JPWO2004014429A1 - Psychiatric disorder vulnerability control agent - Google Patents
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Abstract
脳の発症脆弱性のメカニズムに着目し、既存抗精神病薬の欠点を補い、新規作用機作を担持した精神疾患治療薬を提供する。具体的には、症状が波状出現経過パターンを示す精神疾患に対して、発症脆弱性に相当する進行性脳機能障害を制御することによって寛解期のストレス応答を持続的に安定させ、症状の再燃を抑制する新規メカニズムからなる精神疾患治療薬を新規に見出し、この治療薬が統合失調症（精神分裂病、分裂病、Ｓｃｈｉｚｏｐｈｒｅｎｉａ）、覚醒剤精神病、躁鬱病等の治療への有用性があることから本発明を完成した。すなわち本発明は、発症脆弱性相当進行性脳機能障害を制御する作用を担持する化合物を主成分とする疾患症状が波状出現経過パターンを示す精神疾患用の治療薬を提供する。Focusing on the mechanism of brain onset vulnerability, we provide a therapeutic agent for mental illness that compensates for the shortcomings of existing antipsychotic drugs and carries a new mechanism of action. Specifically, for mental disorders whose symptoms show a wavy appearance pattern, by controlling progressive brain dysfunction corresponding to the onset vulnerability, the stress response during remission is sustained and relapses. A new therapeutic agent for psychiatric disorders consisting of a novel mechanism that suppresses the disease, and this therapeutic agent has utility in the treatment of schizophrenia (schizophrenia, schizophrenia), stimulant psychosis, manic depression, etc. The present invention has been completed. That is, the present invention provides a therapeutic agent for mental illness in which a disease symptom having a wavy appearance pattern is mainly composed of a compound having a function of controlling progressive brain dysfunction corresponding to onset vulnerability.
Description
本発明は、新規作用機作を有する精神疾患治療薬に関する。さらに詳しくは、精神疾患発症脆弱性に相当する脳機能障害の進行を伴って症状が波状出現経過パターンを示す精神疾患に対する治療薬に関する。また、本発明の別の発明は、精神疾患発症脆弱性に相当する脳機能障害の進行を伴って症状が波状出現経過パターンを示す精神疾患に対する治療薬のスクリーニング方法の提供、精神疾患発症脆弱性に相当する進行性脳機能障害の制御をマーカーにする新規化合物又は精神疾患治療薬のスクリーニング方法の提供、及びスクリーニングされた新規化合物又は精神疾患治療薬に関する。 The present invention relates to a psychiatric remedy having a novel mechanism of action. More specifically, the present invention relates to a therapeutic agent for a mental illness whose symptoms show a wavy appearance pattern with the progress of brain dysfunction corresponding to vulnerability to the onset of mental illness. Further, another invention of the present invention provides a method for screening a therapeutic agent for a mental disorder in which the symptom shows a wavy appearance pattern with progression of brain dysfunction corresponding to the vulnerability to the onset of mental disorder, The present invention relates to the provision of a screening method for a novel compound or therapeutic agent for psychiatric disorders using as a marker the control of progressive brain dysfunction corresponding to the above, and the screened novel compound or therapeutic agent for psychiatric disorders.
従来、統合失調症（精神分裂病、分裂病、Ｓｃｈｉｚｏｐｈｒｅｎｉａ）治療薬の主たる開発指標は幻覚・妄想状態として表出するいわゆる陽性症状に対する抑制効果であり、動物実験における評価指標としてもアポモルフィン、アンフェタミン類などのドーパミン系直接または間接アゴニストの急性薬理効果として惹起される行動変化に対する拮抗作用が重視されてきた。実際、こうした指標によって開発された抗精神病薬は陽性症状に対する良好な改善効果を示す一方、高い再発率が問題となっている（Ｍａｒｄｅｒ ＳＲ．Ａｎｔｉｐｓｙｃｈｏｔｉｃ ｄｒｕｇｓ ａｎｄ ｒｅｌａｐｓｅ ｐｒｅｖｅｎｔｉｏｎ．Ｓｃｈｉｚｏｐｈｒ Ｒｅｓ ３５，Ｓ８７−Ｓ９２，１９９９）。
このことは、寛解期においても発症脆弱性の改善は多くの患者において達成されていないことを示唆しており、既存抗精神病薬の弱点を示唆している。Ｌａｒｕｅｌｌｅは急性期統合失調症患者ではアンフェタミンによるドーパミン放出の亢進が認められるのに対して、寛解期では正常コントロール群と差が認められないことから、薬物治療中断後に再発の準備状態として内因性の感作成立過程が再開される可能性を示し、再発を防止するには急性期の症状抑制効果を指標とした治療に替わる方法が必要であることを述べている（Ｌａｒｕｅｌｌｅ Ｍ．Ｔｈｅ ｒｏｌｅ ｏｆ ｅｎｄｏｇｅｎｏｕｓ ｓｅｎｓｉｔｉｚａｔｉｏｎ ｉｎ ｔｈｅ ｐａｔｈｏｐｈｙｓｉｏｌｏｇｙ ｏｆ ｓｃｈｉｚｏｐｈｒｅｎｉａ：ｉｍｐｌｉｃａｔｉｏｎｓ ｆｒｏｍ ｒｅｃｅｎｔ ｂｒａｉｎ ｉｍａｇｉｎｇ ｓｔｕｄｉｅｓ．Ｂｒａｉｎ Ｒｅｓ Ｒｅｖ３１，３７１−３８４，２０００．）。
統合失調症（精神分裂病、分裂病、Ｓｃｈｉｚｏｐｈｒｅｎｉａ）の主因は、脳の精神疾患発症脆弱性（ｖｕｌｎｅｒａｂｉｌｉｔｙ）にあり、病前期において、この発症脆弱性は心理社会的ストレスとの相互作用によって形成されていく。そして、病相期に精神病エピソード（ｐｓｙｃｈｏｔｉｃ ｅｐｉｓｏｄｅ）を経験することが病後の脆弱性の増強・維持にフィードバックされ、再発（ｒｅｌａｐｓｅ）準備状態となる。このような系が、統合失調症ストレス脆弱性モデルとして知られる（Ｃｉｏｍｐｉ Ｌ．Ｔｈｅ ｄｙｎａｍｉｃｓ ｏｆ ｃｏｍｐｌｅｘ ｂｉｏｌｏｇｉｃａｌ−ｐｓｙｃｈｏｓｏｃｉａｌ ｓｙｓｔｅｍｓ：Ｆｏｕｒ ｆｕｎｄａｍｅｎｔａｌ ｐｓｙｃｈｏ−ｂｉｏｌｏｇｉｃａｌ ｍｅｄｉａｔｏｒｓ ｉｎ ｔｈｅ ｌｏｎｇ−ｔｅｒｍ．Ｂｒ Ｊ Ｐｈｓｙｃｈｉａｔｒｙ １５５，１５−２１，１９８９）。
既存の抗精神病薬には、このような脳の精神疾患発症脆弱性の制御を達成した医薬品はない。既存抗精神病薬は、一般的に長期予後改善が不十分で、またＱＯＬ（ｑｕａｌｉｔｙ ｏｆ ｌｉｆｅ、生活の質）においても不十分であった。Conventionally, the main development index of drugs for treating schizophrenia (schizophrenia, schizophrenia) is a suppressive effect on so-called positive symptoms expressed as hallucinations and delusions. Apomorphine and amphetamines are also used as evaluation indices in animal experiments. There has been an emphasis on antagonism against behavioral changes induced by the acute pharmacological effects of dopamine-based direct or indirect agonists. In fact, antipsychotic drugs developed with these indicators have a good ameliorating effect on positive symptoms, while high recurrence rates are a problem (Marder SR. Antipsychotic drugs and relax prevention. Schizophr Res 35, S87-S92, 1999).
This suggests that improvement in the onset vulnerability has not been achieved in many patients even during remission, suggesting a weakness of existing antipsychotic drugs. Laurele has an increased dopamine release due to amphetamine in patients with acute schizophrenia, whereas there is no difference from the normal control group in the remission phase. It shows the possibility that the process of creating sensation will be resumed and states that in order to prevent recurrence, a method that replaces the treatment with the symptom suppression effect in the acute phase as an index is necessary (Laruelle M. The role of endogenous) Sensitization in the pathology of schizophrenia: implications from recent brain imaging studies. Brain Res Rev 31, 371-384, 2000.).
The main cause of schizophrenia (schizophrenia, schizophrenia) is the brain vulnerability of psychiatric disorders (vulnerability). In the early stage of the disease, this vulnerability is formed by interaction with psychosocial stress. To go. Then, experiencing a psychotic episode in the phase of the disease is fed back to the enhancement and maintenance of vulnerability after the disease, and is ready for relapse. Such a system is known as a schizophrenia stress vulnerability model (Ciompi L. The dynamics of biologic-physical-physical-psycho-biological-l5, 1989).
There are no existing antipsychotic drugs that have achieved such control of the onset vulnerability of brain mental disorders. Existing antipsychotic drugs are generally insufficient in improving long-term prognosis and also in QOL (quality of life, quality of life).
本発明は前記の如き、脳の精神疾患発症脆弱性のメカニズムに着目し、既存抗精神病薬の欠点を補い、新規作用機作を担持した精神疾患治療薬を提供しようとするものである。
本発明は、症状が波状出現経過パターンを示す精神疾患に対して、精神疾患発症脆弱性に相当する進行性脳機能障害を制御することによって寛解期のストレス応答を持続的に安定させ、症状の再燃を抑制する新規メカニズムからなる精神疾患治療薬を新規に見出し、この治療薬が統合失調症（精神分裂病、分裂病、Ｓｃｈｉｚｏｐｈｒｅｎｉａ）、覚醒剤精神病、躁鬱病等の治療への有用性があることから本発明を完成した。
すなわち本発明は、
１．精神疾患発症脆弱性に相当する進行性脳機能障害を制御する作用を担持する化合物を主成分とする疾患症状が波状出現経過パターンを示す精神疾患用の治療薬、
２．精神疾患発症脆弱性に相当する進行性脳機能障害の制御が、脆弱性相当脳機能障害の抑制である前項１に記載の精神疾患用治療薬、
３．モデル動物において精神疾患発症脆弱性に相当する進行性脳機能障害が惹起される投薬手段が施され、その後該投薬手段の休薬期間中での候補化合物の投薬によって、その後のストレス負荷に対して、精神疾患発症脆弱性相当進行性脳機能障害の指標である行動感作の成立を特異的に防止する薬理効果を担持する化合物を主成分とする前項１又は２に記載の精神疾患用治療薬、
４．投薬手段がアンフェタミン類化合物の投与である前項３に記載の精神疾患用治療薬、
５．ストレス負荷が、アンフェタミン類化合物投与、アポモルフィン投与、ノミフェンシン投与、その他の直接または間接ドーパミンアゴニスト投与、尻尾のクリッピングから選ばれる前項３又は４に記載の精神疾患用治療薬、
６．波状出現経過パターンを示す精神疾患が、統合失調症（精神分裂病、分裂病、Ｓｃｈｉｚｏｐｈｒｅｎｉａ）、覚醒剤精神病、躁鬱病、又は自閉症である前項１〜５の何れか一に記載の精神疾患用治療薬、
７．化合物が５−ＨＴ３受容体遮断薬である前項１〜６の何れか一に記載の精神疾患用治療薬、
８．５−ＨＴ３受容体遮断薬が、オンダンセトロンである前項７に記載の精神疾患用治療薬、
９．精神疾患発症脆弱性に相当する進行性脳機能障害を制御する作用をマーカーにすることを特徴とする新規化合物又は疾患症状が波状出現経過パターンを示す精神疾患用の治療薬のスクリーニング法、
１０．精神疾患発症脆弱性に相当する進行性脳機能障害の制御が、脆弱性相当進行性脳機能障害の抑制である前項９に記載のスクリーニング法、
１１．モデル動物において精神疾患発症脆弱性に相当する進行性脳機能障害が惹起される投薬手段が施され、その後該投薬手段の休薬期間中での候補化合物の投薬によって、その後のストレス負荷に対して、精神疾患発症脆弱性相当進行性脳機能障害の指標である行動感作の成立を特異的に防止する薬理効果を担持する化合物を選択する前項９又は１０に記載のスクリーニング法、
１２．投薬手段がアンフェタミン類化合物の投与である前項１１に記載のスクリーニング法、
１３．ストレス負荷が、アンフェタミン類化合物投与、アポモルフィン投与、ノミフェンシン投与、その他の直接または間接ドーパミンアゴニスト投与、尻尾のクリッピングから選ばれる前項１１又は１２に記載のスクリーニング法、
１４．前項９〜１３の何れか一に記載のスクリーニング方法で得られる新規化合物又は疾患症状が波状出現経過パターンを示す精神疾患用の治療薬、からなる。The present invention aims to provide a therapeutic agent for mental illness that has a novel mechanism of action and compensates for the shortcomings of existing antipsychotic drugs by paying attention to the mechanism of the onset vulnerability of psychiatric disorders in the brain as described above.
The present invention continuously stabilizes the stress response in the remission phase by controlling progressive brain dysfunction corresponding to vulnerability to the onset of psychiatric diseases, with respect to psychiatric diseases whose symptoms show a wavy appearance pattern. A new psychiatric treatment with a new mechanism to suppress relapse is found, and this treatment has utility in the treatment of schizophrenia (schizophrenia), stimulant psychosis, manic depression, etc. Thus, the present invention has been completed.
That is, the present invention
1. A therapeutic agent for a mental illness in which a disease symptom having a wavy appearance course pattern, the main component of which is a compound having a function of controlling progressive brain dysfunction corresponding to the onset vulnerability of mental illness,
2. 2. The therapeutic agent for mental disease according to
3. In a model animal, a medicinal means for causing progressive brain dysfunction corresponding to the vulnerability to the onset of mental illness is applied, and then the candidate compound is administered during the drug withdrawal period of the medicinal means to prevent subsequent stress load. 3. The therapeutic agent for psychiatric disorders according to 1 or 2 above, comprising as a main component a compound having a pharmacological effect that specifically prevents establishment of behavioral sensitization, which is an index of progressive brain dysfunction corresponding to the onset of mental illness ,
4). The therapeutic agent for psychiatric disorders according to item 3, wherein the administration means is administration of an amphetamine compound,
5. The therapeutic agent for psychiatric disorders according to 3 or 4 above, wherein the stress load is selected from amphetamine compound administration, apomorphine administration, nomifensine administration, other direct or indirect dopamine agonist administration, tail clipping,
6). The mental disease according to any one of the preceding
7. The therapeutic agent for psychiatric disorders according to any one of 1 to 6 above, wherein the compound is a 5-HT3 receptor blocker,
8.5 The therapeutic agent for psychiatric disorders according to item 7 above, wherein the 5-HT3 receptor blocker is ondansetron,
9. A novel compound characterized by controlling the progressive brain dysfunction corresponding to the onset vulnerability of mental illness as a marker, or a screening method for a therapeutic agent for psychiatric illness in which a disease symptom exhibits a wavy appearance pattern,
10. The screening method according to item 9 above, wherein the control of progressive brain dysfunction corresponding to psychiatric disorder onset vulnerability is suppression of vulnerability-related progressive brain dysfunction;
11. In a model animal, a medicinal means for causing progressive brain dysfunction corresponding to the vulnerability to the onset of mental illness is applied, and then the candidate compound is administered during the drug withdrawal period of the medicinal means to prevent subsequent stress load. The screening method according to 9 or 10 above, which selects a compound having a pharmacological effect that specifically prevents establishment of behavioral sensitization, which is an indicator of mental illness onset vulnerability equivalent progressive brain dysfunction,
12 12. The screening method according to 11 above, wherein the administration means is administration of an amphetamine compound.
13. The screening method according to the above item 11 or 12, wherein the stress load is selected from amphetamine compound administration, apomorphine administration, nomifensine administration, other direct or indirect dopamine agonist administration, tail clipping,
14 The novel compound obtained by the screening method as described in any one of 9 to 13 above or a therapeutic agent for a mental illness in which a disease symptom exhibits a wavy appearance course pattern.
（図１）
投薬スケジュールを示した。
（図２）
行動評価結果を示した。ＭＡＰ断薬期間中に投与したｈａｌｏｐｅｒｉｄｏｌ、ｃｌｏｚａｐｉｎｅおよびｏｎｄａｎｓｅｔｒｏｎがＭＡＰ誘発行動感作成立におよぼす影響。数値は平均値±標準誤差で示す（ｎ＝１０）。＊＊ｐ＜０．０１、＊＊＊ｐ＜０．００１ｖｓ各生理食塩水前処理群（ｔ−ｔｅｓｔ）、†ｐ＜０．０５、†††ｐ＜０．００１ｖｓ ＭＡＰ−ｈａｌｏｐｅｒｉｄｏｌ群（Ｔｕｋｅｙ ｔｅｓｔ）。Ｎ．Ｓ．，統計的有意差なし。(Figure 1)
The dosing schedule was shown.
(Figure 2)
The behavioral evaluation results are shown. Effect of haloperidol, clozapine and ondansetron administered during the MAP withdrawal period on the creation of MAP-induced behavioral feeling. Numerical values are shown as mean ± standard error (n = 10). ** p <0.01, *** p <0.001 vs. physiological saline pretreatment group (t-test), † p <0.05, ††† p <0.001 vs MAP-haloperidol group (Tukey) test). N. S. , No statistically significant difference.
本発明の新規メカニズムからなる精神疾患用治療薬の提供は、ストレス脆弱性モデルに対する神経科学的アプローチによって達成された。つまり統合失調症（精神分裂病、分裂病、Ｓｃｈｉｚｏｐｈｒｅｎｉａ）における発症脆弱性の実体（ｆｅｅｄ−ｆｏｒｗａｒｄ ａｎｄ ｆｅｅｄ−ｂａｃｋ ｌｏｏｐｓ）の少なくとも一部は覚醒剤精神病と共通する神経可塑的変化であること、および覚醒剤精神病における神経可塑的変化は実験動物における行動感作現象として再現可能であることを基礎とする。統合失調症において、健常人では精神病状態を惹起しない少量のアンフェタミン類などの中枢刺激薬（ｐｓｙｃｈｏｓｔｉｍｕｌａｎｔ）に応答して精神病状態が惹起され、また心理社会的ストレスにも鋭敏に応答するなど、発症脆弱性が認められる（Ｌｉｅｂｅｒｍａｎ ＪＡ，Ｓｈｅｉｔｍａｎ ＢＢ，Ｋｉｎｏｎ ＢＪ．Ｎｅｕｒｏｃｈｅｍｉｃａｌ ｓｅｎｓｉｔｉｚａｔｉｏｎ ｉｎ ｔｈｅ ｐａｔｈｏｐｈｙｓｉｏｌｏｇｙ ｏｆ ｓｃｈｉｚｏｐｈｒｅｎｉａ：Ｄｅｆｉｃｉｔｓ ａｎｄ ｄｙｓｆｕｎｃｔｉｏｎ ｉｎ ｎｅｕｒｏｎａｌ ｒｅｇｕｌａｔｉｏｎ ａｎｄ ｐｌａｓｔｉｃｉｔｙ．Ｎｅｕｒｏｐｓｙｃｈｏｐｈａｒｍａｃｏｌｏｇｙ １７，２０５−２２９，１９９７．）。覚醒剤精神病（Ａｍｐｈｅｔａｍｉｎｅ ＰｓｙｃｈｏｓｉｓもしくはＭｅｔｈａｍｐｈｅｔａｍｉｎｅ Ｐｓｙｃｈｏｓｉｓ）においても同様に、健常人より鋭敏に中枢刺激薬に応答して精神病状態が惹起され、また心理社会的ストレスによっても健常人では認められない精神病状態の再燃が起きる（Ｓａｔｏ Ｍ，ＣｈｅｎＣ−Ｃ，Ａｋｉｙａｍａ Ｋ，Ｏｔｓｕｋｉ Ｓ．Ａｃｕｔｅ ｅｘａｃｅｒｂａｔｉｏｎ ｏｆ ｐａｒａｎｏｉｄ ｐｓｙｃｈｏｔｉｃ ｓｔａｔｅ ａｆｔｅｒ ｌｏｎｇ−ｔｅｒｍ ａｂｓｔｉｎｅｎｃｅ ｉｎ ｐａｔｉｅｎｔｓ ｗｉｔｈ ｐｒｅｖｉｏｕｓ ｍｅｔｈａｍｐｈｅｔａｍｉｎｅ ｐｓｙｃｈｏｓｉｓ．Ｂｉｏｌ Ｐｓｙｃｈｉａｔｒｙ １８，４２９−４４０，１９８３．）。実験動物においては、一旦アンフェタミン類の亜慢性投与を経験することによって、その後経験する中枢刺激薬に対する行動上の感受性が亢進し、少量の薬物によって通常の動物では認められない強い行動変化が誘導され、また、薬物を用いない物理的ストレス負荷によっても通常の動物では認められないストレス応答行動が惹起される（Ｖａｎｄｅｒｓｃｕｒｅｎ ＬＪＭＪ，Ｋａｌｉｖａｓ ＰＷ．Ａｌｔｅｒｎａｔｉｏｎｓ ｉｎ ｄｏｐａｍｉｎｅｒｇｉｃ ａｎｄ ｇｌｕｔａｍａｔｅｒｇｉｃ ｔｒａｎｓｍｉｓｓｉｏｎ ｉｎ ｔｈｅ ｉｎｄｕｃｔｉｏｎ ａｎｄ ｅｘｐｒｅｓｓｉｏｎ ｏｆ ｂｅｈａｖｉｏｒａｌ ｓｅｎｓｉｔｉｚａｔｉｏｎ；ａｃｒｉｔｉｃａｌ ｒｅｖｉｅｗ ｏｆ ｐｒｅｃｌｉｎｉｃａｌ ｓｔｕｄｉｅｓ．Ｐｓｙｃｈｏｐｈａｒｍａｃｏｌｏｇｙ １５１，９９−１２０，２０００．）。従って、統合失調症における精神疾患発症脆弱性と同様な神経科学的変化は覚醒剤精神病においても生じている事が推定され、この精神疾患発症脆弱性に相当する脳機能障害は実験動物にアンフェタミン類を亜慢性投与することによって実験的に評価可能であると判断できる。
以上の認識を元に、本発明者は仮説をたて、症状が波状出現経過パターンを示す精神疾患における発症脆弱性制御の実験動物モデルを覚醒剤複数回投与と覚醒剤休薬期間での薬理操作によって確立し、これにより精神疾患発症脆弱性相当脳機能障害の制御と再発（ｒｅｌａｐｓｅ）の関係を動物モデルとして確立した。この系を使い、この精神疾患発症脆弱性相当脳機能障害を特異的に制御する化合物の評価を行い、新規作用機作からなる精神疾患用治療薬を提供し本発明を完成した。
本発明で、精神疾患発症脆弱性に相当する脳機能障害とは、精神病状態経験に伴って起きる生体機能の長期持続的な変化に基づく精神病状態再発抵抗性の脆弱化の進行を意味する。その進行とは脆弱度の強くなること、抵抗性のより低下を意味する。これを制御する作用は、例えば動物モデル系において精神疾患発症脆弱性に相当する進行性脳機能障害が惹起される投薬手段が施され、その後該投薬手段の休薬期間中での候補化合物の投薬によって、その後のストレス負荷に対して、特異的に精神疾患発症脆弱性相当進行性脳機能障害の指標である行動感作の成立を防止する薬理効果の有無によって確認できる。そして、候補化合物からこのような薬理効果の有無によって選別された化合物は疾患症状が波状出現経過パターンを示す精神疾患用の治療薬となりうる。
精神疾患発症脆弱性に相当する進行性脳機能障害が惹起される投薬手段とは、例えばアンフェタミン類化合物（例えば、アンフェタミン、メタンフェタミン）の皮下または腹腔内投与によって行われる。その手段は、モデル動物によっても異なるが、例えば動物モデルがラットを使った場合、０．５〜１０ｍｇ／ｋｇ体重／日で３日〜数週間（ケースによっては、３〜５日、或は１０日〜２週間）に渡り複数回（３〜５回）の投薬によって行われる。この投薬により、精神疾患発症脆弱性に相当する進行性脳機能障害の原因が導入され、投薬の停止以降、すなわち休薬中に脆弱性相当脳機能障害が進行するものと推定される。
本発明からなる精神疾患治療薬は、この休薬中における候補化合物の投薬によって効力を発揮することから特異的に選択される。従って、精神疾患発症脆弱性相当脳機能障害の進行に対して制御能をもち、精神疾患の寛解期に進行する発症脆弱性の増大に対して拮抗する。候補化合物は、個々薬剤に依存するが、一般的には０．０５ｍｇ〜３０ｍｇ／ｋｇ体重／日で３日〜数週間（ケースによっては、３〜５日、或は１０日〜２週間）に渡り複数回（３〜５回）の投薬によって行われる。
候補化合物の投薬後、３日〜数週間（ケースによっては、３〜５日、或は１０日〜２週間）の完全休薬（精神疾患発症脆弱性に相当する脳機能障害が惹起される投薬も精神疾患治療薬候補化合物投薬も行わない）後、ストレス負荷が行われる。ストレス負荷は、例えば精神疾患発症脆弱性に相当する進行性脳機能障害が惹起される投薬手段のかなり軽度の手段で十分である（アンフェタミン類化合物投与の場合の１００分の１〜１０）が、一般的に知られるアポモルフィン投与、ノミフェンシン投与、その他の直接または間接ドーパミンアゴニスト投与、尻尾のクリッピング等でもよい。このストレス負荷に対するモデル動物の行動感作（例えば自発運動量）の成立に対して抑制に働くか、促進に働くかで、候補化合物の精神疾患発症脆弱性相当脳機能障害の進行に対する薬理効果の有無が確認される。
かくして選択された精神疾患発症脆弱性に相当する脳機能障害を制御し、その進行を防止する薬理効果をもつ化合物は症状が波状出現経過パターンを示す精神疾患に対して有効である。本発明からなる精神疾患治療薬は、症状が波状出現経過パターンを示す精神疾患に対して、進行性の精神疾患発症脆弱性相当脳機能障害を抑制することで、精神疾患の寛解期におけるストレス応答を持続的に安定化させ、症状の再燃（再発）を抑制する作用効果をもつ。そして、波状出現経過パターンを示す精神疾患は一般的に統合失調症（精神分裂病、分裂病、Ｓｃｈｉｚｏｐｈｒｅｎｉａ）、覚醒剤精神病、躁鬱病、又は自閉症であることが知られていることから、上記のような作用機作を担持する化合物からなる精神疾患用治療薬は、統合失調症（精神分裂病、分裂病、Ｓｃｈｉｚｏｐｈｒｅｎｉａ）、覚醒剤精神病、躁鬱病、又は自閉症の治療薬として有用である。
本発明の精神疾患治療薬は、精神疾患発症脆弱性制御剤あるいは精神疾患寛解期安定薬とも呼べるもので、精神疾患の寛解期に投与されることで再発の予防を実現する。投与方法は、一般的には製剤学的改良によって、自体公知の経口、非経口製剤が調製されるが、予防薬としてのその機能から経口投与が好適である。投与量は、各候補化合物の最適投与量が精神疾患発症脆弱性進行抑制能と毒性との相関により決定される。一般的には、経口の場合、０．０１〜１ｍｇ／ｋｇが想定される。
本発明では、上記系（覚醒剤誘導異常行動）を使い分析した結果、５−ＨＴ３受容体遮断薬は発症脆弱性に相当する脳機能障害の進行を制御する作用を担持する化合物であって、波状出現経過パターンを示す精神疾患の治療薬になる可能性があることを確認した。そして、５−ＨＴ３受容体遮断薬の例示としてはオンダンセトロンが具体的なものとして例示されたが、今後開発される新規な５−ＨＴ３受容体遮断薬も本発明に包含される。
本発明では、精神疾患発症脆弱性に相当する進行性脳機能障害を制御する作用と疾患症状が波状出現経過パターンを示す精神疾患用の治療薬との関係を明らかにしたから、精神疾患発症脆弱性に相当する進行性脳機能障害を制御する作用をマーカーにすれば新規化合物又は疾患症状が波状出現経過パターンを示す精神疾患用の治療薬のスクリーニング法として有用である。これには上記の精神疾患発症脆弱性相当進行性脳機能障害が惹起される投薬手段の適用、この手段の休薬中における候補化合物の投薬、そして再度のストレス負荷とそれへの応答をマーカーにしてスクリーニングが可能である。好適な系としては精神疾患発症脆弱性相当進行性脳機能障害が哺乳動物にアンフェタミン類化合物の複数回投与によっておこされたモデル系が利用できる。かくしてこのようなスクリーニング方法で得られる新規化合物又は疾患症状が波状出現経過パターンを示す精神疾患用の治療薬が提供される。The provision of a therapeutic agent for psychiatric disorders comprising the novel mechanism of the present invention has been achieved by a neuroscientific approach to a stress vulnerability model. That is, at least some of the feed-forward and feed-back loops in schizophrenia (schizophrenia, schizophrenia) are neuroplastic changes in common with stimulant psychosis, and stimulants It is based on the fact that neuroplastic changes in psychosis can be reproduced as behavioral sensitization phenomena in experimental animals. In schizophrenia, psychosis is caused in response to central stimulants such as amphetamines that do not cause psychosis in healthy individuals, and is sensitive to psychosocial stress. sex is observed (Lieberman JA, Sheitman BB, Kinon BJ.Neurochemical sensitization in the pathophysiology of schizophrenia: Deficits and dysfunction in neuronal regulation and plasticity.Neuropsychopharmacology 17,205-229,1997.). Similarly, in stimulant psychosis (Amphhetamine Psychosis or Methamphetamine Psychosis), a psychotic state is caused in response to a central stimulant more sensitively than a normal person, and a relapse of a psychotic state that is not recognized in a normal person by psychosocial stress. Occurring (Sato M, ChenC-C, Akiyama K, Otsuki S. Act excerbation of paranoid psychostatic state after 18th biostimi ent. In experimental animals, once a subchronic administration of amphetamines is experienced, subsequent behavioral sensitivities to central stimulants are enhanced, and small amounts of drugs induce strong behavioral changes that are not observed in normal animals. In addition, stress response behavior that is not observed in normal animals is induced by physical stress load without using drugs (Vandersclen LJMJ, Kalivas PW. Alternatives in Dopaminergic and Intensiveness Induction of Inducitivity in the indication review of preclinical studies.Psych pharmacology 151, 99-120, 2000.). Therefore, it is presumed that neurological changes similar to the psychiatric illness vulnerability in schizophrenia have also occurred in stimulant psychosis, and brain dysfunction corresponding to this psychiatric illness vulnerability causes amphetamines to be added to experimental animals. It can be judged that it can be experimentally evaluated by subchronic administration.
Based on the above recognition, the present inventor made a hypothesis and developed an experimental animal model for controlling onset vulnerability in mental illness in which symptoms show a wavy appearance pattern by pharmacological manipulations during multiple stimulant and stimulant drug withdrawal periods. As a result, the relationship between the control of cerebral illness vulnerability equivalent brain dysfunction and relapse was established as an animal model. This system was used to evaluate a compound that specifically controls the brain dysfunction corresponding to the onset of mental illness, to provide a therapeutic agent for mental illness having a novel mechanism of action, thereby completing the present invention.
In the present invention, cerebral dysfunction corresponding to the vulnerability to the onset of mental illness means the progress of weakening of the resistance to relapse of the psychotic state based on a long-term and continuous change in the biological function caused by the experience of the psychotic state. The progress means that the degree of vulnerability becomes stronger and the resistance is further lowered. The effect of controlling this is, for example, by administering a medicinal means that causes progressive brain dysfunction corresponding to vulnerability to the onset of mental illness in an animal model system, and then administering the candidate compound during the drug withdrawal period of the medicinal means. Can be confirmed by the presence or absence of a pharmacological effect that specifically prevents the establishment of behavioral sensitization, which is an index of progressive brain dysfunction corresponding to vulnerability to the onset of mental illness against subsequent stress loads. A compound selected from the candidate compounds based on the presence or absence of such a pharmacological effect can be a therapeutic agent for mental illness in which the disease symptoms show a wavy appearance pattern.
The medication means for causing progressive brain dysfunction corresponding to the onset vulnerability of mental illness is performed, for example, by subcutaneous or intraperitoneal administration of an amphetamine compound (eg, amphetamine, methamphetamine). The means varies depending on the model animal. For example, when the animal model is a rat, 0.5 to 10 mg / kg body weight / day for 3 days to several weeks (depending on the case, 3 to 5 days or 10 It is performed by multiple doses (3-5 times) over a day to 2 weeks. This medication introduces a cause of progressive brain dysfunction corresponding to psychiatric onset vulnerability, and it is presumed that fragility equivalent brain dysfunction progresses after cessation of medication, that is, during drug withdrawal.
The therapeutic agent for psychiatric disorders according to the present invention is specifically selected because it exerts its efficacy by the administration of a candidate compound during this drug withdrawal. Therefore, it has the ability to control the progression of cerebral dysfunction-equivalent cerebral dysfunction, and antagonizes the increase in onset vulnerability that progresses during remission of mental illness. Candidate compounds depend on the individual drug, but generally 0.05 mg to 30 mg / kg body weight / day for 3 days to several weeks (3 to 5 days or 10 to 2 weeks depending on the case) It is performed by multiple doses (3-5 times).
Complete drug withdrawal for 3 days to several weeks (3-5 days or 10 days to 2 weeks depending on the case) after administration of the candidate compound (medication that causes cerebral dysfunction equivalent to vulnerability to mental illness) Stress medication is also performed after administration of candidate compounds for psychiatric disorders. For the stress load, for example, a rather mild means of administration that causes progressive cerebral dysfunction corresponding to vulnerability to the onset of mental illness is sufficient (1 to 100th in the case of administration of amphetamine compounds), Commonly known apomorphine administration, nomifensine administration, other direct or indirect dopamine agonist administration, tail clipping and the like may be used. Whether or not the candidate compound has a pharmacological effect on the progression of cerebral dysfunction corresponding to the onset of mental illness, depending on whether it acts to suppress or promote the establishment of behavioral sensitization (for example, locomotor activity) of a model animal against this stress load Is confirmed.
A compound having a pharmacological effect that controls and prevents the progression of brain dysfunction corresponding to the vulnerability to the onset of mental illness thus selected is effective against psychiatric illness whose symptoms show a wavy appearance pattern. The therapeutic agent for psychiatric disorders according to the present invention suppresses brain dysfunction equivalent to the onset of progressive mental illness against psychiatric disorders whose symptoms show a wavy appearance pattern, thereby causing a stress response in the remission phase of psychiatric disorders Has the effect of continuously stabilizing and suppressing relapse (recurrence) of symptoms. And since it is known that mental disorders showing a wavy appearance pattern are generally schizophrenia (schizophrenia, schizophrenia), stimulant psychosis, manic depression, or autism, Is a therapeutic agent for psychiatric disorders comprising a compound having a mechanism of action such as schizophrenia (schizophrenia), stimulant psychosis, manic depression, or autism .
The therapeutic agent for psychiatric disorders of the present invention can be called a psychiatric disorder onset vulnerability control agent or a psychiatric disorder remission period stabilizing agent, and can prevent recurrence by being administered during the psychiatric disorder remission period. Generally, oral and parenteral preparations known per se are prepared by pharmacological improvements, and oral administration is preferred because of its function as a prophylactic agent. The dosage is determined based on the correlation between the optimum dosage of each candidate compound and the ability to inhibit the progression of psychiatric illness vulnerability and toxicity. Generally, in the case of oral, 0.01 to 1 mg / kg is assumed.
In the present invention, as a result of analysis using the above system (stimulant-induced abnormal behavior), the 5-HT 3 receptor blocker is a compound carrying an action to control the progression of brain dysfunction corresponding to the onset vulnerability, It was confirmed that it may be a remedy for mental illness with a wavy appearance pattern. Ondansetron is exemplified as a specific example of the 5-HT 3 receptor blocker, but a novel 5-HT 3 receptor blocker developed in the future is also included in the present invention.
In the present invention, since the relationship between the action to control progressive brain dysfunction corresponding to the vulnerability to the onset of mental illness and the therapeutic agent for mental illness in which the disease symptom has a wavy appearance pattern is clarified, If the effect of controlling progressive brain dysfunction corresponding to gender is used as a marker, it is useful as a screening method for a therapeutic agent for a psychiatric disorder in which a novel compound or a disease symptom exhibits a wavy appearance pattern. This includes the application of a medication means that causes the above-mentioned mental illness vulnerability and progressive brain dysfunction, administration of the candidate compound during the withdrawal of this means, and re-stress and response to it. Screening is possible. As a suitable system, a model system in which progressive brain dysfunction corresponding to the onset of psychiatric disorder is caused by multiple administrations of amphetamine compounds to mammals can be used. Thus, a novel compound obtained by such a screening method or a therapeutic agent for psychiatric disorders in which disease symptoms show a wavy appearance pattern is provided.
以下に本発明を実施例で具体的に説明するが、これはその代表例を示すものであって、本発明はこの実施例に限定されるものではない。 EXAMPLES The present invention will be specifically described below with reference to examples, but these are representative examples, and the present invention is not limited to these examples.
（実験方法）
材料と方法
図１の実験スケジュールに基づき、投薬及び評価を実施した。Ｗｉｓｔａｒ系雄性ラット（ｎ＝１０）に対し、生後２４日齢から１日１回、１０日間メタンフェタミン（ＭＡＰ：２．０ｍｇ／ｋｇ体重）（コントロールとしてＭＡＰの溶媒として用いた生理食塩水）を皮下連投した。その後ＭＡＰ投与を２０日間休薬し、一方で候補化合物を１０日間連投した。投与化合物は、ハロペリドール（ｈａｌｏｐｅｒｉｄｏｌ）（１．０ｍｇ／ｋｇ体重）、クロザピン（ｃｌｏｚａｐｉｎｅ）（２０ｍｇ／ｋｇ体重）、オンダンセトロン（ｏｎｄａｎｓｅｔｏｒｏｎ）（０．１ｍｇ／ｋｇ体重）、コントロール（ｖｅｈｉｃｌｅ：各薬剤の溶媒に用いた０．１ＮＨＣＬを含む生理食塩水をＮａＯＨでｐＨを中性付近に調整したものを使用）を一日一回腹腔内投与した。さらに１０日間Ｄｒｕｇ−ｆｒｅｅの期間をおいて安定させ、３１日目（生後５４日齢）に全ての被験動物に少量のメタンフェタミン（０．１６ｍｇ／ｋｇ）を再度皮下投与した。投与後２０分間の行動（自発運動量）を小動物運動量測定システム（メルクエスト、富山）を用いて透明飼育ケージ内にて光線通過回数として測定し、評価した。
行動評価（自発運動量）を統計解析で以下のように行った。自発運動量データは前処理（生理食塩水またはＭＡＰ亜慢性投与）の効果に対する薬剤処理（ｈａｌｏｐｅｒｉｄｏｌ、ｃｌｏｚａｐｉｎｅ、ｏｎｄａｎｓｅｔｒｏｎまたはｖｅｈｉｃｌｅ各亜慢性投与）の影響を検出するために、薬物処理ごとに対応のないｔ−検定を行い、各薬物処理条件下での行動感作成立の有無を個別に判別した。薬物処理の影響が見出された場合にはさらに生理食塩水又はＭＡＰ前処理ごとにＴｕｋｅｙ検定を用いた多重比較を実施し、薬物処理間の差の有意性を判別した。
評価の結果、コントロールであるｖｅｈｉｃｌｅ処理動物において、ＭＡＰチャレンジで誘発される自発運動量は生理食塩水前処理群に対してＭＡＰ前処理群で有意に増加しており、１０日間のＭＡＰ亜慢性投与による行動感作成立が確認された。ｈａｌｏｐｅｒｉｄｏｌおよびｃｌｏｚａｐｉｎｅ処理動物においても同様にＭＡＰ行動感作が成立し、一方、ｏｎｄａｎｓｅｔｒｏｎ処理動物ではＭＡＰ行動感作の成立が認められなかった。さらに、ｈａｌｏｐｅｒｉｄｏｌ処理はｖｅｈｉｃｌｅ処理群と比較してＭＡＰ行動感作動物で誘発される運動量が有意に増大しており、一方、生理食塩水前処理動物においては薬物処理群間での有意な差が検出されなかったことから、ｈａｌｏｐｅｒｉｄｏｌ処理によるＭＡＰ行動感作の増強が示された（図２）。
定型および非定型抗精神病薬としてそれぞれ代表的であるｈａｌｏｐｅｒｉｄｏｌ、ｃｌｏｚａｐｉｎｅはいずれもＭＡＰ亜慢性投与後の断薬期間中の投与では発症脆弱性に相当する脳機能障害のモデルである行動感作の成立を阻止できなかったことから、これらの抗精神病薬では、急性期の陽性症状に対する拮抗作用は認められても、発症脆弱性の改善効果は期待できないことを示唆した。また、非定型抗精神病薬であるｃｌｏｚａｐｉｎｅは定型抗精神病薬であるｈａｌｏｐｅｒｉｄｏｌと比較して再発率が低いとの報告があるが、本試験において断薬期間中に投与したｈａｌｏｐｅｒｉｄｏｌは行動感作をむしろ増強しており、ｈａｌｏｐｅｒｉｄｏｌ投与患者における高い再発率の要因にはコンプライアンスの低さに加えて発症脆弱性の増大効果がある可能性を示した。
５−ＨＴ３受容体遮断薬であるｏｎｄａｎｓｅｔｒｏｎは、本試験において、ＭＡＰ断薬期間中に進行する行動感作の成立を阻止していた。(experimental method)
Materials and Methods Medication and evaluation were performed based on the experimental schedule in FIG. Wistar male rats (n = 10) were subcutaneously administered methamphetamine (MAP: 2.0 mg / kg body weight) once daily from 24 days of age for 10 days (physiological saline used as a solvent for MAP as a control). I cast it continuously. Thereafter, MAP administration was withdrawn for 20 days, while the candidate compound was continuously administered for 10 days. The administered compounds were haloperidol (1.0 mg / kg body weight), clozapine (20 mg / kg body weight), ondansetron (0.1 mg / kg body weight), control (vehicle: each drug) A physiological saline solution containing 0.1 NHCL used as a solvent and having a pH adjusted to near neutral with NaOH was used intraperitoneally once daily. Further, the drug-free period was stabilized for 10 days, and a small amount of methamphetamine (0.16 mg / kg) was subcutaneously administered again to all the test animals on the 31st day (54 days of age). The behavior (spontaneous momentum) for 20 minutes after the administration was measured and evaluated as the number of times the light passed in a transparent breeding cage using a small animal momentum measurement system (Merquest, Toyama).
Behavioral evaluation (spontaneous momentum) was performed by statistical analysis as follows. Spontaneous momentum data are not associated with each drug treatment to detect the effect of drug treatment (haloperidol, clozapine, ondansetron or vehicle subchronic administration) on the effect of pretreatment (saline or MAP subchronic administration). -Tests were performed to individually determine the presence or absence of behavioral feeling under each drug treatment condition. When the effects of drug treatment were found, multiple comparisons using the Tukey test were further performed for each physiological saline or MAP pretreatment to determine the significance of the difference between drug treatments.
As a result of the evaluation, in the control vehicle-treated animals, the amount of locomotor activity induced by the MAP challenge was significantly increased in the MAP pretreatment group compared to the physiological saline pretreatment group. The creation of a sense of action was confirmed. MAP behavioral sensitization was similarly established in haloperidol and clozapine-treated animals, whereas establishment of MAP behavioral sensitization was not observed in ondantron-treated animals. Furthermore, the haloperidol treatment significantly increased the amount of exercise induced by the MAP behavioral agonist compared to the vehicle treatment group, whereas in saline pretreated animals there was a significant difference between the drug treatment groups. Since it was not detected, enhancement of MAP behavioral sensitization by haloperidol treatment was shown (FIG. 2).
Haloperidol and clozapine, which are typical as typical and atypical antipsychotics, are both established as behavioral sensitization that is a model of brain dysfunction equivalent to onset vulnerability when administered during the withdrawal period after subchronic administration of MAP. Therefore, these antipsychotics suggested that even if antagonism against positive symptoms in the acute phase was observed, the effect of improving onset vulnerability could not be expected. In addition, clozapine, which is an atypical antipsychotic, has been reported to have a lower recurrence rate than haloperidol, which is a typical antipsychotic. However, haloperidol administered during the withdrawal period in this study rather than behavioral sensitization. In addition to low compliance, there was a possibility that the factor of high recurrence rate in patients treated with haloperidol had the effect of increasing onset vulnerability.
In this study, ondansetron, which is a 5-HT3 receptor blocker, prevented the establishment of behavioral sensitization that progressed during the MAP withdrawal period.
以上のデータより、本発明者は既存抗精神病薬の欠点を補う新しいタイプの精神疾患治療薬として寛解期安定薬、ｐｓｙｃｈｏｓｔａｂｉｌｉｚｅｒという概念の確立を達成した。すなわち、本研究において用いたプロトコールのように、アンフェタミン類亜慢性投与後の断薬期間中の投与によって行動感作の発達・成立に対して阻害的効果を示す薬剤は、臨床において統合失調症（精神分裂病、分裂病、Ｓｃｈｉｚｏｐｈｒｅｎｉａ）ならびに覚醒剤精神病の寛解期に進行する発症脆弱性の増大に対して拮抗し、ＱＯＬ（生活の質）を高い状態に維持したまま再発を抑制するという既存抗精神病薬にはみられなかった効果を期待できる。かくして本発明は新規作用機作を有する精神疾患治療薬を提供し、発症脆弱性の進行に伴い波状出現経過パターンを示す精神疾患に関与するモデル動物系を使った発症脆弱性相当進行性脳機能障害の制御をマーカーにする新規化合物又は精神疾患治療薬のスクリーニング方法の提供、及びスクリーニングされた新規化合物又は精神疾患治療薬を提供するから、精神疾患治療薬の革新技術を提供するものである。 Based on the above data, the present inventor has achieved the establishment of the concept of a remission-phase stabilizer, psychosabilizer, as a new type of psychiatric disease treatment that compensates for the shortcomings of existing antipsychotic drugs. In other words, as shown in the protocol used in this study, drugs that have an inhibitory effect on the development and establishment of behavioral sensitization by administration during the withdrawal period after subchronic administration of amphetamines are clinically treated with schizophrenia ( Existing antipsychotics that antagonize the increased vulnerability of schizophrenia, schizophrenia) and stimulant psychosis in the onset of remission and suppress relapse while maintaining high quality of life (QOL) Expected to have an effect not seen in medicine. Thus, the present invention provides a psychiatric remedy having a novel mechanism of action, and a progressive brain function corresponding to susceptibility to onset vulnerability using a model animal system involved in psychiatric illness that shows a wavy appearance pattern as the onset vulnerability progresses The present invention provides a screening method for a novel compound or a psychiatric disorder drug that uses disorder control as a marker, and provides a screened novel compound or a psychiatric disorder drug, thereby providing an innovative technology for a psychiatric disorder drug.
Claims (14)
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