- Overview
- Properties
- Genetics
- Related Genes
- Related Drugs
- Related Diseases
- Datasets
- Downloads/LinkOuts
Overview
| Generic Names: | Clozapin |
|---|---|
| Trade Names: | Asaleptin; Clozaril; Fazaclo ODT; Iprox; Leponex; Lepotex |
| PharmGKB Accession Id: | PA449061 |
Description
A tricylic dibenzodiazepine, classified as an atypical antipsychotic agent. It binds several types of central nervous system receptors, and displays a unique pharmacological profile. Clozapine is a serotonin antagonist, with strong binding to 5-HT 2A/2C receptor subtype. It also displays strong affinity to several dopaminergic receptors, but shows only weak antagonism at the dopamine D2 receptor, a receptor commonly thought to modulate neuroleptic activity. Agranulocytosis is a major adverse effect associated with administration of this agent. PubChem (source: Drug Bank)
Indication
For the management of severely ill schizophrenic patients who fail to respond adequately to standard drug treatment for schizophrenia (source: Drug Bank)
ATC Therapeutic Category
- N05AH:Diazepines, oxazepines and thiazepines
Pharmacology, Interactions, and Contraindications
Mechanism Of Action
The mechanism of action of Clozapine, as with other drugs used to treat schizophrenia, is unknown. However, it has been proposed that the drug's therapeutic activity in schizophrenia is mediated through a combination of dopamine Type 2 (D2) and serotonin Type 2 (5HT<sub>2</sub>) receptor antagonism. (source: Drug Bank)
Pharmacology
Clozapine is a psychotropic agent belonging to the chemical class of benzisoxazole derivatives and is indicated for the treatment of schizophrenia. Clozapine is a selective monoaminergic antagonist with high affinity for the serotonin Type 2 (5HT<sub>2</sub>), dopamine Type 2 (D2), 1 and 2 adrenergic, and H1 histaminergic receptors. Clozapine acts as an antagonist at other receptors, but with lower potency. Antagonism at receptors other than dopamine and 5HT<sub>2</sub> with similar receptor affinities may explain some of the other therapeutic and side effects of Clozapine. Clozapine's antagonism of muscarinic M1-5 receptors may explain its anticholinergic effects. Clozapine's antagonism of histamine H1 receptors may explain the somnolence observed with this drug. Clozapine's antagonism of adrenergic a1 receptors may explain the orthostatic hypotension observed with this drug. (source: Drug Bank)
Food Interactions
Avoid alcohol.
Limit caffeine intake (may reduce clozapine matabolism).
Take without regard to meals.
(source:
Drug Bank)
Absorption, Distribution, Metabolism, Elimination & Toxicity
Biotransformation
Hepatic (source: Drug Bank)
Protein Binding
97% (bound to serum proteins) (source: Drug Bank)
Absorption
Rapid and almost complete (source: Drug Bank)
Isomeric SMILES Code:
CN1CCN(CC1)C2=Nc3cc(ccc3Nc4c2cccc4)Cl (source: Drug Bank)
Curated Annotations (
)
-
rs4606
at chr1:191047795
in
RGS2
This variant is located in the 3'-regulatory region of RGS2, and is known to influence RGS2 mRNA levels and protein expression. It has been shown to be associated antipsychotic-induced parkinsonism (AIP) with possible protective effect of the minor G allele of rs4606.- Related Drugs:
- clozapine, olanzapine, risperidone
- Related Diseases:
- Parkinson Disease, Psychotic Disorders
- Evidence:
-
PMID:18347610
-
rs6280
at chr3:115373505
in
DRD3
Risk or phenotype-associated allele: Phenotype: This meta-analysis showed no difference in clozipine response between the Ser and Gly allele. Study size: 758 Study population/ethnicity: Patients with Schizophrenia Significance metric(s): OR = 0.82, 95% confidence interval (CI): 0.65-1.04; p = 0.1 Type of association: PD- Variant Name:
- DRD3:Ser9Gly
- Related Drugs:
- clozapine
- Related Diseases:
- Schizophrenia
- Evidence:
-
PMID:20029384
-
rs742105
at chr6:15681053
in
DTNBP1
Patients with diplotype ACCCTC/GTTGCC, genotypes T/T+T/C, or allele T of marker rs742105 showed a better response to clozapine (0.005- Related Drugs:
- clozapine
- Related Diseases:
- Schizophrenia
- Evidence:
- PMID:19369910
-
rs2228622
at chr9:4554432
in
SLC1A1
Risk or phenotype-associated variant: A. Phenotype: The A/C/G haplotype at rs2228622-rs3780413-rs3780412 showed a significant association with atypical antipsychotic-induced obsessive compulsive symptoms. Study size: 94. Study population/ethnicity: Patients with schizophrenia receiving atypical antipsychotics; Asian; Korea. Significance metric(s): p = 0.04. Type of association: CO.- Variant Name:
- SLC1A1:rs2228622G>A, SNP2, Exon 4(syn)
- Related Drugs:
- clozapine, olanzapine, risperidone
- Related Diseases:
- Obsessive-Compulsive Disorder, Schizophrenia
- Evidence:
-
PMID:19884611
-
rs3780413
at chr9:4557353
in
SLC1A1
Risk or phenotype-associated variant: C. Phenotype: The A/C/G haplotype at rs2228622-rs3780413-rs3780412 showed a significant association with atypical antipsychotic-induced obsessive compulsive symptoms. Study size: 94. Study population/ethnicity: Patients with schizophrenia receiving atypical antipsychotics; Asian; Korea. Significance metric(s): p = 0.04. Type of association: CO.- Variant Name:
- SLC1A1:rss3780413C>G, SNP3, Intron 5
- Related Drugs:
- clozapine, olanzapine, risperidone
- Related Diseases:
- Obsessive-Compulsive Disorder, Schizophrenia
- Evidence:
-
PMID:19884611
-
rs3780412
at chr9:4562480
in
SLC1A1
Risk or phenotype-associated variant: G. Phenotype: The A/C/G haplotype at rs2228622-rs3780413-rs3780412 showed a significant association with atypical antipsychotic-induced obsessive compulsive symptoms. Study size: 94. Study population/ethnicity: Patients with schizophrenia receiving atypical antipsychotics; Asian; Korea. Significance metric(s): p = 0.04. Type of association: CO.- Variant Name:
- SLC1A1:rs3780412A>G, SNP4, Intron 7
- Related Drugs:
- clozapine, olanzapine, risperidone
- Related Diseases:
- Obsessive-Compulsive Disorder, Schizophrenia
- Evidence:
-
PMID:19884611
-
rs1800497
at chr11:112776038
in
ANKK1
Phenotype: A meta-analysis, including eight individual studies, was not able to detect an association between clinical response to antipsychotics and the Taq1A variant. Study size: meta-analysis included 8 individual studies, 748 patients total.- Variant Name:
- TaqIA (C/T)
- Related Drugs:
- aripiprazole, Bromperidol, chlorpromazine, clozapine, haloperidol, nemonapride, risperidone
- Related Diseases:
- Schizophrenia
- Evidence:
-
PMID:20194480
-
rs1800497
at chr11:112776038
in
ANKK1
Risk or phenotype-associated allele: T. Phenotype: In the combined medication group patients with the A1 (T) allele had 40% higher prolactin levels than patients without this allele. Study size: 144 schizophrenic patients. Study population: White patients.- Variant Name:
- Taq1A (32806C>T)
- Related Drugs:
- antipsychotics, clozapine, olanzapine, risperidone
- Related Diseases:
- Hyperprolactinemia
- Evidence:
-
PMID:15286066
-
rs1800497
at chr11:112776038
in
ANKK1
Risk or phenotype-associated allele: T. Phenotype: The T allele was associated with weight gain of at least 7% in schizophrenia patients treatment with clozapine or olanzapine. Study size: 206. Study population/ethnicity: European american; German; Schizophrenia. Significance metric(s): OR = 2.18 (CI: 1.00-4.75). Type of association: PD.- Variant Name:
- TaqIA
- Related Drugs:
- antipsychotics, clozapine, olanzapine
- Related Diseases:
- Weight gain
- Evidence:
-
PMID:20714340
-
rs6277
at chr11:112788669
in
DRD2
Risk or phenotype-associated allele: CC. Phenotype: The CC genotype was associated with weight gain of at least 7% in schizophrenia patients treatment with clozapine or olanzapine. Study size: 206. Study population/ethnicity: European american; African American; German; Schizophrenia. Significance metric(s): OR = 3.37 (CI = 1.00-11.36). Type of association: PD.- Variant Name:
- C957T
- Related Drugs:
- antipsychotics, clozapine, olanzapine
- Related Diseases:
- Weight gain
- Evidence:
-
PMID:20714340
-
rs1079598
at chr11:112801484
in
DRD2
Risk or phenotype-associated allele: C. Phenotype: The C allele was associated with weight gain of at least 7% in schizophrenia patients treatment with clozapine or olanzapine. Study size: 206. Study population/ethnicity: European american; African American; German; Schizophrenia. Significance metric(s): OR = 3.44 (CI: 1.46-8.11). Type of association: PD.- Related Drugs:
- antipsychotics, clozapine, olanzapine
- Related Diseases:
- Weight gain
- Evidence:
-
PMID:20714340
-
rs4436578
at chr11:112811975
in
DRD2
Risk or phenotype-associated allele: C Phenotype: Patients homozygous for the rs4436578-C allele were at increased risk of body weight gain as compared with the heterozygotes and those of the rs4436578-TT genotype after atypical antipsychotics treatment Study size: 479 chronic inpatients with schizophrenia Study population/ethnicity: Chinese Significance metric(s): OR = 3.36 (95% confidence interval=1.62 approximately 7.00) Type of association: GN- Related Drugs:
- antipsychotics, clozapine, risperidone
- Evidence:
-
PMID:20375926
-
rs1799732
at chr11:112851462
in
DRD2
Phenotype: No association was found between the -141C Ins/Del polymorphism and clinical response to clozapine in 151 schizophrenic patients of British origin. Study size: 151 schizophrenics; 95 controls. Study population: Caucasian.- Variant Name:
- DRD2: -141C Ins/Del
- Related Drugs:
- clozapine
- Related Diseases:
- Schizophrenia
- Evidence:
-
PMID:9918131
-
rs1799732
at chr11:112851462
in
DRD2
Phenotype: No association was found between the -141C Ins/Del polymorphism and clozapine response in either the Caucasian or African-American population sample. Study size and population: 183 Caucasian and 49 African-American.- Variant Name:
- DRD2: -141C Ins/Del
- Related Drugs:
- clozapine
- Related Diseases:
- Schizophrenia
- Evidence:
-
PMID:15830237
-
rs1799732
at chr11:112851462
in
DRD2
Phenotype: Results of this meta-analysis showed that the group of Del allele carrier was significantly associated with poorer antipsychotic drug response relative to the Ins/Ins genotype. Study size: meta-analysis included six individual studies, 687 patients total.- Variant Name:
- DRD2: -141C Ins/Del
- Related Drugs:
- aripiprazole, chlorpromazine, clozapine, olanzapine, risperidone
- Related Diseases:
- Schizophrenia
- Evidence:
-
PMID:20194480
-
rs72547516
at chr15:72831631
in
CYP1A2
Risk or phenotype-associated allele: T Phenotype: In an in vitro system, this variant showed no activity for the drug substrates clozapine or phenacetin even at the highest substrate and double membrane concentrations, it also showed reduced expression of holoprotein in bacterial cells. Type of association: FA- Variant Name:
- CYP1A2:Ile386Phe, CYP1A2*4, rs72547516 A>T)
- Related Drugs:
- clozapine, phenacetin
- Evidence:
-
PMID:20125119
-
rs72547517
at chr15:72834298
in
CYP1A2
Risk or phenotype-associated allele: A Phenotype: In an in vitro system, this variant showed no activity for the drug substrates clozapine or phenacetin even at the highest substrate and double membrane concentrations, it also showed reduced expression of holoprotein in bacterial cells. Type of association: FA- Variant Name:
- CYP1A2:Arg456His, CYP1A2*8, rs72547517 G>A
- Related Drugs:
- clozapine, phenacetin
- Evidence:
-
PMID:20125119
-
rs1414334
at chrX:114044400
in
HTR2C
In a pooled analysis of two studies the variant C allele was specifically associated with the metabolic syndrome in patients using clozapine or risperidone.- Related Drugs:
- clozapine, risperidone
- Related Diseases:
- metabolic syndrome
- Evidence:
-
PMID:19142101
The following genes are in curated knowledge about this drug.
A list of non-curated publications that mention this drug along with other genes is available.
Drug Targets
The following drugs are in curated knowledge about this drug.
| Drug | Relationship | Evidence | |
|---|---|---|---|
|
tamoxifen |
|
Publications |
A list of non-curated publications that mention this drug along with other drugs is available.
Drug Interactions
| Drug | Description | |
|---|---|---|
| alprazolam |
|
Increased risk of toxicity (source: Drug Bank) |
| bromazepam |
|
Increased risk of toxicity (source: Drug Bank) |
| caffeine |
|
Caffeine increases the effect and toxicity of clozapine (source: Drug Bank) |
| carbamazepine |
|
Carbamazepine decreases the effect of clozapine, hematologic toxicity (source: Drug Bank) |
| chlordiazepoxide |
|
Increased risk of toxicity (source: Drug Bank) |
| cimetidine |
|
Cimetidine increases the effect of clozapine (source: Drug Bank) |
| cinolazepam |
|
Increased risk of toxicity (source: Drug Bank) |
| ciprofloxacin |
|
Ciprofloxacin may increase clozapine serum levels (source: Drug Bank) |
| citalopram |
|
The antidepressant increases the effect of clozapine (source: Drug Bank) |
| clobazam |
|
Increased risk of toxicity (source: Drug Bank) |
| clonazepam |
|
Increased risk of toxicity (source: Drug Bank) |
| clorazepate |
|
Increased risk of toxicity (source: Drug Bank) |
| diazepam |
|
Increased risk of toxicity (source: Drug Bank) |
| donepezil |
|
Possible antagonism of action (source: Drug Bank) |
| erythromycin |
|
Erythromycin increases the effect of clozapine (source: Drug Bank) |
| estazolam |
|
Increased risk of toxicity (source: Drug Bank) |
| ethotoin |
|
Hydantoin decreases the effect of clozapine (source: Drug Bank) |
| flunitrazepam |
|
Increased risk of toxicity (source: Drug Bank) |
| fluoxetine |
|
The antidepressant increases the effect of clozapine (source: Drug Bank) |
| flurazepam |
|
Increased risk of toxicity (source: Drug Bank) |
| fluvoxamine |
|
The antidepressant increases the effect of clozapine (source: Drug Bank) |
| fosphenytoin |
|
Hydantoin decreases the effect of clozapine (source: Drug Bank) |
| galantamine |
|
Possible antagonism of action (source: Drug Bank) |
| halazepam |
|
Increased risk of toxicity (source: Drug Bank) |
| haloperidol |
|
Increases the effect and toxicity of haloperidol (source: Drug Bank) |
| josamycin |
|
Erythromycin increases the effect of clozapine (source: Drug Bank) |
| ketazolam |
|
Increased risk of toxicity (source: Drug Bank) |
| lamotrigine |
|
Lamotrigine increases the effect and toxicity of clozapine (source: Drug Bank) |
| lisinopril |
|
Lisinopril increases the effect and toxicity of clozapine (source: Drug Bank) |
| lorazepam |
|
Increased risk of toxicity (source: Drug Bank) |
| mephenytoin |
|
Hydantoin decreases the effect of clozapine (source: Drug Bank) |
| midazolam |
|
Increased risk of toxicity (source: Drug Bank) |
| modafinil |
|
Modafinil increases the effect and toxicity of clozapine (source: Drug Bank) |
| nitrazepam |
|
Increased risk of toxicity (source: Drug Bank) |
| norfloxacin |
|
Ciprofloxacin may increase clozapine serum levels (source: Drug Bank) |
| oxazepam |
|
Increased risk of toxicity (source: Drug Bank) |
| phenytoin |
|
Hydantoin decreases the effect of clozapine (source: Drug Bank) |
| prazepam |
|
Increased risk of toxicity (source: Drug Bank) |
| quazepam |
|
Increased risk of toxicity (source: Drug Bank) |
| rifabutin |
|
Rifabutin decreases the effect of clozapine (source: Drug Bank) |
| rifampin |
|
Rifampin decreases the effect of clozapine (source: Drug Bank) |
| ritonavir |
|
Ritonavir increases the effect and toxicity of clozapine (source: Drug Bank) |
| rivastigmine |
|
Possible antagonism of action (source: Drug Bank) |
| sertraline |
|
The antidepressant increases the effect of clozapine (source: Drug Bank) |
| temazepam |
|
The benzodiazepine, Temazepam, may increase the adverse effects of Clozapine. Monitor for respiratory depression and hypotension if concomitant therapy is initiated. (source: Drug Bank) |
| triazolam |
|
Increased risk of toxicity (source: Drug Bank) |
Curated Information
The following diseases are in curated knowledge about this drug.
| Disease | Relationship | Evidence | |
|---|---|---|---|
|
|
Agranulocytosis |
|
Publications |
|
|
Body Weight Changes |
|
Publications |
|
|
metabolic syndrome |
|
Publications, Variants |
|
|
Obsessive-Compulsive Disorder |
|
Publications |
|
|
Parkinson Disease |
|
Publications, Variants |
|
|
Psychotic Disorders |
|
Publications, Variants |
|
|
Schizophrenia |
|
Publications, Variants |
|
|
tardive dyskinesia |
|
Publications |
|
|
Weight gain |
|
Publications, Variants |
Non-Curated Information
A list of non-curated publications that mention this drug along with other diseases is available.
Additional Datasets
These datasets are minimally curated and are sorted alphabetically by title.
LinkOuts
Common Searches
Search PubMed
Search Medline Plus
Search PubChem
Search CTD
Non-Curated Publications
A list of non-curated publications that mention this drug is available.