Aim: Amisulpride at low dosages enhances dopaminergic neurotransmission by preferentially blocking presynaptic D2/D3 receptors. Thus, low dosages of amisulpride are expected not to increase prolactin levels. The aim of this study was to examine whether low dosages of amisulpride can increase serum levels of prolactin or not clinically in Korean patients. Method: Serum prolactin levels were measured in 20 Korean patients (12 men and eight women) with various diagnoses who were treated with less than 300 mg of amisulpride per day. Results: The mean dosage of amisulpride was 195.0 ± 51.0 mg/day, and serum level of prolactin was 76.1 ± 43.4 ng/mL. The prolactin level was significantly higher in women (110.7 ± 49.3 ng/mL) than in men (53.1 ± 15.9 ng/mL) after administering amisulpride (P = 0.021), while the dosage of amisulpride did not differ significantly between men (200.0 ± 42.6 mg/day) and women (187.5 ± 64.1 mg/day) (P = 0.576). Conclusions: The low dosages of amisulpride elevate serum prolactin level in the majority of patients. This finding indicates that the dose‐reduction of amisulpride has little effect to relieve amisulpride‐induced hyperprolactinemia at therapeutic dosages. Clinicians should monitor serum prolactin level even when low dosages of amisulpride are administered.
Keywords: amisulpride; antipsychotics; hyperprolactinemia; prolactin
SOME ANTIPSYCHOTIC AGENTS have the potential to increase plasma prolactin levels, which can induce a range of short‐term and long‐term adverse effects. The short‐term adverse effects of hyperprolactinemia include galactorrhea, gynecomastia, menstrual irregularities, and sexual dysfunction. In addition, the long‐term adverse effects have been reported as the following: loss of bone density, pituitary tumor, breast cancer, and prostate cancer.[
Amisulpride, a substituted benzamide derivative, is a unique atypical antipsychotic agent in that it lacks the combined antagonism of 5HT2/D2 receptors.[[
Low dosages of amisulpride can enhance dopaminergic neurotransmission theoretically,[
The aim of this study was to examine whether amisulpride at low dosages can increase serum levels of prolactin or not clinically in Korean patients.
This study identified 20 Korean patients (12 men and eight women) who underwent measurement of serum prolactin levels on receiving less than 300 mg/day amisulpride as maintenance treatment from 2008 to 2009. Each subject had various diagnoses according to DSM‐IV, such as schizophrenia, bipolar disorder, and major depressive disorder (Table 1). None of the subjects had a medical condition known to affect prolactin levels (e.g. primary hypothyroidism, adrenal insufficiency, pituitary tumor, renal failure, and hepatic insufficiency) or a physiological condition that could cause hyperprolactinemia (e.g. pregnancy). They did not take any medication that influences the prolactin level, such as haloperidol or levosulpride, at least 2 weeks before the inclusion in this study. The subjects were aged 36.1 ± 16.7 years (34.9 ± 17.6 years for men and 37.9 ± 16.3 years for women). The study protocol was approved by the ethics committee of Inje University Ilsan‐Paik Hospital.
1 Demographic variables, clinical parameters, and serum prolactin levels of the subjects
Patient Sex Age Diagnosis Comedication Amisulpride dosage (mg/day) Duration of medication (days) Prolactin (ng/mL) at baseline Prolactin (ng/mL) after amisulpride 1 M 27 Bipolar disorder Lamotrigene, buspirone 100 580 NA 48.2 2 M 29 Bipolar disorder Lithium 200 180 NA 16.8 3 M 23 Bipolar disorder Lithium, lorazepam 200 900 NA 64.2 4 M 22 Bipolar disorder Valproate 200 29 NA 74.6 5 M 23 Bipolar disorder Lithium, lorazepam 200 940 NA 64.2 6 M 35 Psychotic disorder NOS Lorazepam 200 16 6.8 48.9 7 M 53 Schizophrenia Lorazepam 200 7 32.1 45.4 8 M 56 Bipolar disorder Valproate, lorazepam 200 13 4.6 49.4 9 M 77 Major depressive disorder Venlafaxine, paroxetine 200 14 12.1 48.6 10 M 27 Bipolar disorder Lithium, clonazepam 200 70 NA 70.9 11 M 24 Bipolar disorder Lithium 200 28 17.3 40.4 12 M 23 Bipolar disorder Lithium 300 97 NA 65.0 13 F 32 Schizoaffective disorder None 100 400 17.4 33.3 14 F 34 Bipolar disorder Lithium, lorazepam 100 15 NA 62.6 15 F 30 Schizophrenia Clozapine, lorazepam, topiramate 200 270 NA 126.8 16 F 24 Bipolar disorder Valproate 200 7 36.2 165.1 17 F 59 Schizophrenia Lorazepam 200 140 NA 122.0 18 F 68 Schizophrenia Lorazepam 200 7 5.4 147.4 19 F 30 Major depressive disorder Fluoxetine, alprazolam 200 130 NA 69.7 20 F 26 Schizophrenia None 300 90 28.9 159.0
1 Duration of medication means duration of medication with amisulpride.
2 F, female; M, male; NA, not assessed; NOS, not otherwise specified.
Serum prolactin levels were measured at one time‐point. All patients had taken the same dosage of amisulpride for at least 1 week when their blood was drawn. Among 20 subjects, only nine had baseline prolactin level examined before the medications in the medical charts. A blood sample was taken in the morning and then centrifuged to separate serum. The normal range of the prolactin level in the hospital laboratory is 4.0–15.2 ng/mL in men and 4.8–23.3 ng/mL in women. In addition, we requested information on hyperprolactinemia‐associated symptoms, such as galactorrhea, menstrual irregularity, amenorrhea, gynecomastia, diminished sexual desire, or erectile dysfunction.
The sample size in this study was small, and then we analyzed the data with the non‐parametric methods. We used the Mann–Whitney test to compare the prolactin levels between male and female subjects. Spearman's correlation coefficients were calculated to examine the correlations between the prolactin levels and the amisulpride dosage. All of the analyses were performed using standard software (spss for Windows), and P‐values smaller than 0.05 were considered statistically significant.
The mean dosage of amisulpride was 195.0 ± 51.0 mg per day. Among 20 patients, three subjects received 100 mg/day of amisulpride, 15 received 200 mg/day, and two received 300 mg/day. The dosage of amisulpride did not differ significantly between men (200.0 ± 42.6 mg/day) and women (187.5 ± 64.1 mg/day) (Z = −0.560, P = 0.576).
Prolactin levels of nine patients were increased significantly from 17.9 ± 12.0 ng/mL at the baseline to 81.9 ± 56.8 ng/mL after administering amisulpride (Z = −2.666, P = 0.008). The mean of prolactin level after the medication of amisulpride was 76.1 ± 43.4 ng/mL. All had elevated prolactin level (16.8–165.1 ng/mL) above the normal range (Table 1). Prolactin levels were significantly higher in women (110.7 ± 49.3 ng/mL) than in men (53.1 ± 15.9 ng/mL) (Z = −2.315, P = 0.021). However, one patient (patient 20) complained of menstrual irregularity, while the other patients reported none of hyperprolactinemia‐associated symptoms.
The prolactin levels had a significant increase according to the daily dosage of amisulpride (48.0 ± 14.6 ng/mL of the mean prolactin at 100 mg/day amisulpride, 77.0 ± 43.1 ng/mL at 200 mg/day, and 112.0 ± 66.4 ng/mL at 300 mg/day, respectively) (r
This study shows that even low‐dosage amisulpride below 300 mg/day can increase serum prolactin level. This finding is consistent with the previous reports indicating that low‐dosage amisulpride elevates serum prolactin levels.[[
Some authors reported that the prolactin level after treatment of amisulpride was significantly higher in women than in men.[[
The amisulpride with low dosage does not seem to elevate the prolactin level since a low dosage of amisulpride can antagonize the presynaptic D2/D3 receptors and then enhances dopaminergic neurotransmission.[
Our patients, except one patient, reported no hyperprolactinemia‐associated symptoms, although many patients had marked elevated prolactin level above 100 ng/mL.[
The guidelines of the American Psychiatric Association recommend that the prolactin level needs to be measured only in the presence of typical elevated prolactin‐associated symptoms.[
Approaches for antipsychotic‐induced hyperprolactinemia include the following: discontinuation or dose reduction of the current antipsychotic agent; switching to a prolactin‐sparing antipsychotic; addition of a dopamine agonist or aripiprazole; or addition of female hormone replacement.[[
This study had several limitations. First, the cross‐sectional design was the major limitation in this study. Then, the baseline prolactin levels were not measured in 11 subjects. Also, long‐term adverse consequences could not be evaluated. Patients with various psychiatric disorders, including schizophrenia, bipolar disorder, and major depressive disorder were enrolled. However, hyperprolactinemia is not a trait marker of specific diseases.[
Our findings suggest that low dosages of amisulpride elevate serum prolactin levels. This increase of serum prolactin is pronounced in female patients. Our findings indicate that the dosage‐reduction of amisulpride can have little effect to relieve amisulpride‐induced hyperprolactinemia at therapeutic dosages. Clinicians should measure the baseline prolactin level routinely as well as monitor the serum prolactin level, even when low dosages of amisulpride are administered.
This study was supported by a grant from National Research Foundation of Korea (NRF) (No. 431‐2010‐1‐E00027).
By Bun‐Hee Lee; Seung‐Gul Kang; Tae‐Woo Kim; Heon‐Jeong Lee; Ho‐Kyoung Yoon and Young‐Min Park
Reported by Author; Author; Author; Author; Author; Author