New Treatment Approaches

1

• Section 3
• New Treatment Approaches

2
Treating Acute Bipolar Depression

• Great need still exists for evidence-based
  approaches to this common clinical problem
• Limited data support traditional antidepressants
  as monotherapy
• Positive data in clinical trials for OFC and
  quetiapine
• Clinicians need effectiveness trials to explore
  the common practice of polypharmacy for acute
  bipolar depression

3
Evidence Based Therapies

• Impact relapse and rehospitalization rates
• Group psychoeducation
• 25 hospitalized vs 35 in unstructured group1
• Cognitive behavioral therapy (CBT)
• 1 year relapse 44 vs 75 usual care2
• Family focused treatment (FFT)
• 2 year relapse 28 with FFT vs 60 unsupportive3
• Perceived criticism may be an indicator4

1. Colom F, et al. Arch Gen Psychiatry.
200360402-407. 2. Lam DH, et al. Arch Gen
Psychiatry. 200360145-152. 3. Rea M, et al. J
Consult Clin Psychol. 200371482-492. 4.
Miklowitz DJ, et al. Psychiatry Res.
2005136101-111.
4
Interpersonal Social Rhythm Therapy

• RCT, IPSRT vs ICM, n 175 BP1, 2 years
• Effect size of .58
• After controlling marital status, index polarity,
  anxiety, medical burden
• Mediated by improved social rhythms
• Not adherence
• Better if married
• Best initiated in early maintenance
• ICM better if medically ill and anxious
• Intensive clinical management

Frank E, et al. Arch Gen Psychiatry.
200562996-1004.
5
Psychotherapy Reduces Relapse Rate

• Effect size in large Randomized Control Trials
  .37

Citation Total N
Effect P-value
ltgt ltgt
.01 0.1 1
Colom F, et al. Arch Gen Psychiatry.
200360402-407 Lam DH, et al. Arch Gen
Psychiatry. 200360145-152. Miklowitz DJ, et al.
Psychiatry Res. 2005136101-111. Scott J,
Gutierrez MJ. Bipolar Disord. 20046498-503.
6
Psychotherapy Interventions

• Therapies may use some or all
• Adjust to Dx and Rx
• Enhance adherence
• Improve self-esteem
• Reduce risky behaviors
• Modify destabilizing biopsychosocial factors

• Manage stressors
• Teach coping strategies
• Teach early recognition
• Modify attitudes/beliefs
• Homework (eg, mood charting)

Scott J, Gutierrez MJ. Bipolar Disord.
20046498-503.
7
Essential Qualities of an Effective
Patient/Provider Relationship as Expressed by
Individuals With Bipolar Disorder
Sajatovic M, et al. Compr Psychiatry.
200546272-277.
8
Therapies With Bipolar Disorder Indications
Limited data Emerging data Submitted for
approval on 12/05 Physicians Desk Reference.
60th ed. Montvale, NJ Medical Economics Co 2006.
9
Lithium Meta-analysis

• Five RCTs, Li vs placebo, n 770
• One relapse prevented for every 14 patients
  treated 12 years
• One mania for every 10 patients
• One depression for every 14 patients

Geddes JR, et al. Am J Psychiatry.
2004161217-222.
10
Treatment of Bipolar Depression

• Fewer studies than for mania
• Limited approved treatments
• Traditional antidepressants lack evidence and may
  cause mood destabilization

Ghaemi SN, et al. J Clin Psychiatry.
200162565-569. Ghaemi SN, et al. Am J
Psychiatry. 2004161163-165.Muzina DJ,
Calabrese JR. Int J Neuropsychopharmacol.
20036285-291.
11
TIMA Bipolar 2005Acute Depression
Stage 1
OtherAntimanic
No Antimanic, Severe or Recent Mania
No Antimanic,No Severe or Recent Mania
Taking Li
(Increase Li to 0.8 mEq/L)
(continue)
Antimanic Lamotrigine
Lamotrigine
Lamotrigine is a mood stabilizer not
antimanic Lithium is an antimanic If history
of recent or severe mania, add or optimize
antimanic Otherwise, lamotrigine monotherapy
may be appropriate
Suppes T, et al. J Clin Psychiatry.
200566870-886.
12
TIMA Bipolar 2005Acute Depression
?
Partial Response Or Nonresponse
Stage 2
Quetiapine or Olanzapine/Fluoxetine
Response
Partial Response Or Nonresponse
CONT
Stage 3
Combination from Li, LTG, QTP, or OFC

• Designed to minimize cycle risk
• Note no anticonvulsant except LTG until Stage 4
• Overlap and taper
• Follow ADA guidelines regarding metabolic
  monitoring

Suppes T, et al. J Clin Psychiatry.
200566870-886.
13
TIMA Bipolar 2005Acute Depression
Response
CONT
Partial Response Or Nonresponse
Li, LTG, QTP, OFC, VPA, or CBZ SSRI, BUP, or
VEN or ECT
Stage 4

• Combinations (OFC combinations 3 drugs)
• Lamotrigine should not be combined with AD
  without antimanic
• Includes VPA and CBZ at this point
• SSRIs include CTP, FLX, PRX, SRT, and FLV
• Some advocate the use of AD earlier but
  evidence is lacking
• Venlafaxine associated with more mania
  induction

BUP bupropion CBZ carbamazepine ECT
electroconvulsive therapy Li lithium LTG
lamotrigine OFC olanzapine-fluoxetine
combination QTP quetiapine SSRI selective
serotonin reuptake inhibitor VEN venlafaxine
VPA valproate Suppes T, et al. J Clin
Psychiatry. 200566870-886.
14
TIMA Bipolar 2005Acute Depression
MAOIs, Tricyclics, Pramipexole, Other AAPs,
OXC, Other Combinations Inositol, Stimulants,
Thyroid
Stage 5

• Options with limited empirical support or safety
  problems
• MAOIs effective but with safety/tolerability
  concerns
• TCAs effective but more hazardous in OD, etc
• Omega 3 fatty acid dropped

MAOI monoamine oxidase inhibitor OXC
oxcarbazepine Suppes T, et al. J Clin Psychiatry.
200566870-886.
15
Olanzapine-fluoxetine CombinationTreatment for
Bipolar I Depression
Source
Review
0
Placebo (N 355)
-2
Olanzapine (N 351)

-4
OFC (N 82)
-6
Reviewer Memo

-8



MADRS Change From Baseline
-10

-12

-14


-16
-18
-20
0
1
2
3
4
5
6
7
8
Week
P lt 0.05 olanzapine vs placebo P lt 0.05 vs OFC
Tohen M, et al. Arch Gen Psychiatry.
2003601079-1088.
Slide Modified
Memo
16
Quetiapine for BP I and II Depression
Study Week
1
2
4
3
6
5
7
8
0
0
Placebo (n 169)
Quetiapine 300 mg (n 172)
-5
Quetiapine 600 mg (n 170)

MADRS Mean Change From Baseline
-10










-15





P lt 0.001 (vs placebo)
-20
ITT, intent-to-treat. LOCF, last observation
carried forward MADRS, Montgomery-Asberg
Depression Rating Scale
Calabrese JR, et al. Am J Psychiatry.
20051621351-1360.
17
Bipolar Depression Quetiapine Effective in a
Broad Range of Symptoms

Apparent sadness


Reported sadness


Inner tension



Reduced sleep
Reduced appetite

Quetiapine 600 mg (n 170)
Concentration difficulties

Quetiapine 300 mg (n 172)

Lassitude
Placebo (n 169)

P lt 0.001 P lt 0.01 (vs placebo)
Inability to feel


Pessimistic thoughts



Suicidal thoughts
0
10
20
30
40
50
60
70
80
ITT, LOCF
Mean Percent Change in MADRS Item Score
Calabrese JR, et al. Am J Psychiatry.
20051621351-1360.
18
Bipolar Depression Quetiapine inRapid vs
Nonrapid Cycling
Rapid Cyclingn 108
Nonrapid Cyclingn 403
0
-5
MADRS Mean Change From Baseline
-10
-15
Quetiapine 600 mg


Quetiapine 300 mg


-20
Placebo
P lt 0.001, P lt 0.01 (vs placebo)
ITT, LOCF
Calabrese JR, et al. Am J Psychiatry.
20051621351-1360.
19
BOLDER II MADRS Total Score
Study Week
1
2
4
3
6
5
7
8
0
0
LS Mean Change From Baseline
Quetiapine 300 mg (n155)
-4
Quetiapine 600 mg (n151)
Placebo (n161)
-8



-12
Improvement







-16






-20
Plt0.001 vs placebo
ITT, LOCF
Thase ME, et al. Presented at 159th American
Psychiatric Association Annual Meeting May
21-25, 2006 Toronto, Ontario, Canada.
20
BOLDER II MADRS Items
Apparent sadness

Reported sadness


Inner tension

Reduced sleep


Reduced appetite

Quetiapine 300 mg (n155)

Concentration difficulties

Quetiapine 600 mg (n151)
Lassitude

Placebo (n161)

Inability to feel

Pessimisticthoughts


Suicidal thoughts
0
10
20
30
40
50
60
70
80
ITT, LOCF
Improvement from Baseline in Mean Score
P lt 0.05 P lt 0.01 P lt 0.001 vs placebo
(P-values ANCOVA, change from baseline) Thase
ME, et al. Presented at 159th American
Psychiatric Association Annual Meeting May
21-25, 2006 Toronto, Ontario, Canada.
21
BOLDER II Study

• Quetiapine monotherapy (300 mg and 600 mg)
  demonstrated significant improvement from
  baseline compared to placebo as early as Week 1
  in all depression efficacy measures (MADRS and
  HAM-D)
• Significant improvements were seen in patients
  with bipolar I and bipolar II disorder and in
  patients with and without a rapid cycling disease
  course
• Improvements were seen in a broad range of
  depressive symptoms
• There were no major differences between the
  quetiapine dose groups
• Safety and tolerability findings were similar to
  BOLDER I
• Most common adverse events reported were dry
  mouth, sedation, somnolence, dizziness, and
  constipation
• Incidence of treatment-emergent mania was
  comparable to placebo

Thase ME, et al. Presented at 159th American
Psychiatric Association Annual Meeting May
21-25, 2006 Toronto, Ontario, Canada.
22
Bipolar Depression Lithium With Antidepressants
(N 117)
70
Li PBO
60
Li PAR
50
Li IMI
Percent Reduction of HAMD Score
40
30
20
10
0
Li ? 0.8 mEq/L
Efficacy Overall

• Greater relapse prevention in mania vs depression
• Switch rate 0 paroxetine 3 placebo 7
  imipramine
• Mean Li level 0.78 mEq/L

Li lithium IMI imipramine PAR paroxetine
PBO placebo Nemeroff CB, et al. Am J
Psychiatry. 2001158906-912.
23
Adding a Second Mood Stabilizer vs Adding an
Antidepressant
25
Hamilton Rating Scale for Depression
Two mood stabilizers Mood stabilizer
and paroxetine
(16)
20
Young Mania Rating Scale Two mood
stabilizers Mood stabilizer and
paroxetine
(11)
(15)
15
(11)
(12)
(11)
Score
10
(11)
(11)
(11)
(11)
(11)
n 27
(10)
5
(10)
(10)
0
Baseline
1
2
3
4
5
6
Duration of Treatment (weeks)
Parenthetical numbers indicate numbers of the
remaining 27 subjects, but the data points
include imputed (last observation carried
forward) data on dropouts. Medications used are
valproate lithium Young LT, et al. Am J
Psychiatry. 2000157124-126.
24
Bipolar Depression and Antidepressants General
Guidelines and Risks
?

• Always use mood stabilizer in bipolar I patients,
  even while depressed
• Promptly wean the antidepressant if evidence of
  hypomania or mania emerges
• Antidepressants may trigger mania (mood
  destabilization) or accelerate mood cycle
• Up to 33 of patients with bipolar disorder may
  be susceptible to antidepressant-induced manias
• Possibly less efficacious in BP than UP
  depression
• Few standard antidepressants have been studied in
  bipolar depression

Dantzler A, Osser DN. Psychiatr Ann.
199929270-284. Frances AJ, et al. J Clin
Psychiatry. 199859(suppl 4)73-79. Goldberg JF,
Ernst CL. J Clin Psychiatry. 200263985-991. Gold
berg JF, Truman CJ. Bipolar Disord.
20035407-420. Möller HJ, et al. J Affect
Disord. 200167141-146.
25
General Principles

• Maintenance
• Continue effective acute phase treatment(s) or
  
• Switch to one with evidence of maintenance
• efficacy
• Varies by polarity of most recent episode
• Simplify medication regimen
• Improve tolerability and adherence
• Little data on combinations in maintenance

Suppes T, et al. J Clin Psychiatry.
200566870-886.
26
Complexities of Antipsychotic Therapy in
Long-Term Management of Bipolar Disorder
Dose and switching medication
EPS, TD, and prolactin
Weight gain, diabetes, lipids
Broad symptom profile
OPTIMUM CLINICAL OUTCOME
Efficacy
Tolerability
27
Antipsychotic-induced Neurologic Complications

• Movement disorders
• Limited reactionsacute dystonia reaction
• Idiosyncratic eventsneuroleptic malignant
  syndrome
• Toxic effects
• ? Parkinsonism
• ? Acute akathisia
• Tardive syndromes
• Cognitive impairment
• Stroke

Nasrallah HA. Ann Clin Psychiatry. 20061857-62.
28
Neuroleptic-induced Dystonia
30
N 46
Patients with bipolar disorder are 5 times more
susceptible to EPS than patients with
schizophrenia
25
Percent With Dystonia
20
15
10
N 135
5
0
Schizophrenia
Mania
Nasrallah HA, et al. Am J Psychiatry.
19881451455-1456.
29
Estimated Mean Weight Gain at 10 Weeks With
Antipsychotics
6
5
4
3
Mean Change in Body Weight (kg)
2
1
0
1
2
3
Placebo
Molindone
Sertindole
Clozapine
Haloperidol
Olanzapine
Ziprasidone
Thioridazine
Risperidone
Fluphenazine
Chlorpromazine
Conventional antipsychotics Second-generation
antipsychotics
Allison DB, et al. Am J Psychiatry.
19991561686-1696.
30
Atypicals 52-Week Weight Gain Mean Change From
Baseline Weight
14 -
Olanzapine (12.5-17.5 mg) Olanzapine (all
doses) Quetiapine Risperidone Ziprasidone Aripipra
zole
- 27
12 -
- 22
10 -
- 20
8 -
- 16
Change From Baseline Weight (kg)
Change From Baseline Weight (lb)
6 -
- 12
4 -
- 8
2 -
- 4
0 -
- 0
Weeks
Nemeroff CB. J Clin Psychiatry. 199758(suppl
10)45-49.
Jones M, et al.
Poster presented at ICBD. 2003.
31
Obesity as a Risk Factor for Antipsychotic
Noncompliance
Noncompliant Respondents According to BMI Category
60

50

40
30
Noncompliance ()
20
10
0
Normal(N 62)
Overweight(N 88)
Obese(N 89)
P 0.01 vs normal Chi-square P 0.03 Test
for linearity P 0.01 Schizophrenia
population Weiden PJ, et al. Schizophr Res.
20046651-57.
32
Second-generation Antipsychotics Associated
Adverse Events

• Olanzapine
• Weight gain, somnolence, diabetes, hyperlipidemia
• Risperidone
• EPS, ? prolactin, weight gain
• Quetiapine
• Somnolence, hypotension, weight gain
• Ziprasidone
• Akathisia, ? QTc
• Aripiprazole
• Akathisia, insomnia, nausea

Dose-related EPS. Adverse effects with
moderate/high frequencies listed. Bold face
indicates marked significance. EPS
extrapyramidal syndrome Akathisia is noted in
all atypical antipsychotics Adapted from
Nasrallah HA, et al. Ann Clin Psychiatry.
200113215-227. Adapted from Halbreich UM, et
al. Psychoneuroendocrinology. 20032853-67.
33
Second-generation AntipsychoticsMetabolic
Syndrome

• Recent reports by the FDA, ADA, APA, AACE, and
  NAASO have raised concerns regarding obesity,
  diabetes, and dyslipidemia as adverse effects of
  atypical antipsychotic agents1
• In addition, the metabolic syndrome appears to be
  more common in patients with schizophrenia and
  bipolar disorder
• Monitoring is now recommended1,2

AACE American Association of Clinical
Endocrinologists NAASO North American
Association for the Study of Obesity 1. American
Diabetes Association. Diabetes Care.
200427596-601. 2. Buse JB. J Clin Psychiatry.
200263(suppl 4)37-41.
34
Medical Comorbidities With Bipolar Disorder

• Cardiovascular disease
• Relative cardiovascular mortality in male
  inpatients with bipolar disorder 1.87
• Obesity
• Central obesity more common, especially with
  patients on antipsychotics
• Diabetes
• Prevalence 9.9 expected frequency 3.4
• Neurological disorders
• Migraine prevalence 25 of men, 27 of women
  rate in men is almost 5x general population
• Chronic pain syndromes

Elmslie JL, et al. J Clin Psychiatry.
200061179-184 Cassidy F, et al. Am J
Psychiatry 19991561417-1420 Weeke A, et al. J
Affect Disord 198713287-292 Mahmood T, et al.
J Affect Disord. 199952239-241 Schiffer RB, et
al. Am J Psychiatry. 198614394-95.
35
Correlates of Obesity in Patients With Bipolar
Disorder

• Male
• Hypertension
• Arthritis
• Diabetes mellitus
• gt 4 manic episodes
• 1 suicide attempt

• Exposure to 1 weight-increasing psychotropic
• Limited occupational functioning
• Comorbid binge-eating disorder

Stanley Foundation Bipolar Treatment Outcome
Network (N 644) McElroy SL, et al. J Clin
Psychiatry. 200263207-213.
36
Prevalence of Overweight and Abdominal Obesity in
Bipolar Patients
Waist-to-hip Ratio
Overweight
Obese
70
70


60
60
50
50

40
40
30
30
Percent ()
Percent ()


20
20
10
10
0
0
Bipolar
Reference
Bipolar
Reference
Females
Males
P lt 0.05 N 89 bipolar disorder, 445 reference
subjects
Elmslie JL, et al. J Clin Psychiatry.
200061179-184.
37
Obesity as a Marker for Recurrence in Bipolar
Disorder
Non-obese (N 79) Obese (N 46)
1.0
0.8
0.6
Cumulative Proportion Remaining Well
0.4
0.2
0.0
120
80
60
100
40
20
0
0
Weeks in Preventive Treatment
Obese patients had shorter time to recurrence of
depression than non-obese patients
Log-rank Chi-square 7.33 df 1 P lt
0.007 Fagiolini A, et al. Am J Psychiatry.
2003160112-117.
38
Bipolar Disorder and Type II DM
BP bipolar disorder, SZ schizophrenia, GP
general population 1. Poulin MJ, et al. Can J
Psychiatry. 200550555-562. 2. Kilbourne AM, et
al. Bipolar Disord. 20046368-373.
39
Metabolic Effects of Divalproex vs Olanzapine in
Bipolar Disorder

• Treatment of Mania (N 120)

OLZ (N 57)
DVP (N 61)
Metabolic Parameter
P-Values
Total cholesterol (mg/dL) -1.69 13.29 0.019 LDL
(mg/dL) -4.43 8.78 0.022HDL (mg/dL) -0.93 -0.79
0.945 Glucose (mg/dL) 4.40 10.50 0.480 Weight
(lb) 5.50 8.80 0.049 Triglycerides
(mg/dL) 13.9 24.3 0.096 Total
protein (g/dL) -0.23 0.09 0.009 AST/ALT (IU/L)

NS
Mean change from baseline to final 84 DVP 2115
mg, OLZ 14.7 mg days, mean maximum daily drug
dosages Zajecka JM, et al. J Clin Psychiatry.
2002631148-1155.
40
Second-generation Antipsychotics Adverse Events

• Weight gain
• Sedation
• Diabetes
• Cardiac
• Akathisia
• Hyperprolactinemia
• NMS
• Cerebrovascular

Warning in prescribing information
41
Prevalence of Early Onset Menstrual Cycle
Dysfunction in Women With Bipolar Disorder
40
34.2
35
30
Depression vs healthy controls, P
.37 Bipolar disorder vs healthy controls, P lt
.0001 Bipolar disorder vs depression, P .01
24.5
25
21.7
Proportion With MenstrualDysfunction ()
20
15
10
5
0
Healthy Controls
Bipolar Disorder
Depression
Joffe H, et al. J Clin Psychiatry.
200667297-304.
42
FDA Black Box Warnings

• Clozapine
• Agranulocytosis (1.3 of patients)
• Seizures
• Hypotension
• Myocarditis
• Valproate
• Fetal neural tube defects (12)
• Hepatic failure (1 per 10,000 patients treated
  per year)
• Hemorrhagic pancreatitis (1 per 40,000 patients
  treated per year)

Prescribing Information. In Physicians Desk
Reference. 59th ed. Montvale, NJ Medical
Economics Co 2005 Pellock JM. Epilepsia.
198728(suppl 3)S64-S70 Leppik I. Contemporary
Diagnosis and Management of the Patient With
Epilepsy. Newtown, PA Handbooks in Health Care
2001.
43
FDA Black Box Warnings (cont)

• Lamotrigine
• Serious rashes (0.8 per 1,000 monotherapy and 1.3
  per 1,000 adjunctive therapy in adult bipolar
  patients)
• Lithium
• Toxicity close to therapeutic levels
• Carbamazepine
• Agranulocytosis (1.4 per 1 million patients
  treated per year)
• Aplastic anemia (5.1 per 1 million patients
  treated per year)

Prescribing Information. In Physicians Desk
Reference. 59th ed. Montvale, NJ Medical
Economics Co 2005 Pellock JM. Epilepsia.
198728(suppl 3)S64-S70 Leppik I. Contemporary
Diagnosis and Management of the Patient With
Epilepsy. Newtown, PA Handbooks in Health Care
2001.
44
Bipolar Disorder MedicationsAdverse Events

• Second-generation antipsychotics
• Hyperglycemia and diabetes mellitus
• Neuroleptic malignant syndrome and tardive
  dyskinesia
• Increased risk of death in elderly patients with
  dementia
• Aripiprazole, olanzapine, and risperidone
  cerebrovascular adverse events in elderly
  patients with dementia
• Ziprasidone QTc prolongation, EKG changes
• Clozapine orthostatic hypotension
• Lamotrigine acute multiorgan failure
• Valproate urea cycle disorders, somnolence in
  the elderly, thrombocytopenia, intrauterine
  developmental delay
• Carbamazepine do not use with other
  carbamazepine products

Source Prescribing Information. In Physicians
Desk Reference. 59th ed. Montvale, NJ Medical
Economics Co 2005 Pellock JM. Epilepsia.
198728(suppl 3)S64-S70 Leppik I. Contemporary
Diagnosis and Management of the Patient With
Epilepsy. Newtown, PA Handbooks in Health Care
2001. Farah A. Prim Care Companion J Clin
Psychiatry. 20057268-274.
45
Summary

• Evidence-based treatment for bipolar depression
  includes lithium and lamotrigine
• Quetiapine and OFC are emerging as viable
  alternatives for bipolar depression
• Monotherapy standard antidepressants may cause
  problems in terms of mood destabilization in
  bipolar depression
• Using antidepressants in bipolar depression is
  better than nothing, but not better than using
  lithium or a mood stabilizer
• Some novel antipsychotics may have a role in
  treating bipolar depression as monotherapy while
  stabilizing mania
• Goal is to stabilize depression without causing
  mania and minimizing side effects