The Neuroprotective Effects of Mood...
Transcript of The Neuroprotective Effects of Mood...
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
The Neuroprotective Effects
of Mood Stabilizers
(page 101 in syllabus)
Rona J. Hu, MD
Clinical Associate Professor, Department of Psychiatry and Behavioral Sciences;
Medical Director, Acute Psychiatric Inpatient Unit, Stanford University School of Medicine
Sponsored by the Neuroscience Education Institute
Additionally sponsored by the American Society for the Advancement of Pharmacotherapy
This activity is supported solely by the sponsor, Neuroscience Education Institute.
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Faculty Editor / Presenter
Rona J. Hu, MD, is a clinical associate professor in the department of
psychiatry and behavioral sciences and medical director of the acute
psychiatric inpatient unit at Stanford University School of Medicine in
Standford, CA
Consultant/Advisor: Alexza/Biovail, Beta Healthcare, Sepracor/Sunovion
Individual Disclosure Statement
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Learning Objectives
• Recognize bipolar disorder as a neuroprogressive
illness
• Identify the biochemical processes involved in the
neuroprogression of bipolar disorder
• Identify the mechanisms by which mood stabilizing
treatment can target those biochemical processes to
alter the course of bipolar disorder
• Select mood stabilizing treatment strategies that are
consistent with evidence-based practice guidelines
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Pretest Question 1
A 34-year-old man has recently been diagnosed with bipolar
disorder, six years after his symptoms began. He has had
no mood stabilizing treatment in that time. According to the
kindling model and the allostatic load hypothesis, which
progressive pattern of illness would you expect this patient
to have exhibited over the last six years?
1. Longer interval between episodes, worsened emotionality,
minimal change in cognitive impairment
2. Shorter interval between episodes, worsened emotionality,
minimal change in cognitive impairment
3. Longer interval between episodes, worsened emotionality,
worsened cognitive impairment
4. Shorter interval between episodes, worsened emotionality,
worsened cognitive impairment
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
A 28-year-old woman with bipolar disorder recently
began taking a mood stabilizer and has
experienced improvement in her symptoms. Which
of the following are mechanisms by which different
mood stabilizers may prevent mitochondrial
dysfunction in bipolar disorder?
1. Increasing levels of anti-apoptotic proteins
2. Decreasing levels of pro-apoptotic proteins
3. Increasing levels of key antioxidants
4. 1 and 2
5. 1, 2, and 3
Pretest Question 2
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
A 28-year-old woman presents with a depressive
episode. She has previously been hospitalized and
treated for a manic episode, but she is not currently
taking any medication. Practice guidelines
consistently agree on the preferential use of which of
the following to treat bipolar depression?
1. Lamotrigine, quetiapine
2. Quetiapine, olanzapine
3. Olanzapine, lithium
4. Lithium, valproate
5. Valproate, lamotrigine
Pretest Question 3
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Progressive Course of Bipolar Disorder
Worsened cognitive impairment
Reduced treatment response
Post RM. Neurosci Biobehav Rev 2007;31:858-73; Kapczinksi F et al. Neurosci Biobehav Rev 2008;32:657-92.
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Chronic Bipolar Disorder:
Structural Brain Changes
Bora E et al. Biol Psychiatry 2010;67:1097-1105.
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Bipolar Disorder Is Neuroprogressive:
Kindling Model
Post RM. Neurosci Biobehav Rev 2007;31:858-73.
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Bipolar Disorder Is Neuroprogressive:
Allostatic Load Hypothesis
Post RM. Neurosci Biobehav Rev 2007;31:858-73; Kapczinksi F et al. Neurosci Biobehav Rev 2008;32:657-92.
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Biochemical Processes Underlying
Neuroprogression in Bipolar Disorder
• Oxidative stress
• Mitochondrial dysfunction
• Alterations in dopamine
• Alterations in glutamate
• Increased inflammatory processes
• Decreased neurotrophins
Berk M et al. Neurosci Biobehav Rev 2011;35(3):804-17.
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Neuroprogression in Bipolar Disorder:
Oxidative Stress (and Mitochondrial Dysfunction)
Berk M et al. Neurosci Biobehav Rev 2011;35(3):804-17; Steckert AV et al. Neurochem Res 2010;35:1295-1301.
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Neuroprogression in Bipolar Disorder:
Mitochondrial Dysfunction (and Oxidative Stress)
Berk M et al. Neurosci Biobehav Rev 2011;35(3):804-17; Ulivieri C. Tissue Cell 2010;42:339-47.
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Biochemical Processes Underlying
Neuroprogression in Bipolar Disorder
• Oxidative stress
• Mitochondrial dysfunction
• Alterations in dopamine
• Alterations in glutamate
• Increased inflammatory processes
• Decreased neurotrophins
Berk M et al. Neurosci Biobehav Rev 2011;35(3):804-17.
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Neuroprogression in Bipolar Disorder:
Oxidative Stress and Dopamine
Berk M et al. Neurosci Biobehav Rev 2011;35(3):804-17.
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Biochemical Processes Underlying
Neuroprogression in Bipolar Disorder
• Oxidative stress
• Mitochondrial dysfunction
• Alterations in dopamine
• Alterations in glutamate
• Increased inflammatory processes
• Decreased neurotrophins
Berk M et al. Neurosci Biobehav Rev 2011;35(3):804-17.
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Neuroprogression in Bipolar Disorder:
Oxidative Stress and Glutamate
Berk M et al. Neurosci Biobehav Rev 2011;35(3):804-17; Peng TI, Jou MJ. Ann NY Acad Sci 2010;1201:183-8.
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Biochemical Processes Underlying
Neuroprogression in Bipolar Disorder
• Oxidative stress
• Mitochondrial dysfunction
• Alterations in dopamine
• Alterations in glutamate
• Increased inflammatory processes
• Decreased neurotrophins
Berk M et al. Neurosci Biobehav Rev 2011;35(3):804-17.
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Neuroprogression in Bipolar Disorder:
Inflammatory Processes
Pro-inflammatory
cytokines and chemokines activated activated
Episode-Dependent
Berk M et al. Neurosci Biobehav Rev 2011;35(3):804-17.
Tumor necrosis factor-α
Stage-Dependent
normal
bipolar
Time
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Biochemical Processes Underlying
Neuroprogression in Bipolar Disorder
• Oxidative stress
• Mitochondrial dysfunction
• Alterations in dopamine
• Alterations in glutamate
• Increased inflammatory processes
• Decreased neurotrophins
Berk M et al. Neurosci Biobehav Rev 2011;35(3):804-17.
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Neuroprogression in Bipolar Disorder:
Neurotrophins
Berk M et al. Neurosci Biobehav Rev 2011;35(3):804-17.
BDNF
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Neuroprogression in Bipolar Disorder:
Neurotrophins
Episode-Dependent
Berk M et al. Neurosci Biobehav Rev 2011;35(3):804-17.
bipolar
BDNF
Stage-Dependent
normal
Time
BDNF
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Can Early Treatment Prevent
Neuroprogression in Bipolar Disorder?
Worsened cognitive impairment
Reduced treatment response
Post RM. Neurosci Biobehav Rev 2007;31:858-73; Kapczinksi F et al. Neurosci Biobehav Rev 2008;32:657-92.
early treatment
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Neuroprogression in Bipolar Disorder: Linking Biochemical Processes to Mood Stabilizers
Berk M et al. Neurosci Biobehav Rev 2011;35(3):804-17; Bachman RF et al. Int J Neuropsychopharmacol 2009;12:805-22;
Kim YJ et al. Brain Res Bull 2007;71:633-40; Wei Z et al. J Neurosci Res 2003;74:942-7.
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Clinical Effects of Acute and Maintenance
Treatments
Malhi et al. Drugs 2009;69(15):2063-101.
Efficacy Intolerability
Efficacy Intolerability
Efficacy Intolerability
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Bipolar Mania:
What’s Available
aripiprazole carbamazepine
asenapine
risperidone
quetiapine
lurasidone
iloperidone
lithium
chlorpromazine
olanzapine
valproate
ziprasidone
paliperidone
oxcarbazepine
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Bipolar Mania:
What’s (Relatively) Well Studied
aripiprazole carbamazepine
asenapine
risperidone
quetiapine
lithium
chlorpromazine
olanzapine
valproate
ziprasidone
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Bipolar Mania:
What’s Got Consistent Positive Evidence
aripiprazole carbamazepine
asenapine
risperidone
quetiapine
lithium
chlorpromazine
olanzapine
valproate
ziprasidone
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Bipolar Depression:
What’s Available
aripiprazole carbamazepine
asenapine
risperidone
quetiapine
lurasidone
iloperidone
lithium
fluoxetine
bupropion
lamotrigine
OFC
olanzapine
paroxetine
valproate
ziprasidone
paliperidone
oxcarbazepine
other ADs
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Bipolar Depression:
What’s (Relatively) Well Studied
aripiprazole carbamazepine
quetiapine
lithium
fluoxetine
bupropion
lamotrigine
olanzapine
paroxetine
valproate
ziprasidone
Frye MA et al. New Engl J Med 2011;364:51-9; Fountoulakis KN. J Affect Disord 2011;Epub;
Nivoli AMA et al. J Affect Disord 2010;129:14-26.
OFC
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Bipolar Depression:
What’s Got Consistent Positive Evidence
OFC
quetiapine
Frye MA et al. New Engl J Med 2011;364:51-9; Fountoulakis KN. J Affect Disord 2011;Epub;
Nivoli AMA et al. J Affect Disord 2010;129:14-26.
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Bipolar Depression:
What’s Recommended First-Line
quetiapine
*With lamotrigine
Nivoli AMA et al. J Affect Disord 2010;129:14-26.
lamotrigine
olanzapine
valproate
World Federation of Societies of Biological Psychiatry (WFSBP)
lithium*
OFC
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Bipolar Depression:
What’s Recommended First-Line
*Monotherapy if no mania; adjunct if mania
Nivoli AMA et al. J Affect Disord 2010;129:14-26.
British Association for Psychopharmacology (BAP)
quetiapine
lithium
lamotrigine
valproate ADs*
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Bipolar Depression:
What’s Recommended First-Line
Nivoli AMA et al. J Affect Disord 2010;129:14-26.
Int’l Consensus Group on the Evidence-Based Pharmacologic Treatment
of Bipolar I and II Depression (ISBD)
quetiapine
lithium
lamotrigine
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Bipolar Depression:
What’s Recommended First-Line
*With lithium or valproate. *With SSRI. ***With lithium.
Nivoli AMA et al. J Affect Disord 2010;129:14-26.
Canadian Network for Mood and Anxiety Treatments and Int’l Society for
Bipolar Disorders (CANMAT)
quetiapine
lithium bupropion*
lamotrigine
olanzapine**
valproate*** SSRIs*
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Bipolar Depression:
What’s Recommended First-Line
*With “anti-manic.” **If psychosis is present.
Nivoli AMA et al. J Affect Disord 2010;129:14-26.
National Institute of Clinical Excellence (NICE)
quetiapine*
lamotrigine*
olanzapine**
SSRIs*
risperidone**
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Bipolar Depression:
What’s Recommended First-Line (Summary)
quetiapine
OFC
Nivoli AMA et al. J Affect Disord 2010;129:14-26.
lamotrigine
olanzapine
valproate
WFSBP BAP ISBD CANMAT
quetiapine
lithium
lamotrigine
valproate
ADs
quetiapine
lithium
lamotrigine
NICE
quetiapine
lithium
lamotrigine
olanzapine (w SSRI)
valproate (w Li+)
SSRIs, BUP (adj)
quetiapine (adj)
lamotrigine (adj)
SSRIs (adj)
lithium
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Bipolar Depression:
Practice Guideline Commonalities, First-Line
• Already taking MS
– Optimize dose
– Add quetiapine
• Not taking MS
– Quetiapine
– Lamotrigine
– Lithium
– Olanzapine + antidepressant
– Other anti-manic + antidepressant
Nivoli AMA et al. J Affect Disord 2010;129:14-26.
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Bipolar Depression:
Practice Guideline Commonalities, Second-Line
• Different first-line strategy
• Combination of first-line agents
• Addition of carbamazepine, modafinil,
pramipexole
• Psychotherapy
• ECT for severe depression, catatonia,
suicidality, psychotic features, pregnant women
Nivoli AMA et al. J Affect Disord 2010;129:14-26.
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Bipolar Maintenance:
What’s Available
aripiprazole carbamazepine
asenapine
risperidone
quetiapine
lurasidone
iloperidone
lithium
lamotrigine
OFC
olanzapine
valproate
ziprasidone
paliperidone
oxcarbazepine
psychotherapy
psychoeducation
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Bipolar Maintenance:
What’s (Relatively) Well Studied
aripiprazole carbamazepine
risperidone
quetiapine
lithium
lamotrigine
olanzapine
valproate
ziprasidone
psychotherapy
psychoeducation
Popovic D et al. Psychopharmacol 2011;213:657-67.
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Bipolar Maintenance:
What’s Got Consistent Positive Evidence
aripiprazole
risperidone*
quetiapine
lithium
lamotrigine
olanzapine
valproate
psychotherapy
psychoeducation
*Injectable
Popovic D et al. Psychopharmacol 2011;213:657-67.
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Antipsychotics in Bipolar Maintenance
0
1
2
3
4
5
6
7
8
9
10
Ari (Keck 2007)
Olz (Tohen 2006)
Que adj (Vieta 2008)
Que adj (Suppes
2009)
Que (Weisler 2009)
Ris LA (Quiroz 2010)
Ris LA (MacFadden
2009)
Zip adj (Bowden
2010)
Any Episode Mania Depression
Num
ber
Needed t
o T
reat (s
ig)
Popovic D et al. Psychopharmacol 2011;213:657-67.
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Anticonvulsants and Lithium
in Bipolar Maintenance
0
1
2
3
4
5
6
7
8
9
10
Lam (Bowden 2003)
Lam (Calabrese
2000)
Li (Prien 1973)
Li (Goodwin 2004)
Li (Bowden 2003)
Li (Weisler 2009)
Val (Bowden 2000)
Any Episode Mania Depression
Num
ber
Needed t
o T
reat (s
ig)
Popovic D et al. Psychopharmacol 2011;213:657-67.
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Bipolar Maintenance:
What’s Recommended
aripiprazole*
risperidone***
quetiapine
lithium*
lamotrigine**
olanzapine*
valproate*
*Predominantly mania **Predominantly depression ***Injectable
Popovic D et al. Psychopharmacol 2011;213:657-67.
BAP CANMAT NICE
lithium
olanzapine
valproate
aripiprazole*
quetiapine
lithium
lamotrigine
olanzapine
valproate
ziprasidone
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Bipolar Maintenance
• Maintain medication – Educate on chronicity of disorder
– Help establish routine for taking medication
• Maintain psychoeducation and psychotherapy – Include caregiver psychoeducation
• Monitor for and address adverse effects
• Encourage regular physical and social activity
• Encourage regular sleep pattern
• Address interepisode impairment – Neurocognitive, difficulty with sustained attention
– Sleep disturbance
Swan AC. J Clin Psychiatry 2010;71(12):e35.
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Bipolar Maintenance
• Train to monitor for prodromal symptoms
– Change in motivated activity, sleep cycle, impulsivity,
or interpersonal behavior
– Change in affect (usually later in prodromal stage)
– Usually consistent within individual
• Train to address prodromal symptoms
– Small medication adjustment
– Change in daily routine
– Stress reduction
– Increase in social interaction
Swan AC. J Clin Psychiatry 2010;71(12):e35.
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Summary
• There is both clinical and pathophysiological evidence that bipolar disorder is neuroprogressive
• Mitochondrial dysfunction and oxidative stress, perhaps related to alterations in dopamine and glutamate systems, may underlie the neuroprogressive changes that can occur during the course of bipolar disorder
• Other proposed mechanisms include increased inflammatory processes and decreased expression of neurotrophins
• Many of the existing medications for bipolar disorder, which have seemingly diverse mechanisms of action, share an ability to affect one or more of these factors
• The key is to intervene early, before the disease progresses and positive treatment outcomes become less likely
• Unfortunately, the evidence base for treating bipolar depression and for maintenance is relatively weak, and practice guidelines differ