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1
INTEGRATION OF THE BEST CLINICAL PRACTICES AND
NEUROBIOLOGICAL EVIDENCE IN THE TREATMENT OF
BIPOLAR DISORDERS
SERGE BEAULIEU M.D., Ph.D., FRCPC Dir., Mood
Disorders Programs Dir., Bipolar Disorders
Program Medical Chief, Super Specialized Services
Douglas Hospital Research Center Associate
Professor Dept. of Psychiatry McGill University
2
Disclosures

• Astra Zeneca (Advisory Board, research support
  contracts, speaker)
• Biovail (Speaker, research support)
• Eli Lilly (Advisory Board, speaker, research
  contract support)
• GSK (Advisory Board, speaker)
• Janssen-Ortho (Advisory Board, research
  contracts, speaker)
• Lundbeck (Speaker, research support)
• Merck-Frosst (Research contract)
• Novartis (Research contract)
• Organon (Speaker)
• Oryx (Advisory Board, speaker)
• Pfizer (Research support)
• Wyeth-Ayerst (Speaker)
• Peer-reviewed research funding CIHR, FRSQ,
  NARSAD, RSMQ, STANLEY FOUNDATION

3
CANMAT Guidelines for the Management of Bipolar
Disorder
Since the previous publication of Canadian
Network for Mood and Anxiety Treatments (CANMAT)
guidelines in 1997, there has been a substantial
increase in evidence-based treatment options for
bipolar disorder. The present guidelines review
the new evidence and use criteria to rate
strength of evidence and incorporate
effectiveness, safety, and tolerability data to
determine global clinical recommendations for
treatment of various phases of bipolar disorder.
The guidelines suggest that although
pharmacotherapy forms the cornerstone of
management, utilization of adjunctive
psychosocial treatments and incorporation of
chronic disease management model involving a
healthcare team are required in providing optimal
management for patients with bipolar disorder.
Lithium, valproate and several atypical
antipsychotics are first-line treatments for
acute mania. Bipolar depression and mixed states
are frequently associated with suicidal acts
therefore assessment for suicide should always be
an integral part of managing any bipolar patient.
Lithium, lamotrigine or various combinations of
antidepressant and mood-stabilizing agents are
first-line treatments for bipolar depression.
First-line options in the maintenance treatment
of bipolar disorder are lithium, lamotrigine,
valproate and olanzapine. Historical and symptom
profiles help with treatment selection. With the
growing recognition of bipolar II disorders, it
is anticipated that a larger body of evidence
will become available to guide treatment of this
common and disabling condition. These guidelines
also discuss issues related to bipolar disorder
in women and those with comorbidity and include a
section on safety and monitoring.
Bipolar Disorders 2005 Vol. 7(Suppl. 3) 569
4
Levels of Evidence
Recommendations
Treatments with high levels of evidence may be
downgraded as a recommendation due to clinical
issues, such as side effects or safety profiles
5
Treatment
Hierarchy
VIII. Psychodynamic/ Insight Therapy VII.
Occupational Therapy/ Rehabilitation VI.
Detailed Family/Marital Therapy V. Brief
Family/Marital Psychoeducation IV. CBT or IPT
if indicated After PE or For Depression III.
Patient Psychoeducation (6 sessions) II.
Tailored Health Services (Health Care Team) I.
Pharmacotherapy and Clinical Management
Pharmacotherapy
Bipolar Disorder Treatment Model
(Parikh, 2002)
6
Recommendations for the Pharmacological
Management of Manic Episodes
SECTION 3 Pg. 15
7
Recommendations for Acute Mania - 2005
8
Acute Bipolar Depression
Section 4

• Prominence of the Depressive Phase
• Evolution of Treatment Recommendations
• Algorithms 1997 and 2005
• Pharmacotherapies
• Monotherapies
• Combination therapies
• Limited Role of Antidepressants
• Psychosocial Interventions

9
Impact of Stress and Psychotropic Drugs on Gene
Expression and Brain Structure
Gluco- Stress corticoids Lithium VPA ADs Tra
nscription factor CREB Neurotrophic
factor BDNF Neuroprotective factor
BCL-2 (Anti-Apoptotic) Neurite
sprouting (in vitro) Neurogenesis (in vivo)
Neuronal viability NAA by MRS
(humans) Increased grey matter (humans)
ctx. hippo.
Modified, from Post, R.M. , 2003, with permission.
10
Right Hippocampal N-Acetyl-Aspartate in Bipolar
I Disorder
r - 0.66, n 15, p 0.003
Deicken, R.F. et al., Am. J. Psych. 2003 160
873-882.
11
76 patients with first episode of major
depression (f/u during five years)
29 NONSUPPRESSORS
33 SUPPRESSORS
3
12.1
40
35
HYPOMANIA
MANIA

Moreover, DST NONSUPPRESSION IS ASSOCIATED TO A
GREATER RISK OF SERIOUS SUICIDE ATTEMPTS AND
APPEARANCE OF BIPOLARITY.
W. CORYELL, 1990
12
DST nonsuppression is associated to an increased
risk of suicide
26,8
2,9
Coryell, W. and M. Schlesser. Am. J. Psychiatry.
2001 158 748-753.
13
Effect of DESIPRAMINE (20 mg/kg) given for 2
weeks
STARTLE RESPONSE (mean SEM)
TRIAL
Beaulieu, S. et al., unpublished data
14
Baseline Startle Response
Beaulieu, S. et al. APA Annual Meeting. 2006
15
Stress and Neuronal Degeneration
Duman, R. from Neurobiology of Mental Illness,
1999.
16
Encinas, J.M. et al. PNAS. 2006. 103 8233-8238
17
Encinas, J.M. et al. PNAS. 2006. 103 8233-8238
18
Machado-Veira et al. Biol. Psych. 2006. In
Press. Available on line.
19
Model of receptor-coupled intracellular signal
transduction cascades
NE / 5-HT
BDNF
TrkB
Receptor internalization
Second messengerscAMP,IP3,DAG,CA2
RAF
Protein kinasesPKA,PKC,CAMK
MAP kinases
Regulation of substrate proteins (e.g.,
receptors, ion channels, cytoskeletal proteins,
transcription factors)
Short- and long-term regulation of neuronal
function
G. B. Kaplan and R. P. Jr Hammer. Brain Circuitry
and Signaling in Psychiatry- Basic Science and
Clinical Implications American Psychiatric
Publiching Inc., 2002.
20
Schematic diagram depicting the intracellular
pathways that contribute to the actions of stress
Stress
Glucocorticoid
Glutamate
Unknown
(?)
NMDA
GR
Ca2
Hyperactivation of CA2-dependant enzymes
BDNF
Glucose transporter and glucose uptake
Trophic support
Oxygen free radicals
Energy capacity
Atrophy, endangerment, and death of neurons
G. B. Kaplan and R. P. Jr Hammer. Brain Circuitry
and Signaling in Psychiatry- Basic Science and
Clinical Implications American Psychiatric
Publiching Inc., 2002.
21
Quetiapine and BDNF expression
Xu, H. et al., Neuroscience Letters 2002 321
65-68.
22
Effects of ADPs on MPP -induced activation of
8-oxo-dG DNA glycosylase
Qing, H. et al, European J Neuroscience, 2003,
171563-1570
23
Lamotrigine MonotherapyBipolar I Depression

• Double-blind placebo-controlled study
• n195
• 7 weeks
• LTG 50 mg/day vs. LTG 200 mg/day vs. PBO

Responders ()

plt0.05 vs. placebo
Calabrese JR, Bowden CL, Sachs GS, et al. J Clin
Psychiatry 19996079-88.
24
Lamotrigine vs. Placebo in BP I Depression
(MADRS)
Observed
LOCF
PBO (n65) LTG 50 mg/day (n64) LTG 200 mg/day
(n63)
Change from Baseline
Calabrese JR, Bowden CL, Sachs GS, et al. J Clin
Psychiatry 19996079-88.
25
Antidepressant Augmentation of Mood
Stabilizer(s)

• 549/1078 Treated with an AD in SFBN
• 189 were completers Treated for 60 days
• 84/189 (44) Responders for at least 6 weeks
  on CGI
• (1 normal or 2 minimally ill)
• 84/549 15 Responders in I.T.T. Analysis
• 85 Had Dropped Out for Lack of Response
  Switch into
• Mania Depressive Relapse
  Tolerability/Administrative

AD Discontinuers vs. AD
Continuers
(N 43)
(N 41)
Equal on Gender Severity Diagnosis
Education of Episodes of Hospitalizations
Altshuler, L. et al. , Am. J. Psychiatry 2003,
160 1252-1262
26
Increased Rate of Relapse into Depression in
Bipolar Patients Who Discontinued
Antidepressants
Study 1
Study 2
1.0
One year relapse rates
1.0
One year relapse rates
AD Continuers ( N41)
AD Continuers ( N19)
.8
.8

41

1.0
35

.6
.6
Cumulative Proportion Remaining Well

.8
.4
.4
71
68
AD Discontinuers (N 43)
AD Discontinuers (N 25)
.2
.2
0.0
0.0
360
270
180
90
0
56 112 168 224 280 336
0


Days to Relapse into Depression (CGI ?
moderate severity)






ADs as Adjuncts to Mood Stabilizers







Altshuler et al., 20022003.
27
Olanzapine in the Treatmentof Bipolar
Depression
MADRS Improvement Over 8 Weeks (MMRM)
plt0.05 vs. placebo plt0.05 vs. olanzapine MMRM
Mixed-effects model repeated measures, OFC
Olanzapine fluoxetine combination
Tohen M, Vieta E, Ketter T, et al. Poster
presented at 155th Annual Meeting of the APA,
Philadelphia, PA, May 2002.
28
Quetiapine Antidepressant Effect
Bipolar I (n342)
Bipolar II (n169)

• 8-week, double-blind, randomized, fixed-dose,
  placebo-controlled study
• Bipolar I or II outpatients, /- rapid cycling
• Quetiapine 600 mg/day vs. 300 mg/day vs. placebo

0
-5
-10
-9,8
-12,5
MADRS Change (ITT)
-15
-14
-15,1
Quetiapine 600 mg/day
-17
-18
Quetiapine 300 mg/day
-20

Placebo

plt0.001 vs. placebo Mean baseline scores BP
I30.5 BP II30.2
AstraZeneca data on file Calabrese J, MacFadden
W, McCoy R et al. Abstract presented at APA 2004,
NYC, USA.
29
BOLDER II MADRS Total Score Bipolar I vs II
Disorder
Bipolar disorder II(n152)
Bipolar disorder I (n315)
LS Mean Change From Baseline
Improvement



Quetiapine 300 mg

Quetiapine 600 mg
plt0.05 plt0.01 plt0.001 vs placebo (n at
baseline)
Placebo
MRMM
In-house data, AstraZeneca Pharmaceutical, LP.
December 2005
30
BOLDER II MADRS Total ScoreRapid vs Non-Rapid
Cycling
Non-rapid cycling(n324)
Rapid cycling(n143)
LS Mean Change From Baseline
Improvement

Quetiapine 300 mg


Quetiapine 600 mg

Placebo
plt0.01 plt0.001 vs placebo (n at baseline)
MRMM
In-house data, AstraZeneca Pharmaceutical, LP.
December 2005
31
MADRS variation par rapport aux scores de
départ
Semaine détude
1
2
4
3
6
5
7
8

Variation moyenne par rapport aux valeurs de
départ















p lt 0,001 vs placebo
32
Taux de rémission (MADRS ? 12)














p lt 0,01 p lt 0,001 vs placebo
33
Risperidone combination therapy reduction in
manic/depressive symptoms over 6 months
By index episode
Mania (n249)
Depression (n33)
YMRS
YMRS
Euthymia
HAM-D
HAM-D
Mixed (n31)
Schizoaffective (n183)
YMRS
YMRS
Euthymia
HAM-D
HAM-D
YMRS Young Mania Rating Scale HAM-D Hamilton
Depression Rating Scale
Vieta E, et al. J Clin Psychiatry 20016281825
34
Recovery Rate of patients with treatment-resistant
bipolar depression randomly assigned to
open-label anti-depressant augmentation with
Lamotrigine, Inositol, or Risperdal
Recovery Rate ()
Nierenberg, A.A et Al. Am J Psychiatry 1632,
february 2006
35
Omega-3 in the treatment of Depressed Mood
Parker, G. et Al. Am J Psychiatry 1636, june 2006
36
Riluzole
37
Bipolar Depression First Line Treatments

• Monotherapies
• Lithium
• Lamotrigine

Combination Therapies Lithium / divalproex
SSRI Olanzapine SSRI Lithium
divalproex Lithium / divalproex bupropion
38
Bipolar DepressionRole of Antidepressants

• Limited evidence of efficacy in BD compared to
  Major Depressive Disorder
• Never use Antidepressants in monotherapy for
  Bipolar I depression but combination therapy with
  a mood stabilizer or an atypical is appropriate
• SSRIs and bupropion are less likely to induce
  switching or rapid cycling limited support for
  venlafaxine which may have a higher switch rate
• Among MAOIs and TCAs tranylcypromine is more
  effective than imipramine but both classes have
  high switch/cycling rates

39
Recommendations for Bipolar Depression - 2005
40
Maintenance Therapy
Section 5

• General principles
• Comorbidities
• Psychosocial interventions
• Pharmacotherapies
• Monotherapies
• Combination therapies
• Predictors of response
• Dealing with rapid cycling and mixed episodes

41
Maintenance

• Characteristics of effective therapies that
  maximize adherence
• Education
• Self-monitoring
• Recurrence prevention
• Managing side effects
• Identifying and managing stressors
• Addressing belief system and attitudes to illness

42
Study Design Olanzapine vs. Lithium
Tohen M, et al. Presented at 156th APA Annual
Meeting May 17-22, 2003 San Francisco, Calif.
43
Time to Relapse Based on Symptomatic Rating
Scale Criteria
Mania
100
80
60
Probability of Remaining in Remission
40
OLZ
20
Li
plt.001
0
0
50
100
150
200
250
300
350
400
Time to Relapse of Mania (Days)
Depression
100
80
60
Probability of Remaining in Remission
40
OLZ
Li
20
Olanzapine (n217)
p.889
0
Lithium (n214)
0
50
100
150
200
250
300
350
400
Time to Relapse of Depression (Days)
Tohen M, et al. Presented at 156th APA Annual
Meeting May 17-22, 2003 San Francisco, Calif.
44
Olanzapine vs Placebo 1 Yr MaintenanceStudy
Design
Study Period II
Study Period III
Study Period I
Screening
Open-label
therapy period
Double-blind therapy period
period
OLZ (5-20 mg/day)
OLZ (5-20 mg/day)
Allpatients
PBO
12 months
2-7 days
6-12 weeks
Visit 2
randomization
Visit 1
Study Period IV
Open-label OLZ therapyrescue period for those
who relapse

Tohen, Calabrese, Sachs et al., Am J Psychiatry,
2006 163(2).
45
Time to Relapse Based on Hospitalization and/or
Symptomatic Rating Scale Criteria
Mania
Mania or Depression
100
OLZ (n225)
plt.001
PBO (n136)
80
23.1
plt.001
60
55.1
Probability of Remaining in Remission
40
Plt.001
62
OLZ (n225)
86.8
PBO (n136)
20
0
0
50
100
150
200
250
300
350
400
0
50
100
150
200
250
300
350
400
Time to Relapse of Mania (Days)
Time to Relapse of Mania or Depression (Days)
Depression
100
OLZ (n225)
PBO (n136)
80
plt.001
45.6
60
Probability of Remaining in Remission
40
p.007
71.9
20
0
0
50
100
150
200
250
300
350
400
Time to Relapse of Depression (Days)
Tohen, Calabrese, Sachs et al., Am J Psychiatry,
2006 163(2).
46
Lamictal Study 606
Bowden CL, Calabrese JR, Sachs G, et al. Lamictal
606 Study Group. Arch Gen Psychiatry.
200360392-400.
47
Recommendations for Maintenance Pharmacotherapy
of Bipolar Disorder
SECTION 5 Pg. 27
48
Maintenance Pharmacotherapy for Bipolar Disorder
with Rapid Cycling
SECTION 5 Pg. 30
49
Maintenance Pharmacotherapy for Bipolar
Disorders with Mixed Episodes
SECTION 5 Pg. 31

• No study specifically examined mixed episode
  patient population
• These patients likely will require combination
  therapy to best address both depressive and manic
  symptoms
• Some evidence of efficacy for olanzapine based on
  post-hoc analysis of controlled trials

50
Bipolar II Disorder Acute and Maintenance
Management
Section 7

• Differential diagnosis of bipolar II
• Hypomanic episode checklist
• Pharmacological treatment
• Management of acute bipolar II depression
• Maintenance treatment of acute bipolar II
  disorder
• How to differentiate between bipolar disorder and
  borderline personality disorder

51
SECTION 7 Pg. 42

Strength of Evidencefor Treatments of Acute
Bipolar II Depression
Scant Data Mainly Level 3
52
Recommendations for Pharmacotherapyof Acute
Bipolar II Depression
SECTION 7 Pg. 43
53
SECTION 7 Pg. 44
Strength of Evidence for Maintenance Treatment of
Bipolar II Disorder
Scant Data Mainly Level 3
54
Recommendations for Maintenance Treatment of
Bipolar II Disorder
SECTION 7 Pg. 44
55
Management of Bipolar II Disorder
SECTION 7 Pg. 42

• Bipolar II is likely a heterogenous group with a
  spectrum between UPD and Bipolar I
• Evidence is poor in quality, and hence an
  increased reliance on expert opinion.
• Management of hypomania unstudied
• Psychotherapy unstudied