Hyperprolactinemia induced by low-dosage amisulpride in Korean psychiatric patients

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.[1] However, hyperprolactinemia and associated clinical symptoms have largely been neglected in both clinical practice and research.[2]

Amisulpride, a substituted benzamide derivative, is a unique atypical antipsychotic agent in that it lacks the combined antagonism of 5HT2/D2 receptors.[[3]] Amisulpride has high and similar affinity for D2/D3 receptors.[3] Furthermore, amisulpride at low dosages (up to 300 mg) enhances dopaminergic neurotransmission by preferentially blocking presynaptic D2/D3 receptors.[5] This fact can explain that the medication of amisulpride is effective for negative symptoms of schizophrenia.[[4], [6]] Amisulpride at higher dosages (≥400 mg) blocks postsynaptic D2/D3 receptors to reduce dopaminergic transmission,[7] and then its medication appears to be effective for positive symptoms in schizophrenia.[[7]]

Low dosages of amisulpride can enhance dopaminergic neurotransmission theoretically,[4] and then can be expected not to increase prolactin level. However, amisulpride at low dosages has been reported to be associated with amisulpride‐induced hyperprolactinemia.[[9]]

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

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) (rs = 0.445, P = 0.049).

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.[[9]] Some studies reported elevated prolactin levels by even 50 mg/day of amisulpride.[[10], [12]] Our data found a significant correlation between the prolactin level and the dosage of amisulpride (P = 0.049).

Some authors reported that the prolactin level after treatment of amisulpride was significantly higher in women than in men.[[10], [12]] This finding is consistent with our result that women had significantly higher prolactin levels than men (P = 0.021).

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.[4] However, our data and the previous findings showed that low dosages of amisulpride induced hyperprolactinemia.[[9]] It is reported that amisulpride has a lack of blood–brain barrier penetration properties, and it has higher D2 receptor occupancy in the pituitary than in the striatum.[[14]] A single photon emission tomography study showed that amisulpride‐induced hyperprolactinemia was uncoupled from its occupancy of the central D2/D3 receptor in patients.[16] These findings suggest that amisulpride has more effect on prolactin elevation, but less effect on extrapyramidal symptoms.

Our patients, except one patient, reported no hyperprolactinemia‐associated symptoms, although many patients had marked elevated prolactin level above 100 ng/mL.[17] There have been reports of clinical cases with asymptomatic incidental hyperprolactinemia[[18]] and antipsychotic‐induced asymptomatic hyperprolactinemia.[20] However, these reports did not suggest clearly why marked hyperprolactinemia did not result in clinical symptoms in some patients. Macroprolactinemia can explain some asymptomatic hyperprolactinemia in some patients.[17] Some authors discussed the time lag between the prolactin elevation and the emergence of clinical symptoms.[21]

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.[22] In addition, the most current guidelines do not recommend measuring baseline prolactin levels.[23] However, our findings and previous reports indicate no correlation between increased prolactin levels and the occurrence of clinical hyperprolactinemia symptoms.[[2], [23]] Moreover, the long‐term increases of prolactin could present adverse effects, such as osteoporosis, pituitary tumor, breast cancer, and prostate cancer.[1] Thus, the baseline assessment and the regular monitoring of prolactin level appear to be necessary in patients receiving antipsychotics, such as amisulpride. Especially, female patients need such a measure of prolactin level because they can have a higher prolactin level.

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.[[11], [24]] Among them, one of the first approaches is the dose reduction of the current antipsychotic drug. However, there is a lack of evidence that this approach is effective.[25] Our findings also suggest that amisulpride‐induced hyperprolactinemia at therapeutic dosages cannot be resolved by lowering the amisulpride dosage.

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.[1] Also, the time to measure the prolactin level after amisulpride administration varied from 7 to 940 days. Furthermore, three women took amisulpride for less than 1 month, and two women were in the post‐climacterium period. Therefore, only four subjects among all the women could be assessed as to whether menstrual irregularities or amenorrhea occurred or not. That could underestimate these side‐effects in the study. Finally, some subjects in this study were outpatients, but we did not evaluate their adherence by using any objective tool.

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).