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Mirtazapine

A Review of its Use in Major Depression

Summary

Abstract

Mirtazapine is a noradrenergic and specific serotonergic antidepressant (NaSSA) which has predominantly been evaluated in the treatment of major depression. The drug had equivalent efficacy to tricyclic antidepressants and it was at least as effective as trazodone in the majority of available short term trials in patients with moderate or severe depression, including those with baseline anxiety symptoms or sleep disturbance and the elderly. A continuation study also showed that sustained remission rates were higher with mirtazapine than with amitriptyline and that the drugs had similar efficacy for the prevention of relapse. There is some evidence for a faster onset of action with mirtazapine than with the selective serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitors (SSRIs). Mirtazapine was more effective than the SSRI fluoxetine at weeks 3 and 4 of therapy and it was also more effective than paroxetine and citalopram at weeks 1 and 2, respectively, in short term assessments (6 or 8 weeks). Preliminary data suggest that the drug may be effective as an augmentation or combination therapy in patients with refractory depression.

Anticholinergic events and other events including tremor and dyspepsia are less common with mirtazapine than with tricyclic antidepressants. There was a greater tendency for SSRI-related adverse events with fluoxetine than with mirtazapine, but, overall, mirtazapine had a similar tolerability profile to the SSRIs. Increased appetite and bodyweight gain appear to be the only events that are reported more often with mirtazapine than with comparator antidepressants. In vitro and in vivo data have suggested that mirtazapine is unlikely to affect the metabolism of drugs metabolised by cytochrome P450 (CYP)2D6, although few formal drug interaction data are available.

Conclusions: Mirtazapine is effective and well tolerated for the treatment of patients with moderate to severe major depression. Further research is required to define the comparative efficacy of mirtazapine in specific patient groups, including the elderly and those with severe depression. Clarification of its efficacy as an augmentation therapy and in patients with refractory depression and its role in improving the efficacy and reducing the extrapyramidal effects of antipsychotic drugs would also help to establish its clinical value. The low potential for interaction with drugs that are metabolised by CYP2D6, including antipsychotics, tricyclic antidepressants and some SSRIs, may also make mirtazapine an important option for the treatment of major depression in patients who require polytherapy. Mirtazapine also appears to be useful in patients with depression who present with anxiety symptoms and sleep disturbance.

Pharmacodynamic Properties

Mirtazapine enhances noradrenergic and 5-HT1A-mediated serotonergic neurotransmission via antagonism of central (α2-adrenergic autoreceptors and heteroreceptors and postsynaptic blockade of 5-HT2 and 5-HT3 receptors. The drug does not inhibit noradrenaline (norepinephrine) or serotonin reuptake. Mirtazapine has low in vitro affinity for central and peripheral dopaminergic, cholinergic and muscarinic receptors, but has high affinity for central and peripheral histamine H1 receptors. However, it appears that the antihistaminergic effects of the drug are counteracted by noradrenergic transmission when the drug is commenced at dosages ≥15 mg/day, i.e. within the recommended dosage range.

Single doses of mirtazapine 15 or 30mg had beneficial effects on symptoms of sleep disturbance commonly seen with depression, including increased nighttime wakenings, a reduction in the amount of slow wave sleep and a reduction in REM latency, according to electrophysiological studies in patients and volunteers. Night-time administration of mirtazapine 15 to 30 mg/day for 15 days produced slight, but statistically significant, impairment in tracking and actual driving performance in healthy volunteers; however, this was not thought to be sufficient to reduce the safety of motor vehicle operation.

There have been no detailed reports of the cardiovascular effects of mirtazapine in humans.

Overview of Pharmacokinetic Properties

Mirtazapine has linear pharmacokinetics over the recommended dose range (15 to 45mg). It has a mean elimination half-life of 20 to 40 hours following oral administration and is therefore suitable for once daily administration. Up to 85% of an oral dose is excreted in the urine and the remainder is excreted in the faeces. In patients with hepatic and renal impairment, the clearance of mirtazapine is reduced and dosage increases should be performed with caution. Steady-state plasma concentrations are reached after approximately 5 days’ therapy. Age, gender and the intake of a high-fat meal do not affect the pharmacokinetic parameters of mirtazapine. In vitro and in vivo studies indicate that mirtazapine is unlikely to affect the metabolism of drugs metabolised by cytochrome P450 (CYP)1A2, CYP3A4 and CYP2D6 isoenzymes (including tricyclic antidepressants, antipsychotics and some SSRIs); however, few formal drug interaction studies are available.

Therapeutic Efficacy

In well designed clinical studies with an antidepressant comparator, the proportion of responders according to the Hamilton Depression Rating Scale (HDRS) generally ranged from 51 to 80% with mirtazapine. In short term studies (4 to 7 weeks), the drug was as effective as amitriptyline, clomipramine and doxepin, and it was at least as effective as trazodone, in patients with moderate or severe depression, including those with baseline anxiety symptoms or sleep disturbance or the elderly. Mirtazapine was less effective than imipramine in a single study performed in a heterogeneous population including previous nonresponders to antidepressants. Single comparisons between mirtazapine and selective serotonin reuptake inhibitors (SSRIs) demonstrated superior efficacy for mirtazapine versus fluoxetine at weeks 3 and 4, versus paroxetine at week 1 and versus citalopram at week 2, suggesting an earlier onset of efficacy with mirtazapine than with the SSRIs (total assessment times were 6 or 8 weeks). Mirtazapine had equivalent efficacy to the SSRIs at study end-point. In trials where additional scales were used to assess antidepressant efficacy, quality of life, general psychopathology, global functioning and global clinical impression, changes in scores correlated with HDRS results.

In a continuation trial, mirtazapine was associated with higher sustained remission rates than amitriptyline and the drugs had similar efficacy for the prevention of relapse. Initial evidence suggests that mirtazapine may also be effective as an augmentation or combination therapy with a number of other classes of antidepressant in patients with refractory depression.

Mirtazapine was more cost effective than fluoxetine or amitriptyline for the treatment of major depression from the perspectives of the national health funder in France and Austria, despite high acquisition costs for the drug in these countries.

Tolerability

Data from meta-analyses of placebo-controlled trials indicate that dry mouth, drowsiness/sedation, increase in appetite and bodyweight gain are the most common adverse experiences with short term (5 to 6 weeks) mirtazapine therapy. A reduction in the incidence of sedation-related symptoms over time with higher mirtazapine dosages was seen in some studies and is thought to have a pharmacological basis.

Anticholinergic symptoms and events such as drowsiness, tremor and dyspepsia tend to occur less frequently with mirtazapine than with tricyclic antidepressants or trazodone. Typical SSRI adverse events were less common with mirtazapine than with fluoxetine and placebo, although overall mirtazapine appears to have a similar tolerability profile to those of the SSRIs fluoxetine, citalopram and paroxetine. Increased appetite and bodyweight are the only events that have been reported to be more common with mirtazapine than with antidepressant comparators. The drug appears to be well tolerated in elderly patients.

Mirtazapine has not been associated with clinically significant changes in vital signs in clinical trials. Changes in laboratory parameters with mirtazapine are rare. The available data indicate that mirtazapine does not increase the incidence of suicide attempts in patients with depression compared with active comparators, although this parameter was not specifically assessed in clinical trials of any antidepressant. Patients have recovered without adverse sequelae from mirtazapine overdose at doses of up to 30 times the recommended daily amount.

Dosage and Administration

The recommended oral dosage of mirtazapine in adults and elderly patients with depression is 15 to 45 mg/day. Elderly patients and those with hepatic or renal insufficiency should be closely supervised when dosages are increased. Mirtazapine should be taken as a single evening dose. The drug should not be given to patients who are taking monoamine oxidase inhibitors or during pregnancy.

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Correspondence to Kristin J. Holm.

Additional information

Various sections of the manuscript reviewed by: H. Ågren, Karolinska Institute, Division of Psychiatry, Huddinge University Hospital, Huddinge, Sweden; S. Agyropoulos, Psychopharmacology Unit, School of Medical Sciences, University of Bristol, Bristol, England; J.D. Bremner, Bremner Research Institute, Olympia, Washington, USA; N. Haddjeri, Department of Psychiatry, McGill University, Montréal, Québec, Canada; R.M.A. Hirschfeld, Department of Psychiatry, University of Texas Medical Branch, Galveston, Texas, USA; S. Hood, Psychopharmacology Unit, School of Medical Sciences, University of Bristol, Bristol, England; O.J. Høyberg, Department of Psychiatry, Fylkes Hospital I Molde, Molde, Norway; S. Kasper, Department of General Psychiatry, University of Vienna, Vienna, Austria; B.E. Leonard, Department of Pharmacology, National University of Ireland, Galway, Ireland; G. Stimmel, School of Pharmacy, University of Southern California, Los Angeles, California, USA; M. Van Moffaert, Department of Psychology, University Hospital, Gent, Belgium; W. Wittgens, Department of Geriatric Psychiatry, Hans-Prinzhorn Hospital, University of Witten-Hedecke, Hemer, Germany.

Data Selection

Sources: Medical literature published in any language since 1966 on mirtazapine, identified using AdisBase (a proprietary database of Adis International, Auckland, New Zealand), Medline and EMBASE. Additional references were identified from the reference lists of published articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug.

Search strategy: AdisBase search terms were ‘mirtazapine’, ‘6-azamianserin’, ‘azamianserin’, ‘mepirzapin’, ‘Org-3770’ and ‘depression’. Medline and EMBASE search terms were ‘mirtazapine’ and ‘depression’. Searches were last updated 11 March 1999.

Selection: Studies in patients with major depression who received mirtazapine. Inclusion of studies was based mainly on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic, pharmacokinetic and pharmacoeconomic data are also included.

Index terms: mirtazapine, depression, pharmacodynamics, pharmacokinetics, therapeutic use, dosage and administration, pharmacoeconomics.

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Holm, K.J., Markham, A. Mirtazapine. Drugs 57, 607–631 (1999). https://doi.org/10.2165/00003495-199957040-00010

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Keywords

  • Adis International Limited
  • Fluoxetine
  • Paroxetine
  • Amitriptyline
  • Mirtazapine