Review article
The role of 5-HT2C receptor polymorphisms in the pharmacogenetics of antipsychotic drug treatment

https://doi.org/10.1016/j.pnpbp.2005.03.019Get rights and content

Abstract

The development of novel, atypical antipsychotics has been welcomed due to their lower incidence of extrapyramidal side effects. However, as with all pharmacotherapy, patient response is often varied and these novel compounds are not without their own side effect profile, most notably weight gain. Inter-individual variations in response to drug treatment are, in part, due to polymorphisms of the genes encoding drug targets. The importance of the serotonin system in psychiatric symptomatology and several side effects of antipsychotic drugs is well established. Thus genetic polymorphisms of two central 5-HT receptors (5-HT2A and 2C), at which many of the newer antipsychotic drugs act, are prime candidates for pharmacogenetic analysis of the effects of these drugs in the treatment of schizophrenia. To date, much work has focussed on the 5-HT2A receptor subtype. However, pharmacological evidence and recent molecular genetic studies would suggest a role for the 5-HT2C receptor in the consequences of antipsychotic treatment, particularly in relation to the development of both drug-induced dyskinesias and weight gain. This review briefly examines the pharmacology and physiology of the 5HT2C receptor in the context of its genetics, with discussion of known polymorphisms of this receptor gene and its promoter region. Associations between these polymorphisms and the development of schizophrenia, the symptom responses to antipsychotic treatment and side effects of such treatment, notably tardive dyskinesia and weight gain, are assessed and related to the presumed functionality of these polymorphisms. Such studies clearly demonstrate the potential of pharmacogenetics in optimising treatment for the individual patient.

Introduction

The past 15 years has seen many changes in the drug treatment of schizophrenia. In that time the introduction of the newer, atypical, antipsychotic drugs has provided medication which in many ways is more tolerable and with reduced incidence of certain side effects. With these new drugs there is no reason why any patient should suffer the acute extrapyramidal motor symptoms (EPS) such as parkinsonism which have been such a limiting side effect of treatment with the older antipsychotics.

While dopamine D2 receptor antagonism remains the major antipsychotic mechanism, the pharmacology underlying the relative freedom from EPS of the newer antipsychotic drugs is not fully understood, although antagonism at 5-HT2 receptors has long been considered to have a, if not the, major contributory action. Other receptor mechanisms have been implicated in this “atypicality” and the improved effects of the atypical drugs; these include alpha2 adrenoceptors, dopamine D3 receptors and low affinity antagonism at the D2 receptor. However, the concept of D2/5-HT2 receptor antagonism as the essential pharmacology underlying effective, atypical antipsychotic action (Meltzer et al., 1989) has had enormous influence on drug development; antagonism at 5-HT2 receptors appears to be a feature common to all the new antipsychotic drugs introduced in the decade or so prior to 2002.

There are two major 5-HT2 receptor subtypes in the human brain: the 5-HT2A and 5-HT2C receptors. Most pharmacological investigation into antipsychotic drug mechanisms has concentrated on the former receptor, partly reflecting the fact that several hallucinatory drugs have 5-HT2A agonist activity (Aghajanian and Marek, 1999). 5-HT2A receptor antagonists can diminish EPS associated with D2 receptor blockade, although both clinical observation and laboratory studies have shown that 5-HT2A antagonism is unable to provide complete protection. Moreover, it is notable that high doses of the classical antipsychotic chlorpromazine can induce 5-HT2A blockade equivalent to that of the atypical clozapine (Trichard et al., 1998), providing a strong argument against the central importance of this receptor in clozapine's freedom from EPS. Antagonism at this receptor is also proposed to ameliorate the negative symptoms of schizophrenia (Gelders, 1989), albeit with little unequivocal evidence from clinical practice.

The 5-HT2C receptor has received less attention in psychopharmacology. This may relate to the inadequacy of specific techniques (e.g. radioligand binding and immunocytochemistry) to determine the receptor in tissue samples. However evidence from a variety of sources has implicated this receptor in several important physiological and psychological processes including motor function, anxiety and ingestive behaviour. In addition, some interesting pharmacogenetic observations, which will be the subject of this review, have focused on the potential importance of this receptor in several aspects of antipsychotic drug action.

Section snippets

The 5-HT2C receptor: functional molecular biology, pharmacology and physiology

The 5-HT2C receptor is found in the choroid plexus, prefrontal cortex and limbic structures of the human brain (Marazziti et al., 1999). Like 5-HT2A, these receptors are postsynaptic with the classical 7-transmembrane spanning domains associated with G-protein coupled receptors. 5-HT2 receptors are excitatory and positively couple via Gq to phospholipase A2 and phospholipase C. Thus stimulation of the receptors leads to an accumulation of inositol phosphates and Ca2+ within the postsynaptic

5-HT2C polymorphisms and their functional effects

There are several polymorphisms of the 5-HT2C receptor gene that have attracted substantial interest in genetic studies. Pharmacogenetic investigations have concentrated primarily on a common single nucleotide polymorphism (SNP) in the coding region (68G/C) resulting in an amino acid substitution at codon 23: cys23ser (Lappalainen et al., 1995). Although this SNP has an effect on the structure of the receptor protein, with a substitution occurring in the extracellular N-terminal region, there

Schizophrenia, symptom response and 5-HT2C polymorphisms

Initial investigation of 5-HT receptor polymorphisms in schizophrenic patients were unable to identify any significant association with the disease itself (Sodhi et al., 1995, Wu et al., 1995). However, the editing of 5-HT2C receptor RNA is reportedly reduced in the brain in schizophrenia, predicting a relatively increased expression of the INI receptor isoform (Sodhi et al., 2001). Whether this is a genetic phenomenon is unclear, since in the absence of mutations or SNP associations it is

Tardive dyskinesia and 5-HT2C polymorphisms

Tardive dyskinesia (TD) is a serious adverse drug effect characterised by the delayed appearance of involuntary movements, affecting roughly 25% of schizophrenic patients chronically treated with classical antipsychotic drugs. Known risk factors predisposing to TD include type, dosage and duration of drug treatment, prior extrapyramidal side effects, age and presence of affective disorder (Owens, 1999). Genetic factors are also important in TD. There is strong concordance for the presence or

Drug induced weight gain and 5-HT2C polymorphisms

Although novel antipsychotics have been associated with a paucity of EPS, they are not entirely free of side effects. One of the most common side effects of these compounds is weight gain, which is likely to contribute to poor treatment adherence as well as having major effects on morbidity including hypertension and late-onset diabetes (Wirshing et al., 1998). Both clozapine and olanzapine can induce profound weight gain and many novel antipsychotics appear to cause more weight gain than

Conclusions and synthesis

There remains substantial interest in the role of 5-HT2C receptor gene polymorphisms in determining several of the consequences of antipsychotic drug treatment of schizophrenia. Although much work has concentrated on the cys23ser polymorphism, recent findings with the promoter region polymorphisms suggest that these may be more informative and provide stronger predictive associations. The success of this approach certainly supports the suggestion that the promoter region polymorphisms do have

Acknowledgements

Some of the research reported here has had support from a grant to ZJZ by the China National Natural Sciences Foundation; LAT is supported by a grant to GPR from Pfizer Pharmaceuticals.

References (56)

  • D. Marazziti et al.

    Distribution and characterization of [3H]mesulergine binding in human brain postmortem

    Eur. Neuropsychopharmacol.

    (1999)
  • M. Masellis et al.

    Serotonin subtype 2 receptor genes and clinical response to clozapine in schizophrenia patients

    Neuropsychopharmacology

    (1998)
  • K. Quirk et al.

    Characterisation of agonist binding on human 5-HT2C receptor isoforms

    Eur. J. Pharmacol.

    (2001)
  • G.P. Reynolds et al.

    Association of antipsychotic drug-induced weight gain with a 5-HT2C receptor gene polymorphism

    Lancet

    (2002)
  • G.P. Reynolds et al.

    Pharmacogenetics of treatment in first-episode schizophrenia: D3 and 5-HT2C receptor polymorphisms separately associate with positive and negative symptom response

    Eur. Neuropsychopharmacol.

    (2005)
  • H.R. Song et al.

    Identification of a new polymorphism in the 3′-untranslated region of the human serotonin receptor 2C (5-HT2C) gene

    Mol. Genet. Metab.

    (1999)
  • S.J. Tsai et al.

     759C/T genetic variation of 5HT(2C) receptor and clozapine-induced weight gain

    Lancet

    (2002)
  • D. Van Oekelen et al.

    5-HT2A and 5-HT2C receptors and their atypical regulation properties

    Life Sci.

    (2003)
  • J. Veenstra-VanderWeele et al.

    Pharmacogenetics and the serotonin system: initial studies and furure directions

    Eur. J. Pharmacol.

    (2000)
  • D.A. Wirshing et al.

    Novel antipsychotics and new onset diabetes

    Biol. Psychiatry

    (1998)
  • B.C-T. Wu et al.

    Analysis of serotonin 5HT2 and 5HT1A receptor coding sequences in schizophrenia patients and control subjects

    Schizophr. Res.

    (1995)
  • E. Xie et al.

    The human serotonin 5-HT2C receptor: complete cDNA, genomic structure, and alternatively spliced variant

    Genomics

    (1996)
  • D.B. Allison et al.

    Antipsychotic-induced weight gain: a comprehensive research synthesis

    Am. J. Psychiatry

    (1999)
  • V.S. Basile et al.

    Genetic dissection of atypical antipsychotic-induced weight gain: novel preliminary data on the pharmacogenetic puzzle

    J. Clin. Psychiatry

    (2001)
  • J.E. Blundell

    Is there a role for serotonin (5-hydroxytryptamine) in feeding?

    Int. J. Obes.

    (1977)
  • S.J. Briddon et al.

    Comparative desensitization of the human 5-HT2A and 5-HT2C receptors expressed in the human neuroblastoma cell line SH-SY5Y

    Br. J. Pharmacol.

    (1998)
  • C.M. Burns et al.

    Regulation of serotonin-2C receptor G-protein coupling by RNA editing

    Nature

    (1997)
  • V.L. Ellingrod et al.

    5HT2A and 5-HT2C receptor polymorphisms and predicting clinical response to olanzapine in schizophrenia

    J. Clin. Psychopharmacol.

    (2002)
  • Cited by (123)

    • Functional pharmacogenetics of serotonin receptors in psychiatric drug action

      2020, Handbook of Behavioral Neuroscience
      Citation Excerpt :

      In a physiologically relevant human neuroblastoma cell line, the minor -759T and -697C alleles demonstrated relatively reduced promoter activity (Hill & Reynolds, 2007), a consequence of the loss of binding of presumed transcription factor proteins (Hill & Reynolds, 2011). In a small study in postmortem tissue reported in Reynolds, Templeman, and Zhang (2005a), a significant association between -759C/T genotype and receptor density in human brain could not be identified. There are several studies of 5-HT2C polymorphisms and their association with drug response.

    • Pharmacogenetics

      2018, Handbook of Clinical Neurology
      Citation Excerpt :

      5HT2C receptors are differentially antagonized by antipsychotic medications, with clinical correlations observed between some medications (i.e., clozapine and olanzapine) with higher 5HT2C affinity and weight gain during treatment. The T allele of a promoter region SNP in HTR2C, rs3813929 (aka -759C > T), that may increase 5HT2C expression, has been repeatedly associated with clinically significant weight gain (> 7% of baseline body weight), with C allele carriers at over three times greater risk (Reynolds et al., 2005; Zhang et al., 2016). These effects of 5HT2C antagonism by antipsychotics are consistent with rodent models suggesting that the absence of 5HT2C receptors results in difficulties in regulating body weight and food intake (Lam et al., 2008).

    View all citing articles on Scopus
    View full text