You are here

Article Text

Article menu

Download PDFPDF

Meta-analysis
Association of the HTR2C-759C/T polymorphism and antipsychotic-induced weight gain: a meta-analysis
  1. Yan Chen,
  2. Yewei Wang,
  3. Xinyu Fang,
  4. Yi Zhang,
  5. Lisheng Song and
  6. Chen Zhang
  1. Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine Affiliated Shanghai Mental Health Center, Shanghai, China
  1. Correspondence to Dr Chen Zhang; zhangchen645{at}gmail.com

Abstract

Background Antipsychotic-induced weight gain (AIWG) is a crucial factor for the medication cessation of patients with schizophrenia. Multiple studies have shown that the functional polymorphism -759 C/T (rs3813929) in the HTR2C promoter region could possibly be correlated with AIWG.

Aim To evaluate the genetic association of the HTR2C-759C/T polymorphism and AIWG in patients with schizophrenia with antipsychotic drugs (APDs) administration.

Methods Eligible studies were identified by searching the following databases: PubMed, Embase, Web of Science, China Nation Knowledge Infrastructure (CNKI), VIP, Wanfang Data, Chinese Biomedical Literature Database (CBM) and the Airiti Library. The quality of studies was evaluated based on the Newcastle-Ottawa Scale. The pooled OR and 95% CI were calculated for the dominant (CT/TT/T vs CC/C) mode, and subgroup analyses were performed based on ethnicity, antipsychotic medication and gender; all statistical analyses were performed using the statistical software STATA V.12.0.

Result A total of 17 studies with 3170 patients with schizophrenia were included in our meta-analysis. The result of the meta-analysis has shown that the association between the -759 C/T polymorphism and AIWG is statistically significant (OR 0.34, 95% CI: 0.20 to 0.57, z=4.11, p<0.001). The subgroup analyses revealed significant correlations between the -759 C/T polymorphism and AIWG in the Caucasian population (OR 0.33, 95% CI: 0.14 to 0.77, z=2.55, p=0.011), the Asian population (OR 0.31, 95% CI: 0.18 to 0.52, z=4.46, p<0.001), the patients with APDs administration (CT/TT/T vs CC/C: OR 0.63, 95% CI: 0.40 to 1.00, z=1.97, p=0.049) and the patients with atypical antipsychotic drug administration (CT/TT/T vs CC/C: OR 0.21, 95% CI: 0.09 to 0.47, z=3.83, p<0.001). The sensitivity analysis showed that the results were stable. Begg’s test (after correction z=1.07, p=0.287) and Egger’s test (t=−2.41, p=0.029) show that the included articles have no significant publication bias.

Conclusion There is a significant genetic association between HTR2C-759C/T and AIWG, and patients with T allele are less likely to have AIWG.

  • schizophrenia
  • meta-analysis as topic
http://creativecommons.org/licenses/by-nc/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

https://doi.org/10.1136/gpsych-2020-100192

Statistics from Altmetric.com

    Request Permissions

    If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.

    Introduction

    Schizophrenia is a highly prevalent complex neuropsychiatric disease, and the pathophysiology is yet to be fully elucidated. Antipsychotic drugs (APDs) are the primary treatment methods for schizophrenia. Nevertheless, antipsychotic-induced weight gain (AIWG), a serious side effect, leads to increased risk for cardiovascular morbidity and social withdrawal and therefore is a crucial factor for the cessation of medication.1 2

    The variability of AIWG among inter-racial and inter-individual along with the results of twin and adoption studies had suggested that the genetic factor plays an important role in AIWG. The gene of 5-hydroxytryptamine 2C receptor (5-HT2CR), HTR2C, is located at chromosome Xq23, and its expression product 5-HT2CR has a role in the mechanism of antipsychotic medication. Furthermore, atypical antipsychotic drugs (AAPs) that are prone to induce AIWG have a better affinity to 5-HT2CR than typical antipsychotic drugs (TAPs).3 Numerous studies have consistently pinpointed that the changes of the serotonin system have a great effect on food and body weight regulation. High activity of 5-HT2CR decreases the appetite of mice, whereas the antagonists have an opposite effect. Furthermore, 5-HT2CR-deficient mice adopted an abnormal control of feeding behaviour, resulting in obesity and hyperglycaemias.4–6 Taken together, previous genetic studies have found that a constellation of single-nucleotide polymorphisms in HTR2C is related to AIWG; the relationship between the -759 C/T (rs3813929) polymorphism and AIWG is an active field of research, but the results are controversial. Two earlier meta-analyses7 8 ignored a number of studies in China; therefore, we performed a meta-analysis applying both English and Chinese databases to assess whether HTR2C -759 C/T is associated with AIWG.

    Methods

    Search strategy

    A literature search of English (PubMed, Embase, Web of Science) and Chinese (China Nation Knowledge Infrastructure (CNKI), Wanfang Data, VIP, Chinese Biomedical Literature Database (CBM), the Airiti Library) databases was conducted for eligible articles published up until 31 December 2018, using key words “Weight gains”, “schizophrenia”, “polymorphism” and “HTR2C”.

    Inclusion and exclusion criteria

    Studies were selected according to the following criteria presented using the acronym, PICOS: Participants (P): adult patients diagnosed with schizophrenia based on the Diagnostic and Statistical Manual of Disorder (DSM), International Statistical Classification of Diseases and Related Health Problems (ICD) or Chinese Classification of Mental Disorders (CCMD), while the HTR2C-759C/T (rs3813928) polymorphism was genotyped. Intervention (I): administration with antipsychotics. Comparison (C): patients with AIWG or not. Outcomes (O): the primary outcome included genotype frequencies, and the number or proportion of patients with weight gain in each genotype group. Study design (S): Case-control studies and cohort studies with meta-analysable data.

    Studies were excluded according to the following criteria: (1) animal experiments; (2) patients enrolled had organic brain disease or were in medical conditions that could affect the weight (ie, hyperthyroidism, diabetes, etc); (3) studies with errors or incomplete data; (4) not published in Chinese or English languages; (5) only select the most complete study if a repeated publication or an overlapping sample existed.

    Assessment of study quality and data extraction

    According to the Newcastle-Ottawa Scale (NOS),9 the quality of the included literature was evaluated based on three aspects: the selection of the research population (full score of 4), the comparability between groups (full score of 2) and the measurement of exposure factors (full score of 3), with a total score of 9 points.

    The following data were extracted: study population characteristics (ie, country, population, gender, age, diagnosis), sample size, prior antipsychotic medication, type of antipsychotic medication, duration of treatment, definition of weight gain, conclusions and NOS score. Genotype or allele frequencies were calculated if not given directly in the articles.

    Quality evaluation and data extraction were completed by two researchers (YC and Y-WW) independently. Inconsistent opinion was resolved by discussion or assistance from a third researcher (XYF).

    Statistical methods

    The presence of AIWG was analysed as a binary variable, which was defined by the original diagnostic definition applied in each study. The relationship between the HTR2C -759 C/T polymorphism and AIWG in patients with schizophrenia was measured by using OR and 95% CI. In addition, multiple studies10–21 demonstrated that the T allele has a dominant effect, indicating that it is more difficult for patients with the T allele (CT/TT/T) to suffer from AIWG than the homozygous wild type (CC/C). Therefore, we applied the dominant mode (CT/TT/T vs CC/C) to calculate ORs and 95% CI.

    Heterogeneity was assessed using the χ2 test–based Cochran Q test. The quantification of heterogeneity was evaluated using an I2 index that approximately had values from 0% to 100%.

    According to the Cochrane Handbook for Systematic Reviews of Interventions, if I2 <40%, it can be considered that the heterogeneity of the included literature is not important; 30%–60% may be considered to have moderate heterogeneity; 50%–90% may be considered to have substantial heterogeneity; 75%–100% may have considerable heterogeneity. If p value >0.10 or I2 <50%, the fixed-effect model (Mantel-Haenszel) was used to pool the data from included studies. Otherwise, the random-effect model (DerSimonian-Laird) was performed. We used Z test to assess the statistical significance of the pooled ORs. Meta-regression was performed to detect the source of heterogeneity.

    Publication bias was detected by using Begg’s funnel plot and Egger’s regression test in the meta-analysis; a p value <0.01 indicates the existence of significant publication bias. Other than the tests for heterogeneity and publication bias, all analyses were two tailed, and the level of significance was set at 0.05.

    All statistical analyses were performed using STATA V.12.0 (Stata, College Station, TX, USA).

    Results

    Results of search

    A total of 374 studies were found, including 319 studies from the English databases and 55 studies from the Chinese databases. After removing duplicated articles, 249 studies remained. Irrelevant studies were subsequently screened based on titles and abstracts and 34 remained. After reviewing full-text articles, 17 of the 34 studies were excluded. Among the 17 studies, 16 of them had incomplete data22-37; one of them employed a repeated sample.38 In the end, 17 articles were included in this meta-analysis (figure 1).

    Figure 1
    Figure 1

    Flowchart of the search process

    Characteristics of eligible studies

    In total, of the 17 studies included in this meta-analysis, 8 of them were studies of Asians10 11 15 16 19 20 39 40 including 1696 patients, and 9 were Caucasian7 12–14 17 18 21 41 42 including 1474 patients. Nine of the studies provide gender group data,7 11 16 18–21 40 41 and seven of the nine studies provide data that could be used for calculating allele frequencies.7 11 16 18 19 40 42 The NOS scores of the eligible studies were distributed between 7 and 9, indicating their relatively high quality. We divided patients into the ADP and AAP groups as different types of antipsychotic medication. The antipsychotic treatments administered in the ADP group consisted of typical antipsychotics (TAPs) or combined with AAPs; nevertheless, patients of the AAP group received monotherapy with AAPs. Details are shown in table 1.

    View this table:
    Table 1

    Characteristics of the eligible studies

    Meta-analysis results

    There is heterogeneity among the eligible studies (I2=67.9%, ph<0.001); therefore, a random-effect model was used to combine the data. The meta-analysis result showed that there is a significant correlation (CT/TT/T vs CC/C: OR 0.34, 95% CI: 0.20 to 0.57, z=4.11, p<0.001) between the HTR2C-759C/T polymorphism and AIWG in patients with schizophrenia; the patients with T allele on -759 C/T (CT/TT/T) are less likely to gain weight.

    We then performed subgroup analyses to evaluate the effect of ethnicity, type of antipsychotic medication and gender. As for ethnicity, we found that patients with T allele are not prone to experience AIWG, whether they are Caucasian (CT/TT/T vs CC/C: OR 0.33, 95% CI: 0.14 to 0.77, z=2.55, p=0.011) or Asian (CT/TT/T vs CC/C: OR 0.31, 95% CI: 0.18 to 0.52, z=4.46, p<0.001). In addition, it is worth mentioning the heterogeneity results—the European population subgroup is highly heterogeneous (I2=75.2%, ph<0.001) while the heterogeneity of the Asian population is not significant (I2=38%, ph=0.127) (figure 2).

    Figure 2
    Figure 2

    Meta-analysis forest plot of the genetic correlation of HTR2C-759C/T polymorphism and antipsychotic-induced weight gain (subgroup analysis based on ethnicity).

    As for the type of antipsychotic medication, the patients were divided into the ADP and AAP groups, and the results showed that the -759 C/T polymorphism is significantly correlated with AIWG in both the population that received ADPs (CT/TT/T vs CC/C: OR 0.63, 95% CI: 0.40 to 1.00, z=1.97, p=0.049) and the population that received AAPs (CT/TT/T vs CC/C: OR 0.21, 95% CI: 0.09 to 0.47, z=3.83, p<0.001). The results of the heterogeneity test suggested that the AAP subgroup population is highly heterogeneous (I2=74.8%, ph<0.001), whereas the ADP subgroup has insignificant heterogeneity (I2=14.4%, ph=0.320) (figure 3).

    Figure 3
    Figure 3

    Meta-analysis forest plot of the genetic association between HTR2C-759C/T polymorphism and antipsychotic-induced weight gain (subgroup analysis based on the type of antipsychotic medication). AAP, atypical antipsychotic drug; APD, antipsychotic drug.

    It is noteworthy that HTR2C is located on chromosome X; of the included studies in this meta-analysis, nine studies provide gender group data and only seven studies provide data that could be used for calculating allele frequencies. The results demonstrated that the HTR2C-759C/T polymorphism is significantly correlated with AIWG in both the male and female populations. However, there was no statistical significance in the result of allele analysis. Details are shown in table 2.

    View this table:
    Table 2

    Results of allele analysis and the subgroup analysis based on gender

    Heterogeneity analysis and sensitivity analysis

    The result of the heterogeneity test (I2=67.9%, ph<0.001) has suggested that there is significant heterogeneity among the included studies. Meta-regression was performed to further explore the source of heterogeneity, and potential confounding variables included population (Asia, America, Europe or mixed samples), type of antipsychotic medication (APDs or AAPs), publication year, sample size, definition of weight gain (7% increase in body weight/body mass index (BMI) or 10% increase in body weight/BMI) and NOS score. It is found that the American population (t=−1.88, p=0.079; corrected R2=17.13%) and type of antipsychotic medication (t=−1.94, p=0.071; corrected R2=17.69%) might be the main sources of heterogeneity, which can explain 17.13% and 17.69% of heterogeneity, respectively. Inserting each study to meta-regression, we found that the study of Kuzman et al 42 is the main source of heterogeneity (t=2.26, p=0.018; corrected R2=47.45%), which can explain 47.75% of heterogeneity.

    In terms of the sensitivity analysis, we conducted the analysis by excluding one included study at a time to determine the impact of each study on the combined effect size (figure 4). The result showed that the Kuzman 2008 study has a great effect on OR value and its 95% CI, further validating that the Kuzman 2008 study was the main source of heterogeneity of this meta-analysis. However, this study had not affected the final direction of the results, so the results of this meta-analysis are relatively stable.

    Figure 4
    Figure 4

    Sensitivity analysis.

    Publication bias

    Publication bias is roughly determined by Begg's funnel plot (figure 5) and identified quantitatively by the combination of Begg’s rank correlation test and Egger’s regression test. Begg's funnel plot showed that the distribution of each study is not completely symmetrical, suggesting the possibility of publication bias. The result of Begg’s rank correlation test (z=1.07, p=0.284) and Egger’s regression test (t=−2.41, p=0.029) suggested that publication bias was not significant in all eligible studies.

    Figure 5
    Figure 5

    Begg’s funnel plot.

    Discussion

    Main findings

    The 5-HT2C receptor has played an important role in regulating the digestion function and the pharmacological mechanism of AAPs. A number of studies have found that the mutation of HTR2C is correlated with AIWG.3–6 The -759 C/T polymorphism is located at the promoter region of HTR2C and associated with the ability to bind the transcription factor, affecting the expression of gene production.21

    This article has unprecedentedly used the complete Chinese database and conducted analyses on the correlation between HTR2C-759C/T and AIWG by using evidence-based medicine methods.

    A quality assessment of the included studies was performed according to the NOS, and the included studies have primarily lost points on the absence of an illustration of the pre-existence of metabolic diseases among the included patients before the experiment, and the confounding factors (such as type of antipsychotic medication) in the research process were not controlled. On average, the scores of the final included articles were within 7–9, indicating that the overall quality is high. Therefore, the results of this meta-analysis were relatively reliable. Among the 17 studies7 10–21 39–42 included, 10 studies10–17 19 showed that T allele had a significant weight protection effect, 2 studies18 20 showed that T allele had a tendency of a weight protection effect, but 5 studies7 39–42 showed that the difference was not statistically significant. The results of the meta-analysis showed that the HTR2C-759C/T polymorphism was significantly correlated with AIWG in schizophrenia, and the patients with T allele are less likely to have an increase in body weight compared with the homozygous wild type (CC/C) in the process of antipsychotic intake medication. Subgroup analyses suggested that the conclusion can be applied to all the groups, and the protective effect of T allele is more significant in the AAP group than in the APD group, for the possible reason that AAPs are more likely to result in weight gain.3 However, there was overlapping in the CIs of the two groups, indicating that there is no statistical significance despite the difference in tendency of the influence magnitude of the -759 C/T polymorphism on AIWG between the two groups.

    Owing to the influence of chromosomes, hormones and different living habits, the occurrence and characteristics of metabolic-related diseases such as weight gain have gender differences.43 44 Furthermore, the HTR2C gene is located on chromosome X; it is necessary to perform a subgroup analysis of gender stratification. Nevertheless, the provision of related data in the included studies is limited, the total sample size is relatively insufficient and the heterogeneity is high. Although the analyses results showed significant correlation between the HTR2C-759C/T polymorphism and AIWG in the male and female populations, and the T allele has a stronger protective effect on weight gain in the female population than the male population, the authenticity is still uncertain. For the possible association with few included data, the allele analysis had not shown significant results.

    Generally, this meta-analysis has suggested that a significant association between the HTR2C-759C/T polymorphism and AIWG. The T allele of HTR2C-759C/T polymorphism has a protective effect on AIWG. Although the heterogeneity test showed that the included studies are of high heterogeneity, the sensitivity analysis and publication bias showed that the results of this study were relatively stable and have no significant publication bias.

    Limitation

    Our meta-analysis must be interpreted with some limitations. First, we use ORs for the estimation of effect size, only including the literature that provided the quantity or proportion of patients with a significant increase on weight or BMI in each genotype group, but not the literature that merely provided specific weight gain data. Although an OR is more clinically meaningful than the standard mean difference, it is undeniable that we have abandoned a lot of meaningful clinical data, resulting in a decrease in the number of included studies and a reduction in the effectiveness of the tests. Second, regarding the publication bias, the relevant results show that the publication bias is not significant, but it still exists, and some negative results may not have been published. In addition, the studies we have included were publicly published and the language is either Chinese or English. This may lead to the omission of relevant literature published in countries in which the native language is not Chinese or English, causing certain biases.

    Implications

    AIWG is a rigorous problem in the treatment of schizophrenia, and there is still not an effective way to reverse AIWG. In response to this situation, conducting genetic research on AIWG is of great significance for identifying the high-risk population so as to guide them in drug selection. In addition, the eventual result direction aligns by comparing this article with the previous meta-analysis, suggesting a significant association between the HTR2C-759C/T polymorphism and AIWG and a protective effect of the T allele against AIWG. In comparison with the previous meta-analyses, this article supplements a lot of Chinese research, and the included studies were more comprehensive, with a larger total sample size and higher power of test.

    References

    1. ↵
      2. Lieberman JA
      . Effectiveness of antipsychotic drugs in patients with chronic schizophrenia: efficacy, safety and cost outcomes of CATIE and other trials. J Clin Psychiatry 2007;68:e04.doi:10.4088/jcp.0207e04 pmid:http://www.ncbi.nlm.nih.gov/pubmed/17335312
      OpenUrlPubMed
    2. ↵
      2. Raben AT ,
      3. Marshe VS ,
      4. Chintoh A , et al
      . The complex relationship between antipsychotic-induced weight gain and therapeutic benefits: a systematic review and implications for treatment. Front Neurosci 2017;11:741.doi:10.3389/fnins.2017.00741 pmid:http://www.ncbi.nlm.nih.gov/pubmed/29403343
      OpenUrlPubMed
    3. ↵
      2. Jeon SW ,
      3. Kim Y-K
      . Unresolved issues for utilization of atypical antipsychotics in schizophrenia: antipsychotic polypharmacy and metabolic syndrome. Int J Mol Sci 2017;18:2174.doi:10.3390/ijms18102174 pmid:http://www.ncbi.nlm.nih.gov/pubmed/29057817
      OpenUrlPubMed
    4. ↵
      2. Puangpetch A ,
      3. Unaharassamee W ,
      4. Jiratjintana N , et al
      . Genetic polymorphisms of HTR2C, Lep and Lepr on metabolic syndromes in patients treated with atypical antipsychotic drugs. J Pharm Pharmacol 2018;70:536–42.doi:10.1111/jphp.12892 pmid:http://www.ncbi.nlm.nih.gov/pubmed/29441581
      OpenUrlPubMed
    5. ↵
      2. Blundell JE
      . Is there a role for serotonin (5-hydroxytryptamine) in feeding? Int J Obes 1977;1:15–42.
      OpenUrlPubMedWeb of Science
    6. ↵
      2. Tecott LH ,
      3. Sun LM ,
      4. Akana SF , et al
      . Eating disorder and epilepsy in mice lacking 5-HT2C serotonin receptors. Nature 1995;374:542–6.doi:10.1038/374542a0 pmid:http://www.ncbi.nlm.nih.gov/pubmed/7700379
      OpenUrlCrossRefPubMedWeb of Science
    7. ↵
      2. Sicard MN ,
      3. Zai CC ,
      4. Tiwari AK , et al
      . Polymorphisms of the HTR2C gene and antipsychotic-induced weight gain: an update and meta-analysis. Pharmacogenomics 2010;11:1561–71.doi:10.2217/pgs.10.123 pmid:http://www.ncbi.nlm.nih.gov/pubmed/21121776
      OpenUrlCrossRefPubMed
    8. ↵
      2. Ma X ,
      3. Maimaitirexiati T ,
      4. Zhang R , et al
      . HTR2C polymorphisms, olanzapine-induced weight gain and antipsychotic-induced metabolic syndrome in schizophrenia patients: a meta-analysis. Int J Psychiatry Clin Pract 2014;18:229–42.doi:10.3109/13651501.2014.957705 pmid:http://www.ncbi.nlm.nih.gov/pubmed/25152019
      OpenUrlPubMed
    9. ↵
      2. Wells GA ,
      3. Shea B ,
      4. O’Coneell D , et al
      . The Newcastle-Ottawa scale (NOS) for assessing the quality of nonrandomized studies in meta-analysis, 2011. Available: www.ohri.ca/programs/clinical_epidemiology/oxford.asp [Accessed 25 Mar 2019].
    10. ↵
      2. Reynolds GP ,
      3. Zhang Z-J ,
      4. Zhang X-B
      . Association of antipsychotic drug-induced weight gain with a 5-HT2C receptor gene polymorphism. Lancet 2002;359:2086–7.doi:10.1016/S0140-6736(02)08913-4 pmid:http://www.ncbi.nlm.nih.gov/pubmed/12086765
      OpenUrlCrossRefPubMedWeb of Science
    11. ↵
      2. Zhang Z ,
      3. Zhang X ,
      4. Yao Z , et al
      . [Association of antipsychotic agent-induced weight gain with a polymorphism of the promotor region of the 5-HT2C receptor gene]. Zhonghua Yi Xue Za Zhi 2002;82:1097–101. Chinese.pmid:http://www.ncbi.nlm.nih.gov/pubmed/12425817
      OpenUrlPubMed
    12. ↵
      2. Ellingrod VL ,
      3. Perry PJ ,
      4. Ringold JC , 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:76–8.doi:10.1002/ajmg.b.20169 pmid:15666332
      OpenUrlPubMed
    13. ↵
      2. Miller DD ,
      3. Ellingrod VL ,
      4. Holman TL , et al
      . Clozapine-induced weight gain associated with the 5HT2C receptor −759C/T polymorphism. Am J Med Genet B Neuropsychiatr Genet 2005;133B:97–100.doi:10.1002/ajmg.b.30115 pmid:15635667
      OpenUrlPubMed
    14. ↵
      2. Templeman LA ,
      3. Reynolds GP ,
      4. Arranz B , et al
      . 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;15:195–200.doi:10.1097/01213011-200504000-00002 pmid:http://www.ncbi.nlm.nih.gov/pubmed/15864111
      OpenUrlCrossRefPubMed
    15. ↵
      2. Ryu S ,
      3. Cho EY ,
      4. Park T , et al
      . −759 C/T polymorphism of 5-HT2C receptor gene and early phase weight gain associated with antipsychotic drug treatment. Prog Neuropsychopharmacol Biol Psychiatry 2007;31:673–7.doi:10.1016/j.pnpbp.2006.12.021 pmid:17275977
      OpenUrlCrossRefPubMed
    16. ↵
      2. Shao P ,
      3. Zhao J-ping ,
      4. Chen J-dong , et al
      . [Association of HTR2C-759C/T and -697G/C polymorphisms with antipsychotic agent-induced weight gain]. Zhong Nan Da Xue Xue Bao Yi Xue Ban 2008;33:312–5. Chinese.
      OpenUrlPubMed
    17. ↵
      2. Godlewska BR ,
      3. Olajossy-Hilkesberger L ,
      4. Ciwoniuk M , et al
      . Olanzapine-induced weight gain is associated with the −759C/T and −697G/C polymorphisms of the HTR2C gene. Pharmacogenomics J 2009;9:234–41.doi:10.1038/tpj.2009.18 pmid:19434072
      OpenUrlCrossRefPubMed
    18. ↵
      2. Opgen-Rhein C ,
      3. Brandl EJ ,
      4. Müller DJ , et al
      . Association of HTR2C, but not Lep or INSIG2, genes with antipsychotic-induced weight gain in a German sample. Pharmacogenomics 2010;11:773–80.doi:10.2217/pgs.10.50 pmid:http://www.ncbi.nlm.nih.gov/pubmed/20504252
      OpenUrlCrossRefPubMed
    19. ↵
      2. Liu WZ ,
      3. HB H ,
      4. ZY H , et al
      . Study of the association between olanzapine-induced weight gain and the −759C/T polymorphism of HTR2C receptor gene. Herald Of Medcine 2013;6:733–7. Chinese.
      OpenUrl
    20. ↵
      2. Kang SH ,
      3. Lee J-il ,
      4. Han HR , et al
      . Polymorphisms of the leptin and HTR2C genes and clozapine-induced weight change and baseline BMI in patients with chronic schizophrenia. Psychiatr Genet 2014;24:249–56.doi:10.1097/YPG.0000000000000053 pmid:http://www.ncbi.nlm.nih.gov/pubmed/25304226
      OpenUrlCrossRefPubMed
    21. ↵
      2. Daray FM ,
      3. Rodante D ,
      4. Carosella LG , et al
      . −759C>T Polymorphism of the HTR2C gene is associated with second generation antipsychotic-induced weight gain in female patients with schizophrenia. Pharmacopsychiatry 2017;50:14–18.doi:10.1055/s-0042-110321 pmid:27414739
      OpenUrlPubMed
    22. ↵
      2. Basile VS ,
      3. Masellis M ,
      4. De Luca V , et al
      . 759C/T genetic variation of 5HT(2C) receptor and clozapine-induced weight gain. Lancet 2002;360:1790–1.doi:10.1016/S0140-6736(02)11706-5 pmid:http://www.ncbi.nlm.nih.gov/pubmed/12480467
      OpenUrlPubMed
    23. ↵
      2. Grădinaru RC ,
      3. Andreescu NI ,
      4. Nussbaum LA , et al
      . −759C÷T polymorphism of the HTR2C gene is not correlated with atypical antipsychotics-induced weight gain, among Romanian psychotic patients. Rom J Morphol Embryol 2016;57:1343–9.pmid:28174802
      OpenUrlPubMed
    24. ↵
      2. Houston JP ,
      3. Kohler J ,
      4. Bishop JR , et al
      . Pharmacogenomic associations with weight gain in olanzapine treatment of patients without schizophrenia. J Clin Psychiatry 2012;73:1077–86.doi:10.4088/JCP.11m06916 pmid:http://www.ncbi.nlm.nih.gov/pubmed/22967772
      OpenUrlCrossRefPubMed
    25. ↵
      2. Kuzman MR ,
      3. Medved V ,
      4. Bozina N , et al
      . Association study of MDR1 and 5-HT2C genetic polymorphisms and antipsychotic-induced metabolic disturbances in female patients with schizophrenia. Pharmacogenomics J 2011;11:35–44.doi:10.1038/tpj.2010.7 pmid:http://www.ncbi.nlm.nih.gov/pubmed/20195292
      OpenUrlCrossRefPubMed
    26. ↵
      2. Laika B ,
      3. Leucht S ,
      4. Heres S , et al
      . Pharmacogenetics and olanzapine treatment: CYP1A2*1F and serotonergic polymorphisms influence therapeutic outcome. Pharmacogenomics J 2010;10:20–9.doi:10.1038/tpj.2009.32 pmid:http://www.ncbi.nlm.nih.gov/pubmed/19636338
      OpenUrlCrossRefPubMed
    27. ↵
      2. Lane H-Y ,
      3. Liu Y-C ,
      4. Huang C-L , et al
      . Risperidone-related weight gain: genetic and nongenetic predictors. J Clin Psychopharmacol 2006;26:128–34.doi:10.1097/01.jcp.0000203196.65710.2b pmid:http://www.ncbi.nlm.nih.gov/pubmed/16633140
      OpenUrlCrossRefPubMedWeb of Science
    28. ↵
      2. Reynolds GP ,
      3. Zhang Z ,
      4. Zhang X
      . Polymorphism of the promoter region of the serotonin 5-HT(2C) receptor gene and clozapine-induced weight gain. Am J Psychiatry 2003;160:677–9.doi:10.1176/appi.ajp.160.4.677 pmid:http://www.ncbi.nlm.nih.gov/pubmed/12668355
      OpenUrlCrossRefPubMedWeb of Science
    29. ↵
      2. Thompson A ,
      3. Lavedan C ,
      4. Volpi S
      . Absence of weight gain association with the HTR2C −759C/T polymorphism in patients with schizophrenia treated with iloperidone. Psychiatry Res 2010;175:271–3.doi:10.1016/j.psychres.2009.03.020 pmid:20045196
      OpenUrlCrossRefPubMedWeb of Science
    30. ↵
      2. Ujike H ,
      3. Nomura A ,
      4. Morita Y , et al
      . Multiple genetic factors in olanzapine-induced weight gain in schizophrenia patients: a cohort study. J Clin Psychiatry 2008;69:1416–22.doi:10.4088/JCP.v69n0909 pmid:http://www.ncbi.nlm.nih.gov/pubmed/19193342
      OpenUrlCrossRefPubMed
    31. ↵
      2. Al-Janabi I ,
      3. Arranz MJ ,
      4. Blakemore AIF , et al
      . Association study of serotonergic gene variants with antipsychotic-induced adverse reactions. Psychiatr Genet 2009;19:305–11.doi:10.1097/YPG.0b013e3283328dcd pmid:http://www.ncbi.nlm.nih.gov/pubmed/19829168
      OpenUrlCrossRefPubMed
    32. ↵
      2. Gregoor JG ,
      3. Mulder H ,
      4. Cohen D , et al
      . Combined HTR2C–LEP genotype as a determinant of obesity in patients using antipsychotic medication. J Clin Psychopharmacol 2010;30:702–5.doi:10.1097/JCP.0b013e3181fa05a2 pmid:21105285
      OpenUrlCrossRefPubMed
    33. ↵
      2. Gunes A ,
      3. Melkersson KI ,
      4. Scordo MG , et al
      . Association between HTR2C and HTR2A polymorphisms and metabolic abnormalities in patients treated with olanzapine or clozapine. J Clin Psychopharmacol 2009;29:65–8.doi:10.1097/JCP.0b013e31819302c3 pmid:http://www.ncbi.nlm.nih.gov/pubmed/19142110
      OpenUrlPubMed
    34. ↵
      2. Mulder H ,
      3. Cohen D ,
      4. Scheffer H , et al
      . HTR2C gene polymorphisms and the metabolic syndrome in patients with schizophrenia: a replication study. J Clin Psychopharmacol 2009;29:16–20.doi:10.1097/JCP.0b013e3181934462 pmid:http://www.ncbi.nlm.nih.gov/pubmed/19142101
      OpenUrlCrossRefPubMed
    35. ↵
      2. Yevtushenko OO ,
      3. Cooper SJ ,
      4. O'Neill R , et al
      . Influence of 5-HT2C receptor and leptin gene polymorphisms, smoking and drug treatment on metabolic disturbances in patients with schizophrenia. Br J Psychiatry 2008;192:424–8.doi:10.1192/bjp.bp.107.041723 pmid:http://www.ncbi.nlm.nih.gov/pubmed/18515891
      OpenUrlAbstract/FREE Full Text
    36. ↵
      2. Zhang H ,
      3. Kang WH ,
      4. Guo LY , et al
      . Role of leptin and 5-HT2C receptor gene in risperidone-induced obesity. Journal of Xi'An JiaoTong University(Medical Sciences) 2010;3:332–5. Chinese.
      OpenUrl
    37. ↵
      2. Radhika A ,
      3. Dkhar SA ,
      4. Rajkumar RP , et al
      . Effect of HTR-2C (5HT2C receptor) genetic polymorphism on risperidone-induced weight gain in patients with schizophrenia and acute psychosis. Indian J Pharmacol 2013;45:S90.
      OpenUrl
    38. ↵
      2. De Luca V ,
      3. Müller DJ ,
      4. Hwang R , et al
      . HTR2C haplotypes and antipsychotics-induced weight gain: X-linked multimarker analysis. Hum Psychopharmacol 2007;22:463–7.doi:10.1002/hup.868 pmid:http://www.ncbi.nlm.nih.gov/pubmed/17702092
      OpenUrlCrossRefPubMed
    39. ↵
      2. Tsai S-J ,
      3. Hong C-J ,
      4. Yu YW-Y , et al
      . −759C/T genetic variation of 5HT(2C) receptor and clozapine-induced weight gain. Lancet 2002;360:1790.doi:10.1016/S0140-6736(02)11705-3 pmid:12480466
      OpenUrlPubMed
    40. ↵
      2. Park Y-M ,
      3. Cho J-H ,
      4. Kang S-G , et al
      . Lack of association between the −759C/T polymorphism of the 5-HT2C receptor gene and olanzapine-induced weight gain among Korean schizophrenic patients. J Clin Pharm Ther 2008;33:55–60.doi:10.1111/j.1365-2710.2008.00872.x pmid:18211617
      OpenUrlCrossRefPubMed
    41. ↵
      2. Theisen FM ,
      3. Hinney A ,
      4. Brömel T , 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;14:139–42.doi:10.1097/00041444-200409000-00003 pmid:15318026
      OpenUrlCrossRefPubMedWeb of Science
    42. ↵
      2. Kuzman MR ,
      3. Medved V ,
      4. Bozina N , et al
      . The influence of 5-HT(2C) and MDR1 genetic polymorphisms on antipsychotic-induced weight gain in female schizophrenic patients. Psychiatry Res 2008;160:308–15.doi:10.1016/j.psychres.2007.06.006 pmid:http://www.ncbi.nlm.nih.gov/pubmed/18718676
      OpenUrlCrossRefPubMed
    43. ↵
      2. Santilli F ,
      3. D'Ardes D ,
      4. Guagnano MT , et al
      . Metabolic syndrome: sex-related cardiovascular risk and therapeutic approach. Curr Med Chem 2017;24:2602–27.doi:10.2174/0929867324666170710121145 pmid:http://www.ncbi.nlm.nih.gov/pubmed/28699503
      OpenUrlPubMed
    44. ↵
      2. Link JC ,
      3. Reue K
      . Genetic basis for sex differences in obesity and lipid metabolism. Annu Rev Nutr 2017;37:225–45.doi:10.1146/annurev-nutr-071816-064827 pmid:http://www.ncbi.nlm.nih.gov/pubmed/28628359
      OpenUrlPubMed

    Dr. Chen Yan obtained a bachelor's degree from Wenzhou Medical University, Zhejiang Province, China in 2017. Since then she has been working as a postgraduate student at the Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine. Her main research interest includes schizophrenia.


    Embedded Image

    Footnotes

    • Contributors YC contributed to the literature search; YC, Y-WW and X-YF contributed to literature screening and data extraction; YC, YZ and L-SS contributed to statistical analysis and writing of this paper; and CZ contributed to the planning and guidance of this paper.

    • Funding This study was funded by National Natural Science Foundation of China (81771450); Science and Technology Commission of Shanghai Municipality (201540029).

    • Competing interests None declared.

    • Patient consent for publication Not required.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Data availability statement No additional unpublished data are available.