1. Primary Prevention: Using APS with a Low Incidence of TESD

While many patients may not be on monotherapy and SD may emerge from a combination of drugs, prevention allows us to optimize the risk for SD when treating an antipsychotic-naïve patient. Although keeping first rank psychotic symptoms under control should be a priority, clinicians should always be wary of the potential for TESD of each drug at this point (Table 2). Overall, risperidone [66,67] and other classical APS [62,68–73] have a higher incidence of TESD when compared with other atypical neuroleptics such as clozapine [73–75], olanzapine [62,68,71,76–82], quetiapine [62,66,71,72,83–86], or aripiprazole [87–89]. When analyzing TESD by each sexual dimension comparing different APS, this becomes even more obvious, given how SD rates are so different for each antipsychotic [52].

Table 2. Mechanisms of action causing SD for each antipsychotic.

LH, luteinizing hormone; FSH, follicle-stimulating hormone.

Risperidone has been associated with other problems in addition to regular sexual dysfunction, like retrograde ejaculation and urinary dysfunctions [90–94]; anejaculation [95,96]; and, on rare occasions, hypersexuality [97,98]. Part of this SD could be related to high levels of blood prolactin [84,99], resulting in complex hormone regulations that decrease testosterone [100]. Some studies question prolactin levels as the sole mechanism of SD in risperidone [34,65,83,101], and it is likely that a blockade of 5HT2A and 5HT2C receptors at the prefrontal cortex may be responsible too [34,102,103]. Nonetheless, hyperprolactinemia also causes a variety of adverse effects and pathologies that go beyond sexual dysfunction, especially in the long-term [1,60].

Paliperidone, a metabolite of risperidone, has also been linked to hyperprolactinemia [104] and sexual dysfunction [105,106], with similar mechanisms involved. Therefore, hyperprolactinemic APS such as risperidone, paliperidone, amisulpride, and classical antipsychotics are not an appropriate first option if we wish to keep sexual function preserved in psychotic patients [1,65]. In turn, the other atypical antipsychotics fare slightly better in comparison [70].

Clozapine’s weaker blockade of D2 dopaminergic receptors in the mesostriatum is supposed to have a lesser incidence of orgasm dysfunction and erectile dysfunction when compared with typical neuroleptics [107,108], although not by a wide margin [109]. A case of hypersexual behavior with clozapine has been reported [110], although it is not a common adverse effect.

Ziprasidone, because of its mechanism of action (5-HT2 receptor antagonism facilitating dopamine release in the cortex), would theoretically improve orgasmic and erectile function, as suggested by some case reports concerning spontaneous ejaculation and priapism [111,112]. However, there is only one study researching its effect on sexual function to our knowledge. In a small (n = 15), 3-month observational study, patients who were antipsychotic-naïve commenced treatment with ziprasidone, preserving sexual functioning across all sexual dimensions, and even slightly improving the minor sexual dysfunction found in baseline [113]. Although promising, these results need further confirmation.

Olanzapine causes less extrapyramidal symptoms [76], less hyperprolactinemia [79,80,114], and less SD than haloperidol [115] and risperidone [68,71,81,116]. Orgasm, ejaculation, and arousal are usually less affected by olanzapine than by risperidone [78,81], as also suggested by some case reports of spontaneous ejaculation [117] and priapism [118]. However, some studies consider these differences to be relatively minor or nonexistent [66,114], especially when olanzapine doses reach 15–20 mg/day [62,82]. These results suggest that olanzapine causes a dose-dependent mild to moderate hyperprolactinemia.

Quetiapine, on the other hand, does not significantly increase prolactin levels [82]. There has been lower reported incidence of SD with quetiapine when compared with typical neuroleptics, and some atypical (risperidone and olanzapine) [72,83,84,119]. With one exception [72], most of the studies agree that, when dosing below 400 mg/day, sexual function is mostly preserved [62,82,84], but when dosing at around 500 mg/day and above, SD may appear with a severity in proportion to dosage [66,120], although usually less so than the previously mentioned antipsychotics [53,121]. Quetiapine has also been described as particularly helpful in preserving sexual arousal [52,66,72].

Aripiprazole, a partial dopamine receptors agonist, as well as its partial 5HT1A agonism and 5HT2A antagonism, has been correlated to no actual increase in prolactin levels [88,119,122]. In fact, when used in combination with another antipsychotic, it has been observed to lower already increased prolactin levels [123]. When dosing at around 15 mg/day, this results in no SD at all [53,87,88], or SD of mild intensity, usually being tolerable for the patient. One study concludes that aripiprazole causes less SD than risperidone, olanzapine, or quetiapine [119]. However, while aripiprazole remains the best option among the researched evidence when trying to prevent TESD [70], several cases of hypersexual behavior have been reported to be directly caused by this drug [123–127], which apparently can manifest at any dose, but seem to be more frequent when dosing above 20 mg/day [125]. Cariprazine, which is another dopamine partial agonist like aripiprazole that does not produce hyperprolactinemia [128,129], still has no published data regarding its effect on sexual function. Although it could be considered similar to aripiprazole, specific studies are needed.

2. Detection and Exploration of TESD

Psychotic patients are a very heterogeneous group in terms of clinical evolutions, treatment response, and sexual activity, so being mindful of this issue and its possible repercussions on adherence becomes difficult at times for both the clinician [46] and the patient. For example, uncompensated patients with acute symptomatology that require hospitalization do not share the same concern for their sexuality as fully stabilized chronic patients do [130–132]; clinicians treating the former may overlook this issue at first while attempting to treat psychotic symptomatology.

That is why, when SD shows up, it is crucial to examine how the patient accepts this adverse effect and how it influences their quality of life and overall functionality. The spontaneous communication rate of SD from patients is low [1,53,133], so medical staff should routinely check with the patients to detect if TESD exists by asking clear questions, such as “How has your sexual life been since you started taking the medication?” and “Have you noticed any change that worries you?” This issue should always be approached in a neutral manner, expressing concern about the patient’s wellbeing and informing them about the potential sexual side effects of APS medication [59]. Gathering a full sexual medical history is useful to thoroughly understand the onset of the first SD symptoms, SD severity, the impact of SD on the sexual lives of the patient and their partner, and the influence of SD on the patient’s quality of life [134]. This thorough evaluation would also help to determine whether SD is in fact a consequence of antipsychotic treatment or is caused by other factors such as comorbidities, substance abuse, or other prescribed medication [3].

To better quantify TESD and measure its degree of acceptance by the patient, several specific validated scales and structured questionnaires can be of use. As the rate of SD can vary depending on which scale is used [68], a combination of several of them would be best in order to best determine its existence and its intensity, especially when researching this issue [65].

A few suitable options for measuring TESD caused by antipsychotics are the following [135]: the Psychotropic-Related Sexual Dysfunction Questionnaire (PRSexDQ-SALSEX, free download at http://sexualidadysaludmental.com/salsex.html)) [136,137]; the Changes in Sexual Functioning Questionnaire (CSFQ) [138]; the Antipsychotics and Sexual Functioning Questionnaire (ASFQ) [139]; the Arizona Sexual Experiences Scale (ASEX) [140–142]; the Nagoya Sexual Function Questionnaire (NSFQ) [143]; and the Antipsychotic Non-Neurological Side Effects Rating Scale for sexual dysfunction (ANNSERS) [144]. The PRSexDQ, ASFQ, and CSFQ cover all stages of sexual functioning, which makes them preferrable [135]. To further measure the severity of SD, the International Index of Erectile Function (IIEF) and the Sexual Encounter Profile (SEP) [145] are valid options for men, and the Sexual Interest and Desire Inventory-Female (SIDI-F) for women [146].

3. Intervention

Once TESD is identified, if it is poorly tolerated by the patient and risks compromising adherence, it may be possible to intervene depending on the particular clinical symptoms of each case. While sometimes, fully restoring previous sexual function is not achievable, partially alleviating the experienced symptoms can satisfy the patient’s expectations without jeopardizing the antipsychotic effect of their treatment. When compared with SD caused by antidepressants, the literature on intervention in TESD caused by APS is scarce, and frequently inconsistent [2,147], although some viable options emerge. Some possible strategies for treating TESD are the following: (1) waiting for spontaneous remission; (2) dose reduction; (3) switching to another APS; and (4) the addition of an antidote (coadjuvant drug). None of these methods is devoid of risks, such as a relapse, so a careful individualized approach is suggested so that patients can make an informed choice.

This entry is adapted from the peer-reviewed paper 10.3390/jcm10020308