Effect of 5-HT           <sub>1A</sub>           Receptor Gene Polymorphism on Negative  and Depressive Symptom Response to Antipsychotic  Treatment of Drug-Naive Psychotic Patients

Reynolds, Gavin P.; Arranz, Belén; Templeman, L.; Fertuzinhos, Sofia; San, Luis

doi:10.1176/ajp.2006.163.10.1826

Cited by 83 publications

(47 citation statements)

References 12 publications

(9 reference statements)

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“…Interestingly, a report shows that the CC-genotype also confers a better response to transcranial magnetic stimulation [142], suggesting that modulation of the 5-HT1A receptor may also participate in treatments that target cortical processes, perhaps via induced expression of the 5-HT1A receptor in cortex and amygdala [143]. The GG-genotype has also been associated with weaker negative symptom improvement in schizophrenia patients treated with atypical antipsychotics [144,145]. Taken together these studies indicate that the G-allele, which is associated with increased 5-HT1A autoreceptor levels, also associates with reduced responses to therapies that modify the 5-HT system.…”

Section: -Ht1a Promoter Polymorphisms and Mental Illnessmentioning

confidence: 99%

Transcriptional Dys-regulation in Anxiety and Major Depression: 5-HT1A Gene Promoter Architecture as a Therapeutic Opportunity

Albert¹,

Fiori

2014

CPD

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The etiology of major depression remains unclear, but reduced activity of the serotonin (5-HT) system remains implicated and treatments that increase 5-HT neurotransmission can ameliorate depressive symptoms. 5-HT1A receptors are critical regulators of the 5-HT system. They are expressed as both presynaptic autoreceptors that negatively regulate 5-HT neurons, and as postsynaptic heteroreceptors on non-serotonergic neurons in the hippocampus, cortex, and limbic system that are critical to mediate the antidepressant actions of 5-HT. Thus, 5-HT1A auto-and heteroreceptors have opposite actions on serotonergic neurotransmission. Because most 5-HT1A ligands target both auto-and heteroreceptors their efficacy has been limited, resulting in weak or unclear responses. We propose that by understanding the transcriptional regulation of the 5-HT1A receptor it may be possible to regulate its expression differentially in raphe and projection regions. Here we review the transcriptional architecture of the 5-HT1A gene (HTR1A) with a focus on specific DNA elements and transcription factors that have been shown to regulate 5-HT1A receptor expression in the brain. Association studies with the functional HTR1A promoter polymorphism rs6295 suggest a new model for the role of the 5-HT1A receptor in susceptibility to depression involving early deficits in cognitive, fear and stress reactivity as stressors that may ultimately lead to depression. We present evidence that by targeting specific transcription factors it may be possible to oppositely regulate 5-HT1A auto-and heteroreceptor expression, synergistically increasing serotonergic neurotransmission for the treatment of depression. KeywordsSerotonin; repressor; enhancer; antidepressant; raphe; autoreceptor SEROTONIN AND MAJOR DEPRESSIONDepression continues to grow as a major health challenge with a lifetime prevalence for major depressive disorder (MDD) estimated at 16 % [1, 2] (Box 1). In developed countries, MDD currently accounts for the second highest lifetime burden of disease, and is predicted

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Section: -Ht1a Promoter Polymorphisms and Mental Illnessmentioning

confidence: 99%

Transcriptional Dys-regulation in Anxiety and Major Depression: 5-HT1A Gene Promoter Architecture as a Therapeutic Opportunity

Albert¹,

Fiori

2014

CPD

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“…A recent study provides support for this theory by reporting association between a 5-HT1A -1019-C/ G polymorphism and antipsychotics improvement of negative symptoms. 115 Further evidence exists of the likely involvement of other serotonin receptors in antipsychotic activity (for example, 5-HT 3A , 5-HT 3B , 5-HT 5A and 5-HT 7 ). However, few genetic studies have attempted to confirm this hypothesis 133,134 and no significant association with antipsychotic response has been reported to date.…”

Section: Pharmacodynamic Factorsmentioning

confidence: 99%

Pharmacogenetics and pharmacogenomics of schizophrenia: a review of last decade of research

2007

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The last decade of research into the pharmacogenetics of antipsychotics has seen the development of genetic tests to determine the patients' metabolic status and the first attempts at personalization of antipsychotic treatment. The most significant results are the association between drug metabolic polymorphisms, mainly in cytochrome P450 genes, with variations in drug metabolic rates and side effects. Patients with genetically determined CYP2D6 poor metabolizer (PMs) status may require lower doses of antipsychotic. Alternatively, CYP2D6 ultrarapid matabolizers (UMs) will need increased drug dosage to obtain therapeutic response. Additionally, polymorphisms in dopamine and serotonin receptor genes are repeatedly found associated with response phenotypes, probably reflecting the strong affinities that most antipsychotics display for these receptors. In particular, there is important evidence suggesting association between dopamine 2 receptor (D2) polymorphisms (Taq I and À141-C Ins/Del) and a dopamine 3 receptor (D3) polymorphism (Ser9Gly) with antipsychotic response and drug-induced tardive dyskinesia. Additionally, there is accumulating evidence indicating the influence of a 5-HT2C polymorphism (À759ÀT/C) in antipsychotic-induced weight gain. Application of this knowledge to clinical practice is slowly gathering pace, with pretreatment determination of individual's drug metabolic rates, via CYP genotyping, leading the field. Genetic determination of patients' metabolic status is expected to bring clinical benefits by helping to adjust therapeutic doses and reduce adverse reactions. Genetic tests for the pretreatment prediction of antipsychotic response, although still in its infancy, have obvious implications for the selection and improvement of antipsychotic treatment. These developments can be considered as successes, but the objectives of bringing pharmacogenetic and pharmacogenomic research in psychiatric clinical practice are far from being realized. Further development of genetic tests is required before the concept of tailored treatment can be applied to psychopharmatherapy. This review aims to summarize the key findings from the last decade of research in the field. Current knowledge on genetic prediction of drug metabolic status, general response and drug-induced side effects will be reviewed and future pharmacogenomic and epigenetic research will be discussed.

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“…We therefore assessed whether the schizophrenia susceptibility gene ZNF804A has a pharmacogenetic importance. Since previous studies with monoamine system genes have shown that a pharmacogenetic role of a given gene may be primarily restricted to the positive or negative symptom response [8,11,14], we queried whether the disease-associated variant of ZNF804A exerts an influence on positive or negative schizophrenia symptoms.…”

Section: Introductionmentioning

confidence: 99%

The schizophrenia risk gene ZNF804A influences the antipsychotic response of positive schizophrenia symptoms

Mößner

Schuhmacher

Wagner

et al. 2011

Eur Arch Psychiatry Clin Neurosci

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Genetic factors determining the response to antipsychotic treatment in schizophrenia are poorly understood. A new schizophrenia susceptibility gene, the zinc-finger gene ZNF804A, has recently been identified. To assess the pharmacogenetic importance of this gene, we treated 144 schizophrenia patients and assessed the response of positive and negative symptoms by PANSS. Patients homozygous for the ZNF804A risk allele for schizophrenia (rs1344706 AA) showed poorer improvement of positive symptoms (7.35 ± 0.46) compared to patients with a protective allele (9.41 ± 0.71, P = 0.022). This provides further evidence that ZNF804A is of functional relevance to schizophrenia and indicates that ZNF804A may be a novel target for pharmacological interventions. is of functional relevance for schizophrenia and indicates that ZNF804A may be a novel target for pharmacological interventions.

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Effect of 5-HT _1A Receptor Gene Polymorphism on Negative and Depressive Symptom Response to Antipsychotic Treatment of Drug-Naive Psychotic Patients

Abstract: These findings identify an important genetic factor predicting much of the response in negative and depressive symptoms to antipsychotic drug treatment.

Cited by 83 publications

References 12 publications

Transcriptional Dys-regulation in Anxiety and Major Depression: 5-HT1A Gene Promoter Architecture as a Therapeutic Opportunity

Transcriptional Dys-regulation in Anxiety and Major Depression: 5-HT1A Gene Promoter Architecture as a Therapeutic Opportunity

Pharmacogenetics and pharmacogenomics of schizophrenia: a review of last decade of research

The schizophrenia risk gene ZNF804A influences the antipsychotic response of positive schizophrenia symptoms

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Effect of 5-HT 1A Receptor Gene Polymorphism on Negative and Depressive Symptom Response to Antipsychotic Treatment of Drug-Naive Psychotic Patients

Abstract: These findings identify an important genetic factor predicting much of the response in negative and depressive symptoms to antipsychotic drug treatment.

Cited by 83 publications

References 12 publications

Transcriptional Dys-regulation in Anxiety and Major Depression: 5-HT1A Gene Promoter Architecture as a Therapeutic Opportunity

Transcriptional Dys-regulation in Anxiety and Major Depression: 5-HT1A Gene Promoter Architecture as a Therapeutic Opportunity

Pharmacogenetics and pharmacogenomics of schizophrenia: a review of last decade of research

The schizophrenia risk gene ZNF804A influences the antipsychotic response of positive schizophrenia symptoms

Contact Info

Product

Resources

About

Effect of 5-HT _1A Receptor Gene Polymorphism on Negative and Depressive Symptom Response to Antipsychotic Treatment of Drug-Naive Psychotic Patients