A randomized open-label comparison of the impact of aripiprazole versus risperidone on sexual functioning (RAS study).
To the Editors: Sexual dysfunction in patients with schizophrenia seems to be related to the disease itself, psychosocial factors, medical health, and to the use of psychotropic medications. Antipsychotics have been associated with sexual dysfunction, such as decreased libido, erectile dysfunction, anorgasmia, and delayed or retrograde ejaculation. Sexual dysfunction is rarely reported spontaneously, leading to underestimation of its prevalence. In contrast, studies using structured interviews or questionnaires result in 30% to 60% of the patients with schizophrenia reporting sexual dysfunctions. The pathogenetic mechanisms of antipsychotic-associated sexual dysfunction may involve postsynaptic dopamine antagonism, >1-antagonism, and prolactin elevation. Most antipsychotics are potent postsynaptic dopamine antagonists and can cause sustained elevation of prolactin. Neuroleptic-induced hyperprolactinemia has been associated with a number of side effects including galactorrhea, menstrual disturbances, amenorrhea, and sexual dysfunction. In line with a high (antagonistic) affinity for the dopamine receptor of risperidone, previous studies showed higher incidences of sexual dysfunctions and higher prolactin levels in patients treated with risperidone compared with patients treated with clozapine, olanzapine, or quetiapine. Aripiprazole is an antipsychotic with dopamine antagonistic and intrinsic agonistic properties, a partial agonist. Aripiprazole usually acts as a dopamine antagonist with a high affinity for the dopamine receptor, working clinically as an antipsychotic agent. In brain regions that have a large receptor reserve for the D2 dopamine receptor; for example, in the anterior pituitary, aripiprazole can act as dopamine agonist. As a consequence, aripiprazole does not induce hyperprolactinemia; it even may lower serum prolactin levels. Aripiprazole’s properties of being a dopamine antagonist with high affinity for postsynaptic dopamine receptors may predict detrimental effects on sexual function, whereas, in contrast, its dopamine agonistic properties may predict no detrimental effects or even some beneficial effects on sexual performance. The net effects of aripiprazole on sexual performance were not known before the start of our study. In this open randomized study, the effects of aripiprazole or risperidone on sexual performance and serum prolactin levels are investigated. Study participants included inpatients and outpatients from the department of psychiatry of the University Medical Center in Groningen, The Netherlands, fulfilling the criteria for schizophrenia (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition) or related psychotic disorders, who started with or were switched to a new antipsychotic for clinical reasons as determined by the attending psychiatrists. Patients could be taking any antipsychotic before entering the study, except depot antipsychotics, aripiprazole, or risperidone. Patients were randomized to either openlabel aripiprazole (starting dose, 15 mg) or risperidone (starting dose, 3 mg). For both groups, the dosage could be adjusted as deemed necessary on a weekly basis by the clinician (aripiprazole, 7.5Y30 mg/d; risperidone, 1Y6 mg/d). Comedication with known effects on sexual performance was not allowed, with the exception of oxazepam (maximum dose, 30 mg/d). The patients’ age ranged from 19 to 46 years. Patients were informed that effects of the medications would be assessed, but they were blinded with regard to any hypothesis to be tested. Along with efficacy evaluated with the Positive and Negative Syndrome Scale at weeks 1 and 6, sexual dysfunction was assessed only at 6 weeks after randomization by a validated, semistructured interview, the Antipsychotics and Sexual Functioning Questionnaire (ASFQ). Prolactin levels were measured after 6 weeks. The Mann-Whitney U test was applied to ordinal outcomes (sexual functioning evaluated with the ASFQ). The W test was applied to nominal outcomes (dichotomized sexual dysfunction evaluated with the ASFQ). The W value was corrected for continuity because the sizes of the tables were all 2 2. The Student t test was used to analyze continuous outcomes including age and prolactin. Prolactin levels were normalized by converting to their natural logarithm. For all analyses, the effects were tested at the 2-sided > level of 0.05. Fifty patients fulfilled inclusion criteria of the study and were asked to participate; 44 patients agreed to enter the study. Three patients (of which, 1 woman) treated with risperidone and 5 patients treated with aripiprazole discontinued in the first week of the study. Reasons for not completing the study were noncompliance (2 patients) and unknown reason (1 patient) in 3 patients treated with risperidone and subjective restlessness in 5 patients treated with aripiprazole (in 1 patient, accompanied by suicidal intentions). Although the study has not been designed to address the frequently reported restlessness, lower dosages of aripiprazole and slower tapering of previous medication seemed to be associated with less reported inner restlessness. Thirty-six patients (18 aripiprazole [5 women] and 18 risperidone [3 women]) completed the study and were included in the final analyses. At 6 weeks, the mean dosage of aripiprazole was 12.6 mg/d (SD, 5.79; range, 7.5Y30 mg/d) and risperidone 3.2 mg/d (SD, 1.15; range, 1Y5 mg/d). No significant differences were found in oxazepam and other comedication use between the 2 groups. Patients in the risperidone group reported significantly more frequent sexual dysfunction than patients in the aripiprazole group (61% vs 6%, respectively; P = 0.001). Prolactin levels were significantly higher in patients treated with risperidone (mean, 1181 [T673]) than in patients treated with aripiprazole (mean, 214 [T148]; P = 0.001). The findings of this prospective open-label randomized study of aripiprazole and risperidone are consistent with previous studies and case reports of hyperprolactinemia occurring in risperidone-treated patients and associating risperidone treatment with sexual dysfunction. Prolactin levels in patients treated with aripiprazole were, on average, even a little below the normal values of the University Medical Center Groningen laboratory. Furthermore, using a Student t test shows a significant difference (P = 0.005) between the mean prolactin levels in male patientswith orwithout sexual dysfunction, indicating a correlation between prolactin levels and sexual dysfunction. Details about sexual performance and prolactin levels at week 6 are presented in Table 1. Although patients with schizophrenia experience more often sexual dysfunction, with or without medication, the difference in the incidence of sexual side effects LETTERS TO THE EDITORS