Here, we report a depressed adolescent female with psychotic symptoms who developed lactation after treatment with blonanserin and lactation management. Blonanserin causes elevated prolactin via the same mechanism as most antipsychotics; both agents reduce the inhibition of prolactin secretion release by antagonizing the D₂ receptor in the nodal funnel pathway, which in turn causes increased prolactin[1]. However, D₂ receptor blockade in the nodal funnel pathway is different because of the presence of the blood‒brain barrier. The B/P (brain/pituitary) ratio of antipsychotics is proposed to reflect the difficulty of entering the brain through the blood–brain barrier; the higher the B/P ratio is, the easier it is for the drug to enter the brain, and the lower the B/P ratio is, the more difficult it is for the drug to enter the brain through the blood–brain barrier. D2 receptor blockade in the pituitary is stronger; for example, the B/P ratio of sulpiride was 0.34, that of risperidone was 1.61, that of olanzapine was 2.70[3], and that of blonanserin was 3.88[4]. The results indicate that blonanserin exhibits a lesser potential to induce prolactin levels as compared to other antipsychotic medications.
Although the pharmacological mechanism indicates that blonanserin increases prolactin levels in patients, this phenomenon has rarely been observed in clinical trials of blonanserin. This is likely due to the antagonistic effect of 5-HT2A receptors, which increase dopaminergic activity[5] and thus reduce elevated prolactin levels, resulting in a less frequently observed prolactin elevation induced by blonanserin in clinical trials.
Short-term hyperprolactinemia causes amenorrhea, decreased libido, and infertility in women and decreased libido and infertility in men, and long-term hyperprolactinemia causes osteoporosis and breast cancer. However, elevated prolactin levels do not necessarily lead to lactation because prolactin, which is synthesized and secreted by the anterior pituitary gland, has a variety of isomeric forms. Among them, the most abundant is monomeric prolactin, which has biological and immunological activities, and less than 10% are tetramers with lower biological activities and polymers of immunoglobulins and monomeric prolactin, called macrolactin[6]. Because the presence of macroprolactin affects the actual detection of prolactin, the Chinese expert consensus recommends that screening for macroprolactin should be considered in cases of elevated prolactin levels without clinical symptoms or in cases where symptoms do not explain the degree of elevation[7]. Therefore, screening for macroprolactin is especially needed in cases in which clinical manifestations cannot be matched with laboratory test results. Currently, when antipsychotics that influence prolactin levels are used, baseline prolactin levels must be measured. If the patient's prolactin level is elevated and < 2000 mIU/L (94.34 ng/ml) after starting antipsychotic therapy and if the patient does not have symptoms of hyperprolactinemia, close follow-up observation can be performed. When patients have symptoms of elevated prolactin > 2000 mIU/L (94.34 ng/ml), clinicians need to consider the need to reduce the antipsychotic dose, switch to a prolactin-sparing antipsychotic, combine with aripiprazole, combine with a dopaminergic drug, and refer patients to an endocrinologist. When the prolactin level is > 2000 mIU/L, the patient needs to be excluded from having a pituitary tumor[8].
Second-generation antipsychotics are increasingly used to treat depression, both as a treatment for depression with psychotic symptoms and as potentiators of antidepressants. Second-generation antipsychotics approved by the Food and FDA for the treatment of schizophrenia in adolescents include aripiprazole, lurasidone, olanzapine, quetiapine, and risperidone. It is particularly important to choose drugs with fewer adverse effects, both in terms of efficacy and improving patient adherence to medication. A randomized, double-blind, placebo-controlled, multicenter study showed that blonanserin was effective in the treatment of acute schizophrenia and had better efficacy for negative symptoms than haloperidol, and blonanserin was well tolerated. The incidence of EPS with 10 mg blonanserin (26.6%) was significantly lower than that with 10 mg haloperidol (53.3%), which resulted in a sustained increase in prolactin levels. However, this phenomenon has not been observed in patients taking blonanserin[9]. Prospective, multicenter, open-label postmarketing surveillance showed that blonanserin significantly improved psychiatric symptoms in female schizophrenic patients between the ages of 18 and 40 years while being well tolerated and that only 1% of the patients in the surveillance had elevated prolactin levels, and no patients were lactating[10]. At present, clinical trials of blonanserin have been conducted for schizophrenic patients; serious adverse reactions leading to lactation were not observed in schizophrenic patients, while clinical trials for adolescent schizophrenic patients did not observe such adverse reactions, and a multicenter, double-blind, randomized, placebo-controlled study showed that adolescent schizophrenic patients who were taking blonanserin after their psychiatric symptoms were effectively controlled. Blonanserin is a second-generation antipsychotic approved for use in adolescents in Japan because it is usually associated with mild adverse events[11]. However, this case suggests that when blonanserin is used, the possibility of developing hyperprolactinemia leading to lactation still needs to be considered.
A study revealed that the use of blonanserin transdermal patches was more effective at reducing the occurrence of EPS than the use of oral tablets[12], which also suggests that transdermal patches can reduce the increase in prolactin levels compared with the use of tablets; however, these findings need to be verified by additional studies. At the same time, the current clinical trials for blonanserin are all for patients with schizophrenia, and the published results of these studies have not shown that blonanserin causes lactation in patients. There is still a gap in clinical trials for depressed patients with psychotic symptoms, and there is still a need to expand the study population and conduct statistical analyses in the future.
This study aims to draw the attention of clinicians to the importance of comprehensive evaluation of adolescent depressed patients before and after antipsychotic use and the management of prolactin.