BAP Guidelines for the Management of Bipolar Disorder · BAP Guidelines for the Management of Bipolar Disorder G.M. Goodwin “Evidenced based guidelines for treating bipolar disorder:

Psychobiology Research Group

Guidelines for the Pharmacological Management of

Bipolar Disorder

R. Hamish McAllister-Williams, MD, PhD, MRCPsych

Reader in Clinical Psychopharmacology Newcastle University

Hon. Consultant Psychiatrist Regional Affective Disorders Service, RVI

Declaration of Interests

• I have received:Speaker fees from:

• Astra Zeneca, BMS, Eli Lilly, GSK, Janssen-Cilag, Lundbeck, Organon, Pfiser, Wyeth

Consultancy fees from:• Astra Zeneca, BMS, Eli Lilly, Janssen-Cilag,

Lundbeck, WyethIndependent investigator led research support from:

• Astra Zeneca, Eli Lilly and Wyeth

BAP Guidelines for the Management of

Bipolar DisorderG.M. Goodwin “Evidenced based guidelines for treating bipolar disorder: recommendations from the BAP.” J Psychopharmacology 17(2) 2003 149-173

NICE Clinical Guideline July 2006

Bipolar Disorder: The management of bipolar

disorder in adults, children and adolescents, in primary

and secondary care

Practice Guidelines for the Treatment of Patients with Bipolar Disorder

HirschfeldHirschfeld et al., Am. J. et al., Am. J. Psychiatry 2002Psychiatry 2002

The Texas Implementation of Medication Algorithms (TIMA):

Update to the algorithms for treatment of bipolar I disorder

Suppes et al. 2005 J. Clin. Psychiatry 66:870-886

Guidance

Common aspects of care for all people with bipolar disorderAssessment, recognition and diagnosisTreatment setting and pathways to carePhysical careTreatment and management of bipolar disorderLong-term managementTreatment and management of women of child-bearing potentialAssessment, diagnosis and treatment of children and adolescents

Guidance


Common aspects of careInformation and informed consent

Provide good information re disorderCollaborative workingInformation about self-help groups

Psychological principlesTherapeutic relationshipIdentify early warning signsAdvice re life style

Appropriate language and written materialSupport for familiesAdvanced statementsComorbid personality disorderDrugs and alcohol

Guidance


Treatment setting and pathways to care

Long-term illness needing long-term careIntegrated primary / secondary care programmesPrimary care registers and telephone supportCMHTs for:

Problems engaging with services, poor adherenceFrequent relapses, poor symptom control, poor functioning, comorbid anxietySubstance misuseSignificant risk

EIP, CAT, AO, IP, day hospitals, rehab. should all be availableTrusts providing specialist mental health care should ensure that clinicians have access to specialist advice

Guidance


Physical care

At presentationSmoking and alcohol historyRenal function, LFTs, TFTs, FBC, Glucose, lipidsBP, height and weightConsider ECG, CXR, drug screening, EEG, CT, MRI

Annual reviewManagement of weight gain

Diet, exercise, diet clinic, dieticianSibutramine and topiramate NOT recommended

Physical care

AntipsychoticsAt initiation: wt, ht, gluc, lipids, (ECG and prolactin)Monitoring: wt every 3/12 for 1 yr, gluc and lipids at 3/12 (olanz at 1/12), prolactin if indicatedBe aware of NMS and DKA

LithiumNot for primary careWarn re probs of stoppingRenal, TFT, ht and wt (ECG, FBC)Levels 0.6 – 0.8 (or 0.8 – 1.0 if poor response)Warn re NSAIDs

Physical care

ValproateAt initiation and 6/12: Ht, wt, FBC, LFTsNot for women under 18 or of child baring potentialLevels if ineffective, poor adherence or toxicity

LamotrigineSlow titration (N.B. S-JS)Beware interaction with OCP

CarbamazepineOnly on specialist adviceAt initiation: FBC, LFTs, ht and wt (repeat at 6/12 with U&Es)Levels every 6 monthsBeware interaction with OCP

Guidance


Mania

Hypomania

Euthymia

Minor Depression

Major Depression

Preliminary Phase Preventative Phase

The course of Bipolar Disorder

Valproate and Lithium in acute mania Bowden et al 1994 Valproate and Lithium in acute mania Bowden et al 1994PERCENTAGE WITH MARKED (>50%) IMPROVEMENT IN MRS SCOREPERCENTAGE WITH MARKED (>50%) IMPROVEMENT IN MRS SCORE

* p=0.025** p=0.004

* p=0.025** p=0.004

00

1010

2020

3030

4040

5050

6060

PlaceboPlacebo LithiumLithium DepakoteDepakote

25%25%

49%*49%* 48%**48%**

Perc

ent

Perc

ent

N.B. Efficacy of Depakote independent to prior responsiveness to Lithium N.B. Efficacy of Depakote independent to prior responsiveness to Lithium

Gabapentin vs PlaceboGabapentin vs Placebo

02468

101214161820

0 1 2 3 4 6 8 10

GabapentinPlacebo

Study Week

YMRS Scores (observed cases)

Pande AC, et al. J Clin Psychopharmacol. 1999;19(4):341-348.

Olanzapine: Mania, acute treatmentOlanzapine: Mania, acute treatmentOlanzapine: Mania, acute treatment

-20-20

-15-15

-10-10

-5-5

00

00 11 22 33 44

Olanzapine 15 mg, n = 54Olanzapine 15 mg, n = 54Placebo, n = 56Placebo, n = 56

Weeks of Double-Blind TherapyWeeks of Double-Blind Therapy

p < .05

p < .01

p < .001

p < .05

p < .01

p < .001

***

*** ***

Compared to placebo, olanzapine patients had a statistically significantly greater LOCF mean improvement at week 1 which was maintained throughout the study Compared to placebo, olanzapine patients had a statistically significantly greater LOCF mean improvement at week 1 which was maintained throughout the study

Mea

n C

hang

e,B

asel

ine

to E

ndpo

int

Mea

n C

hang

e,B

asel

ine

to E

ndpo

int

Impr

ovem

ent

Impr

ovem

ent

***

***

***

***

0

10

20

30

40

50

60

Placebo P=.065

Olanzapine P=.176

Haloperidol P<.001*

Olanzapine P=.038**

Schizophrenia studiesBipolar studies

12.0%11/92 4.4%

5/113

11.9%23/194 6.9%

8/116

54.1% 99/183

38.3%268/700

14.5%218/1501 9.1%

18/197

% o

f Pat

ients

Treatment-Emergent Parkinsonism†: Categorical Analysis of Simpson-Angus Scale Treatment-Emergent Parkinsonism†: Categorical Analysis of Simpson-Angus Scale

*Haloperidol was associated with significantly higher rates of EPS in the bipolar group. **Olanzapine was associated with significantly lower rates of EPS in the bipolar group.†Defined as a score on the Simpson-Angus Scale of ≤3 at baseline >3 anytime thereafter.

*p<0.05; **p<0.01; ***p<0.001Study 104 + 105

-25

-20

-15

-10

-5

0

Day

Change from baseline (YMRS)

Placebo (n=195)Quetiapine (n=208)

14 28 42 56 847 21 704

*

**

****** *** *** ***

******

Brecher & Huizar 2003; Paulsson & Huizar 2003; Jones & Huizar 2003

Quetiapine: Mania, acute treatmentQuetiapine: Mania, acute treatmentQuetiapine: Mania, acute treatment

LOCF analysis; *P<0.01 risperidone vs placebo; Khanna et al. Brit J Psychiatry 2005;187, 229-34

Risperidone studies in the acute treatment of mania

LOCF analysis; *P<0.001 risperidone vs placebo; Hirschfeld RM, et al. Am J Psychiatry 2004;161:1057–65

BL Day 3 Week 1 Week 2 Week 3

0

–5

–10

–15

–20

–25

0

–5

–10

–15

–20

–25

Median dose 4mg/dayBL: Risperidone = 29.1; placebo = 29.2

Median dose 6mg/dayBL: Risperidone = 37.4; placebo = 37.0

Cha

nge

in to

tal Y

MR

S sc

ore

RIS-USA-239 RIS-IND-002

*

* * * *

*

*Risperidone (n=134)Placebo (n=125)

Risperidone (n=146)Placebo (n=144)

BL Day 3 Week 1 Week 2 Week 3

*P<0.01 vs placebo, LOCF analysis.Keck et al.; Am J Psych, in press

-10

-8

-6

-4

-2

0

Day 4 Week 1 Day 10 Week 2 Week 3

Mea

n ch

ange

from

base

line

(SD

)

Aripiprazole (n=123; mean baseline: 28.2)Placebo (n=122; mean baseline: 29.7)

Aripiprazole in Acute Mania: Mean Change From Baseline in YMRS

*

*

** *

CotherapyCotherapy vsvs monotherapy in maniamonotherapy in mania

Atypical antipsychoticAtypical antipsychotic

TohenTohen, 2002b (149/220 51/114), 2002b (149/220 51/114)

Sachs, 2004 (44/81 29/89)Sachs, 2004 (44/81 29/89)

DelBelloDelBello, 2002 (13/15 8/15), 2002 (13/15 8/15)

YathamYatham, 2003 (40/68 30/73), 2003 (40/68 30/73)

SubtotalSubtotal

Risk ratioRisk ratio (95% CI)(95% CI)

StudyStudy

1.51 (1.21, 1.89)1.51 (1.21, 1.89)

1.67 (1.16, 2.39)1.67 (1.16, 2.39)

1.63 (0.97, 2.72)1.63 (0.97, 2.72)

1.43 (1.02, 2.01)1.43 (1.02, 2.01)

1.53 (1.31, 1.80)1.53 (1.31, 1.80)

%% WeightWeight

51.051.0

21.021.0

6.16.1

22.022.0

100.0100.0

FavoursFavours cotherapycotherapyFavoursFavours monotherapymonotherapyRisk ratioRisk ratio

0.50.5 11 22 55

RESPONSERESPONSE

Acute Mania: Those not on anti-manic treatment

Atypical antipsychotic (olanzapine, risperidone, quetiapine) for those with severe mania

If ineffective consider adding Li or valproateValproate or Li if previous good response and compliance

Avoid valproate in women of child baring potentialLi only if less severe

Don’t use carbamazepine routinely and avoid gabapentine, lamotrigine and topiramte

Acute Mania: Those on anti-manic treatment

Optimise treatmentLi level 0.8-1.0Valproate to max. licensed dose (depending on SEs)Don’t generally increase carbamazepine

Add olanzapine, risperidone or quetiapine

Guideline Evolution: Acute mania

• Place of antipsychotics has changed:Only in combination (APA)Alternative to Li or valproate (BAP, TIMA)

• NB olanzapine “1B” in TIMAMain first line option (NICE)

• Valproate has had extra cautions added by NICE

• Carbamazepine has been downgradedlevel “1B” (TIMA)Only on specialist recommendation (NICE)

• Second line fairly consistentLi or valproate + atypical

Depression is THE Problem

Symptomatic47%

Asymptomatic53%

Mixed13%Depressed

67%

Manic/hypomanic

20%

Symptomatic54%Asymptomatic

46%

Bipolar I(Judd et al. Archives of General Psychiatry 59:530-537, 2002)

Bipolar II(Judd LL et al. Archives of General Psychiatry 60:261-269, 2003)

Depressed94%

Hypomanic2% Mixed

4%

Antidepressants and bipolar disorder

Gijsman et al Am J Psychiatry 2004

0

10

20

30

40

50

60

Patie

nts

(%)

Patie

nts

(%)

Lamotrigine 50 mgLamotrigine 50 mgPlaceboPlacebo Lamotrigine 200 mgLamotrigine 200 mg

* P<0.05 vs placebo. † P<0.1 vs placebo.Calabrese et al. J Clin Psychiatry. 1999;60:79-88.

CGICGI--IIHAMHAM--DD--1717 MADRSMADRS

Lamotrigine vs Placebo in Bipolar Depression: Acute Treatment

37%29% 26%

45% 48%*41%†

51% 54%* 51%*

-20-18-16-14-12-10-8-6-4-20

0 1 2 3 4 5 6 7 8Week

MA

DR

S C

hang

e fr

om B

asel

ine Olanzapine (n=351)

Placebo (n=355)OFC (n=82)

Olanzapine + fluoxetine in bipolar depression

*

**

* **

Red markers p < .05 vs. OFC

* p < .05 OLZ vs. PLA

*MMRM = Mixed-Model Repeated MeasuresF1D-MC-HGGY

Tohen M et al. Arch Gen Psychiatry 60:1079-1088, 2003

OFC vs lamotrigine in BPI Depression Brown et al. 2006 J Clin Psychiatry 67;1025-33

Note:• Small

difference in effect

• OFC associated with more AEs, weight gain and metabolic changes than lamotrigine

• N= 205 each arm

Study Week

***p<0.001 vs placebo for both active arms at all time pointsMean baseline scores: BP I 30.5; BP II 30.2

Mean change in MADRS score from baseline (ITT)

Quetiapine monotherapy in bipolar depression Quetiapine monotherapy in bipolar depression

-18-16-14-12-10-8-6-4-20

0 1 2 3 4 5 6 7 8

Seroquel 600 mg/daySeroquel 300 mg/dayPlacebo

***************

***

***

***

Calabrese J et al. 2005 Am J Psychiatry 162;1351-60.

0 10 20 30 40 50 60 70 80

Suicidal thoughts

Pessimistic thoughts

Inability to feel

Lassitude

Concentration difficulties

Reduced appetite

Reduced sleep

Inner tension

Reported sadness

Apparent sadness

0 10 20 30 40 50 60 70 80

Suicidal thoughts

Pessimistic thoughts

Inability to feel

Lassitude

Concentration difficulties

Reduced appetite

Reduced sleep

Inner tension

Reported sadness

Apparent sadness

MADRS Items: Change From BaselineMADRS Items: Change From Baseline

Mean % Change in Score

†

*p<0.05 †p<0.01 §p<0.001 vs placebo

†

†

†

Quetiapine 600 mg (n=170)Quetiapine 300 mg (n=172)Placebo (n=169)

ITT, LOCF

§

§§

§

*

§

§§

§

§§

§§

Acute Depression

First line: SSRI plus antimanic agentIf on antimanic: SSRI or quetiapine (if not on antipsychotic)If recent unstable mood: avoid antidepressants –increase antimanic and consider lamotrigine

NB avoid lamotrigine as a single first line agent in bipolar I but consider this in bipolar II

If doesn’t respond to SSRI switch to mirtazepine or venlafaxine or add quetiapine or olanzapine if not on an antipsychoticTaper antidepressants after symptoms reduced for 8 weeks

Guideline Evolution: Acute Depression

• Much less consensus:Don’t use antidepressant monotherapy esp. in bipolar I

• Change in views over lamotrigineConsider if antidepressants lead to problems (BAP)First line (APA and TIMA)Not first line or single agent in BPI (NICE)

• Increasing role for antipsychoticsConsider, esp if psychotic (BAP)Quetiapine and OFC second line (TIMA)Quetiapine possible alternative to SSRI (NICE)

Guidance


Relationship between cycle length and number of episodes

0

10

20

30

40

50

60

1 2 3 4 5 6 7 8 9 10 11

Kraepelin, 1921Zis et al, 1980Angst, 1981Roy-Byrne et al, 1985

Episode

Cyc

le L

engt

h (M

onth

s)

Mood Disorders: Risk of relapse

Bipolar Disorder, constant risk of relapse over 40yrs; 0.4episodes/year

Angst et al. Eur Arch Psychiatry Clin Neurosci. 2003

Long-term Treatment: When?

Single manic episode with significant risk/consequences2+ episodes in bipolar IIn bipolar II if:

Significant riskFrequent episodesSignificant functional impairment

Lithium v placebo, maintenance in bipolar disorder Lithium v placebo, maintenance in bipolar disorder

Random effects p = 0.10

Lithium Not Clearly Superior to Placeboin Preventing Depression

Geddes J et al. Am J Psychiatry 161:217-222, 2004

10

20

30

40

50

60

70

80

90

100

0 16-20 24-28 32-36 40-44 48-52Weeks

% Symptom Free

Placebo (n=37)Depakote (n=54)Lithium (n=31)

Efficacy of depakote in prophylaxis of bipolar disorder Efficacy of depakote in prophylaxis of bipolar disorder

Time to mania relapse or depression in patientswith history of psychiatric hospitalization

& last episode < 1 year

Greil et al J Affect Disord 1997

Long Term Treatments – Carbamazepine Long Term Treatments – Carbamazepine

Lamotrigine protection against depressive episodes: Combined analysis

* Some patients considered intervention-free for depressive episodes could have had intervention for manic episodes.

39% increase in the percent of patients who remained intervention-free for depression at 18 months compared with placebo

18 mo

Perc

ent o

f pat

ient

s

57

41

70

60

50

40

30

20

10

0

39%

100

90

80

70

60

50

40

30

20

10

01 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17

Month

Estim

ated

% o

f pts

inte

rven

tion-

free

*

Lamotrigine 100-400 mg (n=233)Placebo (n=188)

LTG vs PBO, P=0.009

18

Goodwin et al. 2004 J. Clin. Psychiatry

Lamotrigine protection against manic episodes: Combined analysis

22% increase in the percent of patients who remained intervention-free for mania at 18 months compared with placebo

* Some patients considered intervention-free for manic episodes could have had intervention for depressive episodes.

18 mo

Perc

ent o

f pat

ient

s

70

60

50

40

30

20

10

0

65

53

22%

100

90

80

70

60

50

40

30

20

10

01 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17

Month

Estim

ated

% o

f pts

inte

rven

tion-

free

*

Lamotrigine 100-400 mg (n=223)Placebo (n=188)

LTG vs PBO, P=0.034

18

Goodwin et al. 2004 J. Clin. Psychiatry

Lamotrigine long term treatment in rapid cycling BP disorder

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 2 4 6 8 10 12 14 16 18 20 22 24 26

PBO(n=87)LTG(n=90)

Calabrese JR, et al. J Clin Psychiatry. 2000;61(11):841-850.

0.0

0.2

0.4

0.6

0.8

1.0

0 2 4 6 8 10 12 14 16 18 20 22 24 26

PP = 0.426= 0.426

WeekWeek

Lamotrigine vs. Placebo Overall Survival BPI (n = 125)

Surv

ival

Est

imat

eSu

rviv

al E

stim

ate

Calabrese et al. Calabrese et al. J Clin PsychiatryJ Clin Psychiatry. 2000;61:841. 2000;61:841--50. 50.

PlaceboPlaceboLamotrigineLamotrigine

0.0

0.2

0.4

0.6

0.8

1.0

0 2 4 6 8 10 12 14 16 18 20 22 24 26

PP = 0.015= 0.015

WeekWeek

Surv

ival

Est

imat

eSu

rviv

al E

stim

ate

Calabrese et al. Calabrese et al. J Clin PsychiatryJ Clin Psychiatry. 2000;61:841. 2000;61:841--50.50.

Lamotrigine vs. Placebo Overall Survival BP II (n = 52)

MedianMedian SurvivalSurvival

PlaceboPlacebo 4 weeks4 weeksLamotrigineLamotrigine 15 weeks15 weeks

Olanzapine continuation in bipolar disorder

Tohen M et al. 2006 Am J Psychiatry 163;247-56.

Tohenl et al Am J Psychiatry 2003

Long Term Treatments – Olanzapine vs lithium for mania

Tohenl et al Am J Psychiatry 2003

Long Term Treatments – Olanzapine vs lithium for depression

26 week trial of aripiprazole in recently manic BPI patients (Keck et al. 2006)

Lithium and/or Carbamazepine Maintenance Response Lithium and/or Carbamazepine Maintenance Response

00

1010

2020

3030

4040

5050

6060

Perc

ent C

GI R

espo

nder

sPe

rcen

t CG

I Res

pond

ers

LithiumLithium CBZCBZ Both*Both*

All patientsAll patients Hx of rapid-cyclingHx of rapid-cycling

Randomized (double blind)to Li+ or CBZfor 1 year, then to other, then to both

Randomized (double blind)to Li+ or CBZfor 1 year, then to other, then to both

N = 42 35 29N = 42 35 29*p<.05 if RC hx*p<.05 if RC hx

Long-term Treatment: What?First line: lithium, olanzapine or valproateIf fails monotherapy over 6 months

Li + valp, Li + olanz, Valp + olanzIf combination fails

Consider lamotrigine (esp. BPII), carbamazepine, referral to tertiary centre

NOT antidepressants routinely (unless no mania X 5 yrs)Normally treat for at least 5 years

Guideline Evolution: Long term treatment

• Variations in guidelines due to poor evidence base• Change in role of antipsychotics

Withdraw antipsychotics used in acute episode (APA)Olanzapine as alternative to Li (BAP)Atypical first line (NICE)

• Lithium down gradedFirst line (APA, BAP, TIMA – after mania)Second line (NICE)

• Valproate down gradedFirst line (APA, TIMA – after mania)Consider after Li (BAP)Concern in women (NICE)

• Carbamazepine down gradedFirst line (APA)Poor alternative to Li (BAP)Third or fourth line (TIMA)On specialist advice (NICE)

• Increased caution recommended re use of antidepressants• NICE emphasise the need for physical health monitoring

Mania

Hypomania

Euthymia

Minor Depression

Major Depression



Mania

Hypomania

Euthymia

Minor Depression

Major Depression


Frank E, et al. Biol Psychiatry. 2000;48(6):593-604.


“The study of MEDICINE is prosecuted under two relations,

namely as a Science and as an Art”

The Science and Practice of MedicineW. Aitken

1872

Annual Residential Meeting of the Faculty of

General and Community Psychiatry

The Science and Practice of Psychiatry Twin themes: Vulnerability and Service Delivery

Hilton Hotel and Sage Gateshead Newcastle Gateshead 18-19th October 2007

Documents

BAP Guidelines for the Management of Bipolar Disorder · BAP Guidelines for the Management of Bipolar Disorder G.M. Goodwin “Evidenced based guidelines for treating bipolar disorder: