Association between 5HT2A polymorphism and selective serotonin re-uptake inhibitor (SSRI)-induced sexual desire disorder (SDD) among Malaysian women

Transcription

1 bs_bs_banner Offi cial journal of the Pacifi c Rim College of Psychiatrists Asia Pacific Psychiatry ISSN ORIGINAL ARTICLE Association between 5HT2A polymorphism and selective serotonin re-uptake inhibitor (SSRI)-induced sexual desire disorder (SDD) among Malaysian women Ruziana Masiran 1 MBBS, Hatta Sidi 1 MMed (Psych), Zahurin Mohamed 2 PhD, Suriati Mohamed Saini 1 MMed (Psych) & Nik Ruzyanei Nik Jaafar 1 MMed (Psych) 1 Department of Psychiatry, Kebangsaan Malaysia University Medical Center, Kuala Lumpur, Malaysia 2 Department of Pharmacology, University of Malaya, Kuala Lumpur, Malaysia Keywords 5HT2A polymorphism, major depressive disorder, selective serotonin re-uptake inhibitor-induced female sexual dysfunction, sexual desire disorder Correspondence Hatta Sidi, MBBS, MMed (Psych), Department of Psychiatry, Universiti Kebangsaan Malaysia Medical Center, Jalan Yaakob Latif, Kuala Lumpur 56000, Malaysia. Tel: Fax: hattasidi@hotmail.com DOI: /appy Abstract Introduction: SSRIs are known for their sexual side-effects with a variable rate of sexual dysfunction (SD). 5HT2A (rs6311) single nucleotide polymorphism (SNP) was found to have significant association with SD. The purpose of this study was to determine the prevalence of female SDD, its clinical correlates and association with 5HT2A (rs6311) SNP in patients with major depressive disorder (MDD) treated with SSRIs. Methods: This was a cross-sectional study. We evaluated 95 female outpatients with MDD treated with SSRIs who were in remission. Outcome measures were stratified by the presence or absence of SDD. A buccal swab was obtained from each patient and sent for genotyping in the Pharmacogenomics and Medical Biotechnology Laboratory of Universiti Malaya. Results: The overall prevalence of female SD was 32.6%. The prevalence of female SDD was 62.1%. Those with arousal problem, lubrication problem, sexual satisfaction problem, orgasm problem and problematic marriage were more likely to have sexual desire disorder. The majority of participants who had sexual desire disorder had genotype TT (42.4%) but there was no significant association observed. After controlling for age, number of children, education level, SSRI type, lubrication problem, orgasm problem, satisfaction problem and marital problem, only arousal problem significantly enhanced the presence of sexual desire disorder by 8.5 times (odds ratio = 8.46, 95% confidence interval = ; P = 0.018). Discussion: This study showed that there was no significant association between SDD and the 5HT2A (rs6311) SNP. Arousal problem significantly enhanced the presence of sexual desire disorder. Introduction The Malaysian Clinical Practice Guidelines on the Management of Major Depressive Disorder (Ministry of Health Malaysia 2007) recommended the use of selective serotonin re-uptake inhibitors (SSRIs) as the first-line antidepressant in the treatment of major depressive disorder (MDD). Although they are generally better tolerated, SSRIs are known for their sexual side-effects on both women and men (Clayton et al. 2002; Corona et al. 2009; Osis & Bishop 2010; Serretti & Chiesa 2009; Waldinger & Olivier 1998). SD was not only commonly reported with SSRI use but its rate was higher compared with other antidepressants like bupropion and nefazodone (Clayton et al. 2002). A meta-analysis indicated a significantly higher rate of total and specific treatment-emergent SD compared with placebo for the following drugs (in decreasing order): sertraline, venlafaxine, citalopram, paroxetine, fluoxetine, imipramine, phenelzine, duloxetine, escitalopram and fluvoxamine (Serretti & Chiesa 2009). The same study showed the rate of SD to have ranged 41

2 5HT2A polymorphism, sexual desire disorder R. Masiran et al % (Serretti & Chiesa 2009). SD was found to be more prevalent for women (43%) than men (31%) (Laumann et al. 1999). Types and dosage of SSRI affected different areas of sexual function at different rates (Montejo-González et al. 1997; Serretti & Chiesa 2009). Sexual desire is one of the commonly affected sexual domains, with hypoactive sexual desire disorder defined as deficiency or absence of sexual fantasies and desire for sexual activity (American Psychiatric Association, 2000; p ). In a comparison between fluoxetine and escitalopram, Hatta et al. (2012a and 2012b) reported that fluoxetine therapy and moderate to high dosage of antidepressant were significantly associated with hypoactive sexual desire. Beside medication, interpersonal relationship issues also affect women s sexuality (Burri & Spector 2011) as female SD is a multifactorial phenomenon. The molecular and genetic mechanisms caused SD to differ among individuals and produced variable responses to SSRIs (Abdel-Hamid & Andersson 2009). Pharmacologically, SSRIs work by increasing concentration of synaptic 5HT and facilitating the modulation of post-synaptic receptors (Stahl 2001). Stimulation of 5HT2A receptors is thought to have negative effects on sexual function (Stahl 2001). Recent findings suggest that A-1438G polymorphism could have functional effects on the expression of this 5HT2A receptor in the brain. It was found that persons with a GG genotype of the 5HT2A _1438 single nucleotide polymorphisms (SNP) were having significantly more SD than persons with a GA or AA genotype (Bishop et al. 2006). In addition, 5HT2A _1438 GG genotype significantly predicted lower arousal scores. To date, very few gene studies of sexual desire and function have been conducted. One candidate gene study has linked serotonin polymorphisms (5HT2A) to reduced sexual desire as a side-effect of SSRI medication in both men and women (Bishop et al. 2006). The objectives of this study were to determine the prevalence of female sexual desire disorder, the clinical correlates and its association with 5HT2A polymorphism in patients with MDD taking SSRIs in the psychiatry clinics of two teaching hospitals in Malaysia. Methods This study was conducted in the psychiatry clinics of both the Universiti Kebangsaan Malaysia (National University of Malaysia) Medical Center (UKMMC) and the Universiti Malaya Medical Center (UMMC). The clinics operated 5 days a week from Monday to Friday. Both psychiatrists and trainee psychiatrists provided psychiatric consultations to new cases as well as follow-up care to the residents of Klang Valley. This study is a cross-sectional study of female patients who were diagnosed to have MDD and were prescribed SSRIs. It was conducted over a period of 16 months (1 August 2011 to 30 November 2012). It used a non-probability sampling (universal sampling) method. Subjects were included if they were female outpatients who were diagnosed to have MDD based on the fourth edition of the Diagnostic and Statistical Manual, Fourth Edition, text revised (DSM-IV-TR) by the treating psychiatrist either in UKMMC or UMMC, on SSRI therapy (which consisted of any of the following: fluoxetine, sertraline, fluvoxamine or escitalopram) for at least 4 weeks prior to the enrolment of the study, in remission (defined by the DSM-IV-TR as, during the past 2 months, not having significant signs or symptoms of disturbance and Montgomery Asberg Depression Rating Scale [MADRS] score of 10), aged between 18 and 55 years, married, able to read and understand Malay, and consented to participate in the study. Potential subjects were excluded if they were taking treatment other than SSRIs, suffering from chronic and severe medical illness/illnesses, pregnant or within 2 months of post-partum period, or postmenopausal. Research instruments Sociodemographic questionnaire This brief questionnaire included the subject s name, registration/identification card number, age, race, educational level, employment status, monthly family income and number of children. Clinical data The clinical data included duration of illness (MDD), type of SSRI, SSRI dose and duration of treatment. The dose classification for fluoxetine, sertraline, fluvoxamine and escitalopram followed the categorization by Bloch et al. (2010). However, the low sertraline dose was reduced to mg because many patients were started on 25 mg. Similarly, low dose of fluvoxamine was reduced to mg and that of escitalopram was reduced to 5 15 mg. MADRS The MADRS was developed by Montgomery and Asberg as a rating scale for the assessment of 42

3 R. Masiran et al. 5HT2A polymorphism, sexual desire disorder depression based on a clinical interview. It consists of 10 items; nine are based upon patient s report, and one is based on the rater s observation. The items represent the core symptoms of depression while they are rated on a 0 6 scale (0 = no abnormality, 6 = severe). A cutoff point of 10 or less maximized the level of agreement with the Hamilton rating scale for depression definition of remission (Zimmerman et al. 2004). Malay Version of Female Sexual Function Index (MVFSFI) The MVFSFI is a Malay-translated version of the Female Sexual Function Index, with the latter developed by Rosen (Rosen et al. 2000; Hatta et al. 2007a). Both versions are 19-item, multidimensional, selfreport measures of female sexual functioning. They cover six basic domains of female sexual functioning, namely, desire, arousal, lubrication, orgasm, satisfaction and pain. For each domain, there are two to four questions with five to six options of the most likely answer for the subjects to choose. Each question addresses the female sexual functioning of the subjects within 4 weeks prior to the day they were given the questionnaire. The MVFSFI has been validated and used to assess female SD in Malaysia (Hatta et al. 2007a). It has good discriminant validity as a whole and for each domain. A total score of 55 was taken as the cutoff point for the MVFSFI to distinguish between women with SD and those without (sensitivity = 99%, specificity = 97%). The cutoff point for each domain is as follows: desire problems, 5 or less (sensitivity = 95%, specificity = 89%); arousal difficulties 9 or less (sensitivity = 77%, specificity = 95%); lubrication inadequacy 10 or less (sensitivity = 79%, specificity = 87%); orgasm difficulties, 4 or less (sensitivity = 83%, specificity = 85%); sexual dissatisfaction, 11 or less (sensitivity = 83%, specificity = 85%); and pain, 7 or less (sensitivity = 86%, specificity = 95%). Golombok Rust Inventory of Marital State (GRIMS) The GRIMS is a 28-item questionnaire containing a series of 14 positive and 14 negative statements about marriage. Each item is answered on a 4-point scale from strongly agree, agree, disagree and strongly disagree (Rust et al. 1988). A total score is computed (range, 0 84), with a high score indicating a likely problematic marital relationship. The raw scores are then converted to standard scores (range, 1 9), with a cutoff point of 5. A total transformed score of between 6 and 9 indicates a range of poor marital state to very severe problems in the marriage. The reliability of the GRIMS is 0.91 for men and 0.87 for women, with validity being demonstrated under various situations (Rust et al. 1988). The Malay version of GRIMS is available in Malaysia but it has not yet been validated. Genotyping Genomic DNA was isolated from buccal cells collected with a buccal swab using a protocol by GeneAll (www-.geneall.com). Polymerase chain reaction (PCR) primers used for the 5HT2A-1438G/A polymorphism was Taqman SNP Genotyping Assays (Rack ID: _1) (rs6311). The DNA extraction and PCR design were done in the Pharmacogenomics Laboratory in the Department of Pharmacology UMMC while the reverse transcription PCR (RT PCR) process took place in the DNA Sequencing and Microarray Room of Medical Biotechnology Laboratory of Universiti Malaya. The PCR and sequencing primers for the 5HT2A polymorphism were designed using the Applied Biosystems ( StepOne software ver coupled with the Taqman SNP Genotyping Assays. Using StepOne Plus software, the total reaction mix volume (master mix and assay mix total volume) was calculated for 96 samples. Data were analyzed by viewing the amplification plots. Genotyping of the rs6311 (A1438G) SNP was performed by PCR using a forward primer based on the National Center for Biotechnology Information ( rs6311). Statistical analysis Analysis of the data was done using the Statistical Package for Social Studies ver c 2 -Test was used to determine risk factors for female SD among categorical variables. Overall female SD and sexual desire disorder associated with the use of SSRI were examined as categorical variables. Simple logistic regression analyses, Wald c 2 -test statistics and confidence intervals were done to determine the associations of clinical and genetic variables to SD. Multiple logistic regression analysis with 95% confidence interval (95% CI) was used to assess parameters that were considered as significant predictors of female sexual desire disorder. A two-tailed alpha value of 0.05 or less was used as the threshold for statistical significance. 43

4 5HT2A polymorphism, sexual desire disorder R. Masiran et al. Results One hundred and five subjects were enrolled in this study. However, eight patients did not complete the study due to the following reasons: (i) refusal of buccal swab (two patients); (ii) uncomfortable with the study questionnaire (two patients); (iii) unable to make time (one patient); (iv) being on dual antidepressants (two patients); and (v) had insufficient DNA concentration for laboratory analysis (one patient). The resulting study population included in the analysis consisted of 95 participants, with the majority of them being Chinese (44.25%), aged between 41 and 50 years (43.2%), working (67.4%), had a total monthly income of more than 3,000 Malaysian ringgit (71.6%) and had three or more children (50.5%) (see Table 1). Prevalence of female SD and sexual desire disorder Out of 95 participants interviewed, 31 of them scored less than 55 on the MVFSFI. Therefore, the overall prevalence of female SD was 32.6% (31/95, P = 0.33, 95% CI = ). The prevalence of female sexual desire disorder was 62.1% (59/95, P = 0.62, 95% CI = ). Looking at other domains, 36.8% suffered from arousal problem, 28.4% suffered from lubrication problem, 27.4% suffered from orgasm problem, 35.8% suffered from satisfaction problem and 21.1% suffered from pain problem. Sexual desire disorder had significant association with arousal problem (c 2 = 15.26, 1 degree of freedom [d.f.], P < 0.001), lubrication problem (c 2 = 10.63, 1 d.f., P = 0.001), sexual satisfaction problem (c 2 = 10.69, 1 d.f., P = 0.001), orgasm problem (c 2 = 6.88, 1 d.f., P = 0.009) and problematic marriage (c 2 = 4.83, 1 d.f., P = 0.028) (see Table 3). It is worth noting that marital problems greatly influenced sexual desire disorder (c 2 = 4.84, 1 d.f., P = 0.028) but this effect was not seen after controlling for other significant factors. There also seemed to be a significant difference in terms of presence of female SD (c 2 = 11.75, 1 d.f., P = 0.001), however, it was found that there was only one participant without sexual desire disorder who actually scored less than 55 on the total MVFSFI. There were no significant differences in term of race (c 2 = 2.58, 1 d.f., P = 0.275), employment status (c 2 = 1.03, 1 d.f., P = 0.311), number of children (c 2 = 0.25, 1 d.f., P = 0.615), education level (c 2 = 1.00, 1 d.f., P = 0.607), monthly family income (c 2 = 0.68, 1 d.f., P = 0.408), duration of illness (c 2 = 2.72, 1 d.f., P = 0.099), SSRI type (c 2 = 3.34, 1 d.f., P = 0.342), SSRI dose (c 2 = 1.03, 1 d.f., P = 0.597), treatment duration (c 2 = 1.36, 1 d.f., P = 0.244) and genotype groups (c 2 = 0.70, 1 d.f., P = 0.704). Further analysis of the genotype groups revealed that majority of participants who had sexual desire disorder had genotype TT (42.4%) as compared to CT (39.0%) and CC (18.6%) genotypes. However, there was no significant association observed between the sexual desire disorder and the genotypes (Table 4). Adjusted odds ratio (OR) was calculated by performing a multiple logistic regression analysis using Enter method, as shown in Table 3. Only statistically significant (P < 0.05) and clinically relevant sociodemographic and clinical variables were included in the multivariate analysis. After controlling for age, number of children, education level, SSRI type, lubrication problem, orgasm problem, satisfaction problem and marital problem, only arousal problem significantly enhanced the presence of sexual desire disorder by 8.5 times (adjusted OR = 8.46, 95% CI = , P = 0.018). Discussion Our results showed that the prevalence of SD among female patients with MDD on SSRIs was 32.6%, which was within the range reported in the previous studies, namely, between 24% and 80.3% (Balon 2006; Clayton et al. 2002; Hatta et al. 2012a; Ishak et al. 2010, Strohmaier et al. 2011). On the contrary, the prevalence of sexual desire disorder was 62.1%, approximately 10% higher than that found in recent studies performed among female patients on fluoxetine and escitalopram (Hatta et al. 2007b, 2012b) which reported a 50.9% desire problem in their study population. Perhaps this discrepancy is due to some difference in the demographic characteristics in the populations being studied. Unlike the latter study, 50.5% of this study s participants had three or more children, although other factors like age and race were comparable. As shown by Hatta et al. (2007a), having more children was associated with sexual problem among women. Unlike previous studies (Hatta et al. 2007a; Hatta et al. 2012a and 2012b), results from this study showed that age, number of children, education level, SSRI type and SSRI dosing did not influence the total MVFSFI score or contribute to sexual desire disorder in particular. Participants with sexual desire disorder also scored less on other domains of MVFSFI (i.e. arousal, lubrication, orgasm and satisfaction) and had more problematic marriage. Univariate analysis confirmed that problematic marriage seemed to enhance SD 44

5 R. Masiran et al. 5HT2A polymorphism, sexual desire disorder Table 1. Subjects demographics and clinical characteristics stratified by desire domain Measure No sexual desire disorder Median (IQR) Sexual desire disorder Median (IQR) P-value Duration of illness (months) (60.0) (48.0) a Duration of treatment (months) (48.0) (60.0) a Measure n (%) n (%) Age (years) <31 3 (8.3) 6 (10.2) b (25.0) 18 (30.5) (52.8) 22 (37.3) >50 5 (13.9) 13 (22.0) Race Malay 18 (50.0) 20 (33.9) Chinese 14 (38.9) 28 (47.5) Others 4 (11.1) 11 (18.6) Employment status Unemployed 14 (38.9) 17 (28.8) Employed 22 (61.1) 42 (71.2) Children (n) <3 19 (52.8) 28 (47.5) (47.2) 31 (52.5) Education (highest level achieved) Primary 5 (13.9) 12 (20.3) Secondary 18 (50.0) 24 (40.7) Tertiary 13 (36.1) 23 (39.0) Total monthly family income (RM) (33.3) 15 (25.4) > (66.7) 44 (74.6) SSRI type Fluoxetine 3 (8.3) 3 (5.1) b Sertraline 4 (11.1) 8 (13.6) Fluvoxamine 12 (33.3) 11 (18.6) Escitalopram 17 (47.2) 37 (62.7) SSRI dose classification Low 23 (63.9) 43 (72.9) Medium 12 (33.3) 14 (23.7) High 1 (2.8) 2 (3.4) Arousal domain (MVFSFI) No problem 33 (91.7) 27 (45.8) <0.001* Problem 3 (8.3) 32 (54.2) Lubrication domain (MVFSFI) No problem 34 (94.4) 34 (57.6) <0.001* Problem 2 (5.6) 25 (42.2) Orgasm domain (MVFSFI) No problem 32 (88.9) 37 (62.7) 0.006* Problem 4 (11.1) 22 (37.3) Satisfaction domain (MVFSFI) No problem 31 (86.1) 30 (50.8) 0.001* Problem 5 (13.9) 29 (49.2) Pain domain (MVFSFI) No problem 36 (100.0) 39 (66.1) <0.001* Problem 0 (0.0) 20 (33.9) Female sexual dysfunction Absent 35 (97.2) 29 (49.2) <0.001* Present 1 (2.8) 30 (50.8) GRIMS (interpretation) No problem 15 (41.7) 12 (20.3) 0.025* Problematic marriage 21 (58.3) 47 (79.7) Genotype CC 8 (22.2) 11 (18.6) CT 11 (30.6) 23 (39.0) TT 17 (47.2) 25 (42.4) a Mann Whitney U-test. b Fisher s exact test. *P < GRIMS, Golombok Rust Inventory of Marital State; IQR, interquartile range; MVFSFI, Malay Version of Female Sexual Function Index; SSRI, selective serotonin re-uptake inhibitor. 45

6 5HT2A polymorphism, sexual desire disorder R. Masiran et al. (c 2 = 6.81, 1 d.f., P = 0.009) generally and sexual desire disorder (c 2 = 4.84, 1 d.f., P = 0.028) in particular. However, the differences diminished after adjusting for age, number of children, education level, SSRI types, arousal problem, lubrication problem, orgasm problem, satisfaction problem and GRIMS score. After conducting multiple logistic regressions, the only Table 2. Selective serotonin re-uptake inhibitor (SSRI) dosing Dose classification SSRI Low, n (%) Medium, n (%) High, n (%) Fluoxetine 5 (7.6) 1 (3.8) 0 (0.0) Sertraline 5 (7.6) 6 (23.1) 1 (33.3) Fluvoxamine 16 (24.2) 6 (23.1) 1 (33.3) Escitalopram 40 (60.6) 13 (50.0) 1 (33.3) determinant found to be significantly associated with sexual desire disorder was arousal problem whereby participants with arousal problem had 8.5-times more risk of having sexual desire disorder. With regards to the effects of medications contributing to sexual side-effects, there were four SSRI types being studied: fluoxetine (median dose, mg), sertraline ( mg), fluvoxamine ( mg) and escitalopram (10.00 mg). The dosing classification followed Bloch et al. (2010) (Table 2). Escitalopram was the most frequently prescribed SSRI among the study subjects (56.8%), but SSRI types did not show any significant influence on desire domain in the MVFSFI. This study also did not replicate a previous study which showed significant association between moderate to high dosage of SSRI and female hypoactive Table 3. Analysis of relationship between sexual desire disorder and other clinically relevant variables Simple logistics regression Multiple logistics regression Crude OR (95% CI) c 2 statistics (d.f.) a p-value Adjusted OR (95% CI) c 2 statistics (d.f.) a p-value Age (years) <31 b 1.00 (0.20, 4.95) 0.00 (1) ( ) 0.00 (1) (0.12, 2.63) 0.50 (1) ( ) 1.98 (1) (0.23, 7.31) 0.09 (1) ( ) 0.50 (1) >50 No. of Children <3 b (0.54, 2.84) 0.25 (1) ( ) 2.21 (1) Education level Primary b 0.56 (0.17, 1.86) 0.91 (1) ( ) 0.91 (1) Secondary 0.74 (0.21, 2.56) 0.23 (1) ( ) 1.19 (1) Tertiary SSRI dose Low b Medium 0.62 (0.25, 1.57) 1.00 (1) ( ) 0.83 (1) High 1.07 (0.09, 12.44) 0.00 (1) ( ) 0.01 (1) Arousal No problem b (3.60, 47.27) (1) ( ) 4.77 (1) 0.018* Problem Lubrication No problem b (2.74, 56.96) (1) ( ) 2.16 (1) Problem Orgasm No problem b 4.76 (1.48, 15.26) 6.88 (1) ( ) 1.62 (1) Problem Satisfaction b No problem 5.99 (2.05, 17.54) (1) ( ) 1.05 (1) Problem Marital state b No problem 2.80 (1.12, 7.00) 4.84 (1) ( ) 2.03 (1) Problematic a Wald statistics. b Reference group. *P < CI, confidence interval; d.f., degree of freedom; OR, odds ratio; SSRI, selective serotonin re-uptake inhibitor. 46

7 R. Masiran et al. 5HT2A polymorphism, sexual desire disorder Table 4. Analysis of genotype groups by presence of sexual desire disorder No sexual desire disorder, n = 36 Sexual desire disorder, n = 59 Simple logistics regression Measure n (%) n (%) Crude OR (95% CI) c 2 statistic (d.f.) a P-value CC b 8 (22.2) 11 (18.6) CT 11 (30.6) 23 (39.0) 1.73 (0.51, 5.95) 0.76 (1) TT 17 (47.2) 25 (42.4) 1.90 (0.58, 6.28) (1) a Wald statistics. b Reference group. CI, confidence interval; d.f., degree of freedom; OR, odds ratio; SSRI, selective serotonin re-uptake inhibitor. sexual desire (Hatta et al. 2012a). Perhaps with the majority of participants receiving a low dose of SSRIs, this association could not be properly studied. Interestingly in our study, it was found that marital problem was an important factor contributing to female SD whereby 90.3% of participants with SD reported marital dissatisfaction. Further analysis showed a significant association between marital harmony and SD as well as sexual desire disorder, although these findings diminished after controlling other factors. We did not observe a genetic relationship with sexual desire disorder or the total MVFSFI score. Therefore, we did not replicate the reported relationship between genotype and desire/frequency subscale which was highly correlated (Bishop et al. 2006). The small sample size of this study may not able to detect such association. Second, there are patients who were fast metabolizers for the enzymes responsible for SSRI metabolism leading to lesser risk of sexual side-effects. This fast metabolism of SSRIs could also be the result of any concomitant medications interacting with SSRIs. Lastly, genetic heterogeneity may contribute to this finding. Nevertheless, Bishop et al. (2006) also found that arousal scores significantly predicted desire/frequency scores and this actually corresponded to our findings. There are a number of limitations that are relevant to be mentioned. This study was a point prevalence and cross-sectional analysis which determine sexual problems associated with SSRIs among female patients with MDD who were in remission. Pretreatment rates of SD among the participants were not available for comparison. Arguably, a prospective analysis would be more appropriate to study treatment-emergent SD. Having said this, SD is likely to be a persistent side-effect of SSRIs (Csoka et al. 2008), with over 85 90% of patients who had SD not experiencing resolution after 6 months of treatment (Montejo-Gonzalez et al. 1997; Osis & Bishop 2010). To minimize the confounding effects of residual depressive symptoms, we enrolled only subjects who had been on SSRI for at least 4 weeks so that they would have an adequate chance to respond to the medication and any sexual problem could be possibly attributed to the SSRI they were taking. They were also clinically not depressed based on a MADRS score of 10 or less. However, we may have missed those who discontinued any SSRI before 4 weeks due to sexual side-effects. Nevertheless, although we required that the minimum treatment duration of 4 weeks, it should be noted that the treatment duration in our study was quite variable (median, 36 months; range, months). Hence, it was possible that some of the participants may experience improvement in their sexual problem over time. This possibility could have lowered the point prevalence of SD observed in this study and subsequently minimized the pharmacogenetic relationship seen. The study also did not monitor the subjects treatment compliance. Therefore, participants who did not take SSRIs regularly could also experience sexual problem due to other factors like concomitant medications, medical illness or psychosocial factors. Excluding concomitant medications could be an important consideration because some of the other medications may have unknown sexual side-effects. Finally, our sample was also heavily weighted for escitalopram over other SSRIs which affected the inference of the results on the relationship between the specific type of SSRI and sexual problem and genetic relationship among those treated on different types of SSRIs. Despite these limitations, the present study is a significant contribution to both psychiatry and pharmacogenetic fields. The findings highlighted the magnitude of sexual desire disorder among female patients who received SSRIs and examined the relationship between the sexual desire domain with the other variables and other areas of sexual function through MVFSFI domains. Our subject population was almost completely devoid of confounding medical confounders as those with serious medical illnesses were excluded. In conclusion, we report that in female patients on SSRIs who were in remission, individuals with arousal problems were 8.5-times more likely to 47

8 5HT2A polymorphism, sexual desire disorder R. Masiran et al. have sexual desire disorder than those who did not have arousal problem. Although the female patients on SSRI who experienced SD were overrepresented in genotype TT, there was no significant relationship observed between genotype groups and sexual desire disorder. In the future, a prospective analysis with a larger study population and equally represented SSRI groups would be a better way to determine the presence of relationship between SSRI type, genetic marker and incidence of SD. It would also be beneficial to determine the predictive ability of the genetic markers with regards to SD. Such knowledge would enable us to develop a mechanism to individualize the prescription of antidepressants as patients become more aware of SSRI-related SD. Acknowledgments This research project was approved by the Research Committee, Department of Psychiatry UKMMC, the Research Secretariat Unit, Faculty of Medicine, UKMMC (project code: FF ) and UMMC Ethics Committee (reference no: ). This study received a research grant ( ) from the Faculty of Medicine UKMMC. We would like to thank Nur Elia from the Department of Pharmacology of University of Malaya and Dr Jamaiyah Haniff and her team from the Clinical Epidemiology Unit of the Clinical Research Center. Conflict of interest The authors declare no conflict of interest. References Abdel-Hamid I.A., Andersson K.-E. (2009) Pharmacogenetics and pharmacogenomics of sexual dysfunction: current status, gaps and potential applications. Pharmacogenomics. 10, American Psychiatric Association (2000) Diagnostic and Statistical Manual of Mental Disorders, 4th edn. Text Rev. American Psychiatric Association, Washington, DC. Balon R. (2006) SSRI-associated sexual dysfunction. Am J Psychiatry. 163, Bishop J.R., Moline J., Ellingrod V.L., Schultz S.K., Clayton A.H. (2006) Serotonin 2A-1438 G/A and G-protein Beta3 subunit C825T polymorphisms in patients with depression and SSRI-associated sexual side-effects. Neuropsychopharmacology. 31, Bloch M.H., McGuire J., Landeros-Weisenberger A., Leckman J.F., Pittenger C. (2010) Meta-analysis of the dose-response relationship of SSRI in obsessive-compulsive disorder. Mol Psychiatry. 15, Burri A., Spector T. (2011) Recent and lifelong sexual dysfunction in a female UK population sample: prevalence and risk factors. J Sex Med. 8, Clayton A.H., Pradko J.F., Croft H.A., et al. (2002) Prevalence of sexual dysfunction among newer antidepressants. J Clin Psychiatry. 63, Corona G., Ricca V., Bandini E., et al. (2009) Selective serotonin reuptake inhibitor-induced sexual dysfunction. J Sex Med. 6, Csoka A., Bahrick A., Mehtonen O.-P. (2008) Persistent sexual dysfunction after discontinuation of selective serotonin reuptake inhibitors. J Sex Med. 5, Hatta S., Norni A., Sharifah Ezat W.P., Marhani M. (2007a) The female sexual function index (FSFI): validation of the Malay version. J Sex Med. 4, Hatta S., Sharifah Ezat W.P., Marhani M., Norni A. (2007b) Sexual arousal problem among Malaysian women in a primary care setting. Malays J Psychiatry. 16, Hatta S., Sharifah Ezat W.P., Norni A., Marhani M. (2007c) The prevalence of sexual dysfunction and potential risk factors that may impair sexual function in Malaysian women. J Sex Med. 4, Hatta S., Duni A., Rozita H., Ng C.G. (2012a) Female sexual dysfunction in patients treated with antidepressant comparison between escitalopram and fluoxetine. J Sex Med. 9, Hatta S., Duni A., Rozita H., Nik Ruzyanei J., Ng C.G. (2012b) Hypoactive sexual desire among depressed female patients treated with selective serotonin reuptake inhibitors: a comparison between escitalopram and fluoxetine. Int J Psychiatry Clin Pract. 16, Ishak I.H., Low W.Y., Othman S. (2010) Prevalence, risk factors and predictors of female sexual dysfunction in a primary care setting: a survey finding. J Sex Med. 7, Laumann E.O., Paik A., Rosen R.C. (1999) Sexual dysfunction in the United States: prevalence and predictors. JAMA. 281, Ministry of Health Malaysia (2007) Clinical practice guidelines management of major depressive disorder [Cited 14 August 2010.] Available from URL: 48

9 R. Masiran et al. 5HT2A polymorphism, sexual desire disorder Montejo-González A.L., Llorca G., Izquierdo J.A., et al. (1997) SSRI-induced sexual dysfunction: fluoxetine, paroxetine, sertraline, and fluvoxamine in a prospective, multicenter, and descriptive clinical study of 344 patients (Abstract). J Sex Marital Ther. 23, Osis L., Bishop J.R. (2010) Pharmacogenetics of SSRIs and sexual dysfunction. Pharmaceuticals. 3, Rosen R., Brown C., Heiman J., et al. (2000) The female sexual function index (FSFI): a multidimensional self-report instrument for the assessment of female sexual function. J Sex Marital Ther. 26, Rust J., Golombok S., Collier J. (1988) Marital problems and sexual dysfunction: how are they related? Br J Pychiatry. 152, Serretti A., Chiesa A. (2009) Treatment-emergent sexual dysfunction related to antidepressants. A meta-analysis. J Clin Psychopharmacol. 29, Stahl S.M. (2001) The psychopharmacology of sex, part 2: effects of drugs and disease on the 3 phases of Human sexual response. J Clin Psychiatry. 62, Strohmaier J., Wust S., Uher R., et al. (2011) Sexual dysfunction during treatment with serotonergic and noradrenergic antidepressants: clinical description and the role of the 5-HTTLPR. World J Biol Psychiatry. 12, Early Online: Waldinger M.D., Olivier B. (1998) Selective serotonin reuptake inhibitor-induced sexual dysfunction: clinical and research considerations. Int Clin Psychopharmacol. 13(Suppl 6), S27 S33. Zimmerman M., Posternak M.A., Iwona C. (2004) Derivation of a definition of remission on the Montgomery Asberg depression rating scale corresponding to the definition of remission on the Hamilton rating scale for depression (Abstract). J Psychiatr Res. 38,