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.
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 Psychotropic-Related 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 analysed, scores remained unchanged. These patients had lower baseline scores to start out with.
The authors suggest that quetiapine shows a low frequency of sexual dysfunction during long-term treatment. Limitations of the study include the lack of a control group and the fact that most patients were switched from another antipsychotic. 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, could strengthen the assumption that quetiapine has a low propensity to induce sexual dysfunction. Unfortunately, the authors did not measure prolactin or sex hormones to investigate the connections between these hormones and sexual function.
Kelly and Conley (10) surveyed the effect of quetiapine (400 mg/day), risperidone (4 mg/day) and fluphenazine (12.5 mg/day) on sexual functioning in 27 schizophrenia patients over 12 weeks in a randomized double-blind study. 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). Prior to randomization, subjects were given traditional antipsychotic medication for 4—6 weeks.
Seventy-eight percent of fluphenazine-treated patients reported sexual dysfunction, as well as 42% on risperidone and 50% on quetiapine. Orgasm quality and arousal improved significantly from baseline for quetiapine. When receiving risperidone and quetiapine, 55% and 40% of the patients, respectively, reported they felt better about their sexuality as compared with previous treatment. Thus, the authors submit that quetiapine seems to perform better in specific domains of sexual functioning than other antipsychotics. No correlation was found between prolactin levels and sexual dysfunction.
The small sample size in this study makes it difficult to draw generalizable conclusions. In addition, sex hormones were not measured. On the other hand, results are in line with the report already discussed and an earlier study from the Netherlands (11), all pointing to a fairly benign safety profile of quetiapine regarding sexual functioning.
Atmaca et al. (12) studied 36 patients on quetiapine (mean dose 512 mg/day) over 4 weeks after a 2-week drug-free period. Sexual dysfunction was evaluated using the Arizona Sexual Experience Scale (ASEX) and Udvalg for Kliniske Undersogelser (UKU) Side Effect Rating Scale. Primary organic sexual dysfunctions were excluded. Patients showed high ASEX scores at baseline, corresponding to previous reports that untreated schizophrenia patients suffer from sexual dysfunction as well. The authors found that quetiapine caused a significant increase in ASEX scores after 4 weeks, predominantly driven by diminished libido and erectile dysfunction in men, as well as amenorrhoea in women. Again the small sample and the short observation period, as well as the lack of a control group, make the interpretation of results difficult.
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. (13). Sixty-three male inpatients suffering from schizophrenia were randomized into two groups, one receiving olanzapine (8.5% in combination with a conventional antipsychotic), and the other being treated with conventional antipsychotics (haloperidol or chlorpromazine or both combined). Most of the inpatients had been pretreated, mostly with haloperidol. The mean dose of olanzapine was 17.5 mg/day. Sexual dysfunctions were evaluated by the Dickson Glazer Scale for the Assessment of Sexual Functioning Inventory (DGSFi). The report does not state whether sexual dysfunctions caused by somatic diseases were excluded. Fifty-two patients completed the 9-month study period.
Both groups showed elevated prolactin levels at baseline. After 9 months, prolactin levels were significantly reduced in both groups, mean levels in the conventional group being still elevated. Prolactin levels decreased more rapidly in the olanzapine group over the course of the first 3 months. In the conventional group, no change from baseline to midpoint was found, while levels decreased to endpoint. Sex hormone-binding globuline levels in the conventional group increased significantly over the course of the study.
Results of the DGSFi showed no differences between groups at baseline. Unfortunately, the authors did not give exact scores, but reported ‘sexual complaints’, which they defined as low scores in several items of the DGSFi. In the items described (in more detail ‘strength of desire of sex’, ‘frequency of masturbation’ etc.), no significant differences were found between the groups at endpoint, although the olanzapine-treated group showed a stronger desire for sex and a reduced length of time comfortable with abstinence.
A positive correlation between prolactin, luteinizing hormone levels and time without sexual activity was found.
Limitations of this study include the small sample size and the possibility of receiving more than one antipsychotic in both groups. The olanzapine-conventional combination especially is problematic in this respect. The authors conclude that the only difference between olanzapine and conventional antipsychotics lies in the pace of their hormone-level normalization rates.
In contrast to the papers discussed so far, Bitter et al. (14*) examined sexual functioning among schizophrenia patients treated for the first time, Five hundred and seventy patients, a subgroup of a large-scale naturalistic study, were examined at baseline and after 3 and 6 months of antipsychotic medication. Sexual dysfunction and loss of libido were not rated using a specific rating scale. For this subanalysis, the sample was divided into three groups: olanzapine, risperidone and first-generation antipsychotics. At baseline, prior to any medication 37% of the patients reported sexual dysfunction. After 3 months, differences between treatment groups on investigator-rated and patient-rated loss of libido and sexual dysfunction were significant after adjusting for baseline level, favouring olanzapine over risperidone and conventional antipsychotics. At 6 months, loss of libido as rated by the clinicians favoured olanzapine. These results mirror those from a similar post hoc analysis of a study using the same basic design, which is reported in the following discussion.
A large patient sample of 3828 outpatients was examined by Dossenbach et al. (15*). The outpatients were treated with either olanzapine (n = 2638), risperidone (n = 860), quetiapine (n = 142) or haloperidol (n = 188). Sexual dysfunction was evaluated through patient's and the investigator's perception using the UKU Side Effect Rating Scale. Patients in the olanzapine-treated and quetiapine-treated groups experienced significantly less sexual dysfunction (55, 7 and 60, 2%, respectively) than patients who received risperidone (67, 8%) or haloperidol (71, 1%). The same result could be found regarding menstrual irregularities, Interestingly, a significant difference between patient reports and UKU scores could be found, with investigators underestimating the amount of sexual dysfunction, thereby underscoring the clinically highly relevant point that psychiatrists often overlook sexual dysfunction.
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 addition, the fact that patients in the report by Bitter et al. (14*) were treatment naïve, is a major asset of this study. This is really the only way to differentiate between treatment-induced and illness-induced sexual dysfunction. On the other hand, the design of the studies, in which olanzapine was the drug of choice of the prescriber, while every other patient had to be treated with another antipsychotic, bears the risk of an observer bias, which is why comparative analyses have to be interpreted with caution.
Over the past decade, an increased emphasis has been put on quality of life (QOL) as a treatment outcome in schizophrenia patients. Impotence has been described as even more bothersome than positive symptoms of schizophrenia in this respect (16). Olfson et al. (17) assessed sexual dysfunction and its influence on QOL and relationships in 139 outpatients. Patients were treated with antipsychotic monotherapy (either haloperidol, olanzapine, risperidone or quetiapine). Sexual function was assessed by CSFQ, and QOL by seven items of the Quality of Life Interview.
Of all patients, 45.3% met CSFQ criteria for sexual dysfunction, with the highest rate in the olanzapine-treated group (54.1%). Patients with sexual dysfunction reported poorer QOL and lower levels of enjoyment in life, were less likely to have a romantic partner, and were less satisfied with the quality of their romantic relationships. Of all patients, 36% attributed changes in their sexual functions to antipsychotic medication. Again, as patients were not randomized to the different antipsychotics, comparative risk interpretation has to remain tentative. The fact stands that sexual dysfunctions are common and have a major impact on QOL.
Only a single study published during the last year dealt with the treatment of sexual dysfunction—in this case, erectile dysfunction (18**). 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. Duration and frequency of erections, as well as satisfaction with intercourse, were superior in sildenafil-treated patients. As the drug (up to 50 mg/day) was well tolerated, the authors suggest that sildenafil can be a useful approach in treating erectile dysfunction in schizophrenia patients.
As hyperprolactinemia is frequently related to sexual dysfunction, Kinon et al. (19) conducted a randomized controlled trial, in which they examined whether elevated prolactin levels decrease after switching to olanzapine and, furthermore, if sexual dysfunction improves with prolactin normalization. Fifty-four patients were randomized to either remain on their current therapy (risperidone or conventional antipsychotics) or to switch to olanzapine, 5—20 mg/day. Sexual dysfunction was evaluated through the Global Impressions of Sexual Functions (GISF) scale. In this 4-month trial, prolactin levels decreased in both males and females when switched to olanzapine, but not in the other group. GISF overall scores and scores in the ‘climax items’, which describe experience of sexual climax, of this instrument also improved markedly in the switched group, as did menstrual cycling in women.
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.
A case report by Wahl and Ostroff (21) described the reversal of symptomatic hyperprolactinemia by adding aripiprazole to risperidone therapy. This was explained by aripiprazole's partial agonism at the dopamine D2 receptor, counteracting the prolactin-enhancing effect of a D2 blocking agent. Whether or not this affected sexual functioning was not presented.
When comparing treatment outcome of sertindole and risperidone (22), safety data showed higher frequency of reduced ejaculation volume in sertindole-treated patients (18.5%), which was not associated with reduced libido, erectile dysfunction or anorgasmia.
Zisook et al. (23) investigated depressive symptom patterns in schizophrenia patients with subsyndromal depression. Of all patients, 38% described a loss of libido. Whether or not this was the result of prior antipsychotic treatment or a symptom of the disease is not discussed in their report.
Bitner et al. (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. As this activity was diminished by a selective D4 antagonist, one could speculate that antipsychotics with a strong affinity to the D4 receptor (like clozapine) present with a higher risk for sexual dysfunction.
Though sexual dysfunctions are commonly emphasized as an important problem in schizophrenia patients, not many controlled trials addressing this issue have been published over the course of the last year. Most of the reports reviewed have studied small samples, and thus results need to be interpreted with caution. Only one of the studies dealt with untreated or first-episode patients, thereby ruling out potentially confounding effects of prior medication. Almost every study has used a different rating method to evaluate sexual dysfunction. Clearly, this presents a problem when trying to compare studies. It is also important to bear in mind that many people have problems discussing their sexuality openly. This is likely to apply to patients suffering from schizophrenia as well. Therefore, evaluating sexual dysfunction by an interviewer as opposed to patients completing a presented scale will influence the outcome of such studies. Nevertheless, some of the reviewed papers reemphasize former findings that second-generation antipsychotics seem favourable when compared with conventional antipsychotics regarding sexual dysfunction. As both drug-related and disease-related factors contribute, however, it is important to conduct larger controlled trials, preferentially in both untreated and pretreated patients, to elucidate possible mechanisms leading to sexual dysfunction. The role of prolactin is still unclear, as sexual dysfunctions are also found in patients treated with antipsychotics that do not increase prolactin levels. To aid patients in dealing with this problem, the field awaits further sexual dysfunction-treatment studies.