Dr. Howland is Associate Professor of Psychiatry, University of Pittsburgh School of Medicine, Western Psychiatric Institute and Clinic, Pittsburgh, Pennsylvania.
The author discloses that he has no significant financial interests in any product or class of products discussed directly or indirectly in this activity, including research support.
Address correspondence to Robert H. Howland, MD, Associate Professor of Psychiatry, University of Pittsburgh School of Medicine, Western Psychiatric Institute and Clinic, 3811 O’Hara Street, Pittsburgh, PA 15213; e-mail: HowlandRH@upmc.edu.
The clinical efficacy and tolerability profiles of individual drugs are determined based on evidence from placebo-controlled studies. Simply comparing outcomes from different placebo-controlled studies cannot establish relative efficacy and tolerability among drugs for a particular indication. Head-to-head comparisons of drugs with distinct pharmacological differences often reveal subtle, or not so subtle, differences in efficacy or tolerability. Such differences can often be explained or predicted based on the particular pharmacological properties of each drug. To demonstrate the clinical importance of understanding the distinct pharmacology of a drug, I will describe the pharmacology and clinical profile of the novel antidepressant drug mirtazapine (Remeron®).
Pharmacology of Mirtazapine
Mirtazapine is a 6-aza derivative of mianserin, which is a tetracyclic antidepressant drug that acts primarily at presynaptic alpha-2 adrenergic receptors. Mirtazapine has a unique constellation of neurotransmitter receptor effects that enhance serotonin (5-HT), norepinephrine (NE), and dopamine (DA) transmission, but it has virtually no effect on neurotransmitter reuptake transporters (Anttila & Leinonen, 2001). Mirtazapine blocks inhibitory presynaptic alpha-2 autoreceptors, which increases the release of NE; in addition, it blocks alpha-2 heteroreceptors located on 5-HT neurons, which facilitates 5-HT release. Mirtazapine has low affinity (weak binding) for alpha-1, 5-HT-1A, 5-HT-1B, and 5-HT-1D receptor subtypes but may have mild 5-HT-1A receptor stimulating effects. Because mirtazapine also blocks postsynaptic 5-HT-2 and 5-HT-3 receptors, it focuses 5-HT transmission through 5-HT-1A receptors. Although mirtazapine has a low affinity for DA receptors and reuptake transporters, its NE and 5-HT receptor effects secondarily lead to increased DA transmission in the prefrontal cortex and other brain regions (Borkowska, Drozdz, Ziolkowska-Kochan, & Rybakowski, 2007). Mirtazapine has a high affinity (strong binding) for histamine H-1 receptors but a low affinity for muscarinic cholinergic receptors.
Comparative Efficacy of Mirtazapine for Depression
The antidepressant efficacy of mirtazapine has been established in multiple randomized placebo-controlled studies, as well as in controlled trials using both older and newer generation antidepressant drugs as active controls (Szegedi & Schwertfeger, 2005). Mirtazapine was found to be significantly more effective than trazodone (Desyrel®) in one study and equally effective in another study (Anttila & Leinonen, 2001). Mirtazapine was as effective as the tricyclic antidepressant (TCA) drugs amitriptyline (Elavil®) in five studies, doxepin (Sinequan®) in one study, and clomipramine (Anafranil®) in another study, but superior to clomipramine in a second study and inferior to imipramine (Tofranil®) in an inpatient study (Anttila & Leinonen, 2001; Jin-Hong, Chang-An, & Chun-Ping, 2006).
Numerous studies have now compared mirtazapine and various serotonin reuptake inhibitor (SRI) antidepressant drugs, including fluvoxamine (Luvox®), fluoxetine (Prozac®), paroxetine (Paxil®), sertraline (Zoloft®), and citalopram (Celexa®). One meta-analysis of 10 published studies found statistically similar response rates for mirtazapine (67.1%) and the SRIs (62.1%) (Papakostas, Homberger, & Fava, 2008). A second meta-analysis of 10 published and 3 unpublished studies also found similar response rates for mirtazapine (64.8%) and the SRIs (61.2%), although this small difference was statistically significant because of the large sample of 13 studies (Papakostas, Thase, Fava, Nelson, & Shelton, 2007).
The serotonin norepinephrine reuptake inhibitor (SNRI) venlafaxine (Effexor®) is the only other newer generation antidepressant drug that has been directly compared to mirtazapine. In one study, nonstatistically significant trends favored the mirtazapine-treated patients on the main outcome measures (Guelfi, Ansseau, Timmerman, & Korsgaard, 2001). In a second study, designed to compare the onset of antidepressant action of the two drugs, no difference in outcome was found by the end of the 6-week study (Benkert et al., 2006).
It has been suggested that drugs with mixed neurotransmitter receptor effects may have a more rapid onset of effect compared with single neurotransmitter antidepressant drugs. A retrospective meta-analysis of data from three studies comparing mirtazapine and a different SRI per study demonstrated that mirtazapine had significantly earlier antidepressant effects than the SRIs, although there was no difference by the end of the study periods (Quitkin, Taylor, & Kremer, 2001). Another study, designed to prospectively compare the onset of action of mirtazapine and sertraline, confirmed that mirtazapine has a significantly faster therapeutic onset (Behnke et al., 2003). In the Benkert et al. (2006) study, designed prospectively to compare the onset of antidepressant action, mirtazapine had a significantly faster effect than venlafaxine.
The two main strategies for treating those who do not respond to antidepressant drugs are switching or combining medications. On the basis of pharmacological differences, either switching to or adding mirtazapine to other antidepressant drugs is theoretically justified for nonresponders. Open-label studies have suggested that switching to mirtazapine is effective for patients who have not shown an adequate response to SRIs or other antidepressant drugs (Wan, Kundhur, Solomons, Yatham, & Lam, 2003). In addition, the combination of mirtazapine plus venlafaxine has been suggested as a pharmacologically potent therapy for treatment-resistant depression (Malhi, Ng, & Berk, 2008).
In a randomized controlled trial, patients who had failed to respond to at least 4 weeks of monotherapy with a newer generation antidepressant drug (an SRI, venlafaxine, or bupropion [Wellbutrin®]) continued to take the ineffective drug and were randomly assigned to receive 4 weeks of augmentation with either mirtazapine or placebo (Carpenter, Yasmin, & Price, 2002). Response rates for mirtazapine augmentation (63.6%) were significantly better than for placebo (20%). Of the patients who did not respond to placebo (n = 9) and were treated openly with mirtazapine at the end of the study, 5 (55.6%) remitted.
A more recent study was designed prospectively to compare the efficacy and tolerability of mirtazapine and sertraline in patients with depression who had not responded to an adequate course of therapy with an SRI antidepressant drug (fluoxetine, paroxetine, or citalopram) (Thase, Simmons, Howland, & Fava, in press). Patients were randomly assigned to 8 weeks of double-blind treatment with either mirtazapine or sertraline. There were no significant differences between mirtazapine and sertraline on any efficacy measure by the end of the study, although response and remission occurred significantly faster in mirtazapine-treated patients.
In the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, the efficacy and tolerability of various antidepressant therapies were evaluated through four sequential treatment steps (Rush et al., 2006). For patients who did not respond to the first two treatment steps, the third step involved either switching (to mirtazapine or nortriptyline [Pamelor®]) or augmentation (adding lithium [Eskalith®] or the thyroid hormone liothyronine sodium [Cytomel®]). Remission rates for mirtazapine (12.3%), nortriptyline (19.8%), lithium (15.9%), and liothyronine sodium (24.7%) were not significantly different. Those patients who did not respond to this third step were randomly switched to the monoamine oxidase inhibitor tranylcypromine (Parnate®) or to the combination of venlafaxine plus mirtazapine. Remission rates were not significantly different between the two treatment groups (6.9% for tranylcypromine, 13.7% for venlafaxine plus mirtazapine).
Comparative Tolerability of Mirtazapine
In placebo-controlled studies, the most common side effects reported during mirtazapine therapy are sedation, dizziness, dry mouth, increased appetite, and weight gain (Anttila & Leinonen, 2001). Mirtazapine’s specific adrenergic and antihistaminic effects are the most likely explanation for these side effects. Compared with TCAs, mirtazapine is less likely to cause various anticholinergic side effects or to be associated with adverse cardiovascular effects (Szegedi & Schwertfeger, 2005). The low affinity for alpha-1 receptors explains the low incidence of orthostatic hypotension and tachycardia. The potent antihistamine effects contribute to its sleep enhancing effects, as well as sedation, increased appetite, and weight gain. The weak anticholinergic effects explain the low rates of blurred vision and constipation. Drugs with potent anticholinergic effects can impair cognition. As noted above, mirtazapine secondarily increases DA transmission in the prefrontal cortex, and this effect has been used therapeutically to improve cognition in depression (Borkowska et al., 2007). Fewer treatment-emergent side effects and dropouts due to adverse events occur with mirtazapine compared with TCA drugs in the majority of comparative studies (Anttila & Leinonen, 2001), although side effect attrition rates were similar for mirtazapine and nortriptyline in the STAR*D study (Rush et al., 2006).
Compared with SRI drugs, mirtazapine is more likely to be associated with drowsiness, dry mouth, and weight gain because of its antihistaminic effects, but it is less likely to be associated with insomnia, nausea, diarrhea, headache, agitation, or sexual dysfunction (Papakostas et al., 2008). Blockade of 5-HT-2 and 5-HT-3 receptors may specifically contribute to its sleep promoting and antianxiety effects, antinausea and antiemetic effects, and relative lack of adverse sexual effects. Because mirtazapine is less likely to cause adverse sexual effects compared with SRIs, open-label studies have suggested that adding mirtazapine to SRIs may alleviate sexual dysfunction (Ozmenler et al., 2008); however, a randomized placebo-controlled study found no benefit with the added use of mirtazapine for SRI-associated sexual dysfunction (Michelson, Kociban, Tamura, & Morrison, 2002). Although the side effect profile of mirtazapine and the SRIs are very different, comparative studies have found that overall side effect-related dropout rates are fairly similar.
Compared with venlafaxine, mirtazapine is more likely to be associated with drowsiness and weight gain but less likely to be associated with insomnia, nausea, diarrhea, headache, or sexual dysfunction. In the comparative study by Guelfiet al. (2001), fewer mirtazapine-treated patients dropped out because of side effects. Side effect attrition rates were greater for tranylcypromine compared with the combination of venlafaxine plus mirtazapine in the STAR*D study (Rush et al., 2006).
Mirtazapine is a pharmacologically unique agent among antidepressant drugs. Clinical studies have demonstrated similar overall efficacy for mirtazapine compared with the SRIs and venlafaxine but a more rapid onset of antidepressant effect compared with these drugs and a substantially different side effect profile. Although drug pharmacology might seem an arcane topic for nurses, this knowledge can help them better understand differences in the efficacy and tolerability of various drugs. This knowledge also provides a rationale for clinical decisions such as choosing one drug over another for a particular patient or switching or combining drugs for treating nonresponders or alleviating side effects.
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