A systematic review on clinical management of antipsychotic-induced sexual dysfunction in schizophrenia

ABSTRACT INTRODUCTION: Sexual dysfunction frequently occurs in patients with schizophrenia under antipsychotic therapy, and the presence of sexual side effects may affect compliance. The aim of this study was to review and describe clinical findings relating to the appropriate management of such dysfunctions. MATERIAL AND METHODS: The research was carried out through Medline (from 1966 to March 2005), PsycInfo (from 1974 to March 2005), and Cochrane Library (from 1965 to March 2005) and included any kind of study, from case reports to randomized trials. RESULTS: The most common sexual dysfunctions found in the literature were libido decrease, difficulties in achieving and maintaining erection, ejaculatory dysfunction, orgasmic dysfunction, and menstrual irregularities. Thirteen papers were found: eight of them were open-label studies, four were descriptions of cases, and only one was a randomized clinical trial. All of them were short-term and had small sample sizes. The agents used were: bromocriptine, cabergoline, cyproheptadine, amantadine, shakuyaku-kanzoto, sildenafil and selegiline. DISCUSSION: There was no evidence that those agents had proper efficacy in treating the antipsychotic-induced sexual dysfunction. An algorithm for managing sexual dysfunction induced by antipsychotics is suggested as a support for clinical decisions. Since the outcome from schizophrenia treatment is strongly related to compliance with the antipsychotics, prevention of sexual dysfunction is better than its treatment, since there is a scarcity of data available regarding the efficacy of intervention to deal with these problems.


INTRODUCTION
Schizophrenia treatment needs to cover several psychological and psychosocial interventions, and pharmacological treatment is essential for stabilizing the disease course and decreasing relapses.It is expected that virtually all patients with confi rmed diagnoses of schizophrenia will receive antipsychotic drugs throughout their lives, and the effi cacy of antipsychotic drugs has been confi rmed in a number of randomized controlled trials.][3][4][5][6][7] Sexual dysfunction is often not specifi cally evaluated in clinical studies.When it affects patients on drug therapy, it affects their self-esteem, causes trouble for their sexual partners, interferes with their quality of life and compromises treatment compliance. 8exual dysfunction can be an important source of distress for patients and is one of the factors that must be taken into account when antipsychotic and anticholinergic drugs are selected to treat extrapyramidal symptoms. 9or example, in one study, a questionnaire was answered by 41 patients with schizophrenia under antipsychotic treatment, and it was detected that, among all the adverse effects and symptoms relating to mental disorders, the most important were the genital/sexual effects, and particularly impotence. 10nother publication involving a case-control study on the rates of sexual dysfunction among patients with schizophrenia in comparison with the general population indicated that male patients reported less desire for sex.These patients were less likely to achieve and maintain an erection, were more prone to premature ejaculation, and were less satisfi ed with the intensity of their orgasms.Female patients, however, reported less enjoyment. 11though a high number of patients desire sexual relations (36.6% of men and 36.9% of women), sexual dysfunction is often observed in this population: 21.5% of men complain of erectile dysfunction and 18.7% of ejaculatory dysfunction; 19.3% of women and 15.9% of men complain of orgasmic dysfunction. 12esides, 21.7% of women experience gonadal dysfunction as amenorrhea. 12he aim of this study is to review and to describe clinical fi ndings related to the appropriate management of such dysfunctions.

MATERIAL AND METHODS
A protocol for a systematic review was established in order to review the clinical management of antipsychotic-induced sexual dysfunctions in schizophrenia because of the importance of this subject in psychiatric clinical practice and its implications.The review was performed by seeking and selecting any studies related to this topic, from case reports to randomized clinical trials.The studies were located via electronic data sources, published citations and letters to authors.Reference searching was also added to the review.
Searches were performed in the following electronic databases: Medline (from 1966 to March 2005), PsycInfo (from 1974 to March 2005) and Cochrane Library (from 1965 to March 2005).For each database, studies were obtained and examined.The databases were searched using the following words: #1 -sexual OR erectile OR ejaculatory OR impotence OR menstrual OR hyperprolactinemia OR prolactin OR galactorrhea OR amenorrhea OR endocrine OR endocrinol*; #2 -dysfunct*; #3 -#1 and #2; #4 -antipsychotic* OR neuroleptic* OR dopamine; #5schizophren*; #6 -#4 and #5; and #7 -#3 and #6.The * symbol means that the beginning of the word was used (root term), allowing for the identifi cation of more related terms.

INTRODUCTION:
Sexual dysfunction frequently occurs in patients with schizophrenia under antipsychotic therapy, and the presence of sexual side effects may affect compliance.The aim of this study was to review and describe clinical fi ndings relating to the appropriate management of such dysfunctions.

RESULTS:
The most common sexual dysfunctions found in the literature were libido decrease, diffi culties in achieving and maintaining erection, ejaculatory dysfunction, orgasmic dysfunction, and menstrual irregularities.Thirteen papers were found: eight of them were open-label studies, four were descriptions of cases, and only one was a randomized clinical trial.All of them were short-term and had small sample sizes.The agents used were: bromocriptine, cabergoline, cyproheptadine, amantadine, shakuyaku-kanzoto, sildenafi l and selegiline.
DISCUSSION: There was no evidence that those agents had proper effi cacy in treating the antipsychotic-induced sexual dysfunction.An algorithm for managing sexual dysfunction induced by antipsychotics is suggested as a support for clinical decisions.Since the outcome from schizophrenia treatment is strongly related to compliance with the antipsychotics, prevention of sexual dysfunction is better than its treatment, since there is a scarcity of data available regarding the effi cacy of intervention to deal with these problems.The participants were individuals diagnosed with schizophrenia by any method of diagnosis.Those with schizoaffective disorder, schizophreniform disorder or psychotic illness were also included.All subjects were under treatment using either fi rst or second antipsychotics.The study design was not taken into consideration since such a small number of studies were found.The clinical outcomes were those reported in the original studies on antipsychotic-related sexual dysfunction, and they included: erectile dysfunction, frigidity, anorgasmy, delayed ejaculation and other characteristics described in the studies.
All of the antipsychotics that induced sexual dysfunction and which are described in Table 1 are fi rst-generation antipsychotics, except for risperidone and olanzapine.
Cyproheptadine, a 5HT 2 antagonist with antihistaminergic and adrenolytic properties, has also been used to improve sexual function and anorgasmy caused by antidepressants when taken in doses of 4 mg four times per day. 26As previously mentioned, there is one report in the literature on the use of imipramine in low doses (25-50 mg per day) for thioridazine-induced orgasmic disorder; however, the mechanism of action is not clear. 27mantadine causes dopamine release at neuronal terminals.In patients with schizophrenia, amantadine decreases prolactin levels secondary to treatment with an antipsychotic.Amantadine also seems to improve sexual function when taken in doses of 100 mg per day in male patients. 19Bromocriptine, a dopamine agonist when administered in doses of 2.5 mg two or three times per day, may improve the libido of patients with hyperprolactinemia, normalize the menstrual cycle in amenorrheic patients and increase serum testosterone levels. 14However, it can also exacerbate psychosis.Another dopamine agonist is cabergoline, at a dose of 0.5 mg twice a week.Dopamine agonists such as bromocriptine and cabergoline may be successful in reducing the level of hyperprolactinemia and alleviating symptoms in some patients. 15evious studies 14 have shown that modest doses of bromocriptine may be safely prescribed to patients taking older fi rst-generation agents, and who have symptomatic hyperprolactinemia without exacerbating psychosis.
1][22][23] These pharmacological strategies described above, once initiated, should not be discontinued until a minimum of two weeks of therapy have been administered.
Shakuyaku-kanzo-to (TJ-68) is a Japanese medicine that is composed of two herbs (Radix paeoniae and Radix glycyrrhizae) and has been used to treat acute muscle cramps including menstrual pains.TJ-68 has been investigated in relation to neuroleptic-induced hyper prolactinemia.Although the mechanism is unknown, TJ-68 may have a direct inhibitory effect on prolactin release from the pituitary.Alternatively, the observed effect of TJ-68 may be explained by an indirect action when reducing estradiol. 24,28elegiline is a selective monoamine oxidase-B inhibitor; in low doses it selectively inhibits the oxidation of dopamine and phenylethylamine. 29Its metabolites, L-amphetamine and L-methamphetamine, have sexual arousal properties. 25But in the only double-blind placebo-controlled trial found in the literature, selegiline did not show any effectiveness in improving sexual functioning, despite a signifi cant decrease in prolactin levels. 30 description of the main drugs, respective doses, potential drug interactions and side effects can be found in Table 2. [13][14][15][16][17][18][19][20]23,24,27,[30][31][32][33][34][35][36][37][38]

DISCUSSION
Sexual performance among patients with schizophrenia may differ from the qualitative and quantitative patterns in the normal population.][42][43] In order to eliminate non-pharmacological factors, it is important to identify the factors that originated the sexual dysfunction, through evaluation of the patient's medical history and also physical and laboratory examinations.Both men and women should be asked specifi c questions regarding sexual dysfunction, and menstrual abnormalities should be evaluated during routine clinical evaluation.Furthermore, questions about dysfunction during autoerotic sexual activity (masturbation) and sexual intercourse are recommended in order to verify whether the dysfunction is provoked by the medication or by psychogenic causes.
After identifying the nature of the sexual dysfunction and its cause, it is important to evaluate the degree of patients' dissatisfaction and discomfort.The most common sexual disturbance is ejaculatory dysfunction induced by fi rst-generation antipsychotics. 44Erectile dysfunction in males 45 and loss of libido in both sexes have been documented among patients who use fi rst-generation antipsychotics, 46 including haloperidol, as well as among those who use second-generation antipsychotics (clozapine 47 and risperidone 48 ).Gonadal dysfunctions such as amenorrhea and galactorrhea can be found in these patients as well, and the estimated prevalence of amenorrhea in patients who use fi rst-generation antipsychotics is from 15% to 50%, 49 and 19% for galactorrhea. 50irst-generation antipsychotics seem to create an increase in dose-dependent prolactin secretion 51,52 and this effect suggests that is derived primarily from the pituitary. 53ccording to evidence relating to the use of serotonergic antidepressants, their infl uence on sexual function appear to be associated with decreased libido, erectile dysfunction and orgasmic dysfunction. 54Thus, the most likely explanation is that 5-HT2 receptor antagonism caused by second-generation antipsychotics may somehow contribute to the effect of prolactin elevation.These fi ndings suggest that the specifi city of second-generation antipsychotics, while presenting less dopamine receptor blockade in the tubularinfundibular system, may also exert a minor impact on prolactin levels. 55here are data suggesting that the incidence of sexual dysfunction differs according to the antipsychotic used.59]64 24% of the patients treated with clozapine and 45% of the patients treated with fi rst-generation antipsychotics present with one or more sexual side effects, including erectile and ejaculatory dysfunction. 65Studies have shown different results: Knegtering et al. 57 found olanzapine-induced sexual dysfunction in 27% of their schizophrenic patients; Montejo et al. 59 found it in 10-33%; and Bobes et al. found  Increases dopamine release and reduces dopamine and noradrenaline reuptake into synaptic terminals 18,19,27 Dizziness, insomnia (most common), agitation, anxiety, confusion, depression, dream abnormality, fatigue, hallucinations, headache, irritability, nervousness, nausea (most common), anorexia, constipation, diarrhea, dry mouth, orthostatic hypotension, peripheral edema, neuroleptic malignant syndrome, exacerbation of mental problems, suicide attempts Bupropion: increased risk of adverse effects; zotepine: decreased pharmacological effect of amantadine, may decrease therapeutic effect of antipsychotics Shakuyaku-kanzo-to (TJ-68)

g three times daily
The mechanism is unknown: either a direct inhibitory effect on prolactin release from the pituitary or an indirect action via a reduction in estradiol, or both 24,28 Nausea, pseudo-hyperaldosteronism, 37 myoglobinuria (rare); long term effect: may decrease serum testosterone levels, 38 use is not recommended for pregnant women or for people with liver and kidney disorders 37 No psychiatric drug interactions known Thiazide diuretics: increased potassium loss; digitalis: more sensitivity to digitalis due to hypokalemia Sildenafi l 50 mg/week Phosphodiesterase inhibitor [20][21][22][23] Flushing (4-10%), dizziness (2%), headache (11-16%), diarrhea (4%), dyspepsia (4-8%), abnormal vision, nasal congestion, skin rash (2%), myocardial infarction (rare), priapism (rare)  60 Thus, the fi ndings in the literature indicate that all second-generation antipsychotics except for risperidone induce lower rates of sexual dysfunction. 66However, most of the sexual function evaluation data was not obtained from longitudinal studies, and base data, treatment duration, disease onset and illness severity were not taken into consideration.More studies are needed in order to have a better and clearer understanding.

Conclusion and recommendations
Kaplan 67 observed that several patients suffering from schizophrenia who presented with sexual dysfunction had sought sexual therapy prior to the onset of the psychotic phase of the disease.The author mentioned that sexual therapy should only be administered once it is certain that the illness is in a remission phase and that the sexual dysfunction is not drug-induced or a defense against a possible episode of illness.This author also expressed concern regarding the use of sexual therapy among subjects with sexual dysfunction, since the resolution of these symptoms may interrupt the homeostasis of the patient and ultimately cause a relapse.This risk should be evaluated on behalf of such patients and respective partners, and they should be provided with the necessary information, be advised to practice satisfactory sexual experiences and be warned against inappropriate behavior.
The aim of a systematic review is to thorou ghly assess the best possible evidence about the effects of a healthcare intervention or treatment in a particular healthcare situation, by means of a set procedure.However, in this case, due to the lack of double-blind studies and the bias of non-publication of negative treatments and strategies, it is impossible to estimate the relative effi cacy of the interventions available for treating antipsychotic-induced sexual dysfunction.In order to avoid iatrogenic sexual dysfunction in schizophrenia, patients should fi rst be given the option of an appropriate drug, as discussed above.The patients who present higher risk of sexual disorders are those receiving fi rst-generation antipsychotics and, more specifi cally, those taking high doses of these drugs (dose-dependent effect). 68In cases where a drug-induced sexual dysfunction is present, it is advisable to reduce fi rst-generation antipsychotics to lower doses that are still effective, maintaining the clinical status.Moreover, if the patient can be and more clearly documented.There was an almost complete lack of randomized controlled trials (RCTs) on the clinical management of antipsychotic-induced sexual dysfunction in the literature, and no proper comparisons of the effi cacy of agents.Further clinical trials focusing on the sexual sphere are necessary in order to progress with regard to compliance and distress among patients with schizophrenia.
On the basis of the scarce data available, an attempt was made to design a preliminary algorithm for the clinical management of antipsychotic-induced sexual dysfunction, as described in Figure 1.It is important to point out that such an algorithm should be analyzed within the context of the patient's overall clinical condition, avoiding radical interventions that could threaten the patient's clinical stability.
In conclusion, the fi ndings in the literature indicate that antipsychotics may have different profi les of adverse sexual effects, but the results are inconclusive since most of the maintained on a low dose, the incidence of other adverse symptoms that may interfere in sexual activity, such as sedation and Parkinsonism, will be reduced.
Withdrawal of a fi rst-generation antipsychotic, or switching from a fi rst-generation to a prolactin-sparing second-generation antipsychotic, should be done if hyperprolactinemia is present.Changes in antipsychotic input may also alter sexual function.If the dysfunction persists while the patient is receiving anticholinergics, the drug should be discontinued since there is evidence that anticholinergic properties found in some antidepressants can cause sexual dysfunction. 69Acetylcholine will probably not play a direct role in sexual function; however, it may be important in the adrenergic-cholinergic balance that is necessary for normal sexual function. 70lthough the more favorable benefitversus-risk ratio of the new antipsychotics represents a major improvement over the older neuroleptics, differences need to be addressed sexual function evaluation was not performed in longitudinal studies.Moreover, base data, treatment duration, disease onset and illness severity were not taken into consideration.
Adverse sexual effects must be diagnosed, and should be discussed clearly and treated while maintaining the patient's mental status, treatment compliance and quality of life.More studies are needed in order to provide physicians with better understanding of this problem, thereby leading towards effi cacious and safe solutions.

:
The research was carried out through Medline (from 1966 to March 2005), PsycInfo (from 1974 to March 2005), and Cochrane Library (from 1965 to March 2005) and included any kind of study, from case reports to randomized trials.

Figure 1 .
Figure 1.Clinical management of antipsychotic-induced sexual dysfunction in schizophrenia.

Table 1 .
Description of published articles relating to sexual orgonadal dysfunction and use of antipsychotics

Table 2 .
Main drugs and respective dosages used in treating antipsychotic-induced sexual dysfunction