Transcript Basile, 1999

Association of the MscI
Polymorphism of the
Dopamine D3 Receptor
Gene with Tardive
Dyskinesia in
Schizophrenia
Basile et al (1999)
NEUROPSYCHOPHARMACOLOG
Y. 21 (1): 17
The Nature of
Schizophrenia
• Effects 1% of the population
• One of the most important forms of
psychiatric illness as it affects people from
an early age
• Often chronic and usually highly disabling
• Associated with a neurodevelopment
disorder affecting mainly the cerebral
cortex, and occuring in the first few
months of prenatal development.
• Strong hereditary factor (twin studies)
• Combination of Genetic and Environmental
factors (complex trait)
Clinical features
Positive Symptoms
Delusions ( often paranoid in
nature).
Negative Symptoms
Hallucinations, usually in the
form of voices.
Withdrawal from social
contacts
Thought disorder, comprising
wild trains of thought and
irrational conclusions, often
associated with the feeling that
thoughts are inserted or
withdrawn by an outside
agency.
Flattening of emotional
responses
Causes
Large portion of dopamine
content of the brain is found in
• Pharmacological evidence is
the corpus striatum, a part of the
generally consistent with dopamine
extrapyramidal
system
over activitymotor
hypothesis
concerned with the coordination
of movement.
Dopamine Receptors
G-protein-coupled
transmembrane
receptors
D1 family
D1 & D5
D2 family
D2, D3 &
D4
Hypothalmus
Corpus
striatum
MESOCORTICAL
PATHWAY
Pituitary
gland
Nucleus
accumbens
Tuberohypophyseal
pathway
Mesolimbic/mesocortical
Substantia
Short neurons
pathway
nigrarunning from
Cellarcuate
bodies nucleus
occur inof
groups
in midbrain with
the hypothalamus
to
fibres
projecting,
via
the
Nigrostriatal
pathway
the pituitary
gland
medial forebrain bundle,
75%
dopaminergic
to parts
of the limbic
neurons
ie abundant
system, and
to the in
the
striatum
cortex
Fibres run in the medial
forebrain bundle.
MESOLIMBIC
Hippocampus
Amygdaloid
nucleus
Location of the main
groups of cell bodies
and fibre tracts
Drug therapy
Although there are no cures,
neuroleptic
medications
aredrugs
Neuroleptic
medications
= antipychotic
frequently used to alleviate the
typical neuroleptic drugs =
psychosis.
classical antipychotic drugs
pre-1980 drugs which are very similar in their
properties.
produce motor
disturbances
collectively termed
Extra-pyramidal sideESP can occur within the first
few days(EPS)
or
effects
weeks of treatment, or it can appear after
Dopamine
months and years of antipsychotic
Antagonist
medication use.
Accumulation
More than 60% of the people who
take
of dopamine
conventional antipsychotic medications
metabolites
experience some form of EPS.
Dopamine
EPS can cause a variety of symptoms, e.g.
involuntary movements, tremors and
Dopamine
D
rigidity,
body restlessness, muscle
2
synthesis
contractions and changes in breathing and
Receptor
&
heart rate.
release
Tardive dyskinesia (TD).
• motor
disorderthe
characterized
by abnormal
Although
mechanism
of TD
involuntary movements of the orofacial
remains unknown,
has
musculature,
particularly initthe
jaw,been
lips,
and tongue. Choreoathetoid
movements
postulated
that an over
activityofof
the extremities and/or trunk involvement
dopaminergic
may occur as well. neurotransmission
•
in the basal ganglia may play a
occurs
in predisposed
individuals
during or
crucial
role in the
manifestation
following cessation of prolonged typical
of TD.
neuroleptic treatment.
Group of nuclei lying
deep in the white
matter of the frontal
lobes that organizes
motor behavior.
Basal
Ganglia
http://www.driesen.com/basal_ganglia.htm
The dopamine overactivity
hypothesis for TD
dopamine agonists increase TD severity,
It has
been suggested
the neurolepticwhereas,
dopamine that
antagonists
reduce
induced increase the
in dopamine
symptomsreceptor density
eventually
results in an overactivity of the
Corpus
Substanti
striatum
TD results
from chronic
neuroleptic
blockade
a nigra tract
nigrostriatal
dopaminergic
of dopamine D2-like receptors in the basal
ganglia
long-term blockade results in an
upregulation of dopamine receptors on
postsynaptic membranes
20–30% of patients suffer from
neuroleptic-induced TD
- implying variable
susceptibility
susceptibility and/or protection,
predisposing only certain
patients to TD
Evidence form animal models
Example
Cebus monkey, even after several years of
neuroleptic administration, only some develop this
disorder
Genetic Predisposition
Studies
family studies
localized dopamine D3 mRNA -and protein to the ventral side of
the striatum and the ventral putamen in the basal ganglia.
human postmortem
study illustrated a 45 to 56% increase in
Candidate
Genes
the number of D3 receptors in the basal ganglia of
neuroleptic-treated schizophrenics
- initially D2 receptor gene was thought
to be the most likely candidate.
study revealed a twofold increase in the number of D3
receptors in the basal ganglia of long-term hospitalized
patients with schizophrenia.
dopamine D3 receptors provide an inhibitory effect on
locomotor activity.
- Dopamine D3 receptor
dopamine receptor D3 (DRD3) 3q13.3
This gene encodes the D3 subtype of the dopamine receptor. The D3 subtype
inhibits adenylyl cyclase through inhibitory G-proteins. This receptor is
expressed in phylogenetically older regions of the brain, suggesting that this
receptor plays a role in cognitive and emotional functions. It is a target for drugs
which treat schizophrenia and Parkinson disease. Alternative splicing of this
gene results in five transcript variants encoding different isoforms.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=gene&cmd=Retrieve&dopt=Graphics&list_uids=1814
Predisposing
Polymorphism
The Ser9Gly polymorphism
denotes a serine to glycine amino
acid substitution in the N-terminal
extracellular domain of the D3
receptor additionally allelic
differences in affinity for dopamine
have been shown
Table 1. Demographic Distributions of the Sample
• Patients received at least three periods of
treatment in the preceding 5 years at doses
equivalent to or greater than 1000 mg/d of
chlorpromazine for a period of at least 6 weeks.
• None of the patients had ever been treated with
atypical neuroleptics.
• Patients underwent a washout period of 2–4 weeks
which allows the TD phenotype to be expressed
more fully if they carry a predisposing factor.
• TD severity measured using either the Abnormal
Involuntary Movement Scale (AIMS) or a modified
Hillside Simpson Dyskinesia scale.
• Genotyping
Table 1. Demographic Distributions of the Sample
Interesting Observations
• African Americans in the sample had
higher mean AIMS scores than the other
patients of different ethnic origins
• Significant linear relationship was found
between age and TD severity. More
specifically, as age increased, patients
were more likely to exhibit higher AIMS
scores
• Statistically significant difference between
genotype frequency and ethnic status.
African Americans had a significantly
higher occurrence of the glycine allele of
the Ser9Gly polymorphism than did the
Caucasians.
•
serine to glycine
polymorphism in the DRD3
receptor was significantly
associated with typical
neuroleptic-induced TD.
•
higher mean AIMS scores in
patients homozygous for the
glycine allele of the DRD3
gene when compared to
heterozygous patients and
patients homozygous for the
serine allele.
Figure 1. Mean corrected AIMS scores for each of the genotypic
classes. The variances(s2) for each of the genotypic classes
were as follows: (s2 for Ser/Ser genotype was 18.8; s2 for
Ser/Gly genotype was 28.4; and s2 for Gly/Gly genotype was
156.1). The Levene Test for homogeneity of variances revealed a
significant difference in the variances among the genotypic
classes, thus violating one of the assumptions of the ANCOVA
model. However, a nonparametric alternative, the Kruskal–Wallis
Test, illustrated similar results ( 2 = 13.6644, df = 2, p = .0011, p
= 0.0033 Bonferroni corrected)
To test for effects of
ethnic stratification, we
conducted an analysis
that separated
Caucasians and African
Americans. It was found
that in both Caucasians (n
= 85, F[2,75] = 3.85, p =
.026) and African
Americans (n = 25, F[1,23]
= 8.10, p = .0091), patients
homozygous for the
glycine allele were more
likely to exhibit higher
AIMS scores.
Figure 2. Ethnically stratified analysis. To
address the issue of population stratification, an
analysis separating Caucasians from African
Americans was conducted. It was found that in
both ethnic samples, patients with Gly/Gly
genotypes were more likely to exhibit larger
AIMS scores, thus reducing the possibility of a
false positive attributable to ethnic stratification.
Figure 2A illustrates the Caucasian results, and
Figure 2B gives the African American results
Conclusion
• observed a statistically significant
association between the glycine
variant of DRD3 and TD.
• mean AIMS scores for individuals
homozygous for the glycine variant
were significantly higher than
individuals who were either
serine/serine homozygotes or
serine/glycine heterozygotes.
Parallels
The substitution of a polar serine residue to a nonpolar
glycine residue may alter the tertiary structure of the D3
receptor.
The functional differences in dopamine affinity for each
of these receptor alleles as expressed in CHO cell lines
have been identified
There is a higher dopamine affinity for the glycine
homozygote cells, as compared to both heterozygote
binding and serine/serine homozygotesin these cells.
Problems
• Factors examined
D3 genotype
age
totalsex
neuroleptic
phenotypic
histories for
ethnicity
all patients
heterogeneity
were unavailable
D3 genotype was the only factor that
significantly contributed to the TD
phenotype.
environmental influences ?
• As the data in the study correlates to the CHO cell
study findings perhaps the functional differences may
contribute to the TD phenotype, although it is difficult
to speculate further on the precise mechanism
involved.
• It could be suggested that the higher affinity of the
glycine allele may be involved in the pathogenesis of
TD. Alternatively, this Ser9Gly polymorphism may be
in linkage disequilibrium with another site conferring
susceptibility to TD.
Closing Remarks
• The results presented in this study suggest the
involvement of the Ser9Gly DRD3 polymorphism as a
predisposing risk factor for TD. This genetic
information may, in future, assist clinicians in
determining patient susceptibility to TD and ultimately
may aid in the elucidation of the pathophysiological
mechanisms.