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High Relaps Rates in Bipolar Patients over Decades not Changed

IRPB Lisboa 2015 What medication works best in observational, naturalistic trials in bipolar disorder? Christian Simhandl Bipolar Zentrum Wiener Neustadt, Austria. High Relaps Rates in Bipolar Patients over Decades not Changed. Biological Psychiatry 2000 Volume 48, Issue 6, Pages 445–457.

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High Relaps Rates in Bipolar Patients over Decades not Changed

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  1. IRPB Lisboa 2015What medication works best in observational, naturalistic trials in bipolar disorder?Christian SimhandlBipolar Zentrum Wiener Neustadt, Austria

  2. High Relaps Rates in Bipolar Patients over Decades not Changed Biological Psychiatry 2000 Volume 48, Issue 6, Pages 445–457 “The natural length of affective episodes has probably not changed over the past 120 years… The recurrence of bipolar disorder was always the rule; it now seems to be established that there is some initial shortening of intervals/cycles, followed by an irregular persistent recurrence...”

  3. Meta-analysis of 1375 Bipolar I and II patientsobservational, naturalistic studies Relapse rate in bipolar disorder Amann and Radua, submitted 2015

  4. Comparative efficacy and tolerability of pharmacological treatments in the maintenance treatment of bipolar disorder: a systematic review and network meta-analysis • Tomofumi Miura, Hisashi Noma, Toshi A Furukawa, Hiroshi Mitsuyasu, Shiro Tanaka, Sarah Stockton, Georgia Salanti, Keisuke Motomura, Satomi Shimano-Katsuki, Stefan Leucht, Andrea Cipriani, John R Geddes, Shigenobu Kanba • Lancet Psychiatry 2014; 1: 351–59 • network meta-analysis to investigate the comparative efficacy and tolerability of available pharmacological treatment strategies for bipolar disorder. • randomised controlled trials published before June 28, 2013, that compared active treatments for bipolar disorder (or placebo), either as monotherapy or as add-on treatment, for at least 12 weeks. • The primary outcomes were the number of participants with recurrence of any mood episode, and the number of participants who discontinued the trial because of adverse events. • We assessed efficacy and tolerability of bipolar treatments using a random-effects network meta-analysis within a Bayesian framework.

  5. Tomofumi Miura et al. Lancet Psychiatry 2014 • 114 potentially eligible studies and identified 33 randomised controlled trials, published between 1970 and 2012, • 17 treatments for bipolar disorder (or placebo) in 6846 participants. • Participants assigned to all assessed treatments had a significantly lower risk of any mood relapse or recurrence compared with placebo, except for those assigned to aripiprazole, carbamazepine, imipramine, and paliperidone. • Lamotrigine and placebo were significantly better tolerated than carbamazepine (lamotrigine, placebo,, lithium, or lithium plus valproate.

  6. Tomofumi Miura et al. Lancet Psychiatry 2014

  7. Tomofumi Miura et al. Lancet Psychiatry 2014 • Interpretation: Although most of the drugs analysed were more efficacious than placebo and generally well tolerated, differences in the quality of evidence and the side-effect profiles should be taken into consideration by clinicians and patients. • In view of the efficacy in prevention of both manic episode and depressive episode relapse or recurrence and the better quality of the supporting evidence, lithium should remain the first-line treatment when prescribing a relapse-prevention drug in patients with bipolar disorder, notwithstanding its tolerability profile.

  8. RCTs tell only half of the story

  9. Quetiapin and Classical Mood Stabilizers in the long-term treatment of Bipolar Disorder: A 4-year follow-up naturalistic study.Carlo Altamura et al JAD 2008 110, 135-141 232 DSM-IV BD I (n=91) or BD II (n=141), outpatients, monthly assessed, 2001-2005, HAMD21>8<18, YMRS>10<20 full-syndromal, sub-threshold, n % euthym drop out% mean dosage Quetiapin 41 29.3 56.1 214mg/d Lithium 39 46.2 43.6 0.7mMol/l Sodium valproat 73 32.9 42.5 52.1ng/ml Lamotrigine 31 41.9 38.7 79.2mg/d Quetiapin + Lithium 25 80 24 223.5 + 0.7 Quetiapin + sodium valproat 23 78.3 21.7 215.2 + 60.5ng/ml

  10. Group 5 + 6 Altamura et al 2008 JAD

  11. Group 5 Quet + Li Altamura et al 2008 JAD

  12. Lithium plus valproate combination therapy versus monotherapy for relapse prevention in bipolar I disorder (BALANCE): a randomised open-label trial The Lancet Vol 375, No 9712, p385-395, 2010 Geddes JR, Goodwin GM, Rendell J, Azorin JM, Cipriani A, Ostacher MJ, Morriss R, Alder N, Juszczak E Balance Study

  13. Balance Study, Li v Val v Li+Val, The Lancet Vol 375, No 9712 2010, Geddes et al. 330 patients from 41 sites in UK, France, USA, Italyrandomly allocated, (50% recent Man episode1. open label Lithium monoth. 0.4-1.0 n=1102. open label Valproate monoth. 750-1250mg, n=1103. open label Li + Val n=110 24 monthendpoint: initiation of a new intervention ITT

  14. Balance Study, Li v Val v Li+Val, The Lancet Vol 375, No 9712 2010, Geddes et al. Val 76 (69%) 0·59 (95% CI 0·42–0·83,p=0·0023) 0·71 (0·51–1·00, p=0·0472) Li 65 (59%) 0·82 (0·58–1·17, p=0·27)Li + Val 59 (54%) ...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.

  15. Neunkirchen cohort • start in 2000 as a prospective project • defined catchment area of 200.000 habitants • consecutive recruitment of 515 hospitalized bipolar I • & II patients (ICD-10, MINI) • diagnosis by 2 trained psychiatrists • informed consent • documentation with a semistructured web based • interview • naturalistic setting, no study drug, treatment by the • local physician (specialist, GP)

  16. FOLLOW UP periode 2000-2008 • 366 patients gave IC, 66 (18%) moved, change of diagnosis, could not be reached • 5(1.4%) died, 6 (1.6%) died by suicide • Final analysis: n=300, 158 bipolar I und 142 bipolar II (hospitalised) • follow up every year: personally / telefone web based interview, hospital records, outpatient service, regional physicians,

  17. relapse is the typical part in the course in bipolar disorder in spite of any medication

  18. Mood Stabilizer Monotherapie vs Combination Simhandl C., B. König, B. Amann: A Prospective 4-Year Naturalistic Follow-Up of Treatment and Outcome of 300 Bipolar I and II Patients, J Clin Psychiatry 2014;75(3):254-263

  19. Change of Medikation Simhandl C., B. König, B. Amann: A Prospective 4-Year Naturalistic Follow-Up of Treatment and Outcome of 300 Bipolar I and II Patients, J Clin Psychiatry 2014;75(3):254-263

  20. Summary of Neunkirchen Naturalistic Study204 of 300 patients (68%) relapsed within the observation period of 4 years, with a mean of 208 days (SD = 356.2) until the next affective episode. Relapses correlated in a statistically significant manner with the index episode (χ2 = 57.48, P = .000; bipolar I: χ2 = 20.19, P = .000; bipolar II: χ2 = 106.82, P = .000). A Kaplan survival analysis showed that lithium in monotherapy statistically significantly delayed time to the next affective relapse (P = .002). Survival (time to relapse) was statistically significantly reduced when prophylactic medication was changed by the psychiatrist (P = .000) or stopped by the patient (P = .001).

  21. Discussion • Our data confirm a high risk of relapse of 68% in a naturalistic setting • over 4 years. • Garnham et al JAD 2007: 30% improved on Lithium, naturalistic • STEP-BD Perlis et al 2006 AJP: 48.5% recurrence in 2 years, 34.7 depression • EMBLEM Azorin et al 2009 BMC Psychiatry 66% of BIP I, 34% mixed 2years • Altamura et al JAD 2008 4 years 232 BIPI &II: euthymremained: 29,3% Quet, 46,2% Li, 32.9% Val, 41.9% Lam, Li/Val+Quet 80% • Lithium seems to offer some advantage over other medication in the long-term • treatment of bipolar I and II disorder. • Rybakowski JK 2014 Excelent Lithium responders(M. Alda, P. Grof) ? • Changingofmedicationsbythepsychiatristandstoppingofmedicationbythepatientappeartobeclearriskfactorsfor an earlieraffectiverelapse. • Combinationstrategiesseemtohave a pooroutcome in ourstudy, but... • BALANCE Trial: different, BIP I, eventover 2 years 54% Li+Val, 59% Li, 69% Val

  22. Discussionand open Questions • wecantreatsuccessfullyabout50% ofourpatients • combinationstrategy Li + Val earlier?, Li/Val + AP? • Li/Val or Lam + psychosocialstrategies ? • Kaplan Mayer vsWilcoxonmatchedpairsorboth • Defineothertreatmentgoals reducedfrequency, reducedintensity, < noofhospitalisations reduceddurationofepisodeprolongedfreeintervall socialfunctioning, noresidual symptoms • RCT + naturalisticobservationsnecessary in treatmentguidelines

  23. The authors acknowledge support from the Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM). • They also acknowledge support from the Research Group Industrial Software Engineering of the Technical University of Vienna and their department head Prof DI Dr Thomas Grechenig. • Furthermore, they thank Drs Jutta Bilonoha, Elisabeth Denk, Birgit Gasselseder, Jens Mersch, Klaudia Mitterwachauer, Stephanie Schiebel, Christian Wunsch, Ali Zoghlami, and Daniela Renhofer for data entry. • The authors acknowledge support from Thomas Simhandl, BSc, for the first version of the web-based interview and thank Jules Angst, MD, for reading and discussing the manuscript with the authors. • None of the acknowledged individuals report conflict of interest.

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