
==== Front
Sao Paulo Med J
Sao Paulo Med J
Sao Paulo Med J
São Paulo Medical Journal
1516-3180
1806-9460
Associação Paulista de Medicina - APM

17262163
10.1590/S1516-31802006000500012
Review and Updating Article
A systematic review on clinical management of antipsychotic-induced sexual dysfunction in schizophrenia
Revisão sistemática no manejo clínico de disfunções sexuais induzidas por antipsicóticos na esquizofreniaCosta Anna Maria Niccolai *
de Lima Mauricio Silva *
Mari Jair de Jesus *
Address for correspondence: Anna Maria Niccolai Costa Rua Samia Haddad, 150 — Apto. 142 São Paulo (SP) — Brasil — CEP 05709-050 Tel. (+55 11) 3749-0999 — Fax (+ 55 11) 3744-5677 E-mail: annamariac@globo.com
Conflict of interest: Anna Maria N. Costa is a former Eli Lilly employee and currently she is a Bristol-Myers Squibb employee. Mauricio S. de Lima is an Eli Lilly employee.

07 9 2006
2006
124 5 291297
14 11 2005
14 9 2006
19 9 2006
https://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons license.
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.

RESUMO

INTRODUÇÃO:

Disfunção sexual freqüentemente ocorre em pacientes com esquizofrenia em terapia com antipsicóticos e a presença de efeitos adversos sexuais pode afetar a adesão ao tratamento. O objetivo do estudo é rever e descrever achados clínicos relacionados ao manejo apropriado de tais disfunções.

MATERIAIS E MÉTODOS:

A pesquisa foi feita pelo Medline (de 1966 a março de 2005), PsycInfo (de 1974 a março de 2005) e Biblioteca Cochrane (de 1965 a março de 2005) e incluiu qualquer tipo de desenho de estudo de relato de caso a estudos clínicos randomizados.

RESULTADOS:

As disfunções sexuais mais comuns encontradas na literatura foram diminuição da libido, dificuldades em alcançar e manter ereção, disfunção ejaculatória, orgásmica e irregularidades menstruais. Treze artigos foram encontrados: oito deles eram estudos abertos, quatro descrições de casos e somente um estudo clínico randomizado. Todos eram de curta duração e com tamanho de amostra pequeno. Os agentes usados foram: bromocriptina, cabergolina, ciproheptadina, amantadina, shakuyaku-kanzo-to, sildenafil e selegilina.

DISCUSSÃO:

Não há evidências de eficácia apropriada destes agentes no tratamento da disfunção sexual induzida por antipsicóticos. Um algoritmo foi sugerido para manejo da disfunção sexual induzida por antipsicóticos, suportando decisões clínicas. Como o desfecho da esquizofrenia é fortemente relacionado a adesão ao tratamento com antipsicóticos, a prevenção da disfunção sexual é melhor que seu tratamento, visto que muito poucos dados estão disponíveis sobre a eficácia de intervenções destes problemas.

KEY WORDS:

Schizophrenia
Antipsychotic agents
Sexual and gender disorders
Libido
PALAVRAS-CHAVE:

Esquizofrenia
Agentes antipsicóticos
Transtornos sexuais e da identidade sexual
Libido
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pmcINTRODUCTION

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 confirmed diagnoses of schizophrenia will receive antipsychotic drugs throughout their lives, and the efficacy of antipsychotic drugs has been confirmed in a number of randomized controlled trials. However, such drugs may induce some side effects such as acute Parkinsonism, tardive dyskinesia and neuroleptic malignant syndrome.1-7

Sexual dysfunction is often not specifically 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.8 Sexual 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.9 For 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.10

Another 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 satisfied with the intensity of their orgasms. Female patients, however, reported less enjoyment.11

Although 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.12 Besides, 21.7% of women experience gonadal dysfunction as amenorrhea.12

The aim of this study is to review and to describe clinical findings 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; #5 - schizophren*; #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 identification of more related terms.

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 first 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.

RESULTS

The search resulted in 13 papers: eight 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, as shown in Table 1.13-25 Bromocriptine was involved in the treatment of these dysfunctions in two studies, sildenafil in four, amantadine in two and cyproheptadine, imipramine, shakuyaku-kanzo-to, cabergoline and selegiline in one each.

All of the antipsychotics that induced sexual dysfunction and which are described in Table 1 are first-generation antipsychotics, except for risperidone and olanzapine.

Cyproheptadine, a 5HT2 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.26 As 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.27

Amantadine 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.19 Bromocriptine, 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.14 However, 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.15

Previous studies14 have shown that modest doses of bromocriptine may be safely prescribed to patients taking older first-generation agents, and who have symptomatic hyperprolactinemia without exacerbating psychosis.

Only three case reports and one openlabel trial mentioned the use of sildenafil in antipsychotic-induced dysfunction.20-23 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.24,28

Selegiline is a selective monoamine oxidase-B inhibitor; in low doses it selectively inhibits the oxidation of dopamine and phenyl- ethylamine.29 Its metabolites, L-amphetamine and L-methamphetamine, have sexual arousal properties.25 But in the only double-blind placebo-controlled trial found in the literature, selegiline did not show any effectiveness in improving sexual functioning, despite a significant decrease in prolactin levels.30

A description of the main drugs, respective doses, potential drug interactions and side effects can be found in Table 2.13-20,23,24,27,30-38

DISCUSSION

Sexual performance among patients with schizophrenia may differ from the qualitative and quantitative patterns in the normal population. It may be altered through three main factors: by the disease itself as a consequence of affective and/or cognitive impairment; by antipsychotic drugs; and by other clinical problems (such as diabetes, hypertension, alcohol and drug abuse).39,40- 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 specific 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 first-generation antipsychotics.44 Erectile dysfunction in males45 and loss of libido in both sexes have been documented among patients who use first-generation antipsychotics,46 including haloperidol, as well as among those who use second-generation antipsychotics (clozapine47 and risperidone48). 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 first-generation antipsychotics is from 15% to 50%,49 and 19% for galactorrhea.50 First-generation antipsychotics seem to create an increase in dose-dependent prolactin secretion51,52 and this effect suggests that is derived primarily from the pituitary.53

According to evidence relating to the use of serotonergic antidepressants, their influence on sexual function appear to be associated with decreased libido, erectile dysfunction and orgasmic dysfunction.54 Thus, 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 findings suggest that the specificity of second-generation antipsychotics, while presenting less dopamine receptor blockade in the tubularinfundibular system, may also exert a minor impact on prolactin levels.55

There are data suggesting that the incidence of sexual dysfunction differs according to the antipsychotic used. Second-generation antipsychotics have not been extensively studied with regard to sexual dysfunction, but they certainly differ from first-generation antipsychotics56 and also differ from each other.57-61 Several studies have shown an incidence of sexual dysfunction of 25-60% among patients treated with first-generation antipsychotics45,62,63 or with risperidone.57-59,64 24% of the patients treated with clozapine and 45% of the patients treated with first-generation antipsychotics present with one or more sexual side effects, including erectile and ejaculatory dysfunction.65 Studies 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 it in 35.3% of patients. Quetiapine induced a lower rate of sexual dysfunction (18.2%), and risperidone the highest rate (43.2%).60 Thus, the findings in the literature indicate that all second-generation antipsychotics except for risperidone induce lower rates of sexual dysfunction.66 However, 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.

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

Dysfunction	Induced by	Number of patients and gender	Basic pathology	Therapy and dose	Study design	Results	
Erection, ejaculation, libido (the paper also refers to amenorrhea, galactorrhea, weight change)	Fluphenazine, flupenthixol, pipotiazine, levomepromazine, cyamemazine, sulpiride	20 female
10 male	Mainly schizophrenia and some other psychiatric disorders	Bromocriptine 5-10 mg/day	Open-label non-controlled drug study13	Decreased serum prolactin level, weight loss, Return of menstrual cycle in 55%, relief of galactorrhea in 33%, improvement of erectile and ejaculatory dysfunction was less pronounced	
Erectile (the paper also refers to amenorrhea, galactorrhea)	Probably only first-generation antipsychotics, on the basis of the date of the study	24 female
11 male	Schizophrenia and other psychiatric disorders	Bromocriptine 5-7.5 mg/day	Open-label non-controlled drug study14	Return of menstrual cycle in 70%, relief of galactorrhea in 80% and improvement of impotence in 66%	
Hypogonadism (the paper also refers to hyperprolactinemia)	Risperidone	4 female
1 male	Psychotic disorders	Cabergoline 0.5 mg twice a week or bromocriptine 7.5 mg/d to 25 mg/d	Case series15	In 3 out of 4 patients such additional therapy reduced the prolactin level and alleviated hypogonadism. None of the patients treated with these agents had worsening of psychosis	
Ejaculatory	Flupenthixol	1 male	Schizophrenia	Cyproheptadine 8 mg/day	Case report16	Returned to satisfactory ejaculation	
Orgasmic	Thioridazine	8 male	Schizophrenia	Imipramine 25-50 mg/day	Open-label non-controlled drug study17	50% returned to previous ejaculatory function	
Prolactin-mediated neuroendocrine side effects	Neuroleptic	4 female
6 male	Schizophrenia	Amantadine 200-300 mg/day	Open-label reversal drug study18	Significant reduction in all neuroendocrine side effects: serum prolactin levels, body weight, gynecomastia/galactorrhea, breast tenderness, decreased libido and amenorrhea	
Desire, erection, ejaculation, satisfaction with sexual performance	First-generation antipsychotics (haloperidol, thioridazine, fluphenazine, propericiazine	12 male	Schizophrenia	Amantadine 100 mg/day	Open-label non-controlled drug study19	Improvement in all events evaluated except ejaculation. Decreased serum prolactin	
Decreased libido and erection	Sulpiride
Risperidone	1 male	Schizophrenia	Sildenafil 50 mg/week 50 mg every 3 weeks	Case report20	Improvement in sexual performance	
Erectile	Haloperidol	1 male	Schizoaffective	Sildenafil 50 mg	Case report21	Obtained complete erection and satisfactory sexual intercourse	
Erectile	Olanzapine	10 male	Not mentioned	Sildenafil 50-100 mg	Open-label non-controlled drug study22	40% of the patients were considered to be "very much improved" and 30% "much improved". 80% were receiving 50 mg	
Erectile	Risperidone	12 male	Schizophrenia	Sildenafil starting dose 25 mg with the possibility of increasing the dose to 75 mg	Open-label non-controlled drug study23	67% of the patients exhibited partial or great improvement	
Hyperprolactinemia Sexual dysfunction	Neuroleptic — not mentioned which one	20 male	Schizophrenia	Shakuyaku-kanzo- to (TJ-68)
7.5 g (2.5 g three times daily, orally) for 4 weeks	Open-label non-controlled drug study24	In five patients, prolactin levels decreased by more than 50%. Three of the ten patients who had complained of reduced sexual desire, experienced subjective improvement	
Hyperprolactinemia Sexual dysfunction	Perphenazine or haloperidol	10 male	Schizophrenia	Selegiline 15 mg/day for 3 weeks	Randomized, double-blind, placebo-controlled crossover study25	Not effective in improving any domain of sexual functioning despite a significant decrease in prolactin levels	

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

Drug	Dose	Mechanism of action for sexual dysfunction	Side effects31	Potential psychiatric drug interactions31	
Bromocriptine	2.5 mg 2-3 x/d	Dopaminergic agonist13,14,32-35	Constipation (3-14%), nausea (50%), vomiting, dizziness (17%), fatigue (7%), headache (19%), hypotension, peripheral vasoconstriction, cerebral ischemia, seizures (rare), stroke (rare), confusion, dyskinesia, hallucinations, psychosis, pleuropulmonary changes (long-term use), postpartum myocardial infarction (rare)	May induce or exacerbate psychosis in psychiatric patients, but this occurs primarily in those with a psychotic diathesis and who are not currently receiving neuroleptic medication. Factors to be considered: dose of bromocriptine, duration of treatment, and the clinical state of the patient	
Cabergoline	0.5 mg twice a week	Dopaminergic agonist15,36	Dizziness, fatigue, headache, constipation, nausea, somnolence, depression, orthostatic hypotension (1-10%), pleural effusion (rare), pulmonary fibrosis (rare), abdominal pain (4-5%), vertigo (4-5%)	May decrease therapeutic effect of antipsychotics	
Cyproheptadine	4 mg 4 x/d	Serotonergic antagonist (5-HT2)16	Central nervous system depression, dry mouth, drowsiness, increased appetite, weight gain, nausea, vomiting, diarrhea, abdominal discomfort, thickening of bronchial secretions, hepatitis	Decreased fluoxetine efficacy, prolonged and intensified anticholinergic effects when used with MAOI, reduced paroxetine efficacy	
Amantadine	100-300 mg/d	Increases dopamine release and reduces dopamine and noradrenaline reuptake into synaptic terminals18,19,27	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)	2.5 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 both24,28	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 disorders37	No psychiatric drug interactions known Thiazide diuretics: increased potassium loss; digitalis: more sensitivity to digitalis due to hypokalemia	
Sildenafil	50 mg/week	Phosphodiesterase inhibitor20-23	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)	No psychiatric drug interactions known Nitrates: severe hypotensive effect; clarithromycin, erythromycin: increased risk of sildenafil effects	
Imipramine	25-50 mg/d	Unknown17	Blurred vision, drowsiness, dizziness, weakness, fatigue, headache, dry mouth, constipation, bloating, urinary retention, weight gain, agranulocytosis (rare), arrhythmia, atrioventricular conduction changes, heart block, palpitations, jaundice and hepatic dysfunction (rare), orthostatic hypotension, syncope, hypertension, psychotic reactions (rare), seizures (rare)	Antipsychotic: increased risk of cardiotoxicity; barbiturates: possible decreased TCA serum concentrations and possible additive adverse effects; carbamazepine: decreased imipramine effectiveness; citalopram: increased in the bio-availability and half-life of desipramine; fenfluramine: increased risk of imipramine (sedation); phenothiazine: increased levels and toxicity with either agent; fluvoxamine: increased imipramine levels and signs of toxicity; MAOI: neurotoxicity, seizures or serotonin syndrome; paroxetine: imipramine toxicity; phenytoin: increased risk of phenytoin toxicity; sertraline: modest elevations in imipramine serum levels; St John's wort: increased risk of serotonin syndrome; tobacco: decreased imipramine concentrations; ziprasidone: increased risk of cardiotoxicity; zolmitriptan: increased risk of cardiotoxicity	
Selegiline	15 mg/d	Selective monoamine oxidase B inhibitor30	Abdominal pain, nausea, dizziness, lightheadedness, confusion, hallucinations	TCA: neurotoxicity, seizures, or serotonin syndrome; bupropion: increased bupropion toxicity; carbamazepine: hypertensive urgency, hyperpyrexia, and seizures; citalopram: central nervous system (CNS) toxicity or serotonin syndrome; buspirone, phenelzine, phentermine, amphetamine, and amphetamine-like: hypertensive crisis; antipsychotic: increased risk of cardiotoxicity; fluoxetine, fluvoxamine, sibutramine, sertraline, and paroxetine: CNS toxicity or serotonin syndrome; reboxetine and nefazodone: hyperthermia, rigidity, myoclonus, seizures, fluctuations of vital signs, or mental status changes; phenobarbital: CNS sedation; St John's wort: increased risk of serotonin syndrome and/or increased risk of hypertensive crisis; triptans: serotonin syndrome; tramadol: nausea, vomiting, cardiovascular collapse, respiratory depression, seizures	
MAOI = monoaminooxidase inhibitor; TCA = tryciclic antidepressant.

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

CONCLUSION AND RECOMMENDATIONS

Kaplan67 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 thoroughly 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 efficacy of the interventions available for treating antipsychotic-induced sexual dysfunction. In order to avoid iatrogenic sexual dysfunction in schizophrenia, patients should first be given the option of an appropriate drug, as discussed above. The patients who present higher risk of sexual disorders are those receiving first-generation antipsychotics and, more specifically, those taking high doses of these drugs (dose-dependent effect).68 In cases where a drug-induced sexual dysfunction is present, it is advisable to reduce first-generation antipsychotics to lower doses that are still effective, maintaining the clinical status. Moreover, if the patient can be 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 first-generation antipsychotic, or switching from a first-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.69 Acetylcholine 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.70

Although the more favorable benefit-versus-risk ratio of the new antipsychotics represents a major improvement over the older neuroleptics, differences need to be addressed 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 efficacy 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 findings in the literature indicate that antipsychotics may have different profiles of adverse sexual effects, but the results are inconclusive since most of the 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 efficacious and safe solutions.

Anna Maria Niccolai Costa, MD, PhD. Postgraduate from Department of Psychiatry of Universidade Federal de São Paulo; and currently medical director at Bristol-Myers Squibb Brazil, São Paulo, Brazil.

Mauricio Silva de Lima, MD, PhD. Associate professor, Department of Mental Health, Universidade Federal de Pelotas; associate professor, postgraduate course in Health and Behavior, Universidade Católica de Pelotas; investigator II-A of Brazilian Research Council (CNPq); and Medical Director at Eli Lilly Brazil, São Paulo, Brazil.

Jair de Jesus Mari, MD, PhD. Full professor, Department of Psychiatry, Universidade Federal de São Paulo; and investigator I-A, Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), São Paulo, Brazil.

Universidade Federal de São Paulo, São Paulo, Brazil

Sources of funding: None
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REFERENCES

1 Duggan L Fenton M Dardennes RM El-Dosoky A Indran S Olanzapine for schizophrenia Cochrane Database Syst Rev 2003 1 CD001359 CD001359 12535408
2 Waraich PS Adams CE Roque M Hamill KM Marti J Haloperidol dose for the acute phase of schizophrenia Cochrane Database Syst Rev 2002 3 CD001951 CD001951 12137638
3 Mota NE Lima MS Soares BG Amisulpride for schizophrenia Cochrane Database Syst Rev 2002 2 CD001357 CD001357 12076408
4 Fenton M Coutinho ES Campbell C Zuclopenthixol acetate in the treatment of acute schizophrenia and similar serious mental illnesses Cochrane Database Syst Rev 2001 3 CD000525 CD000525 11686965
5 Bagnall A Lewis RA Leitner ML Ziprasidone for schizophrenia and severe mental illness Cochrane Database Syst Rev 2000 4 CD001945 CD001945
6 Gilbody SM Bagnall AM Duggan L Tuunainen A Risperidone versus other atypical antipsychotic medication for schizophrenia Cochrane Database Syst Rev 2000 3 CD002306 CD002306 10908551
7 Srisurapanont M Disayavanish C Taimkaew K Quetiapine for schizophrenia Cochrane Database Syst Rev 2000 3 CD000967 CD000967
8 Teusch L Scherbaum N Bohme H Bender S Eschmann-Mehl G Gastpar M Different patterns of sexual dysfunctions associated with psychiatric disorders and psychopharmacological treatment. Results of an investigation by semistructured interview of schizophrenic and neurotic patients and methadone-substituted opiate addicts Pharmacopsychiatry 1995 28 3 84 92 7568370
9 Hansen TE Casey DE Hoffman WF Neuroleptic intolerance Schizophr Bull 1997 23 4 567 582 9365996
10 Finn SE Bailey JM Schultz RT Faber R Subjective utility ratings of neuroleptics in treating schizophrenia Psychol Med 1990 20 4 843 848 1980954
11 Macdonald S Halliday J MacEWAN T Nithsdale Schizophrenia Surveys 24: sexual dysfunction. Case-control study Br J Psychiatry 2003 182 50 56 12509318
12 Lingjaerde O Ahlfors UG Bech P Dencker SJ Elgen K The UKU side effect rating scale. A new comprehensive rating scale for psychotropic drugs and a cross-sectional study of side effects in neuroleptic-treated patients Acta Psychiatr Scand Suppl 1987 334 1 100 2887090
13 Beau Y Guillard P Essai de traitement par la bromocriptine des effets secondaires endocriniens des traitements psychotropes. [Trial therapy with bromocriptine of secondary endocrine effects after psychotropic treatment] Ann Med Psychol (Paris) 1980 138 2 179 186 6104463
14 Matsuoka I Nakai T Miyake M Hirai M Ikawa G Effects of bromocriptine on neuroleptic-induced amenorrhea, galactorrhea and impotence Jpn J Psychiatry Neurol 1986 40 4 639 646 2885437
15 Tollin SR Use of the dopamine agonists bromocriptine and cabergoline in the management of risperidone-induced hyperprolactinemia in patients with psychotic disorders J Endocrinol Invest 2000 23 11 765 770 11194712
16 Jeffries JJ Walker C Cyproheptadine and drug-induced anorgasmia Can J Psychiatry 1987 32 1 79 79
17 Aizenberg D Shiloh R Zemishlany Z Weizman A Low-dose imipramine for thioridazine-induced male orgasmic disorder J Sex Marital Ther 1996 22 3 225 229 8880656
18 Correa N Opler LA Kay SR Birmaher B Amantadine in the treatment of neuroendocrine side effects of neuroleptics J Clin Psychopharmacol 1987 7 2 91 95 2884239
19 Valevski A Modai I Zbarski E Zemishlany Z Weizman A Effect of amantadine on sexual dysfunction in neuroleptic- treated male schizophrenic patients Clin Neuropharmacol 1998 21 6 355 357 9844793
20 Benatov R Reznik I Zemishlany Z Sildenafil citrate (Viagra) treatment of sexual dysfunction in a schizophrenic patient Eur Psychiatry 1999 14 6 353 355 10572370
21 Lare SB Labbate LA Sildenafil and erectile dysfunction Am J Psychiatry 2000 157 12 2055 2056
22 Atmaca M Kuloglu M Tezcan E Sildenafil use in patients with olanzapine-induced erectile dysfunction Int J Impot Res 2002 14 6 547 549 12494295
23 Aviv A Shelef A Weizman A An open-label trial of sildenafil addition in risperidone-treated male schizophrenia patients with erectile dysfunction J Clin Psychiatry 2004 65 1 97 103 14744177
24 Yamada K Kanba S Yagi G Asai M Effectiveness of herbal medicine (shakuyaku-kanzo-to) for neuroleptic-induced hyperprolactinemia J Clin Psychopharmacol 1997 17 3 234 235 9169978
25 Angrist B Gershon S Clinical effects of amphetamine and L-DOPA on sexuality and aggression Compr Psychiatry 1976 17 6 715 722 991603
26 Aizenberg D Zemishlany Z Weizman A Cyproheptadine treatment of sexual dysfunction induced by serotonin reuptake inhibitors Clin Neuropharmacol 1995 18 4 320 324 8665544
27 Siever LJ The effect of amantadine on prolactin levels and galactorrhea on neuroleptic-treated patients J Clin Psychopharmacol 1981 1 1 2 7 6117579
28 Yamada K Kanba S Yagi G Asai M Herbal medicine (Shakuyaku-kanzo-to) in the treatment of risperidone-induced amenorrhea J Clin Psychopharmacol 1999 19 4 380 381 10440470
29 Berry MD Juorio AV Paterson IA Possible mechanisms of action of (-)deprenyl and other MAO-B inhibitors in some neurologic and psychiatric disorders Prog Neurobiol 1994 44 2 141 161 7831475
30 Kodesh A Weizman A Aizenberg D Hermesh H Gelkopf M Zemishlany Z Selegiline in the treatment of sexual dysfunction in schizophrenic patients maintained on neuroleptics: a pilot study Clin Neuropharmacol 2003 26 4 193 195 12897639
31 Micromedex® Healthcare Series Thomson Micromedex Available from URL: http://www.micromedex.com/products/hcs/ Accessed in 2006 (Aug 23)
32 Beumont P Bruwer J Pimstone B Vinik A Utian W Bromergocryptine in the treatment of phenothiazine-induced galactorrhea Br J Psychiatry 1975 126 285 288 236061
33 Varia IM Cavenar JO Jr Taska RJ Maltbie AA Bromocriptine in the treatment of haloperidol-induced galactorrhea N C Med J 1982 43 11 769 770 6960257
34 Smith S Neuroleptic-associated hyperprolactinemia Can it be treated with bromocriptine? J Reprod Med 1992 37 8 737 740 1359137
35 Popli A Gupta S Rangwani SR Risperidone-induced galactorrhea associated with a prolactin elevation Ann Clin Psychiatry 1998 10 1 31 33 9622047
36 Cohen LG Biederman J Treatment of risperidone-induced hyperprolactinemia with a dopamine agonist in children J Child Adolesc Psychopharmacol 2001 11 4 435 440 11838826
37 Blumenthal M Busse WR Goldberg A The Complete Commission E Monographs: Therapeutic Guide to Herbal Medicines Boston Integrative Medicine Communications 1998
38 Armanini D Bonanni G Palermo M Reduction of serum testosterone in men by licorice N Engl J Med 1999 341 15 1158 1158 10515764
39 Negrete JC Clinical aspects of substance abuse in persons with schizophrenia Can J Psychiatry 2003 48 1 14 21 12635559
40 Marinow A Diabetes in chronic schizophrenia Dis Nerv Syst 1971 32 11 777 778 5131772
41 McKee HA D'Arcy PF Wilson PJ Diabetes and schizophrenia- -a preliminary study J Clin Hosp Pharm 1986 11 4 297 299 2876011
42 Tsuang MT Perkins K Simpson JC Physical diseases in schizophrenia and affective disorder J Clin Psychiatry 1983 44 2 42 46 6826529
43 Davidson M Risk of cardiovascular disease and sudden death in schizophrenia J Clin Psychiatry 2002 63 Suppl 9 5 11
44 Blair JH Simpson GM Effect of antipsychotic drugs on reproductive functions Dis Nerv Syst 1966 27 10 645 647 4380665
45 Kotin J Wilbert DE Verburg D Soldinger SM Thioridazine and sexual dysfunction Am J Psychiatry 1976 133 1 82 85 1247127
46 Laughren TP Brown WA Petrucci JA Effects of thioridazine on serum testosterone Am J Psychiatry 1978 135 8 982 984 665850
47 Schnieden H Effect of psychoactive drugs on the motility of human spermatozoa ICRS J Int Res Commun 1974 2 5 1322 1322 4154222
48 Kleinberg DL Davis JM de Coster R Van Baelen B Brecher M Prolactin levels and adverse events in patients treated with risperidone J Clin Psychopharmacol 1999 19 1 57 61 9934944
49 Ghadirian AM Chouinard G Annable L Sexual dysfunction and plasma prolactin levels in neuroleptic-treated schizophrenic outpatients J Nerv Ment Dis 1982 170 8 463 467 6124580
50 Windgassen K Wesselmann U Schulze Monking H Galactorrhea and hyperprolactinemia in schizophrenic patients on neuroleptics: frequency and etiology Neuropsychobiology 1996 33 3 142 146 8776743
51 Gruen PH Sachar EJ Langer G Prolactin responses to neuroleptics in normal and schizophrenic subjects Arch Gen Psychiatry 1978 35 1 108 116 23087
52 Langer G Sachar EJ Gruen PH Halpern FS Human prolactin responses to neuroleptic drugs correlate with antischizophrenic potency Nature 1977 266 5603 639 640 193037
53 Rubin RT Prolactin and schizophrenia Meltzer HY Coyle JT Kopin IJ Psychopharmacology: the third generation of progress New York Raven Press 1987 803 806
54 Harrison WM Rabkin JG Ehrhardt AA Effects of antidepressant medication on sexual function: a controlled study J Clin Psychopharmacol 1986 6 3 144 149 3711364
55 Kinon BJ Lieberman JA Mechanisms of action of atypical antipsychotic drugs: a critical analysis Psychopharmacology (Berl) 1996 124 1-2 2 34 8935797
56 Aizenberg D Modai I Landa A Gil-Ad I Weizman A Comparison of sexual dysfunction in male schizophrenic patients maintained on treatment with classical antipsychotics versus clozapine J Clin Psychiatry 2001 62 7 541 544 11488365
57 Knegtering H Blijd C Boks M Sexual dysfunction and prolactin levels in patients using classical antipsychotics, risperidone or olanzapine Schizophr Res 1999 36 1-3 355 356 [abstract]
58 David S Crawford AM Breier A Prolactin levels in olanzapine versus typical and atypical antipsychotics Schizophr Res 1998 29 1-2 153 153 [abstract]
59 Montejo AL Llorca G Izquierdo JA Switching to olanzapine in patients with antipsychotic-induced sexual dysfunction: a prospective and naturalistic study Program and abstracts from the 153rd annual meeting of the American Psychiatric Association 2000 May 13-18 Chicago 2000
60 Bobes J Garc A-Portilla MP Rejas J Frequency of sexual dysfunction and other reproductive side-effects in patients with schizophrenia treated with risperidone, olanzapine, quetiapine, or haloperidol: the results of the EIRE study J Sex Marital Ther 2003 29 2 125 147 12623765
61 Knegtering R Castelein S Bous H A randomized open-label study of the impact of quetiapine versus risperidone on sexual functioning J Clin Psychopharmacol 2004 24 1 56 61 14709948
62 Sandison RA Whitelaw E Currie JD Clinical trials with melleril (TP21) in the treatment of schizophrenia. A two-year study J Ment Sci 1960 106 732 741 14441416
63 Sullivan G Lukoff D Sexual side effects of antipsychotic medication: evaluation and interventions Hosp Community Psychiatry 1990 41 11 1238 1241 1979045
64 Shiwach RS Carmody TJ Prolactogenic effects of risperidone in male patients--a preliminary study Acta Psychiatr Scand 1998 98 1 81 83 9696519
65 Peacock L Solgaard T Lublin H Gerlach J Clozapine versus typical antipsychotics. A retro- and prospective study of extrapyramidal side effects Psychopharmacology (Berl) 1996 124 1-2 188 196 8935815
66 Knegtering H van der Moolen AE Castelein S Kluiter H van den Bosch RJ What are the effects of antipsychotics on sexual dysfunctions and endocrine functioning? Psychoneuroendocrinology 2003 28 Suppl 2 109 123 12650685
67 Kaplan HS The new sex therapy New York Routledge 1974
68 Kane JM Antipsychotic drug side effects: their relationship to dose J Clin Psychiatry 1985 46 5 Pt 2 16 21
69 Gross MD Reversal by bethanechol of sexual dysfunction caused by anticholinergic antidepressants Am J Psychiatry 1982 139 9 1193 1194 7114318
70 Segraves T Effects of psychotropic drugs on human erection and ejaculation Arch Gen Psychiatry 1989 46 3 275 284 2645849
