VA Class:CN609

AHFS Class:

• Antidepressants, Miscellaneous 28:16.04.92

Generic Name(s):

• Mirtazapine

Chemical Name:

• 1,2,3,4,10,14b-Hexahydro-2-methylpyrazino[2,1- a ]pyrido [2,3- c ][2]benzazepine

Molecular Formula:

• C₁₇H₁₉N₃

Mirtazapine is a piperazinoazepine-derivative1,4 tetracyclic antidepressant agent.1,2,3,4,5,6,7,8,9,10

Major Depressive Disorder

Mirtazapine is used in the treatment of major depressive disorder.1,3,5,6,10,11 Efficacy of mirtazapine for the management of major depression has been established by controlled studies of 6 weeks' duration in outpatient settings.1,3,4,5,6,10,11 Results of these studies indicate that the antidepressant effect of mirtazapine (5-35 mg daily) is greater than placebo and comparable to that of tricyclic antidepressants (e.g., amitriptyline [40-280 mg daily]).1,3,4,5,9,10,11 In these studies, no age- or gender-related differences in efficacy were noted.1,11 The manufacturer states that the efficacy of mirtazapine for long-term use (i.e., exceeding 6 weeks) has not been established by controlled studies and that the drug's antidepressant efficacy in hospital settings has not been adequately studied to date.1,11 However, acute depressive episodes generally require several months or longer of sustained antidepressant therapy.1,11 (See Dosage and Administration: Dosage.) If mirtazapine is used for extended periods, the need for continued therapy should be reassessed periodically.1,11 For further information on treatment of major depressive disorder and considerations in choosing the most appropriate antidepressant for a particular patient, including considerations related to patient tolerance, patient age, and cardiovascular, sedative, and suicidal risks, see Considerations in Choosing Antidepressants under Uses: Major Depressive Disorder, in Fluoxetine Hydrochloride 28:16.04.20.

Since hypomanic or manic attacks have been reported rarely in patients receiving mirtazapine, the drug should be used with caution in patients with a history of hypomanic or manic attacks.1,11

Individuals with phenylketonuria (i.e., homozygous genetic deficiency of phenylalanine hydroxylase) and other individuals who must restrict their intake of phenylalanine should be warned that mirtazapine orally disintegrating tablets (Remeron^® SolTab^®) contain aspartame (NutraSweet^®), which is metabolized in the GI tract to provide about 2.6, 5.2, or 7.8 mg of phenylalanine following oral administration of a 15-, 30-, or 45-mg tablet, respectively, of mirtazapine.11,12,13,14,15,16

Administration

Mirtazapine is administered orally as conventional or orally disintegrating tablets.1,11 The drug is administered once daily, usually at bedtime.1,11 Since food does not appear to substantially affect GI absorption of mirtazapine, the drug generally can be administered without regard to meals.1,11

Patients receiving mirtazapine orally disintegrating tablets should be instructed not to remove a tablet from the blister until just prior to dosing; once removed, it cannot be stored.11 With dry hands, the blister backing should be peeled completely off the blister.11 The tablet should then be gently removed and immediately placed on the tongue to dissolve and be swallowed with the saliva; administration with liquid is not necessary.11 In addition, patients should be advised not to break the tablet.11

Dosage

For the management of major depressive disorder in adults, the recommended initial dosage of mirtazapine is 15 mg daily.1,11 If no clinical improvement is apparent, dosage may be increased up to a maximum of 45 mg daily at intervals of not less than 1-2 weeks since elimination half-life of the drug is about 20-40 hours.1,11 Although clearance of mirtazapine may decrease in geriatric patients,1,11 the manufacturer does not make specific recommendations for dosage adjustment in such patients.1,11 However, the manufacturer states that since plasma mirtazapine concentrations may be increased in geriatric patients, the drug should be used with caution in such patients.1,11 While a relationship between dosage and antidepressant effect has not been established, the effective dosage of mirtazapine in controlled clinical studies generally ranged from 15-45 mg daily.1,11 Patients should be advised that although some improvement in their condition may occur within 1-4 weeks, therapy should be continued as directed.1,11

Although the optimum duration of mirtazapine therapy has not been established, acute depressive episodes may require 6 months or longer of sustained antidepressant medication.1,11 Whether the dosage of mirtazapine required to induce remission of depression would be comparable to that required to maintain euthymia currently is not known.1

Patients should be monitored for possible worsening of depression, suicidality, or unusual changes in behavior, especially at the beginning of therapy or during periods of dosage adjustment.19,20,21 (See Suicidality Precautions under Dosage and Administration: Dosage.)

The manufacturer recommends that a drug-free interval of at least 2 weeks elapse when switching a patient from a monoamine oxidase (MAO) inhibitor to mirtazapine or when switching from mirtazapine to an MAO inhibitor.1,11 For additional information on potentially serious drug interactions that may occur between mirtazapine and MAO inhibitors or other serotonergic agents, see Drug Interactions: Drugs Associated with Serotonin Syndrome in Fluoxetine Hydrochloride 28:16.04.20 and the Monoamine Oxidase Inhibitors General Statement 28:16.04.12.

Suicidality Precautions

Worsening of depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior may occur in both adult and pediatric (see Dosage and Administration: Pediatric Precautions) patients with major depressive disorder or other psychiatric disorders, whether or not they are taking antidepressants.19,20,21,22 This risk may persist until clinically important remission occurs.19 Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide.19,20,21 However, there has been a long-standing concern that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment.19 Pooled analyses of short-term, placebo-controlled studies of antidepressants (i.e., selective serotonin-reuptake inhibitors and other antidepressants) have shown an increased risk of suicidality in children, adolescents, and young adults (18-24 years of age) with major depressive disorder and other psychiatric disorders.19,20 An increased suicidality risk was not demonstrated with antidepressants compared with placebo in adults older than 24 years of age, and a reduced risk was observed in adults 65 years of age or older.19,20 It is currently unknown whether the suicidality risk extends to longer-term use (i.e., beyond several months); however, there is substantial evidence from placebo-controlled maintenance trials in adults with major depressive disorder that antidepressants can delay the recurrence of depression.19,20

The US Food and Drug Administration (FDA) recommends that all patients being treated with antidepressants for any indication be appropriately monitored and closely observed for clinical worsening, suicidality, and unusual changes in behavior, particularly during initiation of therapy (i.e., the first few months) and during periods of dosage adjustments.19,20,21 Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be advised to monitor patients on a daily basis for the emergence of agitation, irritability, or unusual changes in behavior as well as the emergence of suicidality, and to report such symptoms immediately to a health-care provider.19,21

Although a causal relationship between the emergence of symptoms such as anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia, hypomania, and/or mania and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality.19,21 Consequently, consideration should be given to changing the therapeutic regimen or discontinuing therapy in patients whose depression is persistently worse or in patients experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, particularly if such manifestations are severe, abrupt in onset, or were not part of the patient's presenting symptoms.19 FDA also recommends that the drugs be prescribed in the smallest quantity consistent with good patient management, in order to reduce the risk of overdosage.1,19

Bipolar Disorder Precautions

It is generally believed (though not established in controlled trials) that treating a major depressive episode with an antidepressant alone may increase the likelihood of precipitating a mixed or manic episode in patients at risk for bipolar disorder.19 Therefore, patients should be adequately screened for bipolar disorder prior to initiating treatment with an antidepressant; such screening should include a detailed psychiatric history (e.g., family history of suicide, bipolar disorder, and depression).19

Pediatric Precautions

Safety and efficacy of mirtazapine in children have not been established.1

FDA has determined that antidepressants increase the risk of suicidal thinking and behavior (suicidality) in children and adolescents with major depressive disorder and other psychiatric disorders.19 However, FDA also states that depression and certain other psychiatric disorders are themselves associated with an increased risk of suicide.19 (See Cautions: Pediatric Precautions, in Fluoxetine Hydrochloride 28:16.04.20) Anyone considering the use of mirtazapine in a child or adolescent for any clinical use must therefore balance the potential risks with the clinical need.19,21,22 (See Suicidality Precautions under Dosage and Administration: Dosage.)

Dosage in Renal and Hepatic Impairment

Although clearance of mirtazapine may decrease in patients with hepatic or moderate to severe renal impairment, the manufacturer does not make specific recommendations for dosage adjustment in such patients.1,11 However, the manufacturer states that since plasma concentrations of mirtazapine may be increased in patients with hepatic or moderate to severe renal impairment, the drug should be used with caution in such patients.1,11

Description

Mirtazapine is a piperazinoazepine-derivative1,4 antidepressant agent.1,2,3,4,5,6,7,8,9,10,11 As a tetracyclic antidepressant agent, the drug differs structurally from selective serotonin-reuptake inhibitors (e.g., fluoxetine, sertraline), monoamine oxidase inhibitors, and tricyclic antidepressant agents.1,11

The exact mechanism of antidepressant action of mirtazapine has not been fully elucidated, but the drug appears to act as an antagonist at central presynaptic α₂-adrenergic autoreceptors and heteroreceptors1,2,7,8,9,10,11 resulting in enhanced central noradrenergic and serotonergic activity.1,2,7,8,11 Mirtazapine is a potent antagonist of serotonin type 2 (5-HT₂) and type 3 (5-HT₃) receptors,1,2,7,10,11 but the drug does not exhibit high affinity for serotonin type 1A (5-HT_1A) or type 1B (5-HT_1B) receptors.1,2,7,11 Mirtazapine is a potent antagonist of histamine H₁ receptors, which may account for the prominent sedative effects of the drug.1,11 In addition, the drug exhibits moderate peripheral α₁-adrenergic blocking activity that may explain the occasional orthostatic hypotension that reportedly has been associated with mirtazapine.1,11 The drug is a moderate antagonist at muscarinic receptors, which may account for the relatively low incidence of anticholinergic effects associated with mirtazapine.1,11

Additional Information

SumMon^® (see Users Guide). For additional information on this drug until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the labeling be consulted for detailed information on the usual cautions, precautions, and contraindications.

1. Organon Inc. Remeron^® (mirtazapine) tablets prescribing information. West Orange, NJ; 1999 Mar.

2. de Boer T, Ruigt GSF. The selectiveα₂-adrenoceptor antagonist mirtazapine (Org 3770) enhances noradrenergic and 5-HT_1A-mediated serotonergic neurotransmission. CNS Drugs . 1995; 4(Suppl 1):29-38.

3. Bremner JD. A double-blind comparison of Org 3770, amitriptyline, and placebo in major depression. J Clin Psychiatry . 1995; 56:519-25. [PubMed 7592505]

4. Smith WT, Glaudin V, Panagides J et al. Mirtazapine vs. amitriptyline vs. placebo in the treatment of major depressive disorder. Psychopharmacol Bull . 1990; 26:191-6. [PubMed 2236455]

5. Claghorn JL, Lesem MD. A double-blind placebo-controlled study of Org 3770 in depressed outpatients. J Affect Disord . 1995; 34:165-71. [PubMed 7560544]

6. Halikas JA. Org 3770 (mirtazapine) versus trazodone: a placebo controlled trial in depressed elderly patients. Hum Psychopharmacol . 1995; 10:S125-33.

7. De Boer T, Ruigt GSF, Berendsen HHG. The α₂-selective adrenoceptor antagonist Org 3770 (mirtazapine, Remeron^®) enhances noradrenergic and serotonergic transmission. Hum Psychopharmacol . 1995; 10(Suppl 2):S107-18.

8. de Montigny C, Haddjeri N, Mongeau R et al. The effects of mirtazapine on the interactions between central noradrenergic and serotonergic systems. CNS Drugs . 1995; 4(Suppl 1):13-7.

9. Frazer A. Pharmacology of antidepressants. J Clin Psychopharmacol . 1997; 17(Suppl 1):2-18S.

10. Burrows GD, Kremer CME. Mirtazapine: clinical advantages in the treatment of depression. J Clin Psychopharmacol . 1997; 17(Suppl 1):34-9S. [PubMed 9004055]

11. Organon Inc. Remeron^® SolTab^™ (mirtazapine) orally disintegrating tablets prescribing information. West Orange, NJ; 2001 Feb.

12. American Medical Association Council on Scientific Affairs. Aspartame: review of safety issues. JAMA . 1985; 254:400-2. [PubMed 2861297]

13. Gossel TA. A review of aspartame: characteristics, safety and uses. US Pharm . 1984; 9:26,28-30.

14. Food and Drug Administration. Aspartame as an inactive ingredient in human drug products; labeling requirements. Proposed rule. [21 CFR Part 201] Fed Regist . 1983; 48:54993-5. (lDIS 178728)

15. Food and Drug Administration. Food additives permitted for direct addition to food for human consumption; aspartame. Final rule. [21 CFR Part 172] Fed Regist . 1983; 48:31376-82. (IDIS 172957)

16. Anon. Aspartame and other sweeteners. Med Lett Drugs Ther . 1982; 24:1-2. [PubMed 7054648]

17. Anon. FDA issues public health advisory entitled: Reports of suicidality in pediatric patients being treated with antidepressant medications for major depressive disorder (MDD). FDA Talk Paper. Rockville, MD: Food and Drug Administration; 2003 Oct 27. From the FDA website. [Web]

18. Anon. Reports of suicidality in pediatric patients being treated with antidepressant medications for major depressive disorder (MDD). FDA Public Health Advisory. Rockville, MD: Food and Drug Administration; 2003 Oct 27. From the FDA website. [Web]

19. Food and Drug Administration. Antidepressant use in children, adolescents, and adults: class revisions to product labeling. Rockville, MD; 2007 May 2. From the FDA web site. [Web]

20. Food and Drug Administration. FDA news: FDA proposes new warnings about suicidal thinking, behavior in young adults who take antidepressant medications. Rockville, MD; 2007 May 2. From the FDA web site. [Web]

21. Food and Drug Administration. Revisions to medication guide: antidepressant medicines, depression and other serious mental illnesses and suicidal thoughts or actions. Rockville, MD; 2007 May 2. From the FDA web site. [Web]

22. Bridge JA, Iyengar S, Salary CB. Clinical response and risk for reported suicidal ideation and suicide attempts in pediatric antidepressant treatment: a meta-analysis of randomized controlled trials. JAMA . 2007; 297:1683-96. [PubMed 17440145]