Transcript Simhandl C
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
“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...”
Relapse rate in bipolar disorder
Meta-analysis of 1375 Bipolar I and II patients
observational, naturalistic studies
Amann and Radua, submitted 2015
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.
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.
Tomofumi Miura et al. Lancet Psychiatry 2014
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 relapseprevention drug in patients with bipolar disorder, notwithstanding its tolerability
profile.
RCTs tell only half of the story
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
Quetiapin
Lithium
Sodium valproat
Lamotrigine
Quetiapin + Lithium
Quetiapin + sodium valproat
41
39
73
31
25
23
% euthym drop out%
29.3
46.2
32.9
41.9
80
78.3
56.1
43.6
42.5
38.7
24
21.7
mean dosage
214mg/d
0.7mMol/l
52.1ng/ml
79.2mg/d
223.5 + 0.7
215.2 + 60.5ng/ml
Group 5 + 6
Altamura et al 2008 JAD
Group 5
Quet + Li
Altamura et al 2008 JAD
Balance Study
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, 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, Italy
randomly allocated, (50% recent Man episode
1. open label Lithium monoth.
0.4-1.0
n=110
2. open label Valproate monoth. 750-1250mg, n=110
3. open label Li + Val
n=110
24 month
endpoint: initiation of a new intervention
ITT
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
Li + Val
65 (59%)
59 (54%)
0·82 (0·58–1·17, p=0·27)
...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.
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)
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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,
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relapse is the typical part in the course in bipolar disorder
in spite of any medication
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
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
Summary of Neunkirchen Naturalistic Study
204 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).
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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: euthym remained: 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) ?
• Changing of medications by the psychiatrist and stopping of medication by the patient
appear to be clear risk factors for an earlier affective relapse.
• Combination strategies seem to have a poor outcome in our study, but...
BALANCE Trial: different, BIP I, event over 2 years 54% Li+Val, 59% Li, 69% Val
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Discussion and open Questions
•
•
•
we can treat successfully about 50% of our patients
combination strategy Li + Val earlier?, Li/Val + AP?
Li/Val or Lam + psychosocial strategies ?
• Kaplan Mayer vs Wilcoxon matched pairs or both
• Define other treatment goals
reduced frequency, reduced intensity, < no of hospitalisations
reduced duration of episode prolonged free intervall
social functioning,
no residual symptoms
• RCT + naturalistic observations necessary in treatment guidelines
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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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