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. 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. The WFSBP Guidelines on the
Biological Treatment of Bipolar
Disorder
Methodology

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. 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. 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. 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. 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. 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. 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. Limitations
 Limitation of evidence
 Incompleteness of information
 Publication bias
 Sponsor bias

12. ……some medication for everyone ?
Study subjects vs. Real world patients

13. Limitations
 Limitation of evidence
 Incompleteness of information
 Publication bias
 Sponsor bias

14. AJP 163 (2006), 185- 194

15. Sources of support
 None- no sponsorship from industry or
any other organization

16. Treatment of mania

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. 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. 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. 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. 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. 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. 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. 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. Combination Treatment

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. 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. Aripiprazole vs placebo add-on to
lithium or valpraote
Vieta et al, 2008

29. CN 138-189: Combination maintenance
treatment
Owen et al, 2010

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. 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. • 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. 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