EFFICACY AND TOLERABILITY OF RISPERIDONE, YOKUKANSAN, AND FLUVOXAMINE FOR THE TREATMENT OF BEHAVIORAL AND PSYCHOLOGICAL SYMPTOMS OF DEMENTIA, AND PHARMACOLOGICAL CONSIDERATION
Authors: Kurita *Masatake , Nishino Satoshi , Teranishi Mika , Takeyoshi Kenji , Sato Tadahiro , Okubo Yoshiro , Tateno Amane 
Published: February 2025

Abstract

Background
Behavioral and psychological symptoms of dementia (BPSD) are seen in about 90% of patients with dementia. In addition to cognitive impairments, individuals with dementia often come to clinical attention because of symptoms of a behavioral disturbance (e.g., irritability, agitation, aggression) or psychosis. Our study was cited as one of the research evidences in the American Psychiatric Association guidelines (Practice Guideline on the Use of Antipsychotics to Treat Agitation or Psychosis in Patients with Dementia).

Aims & Objectives
We aimed to compare the efficacy and tolerability of risperidone, yokukansan, and fluvoxamine used for BPSD in elderly patients with dementia. In this time, I would like to introduce the whole picture of this research from a clinical and pharmacological point of view.

Method
This was an 8-week, rater-blinded, randomized, flexible-dose, triple-group trial. In total, 90 subjects were recruited and subsequently three different drugs were allocated to 82 inpatients with BPSD. We examined BPSD data from patients who completed 8 weeks of treatment. Primary clinical outcome measures were Neuropsychiatric Inventory in Nursing Home Version (NPI-NH) total score and its items. Secondary clinical outcomes measures were cognitive function measured by Mini-Mental State Examination (MMSE), and daily life function measured by Functional Independence Measure (FIM).
Neurological side effects were measured by the Drug Induced Extra-Pyramidal Symptoms Scale (DIEPSS). 82 patients received risperidone, yokukansan or fluvoxamine. At the end of the study, we had analyzed 76 patients (92.7%) in clinical study. For verification of pharmacological effects, we examined BPSD data from patients who COMPLETED 8 weeks of treatment. Therefore, we analyzed 42 patients (yokukansan: 17; risperidone: 9; fluvoxamine: 16) in pharmacological study. Homovanillic acid, a metabolite of dopamine, and 3-methoxy-4-hydroxyphenylglycol, a metabolite of noradrenaline, in their plasma were analyzed by HPLC.

Results
In clinical study, risperidone, yokukansan and fluvoxamine were equally effective in the treatment of BPSD in elderly patients, without impairment in cognition and daily life function. Yokukansan or fluvoxamine for BPSD showed a more favorable profile in tolerability compared with risperidone. Further, we demonstrated differential efficacy of risperidone, yokukansan, and fluvoxamine in the COMPLETED 8 weeks of treatment. In pharmacological study, biomarkers showed mutually different changes. Patients in the yokukansan group had significantly decreased plasma homovanillic acid levels from pretherapeutic levels. Conversely, patients in the risperidone and fluvoxamine groups exhibited no significant changes in plasma homovanillic acid levels from pretherapeutic levels.

Discussion & Conclusion
From clinical study, fluvoxamine has been demonstrated to be effective for delirium patients with dementia. Interestingly, the role of sigma-1 receptors in cognition has been suggested. Fluvoxamine has a unique mechanism distinct from other SSRIs due to its potent sigma-1 receptor agonistic property.
From pharmacological study, yokukansan contains geissoschizine methyl ether, which is known to have a partial agonist effect on dopamine D2 receptors. An improvement in BPSD condition with the intake of yokukansan is suggested to occur through a suppressed dopaminergic function, which is similar to the effect of aripiprazole.

References
Teranishi M, Kurita M, Nishino S, Takeyoshi K, Numata Y, Sato T, Tateno A, Okubo Y. 2013, ‘Efficacy and tolerability of risperidone, yokukansan, and fluvoxamine for the treatment of behavioral and psychological symptoms of dementia: a blinded, randomized trial’, J Clin Psychopharmacol. Vol. 33, no. 5, pp. 600-607. DOI: 10.1097/JCP.0b013e31829798d5.
Takeyoshi K, Kurita M, Nishino S, Teranishi M, Numata Y, Sato T, Okubo Y. 2016, ‘Yokukansan improves behavioral and psychological symptoms of dementia by suppressing dopaminergic function’ Neuropsychiatr Dis Treat. vol. 15, no. 12, pp. 641-649. DOI: 10.2147/NDT.S99032. eCollection 2016.