Transcript Slide 1

COMT and Response to
Antipsychotics in First Episode
Psychosis
Jeffrey R. Bishop, PharmD, MS, BCPP
Assistant Professor
UIC Dept of Pharmacy Practice
UIC Center for Cognitive Medicine
Goal and Objective
• Goal: PGx program development
– Symptom and cognition response to
antipsychotic medications
• Objective: To study the relationship
between an important functional variant in
the catechol-o-methyltransferase (COMT)
gene and symptom improvement in first
episode psychosis patients treated with
antipsychotic medications
Background
• COMT is an important regulator of dopamine
(DA) metabolism
– Breaks down DA
– Expressed throughout the brain
• Predominantly expressed in prefrontal cortex
• Genetic variation in COMT (e.g. Val158Met)
results in thermo-labile form of COMT enzyme
– Valine: less DA (↑ DA metabolism)
– Methionine: more DA (↓ DA metabolism)
Background
• Candidate gene selection: why COMT?
– Regulates DA disposition in the brain
– +/- associations with disease and symptoms
– +/- associations with antipsychotic response
• No PGx studies in “First Episode”
– + associations with “cognition” – e.g. working memory,
processing
Meyer-Lindenberg and Weinberger. Nat Rev Neurosci. 2006; 7:818-827
Study Design
• Pharmacogenetic candidate gene association
study
• Participants: current and past participants of the
UIC and Pittsburgh (WPIC) First Episode studies
– Inclusion criteria:
• DSM-IV dx schizophreniform, schizophrenia, schizoaffective
disorder, bipolar disorder with psychosis
• <12 weeks total lifetime exposure to antipsychotics
– Exclusion criteria:
• Previous brain injury, neurological disorder, substance
dependence in the past 6 mo
• Treatment
– 3-5 day washout if on antipsychotic or mood
stabilizing medications
– 6 weeks of antipsychotic treatment
• Open label flexible dosing design
• Risperidone (n=49), haloperidol (n=8), olanzapine (n=5),
ziprasidone (n=1), fluphenazine (n=1)
Study Design
• Assessments:
– Pre/post treatment clinical ratings
• BPRS Total – Primary outcome for PGx symptom response
– Pre/post neuropsych
• WRAT, Trails A/B, CVLT, Digits F/B
– Pre/post saccade studies
– Pre/post fMRI
– Consensus DSMIV diagnosis
• w/ SCID
– DNA
– Serum
• Risperidone/9-OH-Risperidone
• Hormone Changes
Currently being
scored…for future
analyses
Results
• N=84 participants – 64 completed pre/post
clinical ratings
• Mean age = 24.5±8 yrs
• 68% male
• Race/Ethnicity:
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Caucasian: 47%
African American: 37%
Asian: 6%
Hispanic: 8%
Unknown: 1%
• Baseline BPRS Total: 49.9±9.7
• Baseline BPRS Positive: 13.0±7
• Baseline BPRS Negative: 11.0±6.5
Results
Variable
SchizSpectrum
(n=54)
Bipolar
(n=10)
All
BPRS Total
Change
BPRS Pos
Change
11.2±12.5
13.7±4.3
11.5±12.6
1.3±3.9
4.2±6.3
1.8±4.5
BPRS Neg
Change
20%
Improvement
3.9±4.6
1.6±3.9
3.5±4.5
52%
40%
50%
• Changes significant from baseline
• Not statistically different between diagnostic groups
• Age, medication, race, gender not significantly
associated with symptom change
Results
• Genotypes did not
deviate from HardyWeinberg Equilibrium
(HWE)
• Met/Met (n=16)
Val/Met (n=44) Val/Val
(n=24)
COMT Val158Met Allele
Frequencies
0.45
0.55
Valine
Methionine
Results: All Participants
• BPRS Change scores
(Time1-Time2) for all
participants together
• All p’s>0.18
• Conclusion: COMT not
associated with
symptom improvement
Results: Schizophrenia Spectrum
• BPRS Change scores
(Time1-Time2) for
schizophrenia spectrum
participants
– Schizophrenia + Schizoaffective
• All p’s>0.26
• Conclusion: COMT not
associated with symptom
improvement
Results: Replication in Previously
Ascertained Dataset
• Genotyped previously
described sample1,2
• N=42 subjects with
schizophrenia (~2/3
first episode)
• Predominantly male
Caucasians
• 4-7 day washout prior
to 6 wks of fixed dose
olanzapine
• Results: No difference in
BPRS change scores over
time (p=0.92)
• Conclusion: COMT not
associated with symptom
improvement
1.
Ellingrod et al. Psychopharm Bull. 2003; 37:109-112
2.
Bishop et al. Schizophr Res 2005; 77:253-260
Results In Progress: Cognitive
Biomarkers
• Visually guided saccade
latencies
– Time taken to shift eye focus to
new location
– Measure of mental processing
speed
– Speeded saccadic responses to
visual targets consistent with
impairment of attentional
regulation of sensorimotor
systems1
• Significantly different across
COMT Val158Met genotype
groups (p=0.01)
1. Reilly JL et al. Biol Psychiatry. 2005; 57:145-154
Conclusion and Future Direction
• Conclusion: COMT Val158Met genotype is
not associated with symptom response in
patients with schizophrenia
• Future Directions:
– Investigation of gene-gene interactions
– Focus on relationship of variants in genes
regulating dopamine, glutamate, and
serotonin disposition with symptom and
cognition response to antipsychotic
medications
Acknowledgements
Center for Cognitive Medicine
• Study Participants • UIC
– John Sweeney, PhD
– Robert Marvin, MD
• Funding:
– ACCP Investigator
Development Award
(Bishop PI)
– NIMH R01MH062134
(Sweeney PI)
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Cherise Rosen, PhD
James Reilly, PhD
Margret Harris, MA
Scot Hill, PhD
Sarah Keedy, PhD
Jennifer Barrett
Nick Navarro
Mark Schneiderhan, PharmD, BCPP
• UIC
Pharmacogenomics • University of Pittsburgh
Laboratory
Department of Psychiatry First
– Michael Akroush
Episode Program
– Vishwajit Nimgaonkar, MD, PhD
– Konasale Prasad, MD
– Matcheri S. Keshevan, MD
Thank You