Treating Patients With Bipolar Disorder in Primary Care

1
Treating Patients With Bipolar Disorder in
Primary Care
2
Learning Objective

• Employ current treatment guidelines in the
  management of patients with bipolar disorder to
  improve patient care

3
Practical Therapeutic Objectives

• Goals of Treatment
• (1) Symptomatic remission and wellness
• (2) Full return of psychosocial functioning
• (3) Prevention of relapse and recurrences

Suppes T, et al. J Clin Psychiatry.
200566870-886. American Psychiatric
Association. Am J Psychiatry. 20021591-50.
4
Treatment Objectives

• Primary objectives
• Perform diagnostic evaluation
• Assess patients safety and level of functioning
• Formulate decision regarding optimum treatment
  setting
• Secondary objectives
• Establish and maintain a therapeutic alliance
• Monitor changes in psychiatric status
• Enhance treatment compliance
• Minimize functional impairment

American Psychiatric Association. Am J
Psychiatry. 20021591-50.
5
Current Guidelines for the Treatment of Bipolar
Disorder
6
What Exactly Is a Mood Stabilizer?

• The term mood stabilizer is widely used in the
  context of treating bipolar disorder.
• However,
• FDA does not officially recognize the term
• Investigators have no consensus definition
• Substantial debate exists about definition

7
What Exactly Is a Mood Stabilizer?

• Some authorities suggest 2 out of 3 of the
  following properties
• Antimanic, antidepressive, prophylactic
• Other experts are more stringentrequiring
• Treatment of acute mania,
• Treatment of acute depression, AND
• Prevention of recurrent mania and depression
• Lithium remains the gold standard
• Recommended in all phases of treatment according
  to current guidelines

Bauer MS, Mitchner L. Am J Psychiatry.
20041613-18. Young LT. J Psychiatry Neurosci.
20042987-88.
8
Guidelines for the Treatment of Mania
9
TIMA Algorithm for Treatment of Acute Manic
Episodes
1B Olanzapineor carbamazepine
ResponseContinue with therapy
ResponseContinue with therapy
Use targeted adjunctive treatment as necessary
before moving to next stage. Agitation/Aggression-
clonidine, sedatives Insomnia-hypnotics
Anxiety-benzodiazepines, gabapentin. All agents
in Stage 1A and 1B are indicated for acute mania
associated with bipolar I disorder. Safety and
other concerns led to placement of olanzapine and
carbamazepine as alternate first-stage choices.
Suppes T, et al. J Clin Psychiatry.
200566870-886.
10
TIMA Algorithm for Treatment of Acute Manic
Episodes (Stages 34)
Suppes T, et al. J Clin Psychiatry.
200566870-886.
11
Guidelines for the Treatment of Bipolar
Depression
12
Treating Bipolar Depression

• Monotherapy or combination therapy
• Lithium
• Novel antipsychotics
• Anticonvulsants
• Other strategies
• Add-on antidepressant (not as monotherapy)
• Electroconvulsive therapy (ECT)

While monotherapy is the goal of most
practitioners, the inherent nature of bipolar
disorder makes combination therapy the rule
rather than the exception.
Young LT. J Psychiatry Neurosci.
20042987-88. American Psychiatric Association.
Am J Psychiatry. 20021591-50.
13
Acute Depression and Suicidality

• Bipolar depression and mixed states are
  frequently associated with suicidality
• Assessment of suicide should always be an
  integral part of managing any bipolar patient
• For patients with suicidality or psychosis, ECT
  represents a reasonable alternative

American Psychiatric Association. Am J
Psychiatry. 20021591-50.
14
Therapy Options for Bipolar Depression

• Lithium
• Lamotrigine
• Atypical antipsychotics
• Olanzapine/Fluoxetine
• Quetiapine

15
TIMA Bipolar Treatment of Acute Depressive
Episodes (Stages 13)
Taking no antimanic, with history of severe
and/or recent mania
Taking no antimanic, without history of severe
and/or recent mania
Taking otherantimanic
Taking Li
Increase to 0.8 mEq/L
(continue)
Stage 1
Antimanic LTG
LTG
Stage 2
OFCa or QTPa
Stage 3
Combination from Li, LTG, QTP, or OFC
aNote safety issue described in reference listed
below (ie, olanzapine is associated with weight
gain, quetiapine is associated with sedation and
somnolence). Li lithium LTG lamotrigine OFC
olanzapine-fluoxetine combination QTP
quetiapine.
Suppes T, et al. J Clin Psychiatry.
200566870-886.
16
TIMA Bipolar Treatment of Acute Depressive
Episodes (Stages 45)
Stage 4
Li, LTGb, OFC, VPA, or CBZ SSRIc, BUP, or VEN
or ECT or QTP
Stage 5
MAOIs, tricyclics, pramipexole, other AAPsa,
OXC, other combinations of drugs at stages,
inositol, stimulants, thyroid
aNote safety issue described in reference listed
below (ie, olanzapine is associated with weight
gain, quetiapine is associated with sedation and
somnolence). bLamotrigine has limited antimanic
efficacy and, in combination with an
antidepressant, may require the addition of an
antimanic. cSSRIs include citalopram,
escitalopram, fluoxetine, paroxetine, sertraline,
and fluvoxamine. Evidence supported by
randomized controlled clinical trials with large
effect sizes. AAP atypical antipsychotic BUP
bupropion CBZ carbamazepine CONT
continuation ECT electroconvulsive therapy Li
lithium LTG lamotrigine MAOI monoamine
oxidase inhibitor OFC olanzapine-fluoxetine
combination OXC oxcarbazepine QTP
quetiapine SSRI selective serotonin reuptake
inhibitor VEN venlafaxine VPA valproate.
Suppes T, et al. J Clin Psychiatry.
200566870-886.
17
Bipolar Depression and Antidepressants
18
Bipolar Depression and AntidepressantsGeneral
Guidelines and Risks

• Always use antimanic agents in bipolar I
  patients, even while depressed
• Antidepressants may trigger mania/mood
  destabilization or accelerate mood cycles in up
  to 33 of bipolar patients and are not
  recommended as monotherapy
• Promptly wean the antidepressant if evidence of
  hypomania or mania emerges

Frances AJ, et al. J Clin Psychiatry.
19985973-79. Dantzler A, Osser DN. Psychiatr
Ann. 199929270-284. Goldberg JF, Ernst CL. J
Clin Psychiatry. 200263985-991. Möller HJ, et
al. J Affect Disord. 200167141-146. Goldberg
JF, Truman CJ. Bipolar Disord. 20035407-420.
19
Anticonvulsants for Bipolar Depression
20
The Evidence for Lamotrigine in Bipolar
Depression

• Among antiepileptic drugs, clinical data favor
  lamotrigine as
• first-line treatment for acute bipolar
  depression1
• The first open study in bipolar depressed
  patients reported symptomatic
  improvement in 72 of patients by end of 4 weeks,
  with 63 reported in remission by 6 weeks2
• Lamotrigine has demonstrated efficacy and safety
  in a
• multicenter double-blinded, placebo-controlled
  study of 195
• outpatients with bipolar I disorder,
  depressed3

1. Muzina DJ, et al. Acta Psychiatr Scand.
2005111(suppl 426)21-28. 2. Kusumaker V, Yatham
L. Psychiatry Res. 199772145-148. 3. Calabrese
JR, et al. J Clin Psychiatry. 19996079-88.
21
Bipolar I DepressionLamotrigine Monotherapy
Week
0
0.5
1
2
3
4
5
6
7
0
-2
P lt .05 vs placebo
-4
-6
-8
MADRS Change From Baseline

-10

-12



-14



Placebo
-16

Lamotrigine 50 mg/d
-18
Lamotrigine 200 mg/d
-20
Dose gt 50 mg/d in lamotrigine 200 mg/d group only
after week 3
Calabrese JR, et al. J Clin Psychiatry.
200263(suppl 3)5-9.
22
The Evidence for Lamotrigine in Rapid-Cycling
Bipolar Disorder

• Lamotrigine monotherapy is useful treatment for
  some patients with rapid-cycling bipolar disorder
• Among patients with rapid-cycling bipolar
  disorder, 41 of lamotrigine patients vs 26 of
  placebo patients were stable without relapse for
  6 months of monotherapy
• Overall survival time in study favored
  lamotrigine
• (6 weeks longer than placebo)

Calabrese JR, et al. J Clin Psychiatry.
200061841-850.
23
Atypical Antipsychotics for Bipolar Depression
24
Quetiapine Monotherapy for the Treatment
of Bipolar Depression (BOLDER I)
0
1
2
4
3
6
5
7
8
0
Study Week
Mean BL MADRS
Quetiapine 600 mg (n 170) 30.3
Quetiapine 300 mg (n 172) 30.4
-5
Placebo (n 169) 30.6

Mean Change From Baseline MADRS

-10







-15






P lt 0.001 (vs placebo)

ITT, LOCF
-20
Titration initial dose 50 mg/day to achieve
dose of 600 mg/day by week 1 or 300 mg/day by day
4. This information concerns a use that has not
been approved by the US FDA.
Calabrese JR, et al. Am J Psychiatry.
20051621351-1360.
25
Olanzapine/Fluoxetine Combination (OFC) Study

• Study Design 8-week, randomized, double-blind
  study to compare efficacy and safety of
  olanzapine, placebo, and OFC in bipolar
  depression
• Patients 18 years or older with DSM-IV criteria
  for bipolar I disorder, depressed, with MADRS ?
  20, and history of at least 1 manic or mixed
  episode
• Assessments Primary measure of efficacy was
  change in MADRS total score from baseline to week
  8

Tohen M, et al. Arch Gen Psychiatry.
2003601079-1088.
26
Olanzapine and Olanzapine/Fluoxetine Combination
for Bipolar I Depression
Weeks
0
1
2
3
4
6
8
Mean Dose
0
N OLZ FXT
OLZ 351 9.7 -
-5
PBO 355 - -
OFC 82 7.4 39.3
MADRS Change From BL
-10
-15

-20
P lt 0.001 P lt 0.01 MADRS
Montgomery-Asberg Depression Rating Scale
Tohen M, et al. Arch Gen Psychiatry.
2003601079-1088.
27
Olanzapine and OFC for Bipolar I Depression
Remission Rates

• Olanzapine group 32.8 (115/351)
• Placebo group 24.5 (87/355)
• OFC group 48.8 (40/82)
• Remission defined as a MADRS score of 12 or less
  at an endpoint and completion of at
• least 4 weeks of study
• P 0.02 vs placebo
• P lt 0.001 vs placebo, P 0.007 vs olanzapine

Tohen M, et al. Arch Gen Psychiatry.
2003601079-1088.
28
Acute Treatment of Bipolar Depression March 2006
29
Bipolar Depression Conclusions

• Bipolar depression is more severe and impairing
  than unipolar depression
• The data on use of medications for the acute
  treatment of bipolar depression are limited
• Olanzapine/fluoxetine combination is the only
  treatment with an FDA indication
• Efficacy data are strong for quetiapine
• Efficacy data for lamotrigine are mostly positive
• Data on the efficacy of antidepressants are weak
• Unanswered questions remain on the first-line
  acute treatment of bipolar depression

30
Pharmacological Treatments for Maintenance
Therapy
31
Maintenance Treatment

• FDA-indicated mood stabilizers
• Best evidence supports the use of lithium and
  lamotrigine as first-line therapies for
  maintenance treatment
• Lithium has been used for both acute and
  prophylactic treatment of bipolar disorder
• Atypical antipsychotics (olanzapine,
  aripiprazole) also recommended

American Psychiatric Association. Am J
Psychiatry. 20021591-50. Suppes T, et al. J
Clin Psychiatry. 200566870-886. Yatham LN, et
al. Bipolar Disord. 200575-69.
32
Lithium vs Placebo in Maintenance
1.2
1
0.8
0.6
Probability of Remaining Well
0.4
0.2
0
0
10
20
30
40
50
60
Follow-Up (weeks)
Keck PE Jr, et al. Biol Psychiatry.
200047756-761.
33
Lamotrigine vs Lithium vs Placebo Relapse
Prevention, Maintenance Therapy
1
Li vs PBO, P 0.029 LTG vs PBO, P 0.029 LTG
vs Li, P 0.915
0.9
0.8
0.7
Median 24 weeks
0.6
Median 29 weeks
Survival Estimate
0.5
Li (n 46)
0.4
LTG (n 59)
0.3
PBO (n 70)
0.2
0.1
0
60
70
0
10
20
30
40
50
Week
LTG lamotrigine 100 to 400 mg daily Li
lithium 0.81.1 mEq/L PBO placebo
Time to Intervention for a Mood Episode
Bowden CL, et al. Arch Gen Psychiatry.
200360392-400.
34
Maintenance Treatment

• Atypical antipsychotics
• Olanzapine is recommended as an alternate
  first-line therapy
• Aripiprazole is recommended as a second-line
  therapy
• Other atypical antipsychotics (quetiapine,
  risperidone, ziprasidone) are potential
  maintenance treatments

Suppes T, et al. J Clin Psychiatry.
200566870-886. Yatham LN, et al. Bipolar
Disord. 200575-69.
35
Relapse Into Mania or Depression Scale-Based
Outcomes in 1-Year Olanzapine-Lithium Comparison
50
P .055
Olanzapine (n 217)
Lithium (n 214)
38.8
40
P lt .001

30.0
28.0
30
P .895
Percent of Patients

20
16.1
15.4
14.3
10
0
Overall Relapse
Depressive Relapse
Manic Relapse
Relapse defined by YMRS ? 15 and/or HAM-D ?
15. Tohen M, et al. Am J Psychiatry.
20051621281-1290.
36
Aripiprazole for Maintenance Treatment of Bipolar
Disorder

• Long-term study design
• Open-label stabilization phase
• (6-18 weeks)
• ?
• Double-blind maintenance phase
• (aripiprazole or placebo for 26 weeks)
• Results
• Fewer relapses with aripiprazole
• Significantly longer time to symptom relapse than
  with placebo

Marcus R, et al. Presented at 42nd Annual
Meeting of the American College of
Neuropsychopharmacology December 2003 San Juan,
Puerto Rico. Keck PE Jr, et al. J Clin
Psychiatry. 200667626-637.
37
Maintenance Treatment

• Antidepressants
• Due to risks of mania induction and cycle
  acceleration, antidepressant monotherapy is not
  recommended for maintenance treatment of bipolar
  disorder
• Not recommended, but if used, must be used with
  an antimanic agent

Suppes T, et al. J Clin Psychiatry.
200566870-886. Yatham LN, et al. Bipolar
Disord. 200575-69.
38
Maintenance Treatment

• Anxiolytics
• Systematic evaluation of benzodiazepines as
  prophylactic agents in bipolar disorder has not
  been conducted
• Issues such as dependence, rebound anxiety,
  memory impairment argue against their long-term
  use

Yatham LN, et al. Bipolar Disord. 200575-69.
39
Maintenance Treatment

• Mood stabilizer combinations
• Some efficacy demonstrated
• Lithium plus valproate
• Lithium plus carbamazepine
• Olanzapine-fluoxetine combination has shown
  efficacy

Suppes T, et al. J Clin Psychiatry.
200566870-886.
Yatham LN, et al. Bipolar Disord. 200575-69.
40
Recommendations for Combination Therapy in
Bipolar Disorder

• Combination therapy is the rule, not the
  exception
• Use evidence-based guidelines
• Add drugs to the treatment regimen that
  specifically targets residual symptoms

Bowden CL. J Clin Psychiatry. 20046521-24.
41
Disease Management Strategies
42
Strategies for Pharmacotherapeutic Management of
Bipolar Disorder

• Monitor drug levels/laboratory values lipids,
  blood sugar, metabolic parameters
• Routine weight recording
• Patient education, psychosocial therapy
• Collaborative co-management by PCPs and
  psychiatrists

Nemeroff CB. J Clin Psychiatry. 200364532-539.
43
Principles of Treatment

• Use evidence-based treatments
• Achieving target dose is essential to success
• Combination therapy is often appropriate
• Initiate mood-stabilizing treatment specific to
  the presenting phase of the disorder
• Monitor depressive and manic symptoms at each
  visit
• Antidepressant therapy alone is generally not
  recommended

44
Treatment Options in Bipolar Disorder Key
Messages

• Goal of treatment is for symptomatic remission
  and wellness, full return of psychosocial
  functioning, and prevention of relapse and
  recurrences
• According to TIMA Guidelines, first line
  treatment for mania includes lithium, valproate,
  and atypicals (excluding olanzapine and
  clozapine)
• Treatment for bipolar depression includes
  lithium, lamotrigine, and OFC. Quetiapine is
  emerging as a viable alternative for bipolar
  depression
• Best evidence supports the use of lithium,
  lamotrigine, and olanzapine as first-line
  therapies for maintenance treatment
• Atypical antipsychotics appear to have varying
  side-effect profiles among agents
• Collaborative co-management by PCPs and
  psychiatrists is essential