Sexual Dysfunction with Antipsychotics
MJ is a single, 23 year old Caucasian male who presented with relapse of schizophrenia due to non-adherence to oral antipsychotic medication. He complained of decreased sexual drive as the primary cause of non-concordance. This essay will discuss the evidence for and appropriateness of long-acting injectable antipsychotics in this case. Choice of antipsychotics in the context of sexual dysfunction will also be discussed.
MJ was brought into the emergency department by police after being scheduled under the Mental Health Act (Section 19) during a home visit by the community youth mental health team. His father had requested the visit due to concerns over M’s deteriorating mental state over the preceding two weeks. His father reported that he had been pacing, had not been sleeping and appeared to be hallucinating. This occurred in the context of non-compliance with his oral medication (risperidone 4mg nocte) for approximately six weeks. On assessment, M appeared kempt, well-groomed and appropriately dressed. He appeared perplexed, preoccupied, and was difficult to engage. His affect was blunted and mood dysphoric. He was oriented to time and place. He appeared preoccupied with religious themes, reporting an experience during which he was ‘transported to hell’, and reported visual hallucinations of demons. There was no disorder of thought form, and he was not observed to be responding to internal stimuli. He demonstrated poor insight into his symptoms, denying that he had a mental illness or that he needed to be in hospital or take medication. He admitted that he had not taken his oral medication for eight weeks. He was admitted to hospital as an involuntary patient due to mental illness, and recommenced on oral risperidone.
MJ has had a 14 month history of recurrent admissions to Mental Health Units due to recurrent psychotic episodes. He has a history of poor concordance with treatment both as an inpatient and in the community. He was managed by the youth mental health service, but there is poor engagement. He was first diagnosed with schizophrenia 14 months previously when he was taken to hospital after making threats to harm someone with a knife in his possession. On initial assessment, he was found to be psychotic with paranoid and religious delusions. He was subsequently admitted to hospital and commenced on oral olanzapine. MJ was stabilised in hospital and discharged after five weeks with referral to the community youth team for continued follow-up. Since then, he has had two other admissions due to relapse of psychosis from medication non-concordance, each admission lasting several months. During these admissions, his medication was changed to aripiprazole (oral then depot) then to oral risperidone, with a plan to convert to depot risperidone. However, MJ strongly favoured oral dosage forms, as he felt he was more ‘in control’ of his treatment; he has repeatedly threatened to abscond interstate if depot treatment was forced upon him. During his current admission, he complained of loss of sexual drive as the main reason for non-concordance. He stated that in the past, he would go out with his friends to ‘meet girls and have fun’ but since he started taking antipsychotics, he lacked the desire to engage with women although he still enjoyed socialising with friends. On discussion with the treatment team, he agreed to a trial of oral aripiprazole as it was likely to have the least sexual side effects, and was willing to consider depot dosage form if his symptoms were well controlled.
MJ is otherwise well. He does not take any other medications and has no known drug allergies. There is no family history of mental illness. He lives at home with his parents and two siblings who are supportive, and works part-time in a supermarket stacking shelves. He drinks ten to fifteen standard alcoholic drinks a week and denies illicit drug use. There is no forensic history.
The following discussion will compare the evidence for the three antipsychotics used (risperidone, olanzapine and aripiprazole), and focus on the most appropriate option in the context of MJ’s decreased sexual drive.
The Royal Australian and New Zealand College of Psychiatrists (RANZCP) describes antipsychotic medication as the cornerstone of treatment of schizophrenia (1). However, its extensive side effect profile may pose a significant barrier to treatment concordance for patients. Sexual dysfunction is one of the most common adverse effects with a reported prevalence in 45-80% of males and 30-80% of females (2, 3). This can cause substantial distress for patients and results in diminished quality of life, and is a primary reason for early cessation of treatment of refusal to take medication (4, 5).
The exact pathogenesis of antipsychotic-induced sexual dysfunction is currently not well understood, although this symptom has been extensively described in literature. Proposed mechanisms are based on the pharmacodynamic actions of the drug on neurotransmitter release in the brain. Most antipsychotics are potent antagonists of postsynaptic dopamine receptors. In the mesolimbic pathway, dopamine has an important and complex role in reward, motivation, emotions and the positive symptoms of schizophrenia (for example, hallucinations, delusions, thought disorder) (1). Inhibition of dopamine receptors in the mesolimbic pathway can control these positive symptoms (4); however, it can also interfere with normal motivation and reward responses, leading to loss of sexual drive (libido) (3). A second, indirect mechanism for sexual dysfunction may occur in the tuberoinfundibular pathway (6); inhibition of D2 receptors can lead to decreased inhibition of prolactin (PRL) secretion by the posterior pituitary (7). The resulting hyperprolactinaemia can lead to decreased blood testosterone levels, which have a secondary negative effect on libido, impaired sexual arousal, impotence and anorgasmia (8-11). Current evidence suggests that hyperprolactinaemia is a major contributor to sexual dysfunction with antipsychotic use (3, 6, 8). Several studies have found these effects occur when prolactin levels exceed 60ng/mL (5, 11); one study found 80% of men with PRL blood levels over 50ng/mL had reduced libido (12). However, some studies found no association between prolactin levels and sexual dysfunction (13).
Aside from primary effects on dopamine, antipsychotics interact with other neurotransmitter systems in the brain which can affect sexual function (2, 4, 10). Serotonin agonists have a variable effect depending on receptor subtypes affected, but in general have an inhibitory effect (14). Studies of selective serotonin reuptake inhibitors found that agonists of 5-HT2 receptors are associated with delayed ejaculation, while agonists of 5-HT1a and antagonists of 5-HT2a or 5-HT2c receptors can stimulate sexual behaviour and enhance sexual performance (15). Reduction of negative symptoms of schizophrenia is associated with antagonism of 5-HT2a and 5-HT1a receptors (15).
The role of other receptors affected by antipsychotics is not well understood, in the context of sexual dysfunction (2, 10, 15). Histamine antagonists are associated with decreased sexual function, probably indirectly, through their sedative effects which can decrease desire and motivation (2, 13). Acetylcholine enhances peripheral vasodilation in the corpus cavernosum and thus plays a key role in maintenance of erection (3, 4). In theory, peripheral anticholinergic adverse effects of antipsychotics may cause erectile dysfunction; little is known about central anticholinergic effects on sexual function (3). Alpha-adrenergic receptor antagonists are also thought to cause reduced peripheral vasodilation, with similar effect.
Each antipsychotic has a unique receptor affinity profile, which means they will each have a different range and severity of adverse effects, and different efficacy in treatment of psychosis (10) . Multiple systematic reviews have not been able to show that one antipsychotic is more effective than others, in the treatment of schizophrenia (1, 16). Similarly, there is limited quality data comparing antipsychotic-induced sexual dysfunction; several reviews, meta-reviews and a Cochrane systematic review have observed that most studies to date have been small scale observational studies, small cross-sectional studies or cross-over studies which have not used validated scales for measurement of sexual function, or have lacked long-term follow-up (2-4, 10).
In this case, MJ was first started on oral olanzapine, before changing to risperidone, then aripiprazole. Risperidone has a high affinity for D2 dopamine receptors and variable affinity for serotonin receptors (5-HT2a, 5-HT2c) which contributes to its high risk of raising serum prolactin levels and high incidence of sexual dysfunction (3, 4). One large prospective observation study found that nearly 70% of patients who took risperidone for one year reported sexual dysfunction, with over half reporting loss of libido as the most common side effect (3). This concurs with a cross-sectional study which found 37.8% of males suffered decreased libido (4). Previous clinical trials have found risperidone can increase serum prolactin to 45-80ng/mL at therapeutic doses (17), which is higher than the 50ng/L found in another study to induce sexual dysfunction in males (12). This concurs with several studies that found risperidone-induced hyperprolactinaemia was associated with sexual dysfunction, in particular sexual arousal (3, 4, 10).
Olanzapine has a moderate but more selective affinity for D2 dopamine receptors and high affinity for serotonin receptors (5-HT2a, 5-HT2c), making it effective for treatment of positive and negative symptoms of schizophrenia (10). Its lower D2 affinity compared to risperidone is consistent with its more attenuated effect on prolactin levels. It has been shown to raise prolactin levels on initiation of treatment, but falls to normal levels after a short period (3, 10, 11). One double blind clinical trial found this period could be as short as six weeks, compared to a control group (4). This compares favourably with risperidone, which was found to have the highest rises in prolactin compared to other atypical antipsychotics, and remained higher with continuing treatment (3, 4). One randomised open-label trial which compared the two drugs found that users of olanzapine (n=20) had significantly better sexual function outcomes compared to users of risperidone (n=19) (18). An observational study also found loss of sexual desire was more common in patients prescribed risperidone (35.5%) compared to olanzapine (17.8%) after six months (4). This concurs with evidence from an open-label, prospective study that reported improvement in prolactin levels and sexual functioning when patients changed from risperidone to olanzapine (4).
Aripiprazole is a partial agonist of dopamine D2 receptors, unlike other antipsychotics which act by antagonism of the D2 receptor (10). It binds with equal affinity to the D2 receptor as dopamine, but has a lower intrinsic efficacy, and therefore the magnitude of its response lies in between dopamine and an antagonist (10). It is postulated that partial D2 agonism of the mesolimbic pathway reduces positive symptoms of schizophrenia, and increased dopaminergic activity in the mesocortical pathway reduces negative symptoms (19, 20). Aripiprazole is also an agonist of 5-HT1a receptors, and antagonist of 5-HT2a, which can make it effective in treating negative symptoms. Both olanzapine and risperidone are associated with higher rates of sexual dysfunction compared to aripiprazole. A study that measured prolactin levels during treatment found that patients who were prescribed olanzapine or risperidone as monotherapy had higher prolactin levels compared to aripiprazole (3). This concurs with other studies which found that aripiprazole induced less hyperprolactinaemia and was associated with a lower level of sexual dysfunction (16-27%) compared to olanzapine or risperidone (40-60%). Some double-blind clinical trials have found that aripiprazole does not increase prolactin levels compared to placebo (3, 4). Several trials compared aripiprazole favourably against risperidone and olanzapine in the context of sexual function. One open-label randomised clinical trial found that patients who changed to aripiprazole from another antipsychotic reported significant improvement in sexual dysfunction across all domains including sexual drive and arousal (3). This concurs with another open-label study that showed improvement in sexual desire when switching to aripiprazole (11). However, one study showed a decrease in desire and arousal occurred during treatment with aripiprazole at normal prolactin levels (3).
There have been relatively few comparative trials that have covered all the most commonly prescribed antipsychotics, and while most agree that risperidone has the greatest effect on sexual dysfunction, results of previous studies have been mixed. One review concluded that frequency of sexual dysfunction was highest with risperidone, followed by olanzapine, and aripiprazole was the lowest (3). Several other studies agreed to a similar order of effect (10, 21). In contrast, one large multi-centre randomised trial found no significant difference in sexual function between these antipsychotics (4); and one Japanese study of 352 outpatients treated for schizophrenia had the same finding (10).
MJ’s negative response to treatment with risperidone is consistent with evidence suggesting it was the drug with the highest risk of sexual dysfunction through its induction of high-level, sustained hyperprolactinaemia. It would have been appropriate to measure baseline serum prolactin levels before commencement of risperidone, to compare to his current levels; however, a baseline measurement was not done. Treatment with olanzapine may have been more suitable for MJ, since its effect on raising prolactin levels is temporary and attenuated in comparison to risperidone, and its affinity for serotonin receptors can treat negative symptoms such as anhedonia, which may contribute to decreased sexual drive. However, olanzapine has a higher sedation potential due to its high affinity for histamine H1 receptors (10), which can result in decreased initiative and therefore decreased libido. Of the three drugs for MJ, aripiprazole was the most appropriate choice, as it has the most favourable side effect profile in the context of sexual dysfunction. Evidence suggests that it causes the least effect on serum prolactin levels, and its unique mechanism of partial agonism of D2 receptors may make it effective for treatment of positive and negative symptoms of schizophrenia, while its effects on serotonin receptors may enhance sexual performance, as described above. It also has the least sedating potential, due to its low histaminergic and anticholinergic effects.
Aside from switching to aripiprazole, other strategies to reduce sexual dysfunction with antipsychotic medication include reducing dose, or using adjunctive treatment with a dopamine agonist or phospho-diesterase-5-inhibitor such as sildenafil (10); however, there are limited data to support these options (2, 3, 10). The first two options carry the risk of increased symptoms of psychosis, so it is vital to evaluate risks versus benefits for each individual patient before selecting these regimes (10). For MJ at this stage, these options are not appropriate, as he has yet to be stabilised on a single medication; further, these regimes are most relevant for dopamine antagonists, but aripiprazole is a partial dopamine agonist. A Cochrane Database Systematic Review found one randomised, double-blind, placebo-controlled crossover trial of thirty two married male patients which reported an improvement in erection quality with sildenafil (2). This treatment option is not appropriate for MJ, since his complaint concerns sexual drive and not erectile dysfunction.
At the time of writing this essay, MJ was only just switched to oral aripiprazole from oral risperidone. He will need further ongoing review to determine its effect on his sexual function, before we consider moving to depot dosage form.
Sexual dysfunction is an important side effect of antipsychotics that can have a profound negative effect on patients’ well-being, and poses a significant barrier to treatment concordance. This is especially pertinent for schizophrenic patients, who are generally young at first diagnosis, and expected treatment will be lifelong (1). This essay discussed compared the evidence for three commonly prescribed antipsychotics, in the context of sexual dysfunction.
Currently there is inadequate quality comparative data of the most commonly described antipsychotics and their effect on sexual function. Disparity of outcomes in current studies may be due to differences in study design or method of measurement of sexual dysfunction. Future studies should use randomised controlled trials and include psychosocial interventions as well as pharmacologic treatments, with a longer follow-up period. Ideally, measurement of sexual dysfunction should be validated, and consistent between studies.
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