Dr Takemi Kimura MD, PhD, Division of Clinical Research, Kikuchi National Hospital, 208 Fukuhara, Koshi, Kumamoto 861-1116, Japan. Email: firstname.lastname@example.org
Herein, we present five cases with frontotemporal dementia whose behavioral symptoms were improved by Yokukansan, a traditional Japanese medicine (Kampo). All five patients were prescribed Yokukansan (7.5 g/day) to reduce their symptoms. The patients' symptoms were evaluated comprehensively using the Neuropsychiatric Inventory (NPI) and the Stereotypy Rating Inventory (SRI) before and 4 weeks after Yokukansan treatment. The mean (± SD) scores on the NPI and the SRI before treatment were 55.6 ± 5.4 and 22.2 ± 6.5, respectively. After treatment, these scores were 30.0 ± 7.8 and 11.6 ± 7.5, respectively. Yokukansan was effective for the treatment of clinical symptoms in all five patients without adverse effects and significant changes in laboratory data. Although antipsychotic drugs have been used to control behavioral symptoms, their associated adverse effects frequently impact on the activities of daily living and quality of life of treated patients. The present cases suggest significant improvement of behavioral symptoms in frontotemporal dementia with Yokukansan treatment, leading to probable benefit of the use of Yokukansan in individuals with frontotemporal dementia.
Frontotemporal lobar degeneration (FTLD) is characterized by prominent behavioral disturbances and progressive deterioration of cognitive function in presenile or senile age.1 There are two general categories of FTLD, based on the clinical picture of the symptoms at the beginning of the condition. The first consists of behavioral and personality changes, which is known as frontotemporal dementia (FTD). The other consists of changes in language and communication, which is known as progressive non-fluent aphasia and semantic dementia. Behavioral symptoms of FTD consist of aggression, disinhibition, stereotyped behavior, dietary changes, and apathy. Because of these symptoms, the management and care of patients with FTD present a heavy burden to caregivers. Although antipsychotic drugs have been used to control these symptoms, their associated adverse effects, such as drowsiness, dizziness, ileus, parkinsonism, tardive dyskinesia, malignant syndrome, and rhabdomyolysis, frequently distress patients and lower their activities of daily livings (ADL) and quality of life (QOL). Cholinesterase inhibitors, reported to suppress the progression of Alzheimer's disease, are hardly effective for behavioral symptoms of FTD. Recent neurochemical findings, namely of a decrease of serotonin receptor binding in the frontal and temporal lobes in FTD,2,3 have prompted some researchers to explore the possible benefits of selective serotonin reuptake inhibitors (SSRIs) in FTD patients. Swartz et al.4 and Ikeda et al.5 have shown that SSRIs significantly improve the behavioral symptoms, especially stereotyped behaviors. However, as yet only antipsychotic drugs are used to treat FTD patients, because approximately half the patients do not respond to SSRIs.4
Yokukansan (TJ-54; Tsumura, Tokyo, Japan) is a traditional Japanese medicine (Kampo) that has been prescribed for the treatment of crying infants and insomnia in adults. The efficacy of TJ-54 against mental disturbance and agitation in behavioral and psychiatric symptoms of dementia (BPSD), as reported by Iwasaki et al.,6 prompted us to try using it to control the behavioral symptoms of FTD. In the present paper, we report on five patietns with FTD whose behavioral symptoms were improved by TJ-54.
A 66-year-old female patient presented at our hospital with the purpose of taking medical advice after a 1 year history of squander, shoplifting, and giving up housework. This patient's neuropsychiatric examination showed disinhibition, euphoria, stereotyped behavior, apathy, and frank denial of symptoms. She did not initiate conversations and her responses to questions involved single-word replies. There were no unusual findings on laboratory tests. Cranial magnetic resonance imaging (MRI) exposed left temporally pronounced cortical atrophy (Fig. 1). After TJ-54 (7.5 g/day) treatment for 1 week, the patient started helping her family with the housework, and her shoplifting and stereotyped behavior disappeared.
An 85-year-old female patient presented at our hospital with the intention of taking medical advice after a 3 year history of behavioral changes, such as frequent drinking of beer, excessive punctuality, and giving up housework. The neuropsychiatric examination exposed irritability, disinhibition, euphoria, stereotyped behavior, apathy, dietary changes, and an unawareness of mental symptoms. Laboratory tests and electroencephalogram findings were normal. Cranial MRI revealed bilateral frontal and temporal atrophy with ischemic changes in the deep white matter (Fig. 2). TJ-54 (7.5 g/day) treatment for 1 week relieved the patient's aggression, irritability, and stereotyped behavior.
A 74-year-old female patient visited our hospital in order to take medical advice after a 1 year history of getting angry, wandering, repeated talk, and giving up housework. The neuropsychiatric examination showed delusions of persecution, irritability, disinhibition, stereotyped behavior, apathy, dietary changes, and denial of symptoms. There were no irregular findings on laboratory tests. Cranial MRI showed left frontal and temporal atrophy. After TJ-54 (7.5 g/day) treatment for 2 weeks, the patient started helping her family with the housework and her aggression, irritability, and stereotyped behavior diminished.
An 81-year-old male patient visited our hospital with the intention of taking medical advice after an 8 year history of behavioral changes dominated by getting angry, wandering, repeated movements, and overeating. The neuropsychiatric examination revealed irritability, disinhibition, stereotyped behavior, apathy, dietary changes, and rejection of symptoms. The patient's speech output was limited to short phrases or stereotyped utterances. Findings on laboratory tests were normal. Cranial computed tomography revealed bilateral frontal and temporal atrophy. The patient was hot-tempered and refused to take a Mini-Mental State Examination test. TJ-54 (7.5 g/day) treatment for 1 week relieved his aggression, irritability, and stereotyped behavior.
A 74-year-old female patient visited our hospital in order to take medical advice after a 3 year history of insomnia and behavioral changes, such as repeated questions and washing hands, playing the koto all day long, and giving up housework. The neuropsychiatric examination showed irritability, stereotyped behavior, dietary changes, apathy, and an unawareness of symptoms. There were no aberrant findings on laboratory tests. Cranial MRI demonstrated bilateral frontal atrophy. After TJ-54 (7.5 g/day) treatment for 2 weeks, the patient started to take part in cognitive rehabilitation three times in a week and her insomnia and frequent playing of the koto were relieved.
The clinical data of the patients described in the present study are given in Table 1. TJ-54 treatment was effective in ameliorating the clinical symptoms in all five patients. The mean ( ±SD) scores of the Neuropsychiatric Inventory (NPI) and Stereotypy Rating Inventory (SRI) before treatment were 55.6 ± 5.4 and 22.2 ± 6.5, respectively. After 4 weeks treatment, these scores were 30.0 ± 7.8 and 11.6 ± 7.5, respectively (Table 2; Figs 3,4). Among the NPI subscales, agitation/aggression, apathy/indifference, irritability/lability, and aberrant motor behavior were moderately relieved by TJ-54 treatment (Table 2). We did not find any adverse effects or significant changes in laboratory data for any patient. Serum potassium levels were normal in all patients.
Table 1. Patients' clinical data
Case 4 refused to take the Mini-Mental State Examination (MMSE).
All five cases described herein are characterized by personality changes and disordered social conduct. All five patients presented with a decline in social interpersonal communication, impaired regulation of personal conduct, inappropriate emotional shallowness, and loss of insight in the early stage; none exhibited non-fluent spontaneous speech, loss of word meaning, semantic paraphasias, and prosopagnosia. Therefore, all five patients were diagnosed as having FTD, but not progressive non-fluent aphasia and semantic dementia, according to the clinical diagnostic criteiria of FTLD.1 Frontotemporal dementia consists of a frontal lobe degeneration type, a Pick type, and a motor neuron disease type. The patients in the present study exhibited severe behavioral symptoms and personality changes, as well as apathy and indifference, without motor neuron disease. Cranial MRI findings in these patients were consistent with Pick type FTD, showing striking circumscribed atrophy in the frontal and anterior temporal lobes. These results suggest that the patients had Pick-type FTD.
A major finding of the present study is that TJ-54 treatment significantly improved behavioral symptoms of FTD in all five patients, as evaluated by the NPI and SRI. Iwasaki et al.6 showed that TJ-54 was useful in the treatment of demented patients with BPSD. The patients in the study of Iwasaki et al.6 had Alzheimer's disease, vascular dementia, and dementia with Lewy bodies, but none had FTD. Hence, this is the first case demonstrating the effectiveness of TJ-54 treatment for the symptoms of FTD. The NPI is a clinical rating instrument designed specifically to provide a comprehensive evaluation of neuropsychiatric symptoms in demented patients and has been shown to be sensitive to the effects of pharmacological treatment.7–9 The SRI is psychometrically secure and can be used to assess stereotypic behaviors of FTD efficiently and comprehensively.10 It is therefore taken for granted that the improvement in all patients after TJ-54 treatment was correctly confirmed by a highly comprehensive evaluation using both the NPI and SRI. Clinical improvements were observed in all five patients after 1–2 weeks of TJ-54 administration. This rapid clinical effect is supported by the description that the effects of TJ-54 for BPSD, and also borderline personality disorder, usually start within 2 weeks of the treatment.6,11 This feature of TJ-54 is linked to benefits of the drug for the management of FTD patients.
Behavioral symptoms of FTD, thought to be severe, distress and exhaust caregivers. To reduce the symptoms of FTD, patients are frequently prescribed antipsychotic drugs. However, the adverse effects of these drugs, such as arousal disturbance, ileus, tardive dyskinesia, malignant syndrome, and rhabdomyolisis, result in a decrease in patients' ADL and QOL; in addition, gait disturbances and dizziness caused by the drugs are likely to make patients fall and perhaps break bones. A meta-analysis of randomized placebo-controlled trials has suggested a significantly higher risk of death with atypical antipsychotic drug treatment for dementia than that with placebo treatment,12 leading to advice from the US Food and Drug Administration that demented patients should not be prescribed atypical antipsychotic drugs for the control of BPSD. Even SSRIs have adverse effects, including nausea, drowsiness, sexual dysfunction, hyponatremia, activation syndrome, and discontinuation syndrome. Because SSRIs decrease the activity of various isozymes of cytochrome P450 in the liver, affecting the metabolism and clearance of different kinds of drugs, they possibly bring about unexpected adverse effects in elderly patients who may be taking several types of medication. In contrast, there were no adverse effects or significant changes in laboratory data in the patients in the present study during TJ-54 treatment. Serum potassium levels were normal in all cases. The main adverse effects of TJ-54 have been reported to be nausea and loss of appetite. However, these effects relieve the dietary changes of FTD patients, including overeating and stealing food, leading to a reduction in the behavioral problems of FTD. Based on these results, TJ-54 treatment in FTD is more secure than other pharmacological treatments and exceedingly useful for patients.
Neurotransmitters, such as glutamate, serotonin, dopamine, acetylcholine, GABA, and norepinephrine, play an important role in the transmission of information between neurons in the central nervous system (CNS). An imbalance in these neurotransmitters putatively induces anxiety and excitement, yielding BPSD in demented patients. In particular, disturbances in the dopaminergic, serotonergic and glutamatergic systems in the CNS are intimately related to BPSD. Recent neurochemical studies have shown a decrease in serotonin receptor binding sites in the brain of FTD patients.2,3 A study of brain tissue obtained at autopsy from FTD patients showed a decline in serotonergic synaptic markers in the frontal and temporal lobes, as well as the hypothalamus,13 indicating a plausible link between serotonin dysfunction in these brain regions and behavioral disturbances in FTD. As to the question whether TJ-54 can modulate the function of serotonin in the CNS, it was demonstrated that TJ-54 significantly reduced 5-HT2A receptor agonist-induced head-twitch in mice.14 Furthermore, TJ-54 has been reported to decrease extracellular glutamate in the thalamus of thiamine-deficient rats.15 These findings prompted us to speculate that TJ-54 significantly reduces behavioral symptoms of FTD by modifying glutamate and serotonin dysfunction.
In the present series of patients, TJ-54 was effective in decreasing the aggression, stereotyped behavior, and apathy of FTD patients, whereas fluvoxamine has been reported to reduce stereotyped behaviors, but not apathy.5 It is extremely interesting that TJ-54 lightened not only the excitatory symptoms of FTD, such as aggression and stereotyped behavior, but also the inactive symptoms, including apathy. Although the mechanism by which TJ-54 relieved the apathy of FTD patients remains uncertain, it has been reported that TJ-54 improves disturbances of learning and social contact in the amyloid precursor protein transgenic mouse model for Alzheimer's disease16 and significantly increases the ADL of demented patients.6 Because TJ-54 derivatives have been shown to increase choline acetyltransferase activity and acetylcholine levels in animal experiments,17,18 it is possible to treat apathy of FTD patients with TJ-54, which is caused by suitable stimulation of acetylcholine function.
Our evaluation of five cases of FTD demonstrates the useful pharmacological approach by TJ-54 in addition to SSRIs. We hope that taking these pharmacological approaches and routinizing therapy19 will increase the QOL of FTD patients and ease caregivers' burden. Establishment of the validity of TJ-54 as a first-line treatment for individuals with FTD requires the accumulation of additional cases and controlled studies because of the small sample size in the present report.
The authors thank Professor Manabu Ikeda, Department of Psychiatry and Neuropathobiology, Faculty of Medical and Pharmaceutical Sciences, Kumamoto University, for providing us Japanese versions of the NPI and SRI.