Journal of Sex & Marital Therapy, 29(2): , 2003 Copyright 2003 Brunner-Routledge X/03 $ DOI: /

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1 Journal of Sex & Marital Therapy, 29(2): , 2003 Copyright 2003 Brunner-Routledge X/03 $ DOI: / Frequency of Sexual Dysfunction and Other Reproductive Side-effects in Patients with Schizophrenia Treated with Risperidone, Olanzapine, Quetiapine, or Haloperidol: The Results of the EIRE Study J. BOBES AND M. P. GARCÍA-PORTILLA Department of Psychiatry, University of Oviedo, Spain J. REJAS AND G. HERNÁNDEZ Outcomes Research Unit & Medical Division, Laboratories Pfizer SA, Madrid, Spain M. GARCIA-GARCIA, F. RICO-VILLADEMOROS Brométrica, Barcelona, Spain A. PORRAS Atypical antipsychotics seem to differ mainly in their tolerability profile. The aim of this cross-sectional study, the Estudio de Investigación de Resultados en Esquizofrenia (Outcomes Research This study has been funded by Laboratorios Pfizer SA, Madrid, Spain. Preliminary results were presented at the American Psychiatric Association (APA) Annual Meeting, New Orleans, May 5 10, 2001 and at the International Society for Pharmacoeconomics and Outcomes Research Fourth Annual European Congress (ISPOR), Cannes, France, November 11 13, The authors have written this article on behalf of the EIRE Study Group, whose member include S. Álvarez (Asturias), P. Álvarez (Valladolid), M. T. Bascarán (Asturias), M. Bernardo (Barcelona), J. A. Blanco (Valladolid), J. Bobes (Asturias), J. Busto (Badajoz), F. Campo (Cádiz), M. S. Casares (Madrid), S. Catarineu (Barcelona), M. Cavero (Barcelona), E. Daniel (Cáceres), C. Deza (Burgos), V. Elvira (Alicante), J. C. Espín (Madrid), Z. Fernández (Sevilla), C. Fernández (Zamora), J. I. Franch (Valladolid), F. Galán (Badajoz), M. T. Gallego (Zamora), G. García (Barcelona), M. García (Baleares), M. A. Garzón (Salamanca), J. Gómez-Trigo (Madrid), M. P. G.-Portilla (Asturias), M. González-Quirós (Asturias), L. Gutiérrez (Orense), M. Hemmings (Zamora), O. Herreros (Santa Cruz de Tenerife), C. Iglesias (Asturias), J. J. López (Granada), E. Martín (Madrid), M. Martín (Navarra), F. Martín (Burgos), J. M. Martínez (Zamora), M. J. Martínez (Zamora), J. Matías (Salamanca), J. Medina (Madrid), M. Á. Medina (Burgos), P. Megía (Palencia), M. J. Merino (Asturias), A. Monforte (Zamora), J. Mons (Burgos), A. L. Montejo (Salamanca), J. M. Montes (Madrid), M. A. More (Madrid), A. Muñoz (Madrid), F. Orengo (Madrid), A. Pérez (Pontevedra), J. L. Pérez-Iñigo (Madrid), J. I. Portilla (Asturias), I. Rubio (Madrid), V. Rubio (Zaragoza), F. Ruíz (Palencia), O. Sanz (Burgos), M. Silvestre (Badajoz), J. A. Solana (Salamanca), A. Soto (Valladolid), J. R. Valle (Sevilla), A. Varona (Burgos), F. Vicente (Madrid). Address correspondence to Julio Bobes, Departamento de Psiquiatría, Universidad de Oviedo, C/Julián Clavería, 6, Oviedo 33006, Spain. bobes@correo.uniovi.es 125

2 126 J. Bobes et al. Study in Schizophrenia; EIRE study), was to assess in a clinical setting the frequency of several side-effects related to haloperidol, risperidone, olanzapine, and quetiapine. This article addresses sexual dysfunction and other reproductive side-effects (gynecomastia, menorrhage, amenorrhea, and galactorrhea). We recruited outpatients diagnosed with schizophrenia according to Diagnostic and Statistical Manual of Mental Disorders (DSM-IV; American Psychiatric Association, 1994) criteria and who had received a single antipsychotic (risperidone, olanzapine, quetiapine, or haloperidol) for at least 4 weeks. During a single visit, we collected data, including demographic and clinical characteristics, current antipsychotic and concomitant treatment, and adverse effects listed in a modified version of the UKU Scale. We used a Chi-squared test to determine pairs comparisons of the frequency of adverse reactions between treatments. To estimate risk of a given adverse reaction with a given treatment, we used a logistic regression method. We assessed 636 evaluable patients out of 669 recruited. Frequency of sexual dysfunction was high with haloperidol (38.1%) and also with olanzapine (35.3%), quetiapine (18.2%), and risperidone (43.2%). We found the frequency of other reproductive side-effects to be relatively low with all four drugs: haloperidol (6.9%), olanzapine (6.4%), quetiapine (2.7%), and risperidone (11.7%). Sexual dysfunction appeared to be dose-related with haloperidol, risperidone, and olanzapine. Risperidone and olanzapine showed a higher risk of sexual dysfunction and other reproductive sideeffects than haloperidol. Quetiapine showed a lower risk of sexual dysfunction during short-term treatment (< 12 weeks). However, data on longer-term treatment (> 12 weeks) are lacking. Our results suggest that none of the atypical antipsychotics that we studied significantly improved sexual dysfunction and other reproductive side-effects of the conventional antipsychotic, haloperidol, in stabilized patients during long-term treatment. Quetiapine appears to improve this profile during short-term treatment; however, longterm data, with larger samples, are required with this latter drug. Sexual dysfunction is a common problem among the general population as well as among those suffering for psychiatric disorders and/or receiving psychotropic drugs. Research on sexual dysfunction with the exception of male erectile dysfunction is scarce. There are various aspects that make assessment of sexual dysfunction related to psychotropic drugs difficult. These include the potential biases associated with (a) patient selection (The study may include a greater number of patients who pay more attention to sexual matters and/or who are more willing to report on such matters.); (b) the assessment procedure used (self-report, questionnaire, or direct questioning); (c) the type of measurements used (objective versus subjective mea-

3 The Results of the EIRE Study 127 surements); (d) the gender differences in the assessment (Sexual effects of psychotropic drugs are better documented in men than in women.); and (e) the lack of a baseline assessment (Demyttenaere, De Fruy, & Sienaert, 1998). An added difficulty is the differentiation between the effects of psychopathology and its course and the effects of psychotropic medication (Peuskens, Sienaert, & de Hert, 1998). However, in spite of these limitations in the evaluation and the bias involved, most published studies agree that patients with schizophrenia treated with antipsychotics have a high prevalence of sexual dysfunction, ranging from 25% to 60% (Demyttenaere et al., 1998; Peuskens et al., 1998), and of problems derived from hyperprolactinemia, such as amenorrhea, with an incidence in women even higher than 50% (Ghadirian, Chouinard, & Annable, 1982; Sandison, Whitelaw, & Currier, 1960). Sexual dysfunction and other reproductive problems have been given particularly little attention and often are underestimated in daily clinical practice with schizophrenic patients. This is partly because for years it was assumed that these patients had little sexual activity (Peuskens et al., 1998). However, the few data available, obtained from research on risk behaviors associated with HIV infection, show that 50 60% of these patients have some type of sexual activity (Cournos et al., 1994; Demyttenaere et. al. 1998, Kelly et al., 1992; Susser et al., 1995; Thompson et al., 1997). It has recently been reported that approximately 80% of stabilized psychotic patients of both sexes have partner relations, and over 75% of men have masturbatory activity (Dickson & Glaser, 2000). It was also assumed for years that schizophrenic patients have sexual problems and deviant sexual behavior; however, no clinical evidence has been found to support this assumption (Demyttenaere et al., 1998). On the other hand, until clozapine was introduced in 1975, it was also assumed that hyperprolactinemia was an unavoidable problem associated with antipsychotic treatment. However, with the introduction of clozapine and more recently with the marketing of new atypical antipsychotics the situation seems to have changed; in addition to clozapine, atypical antipsychotics such as olanzapine, quetiapine, and ziprasidone do not appear to be associated with a significant increase in prolactin levels, sexual dysfunction, and other reproductive-related side-effects (Petty, 1999). The data currently available suggest that the incidence of sexual dysfunction differs depending on the antipsychotic used (Knegtering, Blijd, & Boks, 1999; Montejo, 2000; Montejo, Llorca, & Izquierdo, 2000). On one hand, various studies had already shown that the incidence of sexual dysfunction was high, 25 60%, in patients treated with conventional antipsychotics such as thioridazine (Kotin, Wilbert, Verburg, & Soldinger, 1976; Sandison et al., 1960), with conventional drugs other than thioridazine (Ghadirian et al., 1982), with conventional drugs also including thioridazine (Sullivan & Lukoff, 1990), or with risperidone (David, Crawford, & Breier, 1998; Knegtering et al., 1999; Montejo, 2000; Shiwach & Carmody, 1998). On the other hand, the data available suggest atypical antipsychotics are different not only from classical ones (Aizenberg, Modai, Landa, Gil-Ad, & Weizman, 2001); further-

4 128 J. Bobes et al. more, data available suggests that atypical ones differ from one another (David et al., 1998; Knegtering et al., 1999; Montejo, 2000). Systematic data on quetiapine and ziprasidone are lacking; however, in registrational clinical trials with these drugs, frequency of sexual dysfunction appears to be very low (Physicians Desk Reference, 2001). Although clinical trials are essential in assessing the effect and value of an intervention because they provide researchers a methodological control on potential confounding factors and maximize the internal validity, inclusion and exclusion criteria are so limiting, the conditions of treatment administration are so optimized, and the results are so narrowly defined that it is difficult to generalize them (Norquist, Lebowitz, & Hyman, 1999). In addition, in the specific case of sexual dysfunction, findings from clinical trials clearly underestimate this problem because of the nonspecific assessment of these adverse effects; the incidence of sexual dysfunction has been shown to increase when specific assessment measures are used (Knegtering, Boks, & Brink, 1998; Monteiro, Noshirvani, Marks, & Lelliott, 1987; Montejo et al., 1996). Therefore, clinical trials are not always applicable to clinical practice (Fleischhacker & Hummer, 1999). More naturalistic studies are therefore required to test the clinical value of these drugs in routine daily clinical practice as well as to ascertain how the drugs are actually used and how the sideeffects are managed by physicians at their offices. This was the purpose of the Estudio de Investigación de Resultados en Esquizofrenia (Outcomes Research Study in Schizophrenia; EIRE study), conducted in Spain. The results of this study are partially reported in this article. The objectives of this crosssectional study were to assess the frequency of different adverse effects extrapyramidal, weight changes, and sexual dysfunction and other reproductive side-effects that occur with the antipsychotics most commonly used in Spain and to evaluate the management of such adverse effects by the clinical psychiatrist. This article addresses sexual dysfunction and other reproductive side-effects. Investigators and Patients METHODS A Contract Research Organization selected the participating investigators. Participants were informed of the existence of a sponsor, although its name was not disclosed to any of them except the study coordinator until data analysis had been completed. Sixty-one psychiatrists recruited the patients from outpatient clinics during November 5 December 7, We included patients diagnosed with schizophrenia according to DSM-IV (APA, 1994) criteria and who were receiving antipsychotic treatment for at least 4 weeks with a single antipsychotic (risperidone, olanzapine, quetiapine, or haloperidol). The patients were included regardless of what other medication they may have received.

5 The Results of the EIRE Study 129 We conducted a systematic sampling so that each center would include up to 12 patients, including 3 patients for each of the four treatments studied (risperidone, olanzapine, quetiapine, or haloperidol). However, because quetiapine has only recently become available in Spain as an antipsychotic treatment and because the use of haloperidol is increasingly less common, particularly as a single antipsychotic drug, in centers where 3 patients treated with quetiapine and/or haloperidol could not be recruited, we established a priori that inclusion of 3 additional patients treated with olanzapine or risperidone would be allowed. Because of the strictly observational nature of the study, we left to the discretion of the investigator and his/her institution the procedure for obtaining patient consent for study data collection. Study Design and Procedures Each participating investigator received general instructions for the performance of the investigation and one set of case record forms for each patient included in the study. After fulfillment of the eligibility criteria was ensured, the following information was collected during the single visit of the study. Demographic data: age, sex, marital status, current stable partner, and employment status. Clinical characteristics: weight at the time of starting current treatment and at the time of the visit, height, duration of illness, number of previous hospitalizations, schizophrenia subtype, and patient s global severity of illness, according to the Clinical Global Impression Scale (Guy, 1976). Current antipsychotic treatment: drug s name, dose at the time of the visit, duration of present antipsychotic treatment, whether dose-titration was required, and the reason for initiating current treatment (first episode, acute exacerbation, drug substitution). Concomitant treatment at the time of the visit: categorized as antiparkinsonians, antidepressants, antianxiety agents/hypnotics, anticonvulsants, lithium, and other drugs. Modified-UKU, as described below. The patients continued receiving antipsychotic treatment, according to the clinical criterion and standard clinical practice of each investigator. Measurements We collected the adverse effects studied using a modified version of the UKU scale (Lingjærde, Ahlfors, Bech, Dencker, & Elgen, 1987). Specifically, each investigator recorded information on the following adverse reactions: sexual side-effects (increased or diminished sexual desire, erectile, ejaculatory, or orgasmic dysfunction, and vaginal dryness) and other reproductive

6 130 J. Bobes et al. side-effects (menorrhage, amenorrhea, galactorrhea, and gynecomastia). As in the original version of the UKU, each item was scored on a 4-point scale; in general, 0 = none or doubtful, 1 = present to a mild degree, 2 = present to a moderate degree, and 3 = present to a severe degree. We then made a judgment about the casual relationship of each item to the medication, using the terms impossible, possible, or probable. In addition, the modified version of the scale included an ad hoc question on the actions taken by the investigator with the drug as a result of the adverse effect, which included the following categories: no action, dose reduction, switching to another antipsychotic, and use of an antidote. We gave all participating investigators the original manual of the UKU (Lingjærde et al., 1987), which defines each item and provides detailed information of each anchor point. Statistical Analysis After we tabulated the study data and performed quality control, we analyzed the results using SPSS version 10.0 (SPSS for Windows 10.0, 1999). We estimated, in a descriptive analysis, the mean, standard deviation, and range for quantitative variables and the frequency and percentage of patients in each category for qualitative variables. For the between-group comparison of the sample characteristics and the presence of adverse reactions, we performed comparative analyses between the four treatment groups studied (haloperidol, olanzapine, quetiapine, and risperidone). We conducted these analyses via multivariate analysis of variance (MANOVA), using Hotelling s T test with multiple comparisons (Bonferroni s approach) for continuous variables and the Chi-squared test for categorical variables. In order to establish the influence of potential confounding factors, we made stratified analyses of the frequency of adverse reactions by dose and treatment duration using the Chi-squared test. Finally, in order to estimate the risk of a given adverse reaction with a given treatment, we used a logistic regression method that defined haloperidol as the reference category with which comparisons could be made of the risk associated with each of the other three atypical antipsychotics, adjusting by sex and stratifying by dose and duration of treatment. A 2-tailed significance level of less than 0.05 was considered for all tests. RESULTS Evaluable Patients and Distribution by Treatment Groups Sixty-one investigators participating in the study recruited 669 patients. Of these 669 patients, 33 were excluded (4.9%), leaving a total of 636 evaluable

7 The Results of the EIRE Study 131 patients. The treatment group from which the highest number of patients was excluded was the quetiapine group (n = 10, 18.9%), followed by the haloperidol group (n = 8, 5.8%), the olanzapine group (n = 7, 3.0%), and the risperidone group (n = 6, 2.5%). The most common reasons for patient exclusion from the analysis were antipsychotic treatment for less than 4 weeks with any of the study drugs (n = 10, 18.9% for quetiapine; n = 7, 5.0% for haloperidol; n = 6, 2.6% for olanzapine; and n = 6, 2.5% for risperidone), no specified current antipsychotic treatment (n = 2, 0.3% for the total sample), treatment with two or more antipsychotics (n = 1, 0.7% for haloperidol), and no specified diagnosis of schizophrenia (n = 1, 0.4% for olanzapine). Patient Characteristics Table 1 shows statistically significant differences found between treatment groups in the sociodemographic characteristics of the patients. Specifically, the haloperidol group had a higher mean age and a higher proportion of patients receiving a disability allowance than the other three groups of patients. We also found that the quetiapine group had a younger mean age and a higher proportion of patients on work leave than the risperidone group. We also found some statistically significant differences between treatment groups in the clinical characteristics of the patients, which are also shown in Table 1. Specifically, we observed that the haloperidol patients had experienced schizophrenia longer than the risperidone patients, and even longer TABLE 1. Sociodemographic and Clinical Characteristics of Patients by Treatment Characteristic Haloperidol Olanzapine Quetiapine Risperidone n = 130 n = 28 n = 43 n = 232 Sex Men Women Marital status Single Married Divorced (separated) Widow/widower m SD m SD m SD m SD Age OQR H H H Duration of illness, years OQ H H CGI-S R Q Number of previous hospitalizations Statistically significant differences were found between treatments for mean age, time since onset of the disease, and CGI-S scale (MANOVA p < 0.05). Statistically significant differences were found versus H haloperidol, O olanzapine, Q quetiapine, and R risperidone for mean age, time since onset of the disease, and CGI-S scale (Bonferroni s multiple comparison test: p < 0.05).

8 132 J. Bobes et al. than the olanzapine or quetiapine patients. However, it should also be noted that patients treated with quetiapine had more severe schizophrenia, as measured by the mean score in the severity scale of the Clinical Global Impression, compared to those treated with olanzapine and risperidone. The quetiapine group also had a higher proportion of patients with a diagnosis of undifferentiated, disorganized schizophrenia than the other two groups of patients. Characteristics of the Treatments Table 2 shows the doses of the four antipsychotic drugs used, the time elapsed since the start of the treatment, and the type of dose escalation used. The duration of treatment in the haloperidol group was statistically significant and longer than in the patients treated with risperidone, olanzapine, or quetiapine. Dose escalation was more frequent in the quetiapine group (n = 40/43, 93.0%), while this method for starting a new treatment was least used in the olanzapine group (n = 148/225, 65.8%). Moreover, we observed a bimodal dose distribution for olanzapine and risperidone, with peaks of 10 and 20 mg/day for olanzapine (in 36.0% and 28.1% of the patients) and 3 and 6 mg/day for risperidone (in 27.9% and 36.9% of the patients). The most TABLE 2. Description of the Antipsychotic Treatments Studied Characteristic Haloperidol Olanzapine Quetiapine Risperidone n = 131 n = 228 n = 43 n = 234 Dose (mg/day) Mean, SD 10.6, , , , 2.6 Range n, % Low dose 57, 43.8 OQR 123, 53.9 HQR 16, 37.2 HO 82, 35.0 HO Middle dose 33, 25.4 OQR 96, 42.1 HQR 23, 53.5 HO 112, 47.9 HO High dose 40, 30.8 OQR 9, 3.9 HQR 4, 9.3 HO 40, 17.1 HO Duration of current treatment (years) Mean, SD 4.5, 5.4 OQR 1.5, 1.5 HQ 0.1, 0.0 HOR 1.8, 1.6 HQ n, % 12 weeks 10, 7.6 QR 18, 7.9 QR 43, HOR 36, 15.4 HOQ > 12 weeks 121, 92.4 QR 210, 92.1 QR 0, 0 HOR 198, 84.6 HOQ Dose titration (n, %) Yes 92, 73.0 Q 148, 65.8 QR 40, 93.0 HOR 180, 78.3 OQ No 34, 27.0 Q 77, 34.2 QR 3, 7.0 HOR 50, 21.7 OQ Statistically significant differences were found among antipsychotics for duration of current treatment (MANOVA p < 0.05). Statistically significant differences were found versus: H haloperidol, O olanzapine, Q quetiapine, and R risperidone for the duration of current treatment (Bonferroni s multiple comparison test: p < 0.05 and χ 2 : p < 0.05) and for dose escalation (χ 2 : p < 0.05). The doses were defined as: low ( 5, 10, 300, and 3), middle (> 5 and 10, >10 and 20, > 300 and 500, and > 3 and 6), and high (> 10, > 20, > 500, and > 6) for haloperidol, olanzapine, quetiapine, and risperidone, respectively.

9 The Results of the EIRE Study 133 frequent reason for beginning treatment in the haloperidol group was the occurrence of an exacerbation of symptoms under prior medication (n = 81, 61.8%). The treatment most commonly switched to from a previous drug was quetiapine (n = 29, 67.4%), followed by olanzapine (n = 100, 43.9%) and risperidone (n = 92, 39.3%). We found that, with respect to concomitant treatment, a higher proportion of patients on antiparkinsonian treatment was in the haloperidol group (55.7%) than in the risperidone (24.8%), olanzapine (8.3%), and quetiapine (7.0%) groups (χ 2 : p < 0.05). We also found that patients treated with risperidone received more antiparkinsonian treatments than patients treated with olanzapine and quetiapine (χ 2 : p < 0.05). Finally, we found that the proportion of patients receiving antidepressants in conjucntion with the antipsychotics was lower than in the haliperidol group (13.0%) than in the olanzapine group (22.8%) or the risperidone group (20.1%), although the latter group findings were not statistically significant. Only 5 risperidonetreated patients and 2 olanzapine-treated patients were receiving nonpsychotropic medication. Sexual Dysfunction Table 3 shows the frequency of sexual dysfunction seen in the patients overall, by sex and for each antipsychotic treatment studied. We found that 38.1% of the patients experienced some type of sexual dysfunction (44.6% in men and 25.0% in women). We found quetiapine to be the antipsychotic treatment causing the least sexual dysfunction (18.2%) and discovered statistically significant differences between this treatment and haloperidol (38.1%) and risperidone (43.2%). We also found that quetiapine caused fewer sexual side-effects than olanzapine (35.3%); however, this difference did not reach statistical significance (χ 2 : p = 0.55). For the overall sample, the most common sexual dysfunction was a decreased sexual desire (27.8%). In men, the most frequent sexual dysfunction was erectile dysfunction (30.8%) and a decreased sexual desire (30.8%), whereas in women, the most frequent adverse reaction was reduced sexual desire (23.8%). We conducted an additional analysis, stratified by dose range, to assess the potential influence of the dose in the presence of sexual dysfunction, which showed differences for olanzapine between the low ( 10 mg/day; 28.4%) and the middle dose (>10 and 20 mg/day; 47.0%) and for risperidone between the low ( 3 mg/day; 29.3%) and the middle and high doses (>3 and 6, and >6 mg/day, respectively; 48.9% and 53.6%), with a higher frequency of sexual dysfunction in the groups on higher doses (χ 2 : p < 0.05). The frequency of sexual dysfunction in the quetiapine group did not seem to be dose related, although the small number of patients in this group (n = 43) limits our conclusions. Table 4 shows the risk of sexual dysfunction associated with each of the three atypical antipsychotics studied compared to haloperidol. Quetiapine

10 TABLE 3. Frequency of Sexual Dysfunction by Treatment and by Sex Haloperidol (n = 131) Olanzapine (n = 228) Quetiapine (n = 43) Risperidone (n = 234) ne n % ne n % ne n % ne n % Total Sexual dysfunction Q HR Q Increased sexual desire Decreased sexual desire Q OR Q Men Sexual dysfunction Increased sexual desire Decreased sexual desire Erectile dysfunction Ejaculatory dysfunction R O Women Sexual dysfunction Increased sexual desire Decreased sexual desire Q OR Q Orgasmic dysfunction Vaginal dryness ne = the valid evaluable n. The total n of evaluable men was 78 for haloperidol, 140 for olanzapine, 22 for quetiapine, and 149 for risperidone. The total n of evaluable women was 51 for haloperidol, 88 for olanzapine, 21 for quetiapine, and 83 for risperidone. The mean doses in men and in women were, respectively: 12.0 mg/d and 8.4 mg/d (haloperidol), 13.8 mg/d and 12.9 mg/d (olanzapine), mg/ d and mg/d (quetiapine), and 5.5 mg/d and 5.0 mg/d (risperidone). Statistically significant differences were found versus: H haloperidol, O olanzapine, Q quetiapine, and R risperidone (χ 2 : p < 0.05). 134

11 TABLE 4. Risk of Sexual Dysfunction Occurring with Atypical Antipsychotics Compared to Haloperidol as Crude Values and After Adjustment for Sex and Stratification by Treatment Dose and Duration Olanzapine (n = 228) Quetiapine (n = 43) Risperidone (n = 234) OR Sig. IC 95% OR Sig. IC 95% OR Sig. IC 95% Sexual dysfunction No adjustment (crude value) * ** Adjusted for sex and stratified by dose Low dose Middle dose High dose Adjusted for sex and stratified by duration 12 weeks * > 12 weeks NA NA NA * This value has been rounded, exact value is **Statistically significant risk values obtained in the logistic regression model. The doses were defined as: low ( 5, 10, 300, and 3), middle (> 5 and 10, >10 and 20, > 300 and 500, and > 3 and 6) and high (> 10, > 20, > 500, and > 6), for haloperidol, olanzapine, quetiapine, and risperidone, respectively. NA = No patients were treated with quetiapine for > 12 weeks. 135

12 136 J. Bobes et al. appeared to be a protective treatment compared to haloperidol, with a statistically significant difference in both crude value and after adjustment for sex and stratification based on treatment duration. We reached no statistical significance after adjusting for sex and stratification by dose range. Other Reproductive Side-effects Table 5 shows the frequency of other reproductive side-effects for each antipsychotic treatment studied. The treatment with the highest number of patients with problems of this type was risperidone (11.7%), followed by haloperidol (6.9%), olanzapine (6.4%), and quetiapine (2.7%). However, in none of these cases did the differences between the groups reach statistical significance. It should be mentioned that we found statistically significant differences with respect to the occurrence of amenorrhea in women between the risperidone group (present in 28.2% of the cases) and the olanzapine group (present in 11.0% of the cases; χ 2 : p < 0.05). After we stratified the doses, we saw other reproductive side-effects more frequently at high doses for olanzapine (>20 mg/day; 12.5%) and risperidone (>6 mg/day; 17.2%), compared to middle (>10 and 20 mg/day, and >3 and 6 mg/day for olanzapine and risperidone, respectively; 5.9% and 10.0%) and low doses ( 0 and 3 mg/day for olanzapine and risperidone, respectively; 6.3% and 11.5%). Table 6 shows the risk of experiencing any of the problems associated with the three atypical antipsychotics studied, compared to haloperidol. Risperidone appears to have a significantly higher risk of sexual side-effects than haloperidol after adjustment for treatment duration. Management of Adverse Reactions The treatment for which some type of action was most frequently taken was risperidone (72, 45.6%), followed by haloperidol (35, 39.8%) and olanzapine (54, 36.7%). However, these differences were not statistically significant (χ 2 : p > 0.05). No patient in the quetiapine group required any action related to this treatment. DISCUSSION The impact of schizophrenia and its treatment on sexuality and reproductive issues has received inadequate attention (Fenton & Kane, 1997). The EIRE study is one of the few studies available that compares the different commonly used atypical antipsychotics available to a conventional reference antipsychotic and systematically assesses sexual dysfunction and other reproductive side-effects associated with antipsychotic treatment in routine clinical practice.

13 TABLE 5. Frequency of Other Reproductive Side-effects by Treatment and by Sex Haloperidol (n = 131) Olanzapine (n = 228) Quetiapine (n = 43) Risperidone (n = 234) ne n % ne n % ne n % ne n % Total Other reproductive side-effects Men Other reproductive side-effects Gynecomastia Women Other reproductive side-effects R O Menorrhage Amenorrhea R O Galactorrhea ne = the valid evaluable n. The total n of evaluable men was 78 for haloperidol, 140 for olanzapine, 22 for quetiapine, and 149 for risperidone. The total n of evaluable women was 51 for haloperidol, 88 for olanzapine, 21 for quetiapine, and 83 for risperidone. Statistically significant differences were found versus: O olanzapine and R risperidone (χ 2 : p < 0.05). The mean doses in men and women were, respectively: 12.0 mg/d and 8.4 mg/d (haloperidol), 13.8 mg/d and 12.9 mg/d (olanzapine), mg/d and mg/d (quetiapine), and 5.5 mg/d and 5.0 mg/d (risperidone). 137

14 TABLE 6. Risk of Experiencing Other Reproductive Side-effects with Atypical Antipsychotics Compared to Haloperidol in Crude Values and After Adjustment for Sex and Stratification by Treatment Dose and Duration Olanzapine (n = 228) Quetiapine (n = 43) Risperidone (n = 234) OR Sig. 95% CI OR Sig. 95% CI OR Sig. 95% CI Other reproductive side-effects No adjustment Adjusted for sex and stratified by dose Low dose Middle dose NA ** NA ** NA ** High dose NA ** NA ** NA ** Adjusted for sex and stratified by duration 12 weeks NA *** NA *** NA *** > 12 weeks NA **** NA **** NA **** * *Statistically significant risk values obtained in the logistic regression model. The doses were defined as: low ( 5, 10, 300, and 3), means (> 5 and 10, > 10 and 20, > 300 and 500, and > 3 and 6) and high (> 10, > 20, > 500, and > 6), for haloperidol, olanzapine, quetiapine, and risperidone, respectively. **For this dose category, there were no cases of other reproductive side-effects among patients treated with quetiapine. ***For duration 12 weeks there were no cases of other reproductive side-effects among patients treated with Risperidone. ****No patients were treated with quetiapine for > 12 weeks. OR = Odds Ratio; Sig. = Statistical Significance 95%; CI = 95% Confidence Interval. 138

15 The Results of the EIRE Study 139 Our results show a high frequency of sexual dysfunction with all drugs except quetiapine, which is the only atypical antipsychotic that appears to have a reduced risk of sexual dysfunction compared to the reference conventional antipsychotic (haloperidol) in short-term treatment. With respect to other reproductive side-effects, there appear to be no marked differences among the different antipsychotics studied. In our study, other reproductive side-effects occurred with a much lower frequency than sexual dysfunction; risperidone is the drug that appears to show a greater risk, particularly with long-term treatment. Study Limitations The naturalistic character of the study and its cross-sectional design explains most of the differences found in some sociodemographic and clinical characteristics discussed above, which mainly affects the haloperidol and quetiapine groups; the remaining two groups, olanzapine and risperidone, are more homogeneous. Patients treated with haloperidol were more chronic. However, other group differences with the exception of the older age of the group, which could increase the frequency of sexual dysfunction and particularly erectile dysfunction in man, should not significantly affect sexual function. The naturalistic character of the study and its cross-sectional design also are the factors with the greatest potential influence on the results in both the quetiapine group and the other three drug groups together. Because of the relatively short time that quetiapine has been available in Spain, the duration of treatment with quetiapine (0.1 year) was much shorter than that of the other drugs (longer than one year in all cases). Therefore, we are recording short-term adverse effects in less-stabilized patients as opposed to long-term adverse effects. This could have affected the results obtained with this drug, since sexual dysfunction and the other reproductive side-effects being studied are considered to be long-term adverse effects. In a randomized, double-blind study including 1,362 participants allocated in a 1:1 ratio to receive 5 different doses of risperidone (1, 4, 8, 12, or 16 mg daily) or haloperidol (10 mg daily) for 8 weeks, in which the adverse effects were assessed using the UKU (Peuskens, 1995), the reported frequency of common adverse effects ( 10%) on sexual function (decreased libido in both sexes, erectile dysfunction, and ejaculatory dysfunction) in the groups on risperidone 4 and 8 mg/day ( %) was very similar to that for haloperidol ( %) and much lower than that detected in our study ( % and % for risperidone and haloperidol, respectively). The same trend was observed for amenorrhea, with frequencies of % for risperidone and 10.5% for haloperidol, as compared to 28.2% and 14% for risperidone and haloperidol respectively, in our study. Our results also seem to reflect a higher risk of this type of adverse effect with an increased duration of treatment, as shown by the increased odds ratios of sexual dys-

16 140 J. Bobes et al. function and other reproductive side-effects with olanzapine and risperidone in patients with over 12 weeks of treatment (Tables 4 and 6). In sum, the frequency of these types of adverse effects with quetiapine may be underestimated in our study; however, even with short-term treatment (< 12 weeks), quetiapine, unlike olanzapine and risperidone, shows a significantly lower risk of sexual dysfunction than haloperidol (Table 4). In the case of olanzapine, risperidone, and particularly haloperidol, the patients included had been treated for a long time with these drugs. This is therefore a highly selected sample, since patients who best respond to and tolerate these antipsychotics have been selected. We, therefore, may be underestimating the frequency of these adverse effects or including those that are less severe, as will be discussed below. However, from a pragmatic viewpoint, our study would reflect the situation of stabilized patients on antipsychotic treatment. Because of the naturalistic character of the study, we included patients receiving concomitant treatment with other drugs, mainly psychotropic drugs that can affect sexual function. We excluded patients combining other antipsychotics. A high proportion of patients (40 50%) were receiving treatment with anxiolytics/hypnotics, and there were no significant differences among the groups. On the other hand, the relationship between benzodiazepines and sexual dysfunction is not clearly established (Demyttenaere et al., 1998). The frequency of use of antidepressants was similar among the atypical antipsychotics studied ( %) and significantly higher in the case of olanzapine (22.8%), compared to haloperidol (13%). The ability of antidepressants, particularly selective seratonin reuptake inhibitors, to cause sexual dysfunction is well known; however, although the number of cases of sexual dysfunction was increased in our study, no significant differences were found in the frequency of sexual dysfunction among patients receiving antidepressants and those who did not receive them for any of the study drugs (Montejo et al., 1996). Antidepressants may have had an additive effect on the severity of sexual dysfunction, however, we found no significant differences in the severity of the different items of sexual dysfunction and other reproductive side-effects between patients with or without antidepressant therapy. The use of antiparkinsonian drugs (mainly biperidene), as discussed above, varied significantly among the drugs studied and was more common in the haloperidol (55.7%) and risperidone (24.8%) groups. Although antiparkinsonian drugs can cause dryness in the mucosas, which can theoretically lead to a decreased vaginal lubrication, we have not found in the literature (MEDLINE) any reference of biperidene-induced sexual dysfunction. The use of other psychotropic drugs such as anticonvulsants and lithium was uncommon (< 5%) in all groups. The possibility that the use of concomitant medication may have directly or indirectly affected the results of our study through potential interactions cannot be ruled out. In addition, the figures in our study likely underestimate the use of nonpsychotropic medication and pose another potential limitation. Finally, it should be mentioned that, since the study contemplated a wider analysis of tolerability,

17 The Results of the EIRE Study 141 including extrapyramidal effects and effects on weight, and since its design was strictly observational, we do not think that overall sample selection is markedly biased toward inclusion of more erothophilic patients with a greater tendency to report these types of problems. In spite of the mentioned limitations, this study gives an accurate reflection of the problems still caused by the antipsychotic treatments available in actual clinical practice in stabilized patients on the long-term treatment required for this disease. These problems are a challenge to be overcome by future antipsychotic treatments that have been recently marketed such as ziprasidone (Carnahan, Lund, & Perry, 2001; Daniel et al., 1999), which has shown a very low incidence of sexual dysfunction on clinical research (Keck, McElroy, & Arnold, 2001; Levien & Baker, 2001) or other antipsychotics under development, such as iloperidone (Jain, 2000; Sainati, Hubbard, Chi, Grasing, & Brecher, 1995). Differences between Atypical and Conventional Antipsychotics Surprisingly atypical antipsychotics, with the exception of quetiapine, did not differ from each other or from haloperidol in the frequency of sexual dysfunction. It should be stressed that, excluding ejaculatory function, no significant differences were found between olanzapine and risperidone; the few studies in which the effect on sexual function was systematically evaluated show sexual dysfunction rates with risperidone higher than 65% (Knegtering et al., 1999; Montejo, 2000; Mullen, Brar, Vagnucci, & Ganguli, 2001) and higher than those of olanzapine (Knegtering et al., 1999, Montejo, 2000) and haloperidol (Knegtering et al., 1999; Mullen et al., 2001; Wirshing et al., 1999). There may be several explanations for this finding. First, it is possible that the cross-sectional design of our study, as already mentioned, has caused a selection of patients who best tolerate antipsychotics and has specially favored the drug that most frequently causes sexual dysfunction (i.e., risperidone). This would explain the lower frequency of sexual dysfunction with risperidone in our study (43.2%) compared to the studies discussed. Second, the differences among the studies may be because of the different methods used, including the assessment tool. Thus, other studies have reported sexual dysfunction rates with risperidone similar to those of our study (Wirshing et al., 1999) or lower (Peuskens, 1995), however, the latter two studies used more selected samples because participants were patients from clinical trials and because short-term treatments were also given. Finally, sexual dysfunction can be an adverse effect requiring long-term evaluation, and the above-mentioned studies either do not report treatment duration or had a shorter treatment time. The frequency of sexual dysfunction with olanzapine, although slightly higher, was similar to that found in other studies; for example, Knegtering et al. (1999) found a rate of 27% in 15 patients treated with doses of olanzapine 10.2 mg/day and Montejo (2000) found rates of 10% and 33% in patients receiving olanzapine doses of 15 mg/day (n = 47) and at least 16 mg/day (n = 21), respectively.

18 142 J. Bobes et al. Our results pertaining to other reproductive side-effects were similar to those reported by others (Knegtering et al., 1999; Petty, 1999), with a significantly higher frequency of adverse effects in the risperidone group compared to the olanzapine group. The risperidone group also showed a significantly higher risk than the other atypical agents, compared to haloperidol. The data on quetiapine do not appear robust enough because of the small sample size and the above-mentioned limitations to draw conclusions. However, the low frequency of these adverse effects with quetiapine is consistent with the known profile of the drug, because quetiapine does not appear to be associated with increased prolactin plasma levels across its dose range (Arvanitis & Miller, 1997; Kasper & Müller-Spahn, 2000). Management of Sexual Dysfunction and Other Reproductive Side-effects In spite of the high incidence of sexual side-effects, action to change treatment was taken in less than 10% of the patients in any of the treatment groups studied. Since the total sample is highly selected, it is possible that we have only detected mild or moderate adverse effects not requiring any action by the physician. Moreover, the lower recognition of the importance of this problem by physicians could have had an influence to a lesser extent, since psychiatrists, compared with their patients, consistently underestimate the prevalence of sexual and hormonal abnormalities (Hellewell, 1999). Various solutions have been proposed to counteract sexual dysfunction secondary to the use of antipsychotics. Imipramine may be useful in patients with orgasmic dysfunctions secondary to low-dose thioridazine (25 50 mg/ day; Aizenberg, Shiloh, Zemislany, & Weizman, 1996). Other solutions that can address sexual dysfunction secondary to psychotropic drugs include waiting for spontaneous remission over time, dose reduction or the addition of an antidote (serotonin antagonists such as cyproheptadine [Cohen, 1992] or mianserine; partial 5HT1A agonists such as buspirone; adrenergic stimulants such as yohimbine [Savion, Segenreich, Kahan, & Servadio, 1987]; dopaminergic agonists such as amantadine or bromocriptine [Matsuoka, Nakai, Miyake, Hirai, & Ikawa, 1986]; or cholinergic agonists such as betanechol or neostigmine [Sullivan & Lukoff, 1990]). The approach most commonly used in our study was dose reduction, which is consistent with the relationship between the dose and sexual dysfunction and other reproductive side-effects. However, a dose reduction theoretically could be associated with a worsening of symptoms and an increased risk of relapse. The results that we obtained suggest that another therapeutic option may be to switch to quetiapine or any of the new atypical antipsychotics that, unlike conventional antipsychotics, do not appear to be significantly associated with an incidence of sexual dysfunction and other reproductive side-effects.

19 Dose-dependent Differences The Results of the EIRE Study 143 An analysis of the doses that were used in the study is particularly important because of its potential influence on the occurrence of certain adverse effects. The mean doses obtained in our study are similar to those used with haloperidol, olanzapine, and risperidone in clinical practice, as described in other studies. Thus, mean doses have been reported of 9 mg/day for haloperidol (Muller-Siecheneder et al., 1998), of 13.2 mg/day for olanzapine (Nemeroff, 1997) and of 5.9 mg/day of risperidone (Jeste, Klausner, Brecher, Clyde, & Jones, 1997). The information available for quetiapine is limited, but the modal dose of our study (400 mg/day) is the one recommended in the prescribing information and also by experts (McEvoy, Schifler & Frances, 1999). The doses that we used generally agree with those recommended by experts (McEvoy et al., 1999) and are higher, particularly in the case of olanzapine, than those initially recommended and derived from clinical trial findings. The results that we obtained suggest a relationship between the dose and the presence of sexual side-effects for haloperidol, risperidone, and olanzapine. As expected, we observed a higher incidence of side-effects in individuals on higher doses in all treatment groups. Differences According to Treatment Duration Although in some studies no clear association was found between the duration of treatment and sexual side-effects (Lingjærde et al., 1987), as already discussed, our results suggest that such adverse effects mainly occur in the long term. It should be noted that we conducted an analysis of adverse effects stratified by treatment duration (differentiating patients on acute treatment if they have been receiving the medication for 12 weeks and those on maintenance treatment if they have been receiving the medication for > 12 weeks). This analysis showed a higher presence of sexual dysfunction and other nonsexual dysfunction reproductive side-effects for haloperidol than for risperidone during the acute treatment (amenorrhea was seen in 50% of haloperidol patients and in 11.1% of risperidone patients), a result that was reversed in patients on maintenance treatment (where amenorrhea was found in 10% of haloperidol patients, in 30.3% of risperidone patients, and in 11.3% of olanzapine patients). We performed a logistic regression analysis adjusting for treatment duration that pointed to risperidone as a risk factor for side-effects compared to haloperidol in patients on maintenance treatment. Similarly, in patients on acute treatment, sexual function problems also were detected at a higher rate with haloperidol than with risperidone (for example, decreased sexual desire occurred in 44.4% of the haloperidol patients, 41.5% of the olanzapine patients, and 31% of the risperidone patients), a result that was reversed in patients under maintenance treatment (decreased sexual desire occurred in 26.3% of the haloperidol patients, 36% of the olanzapine patients, and 40% of the risperidone patients) and that was

20 144 J. Bobes et al. also supported by the ad hoc regression analysis that we performed adjusting for treatment duration, which confirmed risperidone as a risk factor for sexual dysfunction and other reproductive side-effects studied. This apparent paradox is probably due to the design used. We are actually seeing two different photographs of the profile of these drugs in relation to sexual function and hyperprolactinemia: short- and long-term effects. Both profiles are important, but with respect to sexual function, the long-term effects may be more important, because at the start of treatment the main objective is symptom control. Moreover, in the short term, since symptoms are not fully controlled, the disease itself could cause sexual dysfunction, particularly decreased libido. In spite of the reduction of the sample in this stratified analysis, it seems that neither olanzapine nor risperidone significantly decreases the risk of occurrence of these adverse effects compared to haloperidol. CONCLUSIONS Taking into account all the above limitations, our results suggest that none of the atypical antipsychotics studied significantly improve the profile of sexual dysfunction and other reproductive side-effects of the reference conventional antipsychotic, haloperidol, in stabilized patients on long-term treatment. Quetiapine does appear to significantly improve this profile in short-term treatment; however, long-term and larger sample studies are required to systematically evaluate this profile and confirm our results. Psychiatrists should increase their awareness of sexual dysfunction, which is as distressing for the patient as the symptoms of their disease (Finn, Bailey, Schultz, & Faber, 1990). It is associated with a low satisfaction with treatment (Fakhoury, Wright, & Wallace, 2001) and may therefore cause poor compliance or treatment discontinuation (Breen & Thornhill, 1998). This profile should also be considered when psychiatrists select the most appropriate treatment for these patients. REFERENCES American Psychiatric Association. (1994). Diagnostic and statistical manual of mental disorders (4th ed.). Washington, DC: Author. Aizenberg, D., Modai, I., Landa, A., Gil-Ad, I., & Weizman, A. (2001). Comparison of sexual dysfunction in male schizophrenic patients maintained on treatment with classical antipsychotics versus clozapine. Journal of Clinical Psychiatry, 62, Aizenberg, D., Shiloh, R., Zemishlany, Z., & Weizman, A. (1996). Low-dose imipramine for thioridazine-induced male orgasmic disorder. Journal of Sex & Marital Therapy, 22, Arvanitis, L. A., & Miller, B. G. (1997). Seroquel trial study group. Multiple fixed doses of Seroquel (quetiapine) in patients with acute exacerbation of schizo-