Acute and Maintenance Treatment of Bipolar Depression

Acute and Maintenance

Treatment of Bipolar Depression

Terence A. Ketter, M.D.

Teaching Points

Mood stabilizers are foundational agents and should be

considered first line treatments, with the strongest

evidence supporting the use of lithium and lamotrigine.

Emerging data suggest atypical antipsychotics provide

benefit in acute bipolar depression, with the strongest

evidence supporting the use of quetiapine monotherapy

and the olanzapine plus fluoxetine combination.

The utility of adjunctive antidepressants in bipolar

depression is controversial, as these agents can yield

switching into mania or hypomania in some patients.

Pre-Lecture Exam

Question 1

1. The most pervasive symptoms in bipolar disorder are

those of: (choose one)

A. Mania, hypomania

B. Hypomania

C. Depression

D. Mixed States

E. None of the above

Question 2

Which of the treatments below is the LEAST appropriate strategy in

bipolar depression: (choose one)

A. Mood stabilizer without antidepressant

B. Mood stabilizer with antidepressant

C. Atypical antipsychotic with antidepressant

D. Antidepressant with neither mood stabilizer nor atypical antipsychotic

Question 3

Which antidepressant option carries the greatest risk of

hypomania/mania: (choose one)

A. Tricyclic antidepressants (TCAs)

B. Selective serotonin reuptake inhibitors (SSRIs)

C. Mirtazepine

D. Bupropion

Question 4

Which of the following treatments do NOT have controlled data

suggesting utility in bipolar depression: (choose one)

A. Lithium

B. Lamotrigine

C. Olanzapine plus fluoxetine combination

D. Quetiapine

E. Citalopram

F. Pramipexole

Question 5

Which of the following statements best describes the role of

maintenance adjunctive antidepressants in patients with

bipolar disorder: (choose one)

A. Long-term adjunctive antidepressants are always beneficial.

B. Long-term adjunctive antidepressants are never beneficial.

C. Long-term adjunctive antidepressants are beneficial in most

patients.

D. Long-term adjunctive antidepressants may be beneficial in

some patients.

Overview

Treatment options

– Mood stabilizers

– Atypical antipsychotics

– Adjunctive antidepressants

– Alternative treatments

Treatment of acute bipolar depression

Prevention of bipolar depression

Bipolar disorders symptoms

are chronic and predominantly depressive

Judd et al 2002

53%32%

9%6%

Asymptomatic

Depressed

Hypomanic

Cycling / mixed

% of Weeks

146 Bipolar I Patientsfollowed 12.8 yrs

86 Bipolar II Patientsfollowed 13.4 yrs

46%50%

1% 2%

Judd et al 2003

Treatment Options in Bipolar Depression

Alternative Treatments

Pramipexole

Gabapentin

Omega-3 fatty acids

Phototherapy

Psychotherapy

Sleep deprivation

Thyroid hormones

Mood Stabilizers

Lithium

Lamotrigine

Carbamazepine

Divalproex

ECT

Atypical Antipsychotics

Quetiapine

Olanzapine

Jefferson JW, Greist JH. Textbook of Psychiatry, Washington, DC, American Psychiatric Press, 1994; Post RM, et al.

Neuropsychopharmacology 1998; Worthington JJ III, Pollack MH. Am J Psychiatry 1996; Amsterdam J. J Clin Psychopharmacol

1998; Barbini B, et al. Psychiatry Res 1998; Wirz-Justice A, et al. Biol Psychiatry 1999; Stoll AL, et al. Arch Gen Psychiatry 1999;

Bowden CL. J Clin Psychiatry 1998; Tohen M, et al. Arch Gen Psychiatry 2003;60:1079-88; Calabrese JR, et al. J Clin Psychiatry

1999;60:79-88; Goldberg JF, et al. Am J Psychiatry 2004;161:564-6.

Adjunctive

Antidepressants

Fluoxetine + Olanzapine

Bupropion

SSRIs

Venlafaxine

Nefazodone

Mirtazapine

MAOIs

TCAs

Acute Treatment of Bipolar

Depression

Mendels J. Am J Psychiatry 1976;133:373-81 Watanabe S, et al. Arch Gen Psychiatry 1975;32:659-6682

Lithium in Acute Bipolar Depression

Li > placebo in 5/7 studies (N=158)1

– Pooled data

19% little or no antidepressant effect

81% significant antidepressant effect

Li versus TCA studies1,2

– Some included unipolars

– TCA Li in 3 studies (N=98)1,2

28 Reports* (16,800 Patients)28 Reports* (16,800 Patients)

*19 of 28 reports (16,000 patients) recorded only actual suicides.

Tondo, et al. 1997.

Lithium and Suicide Risk in

Major Affective Disorder

No. ofNo. of Annual riskAnnual risk

reportsreports of suicideof suicide

With lithiumWith lithium 2222 0.26 ± 0.40.26 ± 0.4

Without lithiumWithout lithium 1010 1.68 ± 1.51.68 ± 1.5 }}7 to 8-fold7 to 8-fold

differencedifference

pp<0.0001<0.0001

Suicide and Suicide Attempts

with Randomized Lithium or Carbamazepine

Suicide Suicide Total Suicidal

Attempts Behavior

Lithium 0 0 0

Carbamazepine 5 4 9

Thies-Flechtner et al. Pharmacopsychiatry 1994;29:103-7.

30-month prospective study

in 285 recently hospitalized patients

(175 bipolar, 110 schizoaffective)

Mood Stabilizer Choice and Suicide Events in

Bipolar Disorder Patients in Two Large HMOs

Events per 1,000 pt-years

Goodwin et al. JAMA 2003;290:1467-73

Medication # of

PtÕs

Outpatient

Attempts

Inpatient

Attempts

Completed

Suicides

Lithium 11,308 9.5 4.3 0.7

Divalproex 12,358 26.8* 10.65* 1.75*

Lithium +

Divalproexa

3067 25.8* 11.8* 1.60

aTreatment-resistant patients; *Sig. Diff from Lithium alone (p<.05)

Medication Outpatien t

attempts

Inpatient

attempts

Completed

Suicides

Lithium 1.0 1.0 1.0

Divalproex 1.7* 1.6* 2.6**

Divalproex

+ Lithiuma

2.1* 2.1* 2.6

Risk ratios of events relative to patients on lithium

(Adjusted for age, sex, year of treatment, comedications, comorbidity)

Mood Stabilizer Choice and Suicide Events in

Bipolar Disorder Patients in Two Large HMOs

Goodwin et al. JAMA 2003;290:1467-73

aTreatment-resistant patients; Sig. Diff from Lithium alone (*p<.001; **p<.004)

± p < 0.1 vs PBO, LOCF

-12

-10

-8

-6

-4

-2

0

0 1 2 3 4 5 6 8

Placebo (N=22)

Divalproex 62 ug/mL (N=21)

±±

Week

Mean

Ch

an

ge f

rom

Baselin

e

Baseline - PBO 20.5, DVPX 22.6

Sachs G, et al. 40th Ann ACNP Mtg, December 9-13, 2001, Waikaloa, HI.

8-Week Randomized Double-Blind Divalproex

Monotherapy in Acute Bipolar Depression

Baseline HAM-D: Placebo, 19.9; Divalproex 22.0. Last observation carried forward.

Davis LL, et al. J Affective Disord 2005;85:259-66.

8-Week Randomized Double-Blind Divalproex

Monotherapy in Acute Bipolar DepressionM

ea

n H

AM

-D C

ha

ng

e

Fro

m B

ase

line

(L

OC

F)

Week0 1 2 3 4 5 6 7 8

-12

-10

-8

-6

-4

-2

0

Placebo (N = 12)

Divalproex 82 ug/mL (N = 13)

P = 0.0002

22

36

25

29

24

25

19

29

11

35

4

35

8

25

0%

10%

20%

30%

40%

50%

60%

Q T P

600mg

Q TP

300mg

LTG

200mg

OFC L TG

50mg

Li Pax L i IM I Olz

Active-Placebo Response Rate Difference

Re

sp

on

se

Ra

te

(≥ 5

0%

de

cre

ase in

de

pre

ssio

n r

ati

ng

)

Summary of 4 Acute Bipolar Depression StudiesResponse Rates

Placebo Response Rate

Sachs GS. In Ketter TA (ed). Advances in the Treatment of Bipolar Disorders. Am Psychiatric Press, Inc. 2005.

22

36

Calabrese et al. J Clin Psychiatry. 1999;60:79-88.

Last Observation Carried Forward Observed Cases

MA

DR

S

Ch

an

ge F

rom

Baselin

e

PBO 5%

LTG 50 3%

LTG 200 8%

7-Week Randomized Double-Blind Lamotrigine

Monotherapy in Acute Bipolar I Depression

LTG 50 mg/d (n = 64)

LTG 200 mg/d (n = 63)

Placebo (n = 65)

Week

0

-5

-10

-15

-20

0 1 2 3 4 5 6 7

±

±

*

***

Week

0

-5

-10

-15

-20

0 1 2 3 4 5 6 7

†

** *

*

** *

*

LTG 50 mg/d

LTG 200 mg/d

Placebo

Switch Rates

± P<0.1; † * P<0.05.

16-Week Randomized Open Adjunctive Therapy of

Treatment Resistant Bipolar Depression a

Nierenberg AA, et al. Am J Psychiatry 2006;163;210-6.

138

mg/d

9429

mg/d

1.5

mg/d

23.8%

[5.8-41.8]

17.4%

[2.4-32.4]

4.6%

[0-14.6]

a 54% BPI, 46% BPII.

Lamotrigine 19%

Inositol 13%

Risperidone 13%

Switch Rates

OLZ 9.7 mg

(N = 351)

PBO (N = 355)

OLZ 7.4 mg

+ FLX 39.3 mg

(N = 82)

Week

0 1 2 3 4 6 8

Mean

Ch

an

ge i

n M

AD

RS

Sco

res

-20

-15

-10

-5

0

*

*

**

**

†† †

Tohen M, et al. Arch Gen Psychiatry 2003;60:1079-88.Baseline MADRS 31.3 PBO, 32.6 OLZ, 30.8 OLZ+FLX.* P < 0.05 vs OLN, OLN+FLX. † P < 0.05 vs OLN.

8-Week Randomized Double-Blind Olanzapine ±

Fluoxetine in Acute Bipolar I Depression

PBO 7%

OLZ 6%

OFC 6%

Switch RatesFluoxetine monotherapy arm excluded

due to risk of mania induction.

* P < 0.05 vs OLN, OLN+FLX. † P < 0.05 vs OLN. ITT-LOCF

Responders Remitters

OFC OLN PBO OFC OLN PBO0

10

20

30

40

50

6054%

37%

29%

Pe

rce

nta

ge

of

Pa

tie

nts

47%

31%

23%

*

†

*

†

Tohen M, et al. Arch Gen Psychiatry 2003;60:1079-88.

PBO 7%

OLZ 6%

OFC 6%

Switch Rates

8-Week Randomized Double-Blind Olanzapine ±

Fluoxetine in Acute Bipolar I Depression

LTG 106 mg

(N = 205)

OLZ 10.7 mg

+ FLX 38.3 mg

(N = 205)

Brown EB, et al. J Clin Psychiatry 2006;66:1025-33.

Baseline MADRS 30.9 OFC, 31.4 LTG. *P < 0.05, ***P < 0.001 OFC vs LTG. Trade-off: 3 lbs/MADRS point.

7-Week Randomized Double-Blind Lamotrigine vs

Olanzapine + Fluoxetine in Acute Bipolar I Depression

LTG 5%

OFC 4%

Switch Rates

LTG -0.3***

OFC +3.1

Weight Change (kg)

Week

Mean

Ch

an

ge i

n M

AD

RS

Sco

res

0 1 2 3 4 6 7

-20

-15

-10

-5

0

-25

5

** *

*

*

Responders ≥ 7% Weight Gain

OFC LTG OFC LTG0

10

20

30

40

50

60

69%

60%

Pe

rce

nta

ge

of

Pa

tie

nts

23%

0%

±

***

70

Brown EB, et al. J Clin Psychiatry 2006;66:1025-33.

± P < 0.08, *** P < 0.001 OFC vs LTG. Trade-off: 9% response vs 23% weight gain.

LTG 5%

OFC 4%

Switch Rates

7-Week Randomized Double-Blind Lamotrigine vs

Olanzapine + Fluoxetine in Acute Bipolar I Depression

-20

-15

-10

-5

0

Quetiapine 600 mg (N = 170)

Quetiapine 300 mg (N = 172)

Placebo (N = 169)

†

†

†

†

††

† †

†

†

††

†† † †

0 1 2 43 65 7 8

Study Week

ITT, LOCF

Ch

an

ge F

rom

Baseli

ne

(LS

Mean

s)

Baseline MADRS 30.3 PBO, 30.4 QTP 300, 30.6 QTP 600.

†P<0.001 (quetiapine vs placebo)

8-Week Randomized Double-Blind Quetiapine


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

PBO 4%

QTP 300 4%

QTP 600 2%

Switch Rates

ITT, LOCFBaseline MADRS 29.6 PBO, 31.1 QTP 300, 29.9 QTP 600.

*P<0.01, †P<0.001 (quetiapine vs placebo).



Thase ME, et al. J Clin Psychopharmacol 2006;26:600-9.

Mo

ntg

om

ery

-Asb

erg

Dep

ressio

n R

ati

ng

Scale

Imp

lro

ve

me

nt

PBO 7%

QTP 300 2%

QTP 600 4%

Switch Rates



Thase ME, et al. J Clin Psychopharmacol 2006;26:600-9.

BOLDER I BOLDER II

Pe

rce

nta

ge

of

Pa

tie

nts

Re

sp

on

din

g

(≥ 5

0%

MA

DR

S D

ec

rea

se

)

PBO QTP

300

QTP

600

PBO0

10

20

30

40

50

60 58% 58%

36%40%

37%

24%

***

***

QTP

300

QTP

600

***

Response Rates

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

*p < 0.05, **p< 0.01, *** p < 0.001 vs placebo.

PBO 4%

QTP 300 4%

QTP 600 2% PBO 7%

QTP 300 2%

QTP 600 4%

Switch Rates

Switch Rates

Bipolar Disorder I

(N=657)

Bipolar Disorder II

(N=321)

†

‡

MA

DR

S L

S M

ea

n

Ch

an

ge F

rom

Bas

eli

ne

Imp

rove

me

nt

†p<0.01; ‡p<0.001 vs. placebo (N at baseline); ITT = intent to treat; AstraZeneca (data on file); Thase

ME (2006), Presented at the 159th Annual Meeting of the APA. Toronto, Canada; May 20-25;

Calabrese JE et al. (2005), Am J Psychiatry 162(7):1351-1360

BOLDER I and II: MADRS Total Score

Bipolar I vs. II Disorder

‡

†

Quetiapine 300

Quetiapine 600

Placebo-20

-16

-12

-8

-4

0

Magnitudes of Effects in Controlled Trials in

Acute Bipolar I Depression

1Tohen M, et al. Arch Gen Psychiatry 2003;60:1079-1088; 2Calabrese JR, et al. 157th APA Annual Meeting, May 1-6, 2004,

New York, NY. Abstract NR756. Page 284; 3Calabrese JR, et al. J Clin Psychiatry 1999;60:79-88.

Effect Size

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

OLZ

10 mg

OLZ

7.5 mg

+

FLX

40 mg

QTP

300 mg

QTP

600 mg

LTG

50 mg

LTG

200 mg

Response Rate (%)a

0

10

20

30

40

50

60

70

OLZ

10 mg

OLZ

7.5 mg

+

FLX

40 mg

QTP

300 mg

QTP

600 mg

LTG

50 mg

LTG

200 mg

2Calabrese 2004. 3Calabrese 1999.1Tohen 2003. 2Calabrese 2004. 3Calabrese 1999.1Tohen 2003.

Effect Size (ES) = (improvement over PBO) / (pooled SD)(small <0.4; mod 0.5-0.9; large >1.0). a >50% MADRS decrease

6-week Randomized Double-Blind Adjunctive

Pramipexole in Acute Bipolar Depression

Response Rates

Pe

rce

nt

res

po

nd

ers

(≥ 5

0%

HD

RS

/MA

DR

S d

ec

rea

se

)

20%

(2/10)

67%

(8/12)

P<0.04

Pramipexole Placebo Pramipexole Placebo0

5

10

15

20

25

30

35

40

45

50

60%

(6/10)

9%

(1/11)

60

P<0.02

1.7

mg/d

1.7

mg/d

Zarate CA, et al.

Biol Psychiatry 2004; 56:54-60.

Goldberg JF, et al.

Am J Psychiatry 2004; 161:564-6

70

21 BPII on

Li (N=12, 0.8 mEq/L),

DVPX (N=9, 73 ug/mL)

15 BPI, 7 BPII on

Li (N=6, 0.7 mEq/L),

DVPX (N = 9, 81 ug/mL),

LTG (N=6),

GBP (N=3),

CBZ (N=2)

6-week Randomized Double-Blind Adjunctive

Pramipexole in Acute Bipolar Depression

Switch Rates

Pe

rce

nt

wit

h H

yp

om

an

iao

r M

an

ia

0%

(0/10)

8%

(1/12 mania)

Pramipexole Placebo Pramipexole Placebo0

5

10

15

20

25

30

35

40

45

50

10%

(1/10 hypomania)

18%

(2/11 hypomania)

60

1.7

mg/d

1.7

mg/d

Zarate CA, et al.

Biol Psychiatry 2004; 56:54-60.

Goldberg JF, et al.

Am J Psychiatry 2004; 161:564-6

70

21 BPII on

Li (N=12, 0.8 mEq/L),

DVPX (N=9, 73 ug/mL)

15 BPI, 7 BPII on

Li (N=6, 0.7 mEq/L),

DVPX (N = 9, 81 ug/mL),

LTG (N=6),

GBP (N=3),

CBZ (N=2)

Response Rates

Pe

rce

nt

Res

po

nd

ers

(≥ 5

0%

ID

S d

ec

rea

se

)

*p < 0.05 vs placebo.

Modafinil Placebo

0

10

20

30

40

50

60

22%

44%

177 mg/d

N = 41 N = 44

*

6-week Randomized Double-Blind Adjunctive Modafinil in Acute Bipolar Depression

Frye M, et al. Am J Psychiatry 2007;164:1242-9.

Placebo 11.4%

Modafinil 4.9%

Switch Rates

Response in Randomized Controlled Trialsof Antidepressants vs. Placebo in Bipolar Depression

Gijsman et al, American Journal of Psychiatry. 2004;161:1537-1547.

Paroxetine, Imipramine, Placebo Added to

Lithium in Bipolar Depression

Nemeroff CB, et al. Am J Psychiatry. 2001;158:906-912. *p < 0.05

Li + PXT 33 mg/d (n=35) Li + IMI 167 mg/d (n=39)Li + PBO (n=43)

0

10

20

30

40

50

60

All Subjects

% R

esp

on

der

s

Lithium < 0.8

*

*

Li + PBO 2%

Li + PXT 0%

Li + IMI 8%

Switch Rates

Young, et al. Am J Psychiatry 2000;157:124-6.

Adjunctive Paroxetine vs Second Mood

Stabilizer in Bipolar Depression

Similar Efficacy*

Treatment Duration (wks)

50%

Response

Rates

64%

Ha

mil

ton

De

pre

ss

ion

Sc

ale

(1

7 ite

m)

Double-Blind Adjunctive

2nd Mood Stabilizer

Paroxetine

•

Baseline 1 2 3 4 5 60

5

10

15

20

25

• • • ••

•••

• • • • •

*Last Observation Carried Forward Analysis

Better Tolerability

2nd Mood

Stabilizer

Dro

po

ut

Rate

(%

)

38%(6/16)

0%(0/11)

40

20

0Paroxetine

p < 0.05

Recovery RatesP

erc

en

tag

e o

f P

ati

en

ts

0

5

10

15

20

2568% BPI, 32% BPII

Bupropion - 300 mg/d (median, N = 86)Paroxetine - 30 mg/d (median, N = 93)

26-Week Double-Blind Adjunctive Antidepressant

vs Placebo in Acute Bipolar Depression

30

Adding antidepressant no better or worse than adding placebo to mood stabilizer(s).

P=0.40

NNT = 26

Mood Stabilizer

+ Antidepressant

Mood Stabilizer

+ Placebo

27.3%

(51/187)23.5%

(42/179)

P=0.84

NNH = 167

Mood Stabilizer

+ Antidepressant

Mood Stabilizer

+ Placebo

10.7%

(20/187)10.1%

(18/179)

Switch Rates

Sachs GS, et al. N Engl J Med 2007;356:1711-22.

Miklowitz DJ, et al. Arch Gen Psychiatry 2007;64:419-27.

52-Week Adjunctive Intensive Psychosocial Intervention

vs Collaborative Care in Acute Bipolar Depression

Up to 30sessions

3sessions

N = 163

N = 130p = 0.01Intensive Collaborative

Median time to 50% recovery (days) 169 [138-230] 279 [-]

Median time to 25% recovery (days) 98 [88-112] 125 [105-168]

Recovered at 1 year (%) 64.4 51.5




Up to 30sessions

3sessions

N = 163

N = 130p < 0.05




Up to 30sessions

3sessions

N = 163

N = 130

Odds of Being Well in Any MonthIntensive 1.58 x Collaborative

p = 0.003

Lewis JL, Winokur G. Arch Gen Psychiatry 19821; Prien RF, et al. Arch Gen Psychiatry 1984.

Do Antidepressants Induce Mania?

41% Natural switch rate depression to mania

(on no antidepressants) 1

Switch rate on medications 2

– 53% Imipramine

– 28% Lithium plus imipramine

– 26% Lithium

Switch Rate From Index Depression Into Mania

Angst J. Psychopathology 1985.

Sw

itch

Rate

(%

)

1920 1930 1940 1950 1960 1970 1980

Spontaneous

(N=200)

ECT

(N=100)

Nano-

leptics(N=100)

Tricyclics

(N=509)

0

6

8

4

2

10

Year

By Era and Prevailing Treatment

Peet M. Br J Psychiatry. 1994;164:549-550.

Increased Mania Switch Rates with Tricyclics%

Wit

h M

anic

Sw

itch

0

2

4

6

8

10

12

PBO Sertraline / Paroxetine TCAs

11.2%

(14/125)

3.7%

(9/242)

4.2%

(2/48)

**

** p < 0.01 vs PBO

Switch Rates With Tricyclic vs.

Other Antidepressants

Gijsman et al, American Journal of Psychiatry. 2004; 161: 1537-1547

Manic Switch Rates in Randomized Controlled Trialsof Antidepressants vs. Placebo

Gijsman et al, American Journal of Psychiatry. 2004;161:1537-1547

P = NS.

Bupropion Sertraline Venlafaxine

49%

53%51%

Pe

rce

nta

ge

of

Pa

tie

nts

wit

h

Eit

he

r ≥ 5

0%

ID

S D

ec

rea

se

or

≥ 2

po

int

CG

I Im

pro

ve

me

nt

10-Week Randomized Adjunctive

Antidepressants in Acute Bipolar Depressiona

a 73% Bipolar I, 26% Bipolar II, 1% Bipolar NOS; 82% double-blind, 12% open.

Post RM, et al. Br J Psychiatry 2006;189:124-31.

286 mg/d

N = 51

192 mg/d

N = 58

195 mg/d

N = 65

Response Rates

0

10

20

30

40

50

60

0

10

20

30

40

P = 0.05.

YMRS >13

BUP SERT VEN

4%

7%

15%

Pe

rce

nta

ge

of

Pa

tie

nts

P < 0.01.

CGI-M

Increase ≥ 2

BUP SERT VEN

10% 9%

29%P = 0.03.

YMRS >13 or

CGI-M ≥ 3

BUP SERT VEN

14%

16%

31%

N = 51 N = 51 N = 51N = 58 N = 58 N = 58N = 65 N = 65 N = 65

Switch Rates

10-Week Randomized Adjunctive

Antidepressants in Acute Bipolar Depressiona

a 73% Bipolar I, 26% Bipolar II, 1% Bipolar NOS; 82% double-blind, 12% open.

Post RM, et al. Br J Psychiatry 2006;189:124-31.

Angst J. Psychopathology 19851; Prien RF, et al. Arch Gen Psychiatry 19732;

Wehr TA, Goodwin FK. Psychopharmacol Bull 19873

Do Antidepressants Induce Rapid Cycling?

Increased rapid cycling since TCAs introduced 1

Mania rates over 2 years 2

– 67% Imipramine

– 33% Placebo

– 18% Lithium

Antidepressants induce reversible rapid cycling in double-blind placebo-controlled studies.3

Tricyclics Shorten Cycle Length

Wehr TA, Goodwin FK. Am J Psychiatry 1987.

Tricyclic Treatment Status

Cyc

le L

en

gth

(d

ays

) 300

250

200

150

100

50

0

10 Bipolar Disorder Patients

Off Off OffOn On

TCAs TCAs

Acute Bipolar I Depression Algorithm

Optimize current mood stabilizer (if applicable) before

initiating additional treatment for depression

Patients on Li - optimize (serum Li level ≥ 0.8 mEq/L) to

determine whether adjunctive intervention necessary

Patients with recent and/or severe history of mania - receive

or add an effective antimanic agent

Stage 1

Adjunctive LTG if depression persists after mood stabilizer

optimization

Number of iterations at each level and adjunctive treatment(s) to be determined by clinician judgmentSuppes T, et al. J Clin Psychiatry 2005;66:870-86.


Stage 2: If Stage 1 ineffective or not tolerated*

QTP monotherapy or OFC

Although onset of action faster than LTG, overall efficacy and

long-term tolerability evidence favors LTG (at Stage 1)

Stage 3: If Stages 1 and 2 ineffective or not tolerated*

Combination of two agents already introduced in algorithm

Li, LTG, QTP, and OFC combination

OFC a two-drug combination, so adding another agent yields

three-drug combination



Stage 4: If Stages 1, 2, and 3 ineffective or not tolerated*

ECT and combination therapy ( Li, LTG, QTP, OFC

combination, VPA or CBZ in combined with SSRI, bupropion,

or venlafaxine)

Minority opinion that Stage 4 should precede Stages 2 and 3

Stage 5: If Stages 1, 2, 3, and 4 ineffective or not tolerated*

MAO-I, other atypical antipsychotics not included,

pramipexole, new combinations of drugs included in the

algorithm, inositol, stimulants, and thyroid supplementation


Maintenance Treatment of

Bipolar Depression

Lithium (n=251)

Placebo (n=263)

0

20

40

60

80

100

Overall Relapse Relapse Into Depression Relapse Into Maniaor Hypomania

Perc

en

tag

e o

f P

ati

en

ts

23%

56%

37%

21%

81%

34%

Goodwin FK, Jamison KR: Manic-Depressive Illness, Oxford University Press, New York 1990:688-9.

Summary of Double-Blind Lithium Monotherapy

vs Placebo Maintenance Trials in 1970s

Lithium Compared to Placebo, Primarily After Manic/Mixed Episodes

SuperiorDepressionPrevention

SuperiorEpisode

Prevention

SuperiorMania

Prevention

Lithium Prevention of Any Relapse

in Bipolar Disorder

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

Areas of blue boxes reflect weights of studies in meta-analysis.

bLower confidence interval extends beyond graph (0.08).

Lithium Prevention of Depressive Relapse

in Bipolar Disorder



bLower confidence interval extends beyond graph (0.10).

Lithium Prevention of Manic Relapse

in Bipolar Disorder



DVP = divalproex PBO = placeboGyulai et al. Neuropsychopharmacol 2003;28:1374-82.

LI = lithium

SSRI = selective serotonin reuptake inhibitor

0%

5%

10%

15%

20%

DVP (n=187) PBO (n=94)

Perc

en

tag

e o

f P

ati

en

ts

Dis

co

nti

nu

ing

Du

e t

o D

ep

ressio

n

P = 0.017

Overall Patients Receiving SSRI Rescue

0%

5%

10%

15%

20%

25%

30%

35%

40%

45%

50%

DVP + SSRI

(n=41)

PBO + SSRI

(n=20)

P = 0.03

Perc

en

tag

e o

f P

ati

en

ts

Dis

co

nti

nu

ing

Du

e t

o D

ep

ressio

n

12-Month Double-Blind Divalproex, Lithium

Monotherapy vs Placebo Maintenance

Fewer Dropouts Due to Depression with Divalproex vs Placebo

After Manic/Mixed Episodes

Goodwin GM, et al. J Clin Psychiatry 2004;65:432-41.

Lamotrigine and Lithium

Effective in Bipolar I Prophylaxis

Time to Intervention for Any Episode (pooled recently manic/dep pts)

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 10 20 30 40 50 60 70

Week

Su

rviv

al E

sti

mate

Placebo (n=188)

Lamotrigine 245 mg/d (n=223)

Lithium 0.7 mEq/L (n=164)

LTG v. PBO, p < 0.001

Li v. PBO, p < 0.001

LTG v. Li, p = 0.629

LTG Li PBO0

10

20

30

40

50

22%

42%37%

18 Months

Patients stabilized on lamotrigine prior to randomization.

Some patients considered intervention-free for depression could have had intervention for mania.


Lamotrigine Effective in

Bipolar I Depression Prophylaxis

Time to Intervention for Depression (pooled recently manic/dep pts)

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

0 10 20 30 40 50 60 70

Week

Su

rviv

al E

sti

mate

LTG v. PBO, p = 0.009

Li v. PBO, p = 0.120

LTG v. Li, p = 0.325

LTG Li PBO0

10

20

30

40

50

60

41%

53%57%

18 Months

Placebo (n=188)




Some patients considered intervention-free for mania could have had intervention for depression.


Lamotrigine and Lithium Effective in

Bipolar I Mania Prophylaxis

Time to Intervention for Mania (pooled recently manic/dep pts)

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

0 10 20 30 40 50 60 70

Week

Su

rviv

al E

sti

mate

LTG v. PBO, p = 0.034

Li v. PBO, p < 0.001

LTG v. Li, p = 0.030

Placebo (n=188)



LTG Li PBO0

20

40

60

80

53%

80%

65%

18 Months


Incidence of Mania/Hypomania/Mixed Episodes Reported as Adverse Events

Combined Analysis

0

5

10

15

20

25

Lamotrigine

(n=227)

Lithium

(n=166)

Placebo

(n=190)

In all bipolar controlled trials, adverse events of mania were reported as 5% lamotrigine, 3% lithium, and 4% placebo.



5% 4%

7%

Olanzapine 12.5 mg/d (n=225)

Placebo (n=136)

0

20

40

60

80

100

Overall Relapse Relapse Into Depression Relapse Into Mania

Perc

en

tag

e o

f P

ati

en

ts

p<.001

p=.015

p<.001

16.4%

41.2%47.8%

34.7%

80.1%

46.7%

Stabilized on OLZ before randomization. Relapse criteria - hospitalized or YMRS or HAMD-21 >= 15.

Tohen MF, et al. Am J Psychiatry 2006;163:247-56.

12-Month Double-Blind Olanzapine

Monotherapy vs Placebo Maintenance

Olanzapine Compared to Placebo After Manic/Mixed Episodes

SuperiorDepressionPrevention

SuperiorEpisode

Prevention

SuperiorMania

Prevention

Perc

en

tag

e o

f P

ati

en

ts

Stabilized on OLZ+Li before randomization. Relapse criteria - YMRS or HAMD-21 >= 15.

Tohen MF, et al. Am J Psychiatry 2005;162:1281-90.

0

10

20

30

40

50

14.3%

28.0%

p=.055

p=.895p<.001

Overall Relapse Relapse Into Depression Relapse Into Mania

15.4%16.1%

38.8%

30.0%

Olanzapine 11.9 mg/d (n=217)

Lithium 1103 mg/d (0.77 mEq/L) (n=214)

12-Month Double-Blind Olanzapine vs

Lithium Maintenance Monotherapy

EquivalentDepressionPrevention

Olanzapine Compared to Lithium After Manic/Mixed Episodes

EquivalentEpisode

Prevention

SuperiorMania

Prevention

0

10

20

30

13%12%

6%5%Perc

en

t o

f P

ati

en

ts

43%

25%23%

8%

Relapse into

Mania

40

50

Relapse into

Mixed

Relapse into

Depression

Overall

Relapse

Aripiprazole 24.3 mg/d (n=77)

Placebo (n=83)

p=.013

p=.009

EquivalentDepressionPrevention

SuperiorEpisode

Prevention

EquivalentMixed

Prevention

SuperiorMania

Prevention

Stabilized on ARI before randomization.

Keck PE, et al. 157th APA Annual Meeting; May 1-6, 2004; New York, NY. Abstract NR746.

26-Week Double-Blind Aripiprazole vs Placebo

Continuation/Maintenance Monotherapy

Aripiprazole Compared to Placebo After Manic/Mixed Episodes

Antidepressants After Depression Resolution

Sachs G, 2000. Personal communication.

Disorder / Episode Pattern Begin Taper Comments

Unipolar 6–12 months Maintenance if

≥ 3 episodes

Bipolar

Monophasic 6–12 weeks Repeat if relapse

Biphasic - MDE Maintenance if

repeated relapses

Bipolar

Biphasic - DME 6–12 days Start taper after

Polyphasic first euthymic visit

Hx rapid cycling

Hx iatrogenic mania

Controlled Maintenance Studies of

Antidepressants for Bipolar Depression

Study N, Duration Efficacy Switch

Prien et al ’73 N=44, 24 mo Li > IMI = PBO

Wehr & Goodwin ‘79

N=5, 27 mo Li = Li + DMI Li + DMI >> Li

Quitkin et al ‘81 N=75, 19 mo Li = Li + IMI Li + IMI > Li

Kane et al ‘82 N=22, 11 mo Li > PBO = IMI

Prien et al ‘84 N=117, 30 mo Li = Li + IMI> IMI IMI > Li + IMI = Li

Sachs et al ‘94 N=15, 12 mo Li + BUP= Li + DMI

Li + DMI > Li + BUP

Kane et al Arch Gen Psychiatry 1982;39:1065-9; Prien et al Arch Gen Psychiatry 1984;41:1096-1104; Prien et al Arch Gen Psychiatry 1973;29:420-5; Quitkin et al Arch Gen Psychiatry 1981;38:902-7; Sachs et al J Clin Psychiatry 1994;55:391-3; Wehr & Goodwin Arch Gen Psychiatry 1979;36:555-9.

Bipolar Versus Unipolar

Maintenance Treatment Dissociation

Adapted from Prien et al Arch Gen Psychiatry 1984;41:1096:1104.Li 0.8 mEq/L; IMI 125 mg/d

Bipolar UnipolarIMI+LI Li IMI PBO

Cu

mu

lati

ve P

rob

ab

ilit

y o

f R

em

ain

ing

Well

0

10

20

30

40

50

60

70

80

90

3 6 9 12 15 18 21 23 25 27 30

Months

100

Cu

mu

lati

ve P

rob

ab

ilit

y o

f R

em

ain

ing

We

ll

0

10

20

30

40

50

60

70

80

90

100

3 6 9 12 15 18 21 24 27

Months

Antidepressant Continuation Beneficial

in Some (15%?) Patients

Prospective 1-year follow-up

Remission of MDE with AD

added to mood stabilizer

Tolerated AD ≥ 2 months

Continuation: AD > 6 months

Discontinuation: AD < 6 months

n = 41

(36% relapsed)

n = 43

(70% relapsed)

Altshuler et al. Am J Psychiatry. 2003;160:1252-62.

Treatment of Bipolar Depression

Acute treatment

– Lithium, lamotrigine

– Olanzapine plus fluoxetine, quetiapine

– Adjunctive antidepressants


Maintenance treatment– Lithium, lamotrigine

– Divalproex

– Adjunctive antidepressants (controversial)


New treatment options emerging

Post-Lecture Exam

Question 1

1. The most pervasive symptoms in bipolar disorder are

those of: (choose one)

A. Mania, hypomania

B. Hypomania

C. Depression

D. Mixed States

E. None of the above

Question 2

Which of the treatments below is the LEAST appropriate

strategy in bipolar depression: (choose one)

A. Mood stabilizer without antidepressant

B. Mood stabilizer with antidepressant

C. Atypical antipsychotic with antidepressant

D. Antidepressant with neither mood stabilizer nor atypical

antipsychotic

Question 3

Which antidepressant option carries the greatest risk of

hypomania/mania: (choose one)

A. Tricyclic antidepressants (TCAs)

B. Selective serotonin reuptake inhibitors (SSRIs)

C. Mirtazepine

D. Bupropion

Question 4

Which of the following treatments do NOT have controlled

data suggesting utility in bipolar depression: (choose

one)

A. Lithium

B. Lamotrigine

C. Olanzapine plus fluoxetine combination

D. Quetiapine

E. Citalopram

F. Pramipexole

Question 5

Which of the following statements best describes the

role of maintenance adjunctive antidepressants in

patients with bipolar disorder: (choose one)

A. Long-term adjunctive antidepressants are always

beneficial.

B. Long-term adjunctive antidepressants are never

beneficial.

C. Long-term adjunctive antidepressants are beneficial

in most patients.

D. Long-term adjunctive antidepressants may be

beneficial in some patients.

Answers to Pre & Post Competency Exam

1. C

2. D

3. A

4. E

5. D

Acute and Maintenance Treatment of Bipolar Depression

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