable to this article because no datasets were generated or analyzed during the current study.

Additional information

Funding

This work was supported by the Japan Society for the Promotion of Science (JSPS) KAKENHI (grant number: 20K16629).