Relationship between Prolactin Levels and Subjective Endocrine-Related Adverse Effects in Patients with Schizophrenia Receiving Long-Term Treatment with Amisulpride

• Abstract
• Abbreviations
• Introduction
• Patients and Methods
• Subjects
• Treatment with amisulpride and other interventions
• Measurement of prolactin levels
• Assessment of hormone-related adverse events
• Statistical analysis
• Results
• Demographic and clinical data
• Prolactin levels and LUNSERS scores during acute- and maintenance-treatment phases
• Prolactin levels and LUNSERS scores according to the presence of baseline hyperprolactinemia
• Discussion
• References

Abstract

Introduction:

We have investigated the categorical prevalence of hyperprolactinemia and examined the relationship between prolactin levels and subjective endocrine-related adverse effects in schizophrenia patients treated with amisulpride during a 1-year period.

Methods:

A total of 111 patients with schizophrenia who were either started on or switched to amisulpride were assessed for prolactin levels and endocrine-related adverse effects using 6 items derived from the Liverpool University neuroleptic side-effect rating scale (LUNSERS) at baseline, 8 weeks, and 1 year.

Results:

10 were antipsychotic-naïve, 23 were antipsychotic free for 1 month, 54 discontinued their medication during 1 month prior to study, and 24 maintained their antipsychotics at baseline. At 1 year, hyperprolactinemia was found in 75.9% of men and 85.7% of women. Significant increases in mean prolactin levels at week 8 in both sexes were found; this was followed by a significant decrease over 1 year only in women. The proportions of both sexes with hyperprolactinemia increased from baseline to week 8 but remained unchanged at 1 year. Scores on the endocrine-related items of the LUNSERS improved significantly from baseline to week 8 in both sexes and then remained consistent during maintenance treatment. Prolactin levels were significantly higher in the group with baseline hyperprolactinemia than in the group without baseline hyperprolactinemia at all assessment points.

Conclusions:

Amisulpride commonly induces hyperprolactinemia. Although the percentage of patients with hyperprolactinemia remained unchanged during maintenance treatment, serum prolactin levels significantly decreased among women. Self-reported endocrine-related side effects were not associated with prolactin elevation during amisulpride treatment.

Abbreviations

Introduction

The incidence of hyperprolactinemia in patients with schizophrenia being treated with antipsychotic agents has been the focus of recent widespread discussions, implying that psychiatrists are developing an increased awareness of the clinical impact of increased prolactin levels. It has been established that antipsychotic medications, rather than psychotic conditions per se, constitute one of the most common causes of hyperprolactinemia in patients with psychiatric illnesses [1]. D2 receptor antagonism on pituitary lactotroph cells and subsequent decreases in the inhibition of prolactin synthesis and secretion are primary mechanisms [1] [2] [3] [4]. Atypical antipsychotics such as clozapine, olanzapine, and quetiapine pose a lower risk of prolactin elevation, which is usually mild and transient [1] [2] [5] [6] [7] [8], whereas most conventional antipsychotics can produce more significant and persistent hyperprolactinemia, although partial tolerance has been reported under these treatment protocols. However, it has also been suggested that atypical antipsychotics such as amisulpride and risperidone are related to an increased propensity to demonstrate elevated prolactin levels [1] [2] [5], which may result from a higher peripheral-to-central D2 receptor occupancy ratio of these medications. Effective levels of central D2 occupancy require higher dosages of antipsychotics, which then cause increased peripheral D2 receptor blocking involving the pituitary gland.

Research into the potential impact of antipsychotic-induced hyperprolactinemia has increased in recent years. Increased prolactin levels have been related to a variety of adverse events, including galactorrhea and gynecomastia resulting from its direct effects on tissues, and menstrual irregularity and sexual dysfunction resulting from hypothalamic-pituitary-gonadal axis dysregulation. Behavioral and mood symptoms such as mild hostility, depression, and anxiety may also occur [9] [10]. Of these symptoms, those related to sexual dysfunction such as diminished libido, decreased arousal, orgasmic dysfunction, and impotence were reported most frequently; these may be among the worst adverse events associated with antipsychotic medication, and may contribute to decreased treatment compliance, quality of life and increased risk for relapse [5] [11] [12] [13]. These adverse effects have been identified on the basis of the known physiological and biochemical functions of prolactin or through research on hyperprolactinemia secondary to pathophysiological conditions such as prolactinoma, rather than via clinical studies regarding antipsychotic-induced hyperprolactinemia. The long-term course and clinical impact of antipsychotic-induced hyperprolactinemia has been rarely studied, especially with respect to the sequelae of treatment with amisulpride. Indeed, the association between sexual dysfunction and antipsychotic-induced hyperprolactinemia remains controversial [1] [2] [5] [14] [15] [16] [17] [18] [19] [20] [21] [22]. Very few studies have systematically investigated the role of amisulpride in the relationship between prolactin levels and sexual dysfunction. Schlosser et al. [23] studied long-term changes in prolactin levels during 1 year of amisulpride treatment,but that study was limited by its small sample size (19 subjects) and the absence of categorical data for hyperprolactinemia and a standardized scale for the assessment of sexual side effects. Although understanding the categorical prevalence can be clinically helpful in predicting the risk of developing hyperprolactinemia [24], most randomized controlled studies have noted only mean changes in prolactin levels but have not reported the number of patients with hyperprolactinemia or the severity of their symptoms over time. The few studies that have reported the categorical prevalence of hyperprolactinemia induced by amisulpride were not specifically designed to examine this medication [24] [25] [26] [27].

The present study was designed to estimate the categorical prevalence rate of hyperprolactinemia and the changes in prolactin levels during acute and long-term treatment with amisulpride and to clarify the relationship between prolactin levels and subjective endocrine-related adverse effects.

Patients and Methods

Subjects

This study, part of a non-comparative, open, 1-year, prospective multicenter study in Korea [28], included 111 patients diagnosed with either schizophrenia or schizophreniform disorder according to DSM-IV diagnostic criteria. Participants suffered either first-episode or recurrent psychosis after discontinuation of antipsychotics or needed to switch antipsychotic medication due to side effects, insufficient treatment effectiveness, and/or other reasons. At study entry, 24 patients (21.6%) were being treated with antipsychotic medications. Of the remaining 87 patients, 10 (9%) were antipsychotic naïve, and 23 (20.7%) were antipsychotic free for 1 month before study entry, although they had been treated with antipsychotic medication in the past. The remaining 54 patients (48.6%) had taken antipsychotics up to the last month preceding the study but discontinued by the initiation of the study. We defined the antipsychotic-free group as the 33 patients who were antipsychotic naïve or antipsychotic free for 1 month before study participation and the antipsychotic-medication group as the remaining 78 patients. Patients were excluded from this study if they met criteria for psychotic disorders other than schizophrenia or schizophreniform disorder, or if they experienced medical problems that contraindicated the use of amisulpride such as prolactin-dependent tumors, pheochromocytoma, hypersensitivity to metabolites of amisulpride, severe bradycardia, hyperkalemia, elongated QT intervals in laboratory tests, or electrocardiogram (ECG) abnormalities. Pregnant or breast-feeding women, patients having clinically significant medical or neurological conditions, and those refractory to previous treatment (lack of effectiveness of more than 2 different types of antipsychotic agents for more than 8 weeks) were also excluded. Written informed consent was obtained from all participants prior to their participation, and this study was approved by the institutional review board of each center.

Treatment with amisulpride and other interventions

Dosages of 50–1 200 mg/d of amisulpride (Solian^®, Sanofi-Aventis) were prescribed according to the clinical judgments of investigators, based on individual treatment responses and adverse events, as in actual clinical practice. The baseline data were collected before prescribing the first doses of amisulpride. Patients taking other antipsychotic agents at baseline received concomitant medication with amisulpride only for the first week of the trial. Benzodiazepines (diazepam, oxazepam, lorazepam), zolpidem, zopiclone, anti-parkinsonian drugs, and other drugs were also allowed for anxiety, insomnia, behavior problems, and extrapyramidal symptoms, respectively. However, other psychotropic medications such as antipsychotic agents, antidepressants, mood stabilizers, and levodopa were not permitted during the study.

Measurement of prolactin levels

Blood samples were collected in the morning (between 8:00 am and 9:00 am) for standardization as basal fasting morning prolactin levels and analyzed in the relevant clinical pathology laboratories at each center. Hyperprolactinemia was defined across centers as prolactin levels higher than the upper normal limit of >20 ng/mL for men and >25 ng/mL for women. Levels of plasma prolactin were measured at baseline, week 8, and at 1 year.

Assessment of hormone-related adverse events

This study adopted 6 items from the Korean version of the Liverpool University neuroleptic side effect rating scale (LUNSERS) [29], which was initially developed based on the Udvalg for Kliniske Undersøgelser (UKU) side-effect rating scale, to assess endocrine-related adverse effects. Patients completed full versions of the LUNSERS on 3 occasions: at baseline and at 8-week and 1-year follow-up appointments. The 6 hormone-related items included in the analysis consisted of 4 items for both sexes (swollen or tender chest, item 7; increased sexual drive, item 17; difficulty in achieving climax, item 24; reduced sexual drive, item 46) and 2 items for women (menorrhagia, item 13; amenorrhea, item 50). Items were rated from 0, indicating no symptoms, to 4, indicating very severe symptoms. LUNSERS scores ranged from 0 to 24 among women and from 0 to 16 among men.

Statistical analysis

All data were analyzed using SPSS 12.0 for Windows. Descriptive statistics were used to examine demographic characteristics. Paired t-tests were used to compare continuous variables such as prolactin levels and LUNSERS scores obtained at consecutive assessments. The McNemar test was used for categorical data. The amisulpride dosage prescribed was evaluated using repeated-measures ANOVA based on the observed cases. We calculated Pearson correlation coefficients between changes in prolactin levels and LUNSERS scores during each treatment phase and between demographic factors and prolactin levels at 1 year. Statistical inferences were based on two-tailed tests, and the significance level was set at <0.05.

Results

Demographic and clinical data

Demographic and clinical characteristics, which were analyzed according to the presence of hyperprolactinemia at baseline, are summarized in [Table 1]. A total of 111 patients were included in the analysis, and hyperprolactinemia was found in 60 (54%). 56 patients (50.5%) were men. The mean age was 32.8 years, and the age at onset was 26.1 years. Patients with hyperprolactinemia were older (34.4 years vs. 30.9 years, P=0.034) and reported a later onset of symptoms compared with patients without hyperprolactinemia (28.2 years vs. 23.7 years, P=0.001). 52 (87.6%) in the hyperprolactinemia group and 26 (51.0%) in the non-hyperprolactinemia group were taking antipsychotics (P<0.001). A significant difference was observed in the distribution of antipsychotics (P=0.004). A significant difference was observed in the distribution of antipsychotics (P=0.004). Risperidone (59.6%) was prescribed most frequently for patients with hyperprolactinemia, and olanzapine (38.5%) was prescribed most frequently for patients without this condition. We found no differences between groups in total scores on the positive and negative symptom scale (PANSS) or on the hormone-related items of the LUNDERS at baseline. The mean baseline prolactin level was 40.2 ng/mL; the mean was 65.4 ng/mL in the group with hyperprolactinemia and 10.6 ng/mL in the group without this condition (P<0.001). The mean dose (±SD) of amisulpride prescribed for all patients was 315.3 (±184.5) mg/day at baseline, with an increase at week 8 (508.9±255.3 mg/day), which was maintained at 1 year (515.0±286.8 mg/day). A repeated-measures ANOVA did not show significant differences between groups in the dosages of amisulpride prescribed (F=0.952, P=0.333). There was a significant difference between the antipsychotic-medication and the antipsychotic-medication-free groups at baseline in percentage of hyperprolactinemia (P<0.001) but not in LUNSERS scores (P=0.510).

84 patients completed the study at week 8, and 57 patients completed the study at 1 year. The most common reason for premature discontinuation was loss to follow-up (4 patients at week 8 and 9 patients at 1 year). Less frequent reasons were lack of efficacy (4 at week 8 and 6 at 1 year), failure to follow protocol instructions (4 at week 8 and 5 at 1 year), adverse reactions (4 at week 8 and 3 at 1 year), and other reasons (8 at week 8 and 4 at 1 year). 3 patients did not complete the LUNSERS. The patients who discontinued their participation at week 8 and 1 year did not differ from those who completed the trial on any demographic or clinical factors at baseline.

Prolactin levels and LUNSERS scores during acute- and maintenance-treatment phases

Prolactin levels and total scores on the hormone-related items of the LUNSERS are presented for all patients over time in [Table 2]. 84 patients were included in analyses at week 8, and 57 patients were included at 1 year. Mean prolactin levels increased significantly from baseline to week 8 (43.2 ng/mL to 91.6 ng/mL, P<0.001) and subsequently decreased at 1 year in all patients (90.1 ng/mL to 71.5 ng/mL, P=0.002). Prolactin levels increased significantly in both sexes on an acute basis (P<0.001 in both), but the reduction during the maintenance phase was significant only in women (P<0.001). The prevalence of hyperprolactinemia was roughly 50% at baseline, significantly increased to more than 80% at week 8, and did not change from week 8 to 1 year. At 1 year, the rate of hyperprolactinemia was 75.9% in men and 85.7% in women. Prolactin levels were more than twice as high in women as in men at all assessment points. We found a significant reduction in LUNSERS scores within the initial 8 weeks in both sexes (3.2–1.8 in men, P=0.004; 4.8–3.1 in women, P=0.018), but these scores did not change during the maintenance phase. A separate analysis for items 17 (increased sexual drive) and 46 (reduced sexual drive) revealed a statistically significant reduction only among men in scores on item 46 during the initial 8 weeks (1.2–0.6 in men, P=0.001; 0.9–0.5 in women, P=0.060). In both the baseline antipsychotic-medication and antipsychotic-medication-free groups, changes in prolactin levels were not correlated with changes in LUNSERS scores during either the acute or maintenance-treatment phase (P=0.547 during the acute phase and P=0.550 during the maintenance phase in the antipsychotic-medication group; P=0.055 and P=0.818 in the antipsychotic-free group).

Prolactin levels and LUNSERS scores according to the presence of baseline hyperprolactinemia

Changes in prolactin levels and LUNSERS scores according to the presence of hyperprolactinemia at baseline are shown in [Table 3]. Both groups demonstrated a significant increase in prolactin levels on an acute basis. Significant reductions in prolactin levels during the maintenance phase were evident only among women in the group with baseline hyperprolactinemia (166.5–116.9 ng/mL, P=0.001). The difference in prolactin levels between groups was statistically significant at all assessment points according to additional independent-sample t-tests (data not shown). The gap in prolactin levels was smaller in men than in women.

We found a statistically significant reduction in the scores on the LUNSERS during acute treatment in the group without hyperprolactinemia (3.9–1.8 in men, P<0.002; 4.3–1.8 in women, P<0.028), whereas no such reduction occurred in the other group (2.5–1.9 in men, P<0.324; 5.2–4.0 in women, P<0.219). The change during the maintenance phase showed no statistical significance in both sexes in both groups.

Prolactin levels at 1 year were not correlated with amisulpride dosages at 1 year, duration of illness, or age. We found no significant correlations between changes in amisulpride dosages and prolactin levels from week 8 to 1 year (r=0.239, P=0.068). Levels of prolactin at baseline were significantly correlated with prolactin levels at 1 year (r=0.632, P<0.001).

Discussion

This study suggested that amisulpride treatment is significantly related to the development of hyperprolactinemia in patients with schizophrenia. However, women, especially women with hyperprolactinemia at baseline, also developed long-term tolerance to this effect. We also found that, despite elevations in prolactin levels during the acute phase of treatment, self-reported endocrine-related adverse effects were initially significantly decreased and subsequently maintained, especially in both men and women without hyperprolactinemia. This uncoupling of adverse effects and prolactin levels continued during the maintenance phase. To the best of our knowledge, this is the first report using a large sample during a sufficiently long period of study to focus on amisulpride and systematically investigate the categorical prevalence rate of hyperprolactinemia, long-term changes in prolactin levels, subjective experiences of hormone-related adverse events, and the relationships among these factors.

Our data indicated that the categorical prevalence of hyperprolactinemia was 54% (60/111), with a mean level of 40 ng/mL at baseline. This prevalence rate is higher than the figures reported in 2 recent naturalistic studies, 33% and 38% [24] [25]. This difference in prevalence rates may be attributable to the inclusion at baseline of only patients without the typical symptoms linked to hyperprolactinemia in the 2 naturalistic studies. Additionally, sensitivity to prolactin may differ according to regional characteristics and ethnicity. A recent study reported a 39% prevalence rate for hyperprolactinemia on the basis of a sample in which 94% were white [17]. Indeed, data indicated a higher prevalence of hyperprolactinemia in non-Caucasian women than in Caucasians taking antipsychotics [30]. After 1 year of amisulpride medication, the prevalence of hyperprolactinemia was 76% in men and 86% in women. This figure seems to be slightly lower than those reported in previous studies, which have reported rates between 89% and 100%. The small sizes of the amisulpride cohorts used in previous studies, ranging from 7 to 17 subjects, might have led to overestimates of the prevalence rates of hyperprolactinemia. Additionally, given that most previous studies have been cross-sectional and naturalistic, our 1-year follow-up data should be considered more valid in causal analyses of amisulpride-related prolactin elevation than those of previous studies.

The current study indicates that the initially acute prolactin elevations related to amisulpride treatment at clinically effective dosages decreased significantly with long-term maintenance treatment only in women ([Table 2]). These findings are comparable to previous observations of the long-term prolactin tolerance developed during 1 year of amisulpride treatment [23]. Prolactin tolerance was also observed in a previous study that found a highly significant linear reduction in prolactin levels after initial elevations during 5 years of treatment with risperidone [15]. Several studies have established that chronic treatment with antipsychotic medication can lead to the development of tolerance and that prolactin levels gradually decrease by varying degrees after varying periods of time during extended treatment including conventional and atypical antipsychotics [15] [31] [32] [33] [34]. It has been hypothesized that prolactin tolerance may be attributable to the induction of or supersensitivity to dopaminergic regulation in the striatum and HPA axis [15] [23] [34], differential binding affinity on D2 receptors in the HPA axis [35] [36], and the lipophilicity of antipsychotics [34]. The overall changes in prolactin levels were more remarkable in female patients, and this finding supported the assumption that women are more sensitive than men to the development of hyperprolactinemia related to antipsychotics [15] [23] [37] [38] [39].

We found no correlation between amisulpride-induced prolactin elevation and hormone-related side effects in either sex. Changes in prolactin levels were also not associated with changes in hormone-related side effects regardless of whether participants were receiving antipsychotic medications at enrollment. Similar findings have been reported in previous studies on other conventional and atypical antipsychotics [14] [15] [16] [17]. Schlosser et al. [23] studied changes in prolactin levels during amisulpride treatment over a 1-year period and found long-term tolerance following acute prolactin elevation and an inverse relationship between prolactin levels and sexual side effects. In a study of a 5-year treatment with risperidone, prolactin levels were not correlated with expected sexual or psychological side effects [15]. Johnsen et al. [17] conducted a cross-sectional study among 106 participants who were receiving any antipsychotic medication and found no correlation between medication and hormone-related side effects (r=0.02, P=0.820). The observed uncoupling of prolactin levels and hormone-related side effects may imply that factors unrelated to endocrine functioning also contribute to sexual dysfunction in patients with schizophrenia. Untreated male patients with schizophrenia showed reduced sexual desire compared with both normal controls and patients with schizophrenia treated with antipsychotic medications [40]. This finding is consistent with the results of earlier studies showing the presence of sexual dysfunction in untreated patients with schizophrenia despite normal prolactin levels [37]. In addition, the finding of sexual hypoactivity in patients with schizophrenia has been replicated [18] [40] [41] [42]. It is well known that the core pathological processes of schizophrenia, such as positive symptoms and psychomotor disturbances, influence sexual functioning [5] and that comorbid physical disorders such as diabetes, hypertension, and obesity as well as the effects of antipsychotics and anticholinergics [2] [18] [38] [41] can alter the sexual functioning of individuals with schizophrenia. Indeed, sexual dysfunction in patients with psychiatric illnesses can represent a manifestation of various psychopathological and pathophysiological mechanisms rather than the impact of one measurable cause such as hyperprolactinemia. Thus, as observed in our study, the alleviation of the pathological symptoms of schizophrenia with effective antipsychotic treatment contributes to improved sexual desire and subjective satisfaction with general sexual activity [17] [40]. According to unpublished data collected by our group, the severity of positive symptoms, including hallucinations and delusions, are positively correlated with subjective experiences of side effects, as measured by the LUNSERS. Thus far, definite conclusions about this issue have been elusive, as several previous studies have reported a strong association between hyperprolactinemia and sexual side effects [2] [18] [19] [20] [21] [22] [38], whereas other studies have not found such an association [1] [5]. Amisulpride in particular has not been extensively studied at this point. Thus, we should consider various individual factors that may contribute to the formation of symptoms related to increased prolactin levels rather than focus on prolactin levels per se when making clinical decisions regarding antipsychotic medication, including amisulpride. It has been assumed that individuals taking antipsychotic medication differ with respect to their predisposition to the develop hyperprolactinemia and that the level of prolactin required for symptom formation varies considerably [1]. In the current study, prolactin levels after 1 year of amisulpride treatment were not associated with dosage of amisulpride, duration of illness, or age, and changes in prolactin levels were not correlated with changes in dosage from week 8 to 1 year, which supports previous findings that prolactin responses to antipsychotic medications were independent of age [30], duration of illness, and dosage [15] [27]. However, we found that the level of prolactin at baseline and female sex were significantly correlated with hyperprolactinemia at 1 year. Indeed, female sex has been considered one of the most relevant risk factors for prolactin elevation [2] [15] [26] [27] [30] [43]. The group with baseline hyperprolactinemia showed significantly higher levels of prolactin than did the group without hyperprolactinemia, a result that was observed consistently over time. Because amisulpride was observed to influence prolactin levels only at week 8 and 1 year and not at baseline, individuals with schizophrenia may vary in their susceptibility to prolactin during treatment with amisulpride. Such differences in susceptibility require attention over and above that accorded to elevated prolactin levels per se. Further studies are needed to identify the factors that predict and serve as markers for prolactin response.

This study had several limitations that should be noted. Treatment with antipsychotic agents other than amisulpride upon starting the study may have influenced prolactin levels at baseline. We did not perform comparative tests among the 7 clinical laboratories participating in this study and had no access to data related to other physical dimensions that may be relevant to changes in prolactin levels. Recent studies have recognized that elevated prolactin levels may be associated with loss of bone mineral density, breast cancer, or other symptoms and signs of chronic hypogonadism, but clear conclusions remain to be drawn. Future research on the safety of amisulpride should use objective measures such as those assessing bone mineral density or sex steroid hormones to rigorously investigate the potential acute and long-term effects of amisulpride medication-induced prolactin elevations. The 1-year follow-up period of this study constitutes an additional weakness. 1 year may be not sufficient for assessing long-term changes in prolactin levels; we were thus prevented from determining whether amisulpride-induced prolactin elevations would be totally reversed over the course of several years. Additionally, the potential effects of hyperprolactinemia such as osteoporosis and breast cancer can be revealed only in longer-term studies with larger samples. Finally, endocrine-related adverse events were assessed only with a subjective self-report measure, the LUNSERS. The 6 items used in this study may not have been sufficiently sensitive to detect the multiple facets of symptoms related to prolactin changes, and more objective data such as clinicians’ ratings of sexual dysfunction or menstruation may help to increase the validity of the results of this study.

The results suggest that amisulpride commonly induces hyperprolactinemia. Although the prevalence of hyperprolactinemia remained unchanged during the maintenance-treatment phase, serum prolactin levels decreased in women, especially in women with hyperprolactinemia at baseline. Self-reported endocrine-related side effects significantly decreased during the acute-treatment phase and were not associated with prolactin elevation. Further research using objective measures, such as levels of sex hormones, with larger samples undergoing long-term treatment with amisulpride may provide more evidence regarding the relationship between prolactin levels and subjective endocrine-related adverse effects.

Conflict of Interest

Dr Ahn has received research grants or served as a lecturer for Janssen, Pfizer, Otsuka, GlaxoSmithKline, Servier, Lundbeck, Eli Lilly, Lundbeck and AstraZeneca. Dr Yong Sik Kim has received grants, research support, and/or honoraria from Novartis, Janssen, Eli Lilly, Pfizer, Sanofi-Aventis, Otsuka, AstraZeneca, Organon, GlaxoSmithKline, and Servier, and was also supported by the second stage Brain Korea 21 Project. All other authors have no conflicts of interest. This study was supported by a grant from Sanofi-Aventis Korea.

Acknowledgements

Sanofi-Aventis Korea contributed supplemental funding. Experimental design, data collection, statistical analyses, interpretation and drafting of the results were carried out without input from any pharmaceutical company.

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• 30 Kinon BJ, Gilmore JA, Liu H et al. Prevalence of hyperprolactinemia in schizophrenic patients treated with conventional antipsychotic medications or risperidone. Psychoneuroendocrinology 2003; 28 Suppl 2 55-68
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• 31 Brown WA, Laughren TP. Tolerance to the prolactin-elevating effect of neuroleptics. Psychiatry Res 1981; 5: 317-322
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• 32 Crawford AM, Beasley Jr CM, Tollefson GD. The acute and long-term effect of olanzapine compared with placebo and haloperidol on serum prolactin concentrations. Schizophr Res 1997; 26: 41-54
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• 33 Faraone SV, Brown WA, Laughren TP. Serum neuroleptic levels, prolactin levels, and relapse: a two-year study of schizophrenic outpatients. J Clin Psychiatry 1987; 48: 151-154
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• 34 Rao ML, Brown WA. Stability of serum neuroleptic and prolactin concentrations during short- and long-term treatment of schizophrenic patients. Psychopharmacology (Berl) 1987; 93: 237-242
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• 35 Compton MT, Miller AH. Antipsychotic-induced hyperprolactinemia and sexual dysfunction. Psychopharmacol Bull 2002; 36: 143-164
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• 36 Turrone P, Kapur S, Seeman MV et al. Elevation of prolactin levels by atypical antipsychotics. Am J Psychiatry 2002; 159: 133-135
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• 37 Kuruvilla A, Peedicayil J, Srikrishna G et al. A study of serum prolactin levels in schizophrenia: comparison of males and females. Clin Exp Pharmacol Physiol 1992; 19: 603-606
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• 38 Smith SM, O’Keane V, Murray R. Sexual dysfunction in patients taking conventional antipsychotic medication. Br J Psychiatry 2002; 181: 49-55
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• 39 Wode-Helgodt B, Eneroth P, Fyro B et al. Effect of chlorpromazine treatment on prolactin levels in cerebrospinal fluid and plasma of psychotic patients. Acta Psychiatr Scand 1977; 56: 280-293
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• 40 Aizenberg D, Zemishlany Z, Dorfman-Etrog P et al. Sexual dysfunction in male schizophrenic patients. J Clin Psychiatry 1995; 56: 137-141
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• 41 Knegtering H, van der Moolen AE, Castelein S et al. What are the effects of antipsychotics on sexual dysfunctions and endocrine functioning?. Psychoneuroendocrinology 2003; 28 Suppl 2 109-123
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• 42 Macdonald S, Halliday J, Mac ET et al. Nithsdale Schizophrenia Surveys 24: sexual dysfunction. Case-control study. Br J Psychiatry 2003; 182: 50-56
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• 43 Grunder G, Wetzel H, Schlosser R et al. Neuroendocrine response to antipsychotics: effects of drug type and gender. Biol Psychiatry 1999; 45: 89-97
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Correspondence

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  PubMedSearch in Google Scholar
• 35 Compton MT, Miller AH. Antipsychotic-induced hyperprolactinemia and sexual dysfunction. Psychopharmacol Bull 2002; 36: 143-164
  PubMedSearch in Google Scholar
• 36 Turrone P, Kapur S, Seeman MV et al. Elevation of prolactin levels by atypical antipsychotics. Am J Psychiatry 2002; 159: 133-135
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• 37 Kuruvilla A, Peedicayil J, Srikrishna G et al. A study of serum prolactin levels in schizophrenia: comparison of males and females. Clin Exp Pharmacol Physiol 1992; 19: 603-606
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• 38 Smith SM, O’Keane V, Murray R. Sexual dysfunction in patients taking conventional antipsychotic medication. Br J Psychiatry 2002; 181: 49-55
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• 39 Wode-Helgodt B, Eneroth P, Fyro B et al. Effect of chlorpromazine treatment on prolactin levels in cerebrospinal fluid and plasma of psychotic patients. Acta Psychiatr Scand 1977; 56: 280-293
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