今回は「自閉症の易刺激性に対する抑肝散の有効性について②」です。

私の論文より一部抜粋しております。

Patients with autistic disorder (AD) often exhibit irritation, aggression, deliberate self-injury, and tantrums that impair sociability and adjustments with family life and/or school. These features impair sociability, communication, and adjustments with family life and/or school adjustment and may worsen the characteristic social and behavioral deficits for their age.
Risperidone (RIS) and aripiprazole (APZ) were approved by the U.S. Food and Drug Administration for the treatment of irritability (including aggressive behavior, deliberate self-injury, and temper tantrums) in children and adolescents with AD. In addition, other second-generation antipsychotics (SGA) such as quetiapine and olanzapine have been reported in open-label trials as effective for treating irritability in AD patients.However, children and adolescent patients are sensitive to their adverse effects.
Yokukansan, a traditional Chinese herbal medicine, containing the following seven herbs: Atractylodis lanceae rhizome, Poria, Cnidii rhizome, Angelicae radix, Bupleuri radix, Glycyrrhizae radix, and Uncariae uncis cum ramulus. The Ministry of Health, Labour and Welfare in Japan has approved it as a remedy for neurosis, insomnia, and irritability in children with AD. Yokukansan has been reported to improve behavioural and psychological symptoms of dementia, such as aggression, agitation, irritability and hallucination.Miyaoka et al. reported that yi-gan san (yokukansan in Japanese) might be effective for the treatment of a number of borderline personality disorder symptoms, including low mood, impulsivity, and aggression.Traditional herbal medicines have been used with safety and efficacy for mental disorders. However, no studies have evaluated the effectiveness and safety of yokukansan for treating irritability in Japanese patients with AD. We report a case of AD who was irritable despite receiving standard antipsychotics but improved following yokukansan treatment.

CASE PRESENTATION
The patient, a boy of 15 years and 4 months, was diagnosed with AD. His weight was 62.1 kg. He did not have past medical history and family psychiatric history. He was referred to us by another hospital and was already taking 1 mg RIS at the time of consultation. His score on the Clinical Global Impression Severity Scale (CGI-S) was 5. Psychiatric diagnoses were made according to Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision criteria.5 We used the Aberrant Behavior Checklist-community irritability subscale (ABC-I) scores,6 a subscale of the ABC that provides an informant-rated measure of the severity of irritability commonly observed in patients with AD. In a double-blind comparison study of APZ administration, patients were required to have an ABC-I score of ≥18 at the time of screening and baseline. Mean ABC-I sores decreased from 29.6 at pretreatment to 16.7 post-treatment in the APZ group.
Our patient showed irritability, deliberate self-injury, and impulsivity. His score on ABC-I was 28 at that time, and RIS (2 mg/day) was initiated when symptoms worsened. An increase in the dose to 3.5 mg/day resulted in somnolence for several days resulting in a score of 17 on the ABC-I. Because RIS decreased excitability, we continued administering this drug for 4 weeks; however, his daytime activity decreased remarkably due to the sedative effect. We tapered the dose to 2.0 mg/day. When the dose was gradually reduced to 2.0 mg/day, sedation disappeared in a few days, but self-injury and impulsivity recurred after 1 week. His ABC-I scale score was 24 and CGI-S scale score was 4. Yokukansan was administered orally (7.5 g/day) in addition to RIS (2.0 mg/day). He received 2.5 g yokukansan 3 times a day before meals. The combination of yokukansan and RIS was effective for the irritability. Hyperactivity and irritability improved 3 weeks after yokukansan administration, and laboratory examinations did not reveal abnormal findings such as body weight gain and changes in blood pressure and pulse rate. Moreover, no serious adverse effects were observed during treatment. Symptoms improved remarkably after 5 weeks, and his score on the ABC-I was estimated to be 16 and that on the CGI-S scale was 3. RIS was reduced to 1 mg/day as the patient became more stable. His irritability did not worsen after 6 months of treatment. Because his mother and school teacher conducted the management of the medication, he did not forget to take medicine for 6 months.

DISCUSSION
This is the first report of a case in which yokukansan administration was effective for the irritability of AD in adolescent. Yokukansan contains several herbal medicines. Angelica radix, an important component of yokukansan affects 5-hydroxytryptamine-2 and gamma aminobutyric acid receptors.Central nervous system regulation of serotonin has been implicated in aggressive behavior, and several studies have established an association between serotonin depletion and aggression in both human and animal models.The abnormal development of the serotoninergic system may be involved in the core behavioral abnormalities of autism.11 Thus, the serotonergic effect of yokukansan may be beneficial for treating irritability in patients with AD.
Antipsychotics carry the risk of adverse effects such as oversedation, particularly in children. In some studies, oversadation did not appear.Because oversedation may reduce the activity of patients with AD, yokukansan, which has very few sedative effects, may be advisable.
In this case, we initiated yokukansan at a dose of 7.5 mg/day to treat irritability resulting from AD, and ABC-I improved to 16 points from 24 points. Hyperactivity and irritability improved 5 weeks after initiating yokukansan. In an open trial involving patients with BPD, the effect of yi-gan san was recognized at 2 weeks.In a open trial for schizophrenia, a significant decrease was observed at 2 week in each Positive and Negative Syndrome Scale (PANSS) for Schizophrenia subscale score in the yi-gan san group. In a placebo-controlled double blind comparison involving patients with AD, APZ groups experienced significantly greater reductions in Positive and Negative Syndrome Scale scores compared with the placebo group from week 1 onward.7 The results of this case suggest that yokukansan may take longer than antipsychotic drugs to take effect against irritability and excitement. However, many issues regarding the pathology of AD and efficacy of yokukansan remain to be elucidated and further experience and accumulation of cases are necessary.


コメント
小児の自閉症、自閉性スペクトラム障害の易刺激性（irritability）に対する治療として、リスペリドンやアリピプラゾールは保険適当となっておりますが、漢方も有効な選択肢だと考えられます。副作用の観点からは、漢方だから副作用がないというわけではないですが、やはり抗精神病薬と比較すると副作用は少ないのではないかと思います。
漢方は味にくせがあるので飲ませるのに工夫が必要ですが、意外にそのまま飲める子もいますし、今は服薬しやすくするゼリーのようなものも市販で売っていますので、飲ませやすくなったのではないかと思います。
抑肝散は夜泣きにも効果ありますし、比較的子どもでは使いやすい漢方ではないかと思います。

薬物療法はリスクが０のものはありませんが、必要な時に必要な量を使用できなければ意味がありません。効果と副作用のバランスを見ながら、本人にとって必要だと判断した場合には症状が続くこと自体も一つのリスクであると思いますので、保護者の方はそのあたりを認識しながら使用するタイミングを決めていけばいいのではないかと思います。

記事作成：加藤晃司（医療法人永朋会）
　　　　　専門：児童精神科（日本精神神経学会専門医、日本児童青年期精神医学会認定医、子どものこころ専門医）