Download Decreased brain-derived neurotrophic factor in medicated and drug

Amanda Henke
10/30/09
Bipolar Disorder
 Onset between ages typically 15-30
 Childhood BD more common with advances
in diagnosis - 1% of children
 estimated lifetime cost: (Begley et al., 2001)
 $11,720 for patients with a single manic
episode
 $624,785 for patients with nonresponsive/
chronic episodes
 Often un-diagnosed for about 10 years, causing
damage to life and brain (Ghaemi, 2001)
Manic Phase symptoms
 Elevated or irritable mood with 3-4 of the following:
 Decreased sleep
 Decreased appetite
 Grandiosity
 Distractibility
 Engage excessively in pleasurable,
yet harmful activities
 Spending sprees
 Sexual promiscuity
 Foolish business ventures
 Flight of ideas
 Agitation
Depressive Phase Symptoms
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Sadness
Hopelessness
Suicidal thoughts or behavior
Anxiety
Guilt
Sleep problems
Appetite problems
Fatigue
Loss of interest in daily activities
Problems concentrating
Irritability
Chronic pain without a known cause
Diagnosis
 Type depends on
 length of manic episode
 severity of manic episode
 Number of cycles
 Depression is 3x more common
 1.2–1.5% of population diagnosed, yet
estimated as many as 6% are bipolar
 Don’t seek treatment
 Condition mistaken for depression
 Symptoms don’t meet current
diagnostic criteria
Types
 Bipolar I Disorder
 At least one manic episode lasting at least one week,
with or without previous episodes of depression
 Severe episodes of mania or depression may result
in psychosis
 Bipolar II disorder
 At least one episode of depression and one episode
of hypomania
 much briefer (few days)
 elevated mood, irritability and some changes in
functioning
Other Types
 Cyclothymia
 Mild form with mood swings, but with highs and
lows not as severe for at least 2 years
 Rapid cycling
 Four or more mood swings within 12 months- mood
shifts can occur within hours
 10-20% of bipolar disorders
 Mixed state
 Symptoms of mania and depression occur
simultaneously or in rapid sequence
Comorbid medical conditions
 Smoking and substance
abuse
 Obesity and diabetes - often
caused by therapy
 Sleep apnea and OCD can
confound the presentation
 The suicide rate is 5–17 fold
higher than in general
population
 lifetime risk of 10% to 20%
Risk Factors
 Biological
 80 to 90% of those who suffer from BP have
relatives with some form of depression
 Val66Met SNP in BDNF gene
 Environment - Identical twin studies
 Periods of high stress
 Drug abuse
 Major life changes / significant loss
 Low self-esteem
 Childhood maltreatment
Medications
 Typical regiment
 mood stabilizers – stop mood swings, manic
 Anticonvulsants – stop mood swings, rapid cycling
 Antidepressants – semi-controversial, use in
combination
 Atypical Antipsychotics – severe mania/ psychosis
 hypnotic benzodiazepines – anxiety
 agents used as monotherapy do not produce
longterm responses, with low patient compliance
 rational polypharmacy - adding a drug for a specific
symptom as it appears
Quick Review…
 Enlargement of the 3rd and lateral ventricles
 Reduced gray matter – orbital & medial PFC,
ventral striatum, mesotemporal cortex
 Increased amygdala size, activity & dysfunction
 Reduced hippocampal volume during
adolescence
 Cognitive impairment, related to the severity and
duration of illness, and number manic episodes
BDNF Refresher!
 Brain-derived neurotrpic factor
 Functions:
 Neuronal development & survival
 Membrane potential
 Synaptic plasticity & strength
 Neuronal connectivity
 Dendritic arborization
 Controls 5-HT, DA and Glu systems
 Effects are region specific
 Result:
 Affect learning and memory (cognition)
 Alter information processing  mood disorder
BDNF and Cognition
 High BDNF levels in cerebral
cortex and hippocampus
 Regulate learning, memory
and emotion
 Mice deficient in BDNF or TrkB
- poor performance in Morris
water maze
 Impairment is rescued with
BDNF
Val66met SNP
 Single Nucleotide Polymorphism of valine for
methionine at codon 66 disrupts proBDNF-sortilin
interaction in Golgi (Chen et al., 2006)
 Reduces BDNF secretion
 Occurs in 20 to 30% in Caucasian populations
 Impaired cognitive performance (Rybakowski et al., 2003 )
 Increased risk of rapid cycling (Muller et al., 2006)
 Better responders to lithium prophylaxis
BDNF & Stress
 Sorted & regulated in response to activity, not via
Kauer-Sant’ana et al., 2007
a constitutive pathway
p=0.002
 Experience-dependent
(i.e. stress)
 Numerous studies
document stress decreases
BDNF (Martinowich et al.,
2007 review)
 Prenatal conditions decrease BDNF in hippocampus
 Maternal separation animal model – decreased BDNF
 History of trauma – lower BDNF (see above)
BDNF & Stress
 BDNF expression regulated
by stress-responsive
corticosteroids
 BDNF met/met
polymorphism  higher
HPA activity
 Chronic stress  alterations
in hippocampus, amygdala,
and PFC
 BDNF as a mediator of stress
and mood disorders
BDNF and medications
 Studies have shown that after the
administration of the following medications
can increase BDNF levels:
 Antidepressants
 Mood stabilizers
 Atypical antipsychotics
 However, studies are mixed on whether BDNF
signaling is the direct pharmacological target
Cunha et al. 2006
Methods
 Patients recruited were diagnosed using SCID-I
 Only Bipolar I Disorder patients were used
 Symptoms assessed using:
 YMRS for mania
 HDRS for depression
 Considered euthymic if scored <7 on both scales
 Controls matched for: Age, Gender, Education
 Also, controls were:
 Non-smokers
 Not on medication
 No history of major psychiatric disorders, dementia,
mental retardation, cancer or tumor in their 1st
degree relatives
Cunha et al., 2006
Hashimot et al., 2004
Testing BDNF levels
 BDNF measured in
blood serum samples
 BDNF can cross BBB
 R=0.81 between serum
and cortical levels
(Karege et al., 2002)
 Non-CNS sources for
BDNF= platelets,
lymphocytes & vascular
endothelial cells
 Sandwich-ELISA
ThermoScientific
Results
 BDNF lower in BP
patients compared to
healthy controls and
euthymic patients:
 Manic (p=0.019)
 Depressed (p=0.027)
 BDNF levels  mood
stabilization?
Results
 BDNF serum
level negatively
correlated with
score:
 YMRS (r=0.37, p=0.005)
 HDRS (r=0.30, p=0.033)
 Does BDNF level
dictate mood
state?
Conclusions
 BDNF serum is decreased in BD patients in
manic and depressive phases
 Euthymic BD patients’ ~ control subjects’ BDNF
level
 BDNF level could be related to mood?
 Limitations:
 Serum level BDNF
 Patients taking medication
Oliveira et al. 2009
2009 Paper
 Aim: to determine BDNF serum levels of drugfree BD patients are different than medicated
BD patients or healthy controls
 Hypothesized:
 BP patients would have decreased BDNF serum
levels
 BDNF changes would be more pronounced in
drug-free BD patients than medicated patients
Methods
 No euthymic group
 Drug-free patients
 Did not take any psychotropic medications for 2
weeks
 Off for 5 weeks if taking:
 Prozac- long-acting SSRI to treat depression
 Depots – form of atypical antipsychotics given by
injection, long-acting to promote compliance
 Controls
 Psychiatric assessment with SCID-I non-patient
version
Results
Results
Results
Results
YMRS vs.
BDNF
HDRS vs.
BDNF
Medicated
and Drugfree
r=-0.45,
p=0.002 *
r=-0.33,
p=0.036 *
Medicated
only
r=-0.30,
p=0.08
r= -0.23,
p=0.21
Drug-free
only
r=-0.56,
p=0.001 *
r=-0.50,
p=0.004 *
Group
Conclusions
 BDNF serum levels are lower in patients in manic and
depressive phase
 normalized when mood state is normalized
 BDNF – potential use as a marker for BD and neuronal
dysfunction
 Proposed model for Bipolar Disorder:
Stress &
Mood episode
neurotrophic
activity
Changes in
Brain
 BD treatments that increase BDNF (PKC inhibitors or
glu modulators)  mood stabilizing & cognitive
protective effect
Future Directions
 More patients
 Brain BDNF levels – TrkB ligand & PET scans?
 Overall, BDNF
levels increase
after treatment
for acute mania
 Clinical response
leads to increase
in BDNF?
Pre-treatment
Pre-treatment
Post-treatment
Post-treatment
Tramontina et al 2009
BDNF & Severity of Mania
 Machado-Vieira et al.
(2007) used
unmedicated bipolar
patients during
manic episode
 Plasma BDNF levels
were negatively
correlated with
severity of mood
symptoms