Marys Medicine

For reprint orders, please contact: [email protected] Sexual dysfunction in male schizophrenia: influence of antipsychotic drugs, prolactin and polymorphisms of the dopamine D2 receptor genes Aim: Sexual dysfunction induced by antipsychotic drug treatment is under investigated and under reported.
This study aimed to determine the influence of genetic polymorphisms in the D2 dopamine receptor (DRD2)
and endothelial nitric oxide synthase (eNOS) genes, and the possible role of blood prolactin concentrations
on sexual function in schizophrenic patients. Materials & methods: Male remitted schizophrenic patients
(n = 100), who were living with a sexual partner and receiving antipsychotic drug monotherapy for at
least 6 months, were assessed for sexual and erectile dysfunction using the Arizona Sexual Experience
Scale and the five-item version of the International Index of Erectile Function. Blood samples were taken
for plasma prolactin determination and genotyped for four polymorphisms: DRD2 (-141C Ins/Del and
Taq1A) and eNOS gene (G894T and T-786C). Results: The -141C Ins/Del, but not Taq1A, polymorphism of
the DRD2 gene was significantly associated with sexual dysfunction with the del allele being less frequent
in sexual dysfunction subjects. Neither of the eNOS polymorphisms, G894T or T-786C, was significantly
associated with sexual or erectile dysfunction. Prolactin concentrations were significantly higher in patients
with erectile dysfunction but did not reach significance in those with sexual dysfunction. Prolactin was
also reduced in -141C Del allele carriers. The frequency and severity of sexual dysfunction in the patients
receiving typical antipsychotics was significantly greater than those receiving risperidone or clozapine,
while prolactin concentrations were significantly higher in subjects receiving risperidone compared with
those receiving clozapine or typical antipsychotics. Conclusion: This is the first evidence indicating that
antipsychotic drug treatment in men is associated with a variant in the DRD2 gene in which the -141C Del
allele might be a protective factor. While this may, in part, be mediated by effects on prolactin, other
factors are likely to contribute to the greater sexual dysfunction in patients receiving typical antipsychotics.
Original submitted 25 January 2011; Revision submitted 21 March 2011
KEYWORDS: antipsychotic n DRD2 n eNOS n genetic polymorphism
Xiang Rong Zhang1,2,3,
n sexual dysfunction
Zhi Jun Zhang†1,2,
Rong Xin Zhu4, Yong Gui
Yuan4, Trisha A Jenkins3

Antipsychotic-induced sexual dysfunction (AP- D2 receptor antagonist effect of antipsychotics SD) is a common and serious clinical side effect may be the primary central mechanism, along & Gavin P Reynolds3,5
that is under investigated and under reported. with some indirect neuroendocrine factors, such 1Neuropsychiatric Research Institute,
School of Medicine, Southeast Epidemiological research has reported sub- as elevated prolactin levels [9]. Typical antipsy- University, Nanjing, China stantial variations in the general prevalence of chotics (e.g., haloperidol and thioridazine) are 2Department of Neuropsychiatry, AP-SD, which ranges from approximately 30 generally considered to cause relatively more Affiliated ZhongDa Hospital of Southeast University, Nanjing, China to 80% [1]. SD has important implications for SD than atypical agents (e.g., clozapine, olan- 3Department of Psychiatry, School of satis faction with sexual life and overall quality of zapine and quetiapine) and this has been ascribed Medicine & Dentistry, Queen's University Belfast, UK life [2,3]; it has been demonstrated as one of the to differences in affinity at D2 receptors [1,10]. 4Department of Psychiatry, Nanjing major reasons for treatment noncompliance and Increased prolactin following antipsychotics has Brain Hospital, Nanjing, China 5Biomedical Research Centre, Sheffield inevitably affects clinical outcome and treatment been suggested to suppress every aspect of sexual Hallam University, Sheffield, UK success [4–6]. The differences in individual liabil- function (i.e., desire, erection and orgasm) [11], †Author for correspondence: ity indicate the possible importance of genetic although this proposal remains controversial Tel.: +86 025 8327 2023 factors in determining the emergence of AP-SD.
Two well-studied polymorphisms of the dopa- The mechanisms of AP-SD remain largely mine D2 receptor gene (DRD2), -141C Ins/Del unclear, and current theories derive mainly and Taq1A, have been reportedly associated from studies of general sex physiology and with dopamine D2 receptor density in in vitro psycho–pharmacology. The responses of vari- studies [13] and in human striatum [14,15], respec- ous sexual components are under the control of tively. Decreased dopamine D2 receptor density numerous central and peripheral neural systems could theoretically result in greater vulnerability [7,8]. It has been postulated that a direct dopamine to dopamine blockade and hence an increased 10.2217/PGS.11.46 2011 Future Medicine Ltd Pharmacogenomics (2011) 12(8) 1127–1136 ReseaRch aRticle Zhang, Zhang, Zhu, Yuan, Jenkins & Reynolds For reprint orders, please contact: [email protected] occurrence of significant side effects, possibly by the Remission in Schizophrenia Working including SD. This is supported by the finding Group [23], excepting the requirement for that patients with a DRD2 Taq1 A1 allele, asso- continuous state of remission over 6 months. ciated with decreased brain receptor densities, Patients were excluded if they had one or more had relatively higher prolactin levels following of the following: antipsychotic drug treatment [16].
ƒ Any reported history of SD before anti psychotic We recently demonstrated that the gene expression and activity of nitric oxide synthase (NOS) isoforms are differentially affected by ƒ A general medical condition or history of a chronic antipsychotic treatment in rat penile surgical procedure known to cause SD, for tissues, indicating that peripheral mechanisms example prostatectomy, diabetes, hypertension involving nitric oxide activity might also be or neurological disease; involved in the pathogenesis of sexual side ƒ Any other side effect of antipsychotics, for effects [17]. Interestingly, the eNOS G894T example, tardive dyskinesia, which might polymorphism was the first SNP shown to be indirectly influence sexual function or its associated with an increased risk of erectile dys- function (ED) in two different racial popula-tions [18,19]. The eNOS T-786C polymorphism, a Receiving other psychotropic drugs known to functional promoter SNP [20], has been linked to cause SD, for example antidepressants, an increased risk of developing coronary artery although patients taking other adjunctive disease [21,22], which might also be relevant to medications, such as anticholinergics and the hemodynamics of penile erection.
benzodiazepines, were not excluded; The paucity of reports exploring the ƒ Any history of substance or alcohol abuse.
pharmaco genetics of AP-SD has prompted us to investigate the possible association with male AP-SD of these four potentially functional n Clinical features & sexual function SNPs in two strong candidate genes, in order Subjects were told they would participate in a to better understand the mechanisms contrib- brief survey to evaluate their experiences with uting to individual variability in SD in patients their current psychiatric medications. A medical with schizophrenia.
history was obtained, including: ƒ Demographic information; Materials & methods
ƒ History of past illness and treatment; The subjects were Chinese Han outpatients ƒ Currently prescribed psychotropic medications recruited from the psychiatric outpatient unit and duration of treatment. and four community psychiatric centers. All subjects provided written informed consent The antipsychotic dose was calculated as chlor- for participation in the study, which had been promazine equivalent in mg/day. All patients approved by the Hospital Ethical Committee, were then rated using the Positive and Negative in accordance with the Declaration of Helsinki. Syndrome Scale (PANSS) on the day of recruit-Eligibility criteria for inclusion into the study ment by the senior psychiatrists. The patient's were as follows: psychiatric symptom severity over the previous ƒ A married remitted male schizophrenia out- 6 months was obtained from their treating clini- patient living with a stable sexual partner for cal psychiatrist in the psychiatric outpatient unit the previous 6 months; and community psychiatric centers.
After obtaining demographic and medica- ƒ Aged between 25 and 45 years; tion/treatment information, sexual function was evaluated with a one-time rating of two five-item ƒ Medication with a single antipsychotic drug self-administered questionnaires: the Arizona for at least 6 months. Sexual Experience Scale (ASEX) [24] and the Remitted schizophrenia was defined by abridged five-item version of the International two components: a Diagnostic and Statistical Index of Erectile Function (IIEF-5) [25]. The Manual of Mental Disorders-IV diagnosis of ASEX, assessing the severity of overall SD, schizo phrenia as established by the clinic phy- has established psychometric properties (inter- sician, coupled with a current state of remission nal reliability and construct and convergent defined by the symptomatic criteria proposed validity) in outpatients with schizophrenia or Pharmacogenomics (2011) 12(8)
future science group Sexual dysfunction in male schizophrenia ReseaRch aRticle For reprint orders, please contact: [email protected] schizoaffective disorder [26]. The criterion for normally distributed, while prolactin measures SD, according to the ASEX, is a total score of were log-transformed prior to ana lysis of vari-19 or above, any one item with an individual ance. Chi-square tests were used to compare score of 5, or any three items with individual allele and genotype frequencies, and drug treat-score of 4 [24]. The IIEF-5 focused on ED and ments, between the different sexual function intercourse satisfaction, while each item is scored subgroups. Power ana lysis demonstrated that on a five-point ordinal scale, where lower val- the sample size had 80% power to identify sig- ues represent poorer sexual function. A score of nificant frequency differences in SD with odds
above 21 is considered normal erectile function ratios of approximately 1.75.
and, at or below this threshold, is considered as
ED [25]. Validated versions for China were used Results
in the present study. The participants undertook
n Clinical demographic characteristics this in an individual room with a total guaran- & blood prolactin in male tee of confidentiality. If needed, the psychiatrist schizophrenic patientsprovided any necessary explanation to ensure the A total of 176 psychiatric outpatients meeting questionnaires were understood. the inclusion criteria were initially identified, of whom, 100 subjects finally provided written n Prolactin measurement informed consent and participated in the study. Blood was collected after an overnight fast in Those patients received antipsychotic mono-a 5-ml EDTA vacuum tube from each patient therapy with clozapine (n = 37), risperidone and then centrifuged at 3000 rpm for 5 min to (n = 30), chlorpromazine (n = 21), haloperidol separate the plasma from cells; these were frozen (n = 9) and olanzapine (n = 3). Using the cut-off and stored at -70°C until prolactin measurement level of the ASEX questionnaire, the patients were and genotyping, respectively. Plasma prolactin divided into two groups, the SD group (n = 47) was assayed in duplicate by double antibody with a mean ASEX score of 23.57 (± 3.02) and radio immunoassay. The reagents were provided the normal sexual functioning group (n = 53) in kits from Jiuding Biological Corporation, with a mean ASEX score of 13.19 (± 2.36). China. The inter- and intra-assay coefficients of The clinical features of the SD and non-SD variation were 5.6 and 5.9%.
groups demonstrated no significant differences in age (40.6 ± 5.4 years and 41.0 ± 4.6 years, respectively), length of current drug treatment After extraction of genomic DNA from blood (8.32 ± 3.9 years and 6.91 ± 3.2 years, respec-cells, genotyping was performed by PCR– tively), age of onset, chlorpromazine equivalent restriction fragment length polymorphism tech- dosage or PANSS score. According to the IIEF-5 nique, using methods as previously described: score, 45 patients were in the ED group. Again, DRD2 Taq1A [27,28], DRD2 -141C Ins/Del there were no significant differences found in [13,29], eNOS G894T [30] and eNOS T-786C [31]. any socio–demographic and clinical variables The resulting segments were digested with the between the erectile function groups divided restriction endonuclease TaqI for Taq1A, BstNI according to IIEF-5 criteria. for -141C Ins/Del, BanII for G894T and MspI for T-786C (New England BioLabs, UK) and n Genetic association with products separated by electrophoresis on 3% sexual dysfunctionagarose gel stained with ethidium bromide.
The genetic association of alleles and geno-types of the DRD2 and eNOS polymorphisms n Statistical ana lysis with sexual and erectile function are shown in All statistical analyses were performed using Tables 1 & 2. Where a single homozygous subject
SPSS 11.5 for Windows employing two-tailed was found in the sample studied (for DRD2
tests. Values of demographic characteristics and -141C Del/Del, and for eNOS 894TT), these
questionnaire scores are given as mean ± stan-
samples were included in the heterozygote dard deviation. Differences in clinical variables groups for further ana lysis. For eNOS -786 there or in PANSS scores between patient subgroups were no CC homozygotes within the sample. were evaluated by t-test or ana lysis of vari- The distribution of genotypes in each polymor- ance. Differences in sexual function between phism did not differ significantly from Hardy–allele and genotype groups were evaluated with Weinberg equilibrium. There were no significant Mann–Whitney U and Kruskal–Wallis H associations found for either of the eNOS poly-tests as the ASEX and IIEF-5 scores were not morphisms or the DRD2 Taq1A polymorphism future science group ReseaRch aRticle Zhang, Zhang, Zhu, Yuan, Jenkins & Reynolds For reprint orders, please contact: [email protected] Table 1. Distributions of genotypes and alleles between sexual dysfunction and normal sexual function groups
of schizophrenic patients determined by the Arizona Sexual Experience Scale.

Alleles SD
DRD2 -141C Ins/Del Del/Ins + Del/Del df = 1; p = 0.046 df = 1; p = 0.003 DRD2 Taq1A df = 2; p = 0.793 df = 1; p = 0.488 eNOS T-786C df = 1; p = 0.193 df = 1; p = 0.219 eNOS G894T df = 1; p = 0.793 df = 1; p = 0.996 The different sexual function groups were divided according to the cut-off level of Arizona Sexual Experience Scale. Comparisons between groups were made using c2 tests. Del: Deletion; df: Degrees of freedom; DRD2: D2 dopamine receptor; eNOS: Endothelial nitric oxide synthase; Ins: Insertion; SD: Sexual dysfunction. with either SD or ED. Analysis of the Taq1A Comparison of ASEX outcomes showed worse polymorphism using dominant or recessive sexual function in the Ins/Ins genotype patient
models also showed no significant association. group than the -141C Del carriers (Table 3). The
These polymorphisms also showed no significant analyses also revealed a significant genotype
associations with clinical features of the patients association with three of the five ASEX indi-
studied, or with prolactin measurements (data vidual subitems. Although the IIEF-5 total score
not shown).
did not differ significantly between -141C Del Significant association with SD determined by carriers and Ins/Ins homozygotes, a significant ASEX criteria was found for the -141C Ins/Del difference was found in two IIEF-5 individual
polymorphism in the DRD2 gene (Table 1). The subitems (3 and 4; p = 0.016 and 0.011, respec-
DRD2 -141C Del allele was found to be signifi- tively). The -141C Del carriers had a longer
cantly less frequent in SD patients than non-SD duration of illness than the -141C Ins/Ins geno-
group (odds ratio: 0.258; 95% CI: 0.071–0.945; type group, but no other significant differences
p = 0.003). The genotype distribution reflected in socio–demographic and PANSS scores were
this effect, with a significantly lower frequency found between the two genotype groups.
of Del allele carriers in the SD group (odds ratio:
0.260; 95% CI: 0.068–0.999; p = 0.046). The
n Prolactin & sexual dysfunction same trend towards genotype and allelic asso- The difference in blood prolactin between the SD ciations was apparent for ED determined by (22.4 ± 18.9 ng/ml) and non-SD (17.9 ± 16.5 ng/ml)
IIEF-5 criteria, although results did not quite groups did not reach significance (p = 0.058).
reach statistical significance (Table 2). The dif-
A significant difference in blood prolactin was ference between the two measures was due found between the ED (23.4 ± 19.2 ng/ml) and to two subjects meeting SD criteria but not non-ED (17.0 ± 16.0 ng/ml) groups (p = 0.017). reporting ED. Correlation ana lysis showed significant or Table 2. Distributions of genotypes and alleles between erectile dysfunction and normal erectile function
groups of schizophrenic patients determined by the International Index of Erectile Function-5.

DRD2 -141C Ins/Del Del/Ins + Del/Del df = 1; p = 0.082 Ins df = 1; p = 0.058 DRD2 Taq1A df = 2; p = 0.691 A2 df = 1; p = 0.384 eNOS T-786C df = 1; p = 0.315 T df = 1; p = 0.343 eNOS G894T df = 1; p = 0.324 T df = 1; p = 0.706 The different erectile function groups were divided according to the cut-off level of the International Index of Erectile Function-5. Comparisons between groups were made using c2 tests. Del: Deletion; df: Degrees of freedom; DRD2: D2 dopamine receptor; ED: Erectile dysfunction; eNOS: Endothelial nitric oxide synthase; Ins: Insertion. Pharmacogenomics (2011) 12(8)
future science group Sexual dysfunction in male schizophrenia ReseaRch aRticle For reprint orders, please contact: [email protected] near-significant effects between prolactin concen- Table 3. Comparison of sexual function and clinical features in the
trations and IIEF-5 and ASEX scores (p = -0.191, DRD2 -141C Ins/Del genotype group.
p = 0.028 and p = 0.157, p = 0.059, respectively; Spearman's test, one-tailed). Del/Ins +
Prolactin concentrations were found to be highly significantly associated with the DRD2 -141C polymorphism, with the Ins/Ins geno- type associated with significantly higher values than Del allele carriers (Table 3). No significant
– Penile erection association of prolactin concentrations with any – Orgasm (ability) other polymorphism studied was apparent (data – Orgasm (satisfaction) Total IIEF-5 score – Erection confidence n Effect of antipsychotic drugs on – Erection firmness severity of sexual dysfunction & – Maintenance frequency – Maintenance ability – Intercourse satisfaction To assess whether the drug treatments differen- tially influenced SD, the sample was divided into Age of onset (years) three subgroups: those receiving cloza pine, risper- Duration of schizophrenia idone or typical antipsychotic drugs (chlorprom- azine and haloperidol). Comparison of ASEX Total Positive and Negative and IIEF-5 scores between anti psychotic drug groups revealed a significant treatment effect on Positive subscore severity of SD, as measured by ASEX total scores Negative subscore (p = 0.016) but not by IIEF-5 (p = 0.207). Posthoc tests showed that the ASEX total scores were Prolactin (ng/ml) higher in the typical antipsychotic drug group Data are expressed as mean ± standard deviation. (20.73 ± 5.56) than in the clozapine (17.24 ± 6.08; ASEX: Arizona Sexual Experience Scale; Del: Deletion; DRD2: D2 dopamine receptor; p = 0.018) or risperidone (17.06 ± 5.17; p = 0.007) IIEF-5: International Index of Erectile Function-5; Ins: Insertion. groups, indicating worse sexual function in the typical antipsychotic drug group than the other patients based on ASEX and IIEF-5 rating scales. two subgroups. These findings were reflected in The main findings of our study were in keeping the greater proportion of subjects receiving typical with most previous reports that SD is common antipsychotics reaching threshold criteria for SD in male schizophrenia patients on antipsychotic and ED (66.7 and 60.7%, respectively) than in medication [32], with 47 and 45% reaching the clozapine (40.5 and 37.8%) and risperidone threshold criteria for SD and ED, respectively, (40.0 and 43.3%) groups. higher than the rate of such dysfunction in the Prolactin showed significant differences between general population (10–31%) [33–35]. the drug groups, in which blood concentrations Results are, on the whole, generally consis- in the risperidone group (31.9 ± 22.3 ng/ml) tent between the IIEF-5 (ED) and ASEX (SD) were substantially and significantly higher than measures. As mentioned, the difference between either the typical (17.8 ± 13.0 ng/ml; p = 0.042) those in the ED and SD groups reflects two or the clozapine (12.1 ± 10.1 ng/ml; p < 0.001) subjects reaching criteria for SD but not ED. groups. The effect of prolactin on sexual func- Greater differences are seen in statistical tests tion was explored further within the three drug of the scores from each questionnaire, reflect-groups. An effect was only apparent in the risperi- ing substantial differences between the two done group where correlations between prolac- measures. Thus SD, determined by the ASEX tin concen trations and IIEF-5 and ASEX scores questionnaire, provides a far broader assessment showed significant or near-significant correlations of sexual function than IIEF-5, which focuses (p = -0.384, p = 0.018 and p = 0.304, p = 0.051; solely on erectile function.
Spearman's test, one-tailed).
To our knowledge, this is the first study to investigate genetic mechanisms of AP-SD in remitted male patients with schizophrenia. Our In the present study, the severity and preva- findings indicate a significant involvement of lence of SD in response to antipsychotic agents the DRD2 -141C Ins/Del polymorphism in SD, was evaluated in remitted male schizophrenia following antipsychotic drug treatment. In this future science group ReseaRch aRticle Zhang, Zhang, Zhu, Yuan, Jenkins & Reynolds For reprint orders, please contact: [email protected] Chinese Han population, the prevalence of SD The hormone prolactin has been also regarded in Del allele carriers (Del/Ins + Del/Del) was as a causative factor underlying AP-SD [9]. significantly lower than in Ins/Ins homozygotes The present study demonstrated elevations of with relatively better rating scale scores. Blood blood prolactin in patients with SD, especially prolactin was also lower in Del allele carriers. ED. Previous studies have shown that prolac-Our findings suggested a protective effect of tin can suppress sexual behavior in both male the DRD2 -141C Del allele on sexual function patients [40,41] and rodents [42], although it is following antipsychotic drug administration. still not fully understood how this hormone The -141C Ins/Del polymorphism has been affects the sexual capacity of male subjects. reported to influence dopamine D2 receptor Several studies have found a significant corre-availability, with the Del allele being associated lation between prolactin and male sexual side with a reduction of D2 receptor expression [13]. effects [43–45], while others have failed to confirm However, a PET study performed in healthy these findings [12,46,47]. Interestingly, it has been individuals revealed a higher striatal density of suggested that only severe hyperprolactinemia D2 receptors in -141C Del allele carriers [36]. is associated with human SD [48]. Given that This in vivo study provided the neuroimag- prolactin elevation following antipsychotic ing evidence for the -141C Del allele being a drug treatment is primarily due to dopamine possible indicator of resistant response to anti- D2 receptor antagonism, it seems possible that psychotic medication. There have been several the effect of the DRD2 genotype on SD may be recent studies supporting this hypothesis. A mediated through its effects on prolactin con-study on Chinese Han population reported that centration. However, we found that prolactin schizophrenia patients carrying the Del allele concentrations correlated with ED only within showed less improvement following chlorprom- the risperidone group, in which blood prolactin azine treatment than those who did not; the was substantially higher than in the clozapine frequency of the Del allele was also higher in or typical antipsychotic groups. Moreover, the nonresponders than in responders [37]. Another risperidone group, despite having a higher mean study on patients with first-episode schizophre- level of prolactin, had less SD compared with nia, further indicated that relative to Ins/Ins patients receiving typical antipsychotic drugs. homozygotes, -141C Del carriers took a sig- This is in keeping with a previous report indi- nificantly longer time to respond to olanza pine cating that the increased prolactin associated or risperidone treatment [38]. Taken together, with risperidone treatment does not seem to be these findings indicate that antipsychotics may decisive for SD [47]. These observations strongly be associated with a relative lower pharmaco- suggest that a DRD2-mediated prolactin eleva- logical efficacy in -141C Del alleles carriers and tion is not the only factor contributing to AP-SD further suggest the possibility of the -141C Del in male patients with schizophrenia.
allele as a protective factor for AP-SD.
It is worth noting that both severity and It has been reported that the TaqA1 allele prevalence of SD are generally lower with atypi- of the DRD2 gene is associated with signifi- cal antipsychotics than typical anti psychotics cantly decreased D2 receptor density, which [49,50]. While som may influence D2 receptor antagonism [14]. quency of SD induced by risperidone was higher Patients with the DRD2 A1 allele receiving than the other atypical antipsychotics, such as antipsychotic medications were reported to have clozapine [51] and olanzapine [52], other stud-higher prolactin levels than patients without ies, along with the present finding, suggest that this allele [16], which indicated a possible link risperidone is associated with a degree of SD between the Taq1A polymorphism and AP-SD. similar to clozapine [53], olanzapine [54] and However, we found no significant association quetiapine [49]. The inconsistencies between of the Taq1A poly morphism of the DRD2 these various reports might be attributed to a gene with susceptibility to sexual side effects variety of influences and confounders, includ-in our study. A recent report indicated a pos- ing, clinical factors of schizophrenia (e.g., psy- sible racial effect for the Taq1A polymorphism chiatric symptoms, comorbid conditions and in its association with the overall level of side comedication regimes) [55] and methodological effects (i.e., including SD) due to antipsychotic factors including different assessment tools for medication [39]. This association was found in sexual behavior and differences in study sam-Caucasian subgroups, but disappeared if three ples (e.g., subjects' sex and trial design) [10]. subjects with Asian ethnicity were included in Attempting to address some of these limitations, the statistical ana lysis [39].
the present study evaluated sexual function in Pharmacogenomics (2011) 12(8)
future science group Sexual dysfunction in male schizophrenia ReseaRch aRticle For reprint orders, please contact: [email protected] remitted schizophrenia patients within a stable of SD. While a separate valid hypothesis justi-sexual relationship, using questionnaires that fies the investigation of each gene, there is an had been tested for their reliability and validity element of multiple testing in this study that in schizophrenia. has not been corrected for by adjustment of Apart from DRD2 and prolactin, other mecha- p-values. However, even with the most conser- nisms, including effects at the serotonin (5-HT) vative correction, it is clear that the association 2A receptor, might also contribute to the observed of the D2 -141C allele with SD would remain differences in SD between risperidone and typi- statistically significant. Nevertheless, the cal antipsychotics, counteracting the effects of results of any small study such as this, needs elevated prolactin. Both risperidone and clozapine to be considered as preliminary and awaiting have higher affinities for the 5-HT2A than the replication in further cohorts before robust D2 receptor [56]. 5-HT2A antagonism has been conclusions can be drawn. In addition, larger demonstrated to have a strong stimulating effect samples would be required to ascertain more on male sexual behavior in several animal studies precisely, the genetic effect on sexual function [57,58]. However, further pharmacological mecha- following specific medications, or to deter- nisms, or indirect effects via the elevation of other mine the interactions between D2 receptor risk factors for SD, may well contribute to AP-SD.
genotype, prolactin and drug in contributing The relationship between two SNPs to AP-SD. Given the differences between drugs (G987T and T-786C) of the eNOS gene and in D2 receptor affinity and effects on prolac-AP-SD was also determined. The G894T poly- tin, it may be that receptor genotype would morphism had been reported to be a genetic differentially influence SD following different susceptibility factor for ED in Mexican and drug treatments.
Taiwanese populations [18,19]. However, a study Nevertheless, our findings indicate that the in the German population did not find the typical antipsychotics are more likely to be asso-association of this SNP with ED, but reported ciated with SD in men than the atypical drugs, association of the G894 allele with response including risperidone and clozapine, despite the to sildenafil, a drug acting on the NO-cGMP higher blood prolactin concentrations associ-pathway in erectile tissues [59]. In the pres- ated with risperidone. In addition to pharma- ent study, we did not detect any association cological mechanisms of antipsychotic medica-between either SNP of the eNOS gene and tion, genetic factors may also be important in AP-SD. However, given the evidence impli- determining AP-SD. The present genetic find- cating eNOS in anti psychotic-induced sexual ing may help to predict the possible influence function, it would be premature to rule it out of anti psychotic treatment on sexual function, as a candidate gene for susceptibility to sex- which has implications in the improvement of ual side effects. An important role of eNOS in treatment compliance and the quality of life of
AP-SD has been established by the results of patients with schizophrenia.
our animal study [17]. Moreover, sildenafil has
also been found to be a safe and effective drug Acknowledgements
in the treatment of antipsychotic-induced ED The authors would like to thank John Liddle and Yang Liu,
[60,61]. Therefore, further functional polymor-
for technical assistance in this study. phisms of eNOS or other genes involved in the
NO-cGMP pathway might still be risk factors Financial & competing interests disclosure
for antipsychotic-induced SD.
This work was supported by National Basic Research This study had several limitations; as a cross- Program of China (973 Program, No. 2007CB512308 sectional study, it was not possible to determine and 2010CB529602), National Hi-Tech Research and the direct effect of antipsychotic treatment on Development Program of China (863 Program, No. the extent and severity of SD because of the 2007AA0200Z435), National Natural Science absence of baseline ASEX and IIEF-5 ratings Foundation of China (No. 30900482) and JiangSu prior to treatment. Furthermore, while the Province Natural Science Foundation of China study was powered to identify robust effects of (BK2009280). The authors have no other relevant affili-genetic subgroups on SD, further investigation ations or financial involvement with any organization or of subgroups, or interaction between treatment entity with a financial interest in or financial conflict with and genetic effects for example, was not justi- the subject matter or materials discussed in the manuscript fied with the sample size. The effects of four apart from those disclosed.
polymorphisms in two different genes have No writing assistance was utilized in the production of been tested for their association with measures this manuscript. future science group ReseaRch aRticle Zhang, Zhang, Zhu, Yuan, Jenkins & Reynolds For reprint orders, please contact: [email protected] Ethical conduct of research
human or animal experimental investigations. In addi- The authors state that they have obtained appropriate tion, for investi gations involving human subjects, insti tutional review board approval or have followed the informed consent has been obtained from the participants princi ples outlined in the Declaration of Helsinki for all involved. ƒ Antipsychotic drug treatment is associated with sexual dysfunction, a poorly understood and under investigated but problematic ƒ This study aimed to determine the association of genetic polymorphisms in two candidate genes and sexual dysfunction in male subjects with schizophrenia receiving antipsychotic drugs, who were also in a stable sexual relationship.
ƒ Two polymorphisms in each of the genes for the dopamine D2 receptor (DRD2) and for endothelia nitric oxide synthase (eNOS) were investigated for their association with scores on questionnaires for sexual and erectile dysfunction. Prolactin blood concentrations and their relationship to genotype and drug treatment were also studied.
ƒ A significant genetic association with sexual dysfunction was found with the functional -141Ins/Del promoter region polymorphism of DRD2. Prolactin concentrations were also significantly associated with this polymorphism.
ƒ There was a discrepancy between prolactin and sexual dysfunction related to drug type; prolactin was greatest in those patients receiving risperidone, but sexual dysfunction was greatest in those receiving typical antipsychotic drugs.
ƒ This study identifies one genetic risk factor that may influence antipsychotic-induced sexual dysfunction partly via effects on ƒ Other genetic factors independent of the dopamine system and prolactin secretion are likely to contribute to antipsychotic-induced sexual dysfunction; further systematic search for such factors is needed.
ƒ Identification of genetic polymorphisms influencing the emergence of this problematic side effect is an important step towards the eventual use of genetic testing in identifying at risk subjects, providing valuable information that will inform therapeutic practice. Heaton JP, Adams MA. Update on central 15 Pohjalainen T, Rinne JO, Nagren K et al. The Papers of special note have been highlighted as: function relevant to sex: remodeling the basis A1 allele of the human D2 dopamine receptor of drug treatments for sex and the brain. Int. gene predicts low D2 receptor availability in J. Impot. Res. 15(Suppl. 5), 25–32 (2003).
healthy volunteers. Mol. Psychiatry 3(3), Baggaley M. Sexual dysfunction in 256–260 (1998).
schizophrenia: focus on recent evidence. Cutler AJ. Sexual dysfunction and Hum. Psychopharmacol. 23(3), 201–209 antipsychotic treatment. 16 Young RM, Lawford BR, Barnes M et al. Psychoneuroendocrinology 28, 69–82 (2003).
Prolactin levels in antipsychotic treatment of 10 Kelly DL, Conley RR. Sexuality and patients with schizophrenia carrying the Review of the sexual dysfunction in patients
DRD2*A1 allele. Br. J. Psychiatry 185, receiving antipsychotic drugs.
schizophrenia: a review. Schizophr. Bull. 30(4), 767–779 (2004).
147–151 (2004).
Mallis D, Moisidis K, Kirana PS et al. 17 Zhang XR, Zhang ZJ, Jenkins TA, Moderate and severe erectile dysfunction 11 Knegtering H, van BR, Castelein S et al. Cheng WR, Reynolds GP. The effect of equally affects life satisfaction. J. Sex. Med. Are sexual side effects of prolactin-raising chronic antipsychotic drug administration on 3(3), 442–449 (2006).
antipsychotics reducible to serum prolactin? Psychoneuroendocrinology 33(6), 711–717 nitric oxide synthase activity and gene Olfson M, Uttaro T, Carson WH, Tafesse E. expression in rat penile tissues. Eur. Male sexual dysfunction and quality of life in Neuropsychopharmacol. 20(4), 211–217 schizophrenia. J. Clin. Psychiatry 66(3), 12 Eberhard J, Lindstrom E, Holstad M, 331–338 (2005).
Levander S. Prolactin level during 5 years of risperidone treatment in patients with 18 Lee YC, Huang CH, Wang CJ et al. Perkins DO. Predictors of noncompliance in psychotic disorders. Acta Psychiatr. Scand. The associations among eNOS G894T gene patients with schizophrenia. J. Clin. 115(4), 268–276 (2007).
polymorphism, erectile dysfunction and Psychiatry 63(12), 1121–1128 (2002).
related risk factors. BJU Int. 100(5), 13 Arinami T, Gao M, Hamaguchi H, Toru M. Rosenberg KP, Bleiberg KL, Koscis J, 1116–1120 (2007).
A functional polymorphism in the promoter Gross C. A survey of sexual side effects region of the dopamine D2 receptor gene is 19 Rosas-Vargas H, Coral-Vazquez RM, Tapia R among severely mentally ill patients taking associated with schizophrenia. Hum. Mol. et al. Glu298Asp endothelial nitric oxide psychotropic medications: impact on Genet. 6(4), 577–582 (1997).
synthase polymorphism is a risk factor for compliance. J. Sex. Marital Ther. 29(4), erectile dysfunction in the Mexican Mestizo 289–296 (2003).
The first evidence that the DRD2 -141C
population. J. Androl. 25(5), 728–732 (2004).
Ins/Del polymorphism could influence
Lambert M, Conus P, Eide P et al. Impact of receptor density, although the association with
20 Nakayama M, Yasue H, Yoshimura M et al. present and past antipsychotic side effects on T-786→C mutation in the 5´-flanking region attitude toward typical antipsychotic schizophrenia is not consistently replicated.
of the endothelial nitric oxide synthase gene is treatment and adherence. Eur. Psychiatry 14 Thompson J, Thomas N, Singleton A et al. associated with coronary spasm. Circulation 19(7), 415–422 (2004).
D2 dopamine receptor gene (DRD2) Taq1 A 99(22), 2864–2870 (1999).
polymorphism: reduced dopamine D2 Giuliano F, Rampin O. Central neural 21 Nakayama T, Soma M, Takahashi Y et al. regulation of penile erection. Neurosci. receptor binding in the human striatum Association analysis of CA repeat Biobehav. Rev. 24(5), 517–533 (2000).
associated with the A1 allele. Pharmacogenetics polymorphism of the endothelial nitric 7(6), 479–484 (1997).
Pharmacogenomics (2011) 12(8)
future science group Sexual dysfunction in male schizophrenia ReseaRch aRticle For reprint orders, please contact: [email protected] oxide synthase gene with essential 33 Najman JM, Dunne MP, Boyle FM, 44 Knegtering H, van der Moolen A, hypertension in Japanese. Clin. Genet. Cook MD, Purdie DM. Sexual dysfunction Castelein S, Kluiter H, van den Bosch BR. 51(1), 26–30 (1997).
in the Australian population. Aust. Fam. What are the effects of antipsychotics on 22 Alvarez R, Gonzalez P, Batalla A et al. Physician 32(11), 951–954 (2003).
sexual dysfunctions and endocrine Association between the NOS3 (-786 T/C) 34 Nicolosi A, Glasser DB, Kim SC, Marumo K, functioning? Psychoneuroendocrinology and the ACE (I/D) DNA genotypes and early Laumann EO. Sexual behaviour and 28(Suppl. 2), 109–123 (2003).
coronary artery disease. Nitric Oxide 5(4), dysfunction and help-seeking patterns in 45 Nakonezny PA, Byerly MJ, Rush AJ. 343–348 (2001).
adults aged 40–80 years in the urban The relationship between serum prolactin 23 Andreasen NC, Carpenter WT, Kane JM population of Asian countries. BJU Int. level and sexual functioning among male et al. Remission in schizophrenia: proposed 95(4), 609–614 (2005).
outpatients with schizophrenia or criteria and rationale for consensus. 35 Laumann EO, Paik A, Rosen RC. Sexual schizoaffective disorder: a randomized Am. J. Psychiatry 162(3), 441–449 (2005).
dysfunction in the United States: prevalence double-blind trial of risperidone vs quetiapine. J. Sex. Marital Ther. 33(3), 24 McGahuey CA, Gelenberg AJ, Laukes CA and predictors. JAMA 281(6), 537–544 203–216 (2007).
et al. The Arizona Sexual Experience Scale (ASEX): reliability and validity. J. Sex. 36 Jonsson EG, Nothen MM, Grunhage F et al. 46 Kleinberg DL, Davis JM, de Coster R, Marital Ther. 26(1), 25–40 (2000).
Polymorphisms in the dopamine D2 receptor Van Baelen B, Brecher M. Prolactin levels and adverse events in patients treated with 25 Rosen RC, Cappelleri JC, Smith MD, Lipsky gene and their relationships to striatal risperidone. J. Clin. Psychopharmacol. 19(1), J, Pena BM. Development and evaluation of an dopamine receptor density of healthy 57–61 (1999).
abridged, 5-item version of the International volunteers. Mol. Psychiatry 4(3), 290–296 Index of Erectile Function (IIEF-5) as a 47 Westheide J, Cvetanovska G, Albrecht C et al. diagnostic tool for erectile dysfunction. Int. 37 Wu S, Xing Q, Gao R et al. Response to Prolactin, subjective well-being and sexual J. Impot. Res. 11(6), 319–326 (1999).
chlorpromazine treatment may be associated dysfunction: an open label observational study comparing quetiapine with risperidone. 26 Byerly MJ, Nakonezny PA, Fisher R, with polymorphisms of the DRD2 gene in J. Sex. Med. 5(12), 2816–2826 (2008).
Magouirk B, Rush AJ. An empirical Chinese schizophrenic patients. Neurosci. evaluation of the Arizona sexual experience Lett. 376(1), 1–4 (2005).
A demonstration of the possible relationship
scale and a simple one-item screening test for 38 Lencz T, Robinson DG, Xu K et al. DRD2 between prolactin and antipsychotic-
assessing antipsychotic-related sexual promoter region variation as a predictor of induced sexual dysfunction.
dysfunction in outpatients with schizophrenia sustained response to antipsychotic 48 Corona G, Mannucci E, Fisher AD et al. and schizoaffective disorder. Schizophr. Res. medication in first-episode schizophrenia Effect of hyperprolactinemia in male patients 81(2–3), 311–316 (2006).
patients. Am. J. Psychiatry 163(3), 529–531 consulting for sexual dysfunction. J. Sex. 27 Grandy DK, Zhang Y, Civelli O. PCR Med. 4(5), 1485–1493 (2007).
detection of the TaqA RFLP at the DRD2 Importance of the DRD2 promoter region
49 Kelly DL, Conley RR. A randomized locus. Hum. Mol. Genet. 2(12), 2197 (1993).
polymorphism in the effects of
double-blind 12-week study of quetiapine, 28 Goldman D, Urbanek M, Guenther D, risperidone or fluphenazine on sexual Robin R, Long JC. Linkage and association of 39 Alenius M, Wadelius M, Dahl ML et al. functioning in people with schizophrenia. a functional DRD2 variant [Ser311Cys] and Gene polymorphism influencing treatment Psychoneuroendocrinology 31(3), 340–346 DRD2 markers to alcoholism, substance response in psychotic patients in a abuse and schizophrenia in Southwestern naturalistic setting. J. Psychiatr. Res. 42(11), 50 Aizenberg D, Modai I, Landa A, Gil-Ad I, American Indians. Am. J. Med. Genet. 74(4), 884–893 (2008).
Weizman A. Comparison of sexual 386–394 (1997).
40 Ghadirian AM, Chouinard G, Annable L. dysfunction in male schizophrenic patients 29 Gelernter J, Kranzler H, Cubells JF, Sexual dysfunction and plasma prolactin maintained on treatment with classical Ichinose H, Nagatsu T. DRD2 allele levels in neuroleptic-treated schizophrenic antipsychotics versus clozapine. J. Clin. frequencies and linkage disequilibria, outpatients. J. Nerv. Ment. Dis. 170(8), Psychiatry 62(7), 541–544 (2001).
including the -141CIns/Del promoter 463–467 (1982).
51 Wirshing DA, Pierre JM, Marder SR, polymorphism, in European–American, 41 Nakonezny PA, Byerly MJ, Rush AJ. Saunders CS, Wirshing WC. Sexual side African–American, and Japanese subjects. The relationship between serum prolactin effects of novel antipsychotic medications. Genomics 51(1), 21–26 (1998).
level and sexual functioning among male Schizophr. Res. 56(1–2), 25–30 (2002).
30 Naber CK, Baumgart D, Altmann C et al. outpatients with schizophrenia or 52 Dossenbach M, Dyachkova Y, Pirildar S et al. eNOS 894T allele and coronary blood flow at schizoaffective disorder: a randomized Effects of atypical and typical antipsychotic rest and during adenosine-induced double-blind trial of risperidone vs. treatments on sexual function in patients with hyperemia. Am. J. Physiol. Heart Circ. Physiol. quetiapine. J. Sex. Marital Ther. 33(3), schizophrenia: 12-month results from the 281(5), 1908–1912 (2001).
203–216 (2007).
Intercontinental Schizophrenia Outpatient 31 Marroni AS, Metzger IF, Souza-Costa DC 42 Drago F. Prolactin and sexual behavior: Health Outcomes (IC-SOHO) study. Eur. et al. Consistent interethnic differences in the a review. Neurosci. Biobehav. Rev. 8(4), Psychiatry 21(4), 251–258 (2006).
distribution of clinically relevant endothelial 433–439 (1984).
53 Strous RD, Kupchik M, Roitman S et al. nitric oxide synthase genetic polymorphisms. 43 Knegtering H, Boks M, Blijd C et al. Comparison between risperidone, Nitric Oxide 12(3), 177–182 (2005).
A randomized open-label comparison of the olanzapine, and clozapine in the 32 Ucok A, Incesu C, Aker T, Erkoc S. Sexual impact of olanzapine versus risperidone on management of chronic schizophrenia: a dysfunction in patients with schizophrenia on sexual functioning. J. Sex. Marital Ther. naturalistic prospective 12-week antipsychotic medication. Eur. Psychiatry 32(4), 315–326 (2006).
observational study. Hum. Psychopharmacol. 22(5), 328–333 (2007).
21(4), 235–243 (2006).
future science group ReseaRch aRticle Zhang, Zhang, Zhu, Yuan, Jenkins & Reynolds For reprint orders, please contact: [email protected] 54 Byerly MJ, Nakonezny PA, Bettcher BM et al. 57 Brotto LA, Gorzalka BB. Melatonin enhances placebo-controlled, flexible-dose, two-way Sexual dysfunction associated with sexual behavior in the male rat. Physiol. crossover trial. Am. J. Psychiatry 163(3), second-generation antipsychotics in Behav. 68(4), 483–486 (2000).
494–499 (2006).
outpatients with schizophrenia or 58 Klint T, Larsson K. Clozapine acts as a Demonstrates the therapeutic effect of
schizoaffective disorder: an empirical 5-HT2 antagonist by attenuating DOI- sildenafil in antipsychotic-induced sexual
evaluation of olanzapine, risperidone, and induced inhibition of male rat sexual dysfunction, providing a rationale for
quetiapine. Schizophr. Res. 86(1–3), 244–250 behaviour. Psychopharmacology (Berl.) 119(3), implicating of nitric oxide function in this
291–294 (1995).
side effect.
55 Aizenberg D, Zemishlany Z, 59 Eisenhardt A, Sperling H, Hauck E et al. ACE Dorfman-Etrog P, Weizman A. Sexual 61 Benatov R, Reznik I, Zemishlany Z. gene I/D and NOS3 G894T polymorphisms Sildenafil citrate (Viagra) treatment of sexual dysfunction in male schizophrenic patients. and response to sildenafil in men with erectile dysfunction in a schizophrenic patient. J. Clin. Psychiatry 56(4), 137–141 (1995).
dysfunction. Urology 62(1), 152–157 (2003).
Psychiatry 14(6), 353–355 (1999).
56 Schotte A, Janssen PF, Gommeren W et al. 60 Gopalakrishnan R, Jacob KS, Kuruvilla A, Risperidone compared with new and Vasantharaj B, John JK. Sildenafil in the reference antipsychotic drugs: in vitro and treatment of antipsychotic-induced erectile in vivo receptor binding. Psychopharmacology dysfunction: a randomized, double-blind, (Berl.) 124(1–2), 57–73 (1996).
Citation: Zhang, X, Zhang, Z, Zhu, R, Yuan, Y, Jenkins, T and Reynolds, G 2011, 'Sexual dysfunction in male schizophrenia: influence of antipsychotic drugs, prolactin and polymorphisms of the dopamine D2 receptor genes', Pharmacogenomics, vol. 12, no. 8, pp. 1127-1136. Pharmacogenomics (2011) 12(8)
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Newsletter03 march 2016

Doncaster & District Branch At the top of the Rock of GibraltarBaboon by Chris Donoghue 0845 0505 314 Mob: 07599 543 766 Q: What do you call aMexican that lost his car? Get-together Q: Why do the French eat Not from the Chair 4 A: They don't like fast food. AGM information 7 Danum MS is published on the last Wednesday of each

Microsoft word - treatment of ibs-sibo.doc

Treatment of Bacterial Overgrowth in Patients With Irritable Bowel Syndrome Background: Rifaximin is an effective treatment of irritable bowel syndrome (IBS) with small intestinal bacterial overgrowth (SIBO), yet long-term management has not been well studied. Patients with functional bowel symptoms were characterized by lactulose breath test (LBT), and a comprehensive approach to long-term SIBO therapy was employed. Methods: On day 0, eligible patients completed a baseline symptom questionnaire and were offered rifaximin 1200 mg/d for 10 days followed by tegaserod 3 mg nightly (long-term) plus 1 month of zinc 220 mg/d and a bifidobacteria-based probiotic once daily. Two months later, patients were administered a follow-up questionnaire regarding symptoms at the time of completion of rifaximin therapy and their current symptoms. Results: 161 of 212 patients with an abnormal LBT met Rome II criteria for IBS. High-methane producers were more likely to have constipation. After completion of rifaximin treatment, ≥50% improvement from baseline was reported by 72% of patients for abdominal pain, 67% for flatulence, 62% for bloating, 58% for constipation, 56% for diarrhea, and 53% for fullness. Similar results were reported at 2 months. Global IBS symptoms at 2 months were reported by 60% of patients to be moderately or greatly improved. Moderately or greatly improved symptoms were more frequent among high-methane producers (83%) than high-hydrogen producers (56%) or high producers of both methane and hydrogen (44%). Conclusions: Rifaximin treatment followed by adjunctive therapy was associated with sustained improvement in patients with IBS and SIBO. High-methane producers experienced more frequent constipation and reported greater clinical response compared with high-hydrogen producers.