Pilot study of pharmacological treatment for frontotemporal dementia: Effect of Yokukansan on behavioral symptoms
Specification: psychopharmacology
Abstract
The aim of the present study was to investigate the efficacy of Yokukansan in improving behavioral symptoms of frontotemporal dementia. This study was a prospective, open-label trial of daily Yokukansan for 4 weeks in 20 frontotemporal dementia patients. Yokukansan treatment was found to significantly improve scores for the Neuropsychiatric Inventory and the Stereotypy Rating Inventory. No adverse effects or significant changes in physical findings and laboratory data occurred except for hypokalemia in two cases. The results indicate that Yokukansan can alleviate the behavioral symptoms of frontotemporal dementia. (The clinical trial registration number is UMIN000002704).
FRONTOTEMPORAL DEMENTIA (FTD) is characterized by prominent behavioral disturbance and progressive deterioration of cognitive functions in presenile or senile age.1 Behavioral symptoms of FTD place a heavy burden on caregivers. Although they are used to control symptoms, antipsychotic drugs have adverse effects that frequently add to patient distress, lower their ability to perform activities of daily living, and reduce their quality of life (QOL). A meta-analysis of randomized placebo-controlled trials found a significantly higher risk of death due to atypical antipsychotic drug treatment for dementia,2 leading to the recommendation from the US Food and Drug Administration that atypical antipsychotic drugs should not be prescribed for control of behavioral and psychological symptoms of dementia (BPSD).
Yokukansan (TSUMURA, Tokyo, Japan) is a drug used in Kampo, traditional Japanese herbal medicine, and was used by Iwasaki and colleagues to treat BPSD.3 The patients in the study3 had Alzheimer's disease, vascular dementia, and dementia with Lewy bodies, but none had FTD. In a previous report, we found Yokukansan improved behavioral symptoms in five FTD cases.4 Therefore, we designed a prospective, open-label study with a larger number of cases to evaluate the efficacy of Yokukansan as a treatment for FTD.
METHODS
Subjects
FTD was diagnosed according to the clinical diagnostic criteria for FTD in frontotemporal lobar degeneration.1 The patients exhibited change in character and disordered social conduct. They were recruited from the outpatient clinic at the National Hospital Organization Kikuchi Hospital, Koshi, Japan, between May 2008 and October 2009. The exclusion criteria were: (i) delirium due to metabolic intoxication and drug use; (ii) alcoholism, stroke, depression, manic state, and schizophrenia before the onset of FTD; (iii) previous use of Yokukansan, tranquilizers, and antidepressants; (iv) neoplastic disease and acute inflammation; and (v) hypokalemia.
A total of 20 patients with FTD (seven men) were enrolled. Their age (mean ± SD) was 78.5 ± 6.1 years old (range, 66–87). Their years of education and distress were 11.0 ± 1.7 and 3.8 ± 2.9, respectively. The mean score on the Mini-Mental State Examination (MMSE) was 16.3 ± 5.7 (range, 5–26).
Written informed consent was obtained from all patients or their relatives before entry and patient anonymity was preserved.
Design of study
This was a 4-week, prospective, open-label study. A starting dose of 7.5 g/day Yokukansan was chosen according to the study by Iwasaki.3 During the 4-week period, there was no additional medication, new rehabilitative regimens, hospitalization, or change in care environment. The institutional review board of the National Hospital Organization Kikuchi Hospital approved the study protocol. The study was conducted in accordance with Declaration of Helsinki principles.
Measures
A trained psychologist evaluated behavioral and psychological symptoms, using the Japanese version of the Neuropsychiatric Inventory (NPI)5 and the Stereotypy Rating Inventory (SRI)6 at baseline and 4 weeks after the start of treatment.
Analysis of NPI and SRI scores over time was performed with the Wilcoxon signed-rank test. Spearman rank correlation coefficient was used to estimate the direction and strength of the relationship between two variables. A two-tailed test revealed the significance level set in this study.
RESULTS
All patients completed the present trial. Yokukansan treatment decreased the NPI score in 18 (90.0%) of 20 patients and overall significantly decreased the NPI score and SRI score (Tables 1,2). Yokukansan significantly reduced NPI subscale scores (‘delusions’, ‘agitation/aggression’, ‘apathy/indifference’, ‘disinhibition’, ‘irritability/lability’, and ‘aberrant behavior’[Table 1]) and SRI subscale scores (‘eating and cooking’, ‘speaking’, and ‘movements’[Table 2]). Improvement in NPI was significantly correlated with the baseline MMSE score (rs = 0.51, P = 0.036). There were no adverse effects including gastrointestinal effects (nausea and appetite loss) except hypokalemia in two patients.
| Baseline (mean ± SD) | After treatment (mean ± SD) | P-value† | |
|---|---|---|---|
| NPI total score | 42.8 ± 11.3 | 29.4 ± 11.2 | 0.0002 |
| Delusions | 2.8 ± 4.0 | 1.7 ± 2.7 | 0.0256 |
| Hallucinations | 0.1 ± 0.2 | 0.0 ± 0.0 | NS |
| Agitation/aggression | 6.0 ± 3.8 | 3.4 ± 2.6 | 0.0018 |
| Depression/dysphoria | 0.2 ± 0.7 | 0.1 ± 0.5 | NS |
| Anxiety | 0.2 ± 0.7 | 0.2 ± 0.7 | NS |
| Euphoria | 1.5 ± 2.7 | 1.3 ± 2.6 | NS |
| Apathy/indifference | 8.8 ± 3.1 | 6.7 ± 2.9 | 0.0047 |
| Disinhibition | 6.5 ± 2.8 | 5.2 ± 3.2 | 0.0164 |
| Irritability/lability | 7.8 ± 3.3 | 4.6 ± 3.1 | 0.0003 |
| Aberrant behavior | 9.1 ± 2.6 | 6.2 ± 3.3 | 0.0009 |
- † Wilcoxon signed-rank test.
- NPI, Neuropsychiatric Inventory; NS, not significant.
| Baseline (Mean ± SD) | After treatment (Mean ± SD) | P-value† | |
|---|---|---|---|
| SRI total score | 19.7 ± 7.8 | 14.3 ± 8.2 | 0.0007 |
| Eating and cooking | 4.1 ± 4.0 | 2.6 ± 3.0 | 0.0180 |
| Roaming | 3.4 ± 3.9 | 3.0 ± 3.3 | NS |
| Speaking | 5.8 ± 3.9 | 4.2 ± 3.1 | 0.0117 |
| Movements | 5.2 ± 4.1 | 3.7 ± 3.3 | 0.0117 |
| Daily rhythm | 1.2 ± 2.7 | 0.9 ± 1.9 | NS |
- † Wilcoxon signed-rank test.
- SRI, Stereotypy Rating Inventory; NS, not significant.
DISCUSSION
In the present study, Yokukansan administration significantly decreased the NPI and SRI scores of our patients. NPI is a clinical rating instrument that measures neuropsychiatric symptoms in demented patients and the effects of pharmacological treatment on these symptoms.7–9 SRI is a sound psychometric tool for measuring stereotypic behaviors of FTD patients efficiently and comprehensively.6 It is therefore concluded that our evaluation using NPI and SRI confirmed that Yokukansan treatment improved the behavioral symptoms associated with FTD. The significant correlation between NPI improvement and baseline MMSE score suggests the possibility that Yokukansan is more efficacious and beneficial for FTD patients with high-cognitive ability than for those with low-cognitive ability.
Imbalance of neurotransmitters, such as serotonin, glutamate, and dopamine, in the central nervous system putatively induces anxiety and excitement, and consequently BPSD. A reduced number of serotonin receptors were found in the frontal and temporal lobes and the hypothalamus from FTD patients,10–12 indicating a plausible link between serotonin dysfunction in these brain regions and behavioral disturbance of FTD. Yokukansan appears to modulate serotonin function in the central nervous system. It significantly reduced the head-twitch induced by a 5-hydroxytryptamine (serotonin) 2A receptor agonist in mice13 and decreased the brain glutamate level elevated by potassium stimulation in zinc-deficient rats.14 These findings may indicate that Yokukansan acts by modifying glutamate and serotonin dysfunction.
Several limitations of the study should be considered. First, this study had an open-label design and no control group. Consequently our results may have been partially due to a placebo effect. Second, our sample size was small. Third, this sample might not represent the whole population of FTD patients, as recruitment was from only one outpatient clinic. Therefore, double-blind randomized studies with much larger samples are necessary for the establishment of Yokukansan as a therapy for FTD.
ACKNOWLEDGMENTS
This study was funded by a Grant-in-Aid for Clinical Research from the National Hospital Organization, Japan (Grant No: H20-SEI1(CHOJU)-01).
