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
Review of the results from clinical studies on the efficacy, safety and tolerability of mirtazapine for the treatment of patients with major depression.	1998 Dec	10333982
Behavioral and memory improving effects of mirtazapine in rats.	1999 Nov-Dec	10817523
Third-generation antidepressants: do they offer advantages over the SSRIs?	2001	11735614
Separation anxiety disorder in children and adolescents: epidemiology, diagnosis and management.	2001	11460893
Evidence of early onset of antidepressant effect in randomized controlled trials.	2001	11229783
Incidence of sexual dysfunction associated with antidepressant agents: a prospective multicenter study of 1022 outpatients. Spanish Working Group for the Study of Psychotropic-Related Sexual Dysfunction.	2001	11229449
Mirtazapine for excessive masturbation in an adolescent with autism.	2001 Aug	11501682
An open trial of mirtazapine in menopausal women with depression unresponsive to estrogen replacement therapy.	2001 Dec	11788110
A naturalistic open-label study of mirtazapine in autistic and other pervasive developmental disorders.	2001 Fall	11642476
Screening for detection of new antidepressants, neuroleptics, hypnotics, and their metabolites in urine by GC-MS developed using rat liver microsomes.	2001 Feb	11206046
Treatment of depression in the elderly.	2001 Feb 1	11272296
Following long-term training with citalopram, both mirtazapine and mianserin block its discriminative stimulus properties in rats.	2001 Jan	11271412
Mirtazepine: heir apparent to amitriptyline?	2001 Jan-Feb	11406877
Drug-drug interaction studies with mirtazapine and carbamazepine in healthy male subjects.	2001 Jan-Jun	11554425
Subclinical pancreatitis related to mirtazapine - a case report.	2001 Jul	11518479
A placebo-controlled, crossover trial of granisetron in SRI-induced sexual dysfunction.	2001 Jun	11465525
Efficacy and safety of mirtazapine in major depressive disorder patients after SSRI treatment failure: an open-label trial.	2001 Jun	11465517
SSRI and mirtazapine in PTSD.	2001 Mar	11288766
Efficacy of mirtazapine add on therapy to haloperidol in the treatment of the negative symptoms of schizophrenia: a double-blind randomized placebo-controlled study.	2001 Mar	11236073
Mitrazapine-associated palinopsia.	2001 May	11411821
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
Mirtazapine overdose with benign outcome.	2002 Apr	11973120
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
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
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
Separation of new antidepressants and their metabolites by micellar electrokinetic capillary chromatography.	2002 Jun 15	12015266
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
Dystonia induced by mirtazapine.	2002 May	12019672

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