Adjunctive metformin for antipsychotic-related hyperprolactinemia: A meta-analysis of randomized controlled trials

Abstract

Hyperprolactinemia is a common and severe antipsychotic-induced adverse drug reaction. This meta-analysis of randomized controlled trials systematically examined the efficacy and safety of adjunctive metformin for antipsychotic-related hyperprolactinemia in schizophrenia patients. Two independent investigators searched, extracted, and synthesized data. Weighted mean differences and risk ratios with their 95% confidence intervals were calculated using random effect model. Four randomized controlled trials ( n=509) comparing adjunctive metformin ( n=253) with the control groups ( n=256), lasting 22.7 weeks of treatment, were included in the meta-analysis. The metformin group had significantly lower serum prolactin level at endpoint (four randomized controlled trials, n=501; weighted mean difference: -6.87 ug/L (95% confidence interval: -13.24 to -0.51), p=0.03; I80%) with "moderate quality" based on the grading of recommendations assessment, development, and evaluation system. In patients with menstrual disturbances, the rate of menstruation resumption was 66.7% in the metformin group and 4.8% in the control group. Adverse drug reactions and all-cause discontinuation (three randomized controlled trials, n=339, risk ratio: 0.76 (95% confidence interval: 0.29, 1.97), p=0.57; I= 0%) were similar between the two groups. Adjunctive metformin appears to be effective and safe for reducing antipsychotic-induced hyperprolactinemia and prolactin-related symptoms in schizophrenia patients. Higher quality randomized controlled trials with a large sample size are warranted to confirm these findings.

The impact of pharmacological and non‐pharmacological interventions to improve physical health outcomes in people with schizophrenia: a meta‐review of meta‐analyses of randomized controlled trials

“…Of 3,709 search engine hits, 27 meta‐analyses were included, representing a total of 128 meta‐analyzed trials and 47,231 study participants.…”

“…There were meta‐analytic data for 17 different pharmacological interventions: aripiprazole augmentation, fluoxetine, metformin, nizatidine, NMDA receptor antagonists including amantadine and memantine, ranitidine, topiramate, dextroamphetamine, d‐fenfluramine, famotidine, metformin in combination with sibutramine, orlistat, rosiglitazone, fluvoxamine, glucagon‐like peptide‐1 receptor agonists (GLP‐1 RAs), and switching from olanzapine to quetiapine or aripiprazole.…”

Cardiometabolic risk factors in young women with macroprolactinaemia

“…Unlike elevated levels of monomeric prolactin, which are easy to treat with dopamine agonists, particularly with cabergoline [14], the reduction in big-big prolactin content was observed only in some subjects with macroprolactinaemia [5,30]. Moreover, testosterone [31] and metformin [32] did not affect macroprolactin levels (although metformin was found to reduce concentrations of monomeric prolactin [33,34]), while ethinyl estradiol plus levonorgestrel led to an increase in its content [35].…”

The Impact of Ethinyl Estradiol on Metformin Action on Prolactin Levels in Women with Hyperprolactinemia

“…Unlike the intact pituitary, metformin administered to patients with overactivity of thyrotropes, gonadotropes and lactotropes reduced circulating levels of various pituitary hormones: thyrotropin [6,7], follicle-stimulating hormone [8], luteinizing hormone [8,9] and prolactin [10][11][12][13][14][15]. Metformininduced changes in prolactin levels were observed irrespective of the underlying disorder in hyperprolactinemia induced by prolactin-secreting microadenoma [10], traumatic brain injury [10], empty sella syndrome [10], polycystic ovary syndrome [9,11], as well as in women with hyperprolactinemia induced by antipsychotics [12][13][14][15]. These changes were limited to monomeric prolactin, because in subjects with excess of macroprolactin the drug did not affect circulating levels of prolactin before and after polyethylene glycol precipitation [16].…”