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2012年03月｜ 2012年04月｜2012年05月ブログトップ
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Cycloid psychosis

Cycloid psychosis: an examination of the validity of the concept.

Abstract

The diagnosis of cycloid psychosis has a long tradition in European psychiatry. However, it has been poorly assimilated within the DSM IV and ICD-10 diagnostic systems. Leonhard set the basis for the current conceptualization of the disorder, and Perris and Brockington developed the first operational diagnostic criteria. However, the two conceptualizations of the disorder are not the same and differ across a number of meaningful variables. Cycloid psychosis is a useful concept in that it possesses both clinical and predictive validity. Despite the high prevalence of mood symptoms and syndromes, cycloid psychosis does not equal schizoaffective disorder. Although a substantial body of evidence suggests that cycloid psychosis differs meaningfully from typical schizophrenia, it is less clear whether it differs from major mood disorders or represents an independent nosological entity. The existence of putative subtypes is also likely, and the differentiation between affective and nonaffective subtypes has received some support.

2012-04-20 22:30
共通テーマ：日記・雑感

acute psychosis

Categorical and dimensional diagnostic approach to acute psychosis in view of operational diagnostic criteria

Abstract

"Acute psychosis" is the tentative diagnosis made for the patients presenting acute onset of delusion, hallucination, confusion and emotional instability. "Acute psychosis" was focused in view of operational diagnostic criteria, ie, DSM-IV-TR and ICD-10. The diagnostic categories in the DSM-IV-TR corresponding to "acute psychosis" were brief psychotic disorder, schizophreniform disorder, schizo-affective disorder and mood disorder with psychotic features. Although brief psychotic disorder is representative of "acute psychosis" in the DSM-TR, it lacks in clinical usefulness, because its diagnostic criteria, based on no historical background, lack clinical validity in terms of symptom definition and duration (1 month>). On the other hand, in the ICD-10, a diagnostic category of acute transient psychotic disorder was based on the traditional "acute psychosis" concept that has been bred in the European Psychiatry. Among the acute transient psychotic disorders, acute polymorphic psychotic disorder is the diagnostic category made according to traditional concept of "bouffées délirantes" and cycloid psychosis. It is a clinically useful diagnostic category, because it could predict favorable episode outcome, if a person with fairly good premorbid social adaptation presents acute onset of polymorphic psychotic symptoms. One of the most prominent points of the revision of DSM-IV-TR to DSM-5 is the adoption of dimensional approach evaluation (diagnosis) in a disorder-crossing fashion. In addition to insomnia, depressive mood and anxiety, symptomatic domain such as acute onset, bipolarity, polymorphism of psychotic symptoms, and furthermore such domain as premorbid social adaptation, life event and episode outcome should be evaluated in the course of treatment, contributing to the clinical practice of the patients with acute psychosis.

2012-04-20 22:29
共通テーマ：日記・雑感

The relationship of bulimia and anorexia nervosa with bipolar disorder

The relationship of bulimia and anorexia nervosa with bipolar disorder and its temperamental foundations.

Lunde AV, Fasmer OB, Akiskal KK, Akiskal HS, Oedegaard KJ.

Source

Department of Clinical Psychiatry Risskov, Aarhus University Hospital, Denmark; International Mood Center, University of California, La Jolla, CA, USA.

Abstract

BACKGROUND:

Earlier studies have suggested a relationship between bipolar disorder (BP) and eating disorders (ED), more specifically, bulimia nervosa (BN) and bipolar II disorder (BP-II). In the present report we extend this relationship to broader definitions of bipolarity.

METHODS:

Semi-structured interview of 201 patients with DSM-IV criteria for major affective disorders combined with Akiskal and Mallya criteria for Affective temperaments. To diagnose lifetime comorbid eating disorders DSM-IV criteria for eating disorders (Bulimia Nervosa, BN, Anorexia, AN) were used.

RESULTS:

33 patients had an eating disorder. When compared to patients without ED the patients with ED had a higher prevalence of bipolar disorders. Using strict DSM-IV criteria, this association was only significant for BN (OR) 4.5 (95% CI 1.1-17.6). When using a broader index of bipolarity including patients having affective temperaments, a significant relation was found for BN (OR) 9.1 (95% CI 1.1-73.6), and for patients with a lifetime history of both BN and AN (OR) 8.6 (95% CI 1.1-70.2).We also found patients with ED to have a significantly higher prevalence of affective temperaments, an earlier onset of major affective disorder and to have more depressive episodes.

LIMITATIONS:

Non-blind evaluation of diagnosis for mood, eating disorders and affective temperaments.

CONCLUSION:

In line with previous reports we describe an association between bulimia nervosa and bipolar disorder. Furthermore we report a relationship between lifetime bulimia and anorexia and cyclothymic and related affective temperaments.

2012-04-20 22:22
共通テーマ：日記・雑感

Bulimia nervosa in atypical depression

Bulimia nervosa in atypical depression: the mediating role of cyclothymic temperament.

Perugi G, Toni C, Passino MC, Akiskal KK, Kaprinis S, Akiskal HS.

Source

Department of Psychiatry, Neurobiology, Pharmacology and Biotechnologies, Psychiatry Section, University of Pisa, Pisa, Italy. gperugi@psico.med.unipi.it

Abstract

OBJECTIVE:

Recent data indicate significant clinical, biological, and treatment response overlap between eating and bipolar disorders, especially when soft symptoms of either spectrum disorders are considered. The aim of the present analyses is to evaluate the lifetime prevalence of bulimia nervosa (BN) in patients with atypical depression (AD) and to delineate any demographic, clinical, personality or temperamental factors that may characterize this subgroup.

METHOD:

We examined in a semi-structured format 107 consecutive patients who met DSM-IV criteria for major depressive episode with atypical features and we separated them into two groups according to the co-occurring criteria for BN. They were further evaluated on the basis of the Atypical Depression Diagnostic Scale (ADDS), the Hopkins Symptoms Check-list (HSCL 90), and the Hamilton Rating Scale for Depression (HRSD), coupled with its modified form for reverse vegetative features, as well as Axis I and II comorbidity and temperamental dispositions.

RESULTS:

Seventeen (17.8%) percent of AD met the DSM-IV criteria for Bulimia Nervosa (BN+). These patients, compared with those who did not meet criteria for BN (BN-), were indistinguishable on all demographic and most psychopathologic and clinical features (including bipolar I and II), but were significantly higher in lifetime comorbidity for Narcissistic, Histrionic, Borderline and Dependent personality disorders as well as that for Cyclothymic temperament. BN+ also scored higher on the ADDS items of reactivity of mood and interpersonal sensitivity.

LIMITATIONS:

Correlational clinical study in which doctors could not be entirely blind to the variables under investigation.

CONCLUSIONS:

Cyclothymic temperament and related mood reactivity and interpersonal sensitivity may account for much of the relationship between AD and BN. Narcissistic, histrionic and borderline traits, too, seem to be related to the presence of a cyclothymic disposition. The data overall, in particular the cyclothymic reactivity in the absence of differences in BP-I and II, all support the hypothesis that places BN in the "ultra-soft" bipolar realm.

2012-04-20 22:20
共通テーマ：日記・雑感

作り物に反応する脳

作り物に反応する脳ということを考えると
脳は現実そのものを認知しているのではないのだと
改めて納得する

作り物は本物の薄められたもの
というのがなんとなく正しいような気がするが
人間の脳は果てしなく騙される

脳を最大限に効率良く騙すことが追求されるので
それは脳研究そのものに近くなる

脳にとっては作り物のほうが効率がよく外れがない

しかしDNAが求めているのはそれではない
そこが重要である

2012-04-16 20:45
共通テーマ：日記・雑感

福ネコ　トキソプラズマ　ドーパミン

採録

　昔からネコは、幸運や商売繁盛を呼び込む「福ネコ」としてかわいがられ、魔除けや疫病払いの効果があるとされてきた。一方で、「妊婦がネコを触ると流産する」とする警告もある。ほとんどは、ペットの癒し効果とか、迷信として片付けられてきた。しかし、この2～3年、欧米の研究者からネコのもつ不思議な力の源泉が、病原体の原虫にあるのでは、とする説が提唱されるようになった。

行動を変えるドーパミン仮説

　まずこの仮説のさわりを紹介しよう。動物に寄生する微生物の一種にトキソプラズマという原虫がいる。人をはじめさまざまな動物に寄生するが、最終的にはネコ科の動物が宿主になる。むろん、飼いネコも宿主になり得る。

　健康なネズミはネコの尿の臭いには敏感で、ネコの出没する場所は避けて行動する。天敵のネコに食べられないような回避行動を身につけたのだ。ところが、ネコのフンを食べることなどでトキソプラズマに感染したネズミは、行動が変わってしまう。ネコの尿の臭いに誘われるようにうろうろ徘徊して、ネコに食べられやすくなる。食べられれば、原虫はふたたびネコの体内に戻って繁殖の場を確保できる。つまり原虫は、繁殖のためにネズミを操っているのだ。

　だが、なぜネズミの行動が変わるのかはナゾとされてきた。近年トキソプラズマのDNAの解析が進んだ結果、脳内物質のドーパミンの合成に関与する酵素の遺伝子があることが突きとめられた。この原虫に寄生されたネズミは、ドーパミンを分泌して「威勢よくなって」をネコを恐れなくなったというのが仮説である。

　そして、人もまたトキソプラズマに操られて、ドーパミンによって脳内の化学物質の伝達の一部が変えられている、とする研究論文が増えている。トキソプラズマの慢性感染で人の行動や人格にも変化があらわれ、ときには精神疾患も引き起こすというのだ。まっとうな研究者がかかわっているので「トンデモ説」と無視できないところがミソだ。

モーツァルト効果も？

　ドーパミンは、脳内で神経伝達物質の1つとして極めて重要な役割を果たしている。「脳内麻薬」ともいわれ、人が快感や感動を覚えたときに脳内で放出される。スポーツ観戦で興奮したり音楽を聴いて感動したりしたようなときに、脳内でドーパミンが放出されることは実験的に確かめられている。「自己啓発本」などでは人気のあるテーマだ。

　ドーパミンの役割は、興奮作用のほかに行動を起こす場合の動機づけとして分泌されることも、明らかになってきた。人は無意識のうちに行動を起しているようでも、それぞれの状況でその行動が必要だと判断して動く。このときに、脳内でドーパミンが分泌されるのだ。

　この分泌の多いと、食欲や性欲がわき、やる気がみなぎり、意欲的に生活することができる。ふだんから分泌量の多い人は、あきっぽくてつねに新たな刺激を求め、冒険や探検、転職や転居が大好きで、恋人や自動車をひんぱんにかえ、スリルを求めるタイプだ。

　だが、分泌が過剰になると、言動は異様にハイになり、リスクを恐れなくなって交通事故などが多くなる。日常生活のなかで俳優のような演技的な行動をする「演技性パーソナリティ障害」も起こす。自分が注目されないと、自己破壊的な行動に出ることもある。「統合失調症」はドーパミンの異常分泌がかかわっているともいわれる。

　逆に、脳内のドーパミンの分泌量が少ないと、行動の動機づけも減って意欲が低下し、運動機能が低下する。うつ状態になったり引きこもったりする。分泌量の少ない人は、冒険より安定を好み、急に行動を変えるのが苦手なタイプだ。ドーパミンのレベルが極端に下がると、「手足の震え」や「仮面のような表情」が特徴のパーキンソン病の原因にもなる。

　須藤伝悦著『モーツァルトが求め続けた「脳内物質」』（講談社）には、モーツァルトはドーパミン欠乏に起因する病気を患い、癒すために無意識のうちにドーパミンの分泌をうながす「心地よい曲」を作曲した、という説が述べられている。

　「モーツァルト効果」は、モーツァルトの曲を聴くと「学力が向上した」「病気が好転した」、あるいは「ニワトリの産む卵の数が増えた」「キュウリの糖分が高まった」といった現象だ。しかし、否定的意見も少なくない。

　ドーパミンの受容体は人によって感度の違いがある。感度が低い人はドーパミンを多めに放出しないと情報が伝わり難く、より強い刺激を求めるようになるともいわれる。

　原虫は単細胞の微生物で、この仲間には蚊が媒介するマラリア原虫や女性の陰部に炎症を起こすトリコモナスなどが知られている。トキソプラズマも原虫の一種で、ヒトをはじめ、ブタ、ヒツジ、ヤギ、ネズミ、ニワトリなど、200種以上の動物に寄生する「人畜共通感染症」だ。

　人へはシスト（膜で包まれた休眠中の原虫）で汚染された食肉やネコのフンを介した経口感染が主である。ネズミを捕食したり、生肉を食べているネコからうつるケースもある。ただ、室内だけで飼って、ネコ砂とキャットフードで育てられているネコに感染することはほとんどないといわれる。ただ、放し飼いにしているものは感染の機会がある。

　トキソプラズマに感染した人は、世界人口の3分の1程度と推測されるが、地域によって大きな差がみられる。たとえば、感染率は韓国で国民の6％だが、ガーナでは92％もある。日本人では20～30％と推定される。ネコの放し飼いや生肉を扱うなどの習慣や食文化の差が大きいとみられる。

　健康な成人の場合には、感染しても症状がないか、軽いカゼのような症状が出るぐらいだ。多くはないが妊婦が感染して流産などを引き起こすこともある。肉は20度に冷凍するか66度以上に加熱すれば、感染力はなくなる。妊婦は庭の土や砂場の砂などでネコのふん尿に触れないよう用心する方がよい、と専門家は忠告している。

寄生虫によるマインド・コントロール

　トキソプラズマがネズミを操っているように、脳などに作用して宿主の行動を支配する寄生虫がいろいろとわかってきた。ディクロコエリウムという槍形吸虫がアリに寄生すると、ふだんは葉陰にいるアリが目立つ場所に移動するように行動が変わる。すると、ウシやヒツジが葉もろともアリを食べることで、寄生虫は宿主をウシへ乗り換えて繁殖することができる。

　ロイコクロリディウムはカタツムリに寄生すると、ツノ（触角)に集まってシマ模様になって上へ下へと動き、あたかもイモ虫のような姿に変身する。だまされた鳥が食べると、寄生虫は鳥にすみかを変えることができる。鳥の体内でタマゴを産みそれが排せつされてふたたびカタツムリに寄生する（このコワイ動画がYouTubeにアップされているのでおすすめ）。

　ガラクトソマムの幼虫はイシダイやトラフグなどの魚に寄生する。すると、魚は鳥に捕食されやすい海面をぐるぐる回りながら泳ぐようになり、食べられると寄生虫は鳥の体内に入り込む。

　ブラジルの熱帯林で最近発見されたタイワンアリタケの一種は、アリに感染して脳を支配し、ゾンビ化したアリが菌類の成長と胞子の拡散に適した場所まで移動すると、そこでアリを殺し自分は新天地で繁殖する。

　原虫の一種のマラリア原虫も巧妙な手を使う。人が感染すると何時間かおきに高熱が出て動けなくなる。その間にマラリア蚊がたかって吸血とともに原虫を取り込む。熱のおさまった人は別の場所に移動してふたたび動けなくなり、そこで蚊を通して原虫をばらまく。人は原虫の運搬道具にされている。

ワールドカップと寄生虫の関係

　人の行動をトキソプラズマとの関連で説明する試みも多い。スタンフォード大学の神経科医パトリック・ハウス博士は2010年に南アで開催されたサッカーのワールドカップでの各国の勝率に、こんな解釈をしている。博士によると、国民のトキソプラズマ感染率とサッカーの強さには相関関係がみられるという。

　引き分けのある予選リーグではなく勝敗のつく本戦の試合をみてみると、1回戦の8戦すべてにおいて感染率が高い国が勝利を収めたという。前回のドイツ大会では8戦中7戦で感染率が高い国が勝った。

　FIFAの国別ランキングトップ25を感染率で並べ替えると、上位からブラジル（感染率67％）、アルゼンチン（52％）、フランス（45％）、スペイン（44％）、ドイツ（43％）となり、このなかには過去10回のワールドカップの優勝国がすべて含まれている。ただ、イギリスやイタリアなど感染率が低いサッカーの強豪国があることから、牽強付会（けんきょうふかい）という批判もでそうだ。

　ハウス博士は、トキソプラズマに感染した男性ホルモンの一種であるテストステロンの分泌が増え、より積極的で攻撃的になりそして権威に対して否定的になる傾向がみられるので、これが影響しているのではと推測している。

　人類史のなかでもっともネコを愛した民族は、古代エジプトであろう。そもそもネコはエジプトでリビアネコから家畜化され、女神バステトとして崇拝された。ネコを殺傷することは犯罪として刑罰を受け、火事のときは消火よりもネコの救出が優先された。

　ネコが死ねば飼い主は悲しみを表すために眉を刷り落とし、死体をミイラにして手厚く葬った。1つの遺跡から30万体を超えるネコのミイラが発見されたこともある。輝かしい古代エジプト文明は、ネコから人が感染したトキソプラズマによって「活性化」した人によってもたらされたと唱える説もある。

　カリフォルニア大学サンタバーバラ校のケビン・ラファティ博士のように、ネコからのトキソプラズマ感染は、人の探求心や知的好奇心を形成した重要な要素であり、人をより人らしくした、と主張する研究者もいる。

2012-04-16 13:18
共通テーマ：日記・雑感

もしもの備えは万全ですか　保険は、住宅に次いで高い買い物

　どの保険会社のパンフレットにも、「入院したら多額の費用がかかります」などとした上で、「もしもの備えは万全ですか」と、保険の必要性を訴えている。

　しかしこうした記述は、確かに一面では事実であるものの、別の側面から見ればクロに近いグレーな表現である。たとえば、長期入院などで医療費が膨れ上がったとしても、自己負担する金額は実はそこまで大きくないからだ。

　これは、高額療養費制度というもののおかげ。医療機関に支払う医療費が、所得に応じて決められた一定額を超えたら、超過分の一部が払い戻されるという制度だ。

　たとえば40歳の会社員（標準報酬月額が53万円未満）が入院し、その月にかかった医療費が100万円だった場合、7割の70万円は公的な医療保険でカバーされるものの、残り30万円は窓口で支払わなければならない。

　だが、このうち21万2570円は、後に健康保険組合から払い戻される。つまり、実質的な自己負担は8万7430円にすぎないのだ。

　さらに健康保険組合などの「付加給付」と呼ばれる払い戻しの上乗せ制度を使えば、2万～5万円程度で済んでしまうのだ。

　今では、入院前にあらかじめ健保に申請し、手続きさえ取っていれば、初めから払い戻し分を差し引いた最終的な自己負担分だけを支払えばよくなった。4月からは外来受診に関しても同様で、費用負担は軽減されている。

　こうした仕組みがあるにもかかわらず、パンフレットには小さな文字で、目立たないようにしか書かれていないのだ。

募集パンフレットには数字のマジックが満載

　こうした事情は、「先進医療特約」についても同じだ。

　先進医療とは、厚生労働省により承認された高度な医療技術のことで、がんに対する「陽子線治療」や「重粒子線治療」などが知られている。

　こうした治療は健康保険の適用外で、中には技術料が300万円程度もするものもある。そこでパンフレットには、「先進医療は高額になりがちです」などと書かれている。

　しかし、詳細は後述するが、300万円もする治療は123種類もある先進医療のうち、ほんのわずか。そもそもそうした高額治療を実際に受ける人もそこまで多くはない。

　確かに、「高額になる」とは断言していない。とはいえ、文言の周辺に高額治療だけピックアップした図表を掲載していることを考えれば意図は明白で、消費者が誤解してもおかしくない。

　こうした事例は枚挙にいとまがない。

　たとえば、「死因の3割ががん」で、「いまや2人に1人ががんにかかる」との表現。その上で、入院時の自己負担は多額で、医療費以外にも差額ベッド代や病院までの交通費なども必要になるとし、先進医療まで加えればさらに高額になってしまうと訴えている。

　しかし、がんにかかる割合が高くなるのはあくまでも50歳以上で、若いうちにがん保険などに入る必要性は薄い。

　費用に関しても、前述の通り高額療養費制度があるのでたいしたことはないし、差額ベッドなどは利用しなければいいだけの話。入院時の日用品だって、自宅で使っているものを持っていけば済む。

　また入っている保険によっては給付に制限がある場合もあり、入院や治療で支払ったお金すべてが保険で賄えるわけでもない。

　つまり、保険の募集文書は数字のマジックと、巧みな言葉のレトリックが満載で、真実を伝えているとは言い難いのだ。

　だが、消費者がこうした点を見抜くのは至難の業。消費者の相談に乗るファイナンシャルプランナーでさえも理解できていない人が少なくない。

　しかも、保険商品は極めて複雑怪奇に設計されており、パンフレットを詳細に見てもその全貌を知ることはできない。たとえ営業担当者に疑問をぶつけてみたところで、専門的な言葉で適当にごまかされてしまうのがオチだ。

　保険は、住宅に次いで高い買い物と言われている。にもかかわらず、知識不足に付け込まれ、高いだけで必要のないものを売り付けられているのが現状なのだ。

ーーーーー
　昨年10月末に開かれた衆議院の財務金融委員会。質問に立った自民党のあべ俊子議員は、中塚一宏金融担当副大臣を問いただした。医療保険の募集広告があまりに誇大で、消費者の誤解を招いているのではないかとの趣旨だった。

　こういう側面もあるのかもしれない

2012-04-16 12:35
共通テーマ：日記・雑感

不思議な王子

シンデレラの話でよくわからないのが
ガラスの靴で確認するという仕組みである

第一足のサイズが同じ程度というのは
特異性が低すぎる

第二、足のサイズを確認しないと本人かどうかわからないというのは
王子はなにか部分的に不自由なところでもあったものだろうか
シンデレラとしては、ガラスの靴で本人確認をしないといけないような王子様だと
ちょっと考えるのではないか

第三、こんな事言ってもぶち壊しなんだけど
王子もシンデレラも何に惚れたのか全くわからない
そのあたりからの派生で
ガラスの靴というのはヴァギナのことで
暗闇の中での相手不詳のセックスが良かったけれども
それが忘れられないので探せという命令になり
しかたがないので片っ端からセックスをして確認していったというバージョンもあり
ガラスの靴とぴったり合う足をした女性
というのはつまりはそういうメタファーなのだそうだ

いや、普通に考えると
暗闇でのセックスが良かった女性よりも
昼に笑顔の明るい女性がいいように思うけれども
どうなんだろう

王子は、いろいろと探し歩いているうちに、
ガラスの靴にはぴったりではないけれども、
この人が好きだなと思うような女性はいなかったのだろうか
不思議な王子である

2012-04-16 02:27
共通テーマ：日記・雑感

排卵日に殿を独占する

排卵のある女性が集団で暮らしていると
ある程度排卵日が一致してくる
平安貴族とか江戸大奥とかがそんなものだろう

すると、お世継ぎをうまく産み落とすには
排卵日に殿が来てくれることが大切で
排卵日以外は別のところに行ってくれていてもいいわけだ

しかし排卵日だけは独占しないと
自分が妊娠しないし他の女性に妊娠されてしまうかもしれない

ボスが多数の女性を独占するように見えて
実質は排卵日の独占だけが問題なのだろう

昔のことだから月の満ち欠けと
月経現象が同期して考えられていたはずで
だから月は今よりずっと大切だっただろう

よく知らないが満月の日とかはいろいろしそうな気がする

ーーーーー
排卵日以外でも妊娠しますという方法もいくつか知られていて
お世継ぎを懐妊するならそれでも良かったはずだと思う

ーーーーー
姫よりも殿が欲しかったはずだけれども
そこの辺のデータは乏しいような気がする

成人前に死んでしまう子が多かったから
よくわからないのかもしれない

2012-04-16 02:17
共通テーマ：日記・雑感

蘭の花12個

現在12個　2012-4-13

2012-04-13 19:30
共通テーマ：日記・雑感

メールでの誤解

実際にあって話すと誤解が起こったとしても+-20程度とすると
電話で話した場合は+-50くらい
メールで連絡した場合には+-100くらいだろうと思う

怒っているけれど、本当は許したいんだとか
そのあたりがなかなか伝わらないのだろうと思う

2012-04-13 10:08
共通テーマ：日記・雑感

Psychopharmacology under the microscope

A focus on psychopharmacological agents, antipsychotics in particular, is featured in the Journal this month. Kendall (pp. 266–268) argues that there is no clinical or scientific evidence to justify the notion that atypical antipsychotics represent a distinct antipsychotic class but rather that the drug industry has essentially fabricated new classes for marketing purposes. Supporting this argument, a study based in China provides further evidence of the lack of difference in outcome for those treated with first- v. second-generation antipsychotics (Girgis et al, pp. 281–288). In a randomised clinical trial, individuals presenting with first-episode psychosis were treated with either clozapine or chlorpromazine for up to 2 years and then followed up after a further 7 years of naturalistic treatment. No differences in measures of illness severity or secondary efficacy outcomes were found between the two groups. Leucht & Davis (pp. 269–271) also comment on the implications of this study and agree that the classification of atypical and typical antipsychotics has created confusion but they warn against regarding all antipsychotic drugs as equivalent. They argue that the differences between available drugs should be exploited in the shared decision-making process of prescribing for individual patients.

Frighi et al (pp. 289–295) note that antipsychotics are frequently prescribed for individuals with intellectual disability despite limited evidence of efficacy and little knowledge about safety. In an observational study, metabolic indices were found to be similar between those with intellectual disability treated with antipsychotics and those characterised as antipsychotic-naive. Those treated with amisulpride/sulpiride and risperidone were found to have high rates of hyperprolactinaemia, however. Suzuki et al (pp. 275–280) identify individuals with treatment-resistant psychosis as another patient subgroup for whom little is known with regard to psychopharmacological treatment. Following a review of randomised double-blind trials of antipsychotic medication use in adults with treatment-resistant schizophrenia, the authors found that response peaked early in the course of treatment, in line with other recent studies of antipsychotic response timing.

Finally, Harrison et al (pp. 263–265) contend that psychopharmacological expertise needs to be given greater prominence by psychiatrists, both for the benefit of patients, who should expect safe and effective treatment, and for supporting the future of the specialty, by helping to define psychiatrists among other mental health professionals.

Previous Section

Next Section

The relationship between unipolar depression and bipolar disorder

Relatives of those with bipolar disorder are known to be at elevated risk of unipolar depression and it has long been assumed that the nature of depressive episodes experienced by these two groups is similar. Mitchell et al (pp. 303–309) examined the clinical characteristics of depressive episodes among those with bipolar disorder compared with those with major depression from bipolar pedigrees. In the former group, rates of psychomotor retardation, difficulty thinking, early morning wakening, morning worsening and psychotic features were all higher. The authors also found evidence of two symptom clusters for the major depressive disorder group, possibly representing ‘genetic’ and ‘sporadic’ factors. In a related editorial, Smith & Craddock (pp. 272–274) argue that the distinction between unipolar depression and bipolar disorder may not be as easily delineated as previously thought.

Previous Section

Randomised trials – for self-harm and residual depression

Hatcher et al (pp. 310–316) report on findings from a randomised controlled trial of problem-solving therapy for individuals who present to hospital with self-harm. Compared with usual care, the authors found that therapy did not reduce rates of repeat self-harm presentation at 12 months except among those where the index episode was a repeat self-harm event. For those with medication-refractory residual depression, Watkins et al (pp. 317–322) found that rumination-focused cognitive–behavioural therapy was associated with improvements in residual symptoms and remission rates, with treatment effects being found to be mediated by change in rumination.

2012-04-12 16:20
共通テーマ：日記・雑感

翻訳語

翻訳の言葉を考えて
たとえばoftenをいつもしばしばと訳すのは芸がないので
いろいろと場面に応じて訳し分けたりするのだけれども
考えなおしてみて
oftenはいつでもしばしばと決めてしまえば
読者はしばしばを日本語の意味で解釈しないで
これは英語のoftenと解釈すれば
とても便利なのだと思った

オフンと訳してももいいのだと思う
そんな日本語は嫌だというならそれもいいけれど
しばしばとは頻度が高いことで、などと考えていないで
このしばしばは英語のoftenの意味だなと思うことで
充分なのではないかと思う

ぴったりの日本語がないときに造語して何かの言葉を充てたりするのも
言語を思い出させるのでそれは誤解のない方法だと思う
既存の日本語だと、初学者の場合、その日本語の意味に引きずられることもあるだろう
勉強している人は、この言葉は英語のあれだなと見当がつく

agitation などと言う言葉では
辞書では不穏、興奮、焦燥などといろいろと載っているのだが
激越と訳すと、これはagitation depression のときの言葉だなと見当がつく
激越を鎮めるといえばうつ病なのに興奮しているという奇妙な、一種の混合状態を
鎮めるという意味で
単に不穏でもないし興奮でもない
不穏や興奮は、シゾフレニーでもパニック障害でも認知症でも起こる、一般的な語彙である
激越というだけでそれはagitationのことでしかもdepressionのときの言葉と
だいたい決まっているので話が早い
しかしその事は日本語辞書にはないだろうし
漢字の意味をたどっても分からないと思う

広汎性とpervasiveの関係もそんなものだろう
広汎性の文字から何かを分かろうとしても不正確な話でpervasiveのことだと
一旦理解して、そこからだろう

便利といえば便利なのだが
初心者がささっと理解するには少し不便だろう
今後この方面で仕事をするというのでもなければ
ささっと理解して、結局どうすればいいのかを知ればいいように思う
そんな場合に、このような翻訳後のメカニズムなどは必要なのだと思う

たとえば批判という言葉があるが
これはカントの場合はKritikのことで
別に非難することではなくて、厳密に考えるという意味だけれども
カントの文脈で批判というとクリティークの意味でというのは
業界の決まりになっているので
批判的意見と好意的意見の対比としての批判ではないのだと
分かる仕組みになっている
純粋理性批判といっても純粋理性を悪く言っているのではなくて
純粋理性というものについて厳密に考えてみるという意味で
それを昔から批判という日本語を充てる習慣になっているというだけである
なにか日常用語としては決して使わないような言葉を充てるのも方法だったような気もする
しかし一般初心者が誤解するとしても最初から挫けてしまわないようにする働きもあるのだと思う

たいていとしばしばと頻繁にとよくあることだがと多くの場合と
日本語としても差があるように思うが
その言葉の網の目と
英語のoftenとかfrequentryとかalwaysとかmostlyとかの
意味の分担の網の目は違うのだろうから
そのあたりもややこしい

性格障害、人格障害、のあたりもパーソナリィ障害でまとめようというらしい
性格異常とか人格異常はまたなにか違う意味のにじみがあるようだ

シゾフレニーという言葉は
どこの国でも変化なく使っているのに
日本でだけ用語の変更があって
すると検索の場合とかで不都合が生じる
シゾフレニーを多重人格と混同しているのは日本だけではなくて
アメリカでもイギリスでもあるようで
混同しないようにと啓蒙書には記述がある

疾病と障害の違いは大切なのだが
disease、disorder、impairment　と並べると
やはり言葉の網の目の違いを感じる

ーーーーー
漢字には歴史があり
歴代の王朝で読み方が違い
意味も違うことがある
同じように現代の日本語の言葉を英語の何かの単語に強く結びつけて
意味を拡張することも行われていいことなのではないかと思う

2012-04-12 01:24
共通テーマ：日記・雑感

メールの言葉

その人はメールが苦手で
出来れば電話で話したいし
一番いいのは実際に会って
顔を見て話したいのだという

何が不満かというと
メールでは言葉がただの素っ気ない言葉になっていて
実際に話すときの色合いとか深みとか微妙なところが伝えられなくて
もどかしくてダメなのだとのことだ

MIDI音楽という変なものがあって
だいたい分かるけれども
あまり感動はしない
それと実際の歌との違いくらいのことを
その人はメールと会話の間に感じているらしい

ーーー
言葉の背景にあるコンテクストというものを読み取れない人がいるもので
これも実に興味深いことだと思う

「はい」と答えて、そのままイエスのこともあるし、思いっきりノーのこともあるし
ただ単に「はい」という言葉が投げ出されているのでは
何もわからないと感じる人もいるらしい

逆に「はい」は肯定なのだから、それでいいという人もいる

私として不思議なのは、こんなにも解釈の違う人間が
同じような場所に生きていて
別に不都合もなく生活は進行しているということだ

カラーと白黒くらい違うけれども
それはそれで他人の心の中には踏み込まないで
生きられるものなのだと思う

2012-04-12 00:55
共通テーマ：日記・雑感

Y遺伝子

A家男子YXとして
B家女子X1X2として
女子が生まれると
XX1またはXX2
たとえばXX1が後継になったとして
その配偶者が
C家の男子Y3X3とすると
女子が産まれたとしてX1X3の可能性があり
その女性はB家とC家の子孫ではあるが
A家の子孫とは言いにくいような気がする
つまり3代でA家はB家とC家に乗っ取られる可能性がある
という話をされて、まあ、どうでもいいが、そうかもしれない
XXの間で部分的な交換もあるのだろうからそんなに100%の話でもないのかもしれない
それもよく分からない

実際の話は
男子は子供が自分の子なのかどうか怪しい
しかし数多く残せるので
昔のように子供がたくさん死ぬような環境だと
男子のほうが効率良く遺伝子を残せたかもしれない
しかし誰の子なのかという問題は解決されない
しかしそれを利用して水増しもできる

女子は自分の子であることは確実なのだろうが
数が確保できない
死ぬ確率が高いと女子の相続は不利になる
ところが自分の子であることは確実とは言いながら
生後に取り替えられたりすることはいくらでもあるだろうから
男子ほど怪しくはないとしてもやはりなんとも言えないだろう

昔の人はY遺伝子の話など知らないはずなので
別の理由で決めたものなのだろうし
歴史は現在の都合で作られているものらしいので
ますますよく分からない

2の累乗の計算をしてみるとあっという間に膨大な数字になるので
たとえば20歳で子供を産むとしてみても
あっという間に日本人全部の家系が重複してしまう
一人何役もする以外にないらしい

ーーーーー
昔の話をすれば
生年月日がはっきりしているのは最近になってからのことではないだろうか
記録係がいるような家庭ならば別だが
一般家庭では年齢など曖昧なものだろう
だから若く見えれば若いと判断されたはずだろう

そんなあたり、年齢不詳の世界で面白い

だから妊娠を確認してから入籍などの習慣もあったようだ

2012-04-11 04:50
共通テーマ：日記・雑感

若者は幸せである Happiness is circle Knowledge is ellipse

若者は幸せである
ものを知らないから幸せでいられる
そして将来、知れば幸せになるかもしれないと希望することができるから

老人は不幸である
ものを知ることで不幸であり
不完全にしか知りえないことで二重に不幸である

ーーーーー
若者は幸せである
知らないから

老人は二重に不幸である
知るから
そしてそれが不完全であるから

幸福は円であるが
知識は楕円である
あるいは完成しない円である

Young people are happy

Because they knows nothing
they believe they will know something and become happy

The old man is doubly unfortunate

Because they know something

and what they know is incomplete

Happiness is circle
Knowledge is ellipse or incomplete circle

2012-04-11 01:50
共通テーマ：日記・雑感

フリーズドライ精子

フリーズドライ精子、水で戻してラット出産

読売新聞 4月10日(火)

　食品や医薬品の保存に使われる真空凍結乾燥（フリーズドライ）法で５年間冷蔵した精子を使って、ラットを妊娠・出産させることに、京都大の金子武人特定講師らが成功した。

　液体窒素で凍結しなくても済む簡便な保存法に結びつく成果。１０日の米科学誌プロスワン電子版に発表する。

　金子さんらはラットの精子に対し、ＤＮＡを安定して保存できる液体を混ぜてフリーズドライにして、ガラス容器に入れ冷蔵庫で５年間保管。その後、水で戻して卵子と受精させ、雌の子宮に戻したところ、生殖能力のある子供が生まれた。

　マウスのフリーズドライ精子を使った実験では、常温保存状態で日本から米国へ６日かけて郵送した後に受精させても、正常な子供が生まれた。ただし、５か月に及ぶ常温保存後では妊娠しなかったという。

　金子さんは「今後は冷蔵だけでなく、常温でも長期保存できる方法を探りたい」と話す。

2012-04-10 19:48
共通テーマ：日記・雑感

文学とは何か

以前にも何度か繰り返し書いていることだが
言葉というものは体験や思考を自分のために書き留めたり
他人に理解してもらうために書いたりなど
実用的な側面があり
その端的な例は法律とか命令とかそんなものだろうが
その対極的な言語の使命として
言語は何を語り得るか何を語りえないか
そして言語で語りえない世界をなおも語る試みというものが
長い間続けられてきている
それが言語の歴史であると思う

言語の生成を考えてみると
言語が出来る前に思考は明確にはなかったかもしれない
言語が生成されて思考が成立した
認識が成立した
しかしそれは狭い範囲であった
語彙も少なかった
それが次第に語彙を増やし
メタファーを増やし
語り得ることと語り得ないこととの境界を乗り越えて拡張していった
それが同時に人間の認識世界の拡大でもあった

それは現在でも進行していて
言葉は日々新しく作ら入れているし
外来語の正しい用法もあり誤用もあり
それらすべてを含めて言語世界が、非言語世界を侵食するプロセスである

言語が成立してどれだけ年月が経ったのか正確にはわからないが
それでも未だに言語の外側に壮大な世界が広がっているようである
そして今もなお、日々新しく、昨日までは語り得なかったことを
語り得ることに変更しつつある

それにしてもいつまでも語り得ないいことが
言葉の外側にあるのはどうしてなのだろう

一見すると、語り得ることと認識し得ることは一致していて
語り得ないことは認識し得ないことと考えられるのだが
人間はいつも語り得ないことを感じていて
それを言語世界に変換することに挑み続けているのである

なぜいつでも常に語り得ないことが広がっているのだろう
語り得ることについては語り得た
だからこれから以降、言語の新作もないし、メタファーの新作も必要がない、
そう宣言しても悪くないくらいの歴史だろうと思う
それでも停止せずに常に運動を続けている
それが文学の営みである

すでに共有された言葉で、すでに共有された世界を退屈しのぎに描くことは
消費される娯楽ではあるが
語り得ないことを語り得ることに変換するという
私の定義する文学ではない

私は個人的には言語の拡張的な使用法を試みているつもりである

2012-04-10 01:06
共通テーマ：日記・雑感

地熱発電と噴火

地熱発電を進めるというのだが
火山が噴火する可能性を考えると
結構大変かも

高知県など海の近くは危ないというので
山に登ると今度は噴火が怖い感じはする
何しろ地殻変動が激しいのだから

ーーー
いろいろなデータが出されるたびに
不動産の値段が変動する感じはある

ーーー
どこに逃げても困るだろうなと思いつつ
しかし見方を変えれば
自然が日本人を根絶やしにすることはできないだろうと思う
日本全部が沈没すれば、海外にいる日本人を別にして
日本人全滅だろうが
そうでもなければ
どこかの部分は生き残るだろうから
どの人が生き残るのかは分からないけれども
誰かが生き延びるだろう
集団生存とか集団遺伝学としては、それだけで充分なのだろう

防災設備にどれだけのお金をかけるかという点で言えば
実際難しいところがある

1000年に一度の災害のためにどれだけのお金をかけるのかは
冷静に考えないと
工事を請け負った業者が、どうせ1000年後にしか使わないのだから
手抜き・中抜きでもいいと考えないとも限らない

工事の結果として災害に耐えられるのかどうかを検証するのは難しい
壊れるまで実験しないと分からないところがあるだろう
非破壊的な検査でどこまで分かるか、謎がある
この場面でも、悪徳業者の暗躍が予想される

一時問題になった耐震偽装問題はもう解決されたのだろうか

ーーー
だってふるさとはアフリカだからなと言い出しかねない

2012-04-09 21:48
共通テーマ：日記・雑感

満開の人生の景色

満開の桜の下を歩いて通勤した
桜満開、春、若者、新年度、お酒、出会い、希望、期待、ここまでそろっても
憂うつだというのは大伴家持くらいのものだろう

満開の花が過ぎたあとはもちろん寂しい
しかしだからといって満開の花を見たくないのではない

これが人生の景色なのである

躁病になって自分も大変な目にあい周囲にも迷惑をかけ
友人を失い職を失い
それはもちろん大変なのだけれども
それが人生だという気もする

この満開の花を見ると
そう思う

躁病が満開の花だというのではないが
人生にはいろいろな景色があるものだという思いがある

人生の中で何度か躁病にもなり何度かうつ病にもなり
そのようにして人生の景色が刻まれて
思い出が残る
それでいいような気もする
それで大きな損失が出るとしても
それが人生だろう
死んでしまったあとで平和な人生だったなあと思うのと
起伏のある人生だったなあと思うのと
どちらが悪いとも言えないような気がする

2012-04-09 11:49
共通テーマ：日記・雑感

bipolar vs monopolar

この図を再掲するのだが
この図を見てnormalがゼロでmaniaが+、depressionが-とは
私には見えない
磁石のようにNとSが混ざっているとかも見えない

maior depression のラインがベースラインで
maniaが100とすれば、hypomaniaが75、normalが50、dysthymiaが25、
major depressionが0としか見えない

すると2つの因子を仮定する必要は全くなくて
因子としては1つなのだろうと思う

それが50くらいのときに、人間としては普通くらいの感じということなんだろう

上記のライン以外にも組み合わせとしては無限のバリエーションがあるのだと思うが
それは病気としてわざわざ認定する必要がないからなのだと思う

major depressionで職業的、社交的に機能停止してしまうので一番不都合ということなのだろうと思う
不都合というのは社会にとってが半分で本人にとってが半分

bipolarという呼び方もおかしくて
私にはmonopolarにしか見えない

mania成分が0-100の間で変動しているだけと見える

二極があるといってもこれでは一極なのである
たとえば、セロトニンとノルアドレナリンの量が独立に変動して
二極の合成として示されるというならば
双極性と言う言葉がふさわしい
しかしその場合には
うつの軸とそうの軸を直交させて描いたほうが分かりやすいだろう
そのような書き方がふさわしくないというならば
やはり一極で
変動要素は1つだけなのである

直交させるのが分かりにくいなら
時間軸を横にして
うつとそうの成分をそれぞれ独立にグラフにすれば分かりやすいだろう
そもそも混合状態の時にはそのような書き方をすることもあるのだが
混合状態に関しても、そうが100と25で混じるから混合状態というだけだろう

英語は90点で数学が20点なら混合状態となるのだろう
しかしそんなことはいくらでもある

この話はずっと昔からある話で特段に新しい話でもないのだが
最近はあまり言われないようだと感じている

その昔からの説で言うと
depressionになるのはmaniaがあるからである
maniaがずっと続くはずはないので
いつかは低下する
低下した時が0になるとdepressionで50になるとnoramalということで
たとえば子供の場合には50-100の間くらいで変動していると思う

成人に近くなってmania細胞がそれなりに年をとると
depression phase が始まるのだろう

人によってはmaniaまで上昇しなくても
normalのあたりで活動していてもmania cell にダメージが生じて活動停止になることがある
それが単極性うつ病に見えるということになる

遺伝的に双極性障害と単極性うつ病は分離できそうだという話も当然で
mania cell　の分布は遺伝的に規定されているので
mania cell の性質と量によって単極性に近いか双極性に近いかが決まるのだと思う

お祭り騒ぎが好きな一家とそうでない一家があるというだけのような気がする
それぞれで大うつ病は経験する

その場合、単極性うつ病一族はもともとmania cell が少ないと興奮しないのだから
抗うつ剤を投与しても躁転することもない

極点に言えばうつ病で自殺したり
躁病でお金を使い果たしたりしない限りは
昔と同じく放置しておいても元に戻るので
積極的に薬剤を使用する理由がないといけない
薬剤使用の利益が明確でないといけない

もともと循環性で元に戻るものと定義されていたのだから
反復はするがレベルダウンはしないのである

それを、実はレベルダウンがありますというなら、
かなりの大変更なのである

そして多分実態はレベルダウンがある
昔からそう言われてきていたが
ドイツ精神医学の建前上は一応レベルダウンがないこととして
純粋理念型を立てるということになっていた

なにしろ人間は長生きするようになったし
そのなかで高度情報化されて仕事をしていて
わずかのレベルダウンも敏感に拾い上げる社会構造になっているのだ

だから50年前に比較すると
明らかに個人の機能レベルダウンは把握されやすくなっているし問題になりやすくなっている
そんな背景があるので
躁うつ病にもレベルダウンがあるという話になっている

しかしこのレベルダウンとシゾフレニーでのレベルダウンは
やはり様子が違うだろうと思う
てんかんも含めて、人格水準の低下という点では似ているものなのだけれども
気分障害の場合には顕著ではない

ーーーーー
mania細胞がフル活動している100のとき、人間として最高の能力を発揮するかといえば
必ずしもそうではない
たとえば本を書くという一面的能力ではそう状態のときに有利かもしれないが
その状態で他人に尊敬される、自分で後から思い返してみて誇らしい、
そういう状態ではないだろうと思う

妙に仕事ははかどったけれども、やっぱり病的だったな、という感想だろうと思う

人格水準低下という曖昧な言葉を使うのだけれども
高位脳機能の障害された状態である

その状態のままで普通に行きている人もいくらもいるので
あまり深刻ではないし
幸せになることを考えると、その事自体はあまり障害にはならないのではないかと思う

2012-04-09 02:42
共通テーマ：日記・雑感

Atypical Antipsychotic Drugs and Alzheimer's Disease

Schneider et al. (Oct. 12 issue)1 conclude that the adverse effects of atypical antipsychotic drugs for the treatment of psychosis, aggression, and agitation in patients with Alzheimer's disease offset the advantages. However, they acknowledge that the doses used in the study were lower than some clinicians would have used and that patients could discontinue a study drug (a main outcome) and randomly switch to another of the study drugs. The rate of discontinuation of treatment ranged from 77 to 85% among the four study groups.

An accompanying editorial by Karlawish2 highlights the novelty of this trial's design, with a primary outcome that attempts to reflect actual clinical events — in other words, a situation in which a switch would be made to another atypical neuroleptic agent after 2 to 4 weeks if the first drug had side effects or no apparent benefit.

There will be much discussion of this study in the coming months. One possible interpretation of the findings is that nonpharmacologic interventions and non-neuroleptic drugs should be tried before atypical antipsychotic drugs. Antidepressants, antiepileptic drugs, and the N-methyl-d-aspartate (NMDA) receptor antagonist memantine could be tried in individual patients to reduce the use of antipsychotic drugs. Another study by the Clinical Antipsychotic Trials of Intervention Effectiveness–Alzheimer's Disease (CATIE-AD) study group may be required to demonstrate the effectiveness of these drugs for psychosis, aggression, and agitation in patients with Alzheimer's disease.

2012-04-09 01:23
共通テーマ：日記・雑感

Smoking and Mental Illness — Breaking the Link

“My doctor told me I'm too stressed out to quit smoking,” remarked a woman hospitalized with severe depression. “Well, 43 years later, I'm still stressed and I'm still smoking.” This woman's dilemma is all too familiar to health care providers and patients seeking the ideal time to treat tobacco dependence in the face of chronic mental illness.

Since smoking and mental illness commonly occur together, many clinicians see them as inextricably linked and believe that smoking in the mentally ill is therefore particularly challenging to treat. Little examined are the systemic and treatment factors that have contributed to disparities in tobacco use and tobacco-related morbidity and mortality among people with mental illness.

Twenty years ago, the Joint Commission on the Accreditation of Healthcare Organizations (JCAHO, now the Joint Commission) proposed a national ban on tobacco use in hospitals, noting the contradiction between hospitals' health care mission and their exposing of patients, staff members, and visitors to the harms of secondhand smoke. Patient-advocacy groups for the mentally ill strongly opposed the ban, arguing that tobacco's therapeutic, calming effect was valuable and warning that psychiatric patients who were denied their cigarettes would revolt. JCAHO conceded and exempted psychiatric and drug-treatment units from the smoking ban. Psychiatric hospitals that voluntarily adopted such bans, however, have documented both little-to-no disturbance in patients' behavior and time savings for staff members.

Yet even in smoke-free psychiatric settings, treatment of tobacco use remains relatively rare. In my group's recent studies, among 337 smokers recruited from inpatient psychiatry units, 82% reported having attempted to quit, and 42% reported having done so within the previous year; only 4% reported receiving assistance with quitting smoking from a mental health care or general health care provider. Moreover, there are still outpatient mental health programs that provide cigarettes as an incentive for patients to comply with treatment.

The devastating consequences of tobacco use among smokers with mental illness are evident. Smokers with serious mental illness are at increased risk for cancer, lung disease, and cardiovascular disease, and they die 25 years sooner, on average, than Americans overall. Tobacco use also complicates psychiatric treatment. Components in tobacco smoke accelerate the metabolism of some antidepressant and antipsychotic medications, resulting in lowered blood levels and probably reduced therapeutic benefit. Studies have revealed higher hospitalization rates, higher medication doses, and more severe psychiatric symptoms among patients with schizophrenia who smoke than among those who do not. Though the mechanism is unclear, tobacco use also is one of the strongest predictors of future suicidal behavior.1 Smoking results in substantial social and financial costs to patients, their families, and society. As greater restrictions on exposure to secondhand smoke are implemented in many public areas, tobacco use is further isolating an already-marginalized group.

Five prevailing myths have contributed to continuing tobacco use among people with mental illness. The first is that tobacco is necessary self-medication for the mentally ill. The tobacco industry has fostered this belief by funding research and presentations on the self-medication hypothesis, supporting opposition to the JCAHO smoking ban, publishing articles in the lay press, and marketing cigarettes to people with mental illness.2

Nicotine is a powerful reinforcing drug that transiently enhances concentration and attention, regardless of the smoker's mental health status. But it has proved ineffective as an adjunctive treatment for mental disorders (e.g., depression, schizophrenia, and attention-deficit disorder), possibly because of the rapid decrease in drug response with repeated exposure. The reality is that tobacco is another problem, not a solution.

Myth number two is that people with mental illness are not interested in quitting smoking. Research argues otherwise: studies involving patients recruited from outpatient and inpatient psychiatric settings suggest that they are about as likely as the general population to want to quit smoking.1 In the United States, 20 to 25% of smokers report that they intend to quit smoking in the next 30 days, and another 40% say they intend to do so in the next 6 months. Furthermore, among smokers with mental illness, readiness to quit appears to be unrelated to the psychiatric diagnosis, the severity of symptoms, or the coexistence of substance use.

The third myth is that mentally ill people cannot quit smoking. Although treating tobacco dependence is challenging, several randomized treatment trials and systematic reviews involving smokers with mental illness have documented that success is possible. With a stepped-care intervention tailored to depressed smokers' readiness to quit, a 25% abstinence rate at 18-month follow-up was achieved — a rate significantly higher than that in the group that received usual care (advice to quit and referrals for help doing so) and similar to cessation rates in the general population.1 A cessation intervention integrated into treatment for post-traumatic stress disorder (PTSD) doubled patients' odds of quitting.3 And a meta-analysis of seven randomized controlled trials involving smokers with schizophrenia revealed a nearly threefold increase in abstinence rates 6 months after treatment among those who used bupropion.4

Fourth, many people believe that quitting smoking interferes with recovery from mental illness, eliminating a coping strategy and leading to decompensation in mental health functioning. Five randomized tobacco-treatment trials in patients concurrently receiving mental health treatment have found that smoking cessation did not exacerbate depression or PTSD symptoms or lead to psychiatric hospitalization or increased use of alcohol or illicit drugs.1

Finally, some argue that smoking, which is perceived as having distal effects, is the lowest-priority concern for patients with acute psychiatric symptoms. Yet people with psychiatric disorders are far more likely to die from tobacco-related diseases than from mental illness. Smokers know tobacco use has deadly consequences and expect health care professionals to intervene. Indeed, raising the issue of tobacco use with patients enhances the rapport between patients and clinicians.

There is growing evidence that smokers with mental illness are as ready to quit as other smokers and can do so without any threat to their mental health recovery. Evidence supports the use of most recommended cessation treatments in smokers with mental illness (see table

Recommended Treatments for Tobacco Dependence and the Evidence Base for Use in Smokers with Mental Illness.

Clinicians are therefore encouraged to ask all patients about tobacco use, advise smokers to quit, assess their readiness to quit, tailor assistance accordingly, and arrange for follow-up. Key strategies for smokers who are not ready to quit include focusing on the benefits of change and the risks associated with tobacco use, as well as addressing key barriers to cessation (e.g., stress, fear of weight gain, and nicotine withdrawal). Smokers who are ready to quit should be encouraged to set a quit date in the next 2 weeks, given a prescription for pharmacologic cessation treatment (unless it is contraindicated), and linked with counseling support. Mood-management strategies may also be helpful for smokers with current or past mental illness. Integrating cessation treatment into existing care results in greater engagement, greater use of cessation pharmacotherapy, and increased likelihood of abstinence.3 Ongoing contact allows clinicians to monitor and address any changes in psychiatric symptoms during quitting attempts. Relapse rates may be high, and combined and extended use of cessation medications may be warranted.

There is a critical need to engage health care providers, policymakers, and mental health advocates in the effort to increase access to evidence-based tobacco treatment. The Joint Commission plans to adopt revised hospital standards for tobacco treatment next January. The standards should apply to all hospitalized smokers, regardless of mental health status. More generally, we need greater advocacy for smoke-free environments for mental health treatment; training for clinicians in cessation treatment; and systems for routinely identifying patients who smoke, advising cessation, and providing treatment or referral.

The history of tobacco use in the mental health field is long and troubling. It is time to make effective cessation treatments readily available to all smokers.

2012-04-09 01:21
共通テーマ：日記・雑感

Genomics, Intellectual Disability, and Autism

Intellectual disability, which is characterized by significant limitations in both intellectual functioning and adaptive behavior that begin before the age of 18 years,1 affects 1.5 to 2% of the population in Western countries.2 A diagnosis of intellectual disability is usually made when IQ testing reveals an IQ of less than 70, which means that often the diagnosis is not made until late childhood or early adulthood. However, most persons with intellectual disability are identified early in childhood on the basis of concern about developmental delays, which may include motor, cognitive, and speech delays. A genetic underpinning of this disorder has long been recognized in a subset of cases, with trisomy 21 (Down's syndrome) detectable by chromosomal studies since 1959.3 Trisomy 21 remains the most important chromosomal cause of intellectual disability. Single-gene causes have also been identified for a number of intellectual disability syndromes and include both autosomal and X-linked genes, with the fragile X syndrome being the most common of inherited syndromes caused by a single-gene defect leading to this phenotype in male patients.

Autism spectrum disorders have been estimated to affect as many as 1 in 100 to 1 in 150 children.4,5 Disorders on the autism spectrum share features of impaired social relationships, impaired language and communication, and repetitive behaviors or a narrow range of interests. Many children with autism spectrum disorders also have intellectual disability, and approximately 75% have lifelong disability requiring substantial social and educational support. Thus, autism and intellectual disability together represent an important health burden in the population and are frequent reasons for referral to genetics and developmental pediatrics clinics for a diagnostic workup.

During the past decade, advances in genetic research have enabled genomewide discovery of chromosomal copy-number changes and single-nucleotide changes in patients with intellectual disability and autism as well as in those with other disorders. These technological advances — which include array comparative genomic hybridization (CGH), single-nucleotide-polymorphism (SNP) genotyping arrays, and massively parallel sequencing — have transformed the approach to the identification of etiologic genes and genomic rearrangements in the research laboratory and are now being applied in the clinical diagnostic arena. Here we review these techniques and how they have enabled the rapid discovery of chromosomal and single-gene causes of intellectual disability and autism.

COPY-NUMBER CHANGES

Deletions and Duplications

A copy-number change is defined as a deletion or duplication of a stretch of DNA as compared with the reference human genome. Copy-number changes may range in size from a kilobase (kb) to several megabases (Mb) or even an entire chromosome (trisomies and monosomies) and can involve one or more genes. Deletions may be heterozygous, in which one of the usual two copies is missing; homozygous, in which both copies are missing; or hemizygous (e.g., X-chromosome deletions in a male patient).

Duplications often result in three copies, as compared with the usual two copies, although some regions of the genome are present in more than three copies and the range of observed copy numbers is much greater. Multiple studies of large control cohorts have shown that some regions of the genome are tolerant of copy-number changes and that every person carries many copy-number changes that are, for the most part, benign.6-10 Two individual genomes may differ by several megabases of DNA content because of copy-number changes. In this article, we focus on copy-number changes that underlie intellectual disability and autism and are generally not found in control cohorts.

Changes in chromosomal copy number were first recognized as a cause of intellectual disability in 1959, when it was discovered that an extra copy of chromosome 21 is the cause of Down's syndrome.3 Steady advances in chromosome-banding techniques (see the Glossary) facilitated the detection of unbalanced rearrangements, including translocations, large deletions or duplications, and supernumerary marker chromosomes. The minimum size of disrupted chromosome that can be detected by chromosome banding is approximately 5 to 10 Mb, and such cytogenetically visible rearrangements are responsible for 10 to 15% of cases of intellectual disability.11 It was soon recognized that some patients with syndromic forms of intellectual disability also had deletions in the same chromosomal region, a finding that resolved the molecular cause of microdeletion syndromes, including the Prader–Willi and Angelman syndromes (deletion of 15q11-q13),12 the Williams–Beuren syndrome (deletion of 7q11.23),13 and the Smith–Magenis syndrome (deletion of 17p12).14 It was also noted that 1 to 3% of patients with autism had a maternally inherited duplication involving 15q11-q13.15

Fluorescence in situ hybridization (FISH), which was developed in the 1980s, represented an important advance in the reliable detection of smaller chromosome rearrangements and allowed physicians to rapidly confirm the diagnosis of a suspected microdeletion or microduplication syndrome in a patient. Another assay that FISH permitted was the investigation of subtelomeric deletions and duplications, which were found to cause 2.5 to 5% of previously unexplained intellectual disability.16-18

The more recent introduction of genomewide techniques to identify submicroscopic copy-number changes has revolutionized both the approach used in the laboratory to identify chromosome abnormalities that are responsible for intellectual disability and the diagnostic approach used in the clinic for patients with developmental delays or intellectual disability. The two techniques that are routinely used for discovery of copy-number changes are array CGH and SNP genotyping arrays, collectively referred to as chromosome microarrays (see Chromosome Microarrays). Since their introduction, these techniques have been applied to large case series of patients with intellectual disability or developmental delays.19-24 Numerous studies have also investigated the role of rare copy-number changes in autism.25-30 Identification of specific copy-number changes in affected patients as compared with control subjects has led to a rapid increase in the discovery of novel microdeletion and microduplication syndromes associated with intellectual disability and autism.31 Many of these syndromes are listed in Table 1TABLE 1

Novel Recurrent Copy-Number Changes Associated with Intellectual Disability and Related Disorders.

and several are discussed below.

Role in Intellectual Disability Syndromes

Several novel microdeletions have been identified in patients who have a similar clinical picture. Heterozygous deletions of 17q21.31, which were described by three groups simultaneously,20,23,24 are associated with moderate-to-severe intellectual disability, hypotonia, facial dysmorphic features, occasional cardiac and renal abnormalities, and seizures. The deletion is 500 to 650 kb in size and is not detectable by routine karyotyping. All 17q21.31 deletions that have been identified are de novo, and the deletion has never been seen in healthy control subjects. Its prevalence is estimated to be approximately 1 in 16,000 persons.75 Deletions of 15q24 are much rarer, but patients with 15q24 microdeletions also have an intellectual disability syndrome with recognizable features.55-57,76,77 Common features include developmental delay and intellectual disability that is usually moderate to severe; prolonged speech delay or the absence of speech; dysmorphic features, including a high anterior hairline, prominent forehead, and downslanting palpebral fissures; joint laxity; and hypotonia. Many patients also have some features of autism spectrum disorders. The 15q24 deletions that have been described vary with respect to breakpoints and size, but most include the 1.1-Mb region that is thought to be critical for the phenotype.

Variable Phenotypes

In contrast to the syndromic microdeletions described above, several recurrent microdeletions and duplications have been associated with a wide range of phenotypic features and severity. Deletions of 1q21.1 have been associated with variable degrees of intellectual disability, and some patients have one or more congenital anomalies, including cataracts and congenital heart disease.32,33,78 The deletion is quite often inherited from one of the patient's parents, who may be only mildly affected or unaffected. Deletions of this region have also been associated with schizophrenia.34,35 Duplications in the same region are also associated with mild-to-moderate intellectual disability and autistic features in some patients.32,33 Although dysmorphic features have been reported in many patients, there is no characteristic constellation of features in the majority of patients. A study involving patients with congenital heart disease suggests an increased frequency of the 1q21.1 duplication in this population as well.36

Another example of a copy-number change with highly variable outcomes is the 16p11.2 deletion. Deletions of 16p11.2 were first identified in patients with autism29,79 and are present in up to 1% of those with autism spectrum disorders, but it is now clear that such deletions are also associated with intellectual disability without autistic features.59-62,80 Deletions of the same region are also associated with early-onset obesity in subjects with and those without developmental delays.63,64 The 16p11.2 deletion is associated with dysmorphic features, but like the 1q21.1 rearrangement, it is not associated with a recognizable constellation of clinical features.

Diagnostic Yield and Recommendations

Several large studies have addressed the overall importance of copy-number changes in the diagnostic workup for intellectual disability, autism, and developmental delays,21,22,81,82 and it is clear that the use of CGH has a higher diagnostic yield than the standard karyotype. The International Standards for Cytogenomic Arrays consortium81 reviewed 33 published studies involving 21,698 patients with developmental delays, congenital anomalies, or autism who were tested for copy-number variants with the use of a chromosome microarray. The diagnostic yield (i.e., the rate of a positive genetic diagnosis) was approximately 12% across the studies. Recently, Cooper and colleagues82 looked at data from 15,767 patients who had undergone array CGH analysis as part of the diagnostic workup. Overall, the authors concluded that about 14% of cases of developmental delay can be explained by a detectable copy-number variation; their study provides a genetic morbidity map of developmental delays resulting from copy-number variations. The current recommendation is to perform chromosome microarray analysis instead of standard karyotype analysis early in the diagnostic workup of children with developmental delays, congenital anomalies, intellectual disability, or autism (Figure 1FIGURE 1

A Diagnostic Algorithm for the Evaluation of a Patient with Intellectual Disability of Unknown Cause.

).81,83

THE GENETICS OF RELATED DISORDERS

Array CGH studies have also been applied to other disorders, many of which are related to and often coexist with intellectual disability and autism. Copy-number changes have been identified that are risk factors for schizophrenia,34,35 epilepsy,43,49,69,84 and attention deficit–hyperactivity disorder (ADHD).70,85,86 There is substantial overlap among the copy-number variations that have been identified in each of these disorders and in cases of intellectual disability and autism. For example, microdeletions of 15q13.3 have been associated with intellectual disability,50,51 autism,52-54 and schizophrenia34,35 and occur with increased frequency in patients with generalized epilepsy43,49,84,87 (Table 1).

Similarly, microdeletions of 1q21 are associated with autism, schizophrenia, and epilepsy and, most commonly, with intellectual disability. Deletions of 16p13.11 were first described in patients with autism and intellectual disability,44,71,88 but studies of epilepsy have shown that the frequency of this deletion is also significantly increased in patients with both generalized and focal forms of epilepsy.43,69,84 Duplications of 16p13.11 have also been associated with an increased risk of a range of neuropsychiatric disorders, including intellectual disability, autism, ADHD, and perhaps schizophrenia.44,71,72,86,89 The range of conditions that have been associated with these and other copy-number changes highlights the fact that these disorders are related and that common genetic factors have a causal role. Therefore, it is likely that etiologic sequence changes will be identified in some of the genes and gene networks that have been implicated in these disorders as well.

SINGLE-GENE CAUSES OF INTELLECTUAL DISABILITY

The advent of family-based genetic linkage studies and DNA sequencing in the 1990s led to the identification of increasing numbers of single genes causing intellectual disability. Many of these studies have been focused on identifying genes on the X chromosome, in part because X-linked forms of intellectual disability can be transmitted through unaffected females in families, allowing pedigree analysis. The most well-known example is the fragile X syndrome, which is caused by dynamic triplet-repeat-expansion mutations in the gene FMR1 and is the most common genetic cause of intellectual disability. Clinical trials are under way to test new therapies for the fragile X syndrome on the basis of the known function of FMR1. Another important X-linked cause of syndromic intellectual disability is mutation in MECP2, encoding methyl-CpG–binding protein 2, in Rett's syndrome (affecting girls). In a recent study, Tarpey and colleagues90 sequenced the exons of 718 genes on the X chromosome in 208 families and identified 9 genes associated with X-linked intellectual disability. Their study, which used standard sequencing methods, provided a foreshadowing of the type of data that are now being generated with higher-throughput methods.

Mutations in more than 90 X-linked genes are now known to cause intellectual disability and account for about 10% of cases.91 Autosomal genes have been more difficult to identify, because there are few familial forms of intellectual disability. Many genetic syndromes for which the causative genes are known are characterized by variable intellectual disability. Some examples include neurofibromatosis, myotonic dystrophy, Duchenne's muscular dystrophy, Noonan-spectrum disorders, and tuberous sclerosis. Many autosomal recessive metabolic disorders are also associated with poor developmental outcomes. However, it is thought that the majority of cases of moderate-to-severe intellectual disability are due to de novo mutations, which cannot be detected by means of linkage mapping. Similarly, single-gene causes of autism have been identified. Most notably, mutations in PTEN are associated with autism and macrocephaly in some patients,92 and mutations in SHANK3 have also been identified.93 As described below, new sequencing approaches are facilitating gene discovery in this previously intractable form of inheritance.

MASSIVELY PARALLEL SEQUENCING

Use in Gene Discovery

Sanger sequencing was introduced in the 1970s94 and has been the mainstay of gene sequence analysis for nearly three decades. The technology is robust and reliable but subject to relatively low throughput. It was used to produce the first complete human genome sequence. In the past several years, the development of next-generation sequencing has revolutionized the field and is likely to deliver the so-called $1,000 genome (on the basis of the anticipated cost). The emerging techniques that are enabling whole-genome sequencing have been reviewed in the Journal 95 and elsewhere.96 Briefly, the method that is now widely used is referred to as massively parallel sequencing, which involves highly parallelized sequence analysis of millions of short DNA fragments from the genome.

Whereas sequence analysis of the first human genome required $3 billion and took more than 10 years, whole-genome sequencing with the use of massively parallel sequencing can be completed in a matter of weeks at a cost of $50,000 or less, and the cost is rapidly decreasing. However, sequencing an entire genome with the use of massively parallel sequencing remains a relatively expensive and time-consuming task, both for humans and for computers. A more tractable approach that is making rapid inroads into the practice of medicine is sequencing of the protein-coding parts of the genome, called exome sequencing. The exome refers to the exons, or coding units, of genes, which comprise approximately 30 million base pairs, or 1% of the entire genome. Exome sequencing is accomplished by selectively capturing the exons with the use of one of several array-based or solution-based methods that are now commercially available. The captured DNA is then sequenced by massively parallel sequencing, and SNPs are identified by comparison with the reference genome.

This approach is attractive for several reasons. First, the majority of disease-causing sequence mutations that have been identified occur in exons. Therefore, it is likely that sequence analysis of the exome will continue to be a successful approach to identifying novel disease genes. Second, it is easier to assign functional and therefore clinical significance to changes in coding sequences (exons) than to changes in noncoding DNA, the function of which is largely unknown. In addition, the human and computer requirements for sequencing and analyzing a patient's exome are currently much more tractable than those for an entire genome, with a cost of approximately $1,000. It must be acknowledged that noncoding mutations (i.e., those that occur in promoters, introns, or other nonexonic sequences) will certainly be found to be important for some disorders, and these mutations will not be detected by exome sequencing.

Several experimental approaches have been successfully used for disease identification by means of exome sequencing (Table 2TABLE 2

Studies Using Massively Parallel Sequencing to Identify Genes Associated with Intellectual Disability and Autism.

and Figure 2FIGURE 2

Three Strategies for Exome Sequencing in Gene Discovery.

). The first approach involves sequencing in several unrelated affected subjects with the same phenotype. The sequence data are then analyzed to identify genes in which all or most affected subjects have a potentially deleterious sequence variant. This approach assumes that the phenotype in all (or most) of the subjects being analyzed is a result of mutations in the same gene. Therefore, this approach has been most successful in subjects with recognizable or fairly homogeneous disorders. The first proof-of-principle experiment was successful on the basis of studies in only four subjects with the Freeman–Sheldon syndrome (also known as the whistling-face syndrome and already known to be caused by mutations in MYH3).103 Subsequently, this strategy has been used to identify the causative gene for the Kabuki syndrome (intellectual disability, facial dysmorphisms, and congenital heart disease caused by de novo mutations in MLL2)97 and the Schinzel–Giedion syndrome (severe intellectual disability, facial dysmorphisms, and multiple congenital anomalies caused by de novo mutations in SETBP1).98

In both the Kabuki and Schinzel–Giedion syndromes, the mutation in the child was not seen in either of the parents, and the de novo occurrence of mutations in clinically similar children is strong evidence of causality. The analysis of trios (i.e., genes from the affected patient and his or her parents) has been a particularly successful approach in interpreting the large volumes of exome sequencing data (Figure 2B). This strategy is used when the patient is expected to have a de novo mutation that is unlikely to be found in either parent's exome. It is predicted that the average newborn will harbor no more than one de novo sequence change that alters an amino acid.104 Therefore, the sequencing of the exomes of an affected child and his or her unaffected parents seems to be an efficient method for identifying de novo disease-causing mutations.

Trio analysis is proving to be an effective means of identifying underlying genetic causes in nonsyndromic intellectual disability as well. Vissers and colleagues99 applied this strategy to 10 cases of nonsyndromic intellectual disability without a family history in order to identify de novo changes. In 6 cases, they identified 9 true de novo variants (in 9 different genes). Two patients each had a de novo mutation in a gene with a known association with intellectual disability. In 4 other cases, patients had a de novo variant in a plausible candidate gene. Although each of the candidate genes that were identified in this study requires further study to confirm its role in intellectual disability, the results indicate that trio analysis is an efficient method of detecting de novo mutations and novel candidate genes. O'Roak and colleagues102 used the trio approach to analyze the exome sequence in 20 children with autism and their unaffected parents. In 4 of the 20 children, the authors found arguably compelling de novo mutations in genes that are known to be involved in brain development (FOXP1, 105 GRIN2B, 106 SCN1A, 107 and LAMC3 108).

Exome sequencing has also been used to identify genes associated with recessive diseases (Figure 2C). The first examples were the diagnosis of congenital chloride diarrhea in a child suspected of having another disorder109 and the identification of the gene causing the Miller syndrome, a craniofacial disorder.110 Several studies have used massively parallel sequencing to investigate autosomal recessive intellectual disability. In a large consanguineous family with multiple affected children, Calişkan and colleagues101 sequenced the exomes of the parents to look for heterozygous deleterious mutations within a 2-Mb linkage region. They identified a mutation in TECR that was homozygous in all affected children. Recently, Najmabadi and colleagues100 investigated autosomal recessive intellectual disability in 136 consanguineous families. Because they had linkage data for the families that narrowed the genomic regions of interest, they captured the subset of exons within linkage regions for each family instead of sequencing the entire exome. They found mutations in 23 known intellectual-disability genes in 26 families, providing a definitive diagnosis. In the remaining families, they identified 50 novel candidate genes, each with a homozygous mutation in a single family. Clearly, these candidate genes need to be validated in additional samples, but the study provides a framework for evaluation of recessive forms of intellectual disability.

The value of exome sequencing in the identification of novel gene mutations has been endorsed by the National Institutes of Health, which announced in December 2011 that it will provide $48 million during the next 4 years to three centers for the sequencing of exomes and genomes of persons who have rare disorders with causes that are still unknown (http://mendelian.org).

Use in Clinical Diagnostics

Next-generation sequencing has already moved into clinical diagnostic laboratories. Several laboratories now offer gene panels in which a set of known disease genes (rather than the whole exome) is captured and subjected to massively parallel sequencing. This approach provides simultaneous evaluation of multiple genes rather than the current gene-by-gene analysis that is often required in the clinic. For example, it is now possible to order an X-linked intellectual-disability panel that includes 30, 60, or 90 genes. Exome sequencing is moving very quickly into the clinical arena and is now offered by at least two clinical laboratories at a cost of approximately $10,000 for data generation and interpretation of results.

Although clinical exomes are likely to yield answers in some cases, it will be important to proceed cautiously with careful selection of patients. The studies described above and listed in Table 2 represent the success stories. However, there are challenges in interpreting exome data, and in the studies published to date, not every case has been solved. Each individual exome harbors approximately 20,000 sequence variants as compared with the human reference genome, including some 5000 variants that will affect protein sequence and could be considered potentially deleterious. The variants can be further filtered to exclude those reported in SNP databases or in control exome studies. Once these criteria are applied, each person generally carries 100 to 200 heterozygous private sequence variants that are potentially deleterious, as well as several genes that have potentially damaging recessive mutations. Careful follow-up of individuals and families and studies in additional patients will be necessary to interpret the clinical significance of many of the variants identified by exome sequencing.

SUMMARY

Chromosome microarrays and next-generation sequencing have revolutionized gene discovery in intellectual disability, autism, and other disorders. Chromosome microarray analysis, which is recommended as a first-line test in the genetic workup of children with intellectual disability, developmental delays, autism, or congenital anomalies, provides a molecular diagnosis in 15 to 20% of cases. Exome sequencing has proved to be successful in the research laboratory and is moving rapidly into the diagnostic laboratory. As the data continue to accumulate, our understanding of genes, pathways, and molecular mechanisms will continue to evolve and translate into better diagnosis, prognosis, and therapies for these severe disorders.

CHROMOSOME MICROARRAYS

Array comparative genomic hybridization (CGH): Array CGH is a comparative assay in which DNA from the patient is fluorescently labeled with one fluorescent dye and DNA from a healthy control subject (reference DNA) is labeled with a second fluorescent dye. The samples are cohybridized to an array containing known DNA sequences called probes. The fluorescence intensity of each dye at each spot is measured. Differences in relative fluorescence intensities at a given spot on the array reflect differences in copy number between the genome of the patient and that of the reference DNA. The size of the copy-number change that can be identified by this method varies according to the number and spacing of probes on the array.

Single-nucleotide-polymorphism (SNP) genotyping array: A SNP is a site in the genome at which two different alleles are present in the general population, often referred to as the A allele and the B allele. SNP genotyping arrays are fluorescence-based assays in which the A allele is tagged with one fluorescent dye and the B allele is tagged with another. Analysis of SNP array data includes measurement of the total fluorescence intensity for a site and calculation of the ratio of the fluorescence intensities for the two dyes. At each site, most subjects will have one of three genotypes, or combinations of alleles: AA, AB, or BB. If there is a deletion, the total fluorescence intensity will be lower and the subject will have only one allele (e.g., A−) at all SNP sites within the deleted region. Duplications are represented by an increased total fluorescence intensity and altered ratio of alleles: AAA, AAB, ABB, or BBB. Because SNP arrays provide genotype information, they can also be used to identify large stretches of homozygosity in the genome, which can represent consanguinity or uniparental disomy, neither of which is detectable by means of array CGH.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

2012-04-09 01:19
共通テーマ：日記・雑感

Adjunctive Antidepressant Treatment for Bipolar Depression

Sachs et al. (April 26 issue)1 report that adding an adjunctive antidepressant drug offers no benefit over continued mood-stabilizer monotherapy in the treatment of bipolar depression. This finding contradicts some previous studies and the experience of many clinicians. In his thoughtful accompanying editorial, Belmaker2 identifies possible reasons for this discrepancy, including diagnostic heterogeneity and changes in the manifestation of bipolar disorder during the past 20 years. These observations are perhaps too circumspect.

The past two decades have seen a marked increase in the diagnosis of bipolar disorder by North American psychiatrists.3 This trend has many origins: a reaction to past underdiagnosis, a belief that this disorder is more treatable and less stigmatizing than some alternative diagnoses, and an insufficiently critical application of the diagnostic criteria of the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV), as well as a genuine conviction on the part of some authorities that this is indeed a widely prevalent condition.4 More recently, direct-to-consumer advertising by pharmaceutical companies has exacerbated the trend. To the extent that the diagnostic boundaries of bipolar disorder are allowed to expand, the benefits of specific pharmacologic treatments are likely to decline.

2012-04-09 01:10
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androgen-deprivation therapy can cause major depression

In their review article, Belmaker and Agam (Jan. 3 issue)1 examine several mechanisms involved in depressive disorders, but they do not mention evidence that androgen-deprivation therapy, which is frequently used in the management of prostate cancer, can cause major depression.2 The mechanisms underlying this association may include loss of sexual potency, fatigue, cognitive impairment, and changes in body composition, which lead to deterioration of a patient's perception of his body.3 A direct effect of testosterone, however, cannot be ruled out. A cross-sectional study of the relation between testosterone levels and depressive symptoms in 856 community-dwelling older men showed that depression was inversely associated with bioavailable testosterone independently of age, weight change, and physical activity.4 Bioavailable estradiol was not associated with depressed mood.

2012-04-09 01:01
共通テーマ：日記・雑感

自分撮り　take a picture of yourself instead of writing a diary

治療の一部として日記を書くことはしばしばあるのだけれど
現在であれば、例えば、朝身支度をして出かけようとするときに
自分の姿を写真にとって
自分の身繕いとか表情を確認するという方法も
悪くないのではないかと思う

ーーーーー

しばしば患者は日記を書く。日記は治療の一部である。

現在、例えば、朝身支度をして出かけようとするときに

自分の姿を写真にとることが自分の表情と身繕いと確認する方法としてよい

Patients often write a diary. Diary is part of the treatment.

Currently, for example, when trying to get dressed to go out morning,

it is good as a way to take a picture of yourself and to make sure your facial expression and grooming.

2012-04-08 11:12
共通テーマ：日記・雑感

SmaPG理論

最近いくつかまとめたので
参考に
smapgはスマップ・ジーと読んで、
Stress Management Power Group　の略です。わたしたちのことです。

最近発表したものとしては

　『こころの科学』　ネット社会とこころの悩みとＤＡＭ理論今　　忠　2009
　 http://shinbashi-ssn.blog.so-net.ne.jp/2009-05-21

　英文　My Original Theory-1 DAM　Theory in English　(Depressive-Anankastic-Manic Cells Theory :Conprehensive 　　biological theory for manic depressive disorder ,mood disorder and premorbid character traits) 　　　　　　　　　　　　　　
http://shinagawasn.blog.so-net.ne.jp/2011-10-18-1

　『うつ病治療ハンドブック-診療のコツ』　共著　大野裕編　「統合失調症とうつ」今忠・原田誠一　2011　 http://shinagawa-lunch.blog.so-net.ne.jp/2010-01-21-3

　英文　My Original Theory-2: Pathological Hypothesis of Schizophrenia:
　First/Second World Model, Time-delay　Hypothesis,Temporal profiles of Neurons

　　http://shinagawasn.blog.so-net.ne.jp/2011-12-24-6

躁状態先行仮説：気分障害再考
http://shinagawasn.blog.so-net.ne.jp/2011-07-17-1

「統合失調症とうつ」

イメージ空間測定法

自我障害の話　smapg-time-delay model

http://shinbashi-ssn.blog.so-net.ne.jp/2008-05-04

http://shinbashi-ssn.blog.so-net.ne.jp/2008-05-09-1

嗜癖
http://shinbashi-ssn.blog.so-net.ne.jp/2008-05-30-1

感覚の能動性と脱能動性
http://shinbashi-ssn.blog.so-net.ne.jp/2008-05-30-3

中心感覚と辺縁感覚
http://shinbashi-ssn.blog.so-net.ne.jp/2008-05-30-4

ハリネズミのたとえ
http://shinagawa-lunch.blog.so-net.ne.jp/2010-12-03-7

アンビバレントの汎化
http://shinagawa-lunch.blog.so-net.ne.jp/2011-02-13-8

SMaPG式性格類型の提唱
http://shinagawa-lunch.blog.so-net.ne.jp/2010-11-25-14

2012-04-08 01:33
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My Original Theory-2: Pathological Hypothesis of Schizophrenia: First/Second World Model, Time-delay Hypothesis, Temporal profiles of Neurons

Tadashi Kon(Shinagawa Psychosomatic medicine Clinic)

〒108-0075　2-14-10-10F　Kounan,Minato-Ku,Tokyo,Japan

In this section, the pathological hypotheses studied by Dr. Kon are introduced in

order to explain (1)the process from ARMS to onset of schizophrenia,

(2)disturbances of ego characteristic of schizophrenia,

(3)depressive moods seen with schizophrenia.

First, a pathological model of the process from ARMS to onset of

schizophrenia will be explained. What a person considers to be proper

interpersonal-distance is thought to be relative to the sensitivity of his dopamine receptors.

If a person is sensitive to dopamine, he may tend to take larger interpersonal-distances.

Some people are sensitive to dopamine from birth (for example,

those who possess excessive dopamine receptors), and they have sensitive traits

when coping with the world and others. Even if

they have the same experiences as others, they tend to release

excessive dopamine which makes them suffer. As a result, they tend to

select a lifestyle that involves fewer interpersonal relationships.

In a life in which they tend to be solitary, they may

become familiar with the arts, nature, and animals. In this way, they

grow up with sensitiveness to dopamine and they acquire a lifestyle that

helps them avoid the onset of schizophrenia. However, in adolescence, living

conditions change greatly. “They are given roles and

assignments that require interpersonal relationships,”

“they become sexually mature,” and “they are placed in situations that require more assertiveness and responsibility” etc..

Life and interpersonal relationships become increasingly complicated,

and they come to the point where their withdrawal strategy is no longer sufficient.

In the midst of this, strongly stressful situations related to “sexual affairs,

money, honor, and health” cause excessive dopamine to be emitted, and combined with high sensitivity to dopamine, they face the crisis of the onset of

schizophrenia. In addition, it is easy to predict these kinds of crises exist prior

to the obvious onset. Psychotic-like experiences (PLEs, later ARMS :

at risk mental state), which are attracting attention recently,

possibly correspond to these situations.

Next is the pathological hypothesis of disturbances of the ego, which is

specific to schizophrenia. The animal's nervous system, in general, forms the loop of (1)reception of stimulation at the sensory organ→(2)conditional reaction in the

brain→(3)reaction through motor system, autonomic nervous system, etc.

→(4)real outcomes→(5)reception of stimulation at the sensory organ.

Since there is no part to confirm the generation of self-consciousness in this loop,

the sense of active control of the ego , an obvious experience in humans,

cannot be explained.

“The first world model” and “the second world model” hypothesis is introduced

here, for further discussion. For humans, “the first world model” is the same process of “(1)reception of stimulation through

the sensory organ→(2)conditional reaction in the brain→(3)reaction through motor

system, autonomic nervous system, etc.,” as for other animals.

In addition, humans have “the second world model” in

the brain concurrently, and two kinds of signals from “the first world

model” and “the second world model” are compared. When there are

differences, “the second world model” will be modified to coincide with “the first world

model”. The function of “the second world model” to compare and transcribe the

“the first world model” resembles that of cerebellum transcribing kinetic

signals of cerebrum during exercise.

Further hypothesis is that a time lag exists between the two outputs from “the first

world model” and “the second world model,” and output from “the second

world model” is always begin adjusted so that it reaches the place where comparison is made slightly earlier (than the first world model). Sense of active

control and sense of self in behavior, that is to say,

formation of ego-consciousness can be explained by this time-delay

hypothesis. For example, although the two compulsive computers give

almost the same conclusions, the second evolutionary newer computer

gives the answer slightly earlier and the older one reaches the same

conclusion afterwards. This time-delay generates the sense of active

control and the sense of self that humans experience.

Basically, “the first world model” is good enough for humans to live (as

other animals), but the appearance of “the second world model” generated

self-consciousness, which is the fundamental feature of humans.

Because self-consciousness has been generated at the latest stage

of the evolution, it can be easily destroyed. When self-consciousness breaks down,

the following are seen according to the Jacksonism principle; “negative symptoms of schizophrenia triggered by the break down,” and “positive symptoms

caused by the loss of inhibition”.

Humans can confirm the existence of ego-consciousness because they

express their inner world through words, and other animals (to varying degrees by species) are assumed to have gained some similar mechanisms through the evolutionary process as well. Although animals cannot express themselves clearly, it is possible for them to have a sense of active control and a sense of self.

People also behave unconsciously, when they are out of mind (for

example, people pass through the train station ticket gate without being conscious

of it). This is a situation in which signals from “the second world

model” are weak and, so to say, the brain is nearly in the “automatic-drive” state.

In addition, when people are concentrating intensely and showing

their highly proficient skills, signals of “the second world model” perfectly

coincide with those of “the first world model,” and by contrast,

signals from “the second world model” sometimes feel as if they are being

blocked out. People describe this situation using words such as “I did it

without thinking about it,” “as if in a dream,” ”my body

reacted automatically,” etc. Based on the “time-delay hypothesis,” free

will is an illusion, and disturbance of ego is an experience (filled with

pain) that is generated when illusion is lost. There are many theses

on “rivet experiment,” a passive-consciousness hypothesis, which　is

related to this discussion.

Come to think of it, signals transmitted from each sensory

organ do not reach the brain’s processing site simultaneously.

But the arrival time is supposed to be adjusted to be simultaneous, and thus

a subjective real world is composed. In that case, processing sites

that adjust the time-lag of signals arriving from each sensory organ

are considered to exist in the brain. Similarly, it should

be possible to assume there are sites in the brain, where the signals from

“the first world model” and “the second world model” are compared, and

the time adjusted. Also, it is assumed that trouble at these

sites will cause a disturbance of ego.

When the output from “the second world model” arrive after those of

“the first world model,” the disturbance of ego occurs. According to the

amount and sort of delay, they can be “passivity experiences

(experiences controlled by others), part of obsessive-compulsive

experiences, auditory hallucinations, autochthonous ideas,” and so on.

As for autochthonous ideas, arrival of both output are assumed to be

almost simultaneous. These situations are the first stages of

schizophrenia. For example, auditory hallucinations are explained as

follows; when the contents of what the person wants to say, which are

output of “the second world model,” arrive after those of “the

first world model,” they are perceived as “others are talking” or

“made to listen to.”

Next hypothesis is that “the dopamine antagonist delays the output

of ‘the first world model’ and ‘the second world model’ each to a

different extent because of its pharmacological traits”.

Antipsychotic drugs delay the output of “the first world model”,

but it is assumed to delay those of “the second world model” only

slightly or not at all. This hypothesis would be able

to explain the mechanism of how medicines cure the disturbance of ego.

As facts concerning time-delay hypothesis and medicines’ effects, it

is possible to state the different effects of medicine on the mesolimbic

system and the mesolimbic-cortical system, or to give examples of

different effects to the prefrontal area. For example, aripiprazole is

said to inhibit dopamine at the mesolimbic system and increase it at the

mesolimbic-cortical system; it is possible to explain the medicinal

effect using time-delay hypothesis. As seen in the above discussion,

if we suppose the dopamine system has some role at the site in the brain

where two signals from the first and second world model are compared,

time-delay hypothesis combines with dopamine hypothesis.

As to the last theme, that is, a hypothesis on symptom of depression, localization of

the pathology is not adopted, and a patient’s condition is considered in

terms of neurons’ temporal profile. There might be a localized symptom of

depression caused by a certain site in the brain, but true mechanism is not

clear. The symptoms of depression in the course of schizophrenia can be seen

through all the stages from ARMS to far advanced stage to residual

phase. Usually, depression of ARMS and residual phase is related to

the negative symptoms of schizophrenia, and depression of far advanced stage

is related to the positive symptoms. Examined more precisely,

it is possible to understand as follows; at ARMS, people recognize

their sensitiveness and understand the differences between the world

and themselves at least to some extent, so they think it is dangerous

to express their inner selves without defense; they become passive in

relationships with others in order to avoid being hurt. This extends

to the symptoms of depression at ARMS. You may say, excessive caution resembles

depression. The symptom of depression, at the latter

stage of residual phase, also assumes the same mechanism.

On the other hand, at the far advanced stage of schizophrenia, the

patients are forced to face completely uncommon experiences,

and they experience serious damage and loss of ego.

Neurological mechanism of the symptoms of depression that

occurs at this stage isn’t clear yet. When the acute phase of

schizophrenia is calmed down by an antipsychotic drug, symptoms of

depression also improve. Therefore, the dopamine system tends to be

considered as a contributing factor to depression. However, it is

better understood as a result of sharply blocking increased dopamine at the receptors’ level. So, the sharply increased dopamine is

assumed to trigger symptoms of depression. At the same time,

symptoms of apathy, which occurs along with Parkinson’s disease, are

well known as resembling the symptoms of depression. This is one example of

symptoms of depression accompanied by a decrease in dopamine. Once the

localization of pathology is clarified, it might be possible to propose a hypothesis

that explains these contradicting movements of the dopamine system.

This hypothesis best explains depressive symptoms in the early residual

phase. There, the mechanism that is common to the depressive symptoms

of bipolar disorders is assumed. “A group that responds to repeated

stimulation with increasing reactions” is assumed as a trait of brain neuron cells.

Because in the case of acute phase of schizophrenia and

bipolar disorders maximum stimulation is given to neurons,

the function of “a group which responds to repeated stimulation with

increasing reactions” is possible to break down.

The depressive symptom is supposed to start from here.

From this point of view, the depressive symptoms of schizophrenia

and bipolar disorders are classified into two categories; that is (1)results of

functional breakdown of “a group which responds to repeated

stimulation with increasing reactions,” and the breakdown is triggered

by excessive stimulation; (2)pathology of endogenous origin and positive

onset of depression. Dr. Kon’s hypothesis supposes the former symptoms．

In the case of medical treatment, medicine relevant to the dopamine

system are good for symptoms relating to time-delay, and medicine

relevant to the serotonin system are effective in aiding recovery of exhaustion

depression. When cognitive-behavioral therapy mainly works on

behavioral aspects, the target of therapy is “the first world

model” in the above hypothesis. Whereas, interventions that emphasize cognitive modification mostly target “the second world

model,” and through them attempts are made to alter “the first world model.”

If therapists become very aware of whether to approach “the first

world model” through behavior or to get closer to “the second world

model” through cognition, there may be clinical merits.

If patients understand the above hypothesis through psychoeducation,
the therapeutical effect of cognitive-behavioral therapy

for their schizophrenia may increase.

On the other hand, SST tries to change “the first world

model” through behavior, of which the effect modifies “the second

world model,” resulting in desirable change in cognition.

2012-04-08 01:31
共通テーマ：日記・雑感

My Original Theory-1 DAM　Theory in English　(Depressive-Anankastic-Manic Cells Theory :Conprehensive biological theory for manic depressive disorder ,mood disorder and premorbid character traits)

My Original Theory-1

DAM　Theory　(Depressive-Anankastic-Manic Cells Theory :Conprehensive biological theory for manic depressive disorder ,mood disorder and premorbid character traits)

Tadashi Kon(Shinagawa Psychosomatic medicine Clinic)

〒108-0075　2-14-10-10F　Kounan,Minato-Ku,Tokyo,Japan

1. DAM Cells :Enthusiasm, regularity and the persistence of negative mood are biological indexes

When we assume chronic continued stress to a neuron, three types of neurons are predictable according to the responses to the repeated stimulation.

First, there are neurons whose reaction speed gets gradually faster, such as neurologic kindling (epilepsy) and hysteresis (schizophrenia). I call these types of neurons M (Manic) neurons as they relate to the manic state. They also relate to enthusiasm, excitement (hyperthymia), and energy.

Secondly, there are neurons that always react steadily to the repeated stimulation.

I call these types of neurons A (Anankastic) neurons. A neurons are an element of regularity.

Thirdly, there are neurons whose response to the repeated stimulation rapidly diminishes. I call these types of neurons D (Depressive) neurons because they relate to the duration and weakness of the negative mood. The majority of the human brain neurons are considered to be this D type.

2. DAM Theory : the onset mechanism of depression

When M neurons respond more and more actively to the recurrent sustained stress, the body is in a manic state. When M neurons burn out and stop functioning, D neuron traits emerges, and the body is now in a state of depression. Once M neurons recover from the damage after a sufficient interval, they restart their activities and become in a manic state again. Repetition of this procedure creates symptoms of bipolar disorders. I think that depression doesn’t exist alone. It is always accompanied by a manic state where M neurons are activated, at least immediately before the depression, no matter how subtle the manic state is. The obsession element of A neurons appears and disappears because the obsession comes to the foreground and recedes into the background according to the state of bipolar disorder. When M neurons cease to function and A-type neurons are enough in number, the obsession comes to the foreground instead of depression. If we assume that M neurons are related to circadian rhythm, insomnia and diurnal change (depressive mood and inhibition are strongest in the early morning and remit in the afternoon to the evening) are explained by the lack of M neurons’ element.

3. Explanation of Premorbid Character

Quantity and distribution of M, A, and D neurons in the brain explain part of premorbid characters.　Intermediate types of the three types will exist and they construct a continuous spectrum.

(1) 　Brains with high M neuron elements are enthusiastic, having characters of bipolar and cyclothymia. BP (Bipolar mood disorder) Ⅰ and Ⅱ　belong to this type. BPⅠ consists of a manic state and depressive mood; BPⅡ consists of a hypomanic state and depressive mood. One affected by bipolar disorder with a premorbid character as cycothymia belongs to this type. The immature form of depression is for immature and narcissistic cyclothymia,　and is usually an early-onset type. It is difficult to distinguish the immature form of depression from personality disorders. Avoidant depression is also close to this type.

　When the society itself is in a hypomanic state, that of BPⅡwill be hidden.　From the Meiji era to the high economic growth period, BPⅡ were diagnosed as single episodes of major depressive disorder. Madness towards the war and the devotion to company organizations probably belonged to a hypomanic state. Good adaptation often turns out to be a hypomanic state.

(2) 　Brains with significantly more A neuron elements than M neuron elements are regular and have strong compulsive elements. Typus melancholicus, premorbid character of melancholic type depression, belongs to this type. While A neurons are responding to repeated stimulations, compulsive tendencies are presented. After A neurons get too tired, they cease to function. At that time, usually,　M neurons are also too tired and resting, and they are in a depressive mood. If M neurons recover quickly, mixed episodes of manic-depressive are shown. Retreat neurosis is close to this type.

Tardy and nonchronic type of atypical depression is close to the melancholic type. Premorbid character of juvenile-onset chronic type of depression has not been clearly explained yet. Beard type depression is said to occur in the narcissistic immature type character when the office (workplace) is melancholic (where perfection is required of workers).

(3) 　Brains with relatively few M neuron elements and A neuron elements possess weak characters without strong enthusiasm nor regularity. People with modern weak characters have lost self-confidence superficially, but mostly hold on to exaggerated egos inside them. Sometimes exposure of that exaggerated ego is observed. That is, it is not a unilateral weakness, and it strongly possesses a narcissistic element most of the time. It is a combination of weakness and immature narcissism. When it becomes depression, one may call it an immature narcissistic type of weak character type depression. However in DSM it is close to dysthymic disorder(long lasting mild depressive tendency) as the symptom of the first, Ⅰ axis, and it is close to dysthymia-affinity-depression among modern types of depression.

(4) 　Brains with plenty of M neuron elements and A neuron elements show immodithymic characters with strong enthusiasm and regularity. According to the temporal profile of functional breakdown and recovery of both elements, manic, depressive, mixed episodes of manic-depressive, and further mixed episodes with compulsive tendency are observed. It is difficult to distinguish from personality disorders, if one onsets around 20 years old.

2012-04-08 01:30
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