Monoamine receptor imaging in postpartum depression

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Monoamine receptor imaging in postpartum
depression

• Eydie L. Moses-Kolko, MD
• University of Pittsburgh School of Medicine
• Department of Psychiatry
• MNTP July 2nd, 2008

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Postpartum Lactation
Hormonal Context
Neurobiology
Mood
Serotonin 1A receptors Dopamine-2 receptors
Unipolar bipolar major depression
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High risk of psychiatric hospitalization
postpartum
DSM-IV postpartum onset specifier requires onset
in 1st 4 weeks postpartum Increased risk may
extend to 2 years postpartum
Kendell et al (1987) British Journal of Psychiatry
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Relative risk of postpartum psych hospitalization
Munk-Olsen. JAMA. 2006296(21)2582-2589
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Endocrinology of Childbearing
ESTROGENS
PROGESTINS
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Perinatal neuroendocrine brain changes

• Steroid hormones
• Estrogens, progestins, cortisol
• Neuropeptides
• Oxytocin, prolactin, CRH
• Neurosteroids
• Allopregnanolone

• Neuroplasticity
• Neurogenesis
• Visuopatial function
• Fear reduction
• Maternal behavior

Are the brains of women with mental illness less
malleable?
Do brain preparations for maternity disrupt
monoamine systems (or other systems) in women
with mental illness?
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Serotonin (5HT) system
Stahl. J Affective Disorders 1998
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Why study 5HT1A receptors in PPD?
Reduced in MDD (imaging postmortem)
Antidepressant mechanisms
5HT1A receptor knockout mouse
5HT1A
Altered by cortisol estradiol
Neuroendocrine data
Neuronal integrity
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Characterization of endocrine milieu in
reproductive-aged women

• Confirm euthyroid
• TSH, free T4, thyroid antibodies
• Confirm pre-menopausal
• FSH lt 30 IU/L
• Characterize ovarian activity
• Postpartum
• Lactation history (exclusive vs. partial)
• Bottle feeding women may resume cycling by 6 wks
  postpartum
• Non-postpartum
• Menstrual history (regular periods 25-32 day
  interval)
• Mid-luteal progesterone gt25nmol/L

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Scan scheduling in consideration of endocrine
milieu

• Goal scan during low circulating levels of the
  ovarian steroids estradiol and progesterone
• If lactational amenorrhea ? anytime
• Bottle feeders
• Try to scan before 6 wks postpartum
• blood draws to establish where in cycle? aim for
  early follicular phase
• Non-postpartum
• Early follicular phase days 3-9 of menstrual
  cycle

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PET Scan Procedure
1. Cyclotron 2. Radionuclide 11C 3.
Radiosynthesis 11C WAY100635 4. PET Imaging 5.
Image Reconstruction 6. Image Analysis
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Outcome measure of interest

• Binding Potential (BP)
• BP is proportional to receptor densityaffinity
  (Bmax/KD)

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PET imaging of 5HT1A receptors

• Radioligand in common use is 11CWAY100635
• Limitations
• Binds to internalized receptors thus cant
  capture autoreceptor desensitization
• Small brain regions produce noisy results
• To avoid bias of the SRTM (lower relative BP) and
  to quantify the cerebellar activity (in case of
  group differences) need arterial line

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Selection BiasAttrition of subjects phone
screen ? scan
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Hypotheses

• 5HT1A receptor binding will be lower in
  postpartum compared to non-postpartum controls.
• Depressed women will have lower 5HT1A receptor
  binding than non-depressed women.
• Women with bipolar depression will have more
  extreme 5HT1A receptor reductions relative to
  women with unipolar depression
• Lactation will be associated with increased 5HT1A
  receptor binding

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Postpartum status (?) is associated with ? 5HT1A
receptor binding in controls
Hippocampus Subgenual Cing
Raphe nucleus
5HT1A NP -0.8(region) 13.0 5HT1A PP
-0.8(region) 13.9
Chi2 245.2 p lt 0.00001 r2 0.79
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Reduced 5HT1A binding in PPD
Anterior Cingulate Gyrus
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Postsynaptic 5HT1A receptors are reduced in
postpartum unipolar (?) and bipolar (?) depressed
relative to postpartum controls (?)
Hippocampus Subgenual Cing
Raphe nucleus
F(3,12)13.67, Wilks lambda0.23, p0.0004
Moses-Kolko et al Fertility and Sterility, in
press
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Preliminary data control for lactation
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Future Directions and Challenges

• Further explore relationships between lactation
  and 5HT1A receptor binding
• Evaluate plasticity of the 5HT1A receptor system
  in PPD
• Trait vs. state
• Changes over the puerperium and after depression
  recovery
• Animal model

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Could the system which initiates/supports
maternal behavior also play a role in postpartum
depression?
Non-specific motivation system
Maternal motivation system
Perinatal hormones
STRIATAL DOPAMINE
Numan Beh Coh Neurosci Rev 2006
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Striatal dopamine (DA), MDD, and motherhood

• Primary rewards are associated with DA release in
  the ventral striatum
• Reduced ventral striatal DA possible mediator
  of anhedonia in depression
• Dorsal striatum DA is involved in the learning of
  behavior-outcome contingencies to plan future
  reward-directed behavior
• Less effective learning of reward-related
  behavioral sequences in depression
• Maternal behavior is dependent upon intact
  striatal DA NAc DA increases with maternal
  care-giving

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Central position of striatal dopamine in broader
reward system
oxytocin, prolactin
Adapted from Robbins and Everitt 2003
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Why study D2 receptors?
Altered in MDD (imaging postmortem)
Index of regulatory processes in larger DA system
Altered by estradiol
D2
Antidepressant mechanisms
Highly concentrated in striatum
Heightened neuroendocrine response in PPD
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MR PET
Ventral Striatum Ventral Putamen
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Inverse relationship between DA and raclopride
binding to D2 receptors
What if there are few D2 receptors??
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Hypotheses

• Pregnancy estradiol suppression of D2 receptors
• Postpartum release from estradiol suppression ?
  increased D2 receptors

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In healthy controls, postpartum (?) women have
reduced D2/3 receptor binding
D2/3 NP -0.02(age) 0.16(region) 2.64 D2/3 PP
-0.02(age) 0.16(region) 2.33
Chi2 98.18 p lt 0.00001 r2 0.56
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Reduced ventral striatal D2/3 receptor binding in
depressed women
NPC NPD PPC PPD
D2/3 Control -0.02(age) 2.8 D2/3
Depressed -0.02(age) 2.3
F(2,27) 10.8 p 0.0004 r2 0.44
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Age-associated decrease in D2 receptor BP
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Regional differences
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Future Directions
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Perinatal monkey model
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Future Directions and Challenges

• Image presynaptic dopamine function to guide
  interpretation of findings
• Amphetamine challenge
• Use AMPT depletion to discern pure D2 receptor
  binding
• Examine behavioral correlates
• Reward circuitry during guessing task response
  to infant stimuli

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Risk (stress, genetic)
Central
Hormonal Context
Neurobiology
Mood
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Acknowledgements
UNIVERSITY OF PITTSBURGH Joan Lakoski Anthony
Grace Susan Sereika Walter Kaye
UNIVERSITY OF PITTSBURGH Womens Behavioral
HealthCARE Katherine Wisner Barbara Hanusa
Dorothy Sit Michael Lightfoot Tova Saul Lizz
Omalley PET Facility Julie Price Chet
Mathis Scott Ziolko Carl Becker Shelley
Hulland Michele Bechtold PET techs, nursing staff
chemists
EMORY UNIVERSITY Carolyn Meltzer Sarah Berga Mark
Wilson Tammy Loucks Alicia Corominal NIMH Wayne
Drevets Peter Schmidt SUPPORT NIMH NARSAD NCRR
CTRC to University of Pgh