terence a. ketter, m.d. acute and maintenance treatment of bipolar depression terence a. ketter, m.d

Acute and Maintenance Treatment of Bipolar

Depression

Terence A. Ketter, M.D. Terence A. Ketter, M.D.

Teaching PointsTeaching 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 ExamPre-Lecture ExamQuestion 1Question 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 2Question 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


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


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


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 Bipolar disorders symptoms are chronic and predominantly depressiveare chronic and predominantly depressive

Judd et al 2002

53%32%

9%6%

Asymptomatic

Depressed

Hypomanic

Cycling / mixed

% of Weeks

146 Bipolar I Patients146 Bipolar I Patientsfollowed 12.8 yrsfollowed 12.8 yrs

86 Bipolar II Patients86 Bipolar II Patientsfollowed 13.4 yrsfollowed 13.4 yrs

46%50%

1% 2%

Judd et al 2003

Treatment Options in Bipolar DepressionTreatment 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 riskreportsreports 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-folddifferencedifferencepp<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 studyin 285 recently hospitalized patients

(175 bipolar, 110 schizoaffective)

Mood Stabilizer Choice and Suicide Events in Mood Stabilizer Choice and Suicide Events in Bipolar Disorder Patients in Two Large HMOsBipolar 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 Outpatient 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 Mood Stabilizer Choice and Suicide Events in Bipolar Disorder Patients in Two Large HMOsBipolar 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

Me

an

Ch

an

ge

fro

m B

ase

line

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 8-Week Randomized Double-Blind Divalproex Monotherapy in Acute Bipolar DepressionMonotherapy 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.

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 8-Week Randomized Double-Blind Divalproex Monotherapy in Acute Bipolar DepressionMonotherapy in Acute Bipolar Depression

Mea

n H

AM

-D C

hang

e F

rom

Bas

elin

e (L

OC

F)

Mea

n H

AM

-D C

hang

e F

rom

Bas

elin

e (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 P600mg

Q T P300mg

LTG200mg

OFC L TG50mg

Li Pax L i IM I Olz

Active-Placebo Response Rate Difference

Res

po

nse

Rat

e(≥

50%

dec

reas

e in

dep

ress

ion

rat

ing

)

Summary of 4 Acute Bipolar Depression StudiesSummary of 4 Acute Bipolar Depression Studies Response 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.Calabrese et al. J Clin Psychiatry. 1999;60:79-88.

Last Observation Carried Forward Observed Cases

MA

DR

SM

AD

RS

Ch

an

ge

Fro

m B

ase

line

Ch

an

ge

Fro

m B

ase

line

PBO 5%

LTG 50 3%

LTG 200 8%

7-Week Randomized Double-Blind Lamotrigine 7-Week Randomized Double-Blind Lamotrigine Monotherapy in Acute Bipolar I DepressionMonotherapy in Acute Bipolar I Depression

LTG 50 mg/d (n = 64)LTG 50 mg/d (n = 64)

LTG 200 mg/d (n = 63)LTG 200 mg/d (n = 63)

Placebo (n = 65)Placebo (n = 65)

WeekWeek

0

-5

-10

-15

-20

0 1 2 3 4 5 6 7

±±

±±**

******

WeekWeek

0

-5

-10

-15

-20

0 1 2 3 4 5 6 7

††

**** ** **

**** **

**

LTG 50 mg/dLTG 50 mg/d

LTG 200 mg/dLTG 200 mg/d

PlaceboPlacebo

Switch RatesSwitch Rates

±± P<0.1; P<0.1; †† * P<0.05. * P<0.05.

16-Week Randomized Open Adjunctive Therapy of 16-Week Randomized Open Adjunctive Therapy of Treatment Resistant Bipolar DepressionTreatment Resistant Bipolar Depression a a

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

138mg/d

9429mg/d

1.5mg/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 RatesSwitch 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

Me

an

Ch

an

ge

in M

AD

RS

Sc

ore

s

-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 ± 8-Week Randomized Double-Blind Olanzapine ± Fluoxetine in Acute Bipolar I DepressionFluoxetine 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

60 54%

37%

29%

Per

cen

tag

e o

f P

atie

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 ± 8-Week Randomized Double-Blind Olanzapine ± Fluoxetine in Acute Bipolar I DepressionFluoxetine 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 7-Week Randomized Double-Blind Lamotrigine vs Olanzapine + Fluoxetine in Acute Bipolar I DepressionOlanzapine + Fluoxetine in Acute Bipolar I Depression

LTG 5%

OFC 4%

Switch Rates

LTG -0.3***

OFC +3.1

Weight Change (kg)

Week

Me

an

Ch

an

ge

in M

AD

RS

Sc

ore

s

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%

Per

cen

tag

e o

f P

atie

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 7-Week Randomized Double-Blind Lamotrigine vs Olanzapine + Fluoxetine in Acute Bipolar I DepressionOlanzapine + 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

ang

e F

rom

Bas

elin

e(L

S M

ean

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 8-Week Randomized Double-Blind Quetiapine Monotherapy in Acute Bipolar DepressionMonotherapy in Acute Bipolar Depression

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

ress

ion

Rat

ing

Sca

leIm

plr

ove

men

t

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

Per

cen

tag

e o

f P

atie

nts

Res

po

nd

ing

(≥ 5

0% M

AD

RS

Dec

reas

e)

PBO QTP300

QTP600

PBO0

10

20

30

40

50

60 58% 58%

36%40%

37%

24%

***

***

QTP300

QTP600

***

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

ean

C

han

ge

Fro

m B

asel

ine

Imp

rove

men

t

†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 BOLDER I and II: MADRS Total Score Bipolar I vs. II DisorderBipolar I vs. II Disorder

‡

†

Quetiapine 300Quetiapine 600Placebo-20

-16

-12

-8

-4

0

Magnitudes of Effects in Controlled Trials in Magnitudes of Effects in Controlled Trials in Acute Bipolar I DepressionAcute 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

OLZ10 mg

OLZ7.5 mg

+FLX

40 mgQTP

300 mgQTP

600 mgLTG

50 mgLTG

200 mg

Response Rate (%)a

0

10

20

30

40

50

60

70

OLZ10 mg

OLZ7.5 mg

+FLX

40 mgQTP

300 mgQTP

600 mgLTG

50 mgLTG

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 6-week Randomized Double-Blind Adjunctive Pramipexole in Acute Bipolar DepressionPramipexole in Acute Bipolar Depression

Response RatesP

erce

nt

resp

on

der

s(≥

50%

HD

RS

/MA

DR

S d

ecre

ase)

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

1.7mg/d

1.7mg/d

Zarate CA, et al.Biol Psychiatry 2004; 56:54-60.

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

7021 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 6-week Randomized Double-Blind Adjunctive Pramipexole in Acute Bipolar DepressionPramipexole in Acute Bipolar Depression

Switch RatesP

erce

nt

wit

h H

ypo

man

ia o

r M

ania

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

1.7mg/d

1.7mg/d

Zarate CA, et al.Biol Psychiatry 2004; 56:54-60.

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

7021 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

Per

cen

t R

esp

on

der

s(≥

50%

ID

S d

ecre

ase)

*p < 0.05 vs placebo.

Modafinil Placebo0

10

20

30

40

50

60

22%

44%

177 mg/dN = 41 N = 44

*

6-week Randomized Double-Blind Adjunctive 6-week Randomized Double-Blind Adjunctive Modafinil in Acute Bipolar DepressionModafinil 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 TrialsResponse in Randomized Controlled Trialsof Antidepressants vs. Placebo in Bipolar Depressionof Antidepressants vs. Placebo in Bipolar Depression

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

Paroxetine, Imipramine, Placebo Added to Paroxetine, Imipramine, Placebo Added to Lithium in Bipolar DepressionLithium 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

espo

nder

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 Adjunctive Paroxetine vs Second Mood Stabilizer in Bipolar DepressionStabilizer in Bipolar Depression

Similar Efficacy*

Treatment Duration (wks)

50%

ResponseRates

64%

Ham

ilto

n D

epre

ssio

n S

cale

(17

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

Rat

e (

%)

38%(6/16)

0%(0/11)

40

20

0Paroxetine

p < 0.05

Recovery RatesP

erce

nta

ge

of

Pat

ien

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=0.40NNT = 26

Mood Stabilizer + Antidepressant

Mood Stabilizer+ Placebo

27.3%(51/187)

23.5%(42/179)

P=0.84NNH = 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

itc

h R

ate

(%

)

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 TricyclicsIncreased Mania Switch Rates with Tricyclics%

With

Man

ic S

witc

h

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.Switch Rates With Tricyclic vs.Other AntidepressantsOther Antidepressants

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

Manic Switch Rates in Randomized Controlled TrialsManic Switch Rates in Randomized Controlled Trials of Antidepressants vs. Placeboof Antidepressants vs. Placebo

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

P = NS.

Bupropion Sertraline Venlafaxine

49%

53%51%

Per

cen

tag

e o

f P

atie

nts

wit

hE

ith

er ≥

50%

ID

S D

ecre

ase

or

≥ 2

po

int

CG

I Im

pro

vem

ent

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/dN = 51

192 mg/dN = 58

195 mg/dN = 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%

Per

cen

tag

e o

f P

atie

nts

P < 0.01.

CGI-MIncrease ≥ 2

BUP SERT VEN

10% 9%

29%P = 0.03.

YMRS >13 orCGI-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

eng

th (

day

s)

300

250

200

150

100

50

0

10 Bipolar Disorder Patients

Off Off OffOn On

TCAs TCAs

Acute Bipolar I Depression AlgorithmAcute 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

Pe

rce

nta

ge

of

Pa

tie

nts

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 MonotherapySummary of Double-Blind Lithium Monotherapyvs Placebo Maintenance Trials in 1970svs Placebo Maintenance Trials in 1970s

Lithium Compared to Placebo, Primarily After Manic/Mixed EpisodesLithium Compared to Placebo, Primarily After Manic/Mixed Episodes

SuperiorDepressionPrevention


SuperiorEpisode

Prevention

SuperiorEpisode

Prevention

SuperiorMania

Prevention

SuperiorMania

Prevention

Lithium Prevention of Any RelapseLithium Prevention of Any Relapse

in Bipolar Disorderin 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 RelapseLithium Prevention of Depressive Relapse



Areas of blue boxes reflect weights of studies in meta-analysis.bLower confidence interval extends beyond graph (0.10).

Lithium Prevention of Manic RelapseLithium Prevention of Manic Relapse



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

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

LI = lithiumSSRI = selective serotonin reuptake inhibitor

0%

5%

10%

15%

20%

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

Per

cen

tag

e o

f P

atie

nts

D

isc

on

tin

uin

g D

ue

to

Dep

ress

ion

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

Per

cen

tag

e o

f P

atie

nts

D

isc

on

tin

uin

g D

ue

to

Dep

ress

ion

12-Month Double-Blind Divalproex, Lithium 12-Month Double-Blind Divalproex, Lithium Monotherapy vs Placebo MaintenanceMonotherapy vs Placebo Maintenance

Fewer Dropouts Due to Depression with Divalproex vs Placebo After Manic/Mixed Episodes

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 LithiumLamotrigine and LithiumEffective in Bipolar I Prophylaxis Effective in Bipolar I Prophylaxis

Time to Intervention for Any Episode (pooled recently manic/dep pts)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 70Week

Su

rviv

al E

sti

ma

te

Placebo (n=188)

Lamotrigine 245 mg/d (n=223)

Lithium 0.7 mEq/L (n=164)

LTG v. PBO, p < 0.001Li v. PBO, p < 0.001LTG 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 inLamotrigine Effective inBipolar I Depression Prophylaxis Bipolar I Depression Prophylaxis

Time to Intervention for Depression (pooled recently manic/dep pts)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 70Week

Su

rviv

al E

sti

ma

te

LTG v. PBO, p = 0.009Li v. PBO, p = 0.120LTG 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 inLamotrigine and Lithium Effective inBipolar I Mania Prophylaxis Bipolar I Mania Prophylaxis

Time to Intervention for Mania (pooled recently manic/dep pts)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 70Week

Su

rviv

al E

sti

ma

te

LTG v. PBO, p = 0.034Li v. PBO, p < 0.001LTG 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 Incidence of Mania/Hypomania/Mixed Episodes Reported as Adverse EventsEpisodes Reported as Adverse Events

Combined AnalysisCombined Analysis

0

5

10

15

20

25

Lamotrigine (n=227)

Lithium (n=166)

Placebo (n=190)

Per

cen

t o

f p

atie

nts

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

Pe

rce

nta

ge

of

Pa

tie

nts

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 12-Month Double-Blind Olanzapine Monotherapy vs Placebo MaintenanceMonotherapy vs Placebo Maintenance

Olanzapine Compared to Placebo After Manic/Mixed EpisodesOlanzapine Compared to Placebo After Manic/Mixed Episodes



SuperiorEpisode

Prevention

SuperiorEpisode

Prevention

SuperiorMania

Prevention

SuperiorMania

Prevention

Pe

rce

nta

ge

of

Pa

tie

nts

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 12-Month Double-Blind Olanzapine vs Lithium Maintenance MonotherapyLithium Maintenance Monotherapy

EquivalentDepressionPrevention


Olanzapine Compared to Lithium After Manic/Mixed EpisodesOlanzapine Compared to Lithium After Manic/Mixed Episodes

EquivalentEpisode

Prevention

EquivalentEpisode

Prevention

SuperiorMania

Prevention

SuperiorMania

Prevention

0

10

20

30

13%12%

6%5%Pe

rce

nt

of

Pa

tien

ts

43%

25% 23%

8%

Relapse intoMania

40

50

Relapse intoMixed

Relapse intoDepression

OverallRelapse

Aripiprazole 24.3 mg/d (n=77)

Placebo (n=83)

p=.013

p=.009



SuperiorEpisode

Prevention

SuperiorEpisode

Prevention

EquivalentMixed

Prevention

EquivalentMixed

Prevention

SuperiorMania

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 26-Week Double-Blind Aripiprazole vs Placebo Continuation/Maintenance MonotherapyContinuation/Maintenance Monotherapy

Aripiprazole Compared to Placebo After Manic/Mixed EpisodesAripiprazole 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 Controlled Maintenance Studies of Antidepressants for Bipolar DepressionAntidepressants 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 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 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.Gen Psychiatry 1979;36:555-9.

Bipolar Versus Unipolar Bipolar Versus Unipolar Maintenance Treatment DissociationMaintenance 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

abili

ty o

f R

emai

nin

g W

ell

0

10

20

30

40

50

60

70

80

90

3 6 9 12 15 18 21 23 25 27 30Months

100

Cu

mu

lati

ve P

rob

abili

ty o

f R

emai

nin

g W

ell

0

10

20

30

40

50

60

70

80

90

100

3 6 9 12 15 18 21 24 27Months

Antidepressant Continuation BeneficialAntidepressant Continuation Beneficialin Some (15%?) Patientsin Some (15%?) Patients

Prospective 1-year follow-upRemission of MDE with ADadded to mood stabilizer

Tolerated AD ≥ 2 months

Continuation: AD > 6 monthsDiscontinuation: 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– Alternative treatments

Maintenance treatment

– Lithium, lamotrigine– Divalproex– Adjunctive antidepressants (controversial)– Alternative treatments

New treatment options emerging

Post-Lecture ExamPost-Lecture ExamQuestion 1Question 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


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


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


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


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 ExamAnswers to Pre & Post Competency Exam

1. C

2. D

3. A

4. E

5. D

terence a. ketter, m.d. acute and maintenance treatment of bipolar depression terence a. ketter, m.d

Documents

bipolar i patients

pramipexole slide

atypical antipsychotic

bupropion slide

bipolar disorders symptoms

depression d

following treatments

tricyclic antidepressants