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David Baldwin is a senior lecturer in psychiatry and honorary consultant psychiatrist at the Royal South Hants Hospital, University of Southampton (University Department of Mental Health, Brintons Terrace, Southampton SO14 0YG, UK. Tel: (0)2380 825533; fax: (0)2380 234243; e-mail: dsb1{at}soton.ac.uk). His research interests include the treatment of depression and anxiety disorders, sexual dysfunction and the prevention of suicidal behaviour. He has acted as an advisor to pharmaceutical companies that manufacture antidepressant or antipsychotic drugs. Andrew Mayers is a research psychologist at the Royal South Hants Hospital, University of Southampton. His research interests include depression, anxiety disorders, suicide and sleep. The University of Southampton has received grants from pharmaceutical companies to support research into the relationships between mental health problems and their treatment and sexual dysfunction.
| Abstract |
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The ICD10 (World Health Organization, 1992) uses the term sexual dysfunction to cover the ways in which an individual is unable to participate in a sexual relationship as he or she would wish. This classification has 10 subdivisions (F52.0F52.9), each describing different forms of dysfunction. The DSMIV (American Psychiatric Association, 1994) uses a similar scheme. Whenever possible, doctors should specify which form of sexual dysfunction is present, as these have differing causes and require different treatment approaches.
Some types of dysfunction occur in both men and women, although women tend to present with complaints about the subjective quality of sexual experience (e.g. lack of desire), whereas men often describe the failure of a specific response (such as erection) but a continuing sexual desire.
| Epidemiology of sexual dysfunction |
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A US study found that sexual dysfunction in the general population is more prevalent in women (43%) than men (31%) (Laumann et al, 1999). Using latent class analysis, symptoms during the previous 12 months could be grouped into three categories. In women, these were low sexual desire (22% prevalence), arousal or excitement problems (14%) and sexual pain (7%); in men, they were premature ejaculation (21%), erectile dysfunction (5%) and low sexual desire (5%).
Reported rates of sexual dysfunction vary considerably, reflecting differences in the study population and types of dysfunction being assessed. Other studies with data for both genders show a higher prevalence of sexual dysfunction in women than in men (Ernst et al, 1993; Dunn et al, 1998) and confirm the results for the most common sexual dysfunction in both men and women.
Many factors influence the reported incidence of sexual dysfunction. The first is the method of enquiry. In a prospective study of out-patients with depression, for example, the incidence of sexual dysfunction was 14% when relying on spontaneous reporting. However, this rose to 58% when patients were questioned directly by doctors (Montejo-González et al, 1997). The second factor is that the expectation people have of their sexual performance and their willingness to discuss problems vary between cultures (Bhugra & De Silva, 1993). In the third place, many terms used to define sexual dysfunction are subjective and partly dependent on ideas of what is normal. Finally, temporal trends can occur as increased awareness of sexual matters and availability of treatment increase the number of those who perceive themselves to be suffering from sexual dysfunction.
| Sexual dysfunction in depression |
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In an early study of 132 patients with depressive disorders, loss of sexual interest (characterised by loss of libido or decrease of sexual desire or potency) was reported by 72% of patients with unipolar disorder and 77% of those with bipolar disorder (Casper et al, 1985). Loss of sexual desire may be the presenting complaint in some patients who are found to have significant depressive symptoms only after direct questioning. In others, low sexual desire may pre-date other features of depression (Schreiner-Engel & Schiavi, 1986).
Comparative studies indicate higher levels of sexual dysfunction in patients with depression than in controls (Table 1
). Although the incidence of specific types of sexual dysfunction varies across studies, loss of sexual desire may be more common than disorders of arousal and orgasm. For example, in one comparative study, changes in libido were significantly more common in patients with depression, but the prevalence of impotence, orgasmic or ejaculatory problems did not differ from controls (Mathew & Weinman, 1982). The prospective Zurich cohort study (Ernst et al, 1993) showed that the overall prevalence of sexual problems in subjects with depression (including major depression, dysthymia and recurrent brief depression) was about twice that in controls (50% v. 24%). This difference encompassed emotional problems, sexual dysfunction and both decreased and increased libido. The study findings were from a group of young people (2835 years old) and are not necessarily applicable to older age groups (Angst, 1998).
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| Sexual function in schizophrenia |
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Although sexual delusions and somatic hallucinations can form part of the psychopathology of schizophrenia, the onset of psychosis is often associated with reduced sexual activity (Rozan et al, 1971). Persistent psychosis is also associated with reductions in sexual interest, activity and satisfaction (Lyketsos et al, 1983). Treated and untreated male patients reported decreased sexual desire and behaviour and increased rates of premature ejaculation than did controls. In a comparison with untreated male patients, depot antipsychotic treatment increased sexual thoughts and desire but also resulted in sexual dysfunction (Aizenberg et al, 1995). In another comparison, sexual dysfunction was more common in female patients than in controls, but not in those patients with a satisfactory overall relationship with a sexual partner (Raboch, 1986).
It is unclear whether sexual dysfunction is more or less common in patients with schizophrenia than in those with other forms of mental disorder. A small survey (n=56) of in-patients found that 62% of men and 25% of women with schizophrenia reported sexual or relationship problems, compared with 6375% of men and 50100% of women with affective disorder (Bhui et al, 1995). In a larger study (n=173), sexual problems were significantly more common in patients with schizophrenia who were receiving treatment than in patients with anxiety disorders who were not receiving treatment, but they were as common as in patients with opiate dependence who were receiving methadone (Teusch et al, 1995).
| Neurotransmitters and sexual function |
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-aminobutyric acid, oxytocin, nitric oxide, arg-vasopressin, angiotensin II, gonadotrophin-releasing hormone, substance P, neuropeptide Y and cholecystokinin. Of these, dopamine, serotonin and nitric oxide may have the most important roles in the pathophysiology and treatment of sexual dysfunction arising from antidepressant and antipsychotic drugs (Baldwin et al, 1997). Increased levels of central dopamine can increase sexual arousal and enhance penile erection. Centrally acting dopaminergic compounds have been shown to facilitate sexual behaviour in animal models and the dopaminergic agonist bromocriptine can reduce sexual dysfunction in men with hyperprolactinaemia associated with chronic renal failure (Ramirez et al, 1985). Dopamine antagonists, such as most antipsychotics, can reduce sexual performance both directly and indirectly through inducing hyperprolactinaemia (Segraves, 1989). Increased central serotonergic neurotransmission can reduce sexual behaviour. Activation of 5-HT2 receptors mediates inhibitory actions on sexual behaviour in animal models and 5-HT2 antagonists, such as cyproheptadine, and 5-HT1a agonists, such as buspirone, can reverse sexual dysfunction induced by selective serotonin reuptake inhibitors (SSRIs).
Penile erection involves vasodilatation arising from relaxation of smooth muscle in the corpus cavernosum. The key mediator for this is nitric oxide, which acts by increasing the cellular level of the cyclic nucleotide guanosine monophosphate (cGMP). Increases in cGMP levels can be also be effected by inhibition of phosphodiesterases, which are the enzymes involved in cyclic nucleotide breakdown. Sildenafil is a phosphodiesterase-5 inhibitor that enhances nitric-oxide-mediated vasodilatation in the corpus cavernosum by inhibiting breakdown of cGMP.
| Sexual side-effects of conventional antipsychotics |
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It is unclear whether the untoward sexual effects of antipsychotic drugs arise mainly from direct pharmacological effects (such as dopamine receptor antagonism) or from secondary endocrine disturbances. Hyperprolactinaemia associated with prolactinomata can result in loss of sexual desire, erectile failure and reduced spermatogenesis in men; in women it can lead to altered ovarian cyclic function, amenorrhoea, reduced sexual desire and hirsutism (Petty, 1999). The claim that antipsychotic-induced hyperprolactinaemia may increase the risk of osteoporosis is not yet substantiated, as little research has been performed (Dickson & Glazer, 1999). Conventional antipsychotic drugs can increase prolactin levels to a range associated with sexual dysfunction in non-psychiatric patients, so hyperprolactinaemia is a probable explanation of some of the sexual dysfunction seen during treatment with antipsychotics. However, in many patients, the increase in prolactin levels with antipsychotic treatment is only transient. An early small (n=27) study of male patients with schizophrenia found that those with erectile failure had higher prolactin levels than those without sexual problems (Arato et al, 1979). In a subsequent investigation in male and female patients, elevated prolactin levels were associated with sexual dysfunction in men and menstrual disturbances in women (Ghadirian et al, 1982). A study of sexual function in patients taking conventional neuroleptics found that hyperprolactinaemia was the main cause of sexual dysfunction in women and in men, and that dysfunction occurred in the presence of both normal and elevated prolactin levels. However, elevated prolactin levels were likely to override any other possible causes of sexual dysfunction in these individuals (Smith et al, 2002).
Treatment with butyrophenones or phenothiazines can result in loss of sexual interest. This probably results from direct effects such as dopamine receptor antagonism and secondary hyperprolactinaemia. Other adverse effects such as sedation, extra-pyramidal effects and weight gain can also reduce sexual desire (Baldwin & Birtwistle, 1997).
Erectile failure can often result from phenothiazine treatment: in one study, 38% of men had difficulty in achieving, and 42% in maintaining, erection (Ghadirian et al, 1982). Drug-induced priapism results from
-adrenergic blockade combined with anticholinergic activity. Antipsychotic drugs with this profile (e.g. chlorpromazine or thioridazine) can prevent detumescence but can also cause painful prolonged erection of the penis or clitoris. About 20% of cases of drug-induced priapism are due to antipsychotic drugs; the risk seems independent of dosage or duration of treatment (Patel et al, 1996).
Ejaculatory problems are a common side-effect of conventional antipsychotics. Total inhibition of ejaculation is most common (Mitchell & Popkin, 1983) but reduced ejaculatory volume (Ghadirian et al, 1982) and retrograde ejaculation are not unusual. Spontaneous ejaculation in the absence of sexual stimulation can occur with antipsychotics but this is rare (Keitner & Selub, 1993). Antipsychotic drug treatment is often associated with qualitative changes in orgasm. For example, painful orgasm has been reported during treatment with thioridazine, trifluoperazine and haloperidol (Baldwin & Birtwistle, 1997).
| Sexual side-effects of atypical antipsychotics |
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However, there are case reports of retrograde ejaculation and priapism with clozapine, risperidone and olanzapine (Rosen & Hanno, 1992; Emes & Milson, 1994; Deirmenjian et al, 1998; Compton et al, 2000; Songer & Barclay, 2001).
It is uncertain whether any particular atypical antipsychotic drug is more likely to cause sexual side-effects than others. A controlled treatment study (n=339) comparing olanzapine with risperidone found that sexual dysfunction was significantly less common with olanzapine (Tran et al, 1997). Quetiapine treatment is not associated with hyperprolactinaemia, which may be an advantage. A recent retrospective cross-sectional study indicates that sexual dysfunction is less common with quetiapine (18.2%, mean dose 360.5 mg/day) than with haloperidol (38.1%, 10.6 mg/day), olanzapine (35.3%, 13.5 mg/day) or risperidone (43.2%, 5.3 mg/day) (Bobes et al, 2001). An analysis of treatment studies with amisulpride indicates similar overall rates of all forms of endocrine disorder with amisulpride and risperidone (4% v. 6%); the rate of erectile failure was significantly lower with amisulpride (1% v. 5%) (Coulouvrat & Dondey-Nouvel, 1999). Both amisulpride and risperidone can cause substantial rises in prolactin levels.
| Sexual side-effects of antidepressants |
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Few data have been published on sexual dysfunction occurring with tricyclics, although anorgasmia was common in a study of clomipramine in patients with obsessivecompulsive disorder (Monteiro et al, 1987). The majority of studies have assessed sexual dysfunction with SSRIs, but it is difficult to interpret these findings as the study designs vary considerably. For example, fluoxetine had both the highest (75%) and the lowest (8%) reported prevalence of treatment-emergent sexual dysfunction, one figure being derived from specific questioning about abnormal ejaculation (Patterson, 1993), the other from spontaneous reports of orgasmic problems (Zajecka et al, 1991). Comparative studies of SSRIs have generally found no significant differences between drugs, but one study reported more sexual dysfunction with sertraline than with fluvoxamine (Nemeroff et al, 1995).
Bupropion may be associated with a low incidence of adverse sexual effects, being significantly superior to sertraline in one study (Croft et al, 1999) and to SSRIs in another (Modell et al, 1997). A comparative study with nefazodone and sertraline found nefazodone (a 5-HT2 antagonist) to be significantly superior to sertraline on some measures of sexual function (Feiger et al, 1996). The findings of a randomised controlled trial comparing moclobemide (a reversible inhibitor of monoamine oxidase type A) with the tricyclic doxepin, together with a study in healthy volunteers and post-marketing surveillance, suggest that moclobemide is relatively free of adverse effects on sexual function (Baldwin, 2001).
| Antidepressant augmentation or switching studies |
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Mirtazapine (which also possesses 5-HT2 antagonist properties) may be useful in some patients who develop sexual dysfunction with SSRIs. In a study of 20 patients with SSRI-associated sexual dysfunction who switched to mirtazapine, sexual function improved in 9 out of 12 patients (75%) who completed 6-weeks treatment, although 6 patients developed irritability and 9 reported sedation (Gelenberg et al, 1998). A second study, of 11 patients who stopped SSRIs because of sexual problems, found that mirtazapine did not result in the re-emergence of sexual dysfunction (Koutouvidis et al, 1999). These observations are supported by findings in a group of 25 out-patients with depression, indicating that mirtazapine had beneficial effects on sexual function (Boyarsky et al, 1999).
The largest body of data is for bupropion, where the findings of one augmentation study and two substitution studies suggest that bupropion can ameliorate SSRI-induced sexual dysfunction (Baldwin, 2001). However, not all data are consistent. A retrospective review of 27 patients found that sexual dysfunction occurred in 11 patients (41%) when they were receiving combination bupropionSSRI treatment, which was not significantly different from the rate (52%) when they were taking either agent alone (Bodkin et al, 1997). A recent augmentation study with bupropion (150 mg/day) indicates that it can be usefully combined with venlafaxine, paroxetine or fluoxetine (Kennedy et al, 2002).
| Treatment of psychotropic-induced sexual dysfunction |
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| Box 1 Assessment of sexual dysfunction in a patient taking a psychotropic drug Clinical featureRelevant factor Sexual function before mental health problemsLong-standing erectile failure Severity of primary psychiatric disorderCurrent mild depressive episode Severity of comorbid psychiatric disorderCurrent alcohol dependence Presence of comorbid physical illnessHypertension Prescribed psychotropic medicationFluoxetine Prescribed medication for physical illnessAtenolol Over-the-counter or illicit drug useBenzodiazepine misuse Overall relationship with sexual partnerFrequent arguments and separations
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The role of psychological approaches is outside the scope of this article. The choice of a particular strategy is determined, among other factors, by considering the type and severity of the dysfunction, the nature of the psychiatric diagnosis, the current mental state of the patient, the potential risks of stopping treatment, the risk of untoward drug interactions and the presence or absence of a sexual partner.
Drug holidays, involving brief interruptions of treatment, have been advocated as an approach to SSRI-induced sexual dysfunction (Rothschild, 1995). However, this puts the patient at risk of discontinuation symptoms and possible relapse of depression or schizophrenia. Furthermore, a drug holiday is possible only with drugs with a short half-life. Thus, it is not appropropriate with fluoxetine, for example, where sexual side-effects may not resolve until a few weeks after stopping treatment.
Many adjuvant compounds have been advocated for relieving sexual dysfunction associated with antidepressant or antipsychotic drug treatment, including amantadine, buspirone, cyproheptadine, dexamphetamine, Ginkgo biloba, granisetron, mianserin, neostigmine, olanzapine, prostaglandin E (by intracavernosal injection), sildenafil and yohimbine. However, the results of placebo-controlled studies in this area have generally failed to distinguish between active treatments and placebo. It is wise to be cautious when using unfamiliar treatments. A recent small (n=19) placebo-controlled augmentation study with Ginkgo biloba found no difference between treatments in reversing sexual dysfunction associated with antidepressant treatment (Kang et al, 2002). Another placebo-controlled study found no significant advantage for mirtazapine, yohimbine or olanzapine in relieving sexual dysfunction when taking SSRIs (Michelson et al, 2000).
It seems likely that sildenafil may come to have a role in relieving sexual dysfunction associated with psychotropic drugs. In a sub-group of 136 patients with depression included within the placebo-controlled clinical trial database, 76% described improvements with sildenafil, compared with 18% of the group who received placebo (Price, 1999). In an open study, sildenafil was effective in 10 out of 14 patients with antidepressant drug-induced sexual dysfunction (Fava et al, 1998). The benefits of sildenafil may also apply to patients with schizophrenia, as a case report has described successful treatment of reduced sexual desire and erectile failure in a man with schizophrenia who was receiving antipsychotic drugs (Benatov et al, 1999). A recent double-blind placebo-controlled study of 160 men with erectile dysfunction and comorbid minor depression found that the response of erectile problems to sildenafil treatment was associated with a significant reduction in depressive symptoms (Seidman et al, 2001).
| Conclusions |
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| Box 2 Key points Sexual dysfunction is common in patients with depression or schizophrenia, but is often not reported to doctors; it may be an unrecognised cause of non-adherence to treatment Some antidepressant drugs (moclobemide, nefazodone, mirtazapine) are less likely to cause sexual problems than others and may be useful when patients have developed treatment-emergent sexual dysfunction Certain atypical antipsychotics may cause fewer sexual problems than conventional ones, but whether this is due to a reduced incidence of hyperprolactinaemia remains uncertain Treatment of established sexual dysfunction in a patient with depression or schizophrenia usually requires the combination of pharmacological and psychological approaches
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| Multiple choice questions |
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X. Zhang, Z. Zhang, W. Cheng, X. Mou, and G. P. Reynolds The effect of chronic antipsychotic treatment on sexual behaviour, hormones and organ size in the male rat J Psychopharmacol, June 1, 2007; 21(4): 428 - 434. [Abstract] [PDF] |
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