Agitation represents a significant challenge in the management of patients diagnosed with Parkinson’s disease dementia (PDD) due to several interrelated factors. Due to the risks that neuroleptics bear, our treatment options are limited. Atypical neuroleptics, such as clozapine and quetiapine, characterised by their reduced affinity for dopamine D2 receptors, have demonstrated efficacy in the management of agitation in patients diagnosed with dementia and parkinsonism.^{Reference Carrarini, Russo and Dono1}

Brexpiprazole, a drug that has been approved by the FDA for the treatment of agitation in patients with Alzheimer’s dementia, is a serotonin-dopamine activity modulator with partial agonist properties at the D2 receptor. Consequently, the likelihood of inducing drug-induced parkinsonism is considered minimal.^{Reference Carrarini, Russo and Dono1–Reference Lee, Slomkowski and Hefting4}

In this case report, a patient of advanced age suffering from PDD, who had been experiencing severe agitation and psychotic symptoms, was successfully treated with brexpiprazole without adverse events (AEs).

The patient was a 78-year-old male whose symptoms manifested at 53 years of age on the left lower extremity as bradykinesia. Deep brain stimulation was performed at the age of 74. He was diagnosed with PDD at the age of 75. The patient exhibited an escalation in delusional thoughts, physical and verbal aggression, agitation and insomnia symptoms, which occurred gradually following the onset of PDD and worsened in the last three months. These symptoms manifested with greater intensity during the evening hours and persisted into the early morning. He was taking levodopa 800 mg/d, carbidopa 200 mg/d, entacapone 1000 mg/d, pramipexole 0.750 mg/d and sertraline 100 mg/d for his Parkinson’s disease (PD) and depressive symptoms, whereas pramipexole was discontinued. Although the dopaminergic drugs might be associated with the manifestation of hallucinations and delusions, the dose of the drugs could not be reduced further due to the exacerbation of PD symptoms. The administration of quetiapine 100 mg/d, olanzapine 5 mg/d, trazodone 200 mg/d, mirtazapine 7.5 mg/d, zopiclone 7.5 mg/d, doxylamine 25 mg/d, alprazolam 0.5 mg/d, melatonin 10 mg/d, rivastigmine 3 mg/d and donepezil 5 mg/d proved ineffective in controlling the symptoms, with the patient experiencing intolerable AEs. The patient and his wife declined to use alternative neuroleptics (e.g. clozapine, risperidone) due to the potential for AEs. While his wife was able to manage the psychotic symptoms effectively, the most exhausting symptom for the couple was agitation. The patient and his wife gave consent for the unlabelled use of an antipsychotic agent for the treatment of agitation.

Before and after the administration of brexpiprazole, the Hoehn and Yahr scale and Montreal Cognitive Assessment (MoCA) scores were 4 and 13, respectively. Following the administration of a dose of 0.5 mg/d of brexpiprazole, a 50% reduction in agitation was observed by the third day. The dosage was then gradually increased to 2 mg/d every week to address the patient’s residual nighttime agitation. Clonazepam was administered for the management of insomnia and anxiety symptoms, with the dosage being gradually increased to 1 mg/d without any AEs and with a partial effect on insomnia. It should be noted, however, that clonazepam had previously been associated with agitation when used to treat REM sleep behaviour disorder. Brexpiprazole was increased to 3 mg/d for the treatment of nighttime agitations. The efficacy of these medications was evident, with the symptoms remaining under control for a period of three months. During this period, no instances of sleepiness or exacerbation of PD symptoms were observed.

The severe agitation exhibited by the elderly patient diagnosed with PDD was effectively managed through the administration of brexpiprazole without any AEs. The administration of 3 mg of brexpiprazole per day did not result in the exacerbation of PD-associated motor symptoms.

Brexpiprazole exerts its effects on multiple receptors within the brain, which are implicated in the manifestation of agitation, aggression, impulsivity and psychosis. According to the observations, it exhibits partial agonism at D2, D3 and 5HT1A receptors, in addition to antagonism at 5-HT2A and noradrenergic α1B receptors, with higher affinity for 5-HT1A and 5-HT2A than for D2 and D3 receptors. This pharmacological profile has been associated with a reduction in extrapyramidal AEs. In addition, brexpiprazole has a moderate binding affinity for histamine H1 receptors, suggesting that its effects on agitation are less likely to be due to sedation.^{2–Reference Lee, Slomkowski and Hefting4}

Although low doses of brexpiprazole (0.5–2 mg/d, max. 3 mg/d) have been approved by the FDA,² Lee D et al.^{Reference Lee, Slomkowski and Hefting4} reported significant efficacy without serious AEs at 3 mg/d. However, the literature on the use of brexpiprazole in PDD or dementia with Lewy bodies (DLB) is limited, and there are no studies evaluating the safety and efficacy of brexpiprazole in these patients. Sanagawa et al.^{Reference Sanagawa, Shiraishi, Sekiguchi, Akechi and Kimura5} reported a patient with PD psychosis who responded positively to 2 mg/d of brexpiprazole without exacerbation of motor symptoms, while Jackowiak and Chou^{Reference Jackowiak and Chou6} reported severe worsening of parkinsonism associated with the use of 1–2 mg/d of brexpiprazole. Recently, a patient with psychotic symptoms due to DLB was reported to have improved with a high dose of brexpiprazole (4 mg/d) without AEs.^{Reference Lee, Shih and Shen7}

Doses of brexpiprazole over 2 mg/d have been associated with an increased risk of AEs.^{2,Reference Lee, Slomkowski and Hefting4} In this case, the therapeutic effect was observed to commence at a dosage of 0.5 mg/d, with a complete resolution of daytime agitation achieved at 2 mg. In the case of nocturnal agitation, the dosage was progressively augmented to 3 mg/d, resulting in a favourable response.

In the absence of drug-induced parkinsonism, this case suggests that brexpiprazole is a potential treatment option for managing agitation in patients with PDD-related agitation. In order to verify the safety and efficacy of brexpiprazole in the treatment of PDD-related agitation, it is necessary to conduct further studies.