Vienna practical experience 2007

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Practical Review

Practical Review

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  • BPI n=135 BPII n=71
  • Collaborative care uses the idea of encouraging patients to participate in choosing their medications whenever practical. This is done by sharing the profiles of drugs which are on a menu of resonable choices. STEP will provide practical tables which summarize the profiles of the most commonly used medications. Treating psychiatrists will determine what is reasonable for a given patient and help the patient select the most advantageous treatment. By enlisting the patient and their supports as collaborators in managing their treatment we expect to improve concordance between the treatment plan and patient practice.
  • A good understanding of each individual patient enables clinical decision makers to weigh a wide array of individual factors in selecting medications and other elements of the therapeutic plan. While most of these are widely appreciated some deserve emphasis or explanation.
  • This adaptation of the
  • Pivotal trials show us that treatments for Bipolar mania are more efficacious than placebo and at the same time gives us an estimate of unmet clinical need. We can compute an index of clinical effectiveness by taking the product of the response rate and the completion rate. Then by calculating the number needed to treat to see one additional patient get the benefit of clinical effectiveness we’d find our best treatments require 5-10 patients be treated before treatment contributes an extra patient getting an increment of clinical effectiveness.
  • Risperidone (Risperdal ® , Janssen Pharmaceutica Products, L.P.), an oral dopamine (D 2 ) and serotonin (5HT 2 ) antagonist, represents a milestone in the management of bipolar disorder. Approved by the FDA in December 2003, risperidone is the second atypical antipsychotic indicated as monotherapy or in combination with lithium or valproate for the short-term treatment of acute manic or mixed episodes associated with bipolar I disorder. The efficacy and safety of risperidone in treating acute manic or mixed episodes of bipolar disorder were established in 2 monotherapy trials and in 1 trial in which risperidone was used in combination with either lithium or valproate. The first study, reported by Hirschfeld et al, was a 3-week, placebo-controlled trial in which 262 manic patients with or without psychotic symptoms were randomly assigned to receive either placebo or risperidone (flexible dose of 1 to 6 mg/d). 1 On average, patients taking risperidone (mean 4.1 mg/d) experienced an 11-point reduction in YMRS total score compared with a 5-point reduction among placebo-treated patients ( P <.001). Clinical response, as determined by a ≥50% reduction in total manic symptom scores, was 43% for patients treated with risperidone and 24% in those receiving placebo. Patients with and without psychotic features who received risperidone showed significantly greater improvements in YMRS total score than patients receiving placebo, suggesting that the antimanic effect of risperidone is independent of its antipsychotic effects. The second, similarly designed, monotherapy trial included 290 bipolar I patients with manic or mixed episodes. 2 On average, patients receiving risperidone (median dose 6 mg/day) had a total reduction of 22.7 points in YMRS total score compared with a 10.5-point reduction in patients treated with placebo ( P <.001). Compared with the placebo group, significantly greater improvements in YMRS total scores at weeks 1 and 2 were observed in the risperidone group. At the end of the 3-week study, 73% of patients receiving risperidone achieved a clinical response, compared with 36% taking placebo. The most common side effects experienced in both risperidone monotherapy studies included extrapyramidal symptoms, tremor, insomnia, somnolence, and headache. The investigators concluded that risperidone effectively and safely treats acute bipolar mania, with onset of action as early as week 1. The adjunctive therapy trial will be discussed shortly [refer to Slide 14]. References: 1. Hirschfeld RMA, Keck PE, Karcher K, Kramer ML, Grossman F. Rapid antimanic effect of risperidone monotherapy: a 3-week multicenter, randomized, double-blind, placebo-controlled trial. Am J Psychiatry 2004; 2. Khanna S, Vieta E, Lyons B, Grossman F, Kramer ML. Risperidone in the treatment of acute mania: double-blind, placebo-controlled study. Br J Psychiatry 187:229-34: 2005
  • Pivotal trials show us that treatments for Bipolar mania are more efficacious than placebo and at the same time gives us an estimate of unmet clinical need. We can compute an index of clinical effectiveness by taking the product of the response rate and the completion rate. Then by calculating the number needed to treat to see one additional patient get the benefit of clinical effectiveness we’d find our best treatments require 5-10 patients be treated before treatment contributes an extra patient getting an increment of clinical effectiveness.
  • Our clinic stresses long-term treatment, and our results for lithium suggest interventions in a specialty clinic setting may more than double the median duration of treatment observed by Johnson. HOWEVER, even in with specialized care the majority of New treatments are used less that 6 months. This is all the more remarkable in light of the positive results recorded in more that half the treatments trials.
  • Our clinic stresses long-term treatment, and our results for lithium suggest interventions in a specialty clinic setting may more than double the median duration of treatment observed by Johnson. HOWEVER, even in with specialized care the majority of New treatments are used less that 6 months. This is all the more remarkable in light of the positive results recorded in more that half the treatments trials.
  • Our clinic stresses long-term treatment, and our results for lithium suggest interventions in a specialty clinic setting may more than double the median duration of treatment observed by Johnson. HOWEVER, even in with specialized care the majority of New treatments are used less that 6 months. This is all the more remarkable in light of the positive results recorded in more that half the treatments trials.
  • First ever study addressing treatment for depressed Bipolar patients, not responsive to standard antidepressants
  • The top graph in Figure 3 illustrates a drug with a 3-fold difference in binding affinity for target X versus Y. This drug will always have a greater effect on X than Y. Nevertheless, substantial occupancy of X (i.e., 50% or more) cannot be achieved with such a drug without also producing some occupancy of Y. The middle graph in Figure 3 shows a drug with a 10-fold (i.e., one order of magnitude) difference in binding affinity for X versus Y. With this drug, virtually complete occupancy of X can be achieved at a concentration that produces only minimal occupancy of Y. The bottom graph shows a drug with a 100fold (i.e., two orders of magnitude) difference in affinity for X versus Y. In this case, no detectable occupancy of Y is achieved at a concentration that produces full occupancy of X. Once that degree of separation has been achieved, further increases in selectivity (i.e., three or four orders of magnitude) may be of interest to the researcher but are of doubtful clinical consequence -- a comment that may help to put into proper perspective marketing claims about how "selective" a drug is. As a general rule, approximately 70%-80% occupancy of a site of action appears to be needed for most psychiatric drugs to achieve a clinically meaningful effect.2,4,7 Increases in occupancy above 80% are often associated with more of an increase in adverse effects than in efficacy. This general rule is consistent with the fact that all the fixed dose studies with single mechanism of action drugs (e.g., SSRIs) show a flat dose-response curve with regard to efficacy but an ascending dose-response curve with regard to adverse effects above their usually effective minimum antidepressant dose.8
  • All antipsychotics cause somnolence; however, the incidence may be higher in atypical antipsychotics. These data are extracted from US product labels for the various medications. Specifically, the graph indicates the number of cases needed to see significant rates of somnolence. The fewer the number (the higher the bar in this reverse presentation), the more sedating the compound relative to placebo. As illustrated, olanzapine appears to be associated with the greatest somnolence risk. In acute inpatient settings, antipsychotic-related somnolence may help calm patients and regulate the sleep cycle. However, somnolence in the long term is a liability, particularly in the elderly who may be prone to an increased risk of falls. Further, somnolence may be a reason for low physical activity, which may exacerbate increased weight gain, another effect associated with atypical antipsychotics. References: Sharif ZA. Overview of safety and tolerability of atypical antipsychotics used in primary care. Primary Care Companion J Clin Psychiatry . 2003;5(suppl 3):14-21.
  • This slide summarizes the incidence of clinically significant weight gain according to the prescribing information for aripiprazole, ziprasidone, risperidone, quetiapine, and olanzapine, based on short-term (<8 weeks) placebo-controlled trials. 1-5 Significant weight gain is defined as a  7% increase in weight from baseline. As seen in this graph, compared with placebo, clinically significant weight gain occurred in 29% of the patients taking olanzapine, 1 23% taking quetiapine, 2 18% taking risperidone, 3 10% taking ziprasidone, 4 and 8% taking aripiprazole. 5 With long-term exposure to olanzapine (median 238 days), up to 56% of patients experienced clinically significant weight gain. 1 References: 1. Zyprexa [package insert]. Indianapolis, IN; Eli Lilly and Company; 2004; Seroquel [package insert]. Wilmington, DE; AstraZeneca Pharmaceuticals LP; 2004; Risperdal [package insert]. Titusville, NJ; Janssen Pharmaceutica Products LP; 2003; Geodon [package insert]. New York, NY; Pfizer Inc; 2003; Abilify [package insert]. Princeton, NJ; Bristol-Myers Squibb Company and Otsuka America Pharmaceutical, Inc; 2004.
  • Newcomer et al performed modified oral glucose tolerance tests in 48 schizophrenic patients receiving clozapine, olanzapine, risperidone, or typical antipsychotics and 31 untreated healthy control subjects. Plasma was sampled at 0 (fasting), 15, 45, and 75 minutes after glucose load. Olanzapine-treated patients had significant glucose elevations at all time points compared with patients receiving typical antipsychotics and untreated healthy control subjects. Clozapine-treated patients had significant glucose elevations at fasting and 75 minutes postload also in comparison with patients receiving typical antipsychotics and untreated control subjects. Risperidone-treated patients had elevations in fasting and postload glucose levels, but only in comparison with untreated healthy control subjects. No differences in mean plasma glucose levels were detected when risperidone-treated patients were compared with patients treated with typical antipsychotis. No significant differences in plasma glucose levels were detected at anytime when comparing typical-antipsychotic – treated patients to untreated control subjects. This slide illustrates the effect of atypical versus conventional antipsychotics on insulin resistance using the Homeostasis Model Assessment (HOMA). compared with typical antipsychotics, olanzapine and clozapine demonstrated greater HOMA insulin resistance values. No significant alterations in HOMA insulin resistance values were seen for patients treated with risperidone or typical antipsychotics compared with untreated control subjects. References: Newcomer JW, Haupt DW, Fucetola R, et al. Abnormalities in glucose regulation during antipsychotic treatment of schizophrenia. Arch Gen Psychiatry . 2002;59:337-345.
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  • 1. Practical Experience•Approach to treatment•Evidence of Efficacy and Effectiveness•Pharmacology•Adverse Effects•Activation, Agitation, Akathisia Gary Sachs, MD Associate Professor of Psychiatry, Harvard Medical School Director, Bipolar Clinic and Research Program Massachusetts General Hospital
  • 2. Depression is the most common overt expression of Bipolar Disorders 52% 31% 37:1 BP II BPI 10% BPI 1.4% BPIIJudd et al % weeks % weeksNIMH CDS, 2001 Depression Manic Spectrum
  • 3. Pathways forSystematicTreatment
  • 4. Critical Iterative approach decision point Evidence Individual factors A-F Menu of reasonable choices +++ Option A €€€€ ++ Option B $$$$ +++ Option C ££££ MeasurementEducate Negotiate Intervention
  • 5. Selection of Initial InterventionSequential Care: Urgent Care:Most Benign Most Effective Usually Monotherapy Combination Therapy Usually driven by Aggressive titration Start Low Patient driven by to Go Slow Preference effective dose range Clinician’s responsibility
  • 6. Individual factors• Course • Biomarkers (?) •Polarity Predominance • Prior Treatment Response •Number / Frequency of prior episodes • Acute •Rapid Cycling • Prophylaxis• Index Episode • Adverse Effect Tolerance •Mixed Episodes • General Medical •Psychosis Disorder/Risk factors• Residual Symptoms •Cardiac: Obesity, Hypertension• Female Gender •Endocrine: Thyroid, Diabetes• Comorbid Psychiatric Illness •Hemopoetic/Immune Function •Substance misuse • Therapeutic Priority •Anxiety Disorders - Urgent Care Strategy •ADHD - Sequential Strategy • Concordance
  • 7. Genomics: Chronic IllnessWellcome Trust Data
  • 8. Sufficient to support valid causal inference
  • 9. Quality of evidence made simple A. Double blind placebo controlled trial with adequate sample* B. Double blind comparison studies with adequate sample* C. Open comparison trials with adequate sample* D. Uncontrolled observation or controlled study with ambiguous result E. No published evidence (+/- class effect) F. Available evidence negative* statistical power > 0.8 to detect meaningful differences at p< 0.05
  • 10. Quality of Evidence for Widely Used Psychotropics Prophylaxis Acute Mania /Mixed Acute Bipolar Depression Rapid CyclingLithium A+ A+ B C-Divalproex A- A+ D DCarbamazepine D A+ D DLamotrigine A+ F A AGabapentin E- F D DTopiramate E- D D DOxcarbazepine E- D E- DAripiprazole A A+ D DClozapine D D E DHaloperidol D A E- E-Olanzapine A A+ A DRisperidone E+ A+ D DQuetiapine E+ A+ A DZiprasidone E+ A+ E- E-Omega 3 D E- F F
  • 11. Acute Mania: Placebo controlled trials with adequate* sample sizePositive Negative/Failed• Lithium • Lamotrigine• Valproate • Gabapentin• Carbamazepine • Topiramate • Oxcarbazepine• Olanzapine• Ziprasidone• Aripiprazole• Risperidone• Haloperidol• Quetiapine *power to detect a difference > 0.8
  • 12. Acute Bipolar Depression: Placebo controlled therapy Trials with adequate* sample size Positive Negative or FailedLamotrigine ImipramineOlanzapine Li+ ParoxetineQuetiapine Li+ Imipramine MS+ ParoxetineOlanzapine + Fluoxetine MS+ BupropionMS+ CBTMS+ FFTMS+ IPSRT *power to detect a difference > 0.8
  • 13. Maintenance and continuation phase: Adequate Controlled Clinical trialsPositive Negative/failed• Lithium* • Imipramine• Valproate* • Clonazepam• Lamotrigine* • Lithium• Olanzapine* • Valproate*• Aripirazole** Some but not all outcomes
  • 14. How well does it work?
  • 15. What Is the Most Meaningful to Guide Clinical Practice?Efficacy Outcomes Effectiveness Outcomes Predictors – Response – Treatment – Durable Recovery outcome – Remission – Days well – Adherence – Recovery – Longest well interval – Self harm – Roughening – Mean Duration of use – Resilience – 50% Improvement without – Death• Adverse effects treatment emergent switch – Genes – Safety – Response X completion – Tolerability •Adverse effects Tolerability Safety •Function 20
  • 16. Big Picture vs Detail
  • 17. A Simple Metric for Effect SizeNumber Needed to Treat (NNT)= 1/(Active Response Rate - Placebo Response Rate ) Study Response Rate Tohen 19991 Olanzapine (OLZ)=49% NNT Acute Mania 6.7 Placebo=24% Tohen 20002 OLZ=65% 5.9 Placebo=43% 5.3 Khanna 20053 Risperidone (RIS)=73% 4.8 4.8 4.5 Placebo=36% 4.0 Hirschfeld 20044 RIS=43% Placebo=24% Vieta 20055 Quetiapine (QTP)=48% 2.7 Placebo=31% Keck 20036 Ziprasidone (ZIP)=50% Placebo=35% Keck 20037 Aripiprazole (ARI)=40% Placebo=19% Sachs 20068 ARI=53% Placebo=32% RIS3 OLZ1 OLZ2 ARI7 ARI8 RIS4 QTP5 ZIP61. Tohen M et al. Am J Psychiatry. 1999;156:702-709; 2. Tohen M et al. Arch Gen Psychiatry. 2000;57:841-849; 3. Khanna S etal. Br J Psychiatry. 2005;187:229-234; 4. Hirschfeld RM et al. Am J Psychiatry. 2004;161:1057-1065; 5. Vieta E et al. Curr MedRes Opin. 2005;21:923-934; 6. Keck PE Jr et al. Am J Psychiatry. 2003;160:741-748; 7. Keck PE Jr et al. Am J Psychiatry.2003;160:1651-1658; 8. Sachs G et al. J Psychopharmacol. 2006;epub Feb 14.
  • 18. Risperidone Monotherapy for Acute Mania Same protocol different result Dosing Matters RIS-USA-239 RIS-IND-2 nt t e e in in 1 2 3 lin oi 3 1 2 o el 3 k k k 3 dp k k k dp se ee ee ee ee ee ee as ay y En En Ba Da W W W W W W B D 0 0Change in total YMRS score -5 -5 -10 * -10 * * * -15 * -15 * -20 -20 ** ** -25 -25 ** LOCF analysis. *P<.001 risperidone vs placebo. LOCF analysis. *P<.01; †P<.001 risperidone vs placebo. Hirschfeld RM et al. 2004;161:1057-1065. Am J Psychiatry. Khanna S et al. 2005:187:229-34 Br J Psychiatry.
  • 19. Real-World Pharmaco-Epidemiology New Treatment Starts at MGH Bipolar Clinic N=466 with at least 4 visits/year Median treatment duration (d) Recovered/recovering (%) 197 162 166 127 97 99 67% 59% 53% 54% 57% 47% Lithium Valproate Lamotrigine Atypical Antidepressants Anxiolytics (n=49) (n=38) (n=89) Antipsychotics (n=264) (n=93) (n=216)MGH=Massachusetts General Hospital.Sachs G et al. APA, 2006; Toronto Canada 25
  • 20. MGH Bipolar ClinicAtypical Antipsychotics with least 20 new starts % Recovered ≤ 12 months 111 Median Duration (days) 112 % Recovering ≤ 3 months No significant differences 111 112 84.5 75 64% 65% 65% 59% 51% 43% 43% 33% Olanzapine Risperidone Quetiapine Aripiprazole n=36 n=49 n=77 n=46MGH=Massachusetts General Hospital.Sachs G et al. Presented at: APA 2006 Toronto, Canada 26
  • 21. MGH Bipolar Clinic Antidepressants with least 20 new starts 111 % Recovered ≤ 12 months 111 Median Duration (days) 112 % Recovering ≤ 3 months No significant differences 145 119 109 103 100100 75% 72% 75% 63% 62% 54% 56% 55% 48% 43% Bupropion Paroxetine Venlafaxine Citalopram Trazodone n=52 n=43 n=21 n=20 n=20MGH=Massachusetts General Hospital.Sachs G et al. Presented at: APA 2006 Toronto, Canada 27
  • 22. Pharmacology 2007 Many drugs act as fixed ratio combination agentsUnintended Polypharmacy of Monotherapy
  • 23. Pharmacologic Determinants of Clinical Response Drug IndividualSite of Action Concentration Biology at Site of ActionAffinity for Absorption Geneticsreceptor Distribution Age Metabolism DiseaseIntrinsic Elimination Environmentactivity atsite (ADME) (GADE) Preskorn SH. Clinical Pharmacology of Selective Serotonin Reuptake Inhibitors.
  • 24. Relative Binding Affinity (RBA): The affinity of a drug for a secondary site(s) target in relationship to most potent binding site Kd for secondary receptors RBA = Kd for primary receptor Preskorn S J Psychiat Practice 9:376-384, 2005Preskorn SH. J Psych Pract. 2004
  • 25. Drug Concentration, Receptor Occupancy, and Selectivity =1 3 fold 10 fold 100 fold Target Range of 100% Therapeutic Action 75% Nonselective% Bound 50% Selective 25% Highly Selective 0.01 0.1 1 10 100 1,000 Concentration (nM)
  • 26. In vitro Affinity Profiles: Known receptor affinities relative to most potent binding activity Haloperidol profile relative to its most potent binding Alpha1 5HT2A M-1 H1 5HT1A 5HT2CD2 1 10 100 1,000 10,000 Aripiprazole profile relative to its most potent bindingD2 5HT1A 5HT2A 5HT2C Alpha1 H1 M-1 1 10 100 1,000 10,000 Clozapine profile relative to its most potent binding Alpha1 5HT2AM-1 D2 5HT1A H1 5HT2C 1 10 100 1,000 10,000 Arnt and Sharfeldt 1998; Daniel 1999; Bymaster et al 1996; Seegers et al 1995. Adapted from Preskorn 2006
  • 27. In vitro Affinity Profiles: Known receptor affinities relative to most potent binding activity Olanzapine profile relative to its most potent binding Alpha1 M-1 5HT2A H1 D2 5HT2C 5HT1A 1 10 100 1,000 10,000 Quetiapine profile relative to its most potent bindingAlpha1 H1 M-1 D2 5HT2A 5HT2C 5HT1A 1 10 100 1,000 10,000 Risperidone profile relative to its most potent bindingAlpha1 D2 H1 M-15HT2A 5HT2C 5HT1A 1 10 100 1,000 10,000 Ziprasidone profile relative to its most potent binding 5HT2A 5HT2C 5HT1A D2 Alpha1 H1 M-1 1 10 100 1,000 10,000 Arnt and Sharfeldt 1998; Daniel 1999; Bymaster et al 1996; Seegers et al 1995. Adapted from Preskorn 2006
  • 28. The principles of Sequential and Urgent care dosing
  • 29. Risperidone: Dosing Usual1- 4 mg Effective 0.5 - 3 mg Range 2-4 1-2 mg/q mg/q 1-2 wks 2-4wks 3-4 mg qd Day 22-28 2-4 mg Day 3-28 qd-bid 2-3 mg qd Day 15-21 1-2 mg 1-2 qd Day 8-14 Day 1-7 mg qd- 0.5-2mg qd-bid Day 1-7 bidUrgent Sequential Care Care
  • 30. Aripiprazole: Dosing15-30 mg Usual 15 - 30 mg Effective Range 15 15 mg/q 2-4wks 1-2 wks 15-30 mg qd Day 3-28 15-30 mg Day 8-28 qd 15-30 mg Day 1-7 qd 5-10 mg Day 1-7 qd Urgent Sequential Care Care
  • 31. Olanzapine: Dosing Usual10-30 mg Effective 5 - 20 mg Range 5-10 2 .5 -10 mg/q mg/q 1-2 wks 2-4wks 20-30 mg Day 22-28 15-30 Day 3-28 qd mg qd 10-20 mg Day 8-21 qd 10-20 Day 1-7 mg qd 5-10mg qd Day 1-7 Urgent Sequential Care Care
  • 32. Somnolence as an Adverse Event Number needed to observe=1/(active drug rate - placebo rate) 50 Number of Cases Needed to cause an extra case of Significant Somnolence 33 14 14 6 Olanzapine Quetiapine Ziprasidone Aripiprazole RisperidonePhysicians’ Desk Reference ® 57th ed., Montvale, NJ: Medical Economics; 2003.
  • 33. Clinically Significant Weight Gain (≥7%) Atypical Antipsychotics vs PlaceboNNT 25 20 12 6 4 35 35 35 35 35 30 30 30 30 30Incidence (%) 25 25 25 25 25 20 20 20 20 20 15 15 15 15 15 10 10 10 10 10 5 5 5 5 5 0 0 0 0 0 le ne e e o ue bo nz o as o o e on in on eb eb eb eb zo pi e ap id ac ac ac ac ac rid ra tia ip Pl Pl Pl Pl Pl pe la ip pr is Q O Ar Zi RAbilify® [package insert]. Princeton NJ: Bristol-Myers Squibb and Rockville, Md: Otsuka America Pharmaceutical;2005; Geodon® [package insert]. New York, NY: Pfizer; 2004; Risperdal ® [package insert]. Titiusville, NJ:Janssen Pharmaceutica Products, LP; 2003; Seroquel ® [package insert]. Wilmington DE: AstraZenaca; 2004;Zyrexa® [package insert]. Indianapolis, Ind: Eli Lilly and Company; 2004.
  • 34. Effects on Insulin Resistance 6 HOMA Insulin Resistance, Mean 5 4 * 3 * 2 1 0 Control Typical Risperidone Olanzapine Clozapine*Significant difference vs typicals, adjusted for weight and age (P<.05); Based onhomeostatic model assessment, assessing insulin resistance and beta-cell function.Adapted with permission. Newcomer JW et al. Arch Gen Psychiatry.Vol 59. pp337-345. Copyright © 2002.American Medical Association. All rights reserved.
  • 35. Treatment of Acute Mania: Divalproex, Lithium, vs Placebo Bowden et al, JAMA 1994 30Mania Rating Scale Placebo Lithium Divalproex 14 7 14 21 Days
  • 36. • Adapted from Bowden et alAcute Antimanic Efficacy vs Worsening Marked Improvement >0 <10 WORSE 54% 48% 43% 44% 29% 27% 23% 23% 9% Lithium Divalproex Placebo
  • 37. Antimanic Response to Aripiprazole With High Versus Low Agitation
  • 38. YMRS Total: Mean Change Baseline to Endpoint High or Low Agitation * * * * * **P ≤ 0.0005, unadjusted means.• Including baseline YMRS score as a covariate and least-squaremeans, aripiprazole-treated patients showed significantimprovements at endpoint compared with placebo-treated patientsin both high and low agitation groups
  • 39. Mean CGI-BP Scores:Acutely Manic Patients With High or Low Agitation * * * * **P ≤ 0.05, unadjusted means.• Including baseline CGI-BP Severity score as a covariate and least-square means, aripiprazole-treated patients showed significantimprovements at endpoint compared with placebo-treated patientsin both high and low agitation groups
  • 40. PEC Scores: Mean Change Baseline to Endpoint• Including baseline PEC score as a covariate and least-squaremeans, aripiprazole-treated patients showed significantimprovements at endpoint compared with placebo-treated patientsin both high and low agitation groups
  • 41. Make the Guidelines your own!Customized Self guidance, not imperative directive• Every clinical user can • Define decision points • Weigh options • Discipline assessment and intervention• Utility requires – Concision – Critical Awareness of the evidence • Subject to revision • New data becomes available • New Interventions become available – Integration of Measurement into managementwww.manicdepressive.org