Mirtazapine is a piperazinoazepine-derivative1,4 tetracyclic antidepressant agent.1,3,4,5,6,7,8,9,10
Mirtazapine is used in the treatment of major depressive disorder.1,3,5,6,10
The manufacturer states that mirtazapine is not approved for use in pediatric patients.1
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 Clinical endpoints in these studies included the 21-item Hamilton Depression Rating Scale (HAM-D) total score; HAM-D Depressed Mood item; Clinical Global Impression (CGI) Severity score; and Montgomery and Asberg Depression Rating Scale.1 Results of these studies indicate that the antidepressant effect of mirtazapine (5-35 mg daily) is greater than that of placebo on at least 3 of the 4 clinical endpoints and comparable to that of tricyclic antidepressants (TCAs, e.g., amitriptyline [40-280 mg daily]).1,3,4,5,9,10 In these studies, no age- or gender-related differences in efficacy were noted.1
Efficacy of mirtazapine for major depressive disorder was also evaluated in a longer-term study.1 Patients who responded to an initial 8-12 weeks of acute treatment on mirtazapine were randomized to continue mirtazapine or placebo for up to 40 weeks.1 Clinical efficacy was evaluated based on response and relapse.1 Response was defined as having achieved a HAM-D 17-item total score of ≤8 and a CGI Improvement score of 1 or 2 at 2 consecutive visits.1 Patients in the mirtazapine group had substantially lower relapse rates over 40 weeks as compared to patients in the placebo group.1
Treatment options for major depressive disorder include pharmacological and nonpharmacologic (e.g., psychotherapy) approaches.29,51,52,53 Several classes of antidepressant drugs are available for the treatment of major depressive disorder.29,51,52,53 In general, these drugs have shown similar effectiveness; therefore treatment is guided by specific patient- and drug-related factors.29,52,53
A legacy practice guideline from the American Psychiatric Association (APA) states that effectiveness of antidepressants in the treatment of major depressive disorder is generally comparable between and within classes of these medications, including selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), TCAs, monoamine oxidase (MAO) inhibitors, and other antidepressants (e.g., bupropion, mirtazapine, trazodone).29 Therefore, the initial selection of an antidepressant can be based mainly on the following factors: patient preference; nature of prior response to medication; safety, tolerability, and anticipated adverse effects; concurrent psychiatric and medical conditions; specific properties of the medication (e.g., half-life, actions on cytochrome P-450 [CYP] isoenzymes, other drug interactions); and cost.29
The Department of Veterans Affairs and Department of Defense have developed guidelines for the management of major depressive disorder.51 Treatment of uncomplicated major depressive disorder can be initiated with either psychotherapy (e.g., cognitive behavioral therapy) or pharmacotherapy, depending on patient preference; for patients with severe, persistent, or recurrent major depressive disorder, a combination of pharmacotherapy and psychotherapy is suggested.51 When pharmacotherapy is used as initial therapy, either bupropion, mirtazapine, an SSRI, SNRI, trazodone, vilazodone, or vortioxetine is suggested.51 No evidence is available to suggest superiority of one agent over another.51 The guidelines recommend against using esketamine, ketamine, MAOIs, nefazodone, or TCAs as initial therapy.51 For patients not responding to initial therapy, recommendations include switching to another antidepressant (including MAOIs or TCAs), switching to or augmenting with psychotherapy, or augmenting with a second-generation antipsychotic.51
Mirtazapine has been used in the treatment of panic disorder†.54,55,59 Guidelines from the APA recommend regimens for panic disorder that may include a range of psychosocial and pharmacological interventions.54 Initial pharmacological treatment options include SSRIs and SNRIs.54 TCAs and benzodiazepines have similar efficacy to SSRIs and SNRIs, but are less favorable as initial therapy due to their side effect profiles and warnings for use.54 Other medications, such as mirtazapine, may also be considered in patients who have failed to respond to other therapy or based on other patient-specific factors (e.g., cost, prior treatment history, comorbid conditions).54 While a few short-term, open-label, or small clinical studies have suggested similar efficacy of mirtazapine to paroxetine (an SSRI), mirtazapine is not considered first line due to tolerability concerns (including side effects of somnolence and weight gain).54 International experts state that no recommendation is possible for or against use of mirtazapine in panic disorder as only one underpowered comparison trial exists.55
Mirtazapine has been used in the treatment of social anxiety disorder†.55,59 International experts state that escitalopram, fluvoxamine, paroxetine, sertraline, and venlafaxine have the highest level of evidence for first-line pharmacological treatment of social anxiety disorder.55 Additional treatment options include pregabalin, the SSRI citalopram, and benzodiazepines.55 Based on evidence from one double-blind, placebo-controlled study, international experts provide a limited recommendation for the use of mirtazapine in social anxiety disorder.55
Post-Traumatic Stress Disorder
Mirtazapine has been used in the treatment of post-traumatic stress disorder† (PTSD).56,57,59 Guidelines from the Department of Veterans Affairs and Department of Defense recommend psychotherapies over pharmacological interventions for the treatment of PTSD; however, both treatment modalities are considered effective.56 When pharmacotherapy is indicated, paroxetine, sertraline, or venlafaxine is recommended.56 The guidelines state that there is insufficient evidence to recommend for or against several agents, including mirtazapine.56 International experts state that fluoxetine, paroxetine, sertraline, and venlafaxine have the highest level of evidence for first-line pharmacological treatment of PTSD.57 Based on its efficacy in one double-blind placebo-controlled study, international experts provide a limited recommendation for the use of mirtazapine in PTSD.57
Mirtazapine may be useful in the treatment of obsessive-compulsive disorder† (OCD).57,58,59 Guidelines from the APA list cognitive behavioral therapy and pharmacotherapy as safe and effective first-line treatments for OCD.58 For pharmacotherapy, SSRIs are first-line.58 If a patient does not respond to an SSRI, they may switch to a different SSRI or consider switching to mirtazapine as a second-line treatment.58 The evidence for mirtazapine in the treatment of OCD consists of a small open-label clinical trial and discontinuation study.58 International experts state that escitalopram, fluvoxamine, fluoxetine, paroxetine, and sertraline have the highest level of evidence for first-line pharmacological treatment of OCD.57 Additional treatment options include the TCA clomipramine, the SSRI citalopram, and the SNRI venlafaxine.57 Based on one placebo-controlled study, international experts provide a limited recommendation for the use of mirtazapine in OCD.57
Mirtazapine has been used in the treatment of generalized anxiety disorder (GAD)†,59 amphetamine-type stimulant use disorder†,60 and cancer cachexia†.61 Guidelines from Canadian experts recommend mirtazapine for the treatment of GAD as a third-line option based on a single open-label study.59 According to guidelines from the American Society of Addiction Medicine (ASAM) and the American Academy of Addiction Psychiatry (AAAP), for amphetamine-type stimulant use disorder, mirtazapine may be considered as a treatment option to promote reduced use of amphetamine-type simulants.60 For treatment of cancer cachexia, the American Society of Clinical Oncology (ASCO) states that mirtazapine improved appetite and weight in about one-third of patients in a phase 2 study across different cancer types.61 However, ASCO noted a lack of information on the impact of cancer treatment on mirtazapine use and that further research is being conducted.61
Dispensing and Administration Precautions
Mirtazapine is administered orally as conventional or orally disintegrating tablets.1 The drug is administered once daily, usually at bedtime.1 Since food does not appear to substantially affect GI absorption of mirtazapine, the drug generally can be administered without regard to meals.1
Patients receiving mirtazapine orally disintegrating tablets (ODT) should be instructed not to remove a tablet from the blister until just prior to dosing; once removed, it cannot be stored.1 With dry hands, the blister backing should be peeled completely off the blister.1 The tablet should then be gently removed and immediately placed on the tongue to dissolve and be swallowed with the saliva without chewing or crushing; administration with liquid is not necessary.1 In addition, patients should be advised not to break the tablet.1
Store mirtazapine tablets and orally disintegrating tablets at 20-25°C; excursions permitted between 15-30°C.1
For the management of major depressive disorder in adults, the recommended initial dosage of mirtazapine is 15 mg daily.1 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 to allow sufficient time for evaluation of response to a given dose.1
Dosage Modifications for Drug Interactions
An increase in the dosage of mirtazapine may be needed when used concomitantly with a strong cytochrome P-450 (CYP) 3A inducer (e.g., carbamazepine, phenytoin, rifampin).1 Conversely, a decrease in the dosage of mirtazapine may be needed if the CYP3A inducer is discontinued.1
A decrease in the dosage of mirtazapine may be needed when used concomitantly with strong CYP3A4 inhibitors (e.g., ketoconazole, clarithromycin).1 Conversely, an increase in the dosage of mirtazapine may be needed if the CYP3A4 inhibitor is discontinued.1
A decrease in the dosage of mirtazapine may be needed when used concomitantly with cimetidine.1 Conversely, an increase in the dosage of mirtazapine may be needed if cimetidine is discontinued.1
The dosage of mirtazapine may need to be decreased in patients with moderate to severe hepatic impairment.1
The dosage of mirtazapine may need to be decreased in patients with moderate to severe renal impairment.1
Caution should be used when administering mirtazapine to geriatric patients; dosage selection should be conservative, usually starting at the low end of the dosing range, due to age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.1
Suicidal Thoughts and Behaviors
A boxed warning on the increased risk of suicidal thoughts and behavior in adolescent and young adult patients taking antidepressants is included in the prescribing information for mirtazapine.1 In pooled analyses of placebo-controlled trials of antidepressants (i.e., selective serotonin-reuptake inhibitors [SSRIs] and other drug classes) that included approximately 77,000 adult patients and 4500 pediatric patients, the incidence of suicidal thoughts and behaviors was greater in patients ≤24 years of age treated with an antidepressant compared to those treated with placebo.1 The incidence of suicidal thoughts and behaviors varied across different antidepressants and indications; however, the risk was increased in young patients for most studied drugs, with the highest incidence in patients with major depressive disorder.1 A reduced risk of suicidal thoughts and behaviors was observed with antidepressants compared with placebo in adults 24-65 years of age and ≥65 years of age.1 Whether the risk of suicidal thoughts and behaviors in children, adolescents, and young adults extends to longer-term use (i.e., >4 months) is unknown.1 However, data from placebo-controlled maintenance trials in adults with major depressive disorder demonstrate that antidepressants delay the recurrence of depression and that depression itself is a risk factor for suicidal thoughts and behaviors.1 Monitor all patients treated with antidepressants for any indication of clinical worsening or emergence of suicidal thoughts and behaviors, particularly during initiation of therapy (i.e., the first few months) and during periods of dosage adjustments.1 Counsel families and caregivers to monitor for changes in the patient's behavior, and to report such symptoms to a clinician.1 Consider changing the therapeutic regimen or discontinuing mirtazapine in patients whose depression is persistently worse or in patients experiencing emergent suicidal thoughts or behaviors.1
Other Warnings and Precautions
In clinical trials prior to marketing, there were 2 patients treated who developed agranulocytosis (absolute neutrophil count [ANC] <500/mm3 with signs and symptoms of infection) and 1 patient who developed severe neutropenia (ANC <500/mm3 without any associated symptoms) out of 2796 patients treated with mirtazapine.1 All patients recovered after mirtazapine was stopped.1
Monitor patients for signs and symptoms of agranulocytosis (e.g., sore throat, fever, stomatitis, or other signs of infection along with a low white blood cell count).1 Discontinue treatment of mirtazapine in patients who develop these signs and symptoms and closely monitor these patients.1
Serotonergic antidepressants such as mirtazapine can precipitate serotonin syndrome, a potentially life-threatening condition.1 Serotonin syndrome can occur when these drugs are used alone, but the risk is increased with concurrent use of other serotonergic drugs (e.g., serotonin [5-hydroxytryptamine; 5-HT] type 1 receptor agonists [“triptans”], tricyclic antidepressants [TCAs], fentanyl, lithium, tramadol, tryptophan, buspirone, amphetamines, and St. John's wort [ Hypericum perforatum ]) and with drugs that impair the metabolism of serotonin (i.e., MAO inhibitors).1
Manifestations of serotonin syndrome may include mental status changes (e.g., agitation, hallucinations, delirium, coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and GI symptoms (e.g., nausea, vomiting, diarrhea).1
Concurrent or recent (i.e., within 14 days) use of MAO inhibitors with mirtazapine is contraindicated.1 Do not initiate mirtazapine in patients treated with MAO inhibitors such as linezolid or IV methylene blue.1 If an MAO inhibitor such as linezolid or IV methylene blue is necessary in a patient receiving mirtazapine, discontinue mirtazapine before initiating the MAO inhibitor.1
Monitor all patients receiving mirtazapine for the development of serotonin syndrome.1 If manifestations of serotonin syndrome occur, immediately discontinue treatment with mirtazapine and any concurrently administered serotonergic agents, and initiate supportive symptomatic treatment.1
If concurrent therapy with mirtazapine and other serotonergic drugs is clinically warranted, inform patients of the potential increased risk for serotonin syndrome and monitor for symptoms.1
Antidepressant drugs such as mirtazapine may cause pupillary dilation (mydriasis), which can trigger an angle closure attack in patients without a patent iridectomy with anatomically narrow angles.1
QT Prolongation and Torsades de Pointes
The effect of mirtazapine on QTc interval was assessed in a clinical trial, which reported a positive relationship between mirtazapine concentrations and QTc interval prolongation.1 The degree of QT prolongation observed with doses of mirtazapine of 45 mg and 75 mg (1.67 times the maximum recommended daily dose) was not considered clinically significant.1
Postmarketing cases of QT prolongation, torsades de pointes, ventricular tachycardia, and sudden death have been reported with use of mirtazapine.1 Most cases occurred in association with overdose of mirtazapine or in patients with other risk factors for QT prolongation (e.g., concomitant use of other QT-prolonging medications).1
Mirtazapine should be used with caution in patients with known cardiovascular disease or family history of QT prolongation, and with concomitant use of other drugs that prolong the QTc interval.1
Drug Reaction with Eosinophilia and Systemic Symptoms
Postmarketing cases of drug reaction with eosinophilia and systemic symptoms (DRESS), which is sometimes fatal, have been reported with use of mirtazapine.1 Symptoms of DRESS may include cutaneous reactions (e.g., rash, exfoliative dermatitis), eosinophilia, fever, and/or lymphadenopathy with systemic complications such as hepatitis, nephritis, pneumonitis, myocarditis, and pericarditis.1 Immediately discontinue use of mirtazapine if DRESS is suspected and initiate appropriate treatment.1
Increased Appetite and Weight Gain
In clinical studies, appetite increase was reported in 17% of patients who received mirtazapine versus 2% of patients who received placebo.1 In the same clinical studies, a body weight gain of ≥7% was reported in 7.5% of patients who received mirtazapine, versus 0% of patients who received placebo.1 In pooled data from premarketing studies, 8% of patients who received mirtazapine discontinued the drug due to weight gain.1
In an 8-week clinical trial in pediatric patients, 49% of patients who received mirtazapine had a weight gain of at least 7%, compared to 5.7% of patients who received placebo.1 The safety and effectiveness of mirtazapine in pediatric patients with major depressive disorder have not been established.1
In clinical studies, somnolence was reported in 54% of patients who received mirtazapine versus 18% of patients who received placebo.1 Somnolence resulted in discontinuation of treatment in 10.4% of patients who received mirtazapine versus 2.2% who received placebo in these trials.1 It is unclear whether tolerance develops to the somnolent effects of mirtazapine.1
Caution patients receiving mirtazapine about engaging in activities that require alertness (e.g., operating heavy machinery and motor vehicles), until they are reasonably certain that mirtazapine does not affect them adversely.1 Concomitant use of benzodiazepines or alcohol with mirtazapine should be avoided.1
Activation of Mania and Hypomania
Treating a depressive episode with mirtazapine or another antidepressant in patients with bipolar disorder may activate a mixed/manic episode.1 Symptoms of mania or hypomania were reported in 0.2% of patients receiving mirtazapine during clinical studies, although patients with bipolar were generally excluded.1 Screen patients for any personal or family history of bipolar disorder, mania, or hypomania prior to starting treatment with mirtazapine.1
Use of mirtazapine has not been systematically evaluated in patients with seizures, but 1 seizure was reported during premarketing clinical studies out of 2796 patients treated with mirtazapine.1 Prescribe mirtazapine with caution in patients with a seizure disorder.1
Elevated Cholesterol and Triglycerides
In clinical studies, increases in nonfasting cholesterol to ≥20% the upper limit of normal (ULN) were observed in 15% of patients who received mirtazapine versus 7% of patients who received placebo.1 Increases in nonfasting triglycerides to ≥500 mg/dL were also observed in 6% of patients who received mirtazapine versus 3% who received placebo in these same clinical studies.1
Hyponatremia may occur with use of serotonergic antidepressants, including mirtazapine.1 In many cases, hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH).1 Cases with serum sodium concentrations <110 mmol/L have been reported.1 Geriatric individuals, patients receiving diuretics, and those who are volume-depleted may be at greater risk of developing hyponatremia.1
Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls; more severe and/or acute cases have been associated with hallucinations, syncope, seizure, coma, respiratory arrest, and death.1
Discontinue mirtazapine in patients with symptomatic hyponatremia, and initiate appropriate medical intervention.1
In a pool of short-term, US clinical studies, clinically significant ALT increases (≥3 times ULN) were observed in 2% of patients treated with mirtazapine versus 0.3% of patients treated with placebo.1 Some patients had discontinued treatment with mirtazapine due to the ALT increases; in other cases, enzymes levels returned to normal while patients continued mirtazapine treatment.1 Use mirtazapine with caution in patients with impaired hepatic function.1
Adverse effects have been reported following discontinuance of mirtazapine, particularly when discontinuation was abrupt.1 These withdrawal effects include dizziness, abnormal dreams, sensory disturbances (e.g., paresthesia and electroshock sensations), agitation, anxiety, fatigue, confusion, headache, tremor, nausea, vomiting, and sweating, or other symptoms of clinical significance.1
Gradually reduce dosage (versus abrupt cessation) when discontinuing therapy.1
Use in Patients with Concomitant Illness
Mirtazapine has not been systemically evaluated in patients with a recent history of myocardial infarction (MI) or other significant heart disease.1 Mirtazapine was associated with significant orthostatic hypotension in volunteers in early clinical pharmacology trials.1 In clinical trials of mirtazapine in patients who were depressed, orthostatic hypotension was infrequently observed.1 Use mirtazapine with caution in patients with known cardiovascular or cerebrovascular disease that could be exacerbated by hypotension (e.g., history of MI, angina, ischemic stroke) and in conditions that predispose patients to hypotension (e.g., dehydration, hypovolemia, treatment with antihypertensive medication).1
Mirtazapine orally disintegrating tablets (ODT) contain phenylalanine, a component of aspartame.1 Phenylalanine can be harmful to patients with phenylketonuria (PKU).1 Mirtazapine ODT contains the following amount of phenylalanine based on each tablet strength: 2.6 mg in 15 mg ODT, 5.2 mg in 30 mg ODT, and 7.8 mg in 45 mg ODT.1 In patients with PKU, consider the combined daily amount of phenylalanine from all sources, including mirtazapine ODT, before prescribing.1
A National Pregnancy Registry for Antidepressants is available that monitors pregnancy outcomes in women exposed to antidepressants during pregnancy.1 Clinicians are encouraged to register patients by calling the National Pregnancy Registry for Antidepressants at 1-844-405-6185 or by visiting online at [Web].1
Available evidence has not reliably identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes.1
In animal reproductive studies, no evidence of teratogenic effects were observed when oral mirtazapine was administered during the period of organogenesis at doses up to 20 and 17 times the maximum recommended human dose (MRHD) of 45 mg on a mg/m2 body surface area basis in rats and rabbits, respectively.1 However, there was an increase in postimplantation loss at 20 times the MRHD in rats.1 Also, an increase in pup deaths and a decrease in pup birth weights at doses 20 times the MRHD was observed with oral administration of mirtazapine to rats during pregnancy and lactation.1
There are risks associated with untreated depression in pregnancy.1 In a prospective, longitudinal study, women who discontinued antidepressants during pregnancy were more likely to experience a relapse in major depression than women who continued antidepressants.1 Consider the risk of untreated depression when discontinuing or changing antidepressants during pregnancy and postpartum.1
Mirtazapine is present at low levels in human milk with relative infant doses for mirtazapine ranging from 0.6-2.8% of the maternal weight-adjusted dose.1 There have been no adverse effects on the breast-fed infant reported in most cases of maternal use of mirtazapine.1 There are no data on the effects of mirtazapine on milk production.1
Consider the developmental and health benefits of breast-feeding, the mother's clinical need for mirtazapine, and any potential adverse effects on the breast-fed child from the drug or from the underlying maternal condition.1
The safety and effectiveness of mirtazapine in pediatric patients for the treatment of major depressive disorder have not been established; mirtazapine is not approved for use in pediatric patients.1 In 2 placebo-controlled trials, there were insufficient data to establish the safety and efficacy of mirtazapine for the treatment of major depressive disorder in pediatric patients.1 Additionally, in an 8-week-long clinical trial, 49% of pediatric patients receiving mirtazapine had a weight gain of at least 7% versus 5.7% of pediatric patients receiving placebo.1 The average weight increase for those in the mirtazapine group was 4 kg compared to a 1-kg weight increase in the placebo group.1
An increased risk of suicidal thoughts and behaviors was observed in pediatric patients treated with antidepressants.1
In clinical trials with mirtazapine, approximately 190 patients were ≥65 years of age.1 Mirtazapine is primarily eliminated by kidney excretion; pharmacokinetic studies showed a decreased clearance of mirtazapine in geriatric patients.1
Sedating drugs such as mirtazapine may cause confusion and over-sedation in geriatric patients; geriatric patients may also be at greater risk of developing hyponatremia.1
Mirtazapine should be used with caution in geriatric patients.1 Dosage selection should be conservative in this population, starting at the low end of the dosing range to reflect the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.1
Clearance of mirtazapine is reduced in patients with moderate to severe hepatic impairment and therefore plasma levels of mirtazapine may be increased in these patients.1 In patients with hepatic impairment, following a single 15-mg oral dose of mirtazapine, the oral clearance was decreased by approximately 30% compared to patients with normal hepatic function.1
According to the manufacturer, a decrease in dosage may be necessary when administering mirtazapine in patients with moderate to severe hepatic impairment.1
Clearance of mirtazapine is reduced in patients with moderate to severe renal impairment and therefore plasma levels of mirtazapine may be increased in these patients.1 Compared to patients with normal renal function, patients with a glomerular filtration rate (GFR) of 11-39 mL/minute per 1.73 m2 were found to have total body clearance of mirtazapine reduced by approximately 30%; patients with GFR ≤10 mL/minute per 1.73 m2 were found to have total body clearance reduced by approximately 50%.1
According to the manufacturer, a decrease in dosage may be necessary when administering mirtazapine in patients with moderate to severe renal impairment.1
Adverse effects reported in ≥5% of patients receiving mirtazapine include somnolence, increased appetite, weight gain, and dizziness.1
Mirtazapine is metabolized by cytochrome P-450 (CYP) isoenzymes, principally CYP3A; in vitro studies indicate that CYP2D6 and CYP1A2 are also involved.1
Drugs Affecting Hepatic Microsomal Enzymes
Strong CYP3A Inducers
Concomitant use of mirtazapine with strong CYP3A inducers (e.g., phenytoin, carbamazepine, rifampin) decreases mirtazapine plasma concentrations.1 Concomitant use of phenytoin with mirtazapine increased mirtazapine clearance by approximately 2-fold, resulting in a decrease in average plasma mirtazapine concentrations of 45%.1 Concomitant use of carbamazepine with mirtazapine increased mirtazapine clearance by approximately 2-fold, resulting in a decrease in average plasma mirtazapine concentrations of 60%.1
Increase the dosage of mirtazapine if needed with concomitant use of strong CYP3A inducers.1 Decrease the dosage of mirtazapine if needed if a strong CYP3A inducer is discontinued.1
Strong CYP3A Inhibitors
Concomitant use of mirtazapine with strong CYP3A inhibitors (e.g., itraconazole, ketoconazole, ritonavir, nefazodone) may increase mirtazapine plasma concentrations.1 Concomitant use of ketoconazole with mirtazapine increased the peak plasma levels and area under the curve (AUC) of mirtazapine by approximately 40 and 50%, respectively.1
Decrease the dosage of mirtazapine if needed with concomitant use of strong CYP3A inhibitors.1 Increase the dosage of mirtazapine if needed if a strong CYP3A inhibitor is discontinued.1
Drugs Associated with QT Prolongation
Concomitant use of mirtazapine with other drugs which prolong the QTc interval increases the risk of QT prolongation and/or ventricular arrhythmias including torsades de pointes.1 Caution is advised when using mirtazapine concomitantly with drugs that prolong the QTc interval.1
Concomitant use of benzodiazepines (e.g., diazepam, alprazolam) or alcohol with mirtazapine increases the impairment of cognitive and motor skills produced by mirtazapine when used alone.1 Avoid concomitant use of mirtazapine with benzodiazepines and alcohol.1
Concomitant use of mirtazapine with cimetidine, a CYP1A2, CYP2D6, and CYP3A inhibitor, may increase mirtazapine plasma concentrations.1 When cimetidine was given concomitantly with mirtazapine in healthy male subjects, the AUC of mirtazapine increased by >50%.1 Decrease the dosage of mirtazapine if needed with concomitant use of cimetidine.1 Increase the dosage of mirtazapine if needed when cimetidine is discontinued.1
Concomitant use of serotonergic drugs, including mirtazapine, with monoamine oxidase (MAO) inhibitors (e.g., selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, methylene blue) increases the risk of serotonin syndrome.1 Concomitant use of mirtazapine with MAO inhibitors, including linezolid or IV methylene blue, is contraindicated.1 Use of mirtazapine within 14 days of stopping an MAO inhibitor is contraindicated; in addition, at least 14 days must elapse after stopping mirtazapine before starting an MAO inhibitor.1 If an MAO inhibitor such as linezolid or IV methylene blue is necessary in a patient receiving mirtazapine, discontinue mirtazapine before initiating the MAO inhibitor.1
Mirtazapine does not influence the pharmacokinetics of risperidone.1
Concomitant use of mirtazapine and other serotonergic drugs (e.g., SSRIs, SNRIs, triptans, TCAs, fentanyl, lithium, amphetamines, St. John's Wort [ Hypericum perforatum ], tramadol, tryptophan, buspirone) increases the risk of serotonin syndrome.1
Monitor patients for serotonin syndrome, particularly during treatment initiation and with increases in dosage.1 If serotonin syndrome occurs, consider discontinuation of mirtazapine and any concurrently administered serotonergic agents.1
Concomitant use of warfarin with mirtazapine may increase INR; monitor INR during concomitant use.1
Mirtazapine is a piperazinoazepine-derivative1,4 antidepressant agent.1,3,4,5,6,7,8,9,10 As a tetracyclic antidepressant agent, the drug differs structurally from selective serotonin-reuptake inhibitors (e.g., fluoxetine, sertraline), monoamine oxidase (MAO) inhibitors, and tricyclic antidepressant (TCA) agents.1
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 heteroreceptors1,7,8,9,10 resulting in enhanced central noradrenergic and serotonergic activity.1,7,8 Mirtazapine is a potent antagonist of serotonin type 2 (5-HT2) and type 3 (5-HT3) receptors,1,7,10 but the drug does not exhibit high affinity for serotonin type 1A (5-HT1A) or type 1B (5-HT1B) receptors.1,7 Mirtazapine is a potent antagonist of histamine H1receptors, which may account for the prominent sedative effects of the drug.1 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 The drug is also an antagonist at muscarinic receptors.1
Mirtazapine plasma levels are linear and related to dose over a dosage range of 15-80 mg; steady state plasma levels are attained within 5 days, with about 50% accumulation.1
The absolute bioavailability of mirtazapine is about 50% following oral administration.1 The time to achieve peak plasma concentrations of mirtazapine is about 2 hours after administration.1 Administration of the drug with food has minimal effect on the rate and extent of absorption of mirtazapine.1
Mirtazapine is about 85% protein bound.1 The elimination half-life of the drug is approximately 20-40 hours following oral administration.1 Mirtazapine is extensively metabolized, with demethylation and hydroxylation followed by glucuronide conjugation as its major pathways of biotransformation.1 The cytochrome P-450 (CYP) isoenzymes CYP2D6 and CYP1A2 are involved in the formation of the 8-hydroxy metabolite of mirtazapine, based on in vitro data, and CYP3A is considered responsible for the formation of the N-desmethyl and N-oxide metabolite.1 There are also several unconjugated metabolites present in the plasma at very low levels that possess pharmacological activity.1 Mirtazapine and its metabolites are principally excreted in the urine (75%) and feces (15%).1
Clearance of mirtazapine is reduced in geriatric patients compared to younger adult patients; in geriatric males, clearance was 40% lower compared to younger males, and in geriatric females, clearance was 10% lower compared to younger females.1 Females of all ages exhibit significantly longer elimination half-lives of mirtazapine as compared to males (mean half-life of 37 hours versus 26 hours, respectively).1 The impact of race on mirtazapine pharmacokinetics has not been evaluated.1
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Tablets, film-coated | 7.5 mg* | Mirtazapine Tablets | |
15 mg* | Mirtazapine Tablets | |||
Remeron® (scored) | ||||
30 mg* | Mirtazapine Tablets | |||
Remeron® (scored) | Organon | |||
45 mg* | Mirtazapine Tablets | |||
Tablets, orally disintegrating (ODT) | 15 mg* | Mirtazapine Orally Disintegrating Tablets | ||
Remeron® SolTab | Organon | |||
30 mg* | Mirtazapine Orally Disintegrating Tablets | |||
Remeron® SolTab | Organon | |||
45 mg* | Mirtazapine Orally Disintegrating Tablets | |||
Remeron® SolTab | Organon |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
1. Organon Inc. Remeron® /Remeron SolTab® (mirtazapine) tablets and orally disintegrating tablets prescribing information. Jersey City, NJ; 2021 Nov.
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]
29. American Psychiatric Association. Practice guideline for the treatment of patients with major depressive disorder, third edition. Am J Psychiatry. 2010;167(suppl).
51. Department of Veterans Affairs (VA) and Department of Defense (DoD). VA/DoD Clinical Practice Guideline for the Management of Major Depressive Disorder, 2022. [Web]
52. American Psychological Association. (2019). Clinical practice guidelines for the treatment of depression across three age cohorts. [Web]
53. Drugs for depression. Med Lett Drugs Ther. 2023 Dec 11;65(1691):193-200.
54. Stein MB, Goin MK, Pollack MH, et al. Practice guideline for the treatment of patients with panic disorder. Am J Psychiatry. 2009;166(2):1.
55. Bandelow B, Allgulander C, Baldwin DS, et al. World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for treatment of anxiety, obsessive-compulsive and posttraumatic stress disorders - Version 3. Part I: Anxiety disorders. World J Biol Psychiatry. 2023;24(2):79-117.
56. Department of Veterans Affairs (VA) and Department of Defense (DoD). VA/DOD Clinical Practice Guideline for the Management of Posttraumatic Stress Disorder and Acute Stress Disorder, 2023. [Web]
57. Bandelow B, Allgulander C, Baldwin DS, et al. World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for treatment of anxiety, obsessive-compulsive and posttraumatic stress disorders - Version 3. Part II: OCD and PTSD. World J Biol Psychiatry. 2023;24(2):118-134.
58. Koran LM, Hanna GL, Hollander E, Nestadt G, Simpson HB; American Psychiatric Association. Practice guideline for the treatment of patients with obsessive-compulsive disorder. Am J Psychiatry. 2007;164(7 Suppl):5-53.
59. Katzman MA, Bleau P, Blier P, et al. Canadian clinical practice guidelines for the management of anxiety, posttraumatic stress and obsessive-compulsive disorders. BMC Psychiatry. 2014;14 Suppl 1(Suppl 1):S1.
60. Clinical Guideline Committee (CGC) Members; ASAM Team; AAAP Team; IRETA Team. The ASAM/AAAP Clinical Practice Guideline on the Management of Stimulant Use Disorder. J Addict Med. 2024;18(1S Suppl 1):1-56.
61. Roeland EJ, Bohlke K, Baracos VE, et al. Management of Cancer Cachexia: ASCO Guideline. J Clin Oncol. 2020;38(21):2438-2453.
62. Institute for Safe Medication Practices (ISMP). ISMP list of confused drug names. ISMP; 2024.