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A review of genetic alterations in the serotonin pathway and their correlation with psychotic diseases and response to atypical antipsychotics

Schizophrenia Research, Volume 170, Issue 1, January 2016, Pages 18 - 29

Editorial Comment:
This paper summarizes information on genetic alterations of the serotonin pathway and how these are associated with schizophrenia and bipolar disorder phenotypes. Evidence is also reviewed regarding how specific gene polymorphisms may affect the efficacy of atypical antipsychotics in different ethnic groups as well as the susceptibility to develop weight gain and metabolic syndrome. The paper is in the form of a narrative but systematic review. Some finding have been replicated many times but others are inconsistent and controversial. The latter may reflect differences between studies in terms of laboratory methodology, medication dose, treatment duration and the ethnicity of subjects.  

Prof. Peter Haddad, University of Manchester, UK

Abstract

Serotonin is a neurotransmitter that plays a predominant role in mood regulation. The importance of the serotonin pathway in controlling behavior and mental status is well recognized. All the serotonin elements - serotonin receptors, serotonin transporter, tryptophan hydroxylase and monoamine oxidase proteins - can show alterations in terms of mRNA or protein levels and protein sequence, in schizophrenia and bipolar disorder. Additionally, when examining the genes sequences of all serotonin elements, several single nucleotide polymorphisms (SNPs) have been found to be more prevalent in schizophrenic or bipolar patients than in healthy individuals. Several of these alterations have been associated either with different phenotypes between patients and healthy individuals or with the response of psychiatric patients to the treatment with atypical antipsychotics. The complex pattern of genetic diversity within the serotonin pathway hampers efforts to identify the key variations contributing to an individual's susceptibility to the disease. In this review article, we summarize all genetic alterations found across the serotonin pathway, we provide information on whether and how they affect schizophrenia or bipolar disorder phenotypes, and, on the contribution of familial relationships on their detection frequencies. Furthermore, we provide evidence on whether and how specific gene polymorphisms affect the outcome of schizophrenic or bipolar patients of different ethnic groups, in response to treatment with atypical antipsychotics. All data are discussed thoroughly, providing prospective for future studies.

Keywords: Serotonin, Serotonin pathway, Atypical antipsychotics, Genetic alterations, SNPs, Review.

1. Introduction

Serotonin (or 5-hydroxytryptophan, 5-HT) is a neurotransmitter that regulates several functions, including dopamine release, cognitive function, memory, learning, vascular tone, appetite, coagulation, immune function, arousal, sexual desire (Pucadyil et al., 2005). Serotonin signaling in the brain bridges environmental stimulations to nuclear events through cAMP and CREB and activates the expression of many genes to produce proteins required for neuronal growth and long-lasting structural changes (Kandel, 2001). Serotonin signaling interacts, functionally, with dopamine signaling, as well as other neurotransmitters such as glutamate, acetylcholine, γ-aminobutiric acid (GABA).

In view of its important role in so many physiological processes, the serotonergic system has been implicated in the pathogenesis of psychiatric disorders, including the two major psychotic diseases, schizophrenia (SZ) and bipolar disorder (BD). SZ affects 1% of the general population. It is characterized by positive symptoms (delusions, hallucinations, disorganized thought, etc), negative symptoms (apathy, avolition, anhedonia, etc), and cognitive impairment (in working memory, sustained attention, etc) (Jones and McCreary, 2008). BD affects 1–4% of the population (Geddes and Miklowitz, 2013) and has four different subtypes (Phillips and Kupfer, 2013). It is characterized mainly by mania, hypomania, depression, rapid speech, increased locomotion and cognitive dysfunction (Craddock and Sklar, 2013 and Hayden and Nurnberger, 2006). Several dysfunctions of the serotonin pathway occurring at the molecular-signaling-neuronal firing level in several brain regions have been correlated with both diseases. Furthermore, several genome wide association studies and/or copy number variation studies have investigated correlations between individual genes and psycho-pathogenesis and provided strong support for shared genetic risk across the diseases (Hayden and Nurnberger, 2006, Craddock and Sklar, 2013, and Giusti-Rodríguez and Sullivan, 2013).

The dysfunction of serotonin pathway was potentially linked with SZ phenotype, when lysergic acid diethylamide (LSD), mescalin and psilocybin were observed that could cause various symptoms resembling SZ (such as hallucinations, altered cognition, delusions, paranoia) in healthy individuals (reviewed by Abi-Dargham, 2007). At the same time, particular atypical antipsychotic drugs (AAPs) were shown to modulate the levels of extracellular serotonin which affects their efficiency in improving positive and negative symptoms or cognition (Meltzer et al., 2003). Later on, the AAPs were found that had superior antipsychotic properties compared to typical antipsychotic drugs (APDs), a characteristic that was attributed mainly to their higher affinities for the serotonin receptor type 2 (5-HT2A) than for dopamine D2 receptors (Richtand et al., 2008). Thus, 5-HT2A receptors were firstly proposed to be involved in the pathophysiology of SZ and mood disorders (Serretti et al., 2007). The polymorphisms of the 5-HT2A gene became subject of many studies, some of which showed functional consequences for patients (Williams et al, 1996, Abdolmaleky et al, 2004, and Ghadirivasfi et al, 2011). Meanwhile, numerous studies followed, which tested for associations between the polymorphisms of all serotonin elements (genes and proteins) and the major psychotic disorders.

In this review article, we summarize all genetic alterations found across the serotonin pathway (mRNA and protein levels, protein sequences and the single nucleotide polymorphisms, SNPs). We present data on whether and how these alterations correlate with the development and symptomatology of SZ or BD and, we deduce information from family studies on the contribution of familial relationships on the preferential transmission of these genetic variations. Finally, we provide evidence on whether and how specific gene polymorphisms affect the outcome of the psychotic disease, in response to treatment with AAPs, of schizophrenic or bipolar patients, of different ethnic groups. All data are discussed thoroughly, providing prospective for future studies.

2. Methods

PubMed and MEDLINE constituted the search engines for this review. The search terms consisted of “serotonin receptors and schizophrenia”, “serotonin receptors and bipolar”, “serotonin receptors and SNP”, “antipsychotics and SNP”, “SERT and schizophrenia”, “SERT and bipolar”, “TPH and schizophrenia”, “TPH and bipolar”, “MAO and schizophrenia”, “MAO and bipolar”, “SERT and SNP”, “TPH and SNP”, “MAO and SNP”, “HTR and SNP”, “5-HT and SNP”. Review papers, case control studies, family studies, meta-analysis studies, written in English language and published in peer-reviewed journals, were reviewed. The most comprehensive review papers were selected and included in the study.

3. Serotonergic elements

Serotonin is synthesized from tryptophan, which is firstly converted to 5-hydroxy-L-tryptophan (5-HTP) through the action of the enzymes tryptophan hydroxylase 1 (TPH1) and tryptophan hydroxylase 2 (TPH2). Then, 5-HTP is converted to serotonin, through the action of the enzyme L-amino acid decarboxylase (Jonnakuty and Gragnoli, 2008). In the central nervous system, serotonin is stored in secretory granules at the nerve terminals (presynaptic neurons). Environmental factors stimulate serotonin release into synaptic clefts where it binds on seven types of serotonin receptors, classified as 5-HT1A-F, 5-HT2A-C, 5-HT3A-E, 5-HT4, 5-HT5, 5-HT6, 5-HT7. Serotonin receptors can have further isoforms, due to alternative splicing, or, gene editing, as in the case of 5-HT2C receptor gene (HTR2C) (Hannon and Hoyer, 2008 and Bockaert et al, 2006). Serotonin receptors are all G protein coupled proteins, with seven transmembrane domains connected by three intracellular and three extracellular loops (Bockaert et al., 2006). 5-HT1A, 5-HT1B, 5-HT1D, 5-HT2C, 5-HT4, 5-HT7 receptors form dimmers while, 5-HT3 is an ionotropic receptor (ligand gated ion channel) and it is permeable to calcium, potassium, sodium and lithium (Bockaert et al., 2006). In synapses, excess serotonin binds to the serotonin transporter (SERT or 5-HTT) that transports the neurotransmitter to presynaptic terminals, where it is metabolized to 5-hydroxyindole acetic acid by the enzymes monoamine oxidase A and B (MAOA and MAOB) (Jonnakuty and Gragnoli, 2008). In the periphery, serotonin, mainly, is synthesized and stored in enterochromaffin cells which are located in the gastrointestinal tract. Once released, serotonin is taken by platelets, through its binding to SERT, and is stored in dense granules (Jonnakuty and Gragnoli, 2008).

Serotonergic neurons are found primarily in raphe nuclei and project to almost all brain areas. Serotonergic neurons which originate from dorsal raphe nuclei innervate the cerebral cortex, striatum, thalamus and midbrain dopaminergic nuclei, while those neurons which originate from median raphe nuclei innervate the septum, hippocampus, hypothalamus and other limbic areas (Amato, 2015). Additionally, they inhibit the basal activity of ventral tegmental area and substantia nigra through the regulation of dopamine, an effect mainly attributed to 5-HT2A function (Abi-Dargham, 2007). Apparently, every neuron in the brain may be affected by the serotonergic system, making difficult to determine its exact mechanism of action in the brain.

4. Genetic alterations in the serotonin pathway in SZ and BD

The molecular alterations of the serotonin elements in SZ and BD patients can result to altered function of the serotonin pathway in diseased persons compared to healthy individuals. These alterations have been studied with molecular imaging and postmortem methods, conducted in living individuals or in postmortem brain tissues, respectively. The applied methodology has consisted of positron emission tomography (PET) or, the use of selected radiolabeled ligands, acting as receptor agonists. Relative data, which are summarized in Table 1, have provided evidence on the transcription of the serotonin pathway genes, at various brain areas of patients and controls (as it has been revealed by measuring the respective mRNA levels) and, on the binding affinities for serotonin of the serotonin pathway proteins.

Table 1 Alterations of the serotonin pathway elements detected by imaging or postmortem studies in SZ or BP patients, in various human brain areas.

Element (study) Disease Alterations Brain areas References
HTR1A
 (PM) SZ ↑ Binding Prefrontal cortex, cingulate/motor cortices, dentate gyrus Selvaraj et al. (2014), Abi-Dargham (2007), Joyce et al. (1993)
~ Binding Dentate gyrus, amygdala, cingulum, motor cortex, occipital cortex, putamen, caudate, nucleus accumbens Scarr et al. (2004), Joyce et al. (1993), Hashimoto et al. (1991)
~ mRNA Dorsolateral prefrontal cortex, hippocampus, etc López-Figueroa et al. (2004), Burnet et al. (1996)
↓ mRNA Dentate gyrus López-Figueroa et al. (2004)
BP ↓ mRNA Dorsolateral prefrontal cortex López-Figueroa et al. (2004)
 (PET) SZ ↑ Binding Left and right medial temporal cortex Tauscher et al. (2002)
↓ Binding Amygdala Yasuno et al. (2004)
~ Binding Several brain regions Selvaraj et al. (2014)
BP ↑ Binding Raphe nuclei, hippocampus, dorsolateral prefrontal cortex, amygdala, etc. Sullivan et al. (2009)
↓ Binding Anterior cingulate cortex, anterior insula, left parietal cortex, mesiotemporal cortices Nugent et al. (2013), Drevets et al. (2007)
HTR1B
 (PM) BP, SZ ↑ mRNA Hippocampus López-Figueroa et al. (2004)
SZ ~ mRNA Dorsolateral prefrontal cortex López-Figueroa et al. (2004)
HTR1D
 (PM) SZ ~ Binding Dorsolateral prefrontal cortex, hippocampus Dean et al. (2006), Scarr et al. (2004)
HTR1F
 (PM) SZ ↓ Binding Hippocampus Scarr et al. (2004)
~ Binding Prefrontal cortex Dean et al. (2006)
HTR2A
 (PM) SZ ↓ Binding Prefrontal cortex, frontal lobe, hippocampus Selvaraj et al. (2014), Abdolmaleky et al. (2011), Scarr et al. (2004), Dean et al. (1999a)
↑ Binding Frontal cortex, striatum including the caudate Selvaraj et al. (2014), Muguruza et al. (2013)
~ mRNA Dorsolateral prefrontal cortex
SZ, BP ↓ mRNA Hippocampus López-Figueroa et al. (2004)
BP ↓ mRNA Dorsolateral prefrontal cortex López-Figueroa et al. (2004)
López-Figueroa et al. (2004)
HTR2C
 (PM) SZ ↓ mRNA Prefrontal cortex Castensson et al. (2003)
HTR4
 (PM) SZ ~ Binding Prefrontal cortex, hippocampus Scarr et al. (2004), Dean et al. (1999b)
HTR6
 (PM) SZ ↓ mRNA Hippocampus East et al. (2002a)
~ mRNA Dorsolateral prefrontal cortex East et al. (2002a)
~ Binding Dorsolateral prefrontal cortex East et al. (2002b)
HTR7
 (PM) SZ ↓ mRNA Prefrontal cortex East et al. (2002a)
~ mRNA Hippocampus East et al. (2002a)
↓ Binding Prefrontal cortex (BA9) Dean et al. (2006)
SERT
 (PM) SZ ↓ mRNA Frontal lobe Abdolmaleky et al. (2014)
↓ Affinity Hippocampus Selvaraj et al. (2014), Naylor et al. (1996)
↓ Binding Prefrontal cortex Selvaraj et al. (2014)
~ Binding Prefrontal cortex, caudate nucleus Selvaraj et al. (2014), Dean et al. (1995)
TPH2
 (PM) BP ↑ mRNA Dorsolateral prefrontal cortex De Luca et al. (2005)
MAOB
 (PM) SZ ↑ mRNA Prefrontal cortex Castensson et al. (2003)

Abbreviations: PM, post-mortem; PET, position emission tomography. Symbols: ↑ increased; ↓ decreased; ~ no difference/no change.

Data from Table 1 show that the HTR1A, HTR2A, HTR2C, HTR6, HTR7 and SERT mRNA levels are decreased in psychotic patients, of both diseases, compared to control individuals, an observation that is indicative of decreased transcription of the respective genes. Moreover, mRNA levels of HTR1B in SZ and BD patients, TPH in BD patients and MAO in SZ patients are higher than in the control groups, indicating increased transcription of the respective genes in the diseased groups. The binding affinity of the receptor 5-HT7 for serotonin is decreased in the prefrontal cortex of SZ patients compared to healthy controls, possibly contributing to the observed hypo-activity of frontal cortex in SZ (Minzenberg et al., 2009).

However, the results of most studies are inconsistent and controversial. The observed inconsistencies could reflect either actual differences between various sample populations, or limitations of the applied methodology. Postmortem tissues are subjected to changes due to pH variation, age of the deceased or, postmortem interval (Burnet et al., 1996). Alternatively, differences in binding activities could be the result of low specificity of the radiolabeled ligand used, for example, [3H]8-0H-DPAT binds to both 5-HT1A and 5-HT7 receptors, therefore the observed differences could reflect changes of both receptors (Selvaraj et al., 2014).

On the other hand, the genetic polymorphisms along the serotonin pathway, in SZ and BD patients, show greater diversity than the functional molecular alterations of the serotonin elements, irrespectively whether they result, or not, to different phenotypes between SZ and BD patients, and between patients and healthy controls. This diversity makes the elucidation of the genetic etiology of the psychotic diseases a difficult task. Currently, 153 polymorphisms have been identified within the genes encoding for the serotonin receptors, SERT, TPH and MAO proteins in SZ and BD patients. Relative data are summarized in Table 2.

Table 2 Polymorphisms of the serotonin elements' genes identified in BP or SZ patients and their effects on disease or on molecular phenotypes.

Gene polymorphisms (genotype) Disease Effects References
HTR1A
 − 1019C/G or rs6295 (G allele) BP, SZ ↑ Frequency; ↑ Transcription in healthy individuals Gatt et al. (2015), Kishi et al. (2013), Gu et al. (2013a), Sullivan et al. (2009), Huang et al. (2004), Lemonde et al. (2003)
BP, SZ No effect; ↑ Transcription Kim et al. (2014), Kim and Yoon (2011), Huang et al. (2004)
 Ile28Val BP, SZ No effect Erdmann et al. (1995)
 rs878567C/T BP ↑ Frequency Kishi et al. (2011)
 rs10042486 (C/TC) SZ ↓ Frequency Crisafulli et al. (2012)
 rs10042486, rs6295, rs878567, rs1364043, rs1423691 SZ No effect on PANSS Takekita et al. (2015), Crisafulli et al. (2012)
 Pro16Leu, 294G/A, 549C/T, Gly272Asp SZ No effect Kawanishi et al. (1998)
 rs1423691 (T/C), rs878567(T/C), rs6295 (G/C) SZ No effect on suicide behavior Serretti et al. (2007)
HTR1B
 Phe124Cys BP, SZ No effect; ↓ Affinity of Cys variant for 5-HT Mundo et al. (2001), Brüss et al. (2005)
 G861C or Val287Val BP, SZ No effect Mundo et al. (2001)
 C129T or Ser43Ser and 3 promoter SNPs SZ No effect Duan et al. (2005)
HTR1F
 rs1503433 SZ Effect on age of onset Gilabert-Juan et al. (2011)
 − 78C/T, 528C/T, 783T/A BP, SZ No effect Shimron-Abarbanell et al. (1996)
HTR2A
 T102C or Ser34Ser (C/CC) SZ ↑ Frequency; ↑ mRNA; ~ Protein Abdolmaleky et al. (2011), Golimbet et al. (2007), Abdolmaleky et al. (2004), Zhang et al. (2004), Araga and Narasu (2002), Kouzmenko et al. (1997), Erdmann et al. (1996), Inayama et al. (1996), Williams et al. (1996)
 (C allele) BP No effect; ↑ mRNA; ~ Protein Massat et al. (2000), Tut et al. (2000), Arranz et al. (1997), Mahieu et al. (1997)
 (T/TT) SZ ↑ Frequency, earlier age of onset; ↑ mRNA; ~ Protein Peñas-Lledó et al. (2007), Pae et al. (2005), Baritaki et al. (2004)
 (Both alleles) SZ No effect Malhotra et al. (1996a)
 (CC) SZ ↓ Memory Alfimova et al. (2010)
No effect on positive, negative, affective symptoms Serretti et al. (2000)
 − 1438A/G (G allele) SZ ↑ Frequency; ↑ promoter methylation with ↓ mRNA (Gu et al, 2013a) and (Gu et al, 2013b), Tee et al. (2010), Peñas-Lledó et al. (2007), Sáiz et al. (2007)
BP No effect (Gu et al, 2013a) and (Gu et al, 2013b), Ohara et al. (1998a)
SZ No effect Kim and Yoon (2011), Mata et al. (2004), Ohara et al. (1999)
 His452Tyr or 1354C/T SZ Affective symptoms; ~ positive/negative symptoms Fanous et al. (2004)
 His452Tyr, 516C/T BP ↑ Frequency Ranade et al. (2003)
 Thr25Asn or 74C/A, His452Tyr or 1354C/T, 516C/T, 102C/T BP, SZ No effect Mata et al. (2004), Arranz et al. (1997), Gutiérrez et al. (1997), Erdmann et al. (1996)
HTR2C/HTR1C
 Cys23Ser or rs6318 (Ser variant) BP ↑ Frequency in females, earlier age of onset Massat et al. (2007), Gutiérrez et al. (1996)
BP, SZ No effect Lerer et al. (2001), Vincent et al. (1999), Sodhi et al. (1995)
 HTR2C-INI SZ Exclusively in frontal cortex Sodhi et al. (2001)
 HTR2C-VGV SZ ↓ Levels in dorsolateral prefrontal cortex Dracheva et al. (2003)
 HTR2C-VSV BP SZ ↑ Levels in dorsolateral prefrontal cortex (suicide) Dracheva et al. (2008)
 − 759C/T SZ No effect; effect on mRNA Ellingrod et al. (2004)
 rs547536(A/T), rs2192372(G/A), rs6318(G/C), rs2428707(G/A), rs4272555(T/C), rs1801412(T/G) SZ No effect on suicide Serretti et al. (2007)
HTR3A
 C178T or Pro16Ser (T allele) BP ↑ Frequency Niesler et al. (2001a)
BP No effect Hammer et al. (2012)
 35 SNPs BP, SZ No effect Nothdurfter et al. (2012), Niesler et al. (2001b)
HTR3B
 Tyr129Ser or rs1176744 (Tyr variant) BP ↑ Frequency; ↑ 5-HT response; ↑ Channel opening time; Hammer et al. (2012), Krzywkowski et al. (2008)
↓ Channel deactivation time
 rs3831455 BP ↓ Frequency; Regulation of mRNA translation Frank et al. (2004)
BP No effect Hammer et al. (2012)
HTR3C
 C523A or Asn163Lys (AA), G1248Cor Gly405Ala (GG) SZ Effect on negative and total PANNS score at admission Schuhmacher et al. (2009)
HTR3D
 A380G or His52Arg (Heterozygotes) SZ ↑ Frequency in females Lennertz et al. (2010)
HTR3E
 A450G orThr86Ala (GG) SZ ↑ Age; ↑ cognitive function Lennertz et al. (2010)
HTR4
 SVRSNP2, SVRSNP3, SVRSNP4 (A, T alleles) BP ↑ Frequency in BP Ohtsuki et al. (2002)
 rs14226361, rs6873382 (T,G all.) SZ Risk for suicide attempts Polsinelli et al. (2013)
 15 SNPs No effect Hirata et al. (2010), Suzuki et al. (2003)
HTR5
 C43T or Pro15Ser (Ser variant) SZ ↑ Frequency Iwata et al. (2001)
 − 19G/C (G allele) SZ, BP ↓ Frequency Birkett et al. (2000)
 19G/C, A12T SZ, BP No effect Arias et al. (2001), Birkett et al. (2000)
HTR6
 267C/T (T allele) SZ ↑ Frequency Tsai et al. (1999)
BP, SZ No effect Fukuo et al. (2010), Dubertret et al. (2004a), Vogt et al. (2000), Shinkai et al. (1999)
HTR7
 rs3808932, rs12412496 (A alleles) SZ ↑ Frequency Ikeda et al. (2006a)
SERT
 5-HTTVNTR (allele 10) SZ ↑ Frequency Allen et al. (2008), Shi et al. (2008), Fan and Sklar (2005)
 5-HTTVNTR (allele 12) SZ ↑ Frequency in paranoid SZ Kaiser et al. (2001)
 (allele 9) SZ ↑ Frequency in residual SZ Kaiser et al. (2001)
 5-HTTLPR (LL) BP ↑ Hallucinations and thought disturbance Malhotra et al. (1998)
Kunugi et al. (1997), Collier et al. (1996a), Kunugi et al. (1996)
Bellivier et al. (2002), Rotondo et al. (2002), Bellivier et al. (1998a), Collier et al. (1996b)
 5-HTTVNTR (alleles 12/9) BP ↑ Frequency
 5-HTTLPR (S/SS) ↑ Frequency, earlier onset of disease
 rs3794808 SZ ↑ Delusions Sun et al. (2012)
 rs4583306 SZ ↑ Depression Sun et al. (2012)
 5-HTTVNTR, 5-HTTLPR SZ No effect Vázquez-Bourgon et al. (2010), Lee et al. (2009), Sáiz et al. (2007), Ikeda et al. (2006b), Pae et al. (2005), Tsai et al. (2000), Malhotra et al. (1998), Collier et al. (1996a)
 5-HTTVNTR, 5-HTTLPR BP No effect Seifuddin et al. (2012), Ikeda et al. (2006b), Serretti et al. (2002a), Bellivier et al. (1998a), Furlong et al. (1998a), Hoehe et al. (1998), Ohara et al. (1998b), Bellivier et al. (1997), Stöber et al. (1996)
 rs2054847, rs140700, rs2020942, rs6352 or Asn605Lys and 11 more SNPs SZ No effect Lin et al. (2009), Ikeda et al. (2006b)
TPH1
 A218C or rs1800532 (A/AA) BP ↑ Frequency Chen et al. (2008), Bellivier et al. (1998b)
BP, SZ No effect Kim and Yoon (2011), Shiroiwa et al. (2010), Watanabe et al. (2007), Lai et al. (2005), Serretti et al. (2002b), Souery et al. (2001), Kunugi et al. (1999), Furlong et al. (1998b)
 A218C, rs7933505 SZ ↑ Frequency Saetre et al. (2010), Zaboli et al. (2006)
 5 SNPs SZ No effect Watanabe et al. (2007)
TPH2
 A473T or rs11178997, rs7954758, rs11178998(minor alleles) BP ↑ Frequency Cichon et al. (2008)
 Pro206Ser or rs17110563 (Heterozygotes) BP ↑ Frequency Cichon et al. (2008)
 rs4131348 (CC genotype) BP ↓ Frequency Van Den Bogaert et al. (2006)
 rs4131347 or -8396C/G BP No effect Mann et al. (2008), Cichon et al. (2008)
 15 SNPs SZ No effect Kim and Yoon (2011), Shiroiwa et al. (2010), Tee et al. (2010)
MAOA
 941T/G (T allele) SZ, BP ↑ Frequency Qiu et al. (2009), Müller et al. (2007),
 VNTR SZ No effect Norton et al. (2002)
BP, SZ No effect Seifuddin et al. (2012), Qiu et al. (2009), Müller et al. (2007), Jönsson et al. (2003), Norton et al. (2002), Serretti et al. (2002b), Syagailo et al. (2001)
 1460T/C SZ No effect Qiu et al. (2009)
 CA repeat intron 2 (α5, α6 alleles) BP ↑ Frequency Fan et al. (2010), Preisig et al. (2000), Rubinsztein et al. (1996)
 CA repeat intron 2 (α2 allele) ↓ Frequency Fan et al. (2010), Preisig et al. (2000), Rubinsztein et al. (1996)

Symbols used: ↑ increased or improved; ↓ decreased or worsen; ~ no difference/no change.

The development and symptomatology of the major psychotic diseases has been correlated with 38 polymorphisms (25%), while, only four of them (4/38, 16%, 2.6% of all polymorphisms), the − 1019C/G of HTR1A, the T102C of HTR2A, the tyrosine variant of the Tyr129Ser and the rs3831455 of HTR3B, have resulted in different molecular phenotypes among patients (Table 2). Two other polymorphisms, the Phe124Cys of HTR1B and the -759C/T of HTR2C/HTR1C, do not correlate with any factors related to the psychotic disease, although the genetic variants have resulted in different molecular phenotypes (the Phe124Cys of HTR1B results to different affinities of receptor variants for serotonin and the -759C/T of HTR2C/HTR1C results to different mRNA levels, respectively). Obviously, most of the studied polymorphisms do not correlate significantly with the psychotic phenotype (115/153, 75%), neither result to different molecular phenotypes (147/153, 96%).

Data from Table 2 show that 19 polymorphisms are specific for SZ and 15 polymorphisms are specific for BD. The polymorphisms, which are specifically associated with SZ, but not BD, may play a major role in the pathophysiology of psychosis, while those associated with BD, but not SZ, may play a major role in the pathophysiology of mood dysregulation, as suggested previously (Ivleva et al., 2010).

Eight polymorphisms within genes encoding for the serotonin pathway proteins are shared in common between SZ and BD, the following: 1019C/G of HTR1A, the 1354C/T of HTR2A, the HTR2CVSV of HTR2C, the 19G/C of HTR5, the 5-HTTVNTR and 5-HTTLRP of SERT, the A218C of TPH1 and the 941T/G of MAOA (Table 2). It is worth mentioning that four out of these polymorphisms are observed across various other psychiatric disorders, beyond SZ and BD, such as major depressive disorder and attention deficit hyperactivity disorder (Gatt et al., 2015). These four polymorphisms are the 5-HTTLPR specific allele polymorphism and the SLC6A4 STin2 VNTR in the SERT gene, the C1019G of HTR1A and the A218C of the TPH1 gene. The overall conclusion of these studies is that there is some degree of genetic overlap, among SZ and BD, as well as other specific psychotic disorders, which indicates the existence of shared molecular mechanisms between the diseases.

Remarkably, data for 18 polymorphisms, lying across the whole serotonin pathway, are contradictory since many studies report that they correlate with SZ or BD, while other studies report lack of correlation of these SNPs with the psychotic diseases. Most of the polymorphisms for which the available data are heterogeneous are found within serotonin receptor genes' (two SNPs of HTR1A, four of HTR2A, and one SNP for each one of HTR2C, HTR3A, HTR3B, HTR4, HTR5 and HTR6 respectively), while SERT gene has three such SNPs and TPH1, TPH2 and MAOA genes have one such SNP each one, respectively. The observed heterogeneity could be attributed to factors such as, bias in results extracted from case–control studies and meta-analyses, due to age and gender differences between studied groups, small sample study population, different ethnicities of sample subjects or environmental factors.

4.1. Family studies

Family studies have been conducted in order to identify those genetic alterations that are mainly involved in the psychotic pathogenesis, minimizing the influence of ethnicity or environmental factors. Three SNPs of the 5-HT pathway, the C1354T of HTR2A and the SVRSNP1, SVRSNP4 of HTR4, showed preferential transmission in BD (Ranade et al, 2003, Ohtsuki et al, 2002, Hranilovic et al, 2000, and Kirov et al, 1999) but not in SZ patients (Hirata et al, 2010, Fanous et al, 2004, and Ohtsuki et al, 2002). Moreover, one polymorphism (the T allele of A12T SNP of HTR5) was found to be transmitted specifically to SZ individuals from their parents (Dubertret et al., 2004b). Finally, only one SNP, the 5-HTTVNTR of the SERT gene, was transmitted to both SZ and BD patients (Dubertret et al., 2004a) suggesting a putative role of this polymorphism in preferential transmission of psychosis.

5. Polymorphisms of the serotonin pathway genes and atypical antipsychotics

Serotonin receptors are major pharmacological targets of typical and atypical APDs. AAPs are characterized by a notable binding profile towards serotonin receptor subtypes, which contributes to their superior efficacy and tolerability during treatment compared to the typical APDs. Their pharmacological action includes the low risk of producing extrapyramidal side effects (which is one of the defining characteristics of an AAP drug), the lack of elevation in plasma prolactin levels (with risperidone and 9-hydroxyrisperidone being exceptions) and the ability to improve some domains of cognition in patients with SZ. The most commonly used AAPs are agonists or antagonists of serotonin receptors. The binding characteristics between AAPs and serotonin receptors are strongly associated with the response to treatment of SZ and BD patients.

The polymorphisms of the human serotonin pathway genes that have been studied whether and how affect clinical symptoms of SZ and BD patients, of different ethnicities, in response to treatment with APDs are presented in Table 3. Data for receptors focus on those receptor subtypes that are expressed in the human brain and for which clinically relevant APDs are available. Data from Table 3 show that all studied polymorphisms (54 SNPs) have been tested in patients with SZ, while only two of them have been studied in BD patients. Moreover, most polymorphisms have been studied on Caucasian individuals (36/54, 67%), followed by Asians (30/54, 56%) and African Americans (5/54, 9%). Furthermore, most studies have been conducted on patients treated with AAPs, and the most frequently administered drugs have been risperidone and clozapine. The most frequently evaluated parameters have been PANSS and BPRS, followed by GAS, SAPS and SANS, and the most conclusive results have concerned the onset of metabolic syndrome.

Table 3 Polymorphisms of the human serotonin elements genes in SZ or BP patients, of different ethnicities, studied for their effects on clinical symptoms (disease parameters) in response to treatment with APDs and the statistical impact of their correlation.

Gene Polymorphisms (genotype) Disease Ethnicity Antipsychotic drugsa Disease parameters Impactb References
HTR1A rs878567 (TT) SZ As Several AAPs GCI, ↑ response to treatment Cor Gupta et al. (2012)
− 1019C/G (CC) SZ As, Cau Several APDs PANSS, ↑ improvement Cor Mössner et al. (2009), Wang et al. (2008), Reynolds et al. (2006)
(GG) SZ Cau Clozapine PANSS, ↑ improvement Cor Bosia et al. (2015)
− 1019C/G SZ As Olanzapine SAPS, SANS Not Sumiyoshi et al. (2010)
rs1364043 (T allele) SZ As Perospirone, Aripiprazole PANSS, negative score change Cor Takekita et al. (2015)
rs10042486 (TT) SZ As Several AAPs PANSS, ↑ response Cor Crisafulli et al. (2012)
HTR2A T102C (CC, C allele) SZ As Risperidone CGI, PANSS, ↑ response Cor Kim et al. (2008), Lane et al. (2002)
SZ Cau Clozapine GAS, ↓ response Cor Arranz et al. (2000a), Arranz et al. (1998a)
(CC) SZ As Risperidone BMI, ↓ weight gain Cor Lane et al. (2006)
Af-Am Clozapine GAS scale, BPRS Not Masellis et al. (1998), Malhotra et al. (1996b), Nöthen et al. (1995)
T102C (TT), − 1438 A/G (AA) and T102C (T allele), − 1438 A/G SZ Cau, Olanzapine SANS, BMI, ↑ response, ↑ weight gain (T allele) Cor Ujike et al. (2008), Ellingrod et al. (2003), Ellingrod et al. (2002)
T102C (CC), − 1438 A/G (GG) SZ As Aripiprazole PANSS, ↓ response Chen et al. (2009)
− 1438 A/G (G allele) SZ Cau Clozapine GAS, ↓ response Arranz et al. (1998b)
His452Tyr (Tyr allele) SZ Af-Am, Cau Clozapine GAS, BPRS, PANSS, ↓ response Cor Arranz et al. (2000a), Arranz et al. (1998a), Masellis et al. (1998), Arranz et al. (1996)
SZ Af-Am, Cau Risperidone PANSS Cor Fijal et al. (2009)
SZ Cau Clozapine GAS Not Nöthen et al. (1995)
His452Tyr, Thr25Asn and 516C/T SZ Cau Olanzapine BPRS, SANS Not Ellingrod et al. (2002)
HTR2C − 759C/T or rs3813929 (T allele) SZ As Risperidone, Clozapine, Chlorpromazine PANSS, ↓ response Cor Reynolds et al. (2005)
SZ Af-Am, Olanzapine, Clozapine, BMI, ↓ weigh gain Cor Ryu et al. (2007), Lane et al. (2006), Reynolds et al. (2002)
As, Cau Risperidone Lane et al. (2006), Ellingrod et al. (2005), Templeman et al. (2005), Miller et al. (2005), Reynolds et al. (2003), Reynolds et al. (2002)
SZ Cau Olanzapine BPRS, SANS Not Ellingrod et al. (2002)
SZ As, Cau Risperidone, Clozapine, Olanzapine, Haloperidol BMI, Metabolic Syndrome Not Del Castillo et al. (2013), Gregoor et al. (2011), Yevtushenko et al. (2008), De Luca et al. (2007), Theisen et al. (2004), Basile et al. (2002), Tsai et al. (2002)
Cys23Ser (Ser allele) SZ Cau Clozapine GAS, ↑ response Cor Arranz et al. (2000a), Sodhi et al. (1995)
SZ As Olanzapine BMI, ↑ weight gain Cor Ujike et al. (2008)
SZ Af-Am, Cau Clozapine, Olanzapine, Risperidone PANSS, GAS, BMI Not Fijal et al. (2009), De Luca et al. (2007), Ellingrod et al. (2002), Schumacher et al. (2000), Rietschel et al. (1997)
rs498207 (AA, A allele) SZ Cau Several APs BMI. ↑ weight gain Cor Opgen-Rhein et al. (2010)
− 697G/C (G allele), rs1414334 (C allele), c.1–142,948(GT)n SZ Cau Clozapine, Risperidone, Olanzapine Metabolic syndrome Cor Mulder et al. (2009)Mulder et al. (2007a), Mulder et al. (2007b)
rs498177 SZ As Clozapine Metabolic syndrome Cor Bai et al. (2011)
rs521018, rs2192371, rs12833104, rs5988072 SZ As Clozapine Metabolic syndrome Not Bai et al. (2011)
HTR3A 178C/T or rs1062613 (T allele) SZ As, Cau Clozapine, Risperidone, Haloperidol BPRS, PANSS, ↑ response Cor Rajkumar et al. (2012), Souza et al. (2010), Schuhmacher et al. (2009)
178C/T or rs1062613 (TT) SZ As APDs Requirement of ↑ dose of APDs Cor Ji et al. (2008a)
178C/T, 1596A/G SZ Cau Clozapine GAS Not Gutiérrez et al. (2002)
rs2276302A/G SZ As Clozapine BPRS, ↑ response Cor Rajkumar et al. (2012)
HTR3B Tyr129Ser or rs1176744 (Ser allele) SZ As Several AAPs GCI, ↓ response Cor Gupta et al. (2012)
SZ Cau Haloperidol, Risperidone PANSS Not Schuhmacher et al. (2009)
rs3831455 SZ As APDs ↑ Frequency in treatment resistant SZ Cor Ji et al. (2008b)
HTR3C Asn163Lys SZ Cau Haloperidol, Risperidone PANSS Not Schuhmacher et al. (2009)
HTR3D His52Arg SZ Cau Haloperidol, Risperidone PANSS Not Schuhmacher et al. (2009)
HTR3E A450G or Thr86Ala (GG) SZ Cau Risperidone, Haloperidol PANSS, ↑ early response Cor Schuhmacher et al. (2009)
HTR4 rs2278392, rs3734119 SZ As Clozapine Treatment resistant SZ Not Ji et al. (2008a)
HTR5 A12T, 19G/C SZ, BP Cau Clozapine No effect Not Birkett et al. (2000)
HTR6 267C/T SZ As Risperidone PANSS, BMI, ↑ response Cor Lane et al. (2006), Lane et al. (2004)
SZ As Clozapine ↑ response Cor Yu et al. (1999)
SZ Af-Am Risperidone PANSS Not Fijal et al. (2009), Ikeda et al. (2008)
SZ As, Cau Clozapine BPRS, BMI Not Hong et al. (2001), Masellis et al. (2001)
HTR7 rs12412496 SZ As Risperidone PANNS Not Ikeda et al. (2008)
6 SNPs SZ As Risperidone BPRS Not Wei et al. (2009)
SERT 5-HTTLPR (L allele) SZ As Risperidone BPRS, ↑ response Cor Wang et al. (2007)
5-HTTLPR SZ As Clozapine BMI Not Hong et al. (2001)
5-HTTLPR, 5-HTTVNTR SZ As, Cau Several APS BPRS, SANS, SAPS, PANSS Not Vázquez-Bourgon et al. (2010), Lee et al. (2009), Dolžan et al. (2008), Wang et al. (2007), Kaiser et al. (2001), Arranz et al. (2000b), Tsai et al. (2000)
TPH1 A779C (CA) SZ Cau Typical APDs CGI, ↓ response Cor Anttila et al. (2007)
TPH2 11 SNPs SZ Cau Several AAPs PANSS scale Not Schuhmacher et al. (2012)

a Data for typical and atypical APDs are shown, since many relative studies have reported results on both types of drugs.

b Impact: Cor: the studied polymorphism and disease parameters are significantly correlated; Not: the studied polymorphism and disease parameters are not significantly correlated.

Abbreviations: Af-Am: African-American, As: Asians, AAPS: atypical antipsychotics, APDs: antipsychotic drugs, BMI: body mass index, BPRS: brief psychiatric rating scale, Cau: Caucasians, CGI: clinical global impressions, GAS: global assessment scale, PANSS: positive and negative syndrome scale, SANS: scale for assessment of negative symptoms, SAPS: scale for assessment of positive symptoms. SZF: schizophreniform, *PE: first episode neuro-affective disorder.

Symbols: ↑ increased; ↓ decreased; ~ no difference/no change.

Data show that 23 polymorphisms (23/56, 43%) have been significantly correlated (significant statistical correlation for p < 0.05) with clinical improvement of the disease symptomatology, following pharmacological treatment with particular APDs. On the other hand, 41 polymorphisms (41/56, 73%) have not been correlated with the treatment outcome, or the development of adverse effects, in response to administration of particular APDs. The discrepancies observed between studies in relation to specific polymorphisms and responses to certain APDs, may be attributed to different doses, varying durations of treatment or various ethnic populations studied.

Interestingly, and completely independently of clinical response and outcome, certain polymorphisms have been correlated with the efficiency of specific APDs towards serotonin receptor inhibition. More specifically, clozapine, quetiapine and risperidone showed increased antagonistic potency for Ile197Val (tenfold), Thr25Asn (four fold) and His452Tyr (three fold) receptor variants respectively, compared with the wild type receptor, whereas aripiprazole showed decreased potency for Thr25Asn (30 fold) variant receptor (Davies et al, 2011 and Davies et al, 2006). On the contrary, olanzapine and ziprasidone did not show altered potency for any of the three aforementioned variant receptors (Davies et al., 2006). In the same manner, clozapine and risperidone showed the same affinity for two 5-HT7 variant receptors (Thr92Lys and Pro279Leu) as for the wild type receptor (Brüss et al, 2005 and Kiel et al, 2003). These changes in drug potency were accompanied by small changes in the drug affinities (Ki) for the variant receptors with the exception of aripiprazole (Davies et al, 2011 and Davies et al, 2006). It should be mentioned that the 5-HT2A variants differ significantly in frequencies between Caucasians, African-Americans and Asians (Davies et al., 2011) which may explain differences in the efficiency of the aforementioned APDs worldwide.

In terms of metabolic syndrome induced by APDs, an SNP of HTR2C (rs498177) correlated with the development of metabolic syndrome following treatment with clozapine in Asian and Caucasian SZs (Bai et al, 2011 and De Luca et al, 2007). Moreover, three other SNPs of HTR2C (the C allele of -697G/C, the C allele of rs1414334 and the HTR2C:c.1-142948(GT)n 13 repeat (R) allele, and their combined haplotype) strongly correlated with metabolic syndrome or obesity development in response to clozapine, olanzapine and risperidone treatment in Caucasian patients with SZ (Mulder et al, 2009, Mulder et al, 2007a, and Mulder et al, 2007b).

6. Conclusions

The serotonergic system has a physiological predominant role, and, genetic alterations across the serotonin pathway have been studied as functional candidates in the pathophysiology and etiology of psychiatric disorders. The introduction of AAPs has provided strong evidence for association between the serotonin pathway and the development and symptomatology of SZ and BD. Postmortem and imaging studies on expression and binding of serotonin elements, in certain brain areas, have supported further this evidence. Important alterations in terms of mRNA and protein levels, or DNA and protein sequences (SNPs, isoforms) appear across the serotonin pathway in SZ and BD patients. In accordance with imaging methods, clinical studies have reported correlations between certain genetic variations and psychotic symptomatology. Interestingly, the patients' response to AAPs, such as clozapine, olanzapine, risperidone, in terms of PANSS, GAS, SAPS and SANS scores, as well as, weight gain and metabolic syndrome development, is significantly correlated to particular polymorphisms in HTR1A, HTR2A, HTR2C, HTR3A, HTR3B, HTR3E and SERT genes, respectively. It is worth mentioning that the exact mechanism on how the serotonin system and the respective genetic alterations are implicated in the pathogenesis of psychotic symptoms and in the response to pharmacotherapy is currently unclear. Moreover, it is not known whether any observed alterations result from a direct disruption of the serotonin pathway or are caused, indirectly, through its interaction with the equally important, dopamine neurotransmission system, or other systems. Therefore, further research is required in order to understand the roles of specific genetic variants, as risk factors, in SZ and BD and, their impact in the response of patients to the treatment with antipsychotic medication.

Contributors

MB reviewed the literature and wrote the manuscript; VAB designed the review, inspected writing and critically revised the manuscript; GR contributed to the literature review; PP, TV and VM provided opinions about clinical aspects of psychotic diseases and their treatment and critically read the paper.

Conflict of interest

The authors declare no conflict of interest.

Acknowledgments

This study has been funded by the European Regional Development Fund—ERDF (MIS: 380379) through the Operational Program “THESSALY, MAINLAND GREECE AND EPIRUS 2007–2013” of the National Strategic Reference Framework (NSRF 2007-2013).

References

  • Abdolmaleky et al., 2014 H.M. Abdolmaleky, S. Nohesara, M. Ghadirivasfi, A.W. Lambert, H. Ahmadkhaniha, S. Ozturk, et al. DNA hypermethylation of serotonin transporter gene promoter in drug naïve patients with schizophrenia. Schizophr. Res.. 2014;152(2–3):373-380
  • Abdolmaleky et al., 2011 H.M. Abdolmaleky, S. Yaqubi, P. Papageorgis, A.W. Lambert, S. Ozturk, V. Sivaraman, et al. Epigenetic dysregulation of HTR2A in the brain of patients with schizophrenia and bipolar disorder. Schizophr. Res.. 2011;129(2–3):183-190
  • Abdolmaleky et al., 2004 H.M. Abdolmaleky, S.V. Faraone, S.J. Glatt, M.T. Tsuang. Meta-analysis of association between the T102C polymorphism of the 5HT2a receptor gene and schizophrenia. Schizophr. Res.. 2004;67(1):53-62
  • Abi-Dargham, 2007 A. Abi-Dargham. Alterations of serotonin transmission in schizophrenia. Int. Rev. Neurobiol.. 2007;78:133-164
  • Alfimova et al., 2010 M.V. Alfimova, M.V. Monakhov, L.I. Abramova, S.A. Golubev, V.E. Golimbet. Polymorphism of serotonin receptor genes (5-HTR2A) and dysbindin (DTNBP1) and individual components of short-term verbal memory processes in schizophrenia. Neurosci. Behav. Physiol.. 2010;40(8):934-940
  • Allen et al., 2008 N.C. Allen, S. Bagade, M.B. McQueen, J.P. Ioannidis, F.K. Kavvoura, M.J. Khoury, et al. Systematic meta-analyses and field synopsis of genetic association studies in schizophrenia: the SzGene database. Nat. Genet.. 2008;40(7):827-834
  • Anttila et al., 2007 S. Anttila, O. Kampman, A. Illi, R. Rontu, T. Lehtimäki, E. Leinonen. Association between 5-HT2A, TPH1 and GNB3 genotypes and response to typical neuroleptics: a serotonergic approach. BMC Psychiatry. 2007;7:22
  • Araga and Narasu, 2002 U.S. Araga, M.L. Narasu. Association between the 102T/C polymorphism of serotonin-2A receptor gene and schizophrenia among south Indians. Mol. Psychiatry. 2002;7(6):540-541
  • Arias et al., 2001 B. Arias, D.A. Collier, C. Gastó, L. Pintor, B. Gutiérrez, V. Vallès, et al. Genetic variation in the 5-HT5A receptor gene in patients with bipolar disorder and major depression. Neurosci. Lett.. 2001;303(2):111-114
  • Arranz et al., 2000a M.J. Arranz, J. Munro, J. Birkett, A. Bolonna, D. Mancama, M. Sodhi, et al. Pharmacogenetic prediction of clozapine response. Lancet. 2000;355(9215):1615-1616
  • Arranz et al., 2000b M.J. Arranz, A.A. Bolonna, J. Munro, C.J. Curtis, D.A. Collier, R.W. Kerwin. The serotonin transporter and clozapine response. Mol. Psychiatry. 2000;5(2):124-125
  • Arranz et al., 1998a M.J. Arranz, J. Munro, P. Sham, G. Kirov, R.M. Murray, D.A. Collier, et al. Meta-analysis of studies on genetic variation in 5-HT2A receptors and clozapine response. Schizophr. Res.. 1998;32(2):93-99
  • Arranz et al., 1998b M.J. Arranz, J. Munro, M.J. Owen, G. Spurlock, P.C. Sham, J. Zhao, 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(1):61-66
  • Arranz et al., 1997 M.J. Arranz, J. Erdmann, G. Kirov, M. Rietschel, M. Sodhi, M. Albus, et al. 5-HT2A receptor and bipolar affective disorder: association studies in affected patients. Neurosci. Lett.. 1997;224(2):95-98
  • Arranz et al., 1996 M.J. Arranz, D.A. Collier, J. Munro, P. Sham, G. Kirov, M. Sodhi, et al. Analysis of a structural polymorphism in the 5-HT2A receptor and clinical response to clozapine. Neurosci. Lett.. 1996;217(2–3):177-178
  • Amato, 2015 D. Amato. Serotonin in antipsychotic drugs action. Behav. Brain Res.. 2015;277:125-135
  • Bai et al., 2011 Y.M. Bai, T.T. Chen, Y.J. Liou, C.J. Hong, S.J. Tsai. Association between HTR2C polymorphisms and metabolic syndrome in patients with schizophrenia treated with atypical antipsychotics. Schizophr. Res.. 2011;125(2–3):179-186
  • Baritaki et al., 2004 S. Baritaki, E. Rizos, A. Zafiropoulos, G. Soufla, K. Katsafouros, V. Gourvas, et al. Association between schizophrenia and DRD3 or HTR2 receptor gene variants. Eur. J. Hum. Genet.. 2004;12(7):535-541
  • Basile et al., 2002 V.S. Basile, M. Masellis, V. De Luca, H.Y. Meltzer, J.L. Kennedy. 759C/T genetic variation of 5HT(2C) receptor and clozapine-induced weight gain. Lancet. 2002;360(9347):1790-1791
  • Bellivier et al., 2002 F. Bellivier, M. Leroux, C. Henry, F. Rayah, F. Rouillon, J.L. Laplanche, et al. Serotonin transporter gene polymorphism influences age at onset in patients with bipolar affective disorder. Neurosci. Lett.. 2002;334(1):17-20
  • Bellivier et al., 1998a F. Bellivier, C. Henry, A. Szöke, F. Schürhoff, M. Nosten-Bertrand, J. Feingold, et al. Serotonin transporter gene polymorphisms in patients with unipolar or bipolar depression. Neurosci. Lett.. 1998;255(3):143-146
  • Bellivier et al., 1998b F. Bellivier, M. Leboyer, P. Courtet, C. Buresi, B. Beaufils, D. Samolyk, et al. Association between the tryptophan hydroxylase gene and manic-depressive illness. Arch. Gen. Psychiatry. 1998;55(1):33-37
  • Bellivier et al., 1997 F. Bellivier, J.L. Laplanche, M. Leboyer, J. Feingold, C. Bottos, J.F. Allilaire, et al. Serotonin transporter gene and manic depressive illness: an association study. Biol. Psychiatry. 1997;41(6):750-752
  • Birkett et al., 2000 J.T. Birkett, M.J. Arranz, J. Munro, S. Osbourn, R.W. Kerwin, D.A. Collier. Association analysis of the 5-HT5A gene in depression, psychosis and antipsychotic response. Neuroreport. 2000;11(9):2017-2020
  • Bockaert et al., 2006 J. Bockaert, S. Claeysen, C. Bécamel, A. Dumuis, P. Marin. Neuronal 5-HT metabotropic receptors: fine-tuning of their structure, signaling, and roles in synaptic modulation. Cell Tissue Res.. 2006;326(2):553-572
  • Bosia et al., 2015 M. Bosia, C. Lorenzi, A. Pirovano, C. Guglielmino, F. Cocchi, M. Spangaro, et al. COMT Val158Met and 5-HT1A-R − 1019 C/G polymorphisms: effects on the negative symptom response to clozapine. Pharmacogenomics. 2015;16(1):35-44
  • Brüss et al., 2005 M. Brüss, S. Kiel, H. Bönisch, A. Kostanian, M. Göthert. Decreased agonist, but not antagonist, binding to the naturally occurring Thr92Lys variant of the h5-HT7(a) receptor. Neurochem. Int.. 2005;47(3):196-203
  • Burnet et al., 1996 P.W. Burnet, S.L. Eastwood, P.J. Harrison. 5-HT1A and 5-HT2A receptor mRNAs and binding site densities are differentially altered in schizophrenia. Neuropsychopharmacology. 1996;15(5):442-455
  • Castensson et al., 2003 A. Castensson, L. Emilsson, R. Sundberg, E. Jazin. Decrease of serotonin receptor 2C in schizophrenia brains identified by high-resolution mRNA expression analysis. Biol. Psychiatry. 2003;54(11):1212-1221
  • Chen et al., 2009 S.F. Chen, Y.C. Shen, C.H. Chen. HTR2A A-1438G/T102C polymorphisms predict negative symptoms performance upon aripiprazole treatment in schizophrenic patients. Psychopharmacology. 2009;205(2):285-292
  • Chen et al., 2008 C. Chen, S.J. Glatt, M.T. Tsuang. The tryptophan hydroxylase gene influences risk for bipolar disorder but not major depressive disorder: results of meta-analyses. Bipolar Disord.. 2008;10(7):816-821
  • Cichon et al., 2008 S. Cichon, I. Winge, M. Mattheisen, A. Georgi, A. Karpushova, J. Freudenberg, et al. Brain-specific tryptophan hydroxylase 2 (TPH2): a functional Pro206Ser substitution and variation in the 5′-region are associated with bipolar affective disorder. Hum. Mol. Genet.. 2008;17(1):87-97
  • Collier et al., 1996a D.A. Collier, M.J. Arranz, P. Sham, S. Battersby, H. Vallada, P. Gill, et al. The serotonin transporter is a potential susceptibility factor for bipolar affective disorder. Neuroreport. 1996;7(10):1675-1679
  • Collier et al., 1996b D.A. Collier, G. Stöber, T. Li, A. Heils, M. Catalano, D. Di Bella, et al. A novel functional polymorphism within the promoter of the serotonin transporter gene: possible role in susceptibility to affective disorders. Mol. Psychiatry. 1996;1(6):453-460
  • Craddock and Sklar, 2013 N. Craddock, P. Sklar. Genetics of bipolar disorder. Lancet. 2013;381(9878):1654-1662
  • Crisafulli et al., 2012 C. Crisafulli, A. Chiesa, C. Han, S.J. Lee, M.H. Park, B. Balzarro, et al. Case–control association study for 10 genes in patients with schizophrenia: influence of 5HTR1A variation rs10042486 on schizophrenia and response to antipsychotics. Eur. Arch. Psychiatry Clin. Neurosci.. 2012;262(3):199-205
  • Davies et al., 2011 M.A. Davies, Y. Conley, B.L. Roth. Functional SNPs in genes encoding the 5-HT2A receptor modify the affinity and potency of several atypical antipsychotic drugs. Biol. Res. Nurs.. 2011;13(1):55-60
  • Davies et al., 2006 M.A. Davies, V. Setola, R.T. Strachan, D.J. Sheffler, E. Salay, S.J. Hufeisen, et al. Pharmacologic analysis of non-synonymous coding h5-HT2A SNPs reveals alterations in atypical antipsychotic and agonist efficacies. Pharm. J.. 2006;6(1):42-51
  • Dean et al., 2006 B. Dean, G. Pavey, D. Thomas, E. Scarr. Cortical serotonin7, 1D and 1F receptors: effects of schizophrenia, suicide and antipsychotic drug treatment. Schizophr. Res.. 2006;88(1–3):265-274
  • Dean et al., 1999a B. Dean, T. Hussain, W. Hayes, E. Scarr, S. Kitsoulis, C. Hill, et al. Changes in serotonin2A and GABA(A) receptors in schizophrenia: studies on the human dorsolateral prefrontal cortex. J. Neurochem.. 1999;72(4):1593-1599
  • Dean et al., 1999b B. Dean, E. Tomaskovic-Crook, K. Opeskin, N. Keks, D. Copolov. No change in the density of the serotonin1A receptor, the serotonin4 receptor or the serotonin transporter in the dorsolateral prefrontal cortex from subjects with schizophrenia. Neurochem. Int.. 1999;34(2):109-115
  • Dean et al., 1995 B. Dean, K. Opeskin, G. Pavey, L. Naylor, C. Hill, N. Keks, et al. [3H] paroxetine binding is altered in the hippocampus but not the frontal cortex or caudate nucleus from subjects with schizophrenia. J. Neurochem.. 1995;64(3):1197-1202
  • Del Castillo et al., 2013 N. Del Castillo, M.B. Zimmerman, B. Tyler, V.L. Ellingrod, C. Calarge. 759C/T variants of the serotonin (5-HT2C) receptor gene and weight gain in children and adolescents in long-term risperidone treatment. Clin. Pharmacol. Biopharm.. 2013;2(2):110
  • De Luca et al., 2007 V. De Luca, D.J. Müller, R. Hwang, J.A. Lieberman, J. Volavka, H.Y. Meltzer, et al. HTR2C haplotypes and antipsychotics-induced weight gain: X-linked multimarker analysis. Hum. Psychopharmacol.. 2007;22(7):463-467
  • De Luca et al., 2005 V. De Luca, O. Likhodi, H.H. Van Tol, J.L. Kennedy, A.H. Wong. Tryptophan hydroxylase 2 gene expression and promoter polymorphisms in bipolar disorder and schizophrenia. Psychopharmacology. 2005;183(3):378-382
  • Dolžan et al., 2008 V. Dolžan, A. Serretti, L. Mandelli, J. Koprivsek, M. Kastelic, B.K. Plesnicar. Acute antipyschotic efficacy and side effects in schizophrenia: association with serotonin transporter promoter genotypes. Prog. Neuro-Psychopharmacol. Biol. Psychiatry. 2008;32(6):1562-1566
  • Dracheva et al., 2008 S. Dracheva, N. Patel, D.A. Woo, S.M. Marcus, L.J. Siever, V. Haroutunian. Increased serotonin 2C receptor mRNA editing: a possible risk factor for suicide. Mol. Psychiatry. 2008;13(11):1001-1010
  • Dracheva et al., 2003 S. Dracheva, S.L. Elhakem, S.M. Marcus, L.J. Siever, S.R. McGurk, V. Haroutunian. RNA editing and alternative splicing of human serotonin 2C receptor in schizophrenia. J. Neurochem.. 2003;87(6):1402-1412
  • Drevets et al., 2007 W.C. Drevets, M.E. Thase, E.L. Moses-Kolko, J. Price, E. Frank, D.J. Kupfer, et al. Serotonin-1A receptor imaging in recurrent depression: replication and literature review. Nucl. Med. Biol.. 2007;34(7):865-877
  • Duan et al., 2005 S. Duan, H. Yin, W. Chen, Q. Xing, Q. Chen, T. Guo, et al. No association between the serotonin 1B receptor gene and schizophrenia in a case–control and family-based association study. Neurosci. Lett.. 2005;376(2):93-97
  • Dubertret et al., 2004a C. Dubertret, N. Hanoun, J. Adès, M. Hamon, P. Gorwood. Family-based association study of the serotonin-6 receptor gene (C267T polymorphism) in schizophrenia. Am. J. Med. Genet. B Neuropsychiatr. Genet.. 2004;126B(1):10-15
  • Dubertret et al., 2004b C. Dubertret, N. Hanoun, J. Adès, M. Hamon, P. Gorwood. Family-based association studies between 5-HT5A receptor gene and schizophrenia. J. Psychiatr. Res.. 2004;38(4):371-376
  • East et al., 2002a S.Z. East, P.W. Burnet, R.W. Kerwin, P.J. Harrison. An RT-PCR study of 5-HT(6) and 5-HT(7) receptor mRNAs in the hippocampal formation and prefrontal cortex in schizophrenia. Schizophr. Res.. 2002;57(1):15-26
  • East et al., 2002b S.Z. East, P.W. Burnet, R.A. Leslie, J.C. Roberts, P.J. Harrison. 5-HT6 receptor binding sites in schizophrenia and following antipsychotic drug administration: autoradiographic studies with [125I]SB-258585. Synapse. 2002;45(3):191-199
  • Ellingrod et al., 2005 V.L. Ellingrod, P.J. Perry, J.C. Ringold, B.C. Lund, K. Bever-Stille, F. Fleming, et al. Weight gain associated with the − 759C/T polymorphism of the 5HT2C receptor and olanzapine. Am. J. Med. Genet. B Neuropsychiatr. Genet.. 2005;134B(1):76-78
  • Ellingrod et al., 2004 V.L. Ellingrod, D. Miller, J.C. Ringold, P.J. Perry. Distribution of the serotonin 2C (5HT2C) receptor gene -759C/T polymorphism in patients with schizophrenia and normal controls. Psychiatr. Genet.. 2004;14(2):93-95
  • Ellingrod et al., 2003 V.L. Ellingrod, B.C. Lund, D. Miller, F. Fleming, P. Perry, T.L. Holman, et al. 5-HT2A receptor promoter polymorphism, − 1438G/A and negative symptom response to olanzapine in schizophrenia. Psychopharmacol. Bull.. 2003;37(2):109-112
  • Ellingrod et al., 2002 V.L. Ellingrod, P.J. Perry, B.C. Lund, K. Bever-Stille, F. Fleming, T.L. Holman, et al. 5HT2A and 5HT2C receptor polymorphisms and predicting clinical response to olanzapine in schizophrenia. J. Clin. Psychopharmacol.. 2002;22(6):622-624
  • Erdmann et al., 1996 J. Erdmann, D. Shimron-Abarbanell, M. Rietschel, M. Albus, W. Maier, J. Körner, et al. Systematic screening for mutations in the human serotonin-2A (5-HT2A) receptor gene: identification of two naturally occurring receptor variants and association analysis in schizophrenia. Hum. Genet.. 1996;97(5):614-619
  • Erdmann et al., 1995 J. Erdmann, D. Shimron-Abarbanell, S. Cichon, M. Albus, W. Maier, D. Lichtermann, et al. Systematic screening for mutations in the promoter and the coding region of the 5-HT1A gene. Am. J. Med. Genet.. 1995;60(5):393-399
  • Fan et al., 2010 M. Fan, B. Liu, T. Jiang, X. Jiang, H. Zhao, J. Zhang. Meta-analysis of the association between the monoamine oxidase-A gene and mood disorders. Psychiatr. Genet.. 2010;20(1):1-7
  • Fan and Sklar, 2005 J.B. Fan, P. Sklar. Meta-analysis reveals association between serotonin transporter gene STin2 VNTR polymorphism and schizophrenia. Mol. Psychiatry. 2005;10(10):928-938
  • Fanous et al., 2004 A.H. Fanous, M.C. Neale, R.E. Straub, B.T. Webb, A.F. O'Neill, D. Walsh, et al. Clinical features of psychotic disorders and polymorphisms in HT2A, DRD2, DRD4, SLC6A3 (DAT1), and BDNF: a family based association study. Am J Med Genet B Neuropsychiatr Genet.. 2004;125B(1):69-78
  • Fijal et al., 2009 B.A. Fijal, B.J. Kinon, S. Kapur, V.L. Stauffer, R.R. Conley, H.H. Jamal, et al. Candidate-gene association analysis of response to risperidone in African-American and white patients with schizophrenia. Pharm. J.. 2009;9(5):311-318
  • Frank et al., 2004 B. Frank, B. Niesler, M.M. Nöthen, H. Neidt, P. Propping, B. Bondy, et al. Investigation of the human serotonin receptor gene HTR3B in bipolar affective and schizophrenic patients. Am. J. Med. Genet. B Neuropsychiatr. Genet.. 2004;131B(1):1-5
  • Fukuo et al., 2010 Y. Fukuo, T. Kishi, R. Yoshimura, T. Kitajima, T. Okochi, Y. Yamanouchi, et al. Serotonin 6 receptor gene and mood disorders: case–control study and meta-analysis. Neurosci. Res.. 2010;67(3):250-255
  • Furlong et al., 1998a R.A. Furlong, L. Ho, C. Walsh, J.S. Rubinsztein, S. Jain, E.S. Paykel, et al. Analysis and meta-analysis of two serotonin transporter gene polymorphisms in bipolar and unipolar affective disorders. Am. J. Med. Genet.. 1998;81(1):58-63
  • Furlong et al., 1998b R.A. Furlong, L. Ho, J.S. Rubinsztein, C. Walsh, E.S. Paykel, D.C. Rubinsztein. No association of the tryptophan hydroxylase gene with bipolar affective disorder, unipolar affective disorder, or suicidal behaviour in major affective disorder. Am. J. Med. Genet.. 1998;81(3):245-247
  • Gatt et al., 2015 J.M. Gatt, K.L. Burton, L.M. Williams, P.R. Schofield. Specific and common genes implicated across major mental disorders: a review of meta-analysis studies. J. Psychiatr. Res.. 2015;60:1-13
  • Geddes and Miklowitz, 2013 J.R. Geddes, D.J. Miklowitz. Treatment of bipolar disorder. Lancet. 2013;381(9878):1672-1682
  • Ghadirivasfi et al., 2011 M. Ghadirivasfi, S. Nohesara, H.R. Ahmadkhaniha, M.R. Eskandari, S. Mostafavi, S. Thiagalingam, H.M. Abdolmaleky. Hypomethylation of the serotonin receptor type-2A gene (HTR2A) at T102C polymorphic site in DNA derived from the saliva of patients with schizophrenia and bipolar disorder. Am. J. Med. Genet. B Neuropsychiatr. Genet.. 2011;156B(5):536-545
  • Gilabert-Juan et al., 2011 J. Gilabert-Juan, J.L. Ivorra, A. Tolosa, M. Gratacòs, J. Costas, J. Sanjuán, et al. Potential involvement of serotonin receptor genes with age of onset and gender in schizophrenia: a preliminary study in a Spanish sample. Psychiatry Res.. 2011;186(1):153-154
  • Giusti-Rodríguez and Sullivan, 2013 P. Giusti-Rodríguez, P.F. Sullivan. The genomics of schizophrenia: update and implications. J. Clin. Invest.. 2013;123(11):4557-4563
  • Golimbet et al., 2007 V.E. Golimbet, O.M. Lavrushina, V.G. Kaleda, L.I. Abramova, T.V. Lezheiko. Supportive evidence for the association between the T102C 5-HTR2A gene polymorphism and schizophrenia: a large-scale case–control and family-based study. Eur. Psychiatry. 2007;22(3):167-170
  • Gregoor et al., 2011 J.G. Gregoor, J. van der Weide, H.M. Loovers, H.J. van Megen, T.C. Egberts, E.R. Heerdink. Polymorphisms of the LEP, LEPR and HTR2C gene: obesity and BMI change in patients using antipsychotic medication in a naturalistic setting. Pharmacogenomics. 2011;12(6):919-923
  • Gu et al., 2013a H. Gu, C. Liu, C. Liu, M. Chen, Q. Zhang, J. Zhai, et al. The combined effects of the 5- HTTLPR and HTR1A rs6295 polymorphisms modulate decision making in schizophrenia patients. Genes Brain Behav.. 2013;12(1):133-139
  • Gu et al., 2013b L. Gu, J. Long, Y. Yan, Q. Chen, R. Pan, X. Xie, et al. HTR2A-1438A/G polymorphism influences the risk of schizophrenia but not bipolar disorder or major depressive disorder: a meta-analysis. J. Neurosci. Res.. 2013;91(5):623-633
  • Gupta et al., 2012 M. Gupta, S. Jain, N.S. Moily, H. Kaur, A. Jajodia, M. Purushottam, et al. Genetic studies indicate a potential target 5-HTR(3B) for drug therapy in schizophrenia patients. Am. J. Med. Genet. B Neuropsychiatr. Genet.. 2012;159B(8):1006-1008
  • Gutiérrez et al., 2002 B. Gutiérrez, M.J. Arranz, P. Huezo-Diaz, D. Dempster, P. Matthiasson, M. Travis, et al. Novel mutations in 5-HT3A and 5-HT3B receptor genes not associated with clozapine response. Schizophr. Res.. 2002;58(1):93-97
  • Gutiérrez et al., 1997 B. Gutiérrez, J. Bertranpetit, D. Collier, M.J. Arranz, V. Vallès, R. Guillamat, et al. Genetic variation of the 5-HT2A receptor gene and bipolar affective disorder. Hum. Genet.. 1997;100(5–6):582-584
  • Gutiérrez et al., 1996 B. Gutiérrez, L. Fañanás, M.J. Arranz, V. Vallès, R. Guillamat, J. van Os, et al. Allelic association analysis of the 5-HT2C receptor gene in bipolar affective disorder. Neurosci. Lett.. 1996;212(1):65-67
  • Hammer et al., 2012 C. Hammer, S. Cichon, T.W. Mühleisen, B. Haenisch, F. Degenhardt, M. Mattheisen, et al. Replication of functional serotonin receptor type 3A and B variants in bipolar affective disorder: a European multicenter study. Transl. Psychiatry. 2012;2 e103
  • Hannon and Hoyer, 2008 J. Hannon, D. Hoyer. Molecular biology of 5-HT receptors. Behav. Brain Res.. 2008;195(1):198-213
  • Hashimoto et al., 1991 T. Hashimoto, N. Nishino, H. Nakai, C. Tanaka. Increase in serotonin 5-HT1A receptors in prefrontal and temporal cortices of brains from patients with chronic schizophrenia. Life Sci.. 1991;48(4):355-363
  • Hayden and Nurnberger, 2006 E.P. Hayden, J.I. Nurnberger Jr. Molecular genetics of bipolar disorder. Genes Brain Behav.. 2006;5(1):85-95
  • Hirata et al., 2010 Y. Hirata, R.P. Souza, J.A. Lieberman, H.Y. Meltzer, J.L. Kennedy. Lack of association between HTR4 gene polymorphisms and schizophrenia in case–control and family-based samples. Psychiatry Res.. 2010;175(1–2):176-178
  • Hoehe et al., 1998 M.R. Hoehe, B. Wendel, I. Grunewald, P. Chiaroni, N. Levy, D. Morris-Rosendahl, et al. Serotonin transporter (5-HTT) gene polymorphisms are not associated with susceptibility to mood disorders. Am. J. Med. Genet.. 1998;81(1):1-3
  • Hong et al., 2001 C.J. Hong, C.H. Lin, Y.W. Yu, K.H. Yang, S.J. Tsai. Genetic variants of the serotonin system and weight change during clozapine treatment. Pharmacogenetics. 2001;11(3):265-268
  • Hranilovic et al., 2000 D. Hranilovic, S.G. Schwab, B. Jernej, M. Knapp, B. Lerer, M. Albus, et al. Serotonin transporter gene and schizophrenia: evidence for association/linkage disequilibrium in families with affected siblings. Mol. Psychiatry. 2000;5(1):91-95
  • Huang et al., 2004 Y.Y. Huang, C. Battistuzzi, M.A. Oquendo, J. Harkavy-Friedman, L. Greenhill, G. Zalsman, et al. Human 5-HT1A receptor C(− 1019)G polymorphism and psychopathology. Int. J. Neuropsychopharmacol.. 2004;7(4):441-451
  • Ikeda et al., 2008 M. Ikeda, Y. Yamanouchi, Y. Kinoshita, T. Kitajima, R. Yoshimura, S. Hashimoto, et al. Variants of dopamine and serotonin candidate genes as predictors of response to risperidone treatment in first-episode schizophrenia. Pharmacogenomics. 2008;9(10):1437-1443
  • Ikeda et al., 2006a M. Ikeda, N. Iwata, T. Kitajima, T. Suzuki, Y. Yamanouchi, Y. Kinoshita, et al. Positive association of the serotonin 5-HT7 receptor gene with schizophrenia in a Japanese population. Neuropsychopharmacology. 2006;31(4):866-871
  • Ikeda et al., 2006b M. Ikeda, N. Iwata, T. Suzuki, T. Kitajima, Y. Yamanouchi, Y. Kinoshita, et al. No association of serotonin transporter gene (SLC6A4) with schizophrenia and bipolar disorder in Japanese patients: association analysis based on linkage disequilibrium. J. Neural Transm.. 2006;113(7):899-905
  • Inayama et al., 1996 Y. Inayama, H. Yoneda, T. Sakai, T. Ishida, Y. Nonomura, Y. Kono, et al. Positive association between a DNA sequence variant in the serotonin 2A receptor gene and schizophrenia. Am. J. Med. Genet.. 1996;67(1):103-105
  • Ivleva et al., 2010 E.I. Ivleva, D.W. Morris, A.F. Moates, T. Suppes, G.K. Thaker, C.A. Tamminga. Genetics and intermediate phenotypes of the schizophrenia–bipolar disorder boundary. Neurosci. Biobehav. Rev.. 2010;34(6):897-921
  • Iwata et al., 2001 N. Iwata, N. Ozaki, T. Inada, D. Goldman. Association of a 5-HT(5A) receptor polymorphism, Pro15Ser, to schizophrenia. Mol. Psychiatry. 2001;6(2):217-219
  • Ji et al., 2008a X. Ji, N. Takahashi, S. Saito, R. Ishihara, N. Maeno, T. Inada, et al. Relationship between three serotonin receptor subtypes (HTR3A, HTR2A and HTR4) and treatment-resistant schizophrenia in the Japanese population. Neurosci. Lett.. 2008;435(2):95-98
  • Ji et al., 2008b X. Ji, N. Takahashi, A. Branko, R. Ishihara, T. Nagai, A. Mouri, et al. An association between serotonin receptor 3B gene (HTR3B) and treatment-resistant schizophrenia (TRS) in a Japanese population. Nagoya J. Med. Sci.. 2008;70(1–2):11-17
  • Jonnakuty and Gragnoli, 2008 C. Jonnakuty, C. Gragnoli. What do we know about serotonin?. J. Cell. Physiol.. 2008;217(2):301-306
  • Jones and McCreary, 2008 C.A. Jones, A.C. McCreary. Serotonergic approaches in the development of novel antipsychotics. Neuropharmacology. 2008;55(6):1056-1065
  • Jönsson et al., 2003 E.G. Jönsson, N. Norton, K. Forslund, M. Mattila-Evenden, G. Rylander, M. Asberg, et al. Association between a promoter variant in the monoamine oxidase A gene and schizophrenia. Schizophr. Res.. 2003;61(1):31-37
  • Joyce et al., 1993 J.N. Joyce, A. Shane, N. Lexow, A. Winokur, M.F. Casanova, J.E. Kleinman. Serotonin uptake sites and serotonin receptors are altered in the limbic system of schizophrenics. Neuropsychopharmacology. 1993;8(4):315-336
  • Kaiser et al., 2001 R. Kaiser, P.B. Tremblay, J. Schmider, M. Henneken, M. Dettling, B. Müller-Oerlinghausen, et al. Serotonin transporter polymorphisms: no association with response to antipsychotic treatment, but associations with the schizoparanoid and residual subtypes of schizophrenia. Mol. Psychiatry. 2001;6(2):179-185
  • Kandel, 2001 E.R. Kandel. The molecular biolgogy of memory storage: a dialogue between genes and synapses. Science. 2001;294(5544):1030-1038
  • Kawanishi et al., 1998 Y. Kawanishi, S. Harada, H. Tachikawa, T. Okubo, H. Shiraishi. Novel mutations in the promoter and coding region of the human 5-HT1A receptor gene and association analysis in schizophrenia. Am. J. Med. Genet.. 1998;81(5):434-439
  • Kiel et al., 2003 S. Kiel, H. Bönisch, M. Brüss, M. Göthert. Impairment of signal transduction in response to stimulation of the naturally occurring Pro279Leu variant of the h5-HT7(a) receptor. Pharmacogenetics. 2003;13(2):119-126
  • Kim et al., 2014 Y.K. Kim, J.A. Hwang, H.J. Lee, B.H. Lee, K.S. Na. There is no association between the serotonin receptor gene and bipolar I disorder in the Korean population. Nord. J. Psychiatry. 2014;68(7):488-493
  • Kim and Yoon, 2011 Y.K. Kim, H.K. Yoon. Effect of serotonin-related gene polymorphisms on pathogenesis and treatment response in Korean schizophrenic patients. Behav. Genet.. 2011;41(5):709-715
  • Kim et al., 2008 B. Kim, E.Y. Choi, C.Y. Kim, K. Song, Y.H. Joo. Could HTR2A T102C and DRD3 Ser9Gly predict clinical improvement in patients with acutely exacerbated schizophrenia? Results from treatment responses to risperidone in a naturalistic setting. Hum. Psychopharmacol.. 2008;23(1):61-67
  • Kirov et al., 1999 G. Kirov, M. Rees, I. Jones, F. MacCandless, M.J. Owen, N. Craddock. Bipolar disorder and the serotonin transporter gene: a family-based association study. Psychol. Med.. 1999;29(5):1249-1254
  • Kishi et al., 2013 T. Kishi, R. Yoshimura, Y. Fukuo, T. Okochi, S. Matsunaga, W. Umene-Nakano, et al. The serotonin 1A receptor gene confer susceptibility to mood disorders: results from an extended meta-analysis of patients with major depression and bipolar disorder. Eur. Arch. Psychiatry Clin. Neurosci.. 2013;263(2):105-118
  • Kishi et al., 2011 T. Kishi, T. Okochi, T. Tsunoka, T. Okumura, T. Kitajima, K. Kawashima, et al. Serotonin 1A receptor gene, schizophrenia and bipolar disorder: an association study and meta-analysis. Psychiatry Res.. 2011;185(1–2):20-26
  • Kouzmenko et al., 1997 A.P. Kouzmenko, W.L. Hayes, A.M. Pereira, B. Dean, P.W. Burnet, P.J. Harrison. 5-HT2A receptor polymorphism and steady state receptor expression in schizophrenia. Lancet. 1997;349(9068):1815
  • Krzywkowski et al., 2008 K. Krzywkowski, P.A. Davies, P.L. Feinberg-Zadek, H. Bräuner-Osborne, A.A. Jensen. High-frequency HTR3B variant associated with major depression dramatically augments the signaling of the human 5-HT3AB receptor. Proc. Natl. Acad. Sci. U. S. A.. 2008;105(2):722-727
  • Kunugi et al., 1999 H. Kunugi, S. Ishida, T. Kato, T. Sakai, M. Tatsumi, T. Hirose, et al. No evidence for an association of polymorphisms of the tryptophan hydroxylase gene with affective disorders or attempted suicide among Japanese patients. Am. J. Psychiatry. 1999;156(5):774-776
  • Kunugi et al., 1997 H. Kunugi, M. Hattori, T. Kato, M. Tatsumi, T. Sakai, T. Sasaki, et al. Serotonin transporter gene polymorphisms: ethnic difference and possible association with bipolar affective disorder. Mol. Psychiatry. 1997;2(6):457-462
  • Kunugi et al., 1996 H. Kunugi, M. Tatsumi, T. Sakai, M. Hattori, S. Nanko. Serotonin transporter gene polymorphism and affective disorder. Lancet. 1996;347(9011):1340
  • Lai et al., 2005 T.J. Lai, C.Y. Wu, H.W. Tsai, Y.M. Lin, H.S. Sun. Polymorphism screening and haplotype analysis of the tryptophan hydroxylase gene (TPH1) and association with bipolar affective disorder in Taiwan. BMC Med. Genet.. 2005;6:14
  • Lane et al., 2006 H.Y. Lane, Y.C. Liu, C.L. Huang, Y.C. Chang, P.L. Wu, C.T. Lu, et al. Risperidone-related weight gain: genetic and nongenetic predictors. J. Clin. Psychopharmacol.. 2006;26(2):128-134
  • Lane et al., 2004 H.Y. Lane, C.C. Lin, C.H. Huang, Y.C. Chang, S.K. Hsu, W.H. Chang. Risperidone response and 5-HT6 receptor gene variance: genetic association analysis with adjustment for nongenetic confounders. Schizophr. Res.. 2004;67(1):63-70
  • Lane et al., 2002 H.Y. Lane, Y.C. Chang, C.C. Chiu, M.L. Chen, M.H. Hsieh, W.H. Chang. Association of risperidone treatment response with a polymorphism in the 5-HT(2A) receptor gene. Am. J. Psychiatry. 2002;159(9):1593-1595
  • Lee et al., 2009 H.Y. Lee, D.J. Kim, H.J. Lee, J.E. Choi, Y.K. Kim. No association of serotonin transporter polymorphism (5-HTTVNTR and 5-HTTLPR) with characteristics and treatment response to atypical antipsychotic agents in schizophrenic patients. Prog. Neuro-Psychopharmacol. Biol. Psychiatry. 2009;33(2):276-280
  • Lemonde et al., 2003 S. Lemonde, G. Turecki, D. Bakish, L. Du, P.D. Hrdina, C.D. Bown, et al. Impaired repression at a 5-hydroxytryptamine 1A receptor gene polymorphism associated with major depression and suicide. J. Neurosci.. 2003;23(25):8788-8799
  • Lennertz et al., 2010 L. Lennertz, M. Wagner, I. Frommann, S. Schulze-Rauschenbach, A. Schuhmacher, K.U. Kühn, et al. A coding variant of the novel serotonin receptor subunit 5-HT3E influences sustained attention in schizophrenia patients. Eur. Neuropsychopharmacol.. 2010;20(6):414-420
  • Lerer et al., 2001 B. Lerer, F. Macciardi, R.H. Segman, R. Adolfsson, D. Blackwood, S. Blairy, et al. Variability of 5-HT2C receptor cys23ser polymorphism among European populations and vulnerability to affective disorder. Mol. Psychiatry. 2001;6(5):579-585
  • Lin et al., 2009 C. Lin, W. Tang, J. Hu, L. Gao, K. Huang, Y. Xu, et al. Haplotype analysis confirms association of the serotonin transporter (5-HTT) gene with schizophrenia in the Han Chinese population. Neurosci. Lett.. 2009;453(3):210-213
  • López-Figueroa et al., 2004 A.L. López-Figueroa, C.S. Norton, M.O. López-Figueroa, D. Armellini-Dodel, S. Burke, H. Akil, et al. Serotonin 5-HT1A, 5-HT1B, and 5-HT2A receptor mRNA expression in subjects with major depression, bipolar disorder, and schizophrenia. Biol. Psychiatry. 2004;55(3):225-233
  • Mahieu et al., 1997 B. Mahieu, D. Souery, O. Lipp, K. Mendelbaum, G. Verheyen, V. De Maertelaer, et al. No association between bipolar affective disorder and a serotonin receptor (5-HT2A) polymorphism. Psychiatry Res.. 1997;70(2):65-69
  • Malhotra et al., 1998 A.K. Malhotra, D. Goldman, C. Mazzanti, A. Clifton, A. Breier, D. Pickar. A functional serotonin transporter (5-HTT) polymorphism is associated with psychosis in neuroleptic-free schizophrenics. Mol. Psychiatry. 1998;3(4):328-332
  • Malhotra et al., 1996a A.K. Malhotra, D. Goldman, R. Buchanan, A. Breier, D. Pickar. 5HT 2a receptor T102C polymorphism and schizophrenia. Lancet. 1996;347(9018):1830-1831
  • Malhotra et al., 1996b A.K. Malhotra, D. Goldman, N. Ozaki, A. Breier, R. Buchanan, D. Pickar. Lack of association between polymorphisms in the 5-HT2A receptor gene and the antipsychotic response to clozapine. Am. J. Psychiatry. 1996;153(8):1092-1094
  • Mann et al., 2008 J.J. Mann, D. Currier, L. Murphy, Y.Y. Huang, H. Galfalvy, D. Brent, et al. No association between a TPH2 promoter polymorphism and mood disorders or monoamine turnover. J. Affect. Disord.. 2008;106(1–2):117-121
  • Masellis et al., 2001 M. Masellis, V.S. Basile, H.Y. Meltzer, J.A. Lieberman, S. Sevy, D.A. Goldman, et al. Lack of association between the T–>C 267 serotonin 5-HT6 receptor gene (HTR6) polymorphism and prediction of response to clozapine in schizophrenia. Schizophr. Res.. 2001;47(1):49-58
  • Masellis et al., 1998 M. Masellis, V. Basile, H.Y. Meltzer, J.A. Lieberman, S. Sevy, F.M. Macciardi, et al. Serotonin subtype 2 receptor genes and clinical response to clozapine in schizophrenia patients. Neuropsychopharmacology. 1998;19(2):123-132
  • Massat et al., 2007 I. Massat, B. Lerer, D. Souery, D. Blackwood, W. Muir, R. Kaneva, et al. HTR2C (cys23ser) polymorphism influences early onset in bipolar patients in a large European multicenter association study. Mol. Psychiatry. 2007;12(9):797-798
  • Massat et al., 2000 I. Massat, D. Souery, O. Lipp, S. Blairy, G. Papadimitriou, D. Dikeos, et al. A European multicenter association study of HTR2A receptor polymorphism in bipolar affective disorder. Am. J. Med. Genet.. 2000;96(2):136-140
  • Mata et al., 2004 I. Mata, M.J. Arranz, A. Patiño, T. Lai, M. Beperet, L. Sierrasesumaga, et al. Serotonergic polymorphisms and psychotic disorders in populations from North Spain. Am. J. Med. Genet. B Neuropsychiatr. Genet.. 2004;126B(1):88-94
  • Meltzer et al., 2003 H.Y. Meltzer, Z. Li, Y. Kaneda, J. Ichikawa. Serotonin receptors: their key role in drugs to treat schizophrenia. Prog. Neuro-Psychopharmacol. Biol. Psychiatry. 2003;27(7):1159-1172
  • Miller et al., 2005 D.D. Miller, V.L. Ellingrod, T.L. Holman, P.F. Buckley, S. Arndt. Clozapine-induced weight gain associated with the 5HT2C receptor − 759C/T polymorphism. Am. J. Med. Genet. B Neuropsychiatr. Genet.. 2005;133B(1):97-100
  • Minzenberg et al., 2009 M.J. Minzenberg, A.R. Laird, S. Thelen, C.S. Carter, D.C. Glahn. Meta-analysis of 41 functional neuroimaging studies of executive function in schizophrenia. Arch. Gen. Psychiatry. 2009;66(8):811-822
  • Mössner et al., 2009 R. Mössner, A. Schuhmacher, K.U. Kühn, G. Cvetanovska, D. Rujescu, P. Zill, et al. Functional serotonin 1A receptor variant influences treatment response to atypical antipsychotics in schizophrenia. Pharmacogenet. Genomics. 2009;19(1):91-94
  • Muguruza et al., 2013 C. Muguruza, J.L. Moreno, A. Umali, L.F. Callado, J.J. Meana, J. González-Maeso. Dysregulated 5-HT(2A) receptor binding in postmortem frontal cortex of schizophrenic subjects. Eur. Neuropsychopharmacol.. 2013;23(8):852-864
  • Mulder et al., 2009 H. Mulder, D. Cohen, H. Scheffer, C. Gispen-de Wied, J. Arends, F.W. Wilmink, et al. HTR2C gene polymorphisms and the metabolic syndrome in patients with schizophrenia: a replication study. J. Clin. Psychopharmacol.. 2009;29(1):16-20
  • Mulder et al., 2007b H. Mulder, B. Franke, A.A. van der-Beek van der, J. Arends, F.W. Wilmink, H. Scheffer, et al. The association between HTR2C gene polymorphisms and the metabolic syndrome in patients with schizophrenia. J. Clin. Psychopharmacol.. 2007;27(4):338-343
  • Mulder et al., 2007a H. Mulder, B. Franke, A.A. van der-Beek van der, J. Arends, F.W. Wilmink, A.C. Egberts, et al. The association between HTR2C polymorphisms and obesity in psychiatric patients using antipsychotics: a cross-sectional study. Pharm. J.. 2007;7(5):318-324
  • Müller et al., 2007 D.J. Müller, A. Serretti, T. Sicard, S. Tharmalingam, N. King, P. Artioli, et al. Further evidence of MAO-A gene variants associated with bipolar disorder. Am. J. Med. Genet. B Neuropsychiatr. Genet.. 2007;144B(1):37-40
  • Mundo et al., 2001 E. Mundo, G. Zai, L. Lee, S.V. Parikh, J.L. Kennedy. The 5HT1Dbeta receptor gene in bipolar disorder: a family-based association study. Neuropsychopharmacology. 2001;25(4):608-613
  • Naylor et al., 1996 L. Naylor, B. Dean, K. Opeskin, G. Pavey, C. Hill, N. Keks, et al. Changes in the serotonin transporter in the hippocampus of subjects with schizophrenia identified using [3H]paroxetine. J. Neural Transm.. 1996;103(6):749-757
  • Niesler et al., 2001a B. Niesler, T. Flohr, M.M. Nöthen, C. Fischer, M. Rietschel, E. Franzek, et al. Association between the 5′ UTR variant C178T of the serotonin receptor gene HTR3A and bipolar affective disorder. Pharmacogenetics. 2001;11(6):471-475
  • Niesler et al., 2001b B. Niesler, B. Weiss, C. Fischer, M.M. Nöthen, P. Propping, B. Bondy, et al. Serotonin receptor gene HTR3A variants in schizophrenic and bipolar affective patients. Pharmacogenetics. 2001;11(1):21-27
  • Norton et al., 2002 N. Norton, G. Kirov, S. Zammit, G. Jones, S. Jones, R. Owen, et al. Schizophrenia and functional polymorphisms in the MAOA and COMT genes: no evidence for association or epistasis. Am. J. Med. Genet.. 2002;114(5):491-496
  • Nothdurfter et al., 2012 C. Nothdurfter, I. Giegling, B. Konte, A.M. Hartmann, H. Konnerth, M. Friedl, et al. Lack of association of the 5-HT(3A) receptor with schizophrenia. Am. J. Med. Genet. B Neuropsychiatr. Genet.. 2012;159B(3):310-315
  • Nöthen et al., 1995 M.M. Nöthen, M. Rietschel, J. Erdmann, H. Oberländer, H.J. Möller, D. Nober, et al. Genetic variation of the 5-HT2A receptor and response to clozapine. Lancet. 1995;346(8979):908-909
  • Nugent et al., 2013 A.C. Nugent, E.E. Bain, P.J. Carlson, A. Neumeister, O. Bonne, R.E. Carson, et al. Reduced post-synaptic serotonin type 1A receptor binding in bipolar depression. Eur. Neuropsychopharmacol.. 2013;23(8):822-829
  • Ohara et al., 1999 K. Ohara, M. Nagai, K. Tani, T. Tsukamoto, K. Ohara. Schizophrenia and the serotonin-2A receptor promoter polymorphism. Psychiatry Res.. 1999;85(2):221-224
  • Ohara et al., 1998a K. Ohara, M. Nagai, T. Tsukamoto, K. Tani, Y. Suzuki, K. Ohara. 5-HT2A receptor gene promoter polymorphism–1438G/A and mood disorders. Neuroreport. 1998;9(6):1139-1141
  • Ohara et al., 1998b K. Ohara, M. Nagai, T. Tsukamoto, K. Tani, Y. Suzuki, K. Ohara. Functional polymorphism in the serotonin transporter promoter at the SLC6A4 locus and mood disorders. Biol. Psychiatry. 1998;44(7):550-554
  • Ohtsuki et al., 2002 T. Ohtsuki, H. Ishiguro, S.D. Detera-Wadleigh, T. Toyota, H. Shimizu, K. Yamada, et al. Association between serotonin 4 receptor gene polymorphisms and bipolar disorder in Japanese case–control samples and the NIMH genetics initiative bipolar pedigrees. Mol. Psychiatry. 2002;7(9):954-961
  • Opgen-Rhein et al., 2010 C. Opgen-Rhein, E.J. Brandl, D.J. Müller, A.H. Neuhaus, A.K. Tiwari, T. Sander, et al. Association of HTR2C, but not LEP or INSIG2, genes with antipsychotic-induced weight gain in a German sample. Pharmacogenomics. 2010;11(6):773-780
  • Pae et al., 2005 C.U. Pae, P. Artioli, A. Serretti, T.S. Kim, J.J. Kim, C.U. Lee, et al. No evidence for interaction between 5-HT2A receptor and serotonin transporter genes in schizophrenia. Neurosci. Res.. 2005;52(2):195-199
  • Peñas-Lledó et al., 2007 E.M. Peñas-Lledó, P. Dorado, M.C. Cáceres, A. de la Rubia, A. Llerena. Association between T102C and A-1438G polymorphisms in the serotonin receptor 2A (5-HT2A) gene and schizophrenia: relevance for treatment with antipsychotic drugs. Clin. Chem. Lab. Med.. 2007;45(7):835-838
  • Phillips and Kupfer, 2013 M.L. Phillips, D.J. Kupfer. Bipolar disorder diagnosis: challenges and future directions. Lancet. 2013;381(9878):1663-1671
  • Polsinelli et al., 2013 G. Polsinelli, C.C. Zai, J. Strauss, J.L. Kennedy, V. De Luca. Association and CpG SNP analysis of HTR4 polymorphisms with suicidal behavior in subjects with schizophrenia. J. Neural Transm.. 2013;120(2):253-258
  • Preisig et al., 2000 M. Preisig, F. Bellivier, B.T. Fenton, P. Baud, A. Berney, P. Courtet, et al. Association between bipolar disorder and monoamine oxidase A gene polymorphisms: results of a multicenter study. Am. J. Psychiatry. 2000;157(6):948-955
  • Pucadyil et al., 2005 T.J. Pucadyil, S. Kalipatnapu, A. Chattopadhyay. The serotonin1A receptor: a representative member of the serotonin receptor family. Cell. Mol. Neurobiol.. 2005;25(3–4):553-580
  • Richtand et al., 2008 N.M. Richtand, J.A. Welge, A.D. Logue, P.E. Keck Jr., S.M. Strakowski, R.K. McNamara. Role of serotonin and dopamine receptor binding in antipsychotic efficacy. Prog. Brain Res.. 2008;172:155-175
  • Rubinsztein et al., 1996 D.C. Rubinsztein, J. Leggo, S. Goodburn, C. Walsh, S. Jain, E.S. Paykel. Genetic association between monoamine oxidase A microsatellite and RFLP alleles and bipolar affective disorder: analysis and meta-analysis. Hum. Mol. Genet.. 1996;5(6):779-782
  • Qiu et al., 2009 H.T. Qiu, H.Q. Meng, C. Song, M.H. Xiu, C. Chen da, F.Y. Zhu, et al. Association between monoamine oxidase (MAO)-A gene variants and schizophrenia in a Chinese population. Brain Res.. 2009;1287:67-73
  • Rajkumar et al., 2012 A.P. Rajkumar, B. Poonkuzhali, A. Kuruvilla, A. Srivastava, M. Jacob, K.S. Jacob. Outcome definitions and clinical predictors influence pharmacogenetic associations between HTR3A gene polymorphisms and response to clozapine in patients with schizophrenia. Psychopharmacology. 2012;224(3):441-449
  • Ranade et al., 2003 S.S. Ranade, H. Mansour, J. Wood, K.V. Chowdari, L.K. Brar, D.J. Kupfer, et al. Linkage and association between serotonin 2A receptor gene polymorphisms and bipolar I disorder. Am. J. Med. Genet. B Neuropsychiatr. Genet.. 2003;121B(1):28-34
  • Reynolds et al., 2006 G.P. Reynolds, B. Arranz, L.A. Templeman, S. Fertuzinhos, L. San. Effect of 5-HT1A receptor gene polymorphism on negative and depressive symptom response to antipsychotic treatment of drug-naive psychotic patients. Am. J. Psychiatry. 2006;163(10):1826-1829
  • Reynolds et al., 2005 G.P. Reynolds, Z. Yao, X. Zhang, J. Sun, Z. Zhang. Pharmacogenetics of treatment in first-episode schizophrenia: D3 and 5-HT2C receptor polymorphisms separately associate with positive and negative symptom response. Eur. Neuropsychopharmacol.. 2005;15(2):143-151
  • Reynolds et al., 2003 G.P. Reynolds, Z. Zhang, X. Zhang. Polymorphism of the promoter region of the serotonin 5-HT(2C) receptor gene and clozapine-induced weight gain. Am. J. Psychiatry. 2003;160(4):677-679
  • Reynolds et al., 2002 G.P. Reynolds, Z.J. Zhang, X.B. Zhang. Association of antipsychotic drug-induced weight gain with a 5-HT2C receptor gene polymorphism. Lancet. 2002;359(9323):2086-2087
  • Rietschel et al., 1997 M. Rietschel, D. Naber, R. Fimmers, H.J. Möller, P. Propping, M.M. Nöthen. Efficacy and side-effects of clozapine not associated with variation in the 5-HT2C receptor. Neuroreport. 1997;8(8):1999-2003
  • Rotondo et al., 2002 A. Rotondo, C. Mazzanti, L. Dell'Osso, P. Rucci, P. Sullivan, S. Bouanani, et al. Catechol o-methyltransferase, serotonin transporter, and tryptophan hydroxylase gene polymorphisms in bipolar disorder patients with and without comorbid panic disorder. Am. J. Psychiatry. 2002;159(1):23-29
  • Ryu et al., 2007 S. Ryu, E.Y. Cho, T. Park, S. Oh, W.S. Jang, S.K. Kim, et al. 759 C/T polymorphism of 5-HT2C receptor gene and early phase weight gain associated with antipsychotic drug treatment. Prog. Neuro-Psychopharmacol. Biol. Psychiatry. 2007;31(3):673-677
  • Saetre et al., 2010 P. Saetre, P. Lundmark, A. Wang, T. Hansen, H.B. Rasmussen, S. Djurovic, et al. The tryptophan hydroxylase 1 (TPH1) gene, schizophrenia susceptibility, and suicidal behavior: a multi-centre case–control study and meta-analysis. Am. J. Med. Genet. B Neuropsychiatr. Genet.. 2010;153B(2):387-396
  • Sáiz et al., 2007 P.A. Sáiz, M.P. García-Portilla, C. Arango, B. Morales, V. Alvarez, E. Coto, et al. Association study of serotonin 2A receptor (5-HT2A) and serotonin transporter (5-HTT) gene polymorphisms with schizophrenia. Prog. Neuro-Psychopharmacol. Biol. Psychiatry. 2007;31(3):741-745
  • Scarr et al., 2004 E. Scarr, G. Pavey, D. Copolov, B. Dean. Hippocampal 5-hydroxytryptamine receptors: abnormalities in postmortem brain from schizophrenic subjects. Schizophr. Res.. 2004;71(2–3):383-392
  • Schuhmacher et al., 2012 A. Schuhmacher, T. Becker, D. Rujescu, B.B. Quednow, L. Lennertz, M. Wagner, et al. Investigation of tryptophan hydroxylase 2 (TPH2) in schizophrenia and in the response to antipsychotics. J. Psychiatr. Res.. 2012;46(8):1073-1080
  • Schuhmacher et al., 2009 A. Schuhmacher, R. Mössner, B.B. Quednow, K.U. Kühn, M. Wagner, G. Cvetanovska, et al. Influence of 5-HT3 receptor subunit genes HTR3A, HTR3B, HTR3C, HTR3D and HTR3E on treatment response to antipsychotics in schizophrenia. Pharmacogenet. Genomics. 2009;19(11):843-851
  • Schumacher et al., 2000 J. Schumacher, T.G. Schulze, T.F. Wienker, M. Rietschel, M.M. Nöthen. Pharmacogenetics of the clozapine response. Lancet. 2000;356(9228):506-507
  • Seifuddin et al., 2012 F. Seifuddin, P.B. Mahon, J. Judy, M. Pirooznia, D. Jancic, J. Taylor, et al. Meta-analysis of genetic association studies on bipolar disorder. Am. J. Med. Genet. B Neuropsychiatr. Genet.. 2012;159B(5):508-518
  • Selvaraj et al., 2014 S. Selvaraj, D. Arnone, A. Cappai, O. Howes. Alterations in the serotonin system in schizophrenia: a systematic review and meta-analysis of postmortem and molecular imaging studies. Neurosci. Biobehav. Rev.. 2014;45:233-245
  • Serretti et al., 2007 A. Serretti, L. Mandelli, I. Giegling, B. Schneider, A.M. Hartmann, A. Schnabel, et al. HTR2C and HTR1A gene variants in German and Italian suicide attempters and completers. Am. J. Med. Genet. B Neuropsychiatr. Genet.. 2007;144B(3):291-299
  • Serretti et al., 2002a A. Serretti, R. Lilli, C. Lorenzi, E. Lattuada, C. Cusin, E. Smeraldi. Serotonin transporter gene (5-HTTLPR) and major psychoses. Mol. Psychiatry. 2002;7(1):95-99
  • Serretti et al., 2002b A. Serretti, S. Cristina, R. Lilli, C. Cusin, E. Lattuada, C. Lorenzi, et al. Family-based association study of 5-HTTLPR, TPH, MAO-A, and DRD4 polymorphisms in mood disorders. Am. J. Med. Genet.. 2002;114(4):361-369
  • Serretti et al., 2000 A. Serretti, C. Cusin, C. Lorenzi, E. Lattuada, R. Lilli, E. Smeraldi. Serotonin-2A receptor gene is not associated with symptomatology of schizophrenia. Am. J. Med. Genet.. 2000;96(1):84-87
  • Shi et al., 2008 J. Shi, E.S. Gershon, C. Liu. Genetic associations with schizophrenia: meta-analyses of 12 candidate genes. Schizophr. Res.. 2008;104(1–3):96-107
  • Shimron-Abarbanell et al., 1996 D. Shimron-Abarbanell, H. Harms, J. Erdmann, M. Albus, W. Maier, M. Rietschel, et al. Systematic screening for mutations in the human serotonin 1F receptor gene in patients with bipolar affective disorder and schizophrenia. Am. J. Med. Genet.. 1996;67(2):225-228
  • Shinkai et al., 1999 T. Shinkai, O. Ohmori, H. Kojima, T. Terao, T. Suzuki, K. Abe. Association study of the 5-HT6 receptor gene in schizophrenia. Am. J. Med. Genet.. 1999;88(2):120-122
  • Shiroiwa et al., 2010 K. Shiroiwa, A. Hishimoto, K. Mouri, M. Fukutake, I. Supriyanto, N. Nishiguchi, et al. Common genetic variations in TPH1/TPH2 genes are not associated with schizophrenia in Japanese population. Neurosci. Lett.. 2010;472(3):194-198
  • Sodhi et al., 2001 M.S. Sodhi, P.W. Burnet, A.J. Makoff, R.W. Kerwin, P.J. Harrison. RNA editing of the 5-HT(2C) receptor is reduced in schizophrenia. Mol. Psychiatry. 2001;6(4):373-379
  • Sodhi et al., 1995 M.S. Sodhi, M.J. Arranz, D. Curtis, D.M. Ball, P. Sham, G.W. Roberts, et al. Association between clozapine response and allelic variation in the 5-HT2C receptor gene. Neuroreport. 1995;7(1):169-172
  • Souery et al., 2001 D. Souery, S. Van Gestel, I. Massat, S. Blairy, R. Adolfsson, D. Blackwood, et al. Tryptophan hydroxylase polymorphism and suicidality in unipolar and bipolar affective disorders: a multicenter association study. Biol. Psychiatry. 2001;49(5):405-409
  • Souza et al., 2010 R.P. Souza, V. de Luca, H.Y. Meltzer, J.A. Lieberman, J.L. Kennedy. Influence of serotonin 3A and 3B receptor genes on clozapine treatment response in schizophrenia. Pharmacogenet. Genomics. 2010;20(4):274-276
  • Stöber et al., 1996 G. Stöber, A. Heils, K.P. Lesch. Serotonin transporter gene polymorphism and affective disorder. Lancet. 1996;347(9011):1340-1341
  • Sullivan et al., 2009 G.M. Sullivan, R.T. Ogden, M.A. Oquendo, J.S. Kumar, N. Simpson, Y.Y. Huang, et al. Positron emission tomography quantification of serotonin-1A receptor binding in medication-free bipolar depression. Biol. Psychiatry. 2009;66(3):223-230
  • Sumiyoshi et al., 2010 T. Sumiyoshi, M. Tsunoda, Y. Higuchi, T. Itoh, T. Seo, H. Itoh, et al. Serotonin-1A receptor gene polymorphism and the ability of antipsychotic drugs to improve attention in schizophrenia. Adv. Ther.. 2010;27(5):307-313
  • Sun et al., 2012 J. Sun, K. Jayathilake, Z. Zhao, H.Y. Meltzer. Investigating association of four gene regions (GABRB3, MAOB, PAH, and SLC6A4) with five symptoms in schizophrenia. Psychiatry Res.. 2012;198(2):202-206
  • Suzuki et al., 2003 T. Suzuki, N. Iwata, Y. Kitamura, T. Kitajima, Y. Yamanouchi, M. Ikeda, et al. Association of a haplotype in the serotonin 5-HT4 receptor gene (HTR4) with Japanese schizophrenia. Am. J. Med. Genet. B Neuropsychiatr. Genet.. 2003;121B(1):7-13
  • Syagailo et al., 2001 Y.V. Syagailo, G. Stöber, M. Grässle, E. Reimer, M. Knapp, G. Jungkunz, et al. Association analysis of the functional monoamine oxidase A gene promoter polymorphism in psychiatric disorders. Am. J. Med. Genet.. 2001;105(2):168-171
  • Takekita et al., 2015 Y. Takekita, C. Fabbri, M. Kato, S. Nonen, S. Sakai, N. Sunada, et al. HTR1A gene polymorphisms and 5-HT1A receptor partial agonist antipsychotics efficacy in schizophrenia. J. Clin. Psychopharmacol.. 2015;35(3):220-227
  • Tauscher et al., 2002 J. Tauscher, S. Kapur, N.P. Verhoeff, D.F. Hussey, Z.J. Daskalakis, S. Tauscher-Wisniewski, et al. Brain serotonin 5-HT(1A) receptor binding in schizophrenia measured by positron emission tomography and [11C]WAY-100635. Arch. Gen. Psychiatry. 2002;59(6):514-520
  • Tee et al., 2010 S.F. Tee, T.J. Chow, P.Y. Tang, H.C. Loh. Linkage of schizophrenia with TPH2 and 5-HTR2A gene polymorphisms in the Malay population. Genet. Mol. Res.. 2010;9(3):1274-1278
  • Templeman et al., 2005 L.A. Templeman, G.P. Reynolds, B. Arranz, L. San. Polymorphisms of the 5-HT2C receptor and leptin genes are associated with antipsychotic drug-induced weight gain in Caucasian subjects with a first-episode psychosis. Pharmacogenet. Genomics. 2005;15(4):195-200
  • Theisen et al., 2004 F.M. Theisen, A. Hinney, T. Brömel, M. Heinzel-Gutenbrunner, M. Martin, J.C. Krieg, et al. Lack of association between the -759C/T polymorphism of the 5-HT2C receptor gene and clozapine-induced weight gain among German schizophrenic individuals. Psychiatr. Genet.. 2004;14(3):139-142
  • Tsai et al., 2002 S.J. Tsai, C.J. Hong, Y.W. Yu, C.H. Lin. 759C/T genetic variation of 5HT(2C) receptor and clozapine-induced weight gain. Lancet. 2002;360(9347):1790
  • Tsai et al., 2000 S.J. Tsai, C.J. Hong, Y.W. Yu, C.H. Lin, H.L. Song, H.C. Lai, et al. Association study of a functional serotonin transporter gene polymorphism with schizophrenia, psychopathology and clozapine response. Schizophr. Res.. 2000;44(3):177-181
  • Tsai et al., 1999 S.J. Tsai, H.J. Chiu, Y.C. Wang, C.J. Hong. Association study of serotonin-6 receptor variant (C267T) with schizophrenia and aggressive behavior. Neurosci. Lett.. 1999;271(2):135-137
  • Tut et al., 2000 T.G. Tut, J.L. Wang, C.C. Lim. Negative association between T102C polymorphism at the 5-HT2A receptor gene and bipolar affective disorders in Singaporean Chinese. J. Affect. Disord.. 2000;58(3):211-214
  • Ujike et al., 2008 H. Ujike, A. Nomura, Y. Morita, A. Morio, Y. Okahisa, T. Kotaka, et al. Multiple genetic factors in olanzapine-induced weight gain in schizophrenia patients: a cohort study. J. Clin. Psychiatry. 2008;69(9):1416-1422
  • Van Den Bogaert et al., 2006 A. Van Den Bogaert, K. Sleegers, S. De Zutter, L. Heyrman, K.F. Norrback, R. Adolfsson, et al. Association of brain-specific tryptophan hydroxylase, TPH2, with unipolar and bipolar disorder in a Northern Swedish, isolated population. Arch. Gen. Psychiatry. 2006;63(10):1103-1110
  • Vázquez-Bourgon et al., 2010 J. Vázquez-Bourgon, M.J. Arranz, I. Mata, J.M. Pelayo-Terán, R. Pérez-Iglesias, L. Medina-González, et al. Serotonin transporter polymorphisms and early response to antipsychotic treatment in first episode of psychosis. Psychiatry Res.. 2010;175(3):189-194
  • Vincent et al., 1999 J.B. Vincent, M. Masellis, J. Lawrence, V. Choi, H.M. Gurling, S.V. Parikh, et al. Genetic association analysis of serotonin system genes in bipolar affective disorder. Am. J. Psychiatry. 1999;156(1):136-138
  • Vogt et al., 2000 I.R. Vogt, D. Shimron-Abarbanell, H. Neidt, J. Erdmann, S. Cichon, T.G. Schulze, et al. Investigation of the human serotonin 6 [5-HT6] receptor gene in bipolar affective disorder and schizophrenia. Am. J. Med. Genet.. 2000;96(2):217-221
  • Wang et al., 2008 L. Wang, C. Fang, A. Zhang, J. Du, L. Yu, J. Ma, et al. The − 1019 C/G polymorphism of the 5-HT(1)A receptor gene is associated with negative symptom response to risperidone treatment in schizophrenia patients. J. Psychopharmacol.. 2008;22(8):904-909
  • Wang et al., 2007 L. Wang, L. Yu, G. He, J. Zhang, A.P. Zhang, J. Du, et al. Response of risperidone treatment may be associated with polymorphisms of HTT gene in Chinese schizophrenia patients. Neurosci. Lett.. 2007;414(1):1-4
  • Watanabe et al., 2007 Y. Watanabe, A. Nunokawa, N. Kaneko, T. Someya. The tryptophan hydroxylase 1 (TPH1) gene and risk of schizophrenia: a moderate-scale case–control study and meta-analysis. Neurosci. Res.. 2007;59(3):322-326
  • Wei et al., 2009 Z. Wei, L. Wang, J. Xuan, R. Che, J. Du, S. Qin, et al. Association analysis of serotonin receptor 7 gene (HTR7) and risperidone response in Chinese schizophrenia patients. Prog. Neuro-Psychopharmacol. Biol. Psychiatry. 2009;33(3):547-551
  • Williams et al., 1996 J. Williams, G. Spurlock, P. McGuffin, J. Mallet, M.M. Nöthen, M. Gill, et al. Association between schizophrenia and T102C polymorphism of the 5-hydroxytryptamine type 2a-receptor gene. European Multicentre Association Study of Schizophrenia (EMASS) group. Lancet. 1996;347(9011):1294-1296
  • Yasuno et al., 2004 F. Yasuno, T. Suhara, T. Ichimiya, A. Takano, T. Ando, Y. Okubo. Decreased 5-HT1A receptor binding in amygdala of schizophrenia. Biol. Psychiatry. 2004;55(5):439-444
  • Yevtushenko et al., 2008 O.O. Yevtushenko, S.J. Cooper, R. O'Neill, J.K. Doherty, J.V. Woodside, G.P. Reynolds. Influence of 5-HT2C receptor and leptin gene polymorphisms, smoking and drug treatment on metabolic disturbances in patients with schizophrenia. Br. J. Psychiatry. 2008;192(6):424-428
  • Yu et al., 1999 Y.W. Yu, S.J. Tsai, C.H. Lin, C.P. Hsu, K.H. Yang, C.J. Hong. Serotonin-6 receptor variant (C267T) and clinical response to clozapine. Neuroreport. 1999;10(6):1231-1233
  • Zaboli et al., 2006 G. Zaboli, E.G. Jönsson, R. Gizatullin, M. Asberg, R. Leopardi. Tryptophan hydroxylase-1 gene variants associated with schizophrenia. Biol. Psychiatry. 2006;60(6):563-569
  • Zhang et al., 2004 X.N. Zhang, S.D. Jiang, X.H. He, L.N. Zhang. 102T/C SNP in the 5-hydroxytryptamine receptor 2A (HTR2A) gene and schizophrenia in two southern Han Chinese populations: lack of association. Am. J. Med. Genet. B Neuropsychiatr. Genet.. 2004;126B(1):16-18

Footnotes

a Laboratory of Forensic Medicine & Toxicology, Faculty of Medicine, School of Health Sciences, University of Ioannina, 45110 Ioannina, Greece

b Psychiatric Clinic, University Hospital of Ioannina, 45110 Ioannina, Greece

Corresponding author at: Laboratory of Forensic Medicine & Toxicology, Faculty of Medicine, School of Health Sciences, University of Ioannina, 45110 Ioannina, Greece.