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Psychoneuroendocrinology (2008) 33, 711–717

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Are sexual side effects of prolactin-raisingantipsychotics reducible to serum prolactin?

Henderikus Knegteringa,d,�, Rob van den Boscha, Stynke Casteleina,Richard Bruggemana, Sjoerd Sytemaa,d, Jim van Osb,c

aDepartment of Psychiatry, University Medical Center Groningen, University of Groningen,Hanzeplein 1, PO Box 30.001, 9700 RB Groningen, The NetherlandsbDepartment of Psychiatry and Neuropsychology, South Limburg Mental Health Research and Teaching Network,EURON, Maastricht University, PO Box 616 (KAP2), 6200 MD Maastricht, The NetherlandscDivision of Psychological Medicine, Institute of Psychiatry, De Crespigny Park, London SE5 8AF, UKdRob Giel Research Center, University of Groningen, PO Box 30.001 Groningen, The Netherlands

Received 23 March 2007; received in revised form 17 February 2008; accepted 20 February 2008

KEYWORDSSexual side effects;Antipsychotics;Prolactin;Dopamine

nt matter & 2008uen.2008.02.008

thor. Tel.: +31 50

.Knegtering@psy.

SummaryObjective: To assess the degree to which sexual side effects (SSE) are associated withprolactin-raising antipsychotics, and to what degree such SSE are reducible to serumprolactin levels.Method: A large sample (n ¼ 264) of patients treated for 6 weeks with prolactin-raisingand prolactin-sparing antipsychotics was assessed for changes in sexual performance interms of libido, arousal and orgasm using the Antipsychotics and Sexual FunctioningQuestionnaire. For men also erection and ejaculation were evaluated. At 6 weeks,prolactin levels were assessed and analyzed in relation to sexual performance.Results: Men and women reported SSE (libido and orgasm) with about the same frequency.Prolactin-raising medication induced significantly more SSE than prolactin-sparing medi-cation (adjusted OR ¼ 3.4, 95% CI: 1.8, 6.5) with 43% of emerging SSE attributable toprolactin-raising medication. When adjusted for serum prolactin, the association betweenprolactin-raising medication and SSE was reduced but remained significant (OR ¼ 2.1, 95%CI: 1.0, 4.5); 27% of emerging SSE remained attributable to prolactin-raising medication. Forerectile and ejaculatory dysfunction in men, the attributable fraction due to prolactin-raising medication was 32% before, and 11% after adjustment for serum prolactin.Conclusions: Around 40% of emerging SSE in schizophrenia are attributable to theprolactin-raising properties of antipsychotic medication. Of this attributable fraction,around one-third to two-thirds is directly reducible to the effects of serum prolactin.& 2008 Elsevier Ltd. All rights reserved.

Elsevier Ltd. All rights reserved.

3616161; fax: +31 50 3619722.

umcg.nl (H. Knegtering).

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H. Knegtering et al.712

1. Introduction received laboratory examination as part of the normal

Although it has been suggested that prolactin elevationplays an important role in the occurrence of antipsychotic-induced sexual side effects (SSE) such as diminished libido,diminished arousal (lubrication or erection) and disturbanceof orgasm, the evidence is not conclusive (Wieck andHaddad, 2002; Eberhard et al., 2007). Supportive evidencecomes from the observation that SSE are less common inprolactin-sparing antipsychotics, such as clozapine, olanza-pine and quetiapine, as compared to prolactin-raisingantipsychotics such as first-generation antipsychotics andrisperidone (Knegtering and Bruggeman, 2007; Knegteringet al., 2004, 2006).

Although several studies have suggested an associationbetween (sexual) side effects and prolactin elevation (Burkeet al., 1994; Halbreich et al., 2003), others have failed tosupport this (Kleinberg et al., 1999; Hamner, 2002; Spollenet al., 2004). Several issues may play a role in explainingconflicting results. First, the main mechanism of theantipsychotic activity is thought to be through dopamineblockade in dopaminergic meso-limbic circuits in the brain,and these are also likely involved in salience and motivation,including sexual motivation (sexual drive or libido) andreward (orgasm) (Giuliano and Allard, 2001). Second, someresearchers suggest that it is not prolactin elevation but thesecondary effects of prolactin elevation, i.e., reduction ofplasma levels of testosterone, estrogen, luteinizing hormone(LH), or follicle-stimulating hormone (FSH), that could beheld responsible for SSE (Rinieris et al., 1989; Smith et al.,2002a, b). Third, noradrenergic and histaminergic effectsassociated with antipsychotic drugs are also suggested tochange aspects of sexual performance (Meston and Frohlich,2000). Fourth, the influence of the primary disease,treatment duration, age (age-related decreases in libidoand some sex hormones such as testosterone) and gender(men have lower prolactin levels than women) make it evenmore difficult to interpret the data (Smith et al., 2002a, b).Finally, many studies on sexual dysfunction used sponta-neously reported SSE or general side effect evaluation scalesand poorly validated questionnaires to evaluate SSE ofantipsychotics. These factors are likely to lead to a majorunderestimation of the frequency of SSE (Peuskens et al.,1998).

In studies with small groups of patients or withoutstructured assessment of SSE, it is impossible to unravelmany of the possible different contributing factors. In thecurrent study, data quantifying the influence of prolactin onsexual dysfunction in male and female patients arepresented using indirect (prolactin-sparing or prolactin-raising antipsychotic) and direct measures of prolactin(plasma prolactin levels).

2. Method

Between 1997 and 2002, all in- and outpatient patientstreated with antipsychotics at the University MedicalHospital of Groningen, the Netherlands, for a period of 6weeks and aged between 17 and 55 years, were asked aboutchanges in sexual function after 6 weeks use of antipsycho-tics. All patients were routinely physically examined and

clinical routines. Patients with diseases known to influencesexual performance or treated with medication known toinfluence sexual performance, other than the antipsychoticsstudied, could not enter the study.

Some patients received the medication during normalclinical practice (N ¼ 167), while in others the treatmentwas in the context of a randomized clinical trial (risperidoneversus olanzapine) (N ¼ 46) and risperidone versus quetia-pine (N ¼ 51) (Knegtering et al., 2004, 2006). All patientswere treated at the same clinic and rated by the sameresearch physicians not involved in the treatment of thepatient; given the fact that at inclusion the different patientgroups were comparable with regard to serum prolactin andSSE, both groups were joined together for the purpose of thepresent analyses.

2.1. Assessments

Depending on the origin of the data, symptom severity wasevaluated with the Positive and Negative Syndrome Scale(PANSS) and with the Clinical Global Impression (CGI) scoringbetween 1 (no psychiatric symptoms) and 5 (severe psychia-tric symptoms) (Kay et al., 1987). In patients receiving themedication during normal clinical practice, only CGI scoresbefore treatment and after 6 weeks treatment wereavailable. In all patients clinicians rated the mean GlobalClinical Change (GCC) (range 1 ¼ much worse, 2 ¼ worse,3 ¼ unchanged, 4 ¼ improved, 5 ¼ much improved).

Six weeks after initiating treatment with an antipsycho-tic, variables reflecting sexual function in men and womenwere assessed using the Antipsychotics and Sexual Function-ing Questionnaire (ASFQ), a semi-structured interview basedupon the Udvag for Kliniske Undersøgelser (UKU) (Lingjaerdeet al., 1987). The ASFQ is a reliable and validatedquestionnaire sensible for changes in antipsychotic medica-tion in patients with schizophrenia (Knegtering and Caste-lein, 2003). The inter rater reliability of the ASFQ is 0.82(publication in preparation) and the test–retest reliabilityj ¼ 0.633, p ¼ 0.009 (Knegtering and Castelein, 2003). TheASFQ was administered only once, at 6 weeks, and ratedretrospectively to specifically assess change from baseline.Scoring rules of the ASFQ have been designed specifically toexclude sexual dysfunctions already existing before treat-ment with antipsychotics or likely to be related to causesother than the antipsychotic medications studied (psychia-tric symptoms, medical conditions). The ASFQ includesitems assessing libido reduction and orgasmic dysfunctionin both sexes, erection and ejaculation dysfunction in menand disturbances. Items rating lubrication in women weredeveloped during the first part of the studies and thereforecould not be reliably assessed in all women. Frequently,patients could or would provide only partial answers to thequestions of the ASFQ, depending on the level of sexualexperience, cultural background or psychiatric symptoma-tology. In this report, only changes in sexual functionrelative to baseline and assessed as likely related to themedication were analyzed. The raters were six trainedphysicians who had knowledge about the medication usedbut remained blind for the study hypothesis and prolactinlevels.

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Sexual side effects of antipsychotics and prolactin 713

For the purpose of the present study, libido and orgasmicfunction were assessed in all subjects, these being the mostfrequent SSE affecting both sexes. In addition, data onerectile and ejaculatory dysfunction were available formen. As the number of women included in the studies waslow and for a limited number of women data on lubricationcould be reliable assessed, analysis of data on vaginallubrication was not carried out.

Medication compliance was assessed using interviews andplasma sampling: prolactin and antipsychotic serum levelswere measured at week 6, in the morning, but not atbaseline, as carry-over effects of previously used antipsy-chotics may obscure the interpretation of these data. Byexcluding patients treated with long-acting (depot) anti-psychotics, the influence of carry-over effects from previousantipsychotics at week 6 was minimized. Prolactin levelswere determined by electrochemiluminescence immunoas-say (ECLIA) on the Roche Modular analytics E170 (Elecsysmodule) immunoassay analyzers. When prolactin levelsexceeded 800mU/L, the possible contribution of macro-prolactin was determined through preceding polyethyleneglycol (PEG) precipitation and a two-step chemiluminescentmicroparticle immunoassay (CMIA) technology based assayon the Architect System of Abbott Diagnostics.

Procedures were approved by the standing ethics com-mittee and patients provided oral and written informedconsent.

2.2. Analyses

All standard errors and test statistics were estimated usingthe software package STATA, version 9.1 (StataCorp, 2005).Type of antipsychotic medication was grouped into twocategories: prolactin-raising antipsychotics (consisting ofthe following antipsychotics: risperidone, bromperidol,haloperidol, perphenazine, penfluridol, pimozide, sulpiride,zuclopentixol) and prolactin-sparing antipsychotics (consist-ing of the following antipsychotics: clozapine, olanzapine,quetiapine, sertindole). In order to facilitate interpretationof effect sizes and inspection of dose–response in thedescriptive data, the distribution of the plasma prolactinlevels was divided by its quintiles, creating five quintilegroups. This five-level variable was used in the analyses.Effects of type of antipsychotic medication and serumprolactin were examined in a logistic regression model of adichotomous variable indicating the existence of either lackof libido or orgasmic dysfunction (value ‘‘1’’) or absence ofboth lack of libido and orgasmic dysfunction (value ‘‘0’’)(hereafter: LIBORG). In addition, in men an additionalanalysis was conducted with the dependent variable:erectile or orgasmic dysfunction (value ‘‘1’’) or neithererectile nor orgasmic dysfunction (value ‘‘0’’) (hereafter:EDOD). Effect sizes were expressed as odds ratios from thelogistic regression for dichotomous dependent variables, oras the regression coefficient B from multiple regressionmodels for continuous dependent variables. All analyses,unless specifically mentioned to the contrary, were a prioriadjusted for age and sex. Interactions with sex were fittedand evaluated by Wald test.

The population attributable fraction (PAF) was derivedfrom the associations between types of antipsychotic and

follow-up LIBORG and EDOD (adjusted for age) in the logisticregression models using the AFLOGIT procedure in STATA.This parameter gives a measure of the proportion of SSEcases that could have been prevented, assuming causality,had the exposure of prolactin-raising antipsychotic medica-tion been eliminated completely from the populationexamined. In other words, if the PAF of sexual dysfunctionassociated with prolactin-raising medication were 25.0%,this would mean that 25.0% of sexual dysfunction could beprevented if prolactin-raising medication were not pre-scribed anymore. If we find that the PAF associated withprolactin-raising medication is reduced from 25.0% to 12.5%after adjustment for serum prolactin in the model of sexualdysfunction, it can be concluded that half of the PAFassociated with prolactin-raising medication can be ex-plained by the effect of plasma prolactin. In other words: ifprolactin-raising medication had been prescribed but itseffects on plasma prolactin had been neutralized, half ofthe 25% of preventable cases of sexual dysfunction wouldnot have occurred.

3. Results

3.1. Sample

Of the 264 patients included, the mean age in the group ofmale patients (n ¼ 186) was 28 years (range 17–54), and 26years (range 17–49) in the female group (n ¼ 88). Meanduration of illness was 2.7 years (range 3 months till 10years). At inclusion, 178 patients did not use an antipsycho-tic. All patients had a DSM-IV diagnosis in the schizophreniaspectrum (see Table 1) without large or statisticallysignificant differences in frequency of diagnostic subtypes,age, between men or women, or between types ofantipsychotic used. Forty-five patients were treated withconventional antipsychotics and 215 patients with otherantipsychotics. Mean dosage (mg/day) of antipsychoticswere: clozapine 351 (S.D. ¼ 113; n ¼ 19), olanzapine 11(S.D. ¼ 4; n ¼ 49), quetiapine 565 (S.D. ¼ 208; n ¼ 34),risperidone 3.8 (S.D. ¼ 2; n ¼ 114), sertindole 17 (S.D. ¼ 2;n ¼ 3), bromperidol 9 (n ¼ 1), haloperidol 4 (S.D. ¼ 3;n ¼ 4), perphenazine 12 (S.D. ¼ 3; n ¼ 3), penfluridol 4(n ¼ 1), pimozide 7 (S.D. ¼ 5; n ¼ 19), sulpiride 300(S.D. ¼ 50; n ¼ 3) zuclopentixol 55 (S.D. ¼ 90; n ¼ 13).

Patients treated with olanzapine, quetiapine or risper-idone, included in the randomized clinical trials had a meantotal PANSS score of 65.3 (S.D. ¼ 21.1) at inclusion and posttreatment 59.8 (S.D. ¼ 12.3). This corresponded with themean Clinical Global Impression (CGI) evaluated in allpatients at inclusion of 4.2 (S.D. ¼ 0.72) (moderately ill)and after 6 weeks of treatment 3.2 (S.D. ¼ 0.61) (moder-ately to mildly ill). Clinicians rated the mean Global ClinicalChange 4.17 (S.D. ¼ 0.83) (improved). There were nosignificant differences in improvement between patientgroups treated with different antipsychotics as evaluatedwith the PANSS or Global Clinical Change.

Main demographical and diagnostical data are summar-ized in Table 1. Main findings on antipsychotics and SSE aresummarized in Table 2. Main findings on antipsychotics andprolactin elevation are summarized in Table 3. Details on theincluded studies can be found in Knegtering (2003).

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Table 1 Demographical and diagnostic data summarized per treatment-group and gender.

All antipsychotics Clozapine Olanzapine Quetiapine Risperidone Classical

Women Men Women Men Women Men Women Men Women Men Women Men

No. of patients 88 186 6 13 14 35 12 22 39 75 15 30Mean age(7S.D.)

28(78)

26(76)

28(711)

23(74)

29(710)

26(75)

24(75)

27(75)

29(79)

25(76)

29(78)

28(78)

Diagnosis n (%)Brief psychosis 7 (8) 12 (6) 2 (14) 4 (11) 2 (16) 3 (14) 2 (5) 3 (4) 1 (7) 2 (7)Schizophreniform 9 (10) 24 (13) 1 (7) 4 (11) 2 (9) 6 (15) 12 (16) 2 (13) 6 (20)Schizophrenia 46 (52) 126 (68) 5 (83) 12 (92) 7 (50) 22 (63) 8 (66) 15 (68) 16 (41) 49 (65) 8 (53) 16 (53)Schizoaffective 5 (6) 3 (2) 1 (8) 1 (3) 1 (8) 1 (5) 4 (10) 1 (3)Delusional dis. 2 (1) 1 (5) 1 (1)Other psychosis 21 (24) 19 (10) 1 (17) 4 (28) 4 (11) 1 (8) 11 (30) 10 (13) 4 (26) 5 (17)

No statistical significant differences were found between treatment-groups in gender ratios, age or diagnoses.

Table 2 No. of patients reporting sexual dysfunctions in patients treated with antipsychotics for 6 weeks.

Men and women Men

Libido, n/n total (%) Orgasm, n/n total (%) Erection, n/n total (%) Ejaculation, n/n total (%)

Risperidone 52/105 (49.5%) 41/89 (46.1%) 28/78 (39.4%) 27/67 (40.3%)Classical 15/42 (35.7%) 6/37 (16.2%) 8/29 (27.6%) 5/25 (20.0%)Clozapine 3/19 (15.8%) 1/14 (7.1%) 1/11 (8.3%) 2/11 (18.2%)Olanzapine 7/43 (16.3%) 1/39 (2.6%) 6/30 (20.0%) 2/27 (7.4%)Quetiapine 4/29 (13.8%) 1/25 (4.0%) 2/19 (10.5%) 2/16 (12.5%)

Number of patients experiencing sexual dysfunction (n) versus number able to respond on the specific item (n total), and thecorresponding percentage of patients with a sexual dysfunction attributed to antipsychotic medication (%).

Table 3 Mean serum prolactin levels in men and womenafter 6 week treatment with antipsychotics.

Mean dose inmg/day (7S.D.)

Mean serumprolactin levelsin ME/L�

(7S.D.)

Risperidone 3.8 (71.81) 1101 (7770)Classical 6.05 (75.23)y 738 (7703)Clozapine 351.3 (7112.57) 223 (7127)Olanzapine 10.7 (74.05) 401 (7368)Quetiapine 565.7 (7208.56) 236 (7231)

�Some laboratories use ng/mL to express serum prolactinlevels; 1 ng/mLE20ME/L.yFor classical antipsychotics dosage is reported in haloper-

idol equivalents.

H. Knegtering et al.714

3.2. Prolactin-raising medication and serumprolactin

Of the 264 individuals included, 204 had valid data onLIBORG, serum prolactin and type of antipsychotic medica-tion. All analyses below refer to this risk set of 204. Of the

204, 133 (65%) were men, and 129 (63%) were usingprolactin-raising medication. Exposure to prolactin-raisingmedication was strongly associated with serum prolactin(Table 4; unadjusted OR per serum prolactin quintile group:2.7, 95% CI: 2.0, 3.6), but not with sex (unadjustedOR ¼ 0.8, 95% CI: 0.4, 1.4) or age (unadjusted OR peryear ¼ 1.00, 95% CI: 0.96, 1.05). Serum prolactin was notassociated with age (unadjusted B ¼ 0.05, 95% CI �0.6, 0.7)whereas women displayed higher levels (unadjustedOR ¼ 1.5, 95% CI: 1.2, 1.9).

3.3. Determinants of LIBORG

Of the 204 individuals, LIBORG were emergent in 81 (40%).Emergence of LIBORG was associated with neither sex(unadjusted OR ¼ 1.0, 95% CI: 0.5, 1.8) nor age (unadjustedOR per year ¼ 0.98, 95% CI: 0.94, 1.03). Emergence ofLIBORG was strongly associated with prolactin-raisingmedications (OR ¼ 3.4, 95% CI: 1.8, 6.5) and with serumprolactin (OR per serum prolactin quintile group ¼ 1.6, 95%CI: 1.3, 2.0), and these effects were not moderated by sex(prolactin-raising medications: p ¼ 0.61; serum prolactin:p ¼ 0.99). In the model with both prolactin-raising medica-tion and serum prolactin entered together, thus effectivelyassessing the effect of one adjusted for the other, the effectof both was reduced but not nullified (OR serum

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Table 4 Serum prolactin in quintile groups versus sexual side effects and type of medication.

Serumprolactinquintile group

Men and women Men

Mean serumprolactin (ME/l)

LIBORG�� LIBORG+� Prolactin-sparingmedicationy

Prolactin-raisingmedicationy

EDOD�z EDOD+z

1 126 33 (27%) 8 (10%) 32 (43%) 9 (7%) 20 (24%) 7 (15%)2 267 27 (22%) 14 (17%) 22 (29%) 19 (15%) 26 (31%) 7 (15%)3 515 29 (24%) 12 (15%) 13 (17%) 28 (22%) 22 (26%) 11 (23%)4 925 15 (12%) 26 (32%) 5 (7%) 36 (28%) 11 (13%) 19 (40%)5 1829 19 (16%) 21 (26%) 3 (4%) 37 (29%) 6 (7%) 4 (8%)

�Sexual side effects: lack of libido or orgasmic dysfunction.yProlactin-sparing medications were: clozapine, olanzapine, quetiapine, sertindole; prolactin-raising medications were:

bromperidol, haloperidol, perphenazine, penfluridol, pimozide, risperidone, sulpiride, zuclopentixol.zErectile or ejaculatory dysfunction in men.

Sexual side effects of antipsychotics and prolactin 715

prolactin ¼ 1.4, 95% CI: 1.1, 1.8; OR prolactin-raisingmedication ¼ 2.1, 95% CI: 1.0, 4.5).

The population attributable fraction (PAF) of prolactin-raising medication in the model adjusted for age and sexonly was 43%; in the model with additionally serumprolactin, the PAF was reduced to 27%.

3.4. Determinants of EDOD

Of the 133 men, EDOD were emergent in 53 (40%).Emergence of EDOD was not associated with age (unadjustedOR per year ¼ 0.97, 95% CI: 0.97, 1.09). Emergence of EDODwas strongly associated with prolactin-raising medications(OR ¼ 2.3, 95% CI: 1.1, 5.2) and with serum prolactin(OR per serum prolactin quintile group ¼ 1.6, 95% CI: 1.2, 2.2).In the model with both prolactin-raising medication andserum prolactin entered together, thus effectively assessingthe effect of one adjusted for the other, the effect serumprolactin remained (OR per quintile group ¼ 1.5, 95% CI:1.0, 2.1) but not the effect of prolactin-raising medication(OR ¼ 1.3, 95% CI: 0.5, 3.5).

The population attributable fraction (PAF) of prolactin-raising medication in the model adjusted for age and sexonly was 32%; in the model with additionally serumprolactin, the PAF was reduced to 11%.

4. Discussion

Patients in this study, in line with previous work, reported ahigh incidence of SSE likely attributable to antipsychotics.Prolactin-raising medication induced significantly more SSEthan prolactin-sparing medication (adjusted OR ¼ 3.4, 95%CI: 1.8, 6.5) with 43% of emerging SSE attributable toprolactin-raising medication. When adjusted for serumprolactin, the association between prolactin-raising medi-cation and SSE was reduced but remained significant(OR ¼ 2.1, 95% CI: 1.0, 4.5); 27% of emerging SSE remainedattributable to prolactin-raising medication. For erectileand ejaculatory dysfunction in men, the attributablefraction due to prolactin-raising medication was 32% beforeand 11% after adjustment for serum prolactin.

Around 40% of emerging SSE in schizophrenia are thusattributable to the prolactin-raising properties of antipsy-chotic medication. Of this attributable fraction, around one-third to two-thirds is directly reducible to the effects ofserum prolactin.

Limitations of this study are that the pooled data camefrom open studies. Although the open studies have beenperformed in the same population of patients and thesame clinic, only part of the patients were included in aformal (randomized) clinical trial including more extendedpsychopathology rating scales. Another limitation maybe the fact that although the research physicians wereblind to the hypothesis being tested and prolactinlevels determined, they were not blind for the studymedication. The lack of baseline prolactin levels restrictscorrecting for this possible confounding factor. The ASFQis designed to compare actual sexual performanceduring treatment with antipsychotics with previous normalprevious sexual performance, in this method recall biascannot be ruled out. As this study only includes patientsbeing treated for 6 weeks with the antipsychotic studied,the result cannot necessarily be generalized to patientstreated with antipsychotics for a long period of time. In thisstudy medication dosages have not been included in theanalyses, this was done to keep this article focused. Inthe same population using other statistical techniques weshowed that a higher medication dosage is predicting higherprolactin levels, although prolactin elevation may be asomewhat more powerful predictor (Knegtering et al.,2003).

Despite the methodological limitations, we feel that thefindings of this study are meaningful for the understandingof the physiology and pathophysiology of sexual functioningin patients treated with antipsychotics. The role of serumprolactin in all dimensions of sexual performance evaluatedin this study is at least highly suggestive. The role of serumprolactin in sexual performance is also suggested by thesymptoms of diminished sexual performance in patients withprolactinomas, a condition with no known direct influenceon the dopaminergic system, strongly elevated serumprolactin levels and frequently reported SSE (Netto andClaro, 1993).

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In addition, during the first months of lactation, prolactinlevels are also very high, correlating with a reduction inlibido in most women. Recently, in studies on humanvolunteers, it has been suggested that prolactin may beinvolved in mechanisms indicating sexual satiety (Krugeret al., 2002). Animal studies suggest that serum prolactininfluences dopaminergic output indirectly (Cruz-Cassalazet al., 1999). The dopamine system is involved in manyfunctions of the brain including attention, fine-tuning ofmovements, the reward system, sexual arousal and orgasm.In rats, the involvement of the dopamine system in sexualarousal and orgasm has been elegantly shown, including theinhibiting effects of dopamine antagonists (antipsychotics)on sexual behavior (Damsma et al., 1992; Pfaus and Phillips,1989; Pfaus et al., 1990, 1995). Thus, the data from previoushuman and animal studies as well as from the analysespresented here do suggest that antipsychotics may have amajor influence in decreasing sexual performance throughmechanisms involving blockade of dopamine as well aselevation of serum prolactin. The final impact of thesemechanisms appears to affect all dimensions of sexualperformance. The clinical consequences of these conclu-sions is reflected in recent studies showing a significantreduction of SSE when switching from a prolactin elevatingto a prolactin-sparing antipsychotic (Kim et al., 2002; Ahl etal., 2004; Kinon et al., 2006).

Role of the funding sources

Funding for this study was provided by AstraZeneca and EliLilly; they had no further role in study design; in thecollection, analysis and interpretation of data; in the writingof the report; and in the decision to submit the paper forpublication.

Conflict of interest

Jim van Os is a speaker or member of the advisory board forEli Lilly, Bristol-Myers Squibb, Janssen-Cilag and AstraZene-ca. He received grant or research support from Eli Lilly, GSK,Bristol-Myers Squibb and AstraZeneca.

Rikus Knegtering is speaker or consultant for Eli Lillyand Janssen Cilag and receives research support fromAstraZeneca, Bristol-Myers Squibb, Eli Lilly and Janssen.Dr. Bruggeman is on the speaker’s bureaus of Eli Lilly,Janssen and Organon, and receives research support fromAstraZeneca, Bristol-Myers Squibb, Eli Lilly and Janssen.

Acknowledgments

We thank AstraZeneca and Eli Lilly for an unconditionalresearch grant for two of the studies contributing to thedataset of this article. We thank Han Bous en Miriam Rutgersfor their contributions in the reliability study.

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