WFSBP Guidelines Mania - Prof Grunze

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  • OverviewThis study is the CN138-010 study, which was a 26-wk double blind, placebo controlled study of aripiprazole in prevention of manic relapse. It was followed by a prospective, placebo-controlled 74-week extension phase (total study duration 100 weeks). Efficacy in relapse prevention was therefore evaluated for 100 weeks.MethodsPatients with bipolar 1 disorder, manic or mixed, were treated with aripiprazole 30mg/day for 6-18 weeks (started on 30mg but dose could be reduced to 15mg). Patients achieving stabilisation (defined as YMRS total score ≤ 10 and MADRS ≤ 13 for 4 consecutive visits over a minimum of 6 weeks entered the randomised phase of the study, which was double-blind assignment to either aripiprazole monotherapy (n=77) or placebo (n=83) for 26 weeks. Study primary endpoint was time to relapse of any mood episode (manic, depressive or mixed) at 26 weeks. Discontinuation due to lack of efficacy was defined as relapse. Other endpoints included change from baseline in YMRS, CGI-BP severity of illness (mania, depression and overall score), MADRS, PANSS total score, hostility subscore and cognitive subscore. Patients who discontinued for reasons other than relapse were censored at that time point. Study populationPatients with bipolar 1 disorder, manic or mixed. 17% and 18% of PLA and ARI group were considered rapid cyclers respectively. 22% and 38% were considered mixed mania patientsStudy visits took place at randomisation (day 1 of db phase), then weekly for the first 4 weeks, biweekly from week 6 to 28, monthly from week 28-52 and bimontly after that. The 26 week results of this study were published by Keck et al J. Clin Psych 2006: 67 p626-637Patients without relapse were eligible to enter a further 74-week prospective phase. Of the 67 patients who completed the 26-week phase without relapse, 66 entered the extension phase. They were assigned in a double-blind manner to receive the same dose of aripiprazole they had been receiving or to get placebo. Entrance into the extension phase ended once 45 patients had relapsed but all patients were kept blinded until the LPLV of the 26-week study endpoint had been completed.Lorazepam was allowed during the first 18 weeks of the study, the only other permitted co-medication was anticholinergics. ResultsAt 100 weeks, time to any relapse was significantly longer for aripiprazole than placebo (HR 0.53, 95% CI 0.32-0.87, p=0.11). Number of relapse by 100 weeks was 7 in aripiprazole group and 5 in placebo group. There were more discontinuations due to lack of efficacy in the placebo group vs the ARI group (26% vs 13%). Aripiprazole was superior to placebo in delaying time to manic relapse but not time to depressive relapse. Proportion of patients experiencing relapse by 100 weeks was 52% (43/83) for placebo and 33% (25/77) for aripiprazole patientsMean weight change from baseline to 100 weeks (LOCF) was +0.4 ± 0.8kg with aripiprazole and -1.9 ± 0.8kg with placebo. Main reason for discontinuation was study closure when study had met predefined number of relapses. A total of 12 patients completed full 100 weeks of study, completion rate for ARI 18% and PLA 19%Mean aripiprazole dose at end of 74-week study phase (23.8mg) was similar to start of study (23.6mg)YMRS total score increased (i.e. worsened) significantly more in placebo arm than in ARI arm but there was no difference between groups in MADRS total score. Mean change in PANSS scores by week 100 favoured aripiprazole.
  • WFSBP Guidelines Mania - Prof Grunze

    1. 1. Pharmacological treatment modalities in bipolar disorder: What the WFSBP Guidelines 2009 recommend Bipolar Cave Painting Organised and Funded By Prescribing Information and Averse Event reporting Information can be found on the final slide. ABI/1010/4791/0912 Date of preparation: Oct 2010
    2. 2. Declaration of Conflicts of Interest Heinz Grunze (last updated 20.9.2010)  I have received grants/ research support, consulting fees and honoraria within the last three years from Astra Zeneca, Bial, BMS, Cephalon, Eli Lilly, Gedeon Richter, Janssen-Cilag, Merck, Organon, Pfizer Inc, Sanofi-Aventis, Sepracor, Servier and UBC .  Neither I nor any member of my family have shares in any pharmaceutical company or could benefit financially from increases or decreases in the sales of any psychotropic medication. During this presentation, some medication may be mentioned which are off-label and not or not yet licensed for the specified indication!!
    3. 3. The WFSBP Guidelines on the Biological Treatment of Bipolar Disorder Methodology
    4. 4. WFSBP Task Force on Treatment Guidelines for Bipolar Disorders  Siegfried Kasper (Chairman, Austria), Guy Goodwin (Co-Chairman, United Kingdom), Charles Bowden (Co-Chairman, USA), Heinz Grunze (Secretary, United Kingdom), Hans-Jürgen Möller (WFSBP Past-President, Germany), Eduard Vieta (Spain), Rasmus W. Licht (Denmark).  Hagop Akiskal (USA), José Luis Ayuso-Gutierrez (Spain), Michael Bauer (Germany), Per Bech (Denmark), Michael Berk (Australia), Istvan Bitter (Hungary), Graham Burrows (Australia), Joseph Calabrese (USA), Giovanni Cassano (Italy), Marcelo Cetkovich-Bakmas (Argentina), John C. Cookson (United Kingdom), I. Nicol Ferrier (United Kingdom),Wagner F. Gattaz (Brazil), Frederik K. Goodwin (USA), Gerhard Heinze (Mexico), Teruhiko Higuchi (Japan), Robert M. Hirschfeld (USA), Cyril Hoeschl (Czech Republik), Edith Holsboer-Trachsler (Switzerland), Kay Redfield Jamison (USA), Cornelius Katona (UK), Martin Keller (USA), E. Kostukova (Russia), Hever Kruger (Peru), Parmanand Kulhara (India), Yves Lecruibier (France), Veronica Larach (Chile), Odd Lingjaerde (Norway), Henrik Lublin (Denmark), Mario Maj (Italy), Julien Mendlewicz (Belgium), Roberto Miranda Camacho (Mexico), Philip Mitchell (Australia), S. Mosolov (Russia), Stuart Montgomery (United Kingdom), Charles Nemeroff (USA), Willem Nolen (The Netherlands), Eugene S. Paykel (United Kingdom), Robert M. Post (USA), Stanislaw Puzynski (Poland), Zoltan Rihmer (Hungary), Janusz K. Rybakowski (Poland), Per Vestergaard (Denmark), Peter C. Whybrow (USA), Kazuo Yamada (Japan)
    5. 5. Sources  MEDLINE and EMBASE search  Science Citation Index at Web of Science (ISI) (all until end of 2008)  Recent proceedings of key conferences  Various national and international treatment guidelines  Hand-searching in text books  In addition, www.clinicaltrials.gov was accessed to check for unpublished studies.
    6. 6. Ranking of evidence  Priority for RCT with Placebo control  Additional evidence ( comparator studies, open studies, case reports) only when first line evidence was missing  Metaanalyses were used not as primary, but only supportive evidence.
    7. 7. Common problems with meta-analyses  „File-Drawer“ (Publication bias)  „Garbage in- Garbage out“  „ Apples and pears“ (Heterogenicity of studies)  „Missing data“  Overlapping samples (Not independent samples) Quorum statement; Moher et al, 1999
    8. 8. Category of Evidence Description A Full Evidence From Controlled Studies is based on: 2 or more double-blind, parallel-group, randomized controlled studies (RCTs) showing superiority to placebo (or in the case of psychotherapy studies, superiority to a ‘psychological placebo’ in a study with adequate blinding) and 1 or more positive RCT showing superiority to or equivalent efficacy compared with established comparator treatment in a three-arm study with placebo control or in a well-powered non-inferiority trial (only required if such a standard treatment exists) In the case of existing negative studies (studies showing non-superiority to placebo or inferiority to comparator treatment), these must be outweighed by at least 2 more positive studies or a meta-analysis of all available studies showing superiority to placebo and non-inferiority to an established comparator treatment. Studies must fulfill established methodological standards.The decision is based on the primary efficacy measure. B Limited Positive Evidence From Controlled Studies is based on: 1 or more RCTs showing superiority to placebo (or in the case of psychotherapy studies, superiority to a ‘psychological placebo’) or a randomized controlled comparison with a standard treatment without placebo control with a sample size sufficient for a non-inferiority trial and In the case of existing negative studies (studies showing non-superiority to placebo or inferiority to comparator treatment), these must be outweighed by at least 1 more positive study or a meta-analysis of all available studies showing superiority to placebo or at least one more randomized controlled comparison showing non-inferiority to an established comparator treatment. Hierarchy of evidence based rigor and level of recommendation
    9. 9. C Evidence from Uncontrolled Studies or Case Reports/Expert Opinion C1 Uncontrolled Studies is based on: 1 or more positive naturalistic open studies (with a minimum of 5 evaluable patients) or a comparison with a reference drug with a sample size insufficient for a non-inferiority trial and no negative controlled studies exist C2 Case Reports is based on: 1 or more positive case reports and no negative controlled studies exist C3 Based on the opinion of experts in the field or clinical experience D Inconsistent Results Positive RCTs are outweighed by an approximately equal number of negative studies E Negative Evidence The majority of RCTs studies or exploratory studies shows non-superiority to placebo (or in the case of psychotherapy studies, superiority to a ‘psychological placebo’) or inferiority to comparator treatment ? F Lack of Evidence Adequate studies proving efficacy or non-efficacy are lacking. Hierarchy of evidence based rigor and level of recommendation
    10. 10. Hierarchy of evidence based rigor and level of recommendation Recommendation Grade (RG) Based on: 1 Category A evidence and good risk-benefit ratio 2 Category A evidence and moderate risk-benefit ratio 3 Category B evidence 4 Category C evidence 5 Category D evidence
    11. 11. Limitations  Limitation of evidence  Incompleteness of information  Publication bias  Sponsor bias
    12. 12. ……some medication for everyone ? Study subjects vs. Real world patients
    13. 13. Limitations  Limitation of evidence  Incompleteness of information  Publication bias  Sponsor bias
    14. 14. AJP 163 (2006), 185- 194
    15. 15. Sources of support  None- no sponsorship from industry or any other organization
    16. 16. Treatment of mania
    17. 17. WFSBP Guideline mania Medication Category of Evidence (CE) Recommendation Grade Aripiprazole A 1 Asenapine A 2 Carbamazepine A 2 Haloperidol A 2 Lithium A 2[1] Olanzapine A 2 Quetiapine A 2 Risperidone A 1 Valproate A 1[2] Ziprasidone3 A 1[4] Chlorpromazine B 3 Paliperidone B 3 Phenytoin B 3 Pimozide B 3 Tamoxifen B 3 1. If long term treatment is considered the recommended grade for lithium is 1 2. Use with caution in women of child bearing age 3. Ziprasidone is not licensed in the UK 4. Ziprasidone has a safety rating of 1, but due to concerns over cardiotoxicity, its use is restricted in some countries. In these countries the grade is considered 2 for legal reasons.
    18. 18. WFSBP Guideline mania Amisulpride C1 4 Clonazepam C1 4 Clozapine C1 4 Levetiracetam C1 4 Lorazepam C1 4 Nimodipine C1 4 Oxcarbazepine C1 4 Retigabine C1 4 Zonisamide C1 4 Zotepine C1 4 Verapamil D 5 Lamotrigine E - Topiramate E - Gabapentin E - Tiagabine F - Pregabalin F - ECT C1 4 rTMS E -
    19. 19. Hadjikas et al 2004; McIntyre et al 2005; Tohen et al 1999, 2000; Khanna et al 2003 Weisler et al 2005; Hirschfeld et al 2002; Keck et al 2003; Segal et al 2003 *Data are from different studies and thus cannot be compared directly Efficacy of antimanic agents vs placebo: Response rates* Response rate (%) 0 10 20 30 40 50 60 70 80 QTP OLZ RIS ARI LITH vs DVP ERC- CARB ZIP Pal Placebo
    20. 20. Mean Change From Baseline in Y-MRS Total Score, Efficacy Sample (LOCF) *p<0.05; †p<0.01; ‡p<0.001 vs. placebo; Baseline Y-MRS scores (SE): placebo 28.9 (0.4); lithium 29.4 (0.4); aripiprazole 28.5 (0.4) -16 -14 -12 -10 -8 -6 -4 -2 0 1 32 ChangeinY-MRS FromBaseline Week 0 † ‡ ‡ * ‡ ‡ ‡ ‡ ‡ † Placebo (n=163) Aripiprazole (n=154) Lithium (n=155) Keck PE et al. (2009)
    21. 21. Meta-Analysis of Efficacy: Haloperidol vs. AAP Scherk H et al. (2007), Arch Gen Psychiatry 64(4):442-455 Aripiprazole Olanzapine Quetiapine All SGAs Pooled Risperidone Pooled Risperidone Quetiapine Olanzapine Aripiprazole
    22. 22. Efficacy sample; *p≤0.05; **p≤0.01 vs. placebo Baseline: Placebo=28.8; Aripiprazole=28.4; Haloperidol= 28.0 Aripiprazole: Mean Change in Y-MRS Total Score to Week 12 (LOCF)ChangeinY-MRSTotal ScoreFromBaseline Week Day2 Day4 Day10 1 2 3 4 5 6 8 10 12 -20 -15 -10 -5 0 Placebo (N=152) Aripiprazole (N=166) Haloperidol (N=161) Young et al. (2009)
    23. 23. Aripiprazole in long-term prevention of any mood episodes in bipolar disorder Graph represents a Kaplan-Meier curve for time from randomisation to relapse for any reason *Relapse defined as discontinuation of the study due to lack of efficacy and was indicated by hospital admission due to a mood episode and/or addition to or increase in psychotropic medication other than the study drug, for manic and/or depressive symptoms; HR, Hazard Ratio Keck PE Jr et al. J Clin Psychiatry 2007;68(10):1480–1491 Weeks 10095908580757065605550454035302520151050 0 10 20 30 40 50 60 70 80 90 100 Proportionofpatients withoutrelapse*(%) Log rank p = 0.011 HR = 0.53 (95% CI = 0.32 to 0.87) Aripiprazole (n = 77) Placebo (n = 83)
    24. 24. Efficacy of IM Aripiprazole in Agitated Bipolar Mania+ DBR, PLC controlled study with 301 patients Up to 3 injections/24 hours Primary efficacy measure: PEC score change after 2 hours *p<0.05 vs. placebo; IM = intramuscular; DBR = double-blind, randomized; PEC = Positive and Negative Syndrome Scale Excited Component; Zimbroff DL et al. (2007), J Clin Psychopharmacol 27(2):171-176 +patient population shown in this graph: all patients received 2nd injection including non-responders to 1st injection MeanChangeinPEC ScoreFromBaseline Minutes 0 -1 -2 -3 -4 -5 -6 -7 -8 -10 -9 -11 0 90 12030 60 Placebo (n=73) Aripiprazole 9.75 mg (n=75) Aripiprazole 15 mg (n=75) Lorazepam 2 mg (n=68) * * * * * *
    25. 25. Combination Treatment
    26. 26. Drug combinations in mania  The direct evidence is existing, but largely limited to MS-aAP combinations  Different from most clinical studies, they are often initiated in partial responders to an initial monotherapy  Dosages vary from recommended doses in monotherapy, and there is little evidence from studies about optimal dosages
    27. 27. Smith LA, et al. Acta Psychiatr Scand 2007; 115: 12–20 Add-on therapy vs monotherapy in mania: response rates 5 Olanzapine + MS Tohen, 2002b (149/220 51/114) Subtotal Quetiapine + MS DelBello, 2002 (13/15 8/15) Subtotal Risperidone + MS Sachs, 2004 (44/81 29/89) Yatham, 2003 (40/68 30/73) Subtotal Risk ratio (95% CI)Study 1.51 (1.21, 1.89) 1.51 (1.21, 1.89) 1.63 (0.97, 2.72) 1.63 (0.97, 2.72) 1.67 (1.16, 2.39) 1.43 (1.02, 2.01) 1.55 (1.21, 1.98) % Weight 100.0 100.0 100.0 100.0 48.9 51.1 100.0 Favours co-therapyFavours monotherapy Risk ratio 0.5 1 2 MS, mood stabilisers
    28. 28. Aripiprazole vs placebo add-on to lithium or valpraote Vieta et al, 2008
    29. 29. CN 138-189: Combination maintenance treatment Owen et al, 2010
    30. 30. WFSBP Guideline mania 2009 First choice medication:  Choose monotherapy with a CE “A”, RG “1” medication, considering:  Symptoms of mania (e.g., euphoric, mixed, psychotic) and severity  Previous experience* and patients preference  Evidence for efficacy as maintenance treatment if appropriate  Modifying medical factors and specific safety profile  Route and ease of administration  Tolerability and efficacy in continuation therapy if indicated Grunze et al, 2009* Patient‘s experience and history
    31. 31. Treatment of mania: Algorithm from the WFSBP Monotherapy with RG 1 Individual safety/tolerability issues Previous treatment history Patient preference Subtype Need of prophylaxis Route and ease of administration No response after W 2: Switch to another RG 1 drug Partial response after W 2: Continue and optimize dosage No further improvement after W 5: Consider combination with another RG 1 Still unresponsive after W 4: Consider combination with two RG 1 ETC…. e.g. ECT
    32. 32. • Treatment choices for Bipolar Mania have increased considerably during the last decade. • Important features of a first choice antimanic mediction include short- and long term efficacy, tolerability, safety and practicability • Guidelines may support clinicians in the choice of medication, however, many individual factors as patient’s preference and history of previous treatment response have a decisive impact when it comes to find the optimal solution for an individual patient. Conclusions
    33. 33. PRESENTATION: Tablets: 5mg, 10mg, 15mg, 30mg aripiprazole; orodispersible tablets (ODT): 10mg, 15mg aripiprazole; oral solution (OS): 1mg/ml aripiprazole; solution for injection for intramuscular use (IM): 7.5mg/ml aripiprazole (1.3ml vial containing 9.75mg aripiprazole). INDICATIONS: Oral formulations: Adults: Schizophrenia. Moderate to severe manic episodes in Bipolar I Disorder & prevention of new manic episodes in aripiprazole respondent patients. Paediatric patients: Schizophrenia in adolescents 15 years and older. IM: Rapid control of agitation & disturbed behaviours in schizophrenia or manic episodes in Bipolar I Disorder. DOSAGE: Oral formulations: Adults: Schizophrenia: Usual starting dose is 10 or 15mg once daily with or without food. Effective dose range is 10 to 30mg with a recommended maintenance dose of 15mg. Mania in Bipolar I Disorder: Usual starting dose is 15mg once daily with or without food as monotherapy or combination therapy. For recurrence prevention, continue at same dose. Dose adjustment on basis of clinical status. Paediatric patients: Schizophrenia: Recommended dose is 10 mg/day once daily with or without food. Treatment to be initiated at 2 mg (using ABILIFY Oral Solution 1 mg/ml) for two days, titrated to 5 mg for two more days to reach recommended daily dose of 10 mg. Effective dose range is 10 to 30 mg/day. IM: Initial dose 9.75mg (1.3ml) injection. Effective dose range: 5.25 to 15 mg as single injection. Lower dose of 5.25 mg (0.7 ml) may be given. Second injection may be administered two hours after the first, on basis of individual clinical status. No more than three injections in any 24-hour period. For all formulations (adult and paediatric patients): Maximum daily dose 30mg. No dosage adjustment required in renal or mild to moderate hepatic impairment. Elderly (> 65 years): Efficacy not established. Consider lower starting dose. Not recommended for use in patients below 15 years of age: Safety and efficacy not established. CONTRA-INDICATIONS: Hypersensitivity to any ingredient. WARNINGS AND PRECAUTIONS: Clinical improvement may take several days to some weeks: monitor patient throughout this period. Reduce dose or discontinue if signs of tardive dyskinesia appear. Discontinue if patient develops signs and symptoms indicative of neuroleptic malignant syndrome. Caution in patients with a history of seizure, cardiovascular disorders, conduction abnormalities, diabetes and elderly patients with dementia-related psychosis and those at risk of aspiration pneumonia (see SPC). All risk factors for venous thromboembolism (VTE) should be identified before and during treatment with ABILIFY and preventive measures undertaken. Do not use in pregnancy unless benefit outweighs risk; breastfeeding not advised. Until individual patient response established, caution not to drive or operate machinery. IM: observe patients for orthostatic hypotension and regularly monitor blood pressure, pulse, respiratory rate and level of consciousness. If additional parenteral benzodiazepine therapy is deemed necessary, monitor patients for excessive sedation and for orthostatic hypotension. DRUG INTERACTIONS: Increased hypotensive effect with certain antihypertensives. Caution is advised when combining with alcohol or other CNS medication with overlapping side effects such as sedation; also with certain antifungals, antituberculous drugs, antivirals, anticonvulsants, St John's Wort and medicines known to cause QT prolongation or electrolyte imbalance. Reduce aripiprazole dose with concomitant use of potent CYP3A4 or CYP2D6 inhibitors, e.g. fluoxetine, paroxetine. Increase aripiprazole dose with concomitant use of potent CYP3A4 inducers, e.g. carbamazepine. See SPC. IM: increased sedation when combined with lorazepam. UNDESIRABLE EFFECTS: In adult placebo-controlled trials, the following adverse drug reactions were reported: Tablets, ODT, OS, IM common (>1/100 <1/10): somnolence, dizziness, headache, akathisia, nausea, vomiting; Tablets, ODT, OS common (>1/100 <1/10): restlessness, insomnia, anxiety, extrapyramidal disorder, tremor, sedation, blurred vision, dyspepsia, constipation, salivary hypersecretion, fatigue; Tablets, ODT, OS, IM uncommon (>1/1000 <1/100): tachycardia, orthostatic hypotension; IM uncommon (>1/1000 <1/100): increased diastolic blood pressure, fatigue, dry mouth; Tablets, ODT, OS uncommon (>1/1000 <1/100): depression. In adolescent (13-17 years) placebo-controlled trials, the adverse drug reactions reported were similar to those for adults; the following adverse drug reactions were reported more frequently than for adults: very common (> 1/10): somnolence, sedation, extrapyramidal disorder; common (> 1/100 < 1/10): dry mouth, increased appetite, orthostatic hypotension. Other adverse events from post-marketing surveillance include; allergic reaction (anaphylaxis & angioedema), pancreatitis, priapism, suicide, rhabdomyolysis, hyperglycaemia, diabetes, dysphagia, convulsions, cardiac disorders including arrhythmias & sudden unexplained death, VTE (including pulmonary embolism and deep vein thrombosis), hypertension, hepatitis, leukopenia and thrombocytopenia. Symptoms of dystonia may occur in susceptible individuals during the first few days of treatment with an elevated risk of acute dystonia observed in males and younger age groups. Other findings, see SPC. OVERDOSAGE: Treatment should be symptomatic and supportive: adequate airway maintenance, cardiovascular monitoring and close medical supervision. Activated charcoal reduces serum concentrations. LEGAL CATEGORY: POM AUTHORISATION NUMBERS & BASIC NHS PRICE: 28 tablets; 5mg (EU/1/04/276/002) £95.74, 10mg (EU/1/04/276/007) £95.74, 15mg (EU/1/04/276/012) £95.74, 30mg (EU/1/04/276/017) £191.47. 28 orodispersible tablets; 10mg (EU/1/04/276/025) £95.74, 15mg (EU/1/04/276/028) £95.74. 150mL bottle 1mg/ml oral solution: (EU/1/04/276/034) £102.57. 1.3ml vial 7.5mg/ml solution for injection: (EU/1/04/276/036) £3.42. MARKETING AUTHORISATION HOLDER: Otsuka Pharmaceutical Europe Ltd, Hunton House, Highbridge Business Park, Oxford Road, Uxbridge, Middlesex UB8 1HU. FURTHER INFORMATION FROM: Bristol-Myers Squibb Pharmaceuticals Ltd., Uxbridge Business Park, Sanderson Road, Uxbridge, Middlesex, UB8 1DH. Tel: 0800-731-1736 DATE OF P.I. PREPARATION: January 2010 ABI/1209/4347/1111 ABILIFY (aripiprazole) PRESCRIBING INFORMATION TABLETS, ORODISPERSIBLE TABLETS, ORAL SOLUTION & ABILIFY 7.5 mg/ml SOLUTION FOR INJECTION See Summary of Product Characteristics before prescribing. Adverse events should be reported. Reporting forms and information can be found at www.yellowcard.gov.uk Adverse events should also be reported to Bristol-Myers Squibb Pharmaceuticals Ltd Medical Information on 0800 731 1736 or medical.information@bms.com

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