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双極性障害

著者: 寺尾 岳 大分大学

監修: 上島国利 昭和大学

著者校正/監修レビュー済:2021/02/24
参考ガイドライン:
  1. 日本うつ病学会日本うつ病学会治療ガイドライン Ⅰ. 双極性障害 2020
  1. Canadian Network for Mood and Anxiety Treatments (CANMAT:カナダ気分障害不安障害治療ネットワーク) and International Society for Bipolar Disorders (ISBD:国際双極性障害学会) : Yatham LN, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) 2018 guidelines for the management of patients with bipolar disorder. Bipolar Disord. 2018 Mar;20(2):97-170.
  1. International College of Neuro-Psychopharmacology(CINP:国際神経精神薬理学会):Fountoulakis KN, et al. The International College of Neuro-Psychopharmacology (CINP) Treatment Guidelines for Bipolar Disorder in Adults (CINP-BD-2017), Part 3: The Clinical Guidelines. Int J Neuropsychopharmacol. 2017 Feb 1;20(2):180-195.
患者向け説明資料

概要・推奨   

  1. 双極性障害の発症は10歳代後半が最も多い。
  1. 双極性障害はうつ病の時期が長い。
  1. 再発回数が10回を超える患者には、リチウムは抗躁効果を発揮しにくい(推奨度2)。
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となり
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要と
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要と
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要
  1. 閲覧にはご契約が必要となります。閲覧
薬剤監修について:
オーダー内の薬剤用量は日本医科大学付属病院 薬剤部 部長 伊勢雄也 以下、林太祐、渡邉裕次、井ノ口岳洋、梅田将光による疑義照会のプロセスを実施、疑義照会の対象については著者の方による再確認を実施しております。
※薬剤中分類、用法、同効薬、診療報酬は、エルゼビアが独自に作成した薬剤情報であり、
著者により作成された情報ではありません。
尚、用法は添付文書より、同効薬は、薬剤師監修のもとで作成しております。
※薬剤情報の(適外/適内/⽤量内/⽤量外/㊜)等の表記は、エルゼビアジャパン編集部によって記載日時にレセプトチェックソフトなどで確認し作成しております。ただし、これらの記載は、実際の保険適用の査定において保険適用及び保険適用外と判断されることを保証するものではありません。また、検査薬、輸液、血液製剤、全身麻酔薬、抗癌剤等の薬剤は保険適用の記載の一部を割愛させていただいています。
(詳細はこちらを参照)
著者のCOI(Conflicts of Interest)開示:
寺尾 岳 : 講演料(エーザイ,大塚,武田,大日本住友),研究費・助成金など(サントリー食品インターナショナル)[2021年]
監修:上島国利 : 原稿料(大日本住友製薬)[2021年]

改訂のポイント:
  1. 定期的レビューと最近のガイドラインの呈示を行い、双極性障害抑うつエピソード治療薬としてルラシドン(ラツーダ)の追加を行った。

病態・疫学・診察

疾患情報  
  1. 双極性障害は、躁病ないし軽躁病とうつ病を生じる気分障害である。躁病エピソードのある双極Ⅰ型障害、軽躁病エピソードのある双極Ⅱ型障害から構成されるが、
  1. 双極Ⅱ型障害は、単極性うつ病との鑑別が必ずしも容易でない。
  1. 再発する可能性が高い。
  1. うつ病エピソードの期間が長い。
  1. 軽躁エピソードは把握しにくい。
  1. 躁病エピソードは社会的な破たんにつながる。
  1. 10歳代後半の発症が最も多い。
  1. 自殺のリスクが高い。
  1. 認知症に移行するリスクもある。
 など、診療に困難を伴うことが多い。
  1. 双極Ⅰ型障害の診断には躁病エピソードの存在が必要となり、双極Ⅱ型障害には軽躁病エピソードとうつ病エピソードの存在が必要となるが、診断の項にDSM-5の躁病エピソードと軽躁病エピソードの診断基準を示す( >詳細情報 )。最近は、このような双極性障害の概念をさらに広くとる双極スペクトラムの考え方が浸透しつつある。
 
  1. 双極性障害はうつ病の時期が長い。(参考文献:[1][2]
  1. まとめ:双極性障害ではⅠ型もⅡ型もうつ病の時期が長い。
  1. 研究事例:双極Ⅰ型障害とⅡ型障害を10年以上追跡し、その期間における気分エピソードを調査したところ、いずれもうつ病エピソードの期間が長く、Ⅰ型では1/3、Ⅱ型では1/2を占めた。
  1. 結論:双極性障害はうつ病の期間が長く、躁病や軽躁病の時期は短い。
 
双極型障害患者の長期予後

双極性Ⅰ型障害もⅡ型障害もうつ病の期間が長い。

出典

img1:  The long-term natural history of the weekly symptomatic status of bipolar I disorder.
 
 Arch Gen Psychiatry. 2002 Jun;59(6):530-・・・
img2:  A prospective investigation of the natural history of the long-term weekly symptomatic status of bipolar II disorder.
 
 Arch Gen Psychiatry. 2003 Mar;60(3):261-・・・
 
  1. 双極性障害の発症は10歳代後半が最も多い(推奨度1)。(参考文献:[3]
  1. まとめ:双極性障害は10歳代後半に最も多く発症する。
  1. 研究事例:双極Ⅰ型障害とⅡ型障害の発症年齢を検討した7つの研究をまとめたものである。
  1. 結論:双極性障害は男女ともに10歳代の発症が最も多い。
 
7試験の双極Ⅰ型障害および双極Ⅱ型障害患者における発症年齢(歳)分布

 
  1. 双極性障害の一部は認知症へ移行する(推奨度2)。(参考文献:[4]
  1. まとめ:精神疾患のなかで、最も認知症へ移行しやすいのは、双極性障害である。
  1. 研究事例:デンマークで30歳代に精神科を受診した患者すべてを医療登録制度のデータセットを利用してフォローした結果、認知症の発症率が最も高いのは双極性障害で、単極性うつ病、統合失調症、神経症と続き、これは男女ともに同じ傾向であったが、女性のほうが認知症への移行率が男性よりも多かった。
  1. 結論:双極性障害の患者は男女を問わず認知症へ移行しやすい。
 
30歳で認知症を併存していなかった精神科患者が認知症を発症する割合

a:男性 b:女性

出典

問診・診察のポイント  
  1. 軽躁病エピソードと躁病エピソードの違いを下記の表に示すが、最も異なる点は、躁病エピソードは機能を大きく損なうが、軽躁病エピソードは若干障害する程度で、むしろ機能が改善されることもある。

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文献 

著者: Lewis L Judd, Hagop S Akiskal, Pamela J Schettler, Jean Endicott, Jack Maser, David A Solomon, Andrew C Leon, John A Rice, Martin B Keller
雑誌名: Arch Gen Psychiatry. 2002 Jun;59(6):530-7.
Abstract/Text BACKGROUND: To our knowledge, this is the first prospective natural history study of weekly symptomatic status of patients with bipolar I disorder (BP-I) during long-term follow-up.
METHODS: Analyses are based on ongoing prospective follow-up of 146 patients with Research Diagnostic Criteria BP-I, who entered the National Institute of Mental Health (Bethesda, Md) Collaborative Depression Study from 1978 through 1981. Weekly affective symptom status ratings were analyzed by polarity and severity, ranging from asymptomatic, to subthreshold levels, to full-blown major depression and mania. Percentages of follow-up weeks at each level as well as number of shifts in symptom status and polarity during the entire follow-up period were examined. Finally, 2 new measures of chronicity were evaluated in relation to previously identified predictors of chronicity for BP-I.
RESULTS: Patients with BP-I were symptomatically ill 47.3% of weeks throughout a mean of 12.8 years of follow-up. Depressive symptoms (31.9% of total follow-up weeks) predominated over manic/hypomanic symptoms (8.9% of weeks) or cycling/mixed symptoms (5.9% of weeks). Subsyndromal, minor depressive, and hypomanic symptoms combined were nearly 3 times more frequent than syndromal-level major depressive and manic symptoms (29.9% vs 11.2% of weeks, respectively). Patients with BP-I changed symptom status an average of 6 times per year and polarity more than 3 times per year. Longer intake episodes and those with depression-only or cycling polarity predicted greater chronicity during long-term follow-up, as did comorbid drug-use disorder.
CONCLUSIONS: The longitudinal weekly symptomatic course of BP-I is chronic. Overall, the symptomatic structure is primarily depressive rather than manic, and subsyndromal and minor affective symptoms predominate. Symptom severity levels fluctuate, often within the same patient over time. Bipolar I disorder is expressed as a dimensional illness featuring the full range (spectrum) of affective symptom severity and polarity.

PMID 12044195  Arch Gen Psychiatry. 2002 Jun;59(6):530-7.
著者: Lewis L Judd, Hagop S Akiskal, Pamela J Schettler, William Coryell, Jean Endicott, Jack D Maser, David A Solomon, Andrew C Leon, Martin B Keller
雑誌名: Arch Gen Psychiatry. 2003 Mar;60(3):261-9.
Abstract/Text BACKGROUND: This is the first prospective longitudinal study, to our knowledge, of the natural history of the weekly symptomatic status of bipolar II disorder (BP-II).
METHODS: Weekly affective symptom status ratings for 86 patients with BP-II were based on interviews conducted at 6- or 12-month intervals during a mean of 13.4 years of prospective follow-up. Percentage of weeks at each symptom severity level and the number of shifts in symptom status and polarity were examined. Predictors of chronicity for BP-II were evaluated using new chronicity measures. Chronicity was also analyzed in relation to the percentage of follow-up weeks with different types of somatic treatment.
RESULTS: Patients with BP-II were symptomatic 53.9% of all follow-up weeks: depressive symptoms (50.3% of weeks) dominated the course over hypomanic (1.3% of weeks) and cycling/mixed (2.3% of weeks) symptoms. Subsyndromal, minor depressive, and hypomanic symptoms combined were 3 times more common than major depressive symptoms. Longer intake episodes, a family history of affective disorders, and poor previous social functioning predicted greater chronicity. Prescribed somatic treatment did not correlate significantly with symptom chronicity. Patients with BP-II of brief (2-6 days) vs longer (> or =7 days) hypomanias were not significantly different on any measure.
CONCLUSIONS: The longitudinal symptomatic course of BP-II is chronic and is dominated by depressive rather than hypomanic or cycling/mixed symptoms. Symptom severity fluctuates frequently within the same patient over time, involving primarily symptoms of minor and subsyndromal severity. Longitudinally, BP-II is expressed as a dimensional illness involving the full severity range of depressive and hypomanic symptoms. Hypomania of long or short duration in BP-II seems to be part of the same disease process.

PMID 12622659  Arch Gen Psychiatry. 2003 Mar;60(3):261-9.
著者: L V Kessing, E W Olsen, P B Mortensen, P K Andersen
雑誌名: Acta Psychiatr Scand. 1999 Sep;100(3):176-85. doi: 10.1111/j.1600-0447.1999.tb10843.x.
Abstract/Text OBJECTIVE: The aim of the study was to investigate whether patients with affective disorder have increased risk of developing dementia compared to other groups of psychiatric patients and compared to the general population.
METHOD: In the Danish psychiatric central register, 3363 patients with unipolar affective disorder, 518 patients with bipolar affective disorder, 1025 schizophrenic and 8946 neurotic patients were identified according to the diagnosis at the first ever discharge from psychiatric hospital during the period from 1970 to 1974. The rate of discharge diagnosis of dementia on readmission was estimated during 21 years of follow-up. In addition, the rates were compared with the rates for admission to psychiatric hospitals with a discharge diagnosis of dementia for the total Danish population.
RESULTS: Patients with unipolar and with bipolar affective disorder had a greater risk of receiving a diagnosis of dementia than patients with schizophrenia and those with neurosis. All groups of patients had a higher risk of being given a diagnosis of dementia than gender- and age-matched samples of the general population.
CONCLUSION: Patients with affective disorder appear to be at increased risk of developing dementia.

PMID 10493083  Acta Psychiatr Scand. 1999 Sep;100(3):176-85. doi: 10.1・・・
著者: A C Swann, C L Bowden, J R Calabrese, S C Dilsaver, D D Morris
雑誌名: Am J Psychiatry. 1999 Aug;156(8):1264-6.
Abstract/Text OBJECTIVE: The authors investigated the relationship between number of lifetime episodes of affective disorder and the antimanic response to lithium, divalproex, or placebo.
METHOD: The subjects were 154 of the 179 inpatients with acute mania who entered a 3-week parallel group, double-blind study. The primary efficacy measure was the manic syndrome score from the Schedule for Affective Disorders and Schizophrenia. The relationship between improvement and number of previous episodes was investigated by using nonlinear regression analysis.
RESULTS: An apparent transition in the relationship between number of previous episodes and response to antimanic medication occurred at about 10 previous episodes. For patients who had experienced more episodes, response to lithium resembled the response to placebo but was worse than response to divalproex. For patients who had experienced fewer episodes, however, the responses to lithium and divalproex did not differ and were better than the response to placebo. This differential response pattern was not related to rapid cycling or mixed states.
CONCLUSIONS: A history of many previous episodes was associated with poor response to lithium or placebo but not to divalproex.

PMID 10450271  Am J Psychiatry. 1999 Aug;156(8):1264-6.
著者: Robert M A Hirschfeld, Jeffrey D Baker, Patricia Wozniak, Katherine Tracy, Kenneth W Sommerville
雑誌名: J Clin Psychiatry. 2003 Jul;64(7):841-6.
Abstract/Text BACKGROUND: Previous studies have examined the safety and tolerability of oral-loaded divalproex sodium in the treatment of acute mania, but not the early efficacy of this dosing strategy. The purpose of this study was to evaluate the early efficacy of oral-loaded divalproex.
METHOD: In this pooled analysis, 348 subjects from 3 randomized, double-blind, parallel-group, active- or placebo-controlled studies were used to compare the efficacy, safety, and tolerability of oral-loaded divalproex with standard-titration divalproex, lithium, olanzapine, or placebo. Subjects were inpatients diagnosed with acute mania associated with bipolar I disorder (DSM-III-R or -IV and SADS-Change Version). Patients were administered oral-loaded divalproex (20 or 30 mg/kg/day on days 1 and 2 followed by 20 mg/kg/day, and increased at physician's discretion), standard-titration divalproex initiated at 250 mg t.i.d. and titrated to 40-150 microg/mL, lithium (300 mg t.i.d. initial dose) titrated to 0.4 to 1.5 mEq/L, olanzapine (10 mg q.d. initial dose) up to 20 mg/day, or placebo.
RESULTS: The results demonstrate an early efficacy advantage for oral-loaded divalproex compared to standard-titration divalproex at days 5, 7/8, and 10. Efficacy was improved over lithium on day 7/8. There were no efficacy differences between divalproex loading and olanzapine. Divalproex loading showed greater efficacy than placebo at all time points. Divalproex loading was as well tolerated or better tolerated than the other active treatments as measured by adverse events and changes in laboratory parameters.
CONCLUSION: These results suggest the oral loading of divalproex leads to a more rapid antimanic effect when compared with standard-titration divalproex, lithium, or placebo and is better tolerated than olanzapine and as well tolerated as lithium or standard-titration divalproex.

PMID 12934987  J Clin Psychiatry. 2003 Jul;64(7):841-6.
著者: Andrea Cipriani, Corrado Barbui, Georgia Salanti, Jennifer Rendell, Rachel Brown, Sarah Stockton, Marianna Purgato, Loukia M Spineli, Guy M Goodwin, John R Geddes
雑誌名: Lancet. 2011 Oct 8;378(9799):1306-15. doi: 10.1016/S0140-6736(11)60873-8. Epub 2011 Aug 16.
Abstract/Text BACKGROUND: Conventional meta-analyses have shown inconsistent results for efficacy of pharmacological treatments for acute mania. We did a multiple-treatments meta-analysis, which accounted for both direct and indirect comparisons, to assess the effects of all antimanic drugs.
METHODS: We systematically reviewed 68 randomised controlled trials (16,073 participants) from Jan 1, 1980, to Nov 25, 2010, which compared any of the following pharmacological drugs at therapeutic dose range for the treatment of acute mania in adults: aripiprazole, asenapine, carbamazepine, valproate, gabapentin, haloperidol, lamotrigine, lithium, olanzapine, quetiapine, risperidone, topiramate, and ziprasidone. The main outcomes were the mean change on mania rating scales and the number of patients who dropped out of the allocated treatment at 3 weeks. Analysis was done by intention to treat.
FINDINGS: Haloperidol (standardised mean difference [SMD] -0·56 [95% CI -0·69 to -0·43]), risperidone (-0·50 [-0·63 to -0·38), olanzapine (-0·43 [-0·54 to -0·32], lithium (-0·37 [-0·63 to -0·11]), quetiapine (-0·37 [-0·51 to -0·23]), aripiprazole (-0·37 [-0·51 to -0·23]), carbamazepine (-0·36 [-0·60 to -0·11], asenapine (-0·30 [-0·53 to -0·07]), valproate (-0·20 [-0·37 to -0·04]), and ziprasidone (-0·20 [-0·37 to -0·03]) were significantly more effective than placebo, whereas gabapentin, lamotrigine, and topiramate were not. Haloperidol had the highest number of significant differences and was significantly more effective than lithium (SMD -0·19 [95% CI -0·36 to -0·01]), quetiapine (-0·19 [-0·37 to 0·01]), aripiprazole (-0·19 [-0·36 to -0·02]), carbamazepine (-0·20 [-0·36 to -0·01]), asenapine (-0·26 [-0·52 to 0·01]), valproate (-0·36 [-0·56 to -0·15]), ziprasidone -0·36 [-0·56 to -0·15]), lamotrigine (-0·48 [-0·77 to -0·19]), topiramate (-0·63 [-0·84 to -0·43]), and gabapentin (-0·88 [-1·40 to -0·36]). Risperidone and olanzapine had a very similar profile of comparative efficacy, being more effective than valproate, ziprasidone, lamotrigine, topiramate, and gabapentin. Olanzapine, risperidone, and quetiapine led to significantly fewer discontinuations than did lithium, lamotrigine, placebo, topiramate, and gabapentin.
INTERPRETATION: Overall, antipsychotic drugs were significantly more effective than mood stabilisers. Risperidone, olanzapine, and haloperidol should be considered as among the best of the available options for the treatment of manic episodes. These results should be considered in the development of clinical practice guidelines.
FUNDING: None.

Copyright © 2011 Elsevier Ltd. All rights reserved.
PMID 21851976  Lancet. 2011 Oct 8;378(9799):1306-15. doi: 10.1016/S014・・・
著者: Lesley A Smith, Victoria Cornelius, Adrian Warnock, Angus Bell, Allan H Young
雑誌名: Bipolar Disord. 2007 Jun;9(4):394-412. doi: 10.1111/j.1399-5618.2007.00490.x.
Abstract/Text BACKGROUND: Bipolar disorder (BD) is a leading cause of disability. Systematic reviews of randomized trials for the treatment of the maintenance phase of BD are lacking.
OBJECTIVES: To determine the efficacy and tolerability of mood stabilizers and antipsychotics in the maintenance treatment of BD.
METHODS: We systematically reviewed randomized controlled trials of licensed medications for the treatment of any phase of BD. We included randomized controlled trials comparing a medication to placebo or another medication. Comprehensive searches of electronic databases were conducted to March 2005. Outcomes investigated were relapse due to mania, depression or any mood episode, and withdrawal due to any reason or due to an adverse event. Data were combined through meta-analysis.
RESULTS: Fourteen studies (n = 2,526) met the inclusion criteria. Lithium, lamotrigine, olanzapine and valproate semisodium each demonstrated evidence to support long-term use. Compared with placebo, all medications were more effective at preventing relapse because of any mood episode. Hazard ratios (HR) were 0.68 [95% confidence interval (CI) = 0.53-0.86] for lithium, 0.68 (95% CI = 0.55-0.85) for lamotrigine, and 0.82 (95% CI = 0.57-1.20) for valproate semisodium; for olanzapine, the risk ratio (RR) was 0.58 (95% CI = 0.49-0.69). Lithium and olanzapine significantly reduced manic relapses (HR = 0.53; 95% CI = 0.35-0.79 and RR = 0.37; 95% CI = 0.24-0.57, respectively). Lamotrigine and valproate semisodium significantly reduced depressive relapses (HR = 0.65; 95% CI = 0.46-0.91 and RR = 0.40; 95% CI = 0.20-0.82, respectively). Lithium significantly reduced manic relapses compared with lamotrigine (HR = 0.56; 95% CI = 0.34-0.92) and olanzapine significantly reduced manic relapses compared with lithium (RR = 1.69; 95% CI = 1.12-2.55). Withdrawal due to an adverse event was approximately twice as likely with lithium compared with valproate semisodium (RR = 1.81; 95% CI = 1.08-3.03) and lamotrigine (RR = 2.20; 95% CI = 1.31-3.70). There were few data for carbamazepine or medications given as adjunct therapy.
CONCLUSIONS: Mood stabilizers have differing profiles of efficacy and tolerability, suggesting complementary roles in long-term maintenance treatment.

PMID 17547586  Bipolar Disord. 2007 Jun;9(4):394-412. doi: 10.1111/j.1・・・
著者: BALANCE investigators and collaborators, John R Geddes, Guy M Goodwin, Jennifer Rendell, Jean-Michel Azorin, Andrea Cipriani, Michael J Ostacher, Richard Morriss, Nicola Alder, Ed Juszczak
雑誌名: Lancet. 2010 Jan 30;375(9712):385-95. doi: 10.1016/S0140-6736(09)61828-6. Epub 2010 Jan 19.
Abstract/Text BACKGROUND: Lithium carbonate and valproate semisodium are both recommended as monotherapy for prevention of relapse in bipolar disorder, but are not individually fully effective in many patients. If combination therapy with both agents is better than monotherapy, many relapses and consequent disability could be avoided. We aimed to establish whether lithium plus valproate was better than monotherapy with either drug alone for relapse prevention in bipolar I disorder.
METHODS: 330 patients aged 16 years and older with bipolar I disorder from 41 sites in the UK, France, USA, and Italy were randomly allocated to open-label lithium monotherapy (plasma concentration 0.4-1.0 mmol/L, n=110), valproate monotherapy (750-1250 mg, n=110), or both agents in combination (n=110), after an active run-in of 4-8 weeks on the combination. Randomisation was by computer program, and investigators and participants were informed of treatment allocation. All outcome events were considered by the trial management team, who were masked to treatment assignment. Participants were followed up for up to 24 months. The primary outcome was initiation of new intervention for an emergent mood episode, which was compared between groups by Cox regression. Analysis was by intention to treat. This study is registered, number ISRCTN 55261332.
FINDINGS: 59 (54%) of 110 people in the combination therapy group, 65 (59%) of 110 in the lithium group, and 76 (69%) of 110 in the valproate group had a primary outcome event during follow-up. Hazard ratios for the primary outcome were 0.59 (95% CI 0.42-0.83, p=0.0023) for combination therapy versus valproate, 0.82 (0.58-1.17, p=0.27) for combination therapy versus lithium, and 0.71 (0.51-1.00, p=0.0472) for lithium versus valproate. 16 participants had serious adverse events after randomisation: seven receiving valproate monotherapy (three deaths); five lithium monotherapy (two deaths); and four combination therapy (one death).
INTERPRETATION: For people with bipolar I disorder, for whom long-term therapy is clinically indicated, both combination therapy with lithium plus valproate and lithium monotherapy are more likely to prevent relapse than is valproate monotherapy. This benefit seems to be irrespective of baseline severity of illness and is maintained for up to 2 years. BALANCE could neither reliably confirm nor refute a benefit of combination therapy compared with lithium monotherapy.
FUNDING: Stanley Medical Research Institute; Sanofi-Aventis.

Copyright 2010 Elsevier Ltd. All rights reserved.
PMID 20092882  Lancet. 2010 Jan 30;375(9712):385-95. doi: 10.1016/S014・・・
著者: Lars Vedel Kessing, Gunnar Hellmund, John R Geddes, Guy M Goodwin, Per Kragh Andersen
雑誌名: Br J Psychiatry. 2011 Jul;199(1):57-63. doi: 10.1192/bjp.bp.110.084822. Epub 2011 May 18.
Abstract/Text BACKGROUND: Valproate is one of the most used mood stabilisers for bipolar disorder, although the evidence for the effectiveness of valproate is sparse.
AIMS: To compare the effect of valproate v. lithium for treatment of bipolar disorder in clinical practice.
METHOD: An observational cohort study with linkage of nationwide registers of all people with a diagnosis of bipolar disorder in psychiatric hospital settings who were prescribed valproate or lithium in Denmark during a period from 1995 to 2006.
RESULTS: A total of 4268 participants were included among whom 719 received valproate and 3549 received lithium subsequent to the diagnosis of bipolar disorder. The rate of switch/add on to the opposite drug (lithium or valproate), antidepressants, antipsychotics or anticonvulsants (other than valproate) was increased for valproate compared with lithium (hazard ratio (HR) = 1.86, 95% CI 1.59-2.16). The rate of psychiatric hospital admissions was increased for valproate v. lithium (HR = 1.33, 95% CI 1.18-1.48) and regardless of the type of episode leading to a hospital admission (depressive or manic/mixed). Similarly, for participants with a depressive index episode (HR = 1.87, 95% CI 1.40-2.48), a manic index episode (HR = 1.24, 95% CI 1.01-1.51) and a mixed index episode (HR = 1.44, 95% CI 1.04-2.01), the overall rate of hospital admissions was significantly increased for valproate compared with lithium.
CONCLUSIONS: In daily clinical practice, treatment with lithium seems in general to be superior to treatment with valproate.

PMID 21593515  Br J Psychiatry. 2011 Jul;199(1):57-63. doi: 10.1192/bj・・・
著者: Guy M Goodwin, Charles L Bowden, Joseph R Calabrese, Heinz Grunze, Siegfried Kasper, Robin White, Paul Greene, Robert Leadbetter
雑誌名: J Clin Psychiatry. 2004 Mar;65(3):432-41.
Abstract/Text BACKGROUND: Two clinical trials, prospectively designed for combined analysis, compared placebo, lithium, and lamotrigine for treatment of bipolar I disorder in recently depressed or manic patients.
METHOD: 1315 bipolar I patients (DSM-IV) enrolled in the initial open-label phase, and 638 were stabilized and randomly assigned to 18 months of double-blind monotherapy with lamotrigine (N = 280; 50-400 mg/day fixed dose or 100-400 mg/day flexible dose), lithium (N = 167; serum level of 0.8-1.1 mEq/L), or placebo (N = 191). The primary endpoint was time from randomization to intervention for a mood episode. Data were gathered from August 1997 to August 2001.
RESULTS: Lamotrigine and lithium were superior to placebo for time to intervention for any mood episode (median survival: placebo, 86 days [95% CI = 58 to 121]; lithium, 184 days [95% CI = 119 to not calculable]; lamotrigine, 197 days [95% CI = 144 to 388]). Lamotrigine was superior to placebo for time to intervention for depression (median survival: placebo, 270 days [95% CI = 138 to not calculable]; lithium, median not calculable; lamotrigine, median not calculable). Lithium and lamotrigine were superior to placebo for time to intervention for mania (median survival not calculable for any group). Results of additional analyses adjusted for index mood were similar; however, only lithium was superior to placebo for intervention for mania. There was no evidence that either active treatment caused affective switch. Adverse event analysis indicated more diarrhea (19% vs. 7%, p <.05) and tremor (15% vs. 4%, p <.05) in lithium-treated patients compared with lamotrigine-treated patients.
CONCLUSIONS: Lamotrigine and lithium stabilized mood by delaying the time to treatment for a mood episode. Lamotrigine was effective against depression and mania, with more robust activity against depression. Lithium was effective against mania.

PMID 15096085  J Clin Psychiatry. 2004 Mar;65(3):432-41.

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