Sexual dysfunction as a side-effect of drug treatment of psychosis

Despite the improvement in interpersonal functioning that can be produced by antipsychotic drugs, there is evidence that people receiving medication for schizophrenia frequently suffer sexual dysfunction (Reference Aizenberg, Zemishlany and Dorfman-EtrogAizenberg 1995; Reference Smith, O'Keane and MurraySmith 2002).

Reference GitlinGitlin (1994) lists four ways in which psychotropic medication can affect sexual function:

1. • direct effect on the central nervous system (CNS), e.g. the dopaminergic increase caused by levodopa, resulting in increased libido;

2. • indirect CNS effects, e.g. sedation secondary to histaminic effects of antipsychotics, resulting in decreased sexual activity;

3. • peripheral effects, e.g. α-adrenergic blockade, resulting in priapism;

4. • hormonal effects, e.g. dopamine blockade causes hyperprolactinaemia, which has negative effects on sexual and reproductive function.

Reviewing whether the receptor-binding properties of the prescribed antipsychotic match the type of sexual dysfunction being experienced will assist in determining whether a patient’s sexual dysfunction is a result of their prescribed treatment.

Conventional (typical) antipsychotic medications

Antipsychotics differ in their ability to block adrenergic, histaminic and muscarinic receptors, and therefore differ in their interference with sexual function. Sexual dysfunction is more likely to be seen with high-dose, low-potency drugs such as the aliphatic phenothiazine chlorpromazine. These tend to have less potent dopamine-blocking ability, but significant anti-adrenergic and anti-cholinergic activity (Reference Kotin, Wilbert and VerburgKotin 1976; Reference Lingjaerde, Ahlfors and BechLingjaerde 1987). Antimuscarinic activity promotes dryness of the mucous membranes, which may cause discomfort during coital activity. In men, the anti-adrenergic effects of antipsychotics include ejaculatory dysfunction and priapism (Reference Mitchell and PopkinMitchell 1983).

Raised prolactin levels are associated with sexual dysfunction in both women and men (Reference Ghadirian, Chouinard and AnnableGhadirian 1982). However, a preliminary study found that women have a greater prolactin response to antipsychotics compared with men and therefore may be more likely to suffer sexual dysfunction associated with prolactin increase (Reference Nathan, Sachar and OstrowNathan 1983). This has been confirmed by subsequent research, which showed that rates of sexual dysfunction in antipsychotic-treated individuals were high and that, in women, dysfunction was particularly related to the prolactin-inducing effects of the medication (Reference Smith, O'Keane and MurraySmith 2002).

The well-established physiological and pathological sequelae of sustained high prolactin levels include hypogonadal states with decreased libido, erectile and ejaculatory dysfunction, decreased vaginal response, anorgasmia, menstrual irregularities, galactorrhoea and reduced fertility.

Atypical antipsychotic medications

The newer, second-generation antipsychotics (the atypicals) initially appeared to have less troublesome side-effect profiles than the older drugs. Dopamine (excitatory) and serotonin (inhibitory) are both important neurotransmitters in sexual function. The reciprocal activity of these neurotransmitters in the atypicals seems to reduce the likelihood of raised prolactin levels, and this may be associated with lesser sexual dysfunction. Atypical drugs differ in their effects on prolactin, and divide into those that raise prolactin levels and those that do not. Both olanzapine and quetiapine have been associated with low levels of reported sexual dysfunction (Reference Beasley, Tollefson and TranBeasley 1997; Reference Keller and MonginiKeller 2002). It is of note that both drugs tend not to produce marked increases in prolactin, in common with clozapine, which, together with quetiapine and aripiprazole, is truly prolactin-sparing. Clozapine has been found to be associated with low levels of sexual dysfunction compared with typical antipsychotics, although there have been reports of priapism with this drug (Reference Rosen and HannoRosen 1992; Reference Seftel, Saenz de Tejada and SzetelaSeftel 1992, Reference Compton, Saldivia and BerryCompton 2000).

Risperidone has repeatedly been shown to be associated with significant levels of sexual dysfunction, particularly ejaculatory disturbance (Reference Kim, Pae and ChaeKim 2002; Reference Bobes, Garc and PortillaBobes 2003; Reference Knegtering, Castelein and BousKnegtering 2004). Sertindole is also associated with ejaculatory disturbance, mainly absent ejaculate (Reference Lewis, Bagnall and LeitnerLewis 2000). This is thought to be a result of α-adrenergic blockade.

It is very likely that the endocrine sequelae of anti-psychotic medication have been underestimated. Given the high rate of hyperprolactinaemia among patients taking antipsychotics, hypogonadal states are a likely consequence. In addition to causing sexual dysfunction, this may contribute to the reduced fertility rates seen in schizophrenia (Reference Rao, Bishop and CoppenRao 1980; Reference Smith, Wheeler and MurraySmith 2003).

Anticholinergic medication

Very little is known about the effects of anti-cholinergic medication on sexual function. However, it is likely that concurrent prescription of anticholinergics with antipsychotics will potentiate the effects of antipsychotics on arousal, and may cause impotence or failure of the vaginal response.

Mood stabilisers

Lithium tends not to be associated with sexual dysfunction. One study found that some men taking lithium reported reduced sexual interest, but most who were taking lithium alone had no difficulties with their sexual function (Reference Aizenburg, Sigler and ZemishlanyAizenberg 1996). However, when lithium is taken in combination with other medications, there is a greater risk of sexual dysfunction (Reference Ghadirian, Annable and BelangerGhadirian 1992; Reference Aizenburg, Sigler and ZemishlanyAizenberg 1996). The enzyme-inducing anti-epileptics that are used as mood stabilisers (sodium valproate, carbamazepine) are associated with sexual dysfunction, and this is thought to be a hormonal effect, via suppression of the hypothalamic–pituitary–gonadal axis. Lamotrigine, however, appears to be far less likely to cause sexual dysfunction (Reference LambertLambert 2001).

Psychological and social factors implicated in sexual dysfunction

The finding that poor premorbid sociosexual functioning is an important determinant of long-term outcome lends weight to the argument that lowered fertility rates in schizophrenia are a result of its social, rather than biological, effects (Reference Keefe, Mohs and LosonczyKeefe 1989; Reference Jones, Bebbington and FoersterJones 1993). There is a great deal of evidence pointing to the poor social functioning of people with schizophrenia. Indeed, it is this that makes the illness so very disabling. People with bipolar disorder seem to be more successful at making relationships (although they may have difficulty maintaining them over long periods of time), than those with schizophrenia. They have higher marital rates and higher fertility rates, although studies show that their fertility rates are lower than those in the general population (Reference Lane, Byrne and MulvanyLane 1995; Reference Howard, Kumar and LeeseHoward 2002). Reference VogelVogel (1979) found that earlier onset of illness (psychic disturbance before the age of 15) is associated with a worse reproductive outcome and suggested that this is related to the greater personality disturbance seen in those with early-onset disease. It is of note that duration of illness was unrelated to fertility rates.

A qualitative study of people with severe mental illness found that sexual inactivity could be the result of their feelings of anxiety about having to ‘come out’ about their illness or having to explain their need for psychotropic medication (Reference Wright, Wright and PerryWright 2007). In addition, it was found that some patients felt devalued and expected stigmatisation as a result of their diagnosis, leading to intentional celibacy.

Comorbid psychiatric disorders, including generalised anxiety disorder, depression, gender identity disorder, body dysmorphic disorder and alcohol dependency syndrome, may also contribute to sexual dysfunction.

Evaluation

A sexual history should form part of a thorough initial psychiatric assessment, prior to prescription of medication (Box 2). Change in sexual function should be enquired about on subsequent visits. It may be helpful to use rating scales to monitor any change more accurately (Reference Lingjaerde, Ahlfors and BechLingjaerde 1987; Reference Smith, O'Keane and MurraySmith 2002). Open discussion of the problem may help to reduce non-adherence to medication later on.

Patients are unlikely to spontaneously mention any sexual problems and direct questioning is required to determine their presence (Reference Knegtering, Castelein and BousKnegtering 2004). Inform them that sexual difficulties are common in the general population (Reference Johannes, Araujo and FeldmanJohannes 2000). Let them know that psychiatric medication can cause sexual side-effects just as it can cause other side-effects and that it is therefore important to determine their baseline sexual function. Normalise the experience by reminding them of the usual process of sexual intercourse and the problems that people might encounter if experiencing sexual dysfunction. Remember that lack of sexual activity may be a sign of low libido. Lack of morning erections and delayed or absent ejaculation are more indicative of an organic than of a psychological problem.

In patients with erectile dysfunction (Box 3), a sex hormone profile may help to determine the cause. Hypogonadism is a reversible cause. A morning blood sample (between 08.00 and 11.00 h) should be taken to check testosterone levels. If a low serum testosterone level is found, the test should be repeated along with tests of serum follicle stimulating hormone, luteinizing hormone and prolactin levels (Reference Hackett, Dean and KellHackett 2007). If these results are abnormal, a specialist referral should be considered.

The risk factors for erectile dysfunction are similar to those for cardiovascular disease and include smoking, obesity, metabolic syndrome, hypercholesterolaemia and sedentary lifestyle (Reference Hackett, Dean and KellHackett 2007). Erectile dysfunction may be the first presentation of diabetes, hypertension or cardiovascular disease and is itself a cardiovascular risk factor (Reference Hackett, Dean and KellHackett 2007; Reference HaffnerHaffner 2000; Reference Thompson, Tangen and GoodmanThompson 2005). Therefore, other investigations that should be performed as routine in cases of sexual dysfunction include fasting glucose and lipids, as well as full blood count and liver function tests. If these results are abnormal, a referral to an endocrinologist should be considered.

Managing antipsychotic-induced sexual dysfunction

Sexual dysfunction induced by antipsychotics is often dose-related, and therefore a reduction in dose may relieve the symptoms. After reducing the dose, wait 6–8 weeks to see whether there is any improvement. If there is no improvement within this time, or if the reduction in dose does not provide clinical stability, consider switching to a medication with fewer sexual side-effects. In women, this is likely to be a prolactin-sparing medication such as quetiapine; in men, one with fewer anticholinergic or anti-adrenergic side-effects, such as aripiprazole. If the underlying cause of sexual dysfunction is not clear, the patient should be referred to their general practitioner for a full physical work-up. A specialist referral may follow, if necessary, depending on the organic cause identified, for example to a diabetologist if poorly controlled diabetes is identified as the cause.

In cases of erectile dysfunction, if the patient cannot tolerate a reduction of dose or a switch, it may be necessary to institute a drug to treat it, such as a phosphodiesterase type-5 (PDE-5) inhibitor. A Cochrane review of the evidence base for the management of antipsychotic-induced sexual dysfunction found a dearth of evidence in this area, other than a small trial which reported that sildenafil was helpful (Reference Berner, Hagen and KristonBerner 2007). Drugs that inhibit PDE-5 cause vasodilation, smooth-muscle relaxation and increased arterial blood flow, leading to penile erection (Reference Corbin, Francis and WebbCorbin 2002). These agents have a 75% success rate when used in attempting sexual intercourse (Reference Hackett, Dean and KellHackett 2007). Of the three licensed for use in erectile dysfunction (sildenafil, tadalafil and vardenafil), tadalafil has the longest half-life (17.5 h v. 4 h for the other two) and has been shown to be the agent of preference among patients (Reference Eardley, Mirone and MontorsiEardley 2005; Reference Hackett, Dean and KellHackett 2007). The PDE-5 inhibitors are typically prescribed on a once-weekly basis and all have a maximum of one dose in 24 h (British Medical Association 2010). They are absolutely contraindicated in patients receiving nitrates (e.g. isosorbide mononitrate, glyceryl trinitrate), because of the risk of unpredictable, potentially dangerous, falls in blood pressure (Reference Hackett, Dean and KellHackett 2007). However, they may be taken in conjunction with antihypertensives with only a small risk of significant orthostatic hypotension.

Psychosexual therapy may be indicated if the sexual dysfunction is attributed to psychological or relational difficulties. A Cochrane review of treatment for erectile dysfunction reported that focused group psychosexual therapy plus sildenafil significantly increased rates of successful intercourse compared with sildenafil alone (Reference Melnik, Soares and NaselloMelnik 2007). However, there is no evidence base for this treatment in patients with psychotic disorders and it may not be easy for them to access it.

Many genitourinary medicine (GUM) clinics offer psychosexual therapy on referral by a general practitioner, although the nature of the treatments provided and the referral criteria are likely to vary between clinics. Nevertheless, these clinics may prove a useful first port of call for signposting to local resources such as voluntary agencies that provide psychosexual therapy (usually for a fee).

Sexually transmitted infections

Given the documented high risk of STIs among people with psychotic illnesses, it may be in a patient’s best interests to be screened for infection, particularly if the individual has a known history of risky sexual behaviour. Also, the differential diagnosis of a patient with psychosis may include organic conditions such as HIV infection.

However, it is not difficult to envisage a scenario in which an acutely ill patient holds grandiose or persecutory delusional beliefs that cause them to refuse to have investigations for STIs. They might, for example, believe that their blood will be tampered with, or that they are immune from problems such as STIs. If their reasoning is based on psychotic thinking, then it is highly likely (but not absolutely certain) that they will lack the capacity to make this decision and, for some, it will be considered to be in their best interests to be tested for STIs. Whether it is proportionate to restrain an unwilling, incapacitous individual for the purposes of taking blood for testing will depend on the likelihood that they have an STI and would come to harm because of it if the investigation is delayed until capacity is regained. This will have to be decided on a case-by-case basis. It is essential that the decision-making process is well-documented. In cases where there is a high index of suspicion that a patient lacking capacity has an STI associated with potentially significant morbidity if left undiagnosed or untreated (e.g. HIV), it would be advisable to seek a second opinion on capacity and best interests before reaching a final decision.

Treatment of STIs in patients lacking capacity can be given under the Mental Capacity Act if it is deemed to be in the best interests of the patient and proportionate. If the STI is causing the mental disorder, as in HIV-related cognitive impairment, it may be possible to treat it under the Mental Health Act.

Unwanted pregnancy and contraception

Given that severe mental illness is associated with high-risk sexual behaviour and unwanted pregnancies (Reference Coverdale and AruffoCoverdale 1989), it may be considered appropriate to offer some female patients oral contraceptives. For some women, it will simply be a matter of providing the necessary information to enable them to make a fully informed decision. However, there will be others who, despite the best efforts of the treating psychiatrist or general practitioner, continue to lack capacity to consent to this treatment. This raises potentially challenging issues about best interests as, essentially, one is deciding whether somebody else should be able to become pregnant. In the case of women prescribed highly teratogenic agents such as sodium valproate, the issue is relatively more easily resolved, given the high risks to the fetus and the consequent accepted best practice of co-prescribing contraception in women of child-bearing age. Otherwise, it is understandable that psychiatrists may feel uncomfortable in making such a complex best interests judgement.

Any decision to prescribe contraceptive agents for incapacitous patients should be preceded by exhaustive, documented attempts to maximise the patient’s ability to take part in the decision-making process. Collateral information should be obtained to gain an understanding of what choice the woman would most likely have made if she did have capacity, as this will form the basis of deciding her best interests. It may be advisable to hold a formal best-interests meeting with all interested parties, including carers and next of kin, to ensure transparency and optimal decision-making. This meeting should include the patient’s general practitioner who, as prescriber, will ultimately bear responsibility for the decision to prescribe contraception and for the capacity assessment.