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Correspondence: Ghiorghe TALU

Address: No. 73 Street Alba Iulia, bl. 9, sc. C, ap. 36, Sibiu, Romania
Tel.: +40 788 244 958
Date of Submission: September, 19, 2012 / Acceptance: November, 5, 2012


Ghiorghe TALU, Lavinia DUIC, Florin MITU,
Raul TALU, Daniela NICOAR
Ghiorghe TALU: M. D., Ph. D., Professor, Department of Psychiatry, Lucian Blaga University,
Victor V. Papilian Faculty of Medicine, Sibiu, Romania; Senior Psychiatrist, General Manager of Dr
Gheorghe Preda Psychiatric Hospital, Sibiu, Romania
Lavinia DUIC: M. D., Ph. D., Assistant Professor, Department of Psychiatry, Lucian Blaga
University, Victor V. Papilian Faculty of Medicine, Sibiu, Romania; Senior Psychiatrist, Dr Gheorghe
Preda Psychiatric Hospital, Sibiu, Romania
Florin MITU: M. D., Ph. D., Assistant Professor, Department of Internal Medicine II, Gr. T. Popa
University of Medicine and Pharmacy, Iasi; Senior cardiologist, Department of Cardiology, Clinical
Rehabilitation Hospital, Iasi, Romania
Raul TALU: M. D., Resident in psychiatry, Dr Gheorghe Preda Psychiatric Hospital, Sibiu, Romania
Daniela NICOAR: Senior Psychologist, Department of Psychology, Lucian Blaga University,
Victor V. Papilian Faculty of Medicine, Sibiu, Romania

In the last years, pharmacogenetics represents an important domain of research in psychiatry. As
the most severe disorder in psychiatry, schizophrenia benefits by a large amount of studies that aim to
evaluate genetic factors contributing to the inter-individual variation in clinical outcome of antipsychotic treatment.
Studies of the elements of the dopaminergic system (for example, DR2, DR3) demonstrate some
inconsistent results. Furthermore, pharmacogenetic studies concentrate upon the elements of the serotonergic system (serotonine receptors, especially 5HT2A, 5HT2C and 5HT1A, serotonin transporter
SERT, etc.) in order to investigate a possible association of some genetic polymorphisms and the antipsychotic response.
Keywords: pharmacogenetics, serotonin, genetic polymorphism
n ultimii ani, farmacogenetica a reprezentat un domeniu important de cercetare n psihiatrie.
Fiind cea mai sever tulburare psihiatric, schizofrenia beneficiaz de un numr mare de studii care i


BULETIN DE PSIHIATRIE INTEGRATIV / Bulletin of Integrative Psychiatry

propun s evalueze factorii genetici care contribuie la variaia inter-individual a rspunsului clinic la
tratamentul antipsihotic.
Studiile elementelor sistemului dopaminergic (de exemplu: DR2, DR3) au artat rezultate inconsistente. Mai departe, studiile de farmacogenetic s-au concentrat asupra elementelor sistemului serotonergic (receptori serotonergici, n special 5HT2A, 5HT2C i 5HT1A, transportorul de serotonin SERT
etc.) pentru a investiga posibila asociere ntre unele polimorfisme genetice i rspunsul la tratamentul
Cuvinte-cheie: farmacogenetic, serotonin, polimorfism genetic

Schizophrenia has always represented a major preoccupation both for mental health professionals and for society in general, because the disabilities that the individuals who suffer from
this severe illness affect their personal, familial and professional life. Schizophrenia has been circumscribed by a multitude of neuroimagistic, psychopharmacologic, and pharmacogenetic studies
that aimed to identify the characteristic elements of the biological substratum of schizophrenia.
Up to the present, there were issued a series of biochemical theories, the neurodevelopmental
theory, and other theories that view schizophrenia from different perspectives, but these were not
able to elucidate the mechanisms involved in the mental disarray characteristic to this disorder.
Due to their having brought forth opportunities to create specific substances meant to act upon
certain biochemical disequilibriums, the biochemical theories (dopaminic, serotoninic, glutamatergic, etc.) hold a top place in the psychopharmacological and pharmacogenetic research. Nowadays, the atypical antipsychotics aiming at the dopaminic receptors (D1, D2 type) or serotoninic
receptors (5 HT1A, 5 HT2A, 5HT2C, 5HT3, 5HT6, 5HT7) constitute the first choice drugs in schizophrenia treatment.
However, the clinical studies results reflected an instability of the beneficial effects of these
drugs. This phenomenon is explained by the fact that the dopaminergic or serotonergic biochemical
anomalies play a limited role in the pathophysiology of schizophrenia with its multiple ways of
manifestation. It is also important to note that the individual variability sustained by the genetic
dowry may contribute to the predominance of either favourable or unfavourable effects during the
antipsychotic treatment.
At present, the epidemiological studies concerning the risk factors (the studies were done on
families, twins, and adopted children) have well established that, as far as the contribution of the genetic factors in schizophrenia goes, the modality of the transmission of this disorder is non-Mendelian. This kind of transmission is subordinated to the polygenic model that implies the involvement of many genes with an incomplete penetrance that encodes different protean entities which
take part in the neurotransmission.
Identification of patients who are likely to respond to the therapy or prone to develop adverse
effects may help clinicians to avoid treatment failure and to prevent patient morbidity. Pharmacogenetic studies aimed to evaluate genetic factors contributing to the interindividual variation in clinical outcome of antipsychotic treatment have been focusing on two main aspects so far: genetic variations (insertions, deletions, single nucleotide polymorphisms and copy number variations in the
DNA sequence) of relevance for either the pharmacokinetics or the pharmacodynamics of the drugs.
Once the epidemiological genetic studies stage was overcome, another investigation phase
started, namely the identification phase of the genes involved in the determination of predispositions to schizophrenia through studies linkage and association.
The genes encoding the elements of the dopaminergic system and those involved in other neurotransmission systems that interact with the dopaminergic system, or the genes involved in the
neurodevelopmental process have benefited from a wide investigation by the studies of association.
Polymorphism has been described in several genes in the serotonergic pathway and most of
these genes have been studied to detect the association with schizophrenia. These include serotonin
transporter (SERT or 5-HTT) and serotonin receptors: 5-HT1A (1), 5HT1D beta (2), 5-HT2A (3), 5-HT2C,

The pharmacogenetic aspects of the serotonergic receptors in schizophrenia


5-HT6 (4), 5-HT7 (5). A meta analysis study by Arranz et al. (1996) (6) showed association of the
102-T/C polymorphism of 5- HT2A with clozapine response in extreme responders.
The 5-HT2A receptors are found on apical dendrites and dendritic spines of pyramidal neurons
in both the rat and primate cortex.
Drugs like clozapine, used in schizophrenia treatment, are known to have a high affinity for
HT2A. Therefore, two single-nucleotide polymorphisms, one a T to C change at nucleotide 102 in
the coding region of the gene (7) and the other an A to G change at nucleotide 1438 within the regulatory region of the gene (8) which could influence the expression of the gene and affect the receptor density, have been analysed.
The 5-HT2A serotonergic receptors have received more and more attention within the researches done on schizophrenia, due to the fact that some of these studies marked out a decrease in the
concentration of this receptor in the prefrontal cortex. This decrease emerged as a response to the
administration of atypical antipsychotics and to the discovery of a positive association between the
T/C polymorphism at the 102 nucleotide of the 5-HT2A receptor.
The first evidence of this fact derives from a Japanese study (9). The said hypothesis was reechoed in numerous researches, as it is indicated by the study of Arranz et al. (1998) (10), that revealed the existence of a polymorphism of the 2-allele of the 5-HT2A receptor gene (T102 polymorphism) that is correlated with the resistance to clozapine.
These data were analyzed mostly within the pharmacogenetic zone and according to the effects
that one allelic variant may have upon the pharmacokinetics and pharmacodynamics of the administered
drugs. The results of these data have had consequences in the therapeutic efficiency of the drugs and in
the incidence of the adverse effects.
Moreover, there are no significant differences regarding the contribution of the plasmatic concentration, or the receptoral occupancy degree (11) of the neuroleptics, to the variability of the response to the treatment. Coupled with Meltzers idea that it is more likely to get a good response to
the treatment applied to patients who had previously had a favourable reaction to clozapine (even if
they developed a resistance to it afterwards), than to those who had proved resistant to typical antipsychotics from the start, these observations suggest that the difference in the degree of responsiveness to clozapine are due also to the ethiological type of the disorder.
The pharmacogenetic studies have dwelt upon the 5-HT2A receptor, as it is well-known that
the stimulation of this receptor (for example, the lysergic acid) may mimic psychosis and especially
hallucinations (12), while its inhibition represents the most important characteristic of the atypical
antipsychotics (13).
The pharmacogenomics researches done on the 5-HT2A receptor highlighted 3 polymorphisms: one from the A-1438G promoter level, and the other two from the level of T102C and
His452Tyr coding regions (14).
A less common genetic polymorphism is the His452Tyr from the C terminal region of the 5-HT2A
receptor that is found with a 9 % frequency of the 452-Tyr allele in the caucasians that used to be associated in the past with the serotonine induced intracelullar mobilization of Ca (15). Currently, they take
into account the His452Tyr polymorphism as far as the variability of the response to aripiprazol is
concerned (16).
In addition to the 5-HT2A receptor, other 5-HT receptors, such as 5-HT2C and 5-HT6, have
also been investigated in psychopharmacogenetic studies because atypical antipsychotics also have
high affinity for these receptors. The 5-HT2C receptor has been targeted for study based on the high
densities of this receptor in brain regions implicated in both the pathophysiology of schizophrenia
and the mechanism of action of clozapine, as well as other atypical antipsychotics.
Forty-five per cent of the schizophrenic patients had been treated with various antipsychotics
prior to admission to the hospital. It is therefore not possible to exclude a confounding effect of this
therapy on transporter protein expression. Patients with and without prior treatment, however, did
not differ in the therapeutic outcome with respect to their 5-HTT genotype.


BULETIN DE PSIHIATRIE INTEGRATIV / Bulletin of Integrative Psychiatry

Clozapine may be attributable to activation of 5-HT1A autoreceptors that cause an enhancement of frontocortical dopamine (DA) release; clozapine also has anxiolytic and anticataleptic
properties and may improve cognitive symptoms.
HT1A receptors are localized dendritically as inhibitory autoreceptors on serotonergic cell bodies of the median raphe nucleus, which predominantly innervates the dorsal hippocampus, septum
and hypothalamus, and the dorsal raphe nucleus, which provides a major input to frontal cortex,
ventral hippocampus, and striatum. In addition, postsynaptic 5-HT1A sites are enriched in the frontal
cortex, hippocampus, and other corticolimbic structures implicated in the etiology of schizophrenia
and in the actions of antipsychotic agents. In line with this organization, both pre- and postsynaptic
5-HT1A receptors fulfill an important role in the modulation of mood, cognition, and motor behavior
(17), functions perturbed in schizophrenic patients and profoundly affected by antipsychotic agents
5HTR1A is the coding gene for 5-HT1A receptor, which is coupled with the G protein both in
the presynaptic and in the postsynaptic poles that inhibit the activity of the adenylate-cyclase. The
interest about this receptor, and, additionally, about its synthesizer gene, lies in the role it plays within the range of mood and anxiety disorders (18).
In vitro studies have shown that some typical antipsychotics, such as ziprasidone, do produce
notable clinical effects through their great affinity for the 5-HT1A receptor, whereas clozapine exerts
an agonist partial activity upon this receptor (19).
Moreover, the anxiolytic and antidepressive properties of the agonists of the 5-HT1A receptor
(20) suggest that the HTR1A gene might serve as a molecular target for the development of antipsychotic substances oriented against psychosis and mood disorders (which sometimes co-exist), as it
occurs in the case of schizoaffective or psychotic depressive disorders.
Lemonde S. et al. (2003) brings into discussion the C(-1019)G polymorphism that is situated
in the region of the HTR1A genes transcriptional control. The (-1019)G allele removes the repression of the expression of the 5-HT1A autoreceptor, which leads to the reduction of the serotonergic
neurotransmission. The C(-1019)G polymorphism of the 5-HT1A receptor is more frequent within
the general population for example, in Ontario, Canada, the frequency of the (-1019)G allele was
approximately 37.3 % in the normal subjects (21).
In addition to the 5-HT2A receptor, other 5-HT receptors, such as 5-HT2C and 5-HT6, have
also been investigated in psychopharmacogenetic studies because atypical antipsychotics also have
high affinity for these receptors. The 5-HT2C receptor has been targeted for study based on the high
densities of this receptor in brain regions implicated in both the pathophysiology of schizophrenia
and the mechanism of action of clozapine as well as other atypical antipsychotics.
It follows that a larger psychopathological specter, including schizophrenia and drug abuse, as
well as the therapeutic response to tricyclical antidepressants and SSRI, appear to be associated
with the allelic variance C(-1019)G of the 5-HT1A receptor (22).
The data issued by these pharmacogenetic studies give way to new expectations regarding the
discovery of innovative and potent investigation methods in the case of schizophrenia, and also of
some new and more effective substances for the treatment of disorders that had previously proved
resistant to all known antipsychotics. It is very difficult to connect the information provided by the
domain of pharmacology and that of psychiatry, because this association involves the intercrossing
of the multifactoriality theory and the polygenic aspects of the psychiatric disorders with the plenary manifestation of the human psychic within the dynamics of existence.
The authors declare that they have no potential conflicts of interest to disclose.

The pharmacogenetic aspects of the serotonergic receptors in schizophrenia


1. Erdmann, J., Shimron-Abarbanell, D., Cichon, S., Albus, M., Maier, W., Lichtermann, D. et al. Systematic
screening for mutations in the promoter and the coding region of the 5-HT1A gene. Am J Hum Genet 1995; 60: 393-399.
2. Nothen, M. M., Erdmann, J., Shimron-Abarbanell, D., Propping, P. Identification of genetic variation in the
human serotonin 1D beta receptor gene. Biochem. Biophys. Res. Commun. 1994, 205: 1194-1200.
3. Williams, J., McGuffin, P., Nothen, M., Owen, M. J. Meta-analysis of association between the 5-HT2a receptor
T102C polymorphism and schizophrenia. EMASS Collaborative Group. European Multicentre Association Study of Schizophrenia. Lancet 1997, 349:1221.
4. Shinkai, T., Ohmori, O., Kojima, H., Terao, T., Suzuki, T., and Abe, K. (1999). Association study of the 5HT6 receptor gene in schizophrenia. Am J Med Genet 1999; 88:120-122.
5. Erdmann, J., Nthen, M. M., Shimron-Abarbanell, D., Rietschel, M., Albus, M., Borrmann, M. et al. The human serotonin 7 (5-HT7) receptor gene: genomic organization and systematic mutation screening in schizophrenia and
bipolar affective disorder. Mol Psychiatry 1996; 1: 392 -397.
6. Arranz, M. J., Collier, D. A., Munro, J., Sham, P., Kirov, G., Sodhi, M. S., Roberts, G. W., Price, J., Kerwin,
R. W. Analysis of a structural polymorphism in the 5-HT2A receptor and clinical response to clozapine. Neuroscience
Letters 1996; 217:177-178.
7. Warren, J. T., Peacock, M. L., Rodriguez, L. C., Fink, J. K. An Msp I polymorphism in the human serotonin
receptor gene (HTR2): Detection by DGGE and RFLP analyses. Hum Molec Genet 1993: 2:338.
8. Spurlock, G., Heils, A., Holmans, P., Williams, J., DSouza, U. M., Cardno, A., et al. A family based association study of T102C polymorphism in 5HT2A and schizophrenia plus identification of new polymorphisms in the
promoter. Mol Psychiatry 1999; 3:42-49.
9. Inayama, Y., Yoneda, H., Sakai, T., Ishida, T., Nonomura, Y., Kono, Y., Takahata, R. et al. Positive association between a DNA sequence variant in the serotonin 2A receptor gene and schizophrenia, Am J Med Genet 1996;
10. Arranz, M. J., Munro, J., Owen, M. J., Spurlock, G., Sham, P. C., Zhao, J., Kirov, J. et al. Evidence for association between polymorphisms in the promoter and coding regions of the 5-HT2A receptor gene and response to clozapine, Mol Psychiatry 1998; 3: 61-66.
11. Wolkin, A., Barouche, F., Wolf, A. P., Rotrosen, J., Fowler, J. S., Shiue, C. Y., Cooper, T. B., Brodie, J. D.
Dopamine blockade and clinical response: evidence for two biological subgroups of schizophrenia. Am J Psychiatry
1989; 146:905-908.
12. Aghajanian, G. K., Marek, G. J. Serotonin glutamate interactions: a new target for antipsychotic drugs.
Neuropsychopharmacology 1999; 21:S122S133.
13. Meltzer, H. Y., Alphs, L., Green, A. I., Altamura, A. C., Anand, R., Bertoldi, A., Bourgeois, M., Chouinard, G.,
Zahur, Islam, M., Kane, J., Krishnan, R., Lindenmayer, J. P., Potkin, S. Clozapine treatment for suicidality in schizophrenia. Arch Gen Psychiatry 2003; 60:82-91.
14. Veenstra-Vander Weele, J., Anderson, G. M., Cook, Jr. E. H. Pharmacogenetics and the serotonin system:
initial studies and future directions. Eur J. Pharmacol 2000; 410: 165-181.
15. Ozaki, N., Manji, H., Lubierman, V., Lu, S. J., Lappalainen, J., Rosenthal, N. E. and Goldman, D. A naturally occurring amino acid substitution of the human serotonin 5-HT2A receptor influences amplitude and timing of intracellular calcium mobilization. J Neurochem 1997; 68: 21862193.
16. Reist, C., Ozdemir, V., Wang, E., Hashemzadeh, M., Mee, S., Moyzis, R. Novelty seeking and the dopamine
D4 receptor gene (DRD4) revisited in Asians: Haplotype characterization and relevance of the 2-repeat allele. American
Journal of Medical Genetics Part B: Neuropsychiatric Genetics 2007; 144 (4):453-457.
17. Barnes, N. M., Sharp, T. A review of central 5-HT receptors and their function. Neuropharmacology 1999;
38: 1083-1152.
18. Lesch, K. P., Gutknecht, L. Focus on the 5-HT1A receptor: emerging role of a gene regulatory variant in
psychopathology and pharmacogenetics. Int J Neuropsychopharmacol 2004; 7: 381-385.
19. Richelson, E., Souder, T. Binding of antipsychotic drugs to human brain receptors: focus on newer generation compounds. Life Sci 2000; 68:29-39.
20. Blier, P., Ward, N. M. Is there a role for 5-HT1A agonists in the treatment of depression? Biol Psychiatry
2003; 53:193203.
21. Lemonde, S., Turecki, G., Bakish, D., Du, L., Hrdina, P. D., Bown, C. D. et al. Impaired repression at a 5hydroxytryptamine 1A receptor gene polymorphism associated with major depression and suicide. J Neurosc 2003; 23:
22. Lemonde, S., Du, L., Bakish, D., Hrdina, P., Albert, P. R. Association of the C(1019)G 5-HT1A functional
promoter polymorphism with antidepressant response. Int J Neuropsychopharmacol 2004; 7: 501-506.