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- 1. To maintain fidelity of evidence-based medicine. Systematic analysis of first and second generation of antipsychotic drugs for Schizophrenia. Hiroto Takahashi Columbia University, New York, USA
- 2. To maintain fidelity of evidence-based medicine. Systematic analysis of first and second generation of antipsychotic drugs for Schizophrenia. Hiroto Takahashi Columbia University, New York, USA
- 3. Questions cost-effectiveness: high cost of medical budget (10X than old fashion drugs) uncertain effectiveness of new drugs
- 4. EBM:evidence-based medicine 根拠に基づいた医療 conscientious "conscientious, explicit, and judicious use 良心 of current best evidence" 医学 「良心的に、明確に、分別を持って、最新最良の 分別 医学知見を用いる」 明確 judicious explicit
- 5. Potential Factors • Selection bias • Date irregularities • Publication bias • Inadequate analysis • Location biases • Fraud • English language bias • Artifactual • Citation bias • Choice of effect measure • Multiple publication bias • Chance • True heterogeneity • Size of effect differs according to study size • Intensity of intervention • Differences in underlying risk
- 6. Statistics “The objective of statistical analysis is to discover what conclusions can be drawn from data and to present these conclusions in as simple and lucid a form as is consistent with accuracy.” Cox, D. R.
- 7. Clinical Statistics Meta- Cochrane analysis Review CATIE(Clinical Antipsychotic Trials of Intervention Effectiveness Study) RCT(Randomized Controlled Trial) Conventional Statistics
- 9. Long period monitoring (4-8weeks vs 18 months) Largest number of patients (1,493) randomized in a double-blind Perphenazine as a control drug
- 10. Baseline Demographic and Clinical Characteristics of Randomized Patients
- 12. Analyzed Subjects • Any case Discontinuation • Lack of efficacy of treatment • Intolerability • Patient’s Decision • Positive and Negative Syndrome Scale (PANSS) Efficacy • Clinical Global Impressions (CGI) Scale • serious Adverse effects • Moderate • Other spontaneous report • Neurologic effects • Weight change Side effects • Change vale from lab • Electrocardiographic
- 18. Analyzed Subjects • Any case Discontinuation • Lack of efficacy of treatment • Intolerability • Patient’s Decision • Positive and Negative Syndrome Scale (PANSS) Efficacy • Clinical Global Impressions (CGI) Scale • serious Adverse effects • Moderate • Other spontaneous report • Neurologic effects • Weight change Side effects • Change vale from lab • Electrocardiographic
- 21. Analyzed Subjects • Any case Discontinuation • Lack of efficacy of treatment • Intolerability • Patient’s Decision • Positive and Negative Syndrome Scale (PANSS) Efficacy • Clinical Global Impressions (CGI) Scale • serious Adverse effects • Moderate • Other spontaneous report • Neurologic effects • Weight change Side effects • Change vale from lab • Electrocardiographic
- 24. Summary • patients discontinued drugs at a high rate. • olanzapine appeared to be more effective. • no differences in effectiveness between 1st- and 2nd-generation drugs • no differences in discontinuation time owing to intolerable side effects • olanzapine was associated with side effects
- 25. Conclusion • Clinicians, patients, families, and policymakers evaluate the trade-offs between efficacy and side effects, as well as drug prices, will determine future patterns of use.
- 26. Meta- Cochrane analysis Review CATIE(Clinical Antipsychotic Trials of Intervention Effectiveness Study) RCT(Randomized Controlled Trial) Conventional Statistics
- 28. Meta-analysis All- Effect Pool inclusive size
- 29. Analyzed Subjects • Any case Non double-blind • Lack of efficacy study’s favor • Intolerability • Patient’s Decision • Overall • Positive Efficacy • Negative • Depression • serious Quality of life • Moderate • Other spontaneous report • Neurologic effects • Weight change Side effects • Sedation • Effects of haloperidol
- 30. Non double-blind studies favour second-generation antipsychotic drugs
- 31. Non double-blind studies favour second-generation antipsychotic drugs
- 32. Analyzed Subjects • Any case Non double-blind • Lack of efficacy study’s favor • Intolerability • Patient’s Decision • Overall • Positive Efficacy • Negative • Depression • serious Quality of life • Moderate • Other spontaneous report • Neurologic effects • Weight change Side effects • Sedation • Effects of haloperidol
- 33. Second-generation versus first-generation antipsychotic drugs—efficacy in various domains
- 34. Second-generation versus first-generation antipsychotic drugs—efficacy in various domains
- 35. Analyzed Subjects • Any case Non double-blind • Lack of efficacy study’s favor • Intolerability • Patient’s Decision • Overall • Positive Efficacy • Negative • Depression • serious Quality of life • Moderate • Other spontaneous report • Neurologic effects • Weight change Side effects • Sedation • Effects of haloperidol
- 36. Quality of life
- 37. Quality of life
- 38. Analyzed Subjects • Any case Non double-blind • Lack of efficacy study’s favor • Intolerability • Patient’s Decision • Overall • Positive Efficacy • Negative • Depression • serious Quality of life • Moderate • Other spontaneous report • Neurologic effects • Weight change Side effects • Sedation • Effects of haloperidol
- 41. Weight gain
- 42. Weight gain
- 43. Sedation
- 44. Sedation
- 45. Effects of haloperidol dose on effect sizes of overall symptoms and extrapyramidal side-effects
- 46. Effects of haloperidol dose on effect sizes of overall symptoms and extrapyramidal side-effects
- 47. Olanzapine Quetiapine
- 48. Summary • Some atypical drugs were better than typical drugs. • Efficacy on negative symptoms cannot be a core component of atypicality. • Atypical drugs induced fewer extrapyramidal side- effects than did haloperidol. • Atypical drugs induced more weight gain. • Atypical drugs differed in sedation.
- 49. Conclusion • This meta-analysis provides data that clinicians could use for individualized treatment of patients with schizophrenia based on efficacy, side-effects, and cost of antipsychotic drugs.
- 50. • CATIE and CUtLASS studies suggest that mid- potency first-generation drugs would have been more appropriate, because they are less likely to cause extrapyramidal side-effects. • 1sts are not associated with sedation or weight gain • CATIE and CUtLASS concluded that all antipsychotics are the same.
Editor's Notes
- We have been working in medical field which is closely bounded with human life. No doubt we have responsibility. Today’s talk about medical moral and how should we be. Using a model of antipsychotic drugs for Schizophrenia. Schizophrenia is one of major a mental disease charachterized by hallucinations and delusions due to distraction of thought process and deficient emotional process like this background of slide. so far there is no clitical medication for this desease but we know Dopamin D2 receptor antagonists seems to improve thir symptoms.This is the reason Pharacuitical company has been making drugs tageted to D2 receptor. Keep making good drug is not bad thing. That’s good but here is two issues were stated to focus. One is money theo
- We have been working in medical field which is closely bounded with human life. No doubt we have responsibility. Today’s talk about medical moral and how should we be. Using a model of antipsychotic drugs for Schizophrenia. Schizophrenia is one of major a mental disease charachterized by hallucinations and delusions due to distraction of thought process and deficient emotional process like this background of slide. so far there is no clitical medication for this desease but we know Dopamin D2 receptor antagonists seems to improve thir symptoms.This is the reason Pharacuitical company has been making drugs tageted to D2 receptor. Keep making good drug is not bad thing. That’s good but here is two issues were stated to focus. One is money theo
- Animated vertical list merging with pictures(Intermediate)To reproduce the SmartArt effects on this slide, do the following:On the Home tab, in the Slides group, click Layout, and then clickBlank. On the Insert tab, in the Illustrations group, click SmartArt. In the Choose a SmartArt Graphic dialog box, in the left pane, click List. In the List pane, double-click Vertical Picture List (fifth row, first option from the left) to insert the graphic into the slide. To create a fourth shape in the graphic, select the third shape from the top, and then under SmartArtTools, on the Design tab, in the CreateGraphic group, click the arrow next to AddShape, and then click AddShapeBefore. Repeat this process to create a fifth shape.Select the graphic. Under SmartArt Tools, on the Format tab, click Size, and then do the following:In the Height box, enter 6.38”.In the Width box, enter 7.91”.Under SmartArt Tools, on the Format tab, in the Arrange group, click Align, and then do the following:Click Align to Slide.Click Align Middle. Click Align Center. Select the graphic, and then click one of the arrows on the left border. In the Type your text here dialog box, click each of the second-level bullets and then press DELETE until there are only three first-level bullets remaining (one for each shape). Enter text for each shape into the first-level bullets.On the slide, select the graphic. On the Home tab, in the Font group, select 14 from the Font Size list.Under SmartArtTools, on the Design tab, in the SmartArtStyles group, click More,and then under Best Match for Document click Moderate Effect (fourth option from the left). On the Design tab (the regular Design tab, not that under the SmartArt Tools contextual tab), in the Themes group, click Colors, and then click Civic. (Note: If this action is taken in a PowerPoint presentation containing more than one slide, the theme colors will be applied to all of the slides.) Under SmartArtTools, on the Design tab, in the SmartArtStyles group, click Change Colors, and then under Colorful click Colorful Range – Accent Colors 3 to 4 (third option from the left). Click each of the five picture placeholders in the graphic, and then in the Insert Picture dialog box, select a picture and click Insert.Press and hold CTRL, and then select all five of the pictures on the slide. Under SmartArtTools, on the Format tab, in the Shapes group, click ChangeShape, and then under Rectangles clickRoundDiagonalCornerRectangle (ninth option from the left).Under SmartArtTools, on the Format tab, in the Shape Styles group, click Shape Effects, point to Glow, and then do the following:Under Glow Variations, select 5 pt glow, Accent color 1, (first row, first option from the left).Point to More Glow Colors, and then under Theme Colors click White, Background 1 (first row, first option from the left).Press and hold CTRL, and then select all of the larger rounded rectangles. Under SmartArtTools, on the Format tab, in the Shapes group, click ChangeShape, and then under Rectangles clickRoundDiagonalCornerRectangle (ninth option from the left). To reproduce the animation effects on this slide, do the following:On the Animations tab, in the Advanced Animations group, click Animation Pane.On the slide, select the graphic. On the Animations tab, in the Animation group, click the More arrow at the Effects Gallery, and under Entrance, click Fade.In the Timing group, in the Duration list, enter 01.00.In the Advanced Animations group, click Add Animation, and under Motion Paths, clickLines, then do the following:In the Animation group, click Effect Options and then click Right.In the Timing group, in the Start list, selectWith Previous.Also in the Timing group, in the Duration list, select 01.00. On the slide, right-click the right motion path and then click ReversePathDirection.Press and hold CTRL, and then select the two animationeffects in the Animation Pane. In the Animation group, clickEffect Options and under Sequence, select One by One.Also in the Animation Pane, click the double arrows under each effect to expand the list of effects. Select the first animation effect (fade effect for the first rectangle). On the Animations tab, in the Timing group, in the Start list, select With Previous.Also in the Animation Pane, select the 11th animation effect (motion path for the first picture). On the slide, point to the starting point (green arrow) of the selected motion path until the cursor becomes a two-headed arrow. Press and hold SHIFT to constrain the path to a straight horizontal line, and then drag the starting point to the left of the endpoint (red arrow). Also in the Animation Pane, do the following:Drag the 11th effect until it is second in the list of effects. Drag the 12th effect (motion path for the first large rectangle) until it is fourth in the list of effects. Also in the Animation Pane, select the 13th animation effect (motion path for the second picture). On the slide, point to the starting point (green arrow) of the selected motion path until the cursor becomes a two-headed arrow. Press and hold SHIFT, and then drag the starting point to the left of the endpoint (red arrow), into the same position as the green arrow for the first picture motion path. Also in the Animation Pane, do the following:Drag the 13th animationeffect until it is sixth in the list of effects. On the Animations tab, in the Timing group, in the Start list, select With Previous.Drag the 14th animation effect (motion path for the second large rectangle) until it is eighth in the list of effects. In the Animation Pane, select the 15th animation effect (motion path for the third picture). On the slide, point to the starting point (green arrow) of the selected motion path until the cursor becomes a two-headed arrow. Press and hold SHIFT, and then drag the starting point to the left of the endpoint (red arrow), into the same position as the starting point for the first picture motion path. Also in the Animation Pane, do the following:Drag the 15th animation effect until it is 10th in the list of effects. On the Animations tab, in the Timing group, in the Start list, select With Previous.Drag the 16th animation effect (motion path for the third large rectangle) until it is 12th in the list of effects. Select the 17th animation effect (motion path for the fourth picture). On the slide, point to the starting point (green arrow) of the selected motion path until the cursor becomes a two-headed arrow. Press and hold SHIFT, and then drag the starting point to the left of the endpoint (red arrow), into the same position as the starting point for the first picture motion path. Also in the Animation Pane, do the following:Dragthe 17th animation effect until it is 14th in the list of effects. On the Animations tab, in the Timing group, in the Start list, select With Previous.Drag the 18th animation effect (motion path for the fourth large rectangle) until it is 16th in the list of effects.Select the 19th animation effect (motion path for the fifth picture). On the slide, point to the starting point (green arrow) of the selected motion path until the cursor becomes a two-headed arrow. Press and hold SHIFT, and then drag the starting point to the left of the endpoint (red arrow), into the same position as the starting point for the first picture motion path.Also in the Animation Pane, drag the 19th animation effect until it is 18th in the list of effects. On the Animations tab, in the Timing group, in the Start list, select With Previous.To reproduce the background effects on this slide, do the following:Right-click the slide background area, and then click Format Background. In the Format Background dialog box, click Fill in the left pane, select Gradient fill in the Fill pane, and then do the following:In the Type list, select Radial.Click the button next to Direction, and then click From Top Left Corner (fifth option from the left)in the drop-down list.Under Gradient stops, click Add gradient stop or Remove gradient stop until two stops appear on the slider, then customize the gradient stops as follows:Select the first stop on the slider, and then do the following:In the Position box, enter 0%.Click the button next to Color, and then under Theme Colors click White, Background 1 (first row, first option from the left).Select the last stop on the slider, and then do the following: In the Position box, enter 100%.Click the button next to Color, and then under Theme Colors click White, Background 1, Darker 25%(fourth row, first option from the left).
- There was a concept proposed. Its called EBM.Medicine has been long history since we have been created on the earth. Human beings have to be live with diseases. 医療のあり方をさす治療法が日進月歩で進化医者は常に自らの専門の分野の最新の情報を、関連の医学誌を購読することで熟知していなければならない.これを怠って最新の治療を行わず患者の容態が満足な結果に終わらなかった場合は、患者から訴訟で賠償を請求されるというだけでなく、このような医学誌を参照とすることで適切な治療が行われていたか、裁判で客観的に判断されるという側面を持つ。
- Scientist or clinicians somehow start to distort from the standard, which could happen in either conscious or unconscious. What is bothering to keep floowing the standerd. I named those in here.
- We have to take care large numbers. Conventional statistics will distort the result because of the cariculation depends on numbersRCT母集団に依存した推測統計ーnが大きければ差異がでてしまう.実質的効果が大きいか小さいかについての情報は何も与えてくれない効果量とは，「効果の大きさ」サンプルサイズによって変化することのない指標とはー＞標準化された値つまり効果量.実験の条件によっては，有意差があっても（p < .05），実質的効果があまりない（効果量が小さい）場合もあれば，有意差がなくても（p > .05），効果量が大きい場合も考えられるため，有意差があろうがなかろうが，どちらにしても効果量は報告すべきであるグループごとの平均値の差を標準化した効果量を用いたメタ分析では，d が使われる場合が多いが，最近では相関係数 r が使用されることも多く
- The Clinical Antipsychotic Trials of InterventionEffectiveness (CATIE) between January 2001 and December 2004 at 57clinical sites in the United States16 university clinics, 10 state mental health agencies, 7 Veterans Affairs medical centers, 6 private nonprofit agencies,4 private-practice sites14 mixed-system sitesup to 18 months or until treatment was discon-tinued for any reason (phase 1)Thepresent report is limited to phase 1 results.18 to 65 years of age
- funded by the NIH’s National Institute of Mental HealthAl-though haloperidol is the first-generation agent most commonly used for comparison, we chobecause of its lower potency and moderate side-effect profile.se toPerphenazine as a control due to low potency and moderate side effect profile
- ■exacerbation: 悪化、憤慨SCID: Structured Clinical Interview dignosis
- 1432 went analysis
- Scores for the PANSS can range from 30 to 210, with higher scores indicating more severe psycho-pathology.Scores for the CGI Scale can range from 1 to 7, with higher scores indicating a greater severity of illness.
- Cox‘s proportional hazards model などによる多変量解析で複数の危険因子はリスク比（ハザード比 Hazard Ratio)。それぞれの危険因子が何倍その結果因子の発生を高めるかについては正しい指標である。それぞれのドラックが何倍離脱の発生を高めるのかとういことHow many times each drug will cause discontinuation.
- Kaplan–Meier estimator:全観察対象を死亡または打ち切り時間の小さい順に並べ、死亡発生ごとに生存率を計算するData were alighned from short fluction over mothesThe time to the discontinuation of treatment forany cause was longer in the olanzapine group thanin the quetiapine group (hazard ratio, 0.63; P<0.001),the risperidone group (hazard ratio, 0.75; P=0.002),or the perphenazine group (hazard ratio, 0.78;P = 0.021) (Table 2). the difference be-tween the olanzapine group and the perphenazinegroup was not significant after adjustment for mul-tiple comparisons (required P value, ≤0.017).
- The time to the discontinuation of treatment forlack of efficacy was longer in the olanzapine groupthan in the perphenazine group the difference betweenthe olanzapine and ziprasidone groups was not sig-nificant after adjustment for multiple comparisons
- There were nosignificant differences between groups in time un-til discontinuation owing to intolerable side effects
- The time until discontinuation owingto the patient’s decision (i.e., the patient indepen-dently chose to stop treatment) was similar to thatfor discontinuation for any cause
- Scores for the PANSS can range from 30 to 210, with higher scores indicating more severe psycho-pathology.Scores for the CGI Scale can range from 1 to 7, with higher scores indicating a greater severity of illness.
- Improvement was initially greatest in the olanzapinegroup, but its advantage diminished over time.
- Scores for the PANSS can range from 30 to 210, with higher scores indicating more severe psycho-pathology.Scores for the CGI Scale can range from 1 to 7, with higher scores indicating a greater severity of illness.
- 病気の要因を持つ人が要因のない人と比べてどれだけ病気にかかりやすいかを示す指標。薬を処方された人がNeurologic Side EffectsThere were no significant differences among thegroups in the incidence of extrapyramidal side ef-fects, akathisia, or movement disorders as reflectedby rating-scale measures of severity.薬を処方されなたった人より悪くなる確率はWeight Gain and Metabolic ChangesPatients in the olanzapine group gained moreweight than patients in any other group, with an av-erage weight gain of 2 lb (0.9 kg) per month. A largerproportion of patients in the olanzapine group thanin the other groups gained 7 percent or more of theirbaseline body weight (30 percent vs. 7 to 16 percent,P<0.001)
- There were no substantially different effects of themedications on the corrected QT interval on elec-trocardiography, and torsades de pointes did notdevelop in any patients. There were no significant differencesamong the groups in the rates of suicide attemptsor suicidal ideation reported as serious adverseevents.
- 1) patients with chronic schizophrenia in this study discontinued their antipsychotic study medications at a high rate.2) olanzapine appeared to be more effective than the other drugs studied.3) there were no significant differences in effectiveness between the conventional drug perphenazine and the other second-generation drugs4) There were no significant differences among the drugs in the time until discontinuation of treatment owing to intolerable side effects5) olanzapine was associated with greater weight gain and increases in glycosylated hemoglobin, cholesterol, and triglycerides
- 母集団に依存した推測統計ーnが大きければ差異がでてしまう.実質的効果が大きいか小さいかについての情報は何も与えてくれない効果量とは，「効果の大きさ」サンプルサイズによって変化することのない指標とはー＞標準化された値つまり効果量.実験の条件によっては，有意差があっても（p < .05），実質的効果があまりない（効果量が小さい）場合もあれば，有意差がなくても（p > .05），効果量が大きい場合も考えられるため，有意差があろうがなかろうが，どちらにしても効果量は報告すべきであるグループごとの平均値の差を標準化した効果量を用いたメタ分析では，d が使われる場合が多いが，最近では相関係数 r が使用されることも多く
- 見つかった研究全てを対象とする。恣意的に研究を抽出することを避けるデータを結合し、治療群と対照群それぞれのエンドポイントの平均値を算出する。治療群と対照群の平均値の差異を標準偏差で割る。 標準化する。
- Scores for the PANSS can range from 30 to 210, with higher scores indicating more severe psycho-pathology.Scores for the CGI Scale can range from 1 to 7, with higher scores indicating a greater severity of illness.
- Scores for the PANSS can range from 30 to 210, with higher scores indicating more severe psycho-pathology.Scores for the CGI Scale can range from 1 to 7, with higher scores indicating a greater severity of illness.
- They used Hedges’ g for stand razing data to perform meta-analysis.Negative synmptoms
- Bar length indicate reliability
- Scores for the PANSS can range from 30 to 210, with higher scores indicating more severe psycho-pathology.Scores for the CGI Scale can range from 1 to 7, with higher scores indicating a greater severity of illness.
- Scores for the PANSS can range from 30 to 210, with higher scores indicating more severe psycho-pathology.Scores for the CGI Scale can range from 1 to 7, with higher scores indicating a greater severity of illness.
- All second-generation antipsychotic drugs were associated with much fewer extrapyramidal side-effects than haloperidol.with the exception of clozapine, olanzapine, and risperidone
- Allsgd provide gain weight side effect.
- 鎮静
- Olanzapine:Egger’s regression intercept does not suggest statistically significant asymmetry (df = 26, p=0.259) Quetiapine :Egger’s regression intercept suggests statistically significant asymmetry (df = 9, p=0.295)
- Four of these drugs were better than first-generation antipsychotic drugs.Efficacy on negative symptoms cannot be a core component of atypicality.Second-generation antipsychotic drugs induced fewer extrapyramidal side-effects than did haloperidol.Second-generation antipsychotic drugs induced more weight gain.The second-generation drugs also differed in their sedating properties.
- Can not find a criteria to chose drug because of Second-generation antipsychotic drugs differ in many properties and are not a homogeneous class.