SYMPOSIA

Bulletin of Clinical Psychopharmacology, Vol: 21, Supplement: 2, 2011 - www.psikofarmakoloji.org
Abstracts of the Invited Speakers
The T102C SNP C/C genotype has been associated with no response to clozapine and good response to risperidone and aripiprazole.
The long allele of the serotonin transporter gene has been reported to be associated with better response to antidepressants, but
there are only a few studieson schizophrenic patients. The effectiveness of pharmacogenetics-based combination therapies in patients
unresponsive to treatment has not been studied yet; the DRD2 and DRD3 genes may be candidates for study.
Antipsychotic metabolism: The Met/Met genotype of the COMT gene causes a 3- to 4-fold lower enzyme activity. The met allele carriers
were more likely to respond to clozapine, especially showing improvement in cognitive functions. This polymorphism, seems to deserve
assessment of the effectiveness of combination therapies in dealing with cognitive symptoms.
The CYP2D6 enzyme plays an important role in the metabolism of antipsychotic drugs. Individuals carrying duplicate or multiple
copies of the CYP2D6 gene are known as ultrarapid metabolizers. In ultrarapid metabolizers, due to the decrease in therapeutic efficacy
of antipsychotic drugs, a combination of drugs that are metabolized by the same cytochrome enzyme would not provide further
improvement in drug response.
Antipsychotic-induced side effects: The DRD2 A2 allele of SNP Taq1A, the DRD3 Ser9 Gly Gly allele genetic polymorphisms related to
D2 and D3 receptors, the COMT Val allele and the CYP2D6 gene variants have been reported to be associated with an increased risk of
tardive dyskinesia.
CYP2D6 poor and intermediate metabolizers may be more sensitive to the extrapyramidal side effects of antipsychotics. The 5HT2C gene
(759T SNP) and the leptin gene are the most studied polymorphisms for antipsychotic-induced weight gain. All of the aforementioned
polymorphisms may have implications for choice of rational antipsychotic combinations.
Pharmaco-genetics-based rational antipsychotic combinations may yield promising results for cytochrome enzyme and COMT genes
and the genes associated with side effects in schizophrenia. However, this issue should be supported and confirmed by clinical
pharmacogenetics studies.
Key words: Pharmacogenetics, schizophrenia, antipsychotics, side effects, dopamine, serotonin, polymorphism
Bulletin of Clinical Psychopharmacology 2011;21(Suppl. 2):S62-3
Scientific bases of use of atypical antipsychotics
Ender Taner
Department of Psychiatry, Gazi University Faculty of Medicine, Ankara, Turkey
E-mail: tanerender@yahoo.com
The predominant hypothesis regarding the pathophysiology of schizophrenia is that it is associated with impaired dopamine
neurotransmission. The mesolimbic pathway originates from the midbrain ventral tegmental area and innervates the ventral striatum
(nucleus accumbens), olfactory tubercle, and parts of the limbic system. The mesocortical pathway, also originating from the midbrain
ventral tegmental area, innervates areas of the frontal cortex and has been implicated in learning and memory. Overactivity of the
mesolimbic pathway has been implicated in the development of the positive symptoms of schizophrenia. The negative and some cognitive
symptoms have been associated with a reduction of dopamine activity in the mesocortical pathways together with a hypostimulation
of dopamine receptors in the prefrontal cortex. There are 2 overall goals of treatment: (1) to reduce the activity of hyperactive pathways
mediating psychosis and (2) to increase the activity of hypoactive pathways that seem to mediate negative and cognitive symptoms,
while simultaneously preserving the activity of the pathways that regulate motor movement and prolactin secretion. There is also a
putative interrelationship between N-methyl-D-aspartate (NMDA) hypofunction and dopamine (DA) dysregulation and these processes
may be linked to the pathogenesis of schizophrenia. It has been postulated that NMDA hypofunction in the prefrontal cortex and its
connections may result in a pattern of dopamine dysregulation. In the prefrontal area, this pattern consists of a dopamine deficit and
a hypostimulation of D1 receptors that are linked to the appearance of negative symptoms and cognitive impairment. However, at the
subcortical level, NMDA hypofunction results in dopamine excess, hyperstimulation of D2 receptors, and the appearance of positive
symptoms. It has also been suggested that the prefrontal dopamine deficit and the subcortical dopamine excess feed back, in turn, to the
NMDA circuitry. In addition there is evidence that the deficit in cortical dopamine may also be linked to the generation of a subcortical
dopamine excess. There is a complex modulation of dopamine by different serotonergic receptor systems as well as by nicotinic receptors.
These may be additional sites for effects of antipsychotics. This conference tries to underline the current possible scientific basis for the
use of atypical antipsychotics.
Key words: Atypical antipsychotics, schizophrenia, mechanism of action, scientific basis
Bulletin of Clinical Psychopharmacology 2011;21(Suppl. 2):S63
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