MIRTAZAPINE

Details

Stereochemistry	RACEMIC
Molecular Formula	C17H19N3
Molecular Weight	265.3529
Optical Activity	( + / - )
Defined Stereocenters	0 / 1
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

CN1CCN2C(C1)C3=C(CC4=C2N=CC=C4)C=CC=C3

InChI

InChIKey=RONZAEMNMFQXRA-UHFFFAOYSA-N

InChI=1S/C17H19N3/c1-19-9-10-20-16(12-19)15-7-3-2-5-13(15)11-14-6-4-8-18-17(14)20/h2-8,16H,9-12H2,1H3

HIDE SMILES / InChI

Description
Sources: https://www.ncbi.nlm.nih.gov/pubmed/11607047
Curator's Comment: Description was created based on several sources, including: http://psychiatryonline.org/doi/10.1176/appi.books.9781585623860.as21#u2014-09-19T084532.264-0400d1e2463 http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020415s023s024.pdf

Mirtazapine, originally known as ORG 3770, was first synthesized by the Department of Medicinal Chemistry of NV Organon in the Netherlands (Kaspersen et al. 1989). First approved for use in major depression in the Netherlands in 1994, mirtazapine was introduced in the United States in 1996. The antidepressant mirtazapine has a dual mode of action. It is a noradrenergic and specific serotonergic antidepressant (NaSSA) that acts by antagonizing the adrenergic alpha2-autoreceptors and alpha2-heteroreceptors as well as by blocking 5-HT2 and 5-HT3 receptors. It enhances, therefore, the release of norepinephrine and 5-HT1A-mediated serotonergic transmission. This dual mode of action may conceivably be responsible for mirtazapine's rapid onset of action.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Potency
Adrenergic receptor alpha-2 113 Target ID: CHEMBL2095158 Sources: https://www.ncbi.nlm.nih.gov/pubmed/11607047	Antagonist 2778	7.0 null [pKi]
Serotonin 3 (5-HT3) receptor 59 Target ID: CHEMBL2094132 Sources: https://www.ncbi.nlm.nih.gov/pubmed/11607047	Antagonist 2778	8.62 null [pKi]
Serotonin 2a (5-HT2a) receptor 231 Target ID: CHEMBL224 Sources: https://www.ncbi.nlm.nih.gov/pubmed/11607047	Antagonist 2778	8.1 null [pKi]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Major depressive disorder 173 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020415s023s024.pdf	Primary		Approved 8429	REMERON Approved Use REMERON (mirtazapine) Tablets are indicated for the treatment of major depressive disorder. The efficacy of REMERON in the treatment of major depressive disorder was established in 6-week controlled trials of outpatients whose diagnoses corresponded most closely to the Diagnostic and Statistical Manual of Mental Disorders – 3rd edition (DSM-III) category of major depressive disorder (see CLINICAL PHARMACOLOGY). A major depressive episode (DSM-IV) implies a prominent and relatively persistent (nearly every day for at least 2 weeks) depressed or dysphoric mood that usually interferes with daily functioning, and includes at least 5 of the following 9 symptoms: depressed mood, loss of interest in usual activities, significant change in weight and/or appetite, insomnia or hypersomnia, psychomotor agitation or retardation, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, a suicide attempt, or suicidal ideation. The effectiveness of REMERON in hospitalized depressed patients has not been adequately studied. The efficacy of REMERON in maintaining a response in patients with major depressive disorder for up to 40 weeks following 8 to 12 weeks of initial open-label treatment was demonstrated in a placebo-controlled trial. Nevertheless, the physician who elects to use REMERON for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient (see CLINICAL PHARMACOLOGY). Launch Date 1996

C_max

Value	Dose	Co-administered	Analyte	Population
32.3 μg/L REVIEW https://www.ncbi.nlm.nih.gov/pubmed/10885584	15 mg single, oral dose: 15 mg route of administration: Oral experiment type: SINGLE co-administered:		MIRTAZAPINE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FED

AUC

Value	Dose	Co-administered	Analyte	Population
345 μg × h/L REVIEW https://www.ncbi.nlm.nih.gov/pubmed/10885584	15 mg single, oral dose: 15 mg route of administration: Oral experiment type: SINGLE co-administered:		MIRTAZAPINE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FED

T_1/2

Value	Dose	Co-administered	Analyte	Population
21.2 h REVIEW https://www.ncbi.nlm.nih.gov/pubmed/10885584	15 mg single, oral dose: 15 mg route of administration: Oral experiment type: SINGLE co-administered:		MIRTAZAPINE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FED
30 h DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020415s023s024.pdf	15 mg single, oral dose: 15 mg route of administration: Oral experiment type: SINGLE co-administered:		MIRTAZAPINE plasma	Homo sapiens population: UNKNOWN age: ADULT sex: FEMALE / MALE food status: UNKNOWN

F_unbound

Value	Dose	Co-administered	Analyte	Population
15% REVIEW https://www.ncbi.nlm.nih.gov/pubmed/10885584	15 mg single, oral dose: 15 mg route of administration: Oral experiment type: SINGLE co-administered:		MIRTAZAPINE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FED
15% DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020415s023s024.pdf	15 mg single, oral dose: 15 mg route of administration: Oral experiment type: SINGLE co-administered:		MIRTAZAPINE plasma	Homo sapiens population: UNKNOWN age: ADULT sex: FEMALE / MALE food status: UNKNOWN

Doses

Dose	Population	Adverse events
75 mg single, oral Highest studied dose Dose: 75 mg Route: oral Route: single Dose: 75 mg Sources: https://pubmed.ncbi.nlm.nih.gov/18370465	healthy, 18-35 years Health Status: healthy Age Group: 18-35 years Sex: M Sources: https://pubmed.ncbi.nlm.nih.gov/18370465	Sources: https://pubmed.ncbi.nlm.nih.gov/18370465
15 mg 1 times / day steady, oral Recommended Dose: 15 mg, 1 times / day Route: oral Route: steady Dose: 15 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/32676274	unhealthy, 55 years n = 1 Health Status: unhealthy Age Group: 55 years Sex: F Population Size: 1 Sources: https://pubmed.ncbi.nlm.nih.gov/32676274	Disc. AE: Angle closure glaucoma... AEs leading to discontinuation/dose reduction: Angle closure glaucoma (1 patient) Sources: https://pubmed.ncbi.nlm.nih.gov/32676274
15 mg 1 times / day steady, oral Recommended Dose: 15 mg, 1 times / day Route: oral Route: steady Dose: 15 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/020415s034s036,021208s024s026lbl.pdf	unhealthy, adult n = 453 Health Status: unhealthy Age Group: adult Population Size: 453 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/020415s034s036,021208s024s026lbl.pdf	Disc. AE: Somnolence, Nausea... AEs leading to discontinuation/dose reduction: Somnolence (10.4%) Nausea (1.5%) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/020415s034s036,021208s024s026lbl.pdf
15 mg 1 times / day multiple, oral Recommended Dose: 15 mg, 1 times / day Route: oral Route: multiple Dose: 15 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/020415s034s036,021208s024s026lbl.pdf	unhealthy, children Health Status: unhealthy Condition: major depressive disorde Age Group: children Sex: M+F Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/020415s034s036,021208s024s026lbl.pdf	Other AEs: Suicidal tendency, Suicidal behavior... Other AEs: Suicidal tendency Suicidal behavior Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/020415s034s036,021208s024s026lbl.pdf

AEs

AE	Significance	Dose	Population
Angle closure glaucoma	1 patient Disc. AE	15 mg 1 times / day steady, oral Recommended Dose: 15 mg, 1 times / day Route: oral Route: steady Dose: 15 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/32676274	unhealthy, 55 years n = 1 Health Status: unhealthy Age Group: 55 years Sex: F Population Size: 1 Sources: https://pubmed.ncbi.nlm.nih.gov/32676274
Nausea	1.5% Disc. AE	15 mg 1 times / day steady, oral Recommended Dose: 15 mg, 1 times / day Route: oral Route: steady Dose: 15 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/020415s034s036,021208s024s026lbl.pdf	unhealthy, adult n = 453 Health Status: unhealthy Age Group: adult Population Size: 453 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/020415s034s036,021208s024s026lbl.pdf
Somnolence	10.4% Disc. AE	15 mg 1 times / day steady, oral Recommended Dose: 15 mg, 1 times / day Route: oral Route: steady Dose: 15 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/020415s034s036,021208s024s026lbl.pdf	unhealthy, adult n = 453 Health Status: unhealthy Age Group: adult Population Size: 453 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/020415s034s036,021208s024s026lbl.pdf
Suicidal behavior		15 mg 1 times / day multiple, oral Recommended Dose: 15 mg, 1 times / day Route: oral Route: multiple Dose: 15 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/020415s034s036,021208s024s026lbl.pdf	unhealthy, children Health Status: unhealthy Condition: major depressive disorde Age Group: children Sex: M+F Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/020415s034s036,021208s024s026lbl.pdf
Suicidal tendency		15 mg 1 times / day multiple, oral Recommended Dose: 15 mg, 1 times / day Route: oral Route: multiple Dose: 15 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/020415s034s036,021208s024s026lbl.pdf	unhealthy, children Health Status: unhealthy Condition: major depressive disorde Age Group: children Sex: M+F Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/020415s034s036,021208s024s026lbl.pdf

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1737 inhibitor 1587	substrate 1037	substrate 1217 inhibitor 1852

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
P-gp 1461 CYP1A2 1524	CYP1A2 1054 BCRP 561

Drug as perpetrator

Target	Modality	Activity	Clinical evidence
CYP1A2 1692	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/31587356/	weak
CYP3A4 1925	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/31587356/	weak
CYP2D6 1891	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/31587356/	weak	no (co-administration study) Comment: mirtazapine caused no changes on the pharmacokinetics of paroxetine or amitriptyline Sources: https://pubmed.ncbi.nlm.nih.gov/31587356/
GLUT2 8	supressor 155 Sources: https://pubmed.ncbi.nlm.nih.gov/31231496/	yes
P-gp 1650	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/31587356/	yes

Drug as victim

Target	Modality	Activity	Clinical evidence
CYP3A4 1737	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/020415s034s036,021208s024s026lbl.pdf Page: 18.0	major	yes (co-administration study) Comment: ketoconazole increased mirtazapine AUC 50% Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/020415s034s036,021208s024s026lbl.pdf Page: 18.0
CYP2C9 1037	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/96/020415Orig1s000rev.pdf Page: 540.0	minor
BCRP 561	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/31037729/	yes
CYP1A2 1054	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/020415s034s036,021208s024s026lbl.pdf Page: 17.0	yes	yes (co-administration study) Comment: cimetidine increaes mirtazapine AUC >50% Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/020415s034s036,021208s024s026lbl.pdf Page: 17.0
CYP2D6 1217	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/020415s034s036,021208s024s026lbl.pdf Page: 17, 18	yes	yes (co-administration study) Comment: amitriptyline caused no changes on the pharmacokinetics of mirtazapine Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/020415s034s036,021208s024s026lbl.pdf Page: 17, 18

Sourcing

Vendor/Aggregator	ID	URL
ChEBI	CHEBI:6950	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:6950
ChemicalBook	CB0463388	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB0463388
ChemicalBook	CB7463387	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB7463387
MolPort	MolPort-003-849-233	https://www.molport.com/shop/molecule-link/MolPort-003-849-233
Selleck Chemicals	mirtazapine-remeron-avanza	http://www.selleckchem.com/products/mirtazapine-remeron-avanza.html
eMolecules	591516	https://www.emolecules.com/cgi-bin/more?vid=591516

PubMed

Title	Date	PubMed
Third-generation antidepressants: do they offer advantages over the SSRIs?	2001	11735614
Meta-analytical studies on new antidepressants.	2001	11719915
Meta-analysis of placebo-controlled trials with mirtazapine using the core items of the Hamilton Depression Scale as evidence of a pure antidepressive effect in the short-term treatment of major depression.	2001 Dec	11806859
Comment: serotonin syndrome induced by fluvoxamine and mirtazapine.	2001 Dec	11793645
An open trial of mirtazapine in menopausal women with depression unresponsive to estrogen replacement therapy.	2001 Dec	11788110
First report of mirtazapine-induced arthralgia.	2001 Dec	11777743
Relative safety of mirtazapine overdose.	2001 Dec	11757992
Peripheral edema associated with mirtazapine.	2001 Nov	11724109
The effect of mirtazapine in panic disorder: an open label pilot study with a single-blind placebo run-in period.	2001 Nov	11712626
[Interference in the serotoninergic and noradrenergic system. Faster out of depression].	2001 Nov 1	11732403
Trait anxiety and the effect of a single high dose of diazepam in unipolar depression.	2001 Nov-Dec	11684140
Efficacy of mirtazapine for prevention of depressive relapse: a placebo-controlled double-blind trial of recently remitted high-risk patients.	2001 Oct	11816867
[Pharmacotherapeutical approaches to insomnia patients with cardiac diseases and after heart transplantation].	2001 Oct	11757467
Permutation-validated principal components analysis of microarray data.	2002	11983060
Mania associated with mirtazapine augmentation of fluoxetine.	2002	11816053
Prevalence of sexual dysfunction among newer antidepressants.	2002 Apr	12000211
Mirtazapine overdose with benign outcome.	2002 Apr	11973120
Mirtazapine may have the propensity for developing a restless legs syndrome? A case report.	2002 Apr	11952928
Serotonin syndrome and atypical antipsychotics.	2002 Apr	11925312
Severe serotonin syndrome induced by mirtazapine monotherapy.	2002 Apr	11918514
Induction of hyperlocomotion in mice exposed to a novel environment by inhibition of serotonin reuptake. A pharmacological characterization of diverse classes of antidepressant agents.	2002 Apr	11888558
In the rat forced swimming test, NA-system mediated interactions may prevent the 5-HT properties of some subacute antidepressant treatments being expressed.	2002 Apr	11872334
Spectrophotometric, spectrofluorimetric, HPLC and CZE determination of mirtazapine in pharmaceutical tablets.	2002 Apr 15	11929680
Effects of antidepressants in rats trained to discriminate centrally administered isoproterenol.	2002 Aug	12130722
Determination of mirtazapine and its demethyl metabolite in plasma by high-performance liquid chromatography with ultraviolet detection. Application to management of acute intoxication.	2002 Aug 5	12113982
Intravenous mirtazapine in the treatment of depressed inpatients.	2002 Feb	11788241
Venlafaxine and mirtazapine: different mechanisms of antidepressant action, common opioid-mediated antinociceptive effects--a possible opioid involvement in severe depression?	2002 Feb-Apr	11931344
A survey of prescribing practices in the treatment of depression.	2002 Jan	11853110
Chronic treatment with imipramine or mirtazapine antagonizes stress- and FG7142-induced increase in cortical norepinephrine output in freely moving rats.	2002 Jan	11746735
A double-blind, placebo-controlled study of antidepressant augmentation with mirtazapine.	2002 Jan 15	11822997
Mirtazapine, but not fluvoxamine, normalizes the blunted REM sleep response to clonidine in depressed patients: implications for subsensitivity of alpha(2)-adrenergic receptors in depression.	2002 Jan 31	11850045
Body weight changes associated with psychopharmacology.	2002 Jul	12096167
Mirtazapine in the treatment of panic disorder.	2002 Jul	12090820
Synthesis and pharmacological testing of 1,2,3,4,10,14b-hexahydro-6-methoxy-2-methyldibenzo[c,f]pyrazino[1,2-a]azepin and its enantiomers in comparison with the two antidepressants mianserin and mirtazapine.	2002 Jul 18	12109911
Prevention of the stress-induced increase in the concentration of neuroactive steroids in rat brain by long-term administration of mirtazapine but not of fluoxetine.	2002 Jun	12095071
Separation of new antidepressants and their metabolites by micellar electrokinetic capillary chromatography.	2002 Jun 15	12015266
Sequential catecholamine and serotonin depletion in mirtazapine-treated depressed patients.	2002 Mar	12057033
New antidepressants in the treatment of neuropathic pain. A review.	2002 Mar	11981519
Successful treatment of recurrent brief depression with reboxetine -- a single case analysis.	2002 Mar	11951149
Effect of repeated treatment with mirtazapine on the central alpha1-adrenergic receptors.	2002 Mar	11939713
Heart rate variability as predictor of nonresponse to mirtazapine in panic disorder: a preliminary study.	2002 Mar	11892720
Mirtazapine-induced akathisia.	2002 Mar 4	11999246
[Tolerability and efficacy of combined antidepressant therapy].	2002 Mar-Apr	12028939
Acute and chronic hypertensive headache and hypertensive encephalopathy.	2002 May	12100095
Urinary incontinence with mirtazapine.	2002 May	12019674
Dystonia induced by mirtazapine.	2002 May	12019672
An open-label, crossover trial of mirtazapine (15 and 30 mg) in cancer patients with pain and other distressing symptoms.	2002 May	12007762
Psychotropic drugs and the ECG: focus on the QTc interval.	2002 May	11996627
Mirtazapine, yohimbine or olanzapine augmentation therapy for serotonin reuptake-associated female sexual dysfunction: a randomized, placebo controlled trial.	2002 May-Jun	11886692
Molecular characterisation of antidepressant effects in the mouse brain using gene expression profiling.	2002 May-Jun	11886689

Patents

Sample Use Guides

In Vivo Use Guide

The recommended starting dose for REMERON® (mirtazapine) Tablets is 15 mg/day, administered in a single dose. In the controlled clinical trials establishing the efficacy of REMERON in the treatment of major depressive disorder, the effective dose range was generally 15 to 45 mg/day.

Route of Administration: Oral

In Vitro Use Guide

0.1 uM mirtazapine affects glucocorticoid receptors expression (U937 cells)

Name

Type

Language

MIRTAZAPINE

Official Name

English

ORG-3770

Code

English

MIRTAZAPINE [USAN]

Common Name

English

MIRTAZAPINE ANHYDROUS

Common Name

English

REMERON

Brand Name

English

MIRTAZAPINE, (±)-

Common Name

English

MIRTAZAPINE [ORANGE BOOK]

Common Name

English

MIRTAZAPINE [USP MONOGRAPH]

Common Name

English

ZISPIN

Brand Name

English

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

Common Name

English

MIRATAZ

Brand Name

English

PYRAZINO(2,1-A)PYRIDO(2,3-C)(2)BENZAZEPINE, 1,2,3,4,10,14B-HEXAHYDRO-2-METHYL-

Common Name

English

NORSET

Brand Name

English

MIRTAZAPINE [JAN]

Common Name

English

MIRTAZAPINE [GREEN BOOK]

Common Name

English

MIRTAZAPINE [USP-RS]

Common Name

English

MIRTAZAPINE [MI]

Common Name

English

REXER

Brand Name

English

AVANZA

Brand Name

English

MIRTAZAPIN

Common Name

English

Mirtazapine [WHO-DD]

Common Name

English

ORG 3770

Code

English

mirtazapine [INN]

Common Name

English

6-AZAMIANSERIN

Common Name

English

MIRTAZAPINE [VANDF]

Common Name

English

MIRTAZAPINE [EP MONOGRAPH]

Common Name

English

PROMYRTIL

Brand Name

English

Classification Tree Code System Code

LIVERTOX

NBK548216