Herman G'M' Westenberg

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On the role of dopamine in anxiety disorders
Herman G.M. Westenberg University Medical Center
Utrecht The Netherlands
Utrecht
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What is Social Anxiety Disorder?

• Marked fear of performance or social situations
• Excessive fear of scrutiny or being evaluated
  with the believe that this will be negative and
  humiliating
• results in
• avoidance of feared situation
• or fear is endured with marked distress

I have a social phobia and cannot stand these
large crowds of people. But I will certainly
write a speech. Elfriede Jelinek, Austria 2004
Nobel Prize winner in literature
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Fear of two staring eyes is widespread throughout
the animal kingdom
4
Amygdala activation to angry and contemptuous
faces in generalized SAD
Differences between SAD and healthy controls
Stein et al, 2002
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Fear conditioning the role of dopamine
Fear stimuli
hippocampus
Sensory thalamus
Sensory cortex
amygdala
medial prefrontal cortex
NAS
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Dopamine and fear conditioning

• fear conditioning
• (systemic injection prior to conditioning)
• Dopamine D1 receptor agonist
• SKF 28393 increase
• Dopamine D2 receptor agonist
• Quinpirole decrease
• Indirect dopamine agonist
• Amphetamine increase
• Dopamine D1 receptor antagonist
• SCH 23390 decrease
• Dopamine D2 receptor antagonist
• Haloperidol decrease
• Clozapine decrease
• Cis-flupenthixol decrease

MIczek et a al, 1978 Inoue et al, 1996, Hijzen
et al, 1995 Inoue et al 1996 Davis et alo, 1993
Inoue et al 2000 Borowski et al, 1990
Blackburn etal, 1990 Cavazzuti et al 1999
Nader et al, 1999
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Dopamine and fear conditioning (contd.)

• Amygdala
• Important for the formation and retrieval of fear
  conditioning
• D1 stimulation in the amygdala supports retrieval
  of fear
• D2 antagonists into the amygdala reduce
  conditioned fear if administered before
  acquisition
• D2 agonist attenuate fear conditioning probably
  by stimulation of the autoreceptors in the VTA
• Medial prefrontal cortex
• Lesions of the mPFC delay extinction of fear
  responses
• Dopamine modulates the extinction and expression
  of conditioned fear through projections
  originating in the VTA
• Nucleus Accumbens
• The NAC is probably involved in signaling the
  predictability of an US to a CS it codes the
  predictability that an event might happen and
  guides the behavioral response. It is sensitive
  to both rewarding and aversive stimuli.

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Dopaminergic Involvementin Social Anxiety
Disorder ?

• Decreased CSF HVA levels in introverted patients
  with depression (King et al, 1986)
• Striatal D2 density lower in monkey with a low
  social status ( Grant et al, 1998)
• Timid mice have low dopamine levels (Mayleben et
  al, 1992)
• Striatal D2 binding is associated with
  affiliation on a personality questionnaire (Farde
  et al, 1997)
• D2 receptor binding lower in detached subjects
  (Laakso et al, 200 Breier et al, 1998)
• SAD more common in patients who subsequently
  develop Parkinsons disease
• MAOIs more effective than TCAs
• But dopamine genes do not seem to be associated
  with SAD

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D2 Density and Personal Detachment in Normal
Subjects
70
60
50
Detachment
40
30
20
25
15
35
45
D2-receptor density (pmol ml-1)
Individual values (n 24) for D2-dopamine-recepto
r density plotted against KSP detachment scores.
To adjust for the effect of gender, the scores
were transformed to T scores using normative
data. The T scores have a mean ( s.e.m.) of 50
(10) in the normal population. Farde L, et al.
Synapse. 199725321-325.
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Dominant Monkeys
Subordinate Monkeys
60
4.0
4.0
40
20
Change
3.5
3.5
0
-20
Dopamine D2 receptor DVR
Rank 1
Rank 4
3.0
3.0
2.5
2.5
2.0
2.0
Grouphoused
Grouphoused
Individuallyhoused
Individuallyhoused
Morgan et al. Unpublished data.
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Effect of social status on striatal D2 receptor
binding
Grant et al, 198
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Dopamine in anxiety

• Dopamine decrease could be mediated by
• Decreased social incentive (detachment)
• Submissive behavior
• Conditioned fear
• Patients with SAD do not suffer from a deficit in
  the ability nor in the desire to form social
  affiliation, but their fear of rejection or
  humiliation inhibits them from seeking such a
  relationship
• It is questionable whether social status equates
  to social anxiety. Dominance increases DA and not
  vice versa and is state dependent

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Evidence for dopaminergic dysfunction in SAD

• D2 receptor binding in SAD is decreased (Schneier
  et al, 2002)
• Increased DA release
• Decreased expression
• DAT binding in SAD is increased (Tiihonen et al,
  1997)
• Downregulation DA uptake sites due to decreased
  DA release
• Reduced number of DA neurons (decreased
  expression or degeneration)
• DAT binding in SAD is increased ( Westenberg,
  2006)
• Upregulation DA uptake sites due to increased DA
  release
• Increased number of synapses (increased
  expression)
• Antipsychotics have shown to be efficacious in
  SAD at low doses

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Antipsychotics in SAD

• Olanzapine (5-20 mg/day
• Barnett et al, 2002
• Double-blind placebo controlled pilot trial
• 12 generalized SAD patients
• 8 weeks of treatment
• 7 patients (58) completed the trial
• 3/7 (43 LOCF) were responders to olanzapine
• Drowsiness and dry mouth were most obvious side
  effects
• Quetiapine ( 150-300 mg/day)
• Schutters et al, 2005
• Open-label pilot trial
• 13 patients with generalized SAD
• 12 weeks of treatment
• 10 patients (77) completed the trial
• 9/13 (69 LOCF) were responders to quetiapine 1
  non-responders was non-compliant
• Sedation and dry mouth were reported as side
  effect

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Quetiapine in SAD Open-label study
visit-wise and endpoint LOCF
90
80
70
60
LSAS score
50
40
30
20
E
0
2
4
6
8
10
12
Weeks
Schutters et al , 2005
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Dopamine Transporter
24 hrs after 185 MBq 123I-ß-CIT and 20 mg
paroxetine
4 hr after 185 MBq 123I-ß-CIT.
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Dopamine transporter binding in the basal
ganglia of SAD patients and controls
10
8

CIT binding ratio
6
b-
4
2
Controls Patients
Westenberg et al, submitted
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Dopamine Dysregulation in Social Anxiety Disorder
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14
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Ratios of dopaminereuptake site inbasal ganglia
towhite matter
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11
10
74-75 Years Old
Age-Gender MatchedComparison Subjects
9
8
7
Patients withsocial anxiety disorder(n 11)
Comparisonsubjects(n 28)
Tiihonen, et al. Am J Psychiatry.
1997154239-242.
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D2 Receptor Binding Potential in SAD
Subjects With SAD
Controls
200
1231 IBZMbindingpotentialml/gr
150
100
50
P lt0.05
0
Schneier FR, et al. Am J Psychiatry.
2000157457-459.
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Hypothesis SAD

• SAD is characterized by a dysfunction within the
  system that evaluates the risks and benefits of
  social affiliation
• Dopamine neurons from the VTA are sensitive to
  reinforcers, irrespective of the valence of the
  signal
• Increased DA activity in the VTA signals
  uncertainty and increases fear conditioning
  through amygdala activation and retrieval and
  expression of fear through activation of the
  medial prefrontal cortex
• Da antagonist are efficacious by decreasing
  dopamine function in the amygdala, accumbens andf
  or medial prefrontal cortex

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DSM-IV Diagnostic Criteria for OCD

• Obsessions (unwanted ideas that
  repeatedly well up in the mind)
• compulsions (repetitive behaviors or
  rituals)
• Recognized as excessive or unreasonable
• Causes marked distress, time-consuming (gt1
  hour/day) and/ or interferes with daily
  functioning

Core feature Uncertainty and indecisiveness
American Psychiatric Association DSM-IV, 1994.
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Symptom provocation in OCD
AGP, 1994
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Pathophysiology of OCD
Cortex (OFC- DLPFC-ACC)
Caudate Nucleus
Thalamus
Direct pathway ()
D1
Indirect (-) pathway
D2
Globus Pallidus
Subthalamic nucleus
GABA
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(1)
Is there a primary role for Dopamine in OCD?

• Atypical antipsychotics augment the effects of
  SSRIs in (refractory) OCD patients
• Neuroimaging studies have revealed abnormalities
  in brain regions densely endowed with
  dopaminergic terminals, such as the basal ganglia
• Dopamine D2 receptor binding potential in the
  basal ganglia of OCD patients is decreased
• Dopamine transporter binding potential is
  up-regulated in OCD patients
• Dopamine releasing agents and uptake inhibitors
  exacerbate OCD symptoms

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Is there a primary role for Dopamine in OCD (2)

• Pathological gambling, which may be considered a
  OCD spectrum disorder, has been associated with
  increased dopaminergic activity
• Preclinical studies have shown that uncertainty,
  which is the hallmark of OCD, induces dopamine
  release
• Dopamine receptor agonists elicit compulsive
  behavior in animals

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Neuroimaging dopamine

• DAT binding
• Van der Wee et al 2004 123I- ?-CIT SPECT
  increased binding in the left caudate nucleus
• Kim et al 2003 123I-IPT SPECT increased
  binding left and right caudate nucleus
• Hesse et al 2005 123I- ?-CIT SPECT reduced
  availability in striatum
• Pogarell et al 2003 123I- ?-CIT SPECT no
  change
• Pogarell et al 2005 123I- ?-CIT SPECT SSRI
  treatment enhances DAT binding
• D2 receptor binding
• Denys et al, 2004 123I-IBZM SPECT lower binding
  density

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Left caudate nucleus DAT density In OCD patients
and controls
vd Wee et al, 2003
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123I-IBZM D2 binding potential in OCD patients
and controls left caudate nucleus
0.06
0.05
D2 binding potential
0.04
0.03

0.02
0.01
Controls Patients
Denys et al, 2003
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Dopamine antagonists augment the effect of SSRIs
in OCD
CGI global improvement
Y-BOCS global improvement
4.50
110
4.10
100
3.70
90
3.30
80
2.90
70
2.50
60
0
2
4
6
8
0
2
4
6
8
placebo
quetiapine
placebo
quetiapine
week
week
Denys et al 2004
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Can animal models of OCD Help us delineating the
biology of OCD ?
Aberrant thoughts if present at all, are not
verifiable in animals
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Animal modelsdopamine

• Genetic model
• Campbell et al 1999 transgenic mice
  over-expressing D1 receptors in the cortex and
  amygdala show compulsive behavior
• Behavioral model
• Joel et al 2001, 2003 SCH 23390, a selective D1
  receptor antagonist reduced compulsive lever
  pressing
• Pharmacological model
• Szechtman et al, 1998, 2001 quinpirole, a D2
  receptor agonist induces compulsive behavior in
  rats. Behavior is sensitive to clomipramine
  administration
• Westenberg et al, 2005 quinpirole administration
  results in long-term desensitization of the D2
  autoreceptors in the nucleus accumbens

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Quinpirole induced compulsive behavior
Vehicle treated
Quinpirole treated
After treatment
Westenberg, 2004
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Conclusions

• Animal data show that the amygdala, hippocampus,
  medial prefrontal cortex and nucleus accumbens
  play a crucial role in fear conditioning
• Amygdala evaluates aversive stimuli and is key
  substrate for fear conditioning
• Hippocampus is important for processing
  contextual information
• Medial prefrontal cortex is important for
  retrieval and extinction of fear
• Nucleus accumbens process the predictability of a
  conditioned stimulus and to select to appropriate
  response.
• Clinical data have shown that some of these
  brain regions also play a role in OCD
• Medial prefrontal cortex is relevant for error
  detection
• Accumbens is important for reward prediction
• OFC is important for decision making
• Dopamine projections originating in the VTA
  modulate these brain regions and preclinical data
  have shown that dopamine modulates fear
  conditioning, decision making and predicts
  uncertainty
• Neuroimaging data provide circumstantial evidence
  that dopamine in the basal ganglia is implicated
  in both SAD and OCD
• D2 receptors are decreased and DAT binding is
  increased in both conditions, suggesting that
  dopamine activity is increased in the basal
  ganglia
• Preliminary data suggest that SAD responds to
  treatment with atypical antipsychotics, while
  addition of atypical antipsychotics augment the
  effects of SSRIs in OCD
• Dopamine signals uncertainty and is associated
  with predictability of a reward or aversive
  stimulus it heightens the awareness and guide
  behavior aimed at optimizing the outcome.

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