The Safety of Carbergoline Versus Placebo for Antipsychotic Induced Hyperprolactinemia: A Pragmatic, Randomised, Non-inferiority Trial With Blinded Outcome.

Antipsychotic (AP) medication is the cornerstone of treatment in patients with schizophrenia, but may be used in patients with depression, severe anxiety, or bipolar disorders. The main regulator of prolactin is exerted by the inhibitory effect of hypothalamic dopamine through its agonistic effects on pituitary D2-receptors. The majority of antipsychotic drugs require a 50 to 60% antagonistic occupancy of the D2 receptor for optimal effect, which explains why hyperprolactinemia is observed in 30% to 70% of patients on AP treatment. Hyperprolactinemia may cause gynecomastia, galactorrhea, infertility, menstrual irregularities, osteopenia, sexual dysfunction, and erectile dysfunction in men, while metabolic and cardiovascular disturbances are currently debated5 - serious side effects that may contribute to the low adherence rates of antipsychotic treatment in patients with schizophrenia spectrum disorders. The consistent association between lack of adherence to treatment and hospitalisation, acute care utilization, and relapse prevention highlights the importance of safe antipsychotic treatment with acceptable side effects. Unacceptable side effects to AP treatment may incline patients and physicians to abandon otherwise successful AP treatment and pursue treatment with less potent antipsychotic properties but with fewer and acceptable side effects. Since 2015, the proportion of Danish citizens treated with antipsychotics has increased every year up to 144.000 in 2023, corresponding to an increase of 19% in less than a decade.

While the effect of prolactin on breast tissue is a direct result of prolactin binding to prolactin receptors the other symptoms of hyperprolactinemia are mainly indirect through reduced gonadotropin levels, i.e. estrogen and testosterone; high prolactin levels result in decreased kisspeptin in the hypothalamus and consequently gonadotropin-releasing hormone (GnRH) release is reduced which leads to lower secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), which is then followed by lower levels of estradiol and testosterone. It could also be hypothesised that hyperprolactinemia may have unwarranted metabolic effects, as often observed in patients in antipsychotic treatment. Current strategies for reducing antipsychotic induced hyperprolactinemia include a change of AP treatment, aripiprazole, estrogen or testosterone supplementation, metformin, or a dopamine receptor agonist (DRA) - i.e. cabergoline or bromocriptine. Once effective APT has been established, changing or reducing the drug or dose is often not desirable, and only aripiprazole, metformin, and DRAs will address both direct and indirect effects of hyperprolactinemia. From an endocrine perspective, treatment with DRAs is tempting due to the fast and highly effective prolactin-lowering properties, the low prevalence of side effects, and administration once or twice weekly (cabergoline).

However, from a theoretical point DRA-treatment may be problematic due to the opposing effects of antipsychotics and DRAs on the dopamine receptor, which may cause exacerbations of psychotic symptoms, which is why endocrinologists are reluctant to introduce DRAs for AP-induced hyperprolactinemia. However, several observational studies have shown significant effect of DRAs on prolactin levels and symptoms associated with AP induced hyperprolactinemia without any adverse effects to psychopathological status, while one RCT found worsening of psychotic symptoms in 1/2018 comparing bromocriptine with a herbal product and only one RCT has examined bromocriptine versus placebo in 60 patients without identifying any worsening in psychopathology. None of the RCT's used blinded outcome assessment, and none of the studies used cabergoline, which is the dopamine receptor agonist with the least number of adverse events, and only requires administration once or twice weekly.

Main objective • Assessing the safety of cabergoline for antipsychotic induced hyperprolactinemia in men and pre-menopausal women with schizophrenia spectrum disorders concerning positive and negative symptoms in a randomised, parallel group, non-inferiority trial with blinded outcome assessment.

Main hypothesis