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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


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
 (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)
 (PM) BP, SZ ↑ mRNA Hippocampus López-Figueroa et al. (2004)
SZ ~ mRNA Dorsolateral prefrontal cortex López-Figueroa et al. (2004)
 (PM) SZ ~ Binding Dorsolateral prefrontal cortex, hippocampus Dean et al. (2006), Scarr et al. (2004)
 (PM) SZ ↓ Binding Hippocampus Scarr et al. (2004)
~ Binding Prefrontal cortex Dean et al. (2006)
 (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)
 (PM) SZ ↓ mRNA Prefrontal cortex Castensson et al. (2003)
 (PM) SZ ~ Binding Prefrontal cortex, hippocampus Scarr et al. (2004), Dean et al. (1999b)
 (PM) SZ ↓ mRNA Hippocampus East et al. (2002a)
~ mRNA Dorsolateral prefrontal cortex East et al. (2002a)
~ Binding Dorsolateral prefrontal cortex East et al. (2002b)
 (PM) SZ ↓ mRNA Prefrontal cortex East et al. (2002a)
~ mRNA Hippocampus East et al. (2002a)
↓ Binding Prefrontal cortex (BA9) Dean et al. (2006)
 (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)
 (PM) BP ↑ mRNA Dorsolateral prefrontal cortex De Luca et al. (2005)
 (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
 − 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)
 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)
 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)
 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)
 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)
 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)
 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)
 C523A or Asn163Lys (AA), G1248Cor Gly405Ala (GG) SZ Effect on negative and total PANNS score at admission Schuhmacher et al. (2009)
 A380G or His52Arg (Heterozygotes) SZ ↑ Frequency in females Lennertz et al. (2010)
 A450G orThr86Ala (GG) SZ ↑ Age; ↑ cognitive function Lennertz et al. (2010)
 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)
 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)
 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)
 rs3808932, rs12412496 (A alleles) SZ ↑ Frequency Ikeda et al. (2006a)
 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)
 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)
 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)
 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.


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.


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).


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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.