One of the ironies of clinical practice is the emergence or worsening of the symptoms being initially treated. In the case of depression, the FDA has required that the literature for several antidepressants include warnings about the worsening of depression or even the precipitation of suicide. Although this 2004 advisory is an interim action by the agency, it is intended to encourage careful monitoring of patients using these drugs, especially at the start of therapy or during adjustments in dosing. In addition, it is intended to draw attention to the need for care in diagnosing mental ailments.
The FDA notes that this additional warning in packaging labeling applies to the entire category of antidepressants due to a lack of data that can exclude any particular drug from an associated risk of suicide. Even though it has been proven effective in the treatment of depression, mirtazapine is among the drugs cited in the FDA report.
The currently available antidepressants fall into several general categories: monoamine oxidase inhibitors (MAOIs), tricyclics, selective serotonin reuptake inhibitors, norepinephrine reuptake inhibitors, combined serotonin-norepinephrine inhibitors, and 5-hydroxytryptamine-3 (5-HT-3) antagonists. Mirtazapine is distinct from these categories, representing an alpha-2, 5-HT-2/5-HT-3 antagonist. By apparent increases in both serotonin and norepinephrine neurotransmission, the onset of mirtazapine activity may be increased over previous agents.
Administration and Dosing
Mirtazapine is available in 2 forms for oral administration: conventional and rapidly disintegrating tablets. To treat major depression, the starting dose is 15 mg, administered at bedtime. Dosing may be increased at 2-week intervals to a daily maximum of 45 mg. Food does not appear to affect dosing. Bedtime dosing takes advantage of the sedative effects of mirtazapine. The prolonged half-life of mirtazapine requires careful dosing among the elderly, in whom plasma concentrations may become elevated.
A 2-week interval is recommended when switching to or from mirtazapine and any MAOI drug. Depressive episodes may require up to 6 months of treatment with mirtazapine for full therapeutic benefit.
The rapidly disintegrating tablets should be removed from their blister pack just prior to administration, with care to use dry hands and not to break the tablet. The tablet dissolves rapidly on the tongue and can be swallowed with saliva. Additional water during administration is not considered necessary.
Safety Profile and Drug Interactions
Mirtazapine is a powerful histamine1 receptor blocker in the central nervous system, a trait that accounts for its strong sedative property. Alpha-adrenergic blocking activity may explain the occasional orthostatic hypotension noted with the drug. The moderate antagonism at cholinergic receptors, however, accounts for its comparatively low incidence of anticholinergic activity.
Mirtazapine is associated with a 0.1% risk of agranulocytosis and neutropenia. It may increase appetite, with weight gain occurring in some patients.
Other side effects include increases in serum cholesterol and triglyceride levels, with occasional constipation and xerostomia. Rare cases of pancreatitis have been reported.
Treatment of major depression requires a careful diagnosis to rule out underlying bipolar disease. While patients are on any antidepressant treatment, they should be monitored for any worsening of the condition or even suicidal ideation, especially at the start of treatment or during adjustments in dosing.
Mirtazapine is available in 15-, 30-, and 45-mg doses from Prasco Laboratories.
Mr. Middleton is an instructor of pharmacology for Kellogg Community College in Battle Creek, Mich.
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