Relationship between mirtazapine dose and incidence of adrenergic side effects: An exploratory analysis

INTRODUCTION: Mirtazapine is an antidepressant with US Food and Drug Administration approval for management of major depressive disorder. Low doses of mirtazapine are often used for management of insomnia, with higher doses expected to provide more noradrenergic effect, and thus a higher degree of activation. If so, use of higher doses at bedtime may not be advisable and may worsen certain neuropsychiatric symptoms. No studies have been performed to evaluate these outcomes. METHODS: This study consisted of a retrospective review of data submitted to the US Food and Drug Administration's Adverse Event Reporting System from January 1, 1995, to August 1, 2015. Cases that were deemed by study authors to represent activation of the noradrenergic system, and for which other confounders could not be identified, were included in the final analysis. The frequency of each specific adverse event was evaluated based on dose and compared to recent prescribing rates to determine if likelihood of a side effect increased with higher dose. RESULTS: The study identified 308 incidences of anxiety, agitation, delusion, hallucination, hypertension, insomnia, nightmare, or tachycardia. After controlling for frequency of prescribing at a given dose, there was a statistically significant increase in rates of tachycardia which correlated with dose. However, after correction for multiple comparisons, results were no longer significant. DISCUSSION: This study failed to support the hypothesis that mirtazapine is more activating at higher doses and appears to support the safety of increasing dose without increasing risk of noradrenergic side effects. Prospective studies will be necessary to confirm these findings.