Treatment strategies for antipsychotic-induced hyperprolactinemia.
Hyperprolactinemia is a common adverse effect of long-term antipsychotic treatment in patients with psychotic disorders due to dopamine D2 receptor antagonism in the tuberoinfundibular pathway,1 but is also seen in patients with first-episode psychosis.2 Potential acute effects of hyperprolactinemia are amenorrhea, galactorrhea, sexual dysfunction, decreased fertility, and gynecomastia, and common long-term effects include osteoporosis and hypogonadism.3
Current interventions for treatment of symptomatic and asymptomatic hyperprolactinemia include reducing dose or switching antipsychotic medications, or the use of adjunctive medications. Labad and colleagues4 conducted a systematic review and meta-analysis of various pharmacological treatment strategies for lowering prolactin levels in patients with psychosis and antipsychotic-induced hyperprolactinemia. Additionally, the clinician should always consider other medical etiologies to the hyperprolactinemia, such as the possibility of a pituitary adenoma.
The authors searched PubMed, Scopus, PsycINFO, and ClinicalTrials.gov, and included articles written in English, Spanish, German, or French between January 1980 to March 2020. They included clinical trials and observational studies of 4 therapeutic options for lowering prolactin in patients with psychotic disorders: switching antipsychotic treatment, adding aripiprazole, adding other dopamine agonists, or adding metformin. Studies had information on prolactin levels at baseline and follow-up. They excluded case reports/series (n < 5) and studies where the primary reason for the therapeutic strategy was not hyperprolactinemia.
The primary outcome measure was change in prolactin levels from baseline to last available follow-up. The secondary outcome was withdrawal rates because of safety issues. The authors estimated effect sizes (Hedges’ g) for the change in prolactin for each study and performed a meta-analysis for randomized controlled trials (RCTs) that either used placebo or maintained antipsychotic treatment as a comparator arm. The risk of bias was evaluated using a standardized Cochrane tool and explored potential publication bias with funnel plots.
The authors identified 26 studies, including 7 RCTs. Most studies focused on 1 therapeutic strategy, and on adult patients with chronic, but clinically stable, schizophrenia. Seventeen (65%) studies were conducted in Asian counties. Nine studies explored antipsychotic switching (n = 4 for aripiprazole); 12 studies investigated adjunctive aripiprazole; and 6 studies explored adding other dopamine agonists.
None of the 9 antipsychotic switch studies included a placebo-controlled group; therefore a meta-analysis was not undertaken. However, effect sizes for switching to aripiprazole or quetiapine were higher than those for other agents, with the strongest evidence for switching to aripiprazole. Five RCTs evaluated the addition of aripiprazole. There was evidence for significant reduction in prolactin with this strategy with a large effect size (Hedges’ g = -1.35). One open-label study found greater effect sizes for prolactin reduction for 10 mg to 20 mg versus 5 mg/day.
Using the Oxford Centre for Evidence-Based Medicine (CEBM) guidelines, the authors rated adjunctive aripiprazole at a higher level than a switch to this agent. There were also 3 open-label studies that found adjunctive treatment with the dopamine agonist cabergoline was associated with significant reduction in prolactin, and according to CEBM guidelines this strategy was rated at the same level as switching to aripiprazole. In terms of secondary outcomes, there was an 18% withdrawal rate for switching to aripiprazole (8.1% for worsening psychopathology). In placebo-controlled RCTs, the withdrawal rate for the adjunctive aripiprazole was 10.1%, versus 11.5% for placebo. The withdrawal rate for adjunctive cabergoline was 2.9%.
The authors concluded that the addition of aripiprazole to the antipsychotic had the highest level of evidence for lowering prolactin. Switching to a prolactin-lowering antipsychotic (eg, including aripiprazole) has been less studied, and few studies have considered the addition of dopamine agonists. There is no evidence for difference in safety with the addition of aripiprazole, and the withdrawal rate due to worsening psychopathology with aripiprazole is <10%. The authors noted that the primary limitations of the review are the small number of available RCTs and that the majority of trials of adjunctive aripiprazole in the meta-analysis (n = 4 of 5) were conducted in Asian countries.
The bottom line
Addition of aripiprazole is the best-studied strategy for lowering prolactin in patients with schizophrenia and related psychotic disorders.
Dr Miller is Professor, Department of Psychiatry and Health Behavior, Augusta University, Augusta, GA. He is the Schizophrenia Section Chief for Psychiatric Times. The author reports that he receives research support from Augusta University, the National Institute of Mental Health, the Brain and Behavior Research Foundation, and the Stanley Medical Research Institute.
1. Montgomery J, Winterbottom E, Jessani M, et al. Prevalence of hyperprolactinemia in schizophrenia: association with typical and atypical antipsychotic treatment. J Clin Psychiatry. 2004;65:1491-1498.
2. Gonzalez-Blanco L, Greenhalgh AMD, Garcia-Rizo C, et al. Prolactin concentrations in antipsychotic-naive patients with schizophrenia and related disorders: a meta-analysis. Schizophr Res/ 2016;174:156-160.
3. MelmedS, Casanueva FF, Hoffman AR, et al. Diagnosis and Treatment of Hyperprolactinemia: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2011;96(2):273-88. doi: 10.1210/jc.2010-1692.
4. Labad J, Montalvo I, Gonzalez-Rodriquez A, et al. Pharmacological strategies for lowering prolactin in people with a psychotic disorder and hyperprolactinemia: a systematic review and meta-analysis. Schizophr Res. 2020; https://doi.org/10.1016/j.schres.2020.04.031