Prolactin (PRL) is a hormone mainly secreted by lactotroph cells of the anterior pituitary gland. PRL plays an important role in many biological effects, especially lactation during pregnancy (Capozzi et al., 2015). Hyperprolactinemia (HPRL) refers to an abnormally elevated level of serum PRL. HPRL causes a range of severe symptoms, including breast enlargement, galactorrhea, menstrual disorders, amenorrhea and infertility in female patients; breast feminization, decreased libido, erectile dysfunction and osteoporosis in male patients. Recent studies have shown that elevated PRL levels may also cause cognitive impairment and increase the risk of heart diseases (Montalvo et al., 2018; Toulis et al., 2018).

In pathological conditions, HPRL usually caused by prolactinomas, drugs and endocrinopathies such as primary hypothyroidism and primary adrenocortical insufficiency (Chahal and Schlechte, 2008; Capozzi et al., 2015). The most popular cause of non-tumor HPRL is drugs, especially antipsychotics. Nearly 70% of patients with schizophrenia develop antipsychotic-induced HRPL (Melmed et al., 2011). Dopamine released in the hypothalamus is important for regulating PRL as it can inhibit PRL synthesis and secretion. Antipsychotics with D2 antagonism properties can block dopamine receptors in the tuberoinfundibular pathway of the hypothalamus (Grigg et al., 2017). First-generation antipsychotics and some atypical antipsychotics (risperidone, paliperidone, and amisulpride) can easily lead to HPRL (Voicu et al., 2013). It was reported that the prevalence of HPRL was 59.6% in female schizophrenic patients and 40.0% in male schizophrenic patients (Wang et al., 2014).

Hyperprolactinemia (HPRL) has a significant impact on patients’ health and quality of life. Patients often discontinue their medications as a result, compromising the prognosis of the diseases. Therefore, coping with HPRL during treatment has become a challenge for clinicians. In several guidelines, asymptomatic antipsychotic-induced HRPL has no need to be treated, and clinicians should consider alternative medications for patients with symptomatic HPRL (Melmed et al., 2011; Halperin Rabinovich et al., 2013). Some studies suggested other medication treatments such as aripiprazole (Grigg et al., 2017). However, more research is needed to confirm these strategies.

Metformin is a potential treatment for antipsychotics-induced HRPL. In recent years, it is reported that (2.55–3 g/day) high-dose adjuvant metformin therapy can reduce antipsychotics-induced PRL elevation in patients with diabetes or prediabetes (Krysiak et al., 2016). However, previous studies did not have high level of evidence due to small sample sizes, the absence of a placebo group or patients with other diseases. Therefore, this study was proposed to investigate the efficacy and safety of metformin in the treatment of amisulpride-induced HPRL.

In this trial, 86 schizophrenia patients were collected and assigned randomly to treatment with metformin or placebo. After eight weeks of intervention, we found that the PRL level of the metformin group decreased significantly compared to that of the placebo group. This treatment showed no significant adverse effects.

Prolactin (PRL) is mainly secreted by lactotroph cells of the anterior pituitary gland. Its synthesis and release are controlled by peptides, steroids and neurotransmitters. Dopamine released in the hypothalamus is important for regulating PRL as it can inhibit PRL synthesis and secretion. Antipsychotics with D2 antagonism properties can block dopamine receptors in the tuberoinfundibular pathway of the hypothalamus, and therefore induce HPRL (Besnard et al., 2014). Nearly 70% of patients with schizophrenia develop the antipsychotic-induced HPRL. The elevation degree of PRL depends on the affinity for D2 receptors of antipsychotic drugs. The incidence rate of HPRL is as high as 70%–100% in patients taking risperidone, 10%–40% in patients taking olanzapine and quetiapine, and less than 5% in those taking clozapine with no significant symptoms (Melkersson, 2005; Inder and Castle, 2011). It is found that both high and low doses of amisulpride can cause an increase in serum PRL (Andrade, 2013).

There is still no recognized effective treatment for antipsychotic-induced HPRL, which is a thorny problem in clinical treatment. The exploration of its treatment has been a hot spot of research in recent years, and the following strategies are mainly used: (1) Reduce the dosage of antipsychotic drugs. However, reducing the dosage of antipsychotic drugs may lead to the recurrence of the disease and is detrimental to the prognosis of patients. (2) Switching to other antipsychotic drugs with less possibility of causing HPRL (e.g., olanzapine, clozapine, quetiapine, etc.). However, switching to other drugs may not achieve the desired therapeutic effect and has the risk of causing other side effects such as sedation, weight gain, and even diabetes mellitus (Gianfrancesco et al., 2002; McQuade et al., 2004). (3) Combine with dopamine agonists, such as bromocriptine, amantadine, carte blanche, etc. However, there is evidence that dopamine agonists can exacerbate psychiatric symptoms or causes involuntary movements (Lertxundi et al., 2011). (4) Combine with some traditional Chinese medicine, such as Maiya, Sichuan Pepper, dandelions, Achyranthes Bidentata, Ziyin Rougan decoction, and Xiaoyao pills. However, the current studies lack high-level evidence because of their small samples (Yang et al., 2017). (5) Recent studies have shown that aripiprazole adjuvant therapy can reduce antipsychotic-induced HPRL with good tolerance (Raghuthaman et al., 2015; Jiang et al., 2018). It is also found that aripiprazole is effective in risperidone-induced HPRL, but it is not effective in HPRL induced by benzamide antipsychotics (amisulpride, sulpiride) (Chen et al., 2010). It is shown that the effectiveness of aripiprazole in reducing PRL increased with increasing dose, and the effectiveness was significantly higher in the patients with 10 and 20 mg/day than in patients with 5 mg/day (Chen et al., 2015). However, with increasing dose, its adverse effects increased, such as drowsiness and headache, which is harmful to patients’ compliance (Meng et al., 2015). On the other hand, Tomova and Caldwell (2016) suggested in their guidelines that aripiprazole agitates partially D2 receptors, leads to competitive receptor occupancy and may reduce the efficacy of the other antipsychotic drugs. Although the combination of more than two antipsychotics is common in clinical practice, based on systematic evaluation of safety and tolerability, the combination of antipsychotics should be the last option after the failure of monotherapy, conversion therapy, and combination therapy with non-antipsychotics (Gallego et al., 2012).

In recent years, it is reported that adjuvant metformin therapy is effective in antipsychotic-induced HPRL. Krysiak et al. found that metformin reduced plasma PRL levels in postmenopausal women with elevated PRL (Krysiak et al., 2021). In a previous study, 20 female patients with drug-induced HPRL received high-dose metformin treatment for six months (Krysiak et al., 2016). Their PRL levels and blood glucose reduced significantly, which indicated that metformin may benefit patients with drug-related HPRL. Several meta-analysis studies have evaluated the safety and efficacy of adjunct metformin therapy in the treatment of drug-induced HRPL. It was found that the PRL level decreased significantly with no significant increase in the incidence of side effects, which is consistent with our conclusion (Bo et al., 2016; Zheng et al., 2017).

In fact, metformin may have more benefits for patients with schizophrenia. For example, it is found that metformin is effective for antipsychotic-induced amenorrhea and weight gain in female patients (Wu et al., 2012). Furthermore, in patients with prolactinomas, metformin was reported to be able to reduce PRL levels and shrink the tumor. A hypothesis suggests that metformin may influence the activation of the LKB1/adenosine monophosphate-activated protein kinase (AMPK) pathway, which is involved in the synthesis and secretion of PRL (Liu et al., 2018).

The mechanisms of metformin in drug-induced HRPL are not figured out so far. There are some hypotheses based on current evidence. It is believed that metformin can inhibit the secretory function of overactive lactotrophs by targeting the pituitary, and therefore decrease the secretion of thyrotropin and PRL (Vigersky et al., 2006; Krysiak et al., 2015, 2021). This process is related to the dopaminergic regulation function of metformin (Vigersky et al., 2006; Cappelli et al., 2009). Dopamine is important for the synthesis and secretion of PRL. Drug-induced HRPL will lead to a decrease in the number or affinity of dopamine receptors. Metformin is able to improve the local dopamine action and therefore reduces the PRL level (Krysiak et al., 2016, 2018).

Long-term use of metformin may lead to some side effects, so we investigated the incidence of side effects in this study. We found no significant difference in the incidence of side effects in the metformin group compared with the placebo group. Meanwhile, there was no difference in blood lipids between the two groups. Although the blood glucose showed a significant difference between the two groups after the intervention, the blood glucose levels had relatively minor changes and had few risks of leading to hypoglycemia. These results indicated that the adjuvant metformin therapy has good security.

In conclusion, adjuvant metformin treatment can improve amisulpride-induced HPRL. This strategy has few adverse effects and can be promoted clinically. More research should be investigated in this field. For instance, In this research, participants were middle-aged and elder patients with a long duration of disease. It would be meaningful to investigate the efficacy and safety in different age groups in future studies. In addition, the effect of metformin on HPRL may not be fully revealed as the eight weeks intervention maybe not be long enough, and the decrease of PRL under the influence of drug intervention was significant but not satisfactory enough. In the future, the length of metformin intervention will be extended to six months to further evaluate the effect of long-term metformin administration on the PRL level.

The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding authors.

The studies involving human participants were reviewed and approved by the Ethics Committee of Shanghai Mental Health Center (ethical approval number: 2019-53). The patients/participants provided their written informed consent to participate in this study.

CZ, JZ, and ZJ designed this study. CZ, RL, JZ, ZJ, MJ, and XX performed the experiments. CZ and RL analyzed the data and prepared the manuscript. T-FY revised it critically for important intellectual content and contributed to the final version of this manuscript. All authors have read and approved the manuscript.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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