Peter Malik

Sexual Dysfunction in Schizophrenia

Purpose of review Sexual dysfunctions have been described as being common in schizophrenia patients. The pathophysiology behind their development remains unclear. They can be secondary to the disease itself or an adverse event of antipsychotic medication. Therapeutic interventions are also not well studied. Recent findings Earlier work has suggested that second-generation antipsychotics bear fewer risks for developing sexual dysfunction because of a lower propensity to elevate prolactin levels, although the latter does not apply to amisulpride and risperidone. Only a few controlled trials with larger patient samples have been performed in the past. Summary The review covers studies published from March 2005 to June 2006 focusing on sexual dysfunctions in schizophrenia patients, as well as their possible causes. Treatment options and the impact of sexual dysfunction on quality of life are also covered. The reviewed papers show no clear consistency regarding potential advantages of one drug over another. Many trials suffer from small sample sizes. The field badly needs more and larger studies on this topic.
(Reprinted with permission from Curr Opin Psychiatry 20:138 –142)

INTRODUCTION
Sexual dysfunctions, such as erectile dysfunction, decreased libido or disturbances in ejaculation/orgasm are frequent in both men and women suffering from schizophrenia (1, 2). Whether a disturbance of the menstrual cycle is also considered under this umbrella is a matter of debate, but we have also searched for studies dealing with this issue. Sexual dysfunctions represent an important factor both with regard to adherence to medication, which is highly influenced by side effects of antipsychotics (3, 4), and other outcome variables such as quality of life. An elevation of plasma prolactin levels through D2 receptor antagonism is considered a possible pathophysiological explanation for these adverse events (5, 6). Apart from D2 blockade, sedation due to antihistaminergic or adrenergic effects, as well as serotonergic blockade, are alternative pathways potentially leading to sexual dysfunction (7). As sexual dysfunction can also be observed in untreated schizophrenia patients (8), other factors may play an important role as well: decreased libido through negative symptoms could be one of them. Previous studies have focused primarily on chronically ill patients, and thus little is known about sexual functioning among more recent onset, acutely ill patients.

In this review, last year’s published papers on sexual dysfunction in schizophrenia patients are discussed. As an in-depth literature search through Medline has yielded only a few studies focusing solely on sexual dysfunction, reports with other main aims that, nevertheless, describe findings on sexual dysfunction are also reviewed.

FINDINGS
A Spanish group (9) has examined the effects of quetiapine in 82 outpatients with schizophrenia in a multicenter, noncomparative, open-label, naturalistic study. Patients received open treatment with quetiapine, the mean dose being 525.4 mg, and were followed up to 6 months. Sexual functioning was evaluated using the PsychotropicRelated Sexual Dysfunction Questionnaire (PRSexDQ). This scale includes questions about libido, orgasm, ejaculation, erectile function and general sexual satisfaction, higher scores relating to higher degrees of sexual dysfunction. As the authors state, ‘due to the naturalistic design of the study’, no laboratory tests were performed. It is important to note that most of the recruited patients (n 56) had been treated with antipsychotics before and were switched to quetiapine. PRSexDQ total scores decreased from baseline to end point. When only patients who received quetiapine as their primary medication without having been switched were

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mean levels in the conventional group being still elevated. Limitations of this study include the small sample size and the possibility of receiving more than one antipsychotic in both groups. no significant differences were found between the groups at endpoint. results are in line with the report already discussed and an earlier study from the Netherlands (11). Orgasm quality and arousal improved significantly from baseline for quetiapine. Unfortunately. Patients showed high ASEX scores at baseline. These patients had lower baseline scores to start out with. Thus. prolactin levels were significantly reduced in both groups. Sex hormone-binding globuline levels in the conventional group increased significantly over the course of the study. (13). Again the small sample and the short observation period. Prior to randomization.5 mg/day) on sexual functioning in 27 schizophrenia patients over 12 weeks in a randomized double-blind study. could strengthen the assumption that quetiapine has a low propensity to induce sexual dysfunction. reported they felt better about their sexuality as compared with previous treatment. Kelly and Conley (10) surveyed the effect of quetiapine (400 mg/day). but reported ‘sexual complaints’. Primary organic sexual dysfunctions were excluded. mostly with haloperidol. Results of the DGSFi showed no differences between groups at baseline. Olanzapine and its effects on sexual function and hormonal profile compared with conventional antipsychotics was the main focus of a naturalistic study conducted by Costa et al. Limitations of the study include the lack of a control group and the fact that most patients were switched from another antipsychotic. In the items described (in more detail ‘strength of desire of sex’. although the olanzapine-treated group showed a stronger desire for sex and a reduced length of time comfortable with abstinence. corresponding to previous reports that untreated schizophrenia patients suffer from sexual dysfunction as well. No. A positive correlation between prolactin. 2 235 INFLUENTIAL PUBLICATIONS . Seventy-eight percent of fluphenazine-treated patients reported sexual dysfunction. After 9 months. risperidone (4 mg/day) and fluphenazine (12. The mean dose of olanzapine was 17. In the conventional group.org FOCUS Spring 2008. Atmaca et al. (12) studied 36 patients on quetiapine (mean dose 512 mg/day) over 4 weeks after a 2-week drug-free period.5 mg/day. 55% and 40% of the patients. Prolactin levels decreased more rapidly in the olanzapine group over the course of the first 3 months. Fifty-two patients completed the 9-month study period. subjects were given traditional antipsychotic medication for 4 – 6 weeks. as well as amenorrhoea in women. and the other being treated with conventional antipsychotics (haloperidol or chlorpromazine or both combined). Unfortunately. make the interpretation of results difficult. ‘frequency of masturbation’ etc. The olanzapineconventional combination especially is problematic in this respect. In addition. one receiving olanzapine (8. luteinizing hormone levels and time without sexual activity was found. The authors found that quetiapine caused a significant increase in ASEX scores after 4 weeks. respectively. The authors suggest that quetiapine shows a low frequency of sexual dysfunction during long-term treatment. No correlation was found between prolactin levels and sexual dysfunction. the authors submit that quetiapine seems to perform better in specific domains of sexual functioning than other antipsychotics. The finding that a subsample that received quetiapine as their first treatment showed lower scores that did not change over the course of 6 months.MALIK analysed. Most of the inpatients had been pretreated. The small sample size in this study makes it difficult to draw generalizable conclusions. as well as 42% on risperidone and 50% on quetiapine. The report does not state whether sexual dysfunctions caused by somatic diseases were excluded. Patients included had prolactin levels drawn and were rated on the Changes in Sexual Function Questionnaire (CSFQ) and the Prolactin-Related Adverse Event Questionnaire (PRAEQ). which they defined as low scores in several items of the DGSFi. scores remained unchanged. Both groups showed elevated prolactin levels at baseline. On the other hand. the authors did not give exact scores. Sexual dysfunction was evaluated using the Arizona Sexual Experience Scale (ASEX) and Udvalg for Kliniske Undersogelser (UKU) Side Effect Rating Scale. Vol.psychiatryonline. no change from baseline to midpoint was found. Sexual dysfunctions were evaluated by the Dickson Glazer Scale for the Assessment of Sexual Functioning Inventory (DGSFi). The authors conclude that the only difference between olanzapine and conventional focus.5% in combination with a conventional antipsychotic). the authors did not measure prolactin or sex hormones to investigate the connections between these hormones and sexual function. predominantly driven by diminished libido and erectile dysfunction in men. sex hormones were not measured. while levels decreased to endpoint. When receiving risperidone and quetiapine. as well as the lack of a control group.). Sixty-three male inpatients suffering from schizophrenia were randomized into two groups. VI. all pointing to a fairly benign safety profile of quetiapine regarding sexual functioning.

The strength of both of the studies reviewed above lies in the large sample of patients and the fact that sexual dysfunctions were evaluated both from a subjective and an observer perspective. In this 4-month trial. This is really the only way to differentiate between treatment-induced and illness-induced sexual dysfunction. with the highest rate in the olanzapine-treated group (54. Of all patients. 36% attributed changes in their sexual functions to antipsychotic medication. Fifty-four patients were randomized to either remain on their current therapy (risperidone or conventional antipsychotics) or to switch to olanzapine. 2%. VI. Sexual function was assessed by CSFQ. prior to any medication 37% of the patients reported sexual dysfunction. the authors suggest that sildenafil can be a useful approach in treating erectile dysfunction in schizophrenia patients. prolactin levels decreased in both males and females when switched to olanzapine. as well as satisfaction with intercourse. Patients were treated with antipsychotic monotherapy (either haloperidol. if sexual dysfunction improves with prolactin normalization. 8%) or haloperidol (71. risperidone (n 860). 1%).1%). The same result could be found regarding menstrual irregularities. bears the risk of an observer bias. Vol. in which they examined whether elevated prolactin levels decrease after switching to olanzapine and. Patients in the olanzapine-treated and quetiapine-treated groups experienced significantly less sexual dysfunction (55. (15*). risperidone and first-generation antipsychotics. (14*) examined sexual functioning among schizophrenia patients treated for the first time. Duration and frequency of erections. is a major asset ¨ of this study. the fact that patients in the report by Bitter et al. but not in the other group. 7 and 60. Sexual dysfunction and loss of libido were not rated using a specific rating scale. were less likely to have a romantic partner. risperidone or quetiapine). were examined at baseline and after 3 and 6 months of antipsychotic medication. GISF overall scores and scores in the ‘climax 236 Spring 2008. Sexual dysfunction was evaluated through the Global Impressions of Sexual Functions (GISF) scale. an increased emphasis has been put on quality of life (QOL) as a treatment outcome in schizophrenia patients. Kinon et al. A large patient sample of 3828 outpatients was examined by Dossenbach et al. (19) conducted a randomized controlled trial. and QOL by seven items of the Quality of Life Interview. These results mirror those from a similar post hoc analysis of a study using the same basic design. while every other patient had to be treated with another antipsychotic. quetiapine (n 142) or haloperidol (n 188). erectile dysfunction (18**). the sample was divided into three groups: olanzapine. Of all patients. with investigators underestimating the amount of sexual dysfunction. No. In contrast to the papers discussed so far. furthermore. comparative risk interpretation has to remain tentative. In addition. differences between treatment groups on investigator-rated and patientrated loss of libido and sexual dysfunction were significant after adjusting for baseline level. The outpatients were treated with either olanzapine (n 2638). After 3 months. Five hundred and seventy patients. Over the past decade. thereby underscoring the clinically highly relevant point that psychiatrists often overlook sexual dysfunction. Patients with sexual dysfunction reported poorer QOL and lower levels of enjoyment in life. On the other hand. which is why comparative analyses have to be interpreted with caution. loss of libido as rated by the clinicians favoured olanzapine. At 6 months. olanzapine. favouring olanzapine over risperidone and conventional antipsychotics. As the drug (up to 50 mg/day) was well tolerated.MALIK antipsychotics lies in the pace of their hormonelevel normalization rates. and were less satisfied with the quality of their romantic relationships. At baseline. Sexual dysfunction was evaluated through patient’s and the investigator’s perception using the UKU Side Effect Rating Scale. As hyperprolactinemia is frequently related to sexual dysfunction. The fact stands that sexual dysfunctions are common and have a major impact on QOL. (14*) were treatment naıve.3% met CSFQ criteria for sexual dysfunction. For this subanalysis. the design of the studies. as patients were not randomized to the different antipsychotics. 45. in which olanzapine was the drug of choice of the prescriber. 2 FOCUS THE JOURNAL OF LIFELONG LEARNING IN PSYCHIATRY . Only a single study published during the last year dealt with the treatment of sexual dysfunction—in this case. a subgroup of a large-scale naturalistic study. respectively) than patients who received risperidone (67. Thirty-two patients with erectile dysfunction suffering from schizophrenia or delusional disorder randomly received either sildenafil (1–2 times 25 mg/day) or placebo and were crossed over to the other arm after 2 weeks. Olfson et al. Impotence has been described as even more bothersome than positive symptoms of schizophrenia in this respect (16). which is reported in the following discussion. Again. 5–20 mg/day. a significant difference between patient reports and UKU scores could be found. Bitter et al. were superior in sildenafil-treated patients. Interestingly. (17) assessed sexual dysfunction and its influence on QOL and relationships in 139 outpatients.

Rico-Villademoros F. 11. as did menstrual cycling in women. As both drug-related and disease-related factors contribute. 24:56 – 61. et al. 7. Whether or not this was the result of prior antipsychotic treatment or a symptom of the disease is not discussed in their report. Nithsdale Schizophrenia Surveys 24: sexual dysfunction. Zemishlany Z. Conus P. Impact of present and past antipsychotic side effects on attitude toward typical antipsychotic treatment and adherence. (24) examined dopamine D4 receptor signal transduction pathways in rats and demonstrated that the hypothalamic paraventricular nucleus may be a site of D4 receptor-mediated proerectile activity. Paik A. Br J Psychiatry 2003. 281:1174. 182:50 –56. 2. Hofer A. Clearly. *A very useful study in a large sample of treatment naıve patients. evaluating sexual dysfunction by an interviewer as opposed to patients completing a presented scale will influence the outcome of such studies. Weizman A. VI. No. Eide P. Montejo Gonzalez AL. not many controlled trials addressing this issue have been published over the course of the last year. J Psychopharmacol 2006 [Epub ahead of print]. Atmaca M.psychiatryonline. Int J Impot Res 2005. Effects of atypical and typical antipsychotic treatments on sexual function in patients with schizophrenia: 12-month results from the Intercontinental Schizophrenia focus. preferentially in both untreated and pretreated patients. Bitter I. Erratum in JAMA 1999. Costa AM. Halliday J. Laumann EO. Basson BR. et al. Curr Med Res Opin 2004. Attitudes toward antipsychotics among outpatient clinic attendees with schizophrenia. safety data showed higher frequency of reduced ejaculation volume in sertindole-treated patients (18. as sexual dysfunctions are also found in patients treated with antipsychotics that do not increase prolactin levels.MALIK items’. A case report by Wahl and Ostroff (21) described the reversal of symptomatic hyperprolactinemia by adding aripiprazole to risperidone therapy. Dyachkova Y. et al. Most of the reports reviewed have studied small samples. 55:406 – 413. 63:49 –53. Psychoneuroendocrinology 2006. counteracting the prolactin-enhancing effect of a D2 blocking agent. et al. Jung and colleagues (20) found hyperprolactinemia in 26 out of 28 women and 15 out of 32 men treated with haloperidol as monotherapy over 3 months without reporting sexual dysfunction data. Nevertheless. 9-month follow-up. It is also important to bear in mind that many people have problems discussing their sexuality openly. de Lima MS. Dorfman-Etrog P. published within the annual period of review. A new atypical antipsychotic: quetiapine-induced sexual dysfunctions. 3. A randomized open-label study of the impact of quetiapine versus risperidone on sexual functioning. Conley RR. Dossenbach MR. J Clin Psychiatry 2002. and thus results need to be interpreted with caution. Psychotropic medications and their effects on sexual function: diagnosis. Sexual dysfunction in the United States: prevalence and predictors. 38% described a loss of libido. Dossenbach M. 19:415– 422. Knegtering R. 6 Gitlin MJ. however. Castelein S. Hyperprolactinaemia and antipsychotic therapy in schizophrenia [review]. 12. 13. To aid patients in dealing with this problem. 15. unfortunately no scale for SD was ¨ used. 17:201–203. The role of prolactin is still unclear. Almost every study has used a different rating method to evaluate sexual dysfunction. Only one of the studies dealt with untreated or first-episode patients. 20:189 –197. this presents a problem when trying to compare studies. A 6-month prospective observational study on the effects of quetiapine on sexual functioning. 14. Aizenberg D. Whether or not this affected sexual functioning was not presented. 31:340 –346. 2 237 INFLUENTIAL PUBLICATIONS . JAMA 1999. 9.org FOCUS Spring 2008. Majadas S. This is likely to apply to patients suffering from schizophrenia as well. Hummer M. some of the reviewed papers reemphasize former findings that second-generation antipsychotics seem favourable when compared with conventional antipsychotics regarding sexual dysfunction. A randomized double-blind 12-week study of quetiapine. Tezcan E. Bitner et al. the field awaits further sexual dysfunction-treatment studies.5%). REFERENCES AND RECOMMENDED READING CONCLUSION Though sexual dysfunctions are commonly emphasized as an important problem in schizophrenia patients. it is important to conduct larger controlled trials. Vol. Rosen RC. 56:137– 141. J Clin Psychopharmacol 2004. Therefore. et al. one could speculate that antipsychotics with a strong affinity to the D4 receptor (like clozapine) present with a higher risk for sexual dysfunction. Macdonald S. biology. Cutler AJ. Eder U. et al. Of all patients. When comparing treatment outcome of sertindole and risperidone (22). Faria M. comparing olanzapine and conventional antipsychotics on sexual function and hormonal profile for males with schizophrenia. 5. and treatment approaches [review]. thereby ruling out potentially confounding effects of prior medication. of this instrument also improved markedly in the switched group. 281:537–544. J Clin Psychopharmacol 2005. Kelly DL. Papers of particular interest. which describe experience of sexual climax. Sexual dysfunction in male schizophrenic patients. Kuloglu M. Int Clin Psychopharmacol 2005. Pirildar S. 8. Lambert M. Tafalla M. 25:533–538. 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18. Subjective utility ratings of neuroleptics in treating schizophrenia. Depressive symptom patterns in patients with chronic schizophrenia and subsyndromal depression. Faber R. now using scales. Park JH. NOTES 238 Spring 2008. Improvement in hyperprolactinemia and reproductive comorbidities in patients with schizophrenia switched from conventional antipsychotics or risperidone to olanzapine. Vol. Finn SE. controlled study of sertindole versus risperidone in the treatment of moderate-to-severe schizophrenia. Schultz RT. 66:331–338. J Clin Psychopharmacol 2005. Otte S. 21: 251–258. Tafesse E. flexible-dose. Reversal of symptomatic hyperprolactinemia by aripiprazole. 17. Zisook S. 20. 20:843– 848. The prevalence of hyperprolactinemia after long-term haloperidol use in patients with chronic schizophrenia. 23. two-way crossover trial. Gopalakrishnan R. Int Clin Psychopharmacol 2006. Outpatient Health Outcomes (IC-SOHO) study. Psychoneuroendocrinology 2006. Loft H. Azorin JM. Ostroff R. No. Nyer M. *A similar design to that reported in reference 14. Am J Psychiatry 2006. Maguire GA. 22. et al. Strub N. Sildenafil in the treatment of antipsychotic-induced erectile dysfunction: a randomized. 21. 19. Jung DU. 50: 521–531. Psychol Med 1990. Kinon BJ. Kasckow J. Jacob KS.MALIK 16. 162:1542–1543. Kuruvilla A. Seo YS. J Clin Psychiatry 2005. but not studying treatment naive patients. Male sexual dysfunction and quality of life in schizophrenia. doubleblind. Schizophr Res 2006. 31:577–588. 163:494 – 499. et al. Neuropharmacology 2006. Bailey JM. Olfson M. 25:613– 615. Wahl R. Eur Psychiatry 2006. 2 FOCUS THE JOURNAL OF LIFELONG LEARNING IN PSYCHIATRY . placebo-controlled. et al. Uttaro T. 21:49 –56. Ahl J. VI. Dopamine D4 receptor signaling in the rat paraventricular hypothalamic nucleus: Evidence of natural coupling involving immediate early gene induction and mitogen activated protein kinase phosphorylation. 24. et al. **A well designed study focusing on the treatment of ED. Liu-Seifert H. 86:226 –233. Bitner RS. Am J Psychiatry 2005. Nikkel AL. Carson WH. A double-blind.

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