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
Monotherapy 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).
8-Week Randomized Double-Blind Quetiapine
Monotherapy in Acute Bipolar Depression
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
8-Week Randomized Double-Blind Quetiapine
Monotherapy in Acute Bipolar Depression
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
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 < 0.05
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 = 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.
Acute Bipolar I Depression Algorithm
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
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.
Acute Bipolar I Depression Algorithm
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
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.
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
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 (0.10).
Lithium Prevention of Manic 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.
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.
Goodwin GM, et al. J Clin Psychiatry 2004;65:432-41.
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)
Lamotrigine 245 mg/d (n=223)
Lithium 0.7 mEq/L (n=164)
Patients stabilized on lamotrigine prior to randomization.
Some patients considered intervention-free for mania could have had intervention for depression.
Goodwin GM, et al. J Clin Psychiatry 2004;65:432-41.
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)
Lamotrigine 245 mg/d (n=223)
Lithium 0.7 mEq/L (n=164)
LTG Li PBO0
20
40
60
80
53%
80%
65%
18 Months
Patients stabilized on lamotrigine prior to randomization.
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.
Goodwin GM, et al. J Clin Psychiatry 2004;65:432-41.
Patients stabilized on lamotrigine prior to randomization.
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
– Alternative treatments
Maintenance treatment– Lithium, lamotrigine
– Divalproex
– Adjunctive antidepressants (controversial)
– Alternative treatments
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