Clozapine is an
antipsychoticAn antipsychotic is a tranquilizing psychiatric medication primarily used to manage psychosis , particularly in schizophrenia and bipolar disorder. A first generation of antipsychotics, known as typical antipsychotics, was discovered in the 1950s...
medication used in the treatment of
schizophreniaSchizophrenia is a mental disorder characterized by a disintegration of thought processes and of emotional responsiveness. It most commonly manifests itself as auditory hallucinations, paranoid or bizarre delusions, or disorganized speech and thinking, and it is accompanied by significant social...
, and is also used off-label in the treatment of
bipolar disorderBipolar disorder or bipolar affective disorder, historically known as manic–depressive disorder, is a psychiatric diagnosis that describes a category of mood disorders defined by the presence of one or more episodes of abnormally elevated energy levels, cognition, and mood with or without one or...
. Wyatt. R and Chew. R (2005) tells us there are three pharmaceutical companies that market this drug at present: Novartis Pharmaceuticals (manufacturer), Mylan Laboratories and Ivax Pharmaceuticals (market generic clozapine). The first of the
atypical antipsychoticThe atypical antipsychotics are a group of antipsychotic tranquilizing drugs used to treat psychiatric conditions. Some atypical antipsychotics are FDA approved for use in the treatment of schizophrenia...
s to be developed, it was first introduced in Europe in 1971, but was voluntarily withdrawn by the manufacturer in 1975 after it was shown to cause
agranulocytosisGranulopenia, also known as Agranulosis or Agranulocytosis, is an acute condition involving a severe and dangerous leukopenia , most commonly of neutrophils causing a neutropenia in the circulating blood. It represents a severe lack of one major class of infection-fighting white blood cells...
, a condition involving a dangerous decrease in the number of white blood cells, that led to death in some patients. In 1989, after studies demonstrated that it was more effective than any other antipsychotic for treating schizophrenia, the U.S. Food and Drug Administration (FDA) approved clozapine's use but only for treatment-resistant schizophrenia. The FDA requires blood testing for patients taking clozapine. The FDA also requires clozapine to carry five black box warnings for
agranulocytosisGranulopenia, also known as Agranulosis or Agranulocytosis, is an acute condition involving a severe and dangerous leukopenia , most commonly of neutrophils causing a neutropenia in the circulating blood. It represents a severe lack of one major class of infection-fighting white blood cells...
, seizures,
myocarditisMyocarditis is inflammation of heart muscle . It resembles a heart attack but coronary arteries are not blocked.Myocarditis is most often due to infection by common viruses, such as parvovirus B19, less commonly non-viral pathogens such as Borrelia burgdorferi or Trypanosoma cruzi, or as a...
, for "other adverse cardiovascular and respiratory effects", and for "increased mortality in elderly patients with dementia-related psychosis." In 2002 the FDA approved clozapine for reducing the risk of suicidal behavior for patients with schizophrenia.
Clozapine is usually used as a
last resortDrugs of last resort are drugs only used when all other options are exhausted. Many of the best known are antibiotics, antivirals, or chemotherapy agents. In those cases, they have the most potent antibiotic, antiviral, or anticancer effects, and/or are drugs for which no resistant strains are...
in patients that have not responded to other anti-psychotic treatments due to its danger of causing agranulocytosis as well as the costs of having to have blood tests continually during treatment. It is, however, one of the very effective anti-psychotic treatment choices. Patients are monitored weekly for the first six months. If there are no low counts the patient can be monitored every two weeks for an additional six months. Afterwards, the patient may qualify for every 4 week monitoring. Clozapine has numerous severe side effects including
agranulocytosisGranulopenia, also known as Agranulosis or Agranulocytosis, is an acute condition involving a severe and dangerous leukopenia , most commonly of neutrophils causing a neutropenia in the circulating blood. It represents a severe lack of one major class of infection-fighting white blood cells...
, bowel infarction, seizures, myocarditis, and diabetes. Additionally, it also often causes less serious side effects such as sialorrhea and weight gain.
Medical uses
Clozapine is an atypical antipsychotic drug primarily prescribed to patients who are unresponsive to or intolerant of conventional neuroleptics. It is used principally in treating treatment-resistant schizophrenia, a term used for the failure of symptoms to respond satisfactorily to at least two different antipsychotics; It clearly has been shown to be more effective in reducing symptoms of schizophrenia than the older typical antipsychotics, with maximal effects in those who have responded poorly to other medication; though the relapse rate is lower and patient acceptability better, this has not translated to significant observed benefits in global functioning. There is some evidence clozapine may reduce propensity for substance abuse in schizophrenic patients.
It is also used for reducing the risk of suicide in patients judged to belong to a high-risk group with chronic risk for suicidal behavior. Clozapine was shown to prolong the time to suicidal attempt significantly greater than
olanzapineOlanzapine is an atypical antipsychotic, approved by the FDA for the treatment of schizophrenia and bipolar disorder...
.
Clozapine works well against positive (e.g., delusions, hallucinations) and negative (e.g. emotional and social withdrawal) symptoms of schizophrenia. It has no dyscognitive effect often seen with other psychoactive drugs and is even able to increase the capabilities of the patient to react to this environment and thereby fosters social rehabilitation. There has been one case report of successful use of Clozapine in isolated increase in Creatine Kinase (in absence of Neuroleptic Malignant Syndrome) in a patient with Schizophrenia where other atypical antipsychotics were not successful.
Adverse effects
The use of clozapine is associated with side effects, many of which are minor, though some are serious and potentially fatal: the more common include extreme
constipationConstipation refers to bowel movements that are infrequent or hard to pass. Constipation is a common cause of painful defecation...
, night-time
droolingDrooling is when saliva flows outside the mouth...
,
muscleMuscle is a contractile tissue of animals and is derived from the mesodermal layer of embryonic germ cells. Muscle cells contain contractile filaments that move past each other and change the size of the cell. They are classified as skeletal, cardiac, or smooth muscles. Their function is to...
stiffness,
sedationSedation is the reduction of irritability or agitation by administration of sedative drugs, generally to facilitate a medical procedure or diagnostic procedure...
,
tremorA tremor is an involuntary, somewhat rhythmic, muscle contraction and relaxation involving to-and-fro movements of one or more body parts. It is the most common of all involuntary movements and can affect the hands, arms, eyes, face, head, vocal folds, trunk, and legs. Most tremors occur in the...
s, orthostasis,
hyperglycemiaHyperglycemia or Hyperglycæmia, or high blood sugar, is a condition in which an excessive amount of glucose circulates in the blood plasma. This is generally a glucose level higher than 13.5mmol/l , but symptoms may not start to become noticeable until even higher values such as 15-20 mmol/l...
, and
weight gainWeight gain is an increase in body weight. This can be either an increase in muscle mass, fat deposits, or excess fluids such as water.-Description:...
. The risks of extrapyramidal symptoms such as
tardive dyskinesiaTardive dyskinesia is a difficult-to-treat form of dyskinesia that can be tardive...
are much less with clozapine when compared to the typical antipsychotics; this may be due to clozapine's anticholinergic effects. Extrapyramidal symptoms may subside somewhat after a person switches from another antipsychotic to clozapine.
Clozapine also carries eleven black box warnings for
agranulocytosisGranulopenia, also known as Agranulosis or Agranulocytosis, is an acute condition involving a severe and dangerous leukopenia , most commonly of neutrophils causing a neutropenia in the circulating blood. It represents a severe lack of one major class of infection-fighting white blood cells...
, CNS depression, leukopenia, neutropenia, seizure disorder, bone marrow suppression, dementia, hypotension, myocarditis, orthostatic hypotension and seizures. Lowering of the
seizure thresholdA seizure threshold is the balance between excitatory and inhibitory forces in the brain which affects how susceptible one is to seizures. Those diagnosed with epilepsy or certain other neurological conditions are vulnerable to sudden new seizures if the threshold is upset, and so must be...
may be dose related and slow initial titration of dose may decrease the risk for precipitating seizures. Slow titration of dosing may also decrease the risk for
orthostatic hypotensionOrthostatic hypotension, also known as postural hypotension, orthostasis, and colloquially as head rush or dizzy spell, is a form of hypotension in which a person's blood pressure suddenly falls when the person stands up or stretches. The decrease is typically greater than 20/10 mm Hg, and may be...
and other adverse cardiovascular side effects.
Clozapine may have a synergistic effect with the sedating action of other drugs such as benzodiazepines, and thus respiratory depression may result with concomitant use. Care should be taken, especially if the latter drugs are given parenterally.
Many
maleMale refers to the biological sex of an organism, or part of an organism, which produces small mobile gametes, called spermatozoa. Each spermatozoon can fuse with a larger female gamete or ovum, in the process of fertilization...
patients have experienced ceasure of
ejaculationEjaculation is the ejecting of semen from the male reproductory tract, and is usually accompanied by orgasm. It is usually the final stage and natural objective of male sexual stimulation, and an essential component of natural conception. In rare cases ejaculation occurs because of prostatic disease...
during
orgasmOrgasm is the peak of the plateau phase of the sexual response cycle, characterized by an intense sensation of pleasure...
as a side effect of clozapine, though this is not documented in official drug guides.
Agranulocytosis
Clozapine carries a
black box warningIn the United States, a black box warning is a type of warning that appears on the package insert for prescription drugs that may cause serious adverse effects...
for drug-induced
agranulocytosisGranulopenia, also known as Agranulosis or Agranulocytosis, is an acute condition involving a severe and dangerous leukopenia , most commonly of neutrophils causing a neutropenia in the circulating blood. It represents a severe lack of one major class of infection-fighting white blood cells...
. Without monitoring, agranulocytosis occurs in about 1% of patients who take clozapine during the first few months of treatment; the risk of developing it is highest about three months into treatment, and decreases substantially thereafter, to less than 0.01% after one year. Patients who have experienced agranulocytosis with previous treatment of clozapine should not receive it again.
In 2007, a pharmacogenetic test was introduced to measure the probability of developing agranulocytosis. The test has two gradations - Higher and Lower risk, with a relative agranulocytosis risk of 2.5 and 0.5 compared to general level. The company states that the test is based on two
SNPA single-nucleotide polymorphism is a DNA sequence variation occurring when a single nucleotide — A, T, C or G — in the genome differs between members of a biological species or paired chromosomes in an individual...
s of the
HLAThe human leukocyte antigen system is the name of the major histocompatibility complex in humans. The super locus contains a large number of genes related to immune system function in humans. This group of genes resides on chromosome 6, and encodes cell-surface antigen-presenting proteins and...
-DQB1 gene.
Patients taking clozapine are required to have a blood cell count every week, for the first six months of therapy (in the USA) and for the first 18 weeks (in the UK). After this, they are required to have a blood cell count every other week for the second six months after therapy. After twelve months, blood cell counts need be performed every four weeks. Patients are advised to inform their
doctorA physician is a health care provider who practices the profession of medicine, which is concerned with promoting, maintaining or restoring human health through the study, diagnosis, and treatment of disease, injury and other physical and mental impairments...
if they develop a
sore throatA sore throat or throat pain is a common physical symptom usually caused by acute pharyngitis, or throat inflammation, though it also occurs in a number of other situations, such as post trauma and in diphtheria. It can cause mild to extreme pain....
, or
feverFever is a common medical sign characterized by an elevation of temperature above the normal range of due to an increase in the body temperature regulatory set-point. This increase in set-point triggers increased muscle tone and shivering.As a person's temperature increases, there is, in...
. If the number of white blood-cells drops notably then referral to a
hematologistHematology, also spelled haematology , is the branch of biology physiology, internal medicine, pathology, clinical laboratory work, and pediatrics that is concerned with the study of blood, the blood-forming organs, and blood diseases...
is undertaken. The manufacturers of both the brand and generic clozapine are required by the FDA to track white blood cells counts for patients receiving clozapine, and pharmacies are required to obtain a copy of the CBC prior to dispensing the medication to the patient. The purpose of the monitoring system is to prevent
rechallengeChallenge-dechallenge-rechallenge is a medical testing protocol in which a medicine or drug is administered, withdrawn, then re-administered, while being monitored for adverse effects at each stage...
with clozapine in patients with a history of clozapine-induced agranulocytosis and to detect
leukopenicLeukopenia is a decrease in the number of white blood cells found in the blood, which places individuals at increased risk of infection....
events among patients taking clozapine. In other countries (e.g. in Europe), restrictions have been eased.
It has been suggested that coadministration of clozapine with an antioxidant such as vitamin C (ascorbic acid) can reduce the risk of agranulocytosis.
Cardiac toxicity
A more recently identified and sometimes fatal side effect is that of
myocarditisMyocarditis is inflammation of heart muscle . It resembles a heart attack but coronary arteries are not blocked.Myocarditis is most often due to infection by common viruses, such as parvovirus B19, less commonly non-viral pathogens such as Borrelia burgdorferi or Trypanosoma cruzi, or as a...
, which usually develops within the first month of commencement and presents with signs of cardiac failure and cardiac arrhythmias.
CardiomyopathyCardiomyopathy, which literally means "heart muscle disease," is the deterioration of the function of the myocardium for any reason. People with cardiomyopathy are often at risk of arrhythmia or sudden cardiac death or both. Cardiomyopathy can often go undetected, making it especially dangerous to...
is another potentially fatal cardiac condition that may arise less acutely. More recently, a regular six-monthly echocardiogram is also recommended to detect
myocarditisMyocarditis is inflammation of heart muscle . It resembles a heart attack but coronary arteries are not blocked.Myocarditis is most often due to infection by common viruses, such as parvovirus B19, less commonly non-viral pathogens such as Borrelia burgdorferi or Trypanosoma cruzi, or as a...
.
Gastrointestinal hypomotility
Another underrecognized and potentially life-threatening side effect spectrum is gastrointestinal hypomotility, which may manifest as severe constipation, fecal impaction, paralytic ileus, bowel obstruction, acute megacolon, ischemia or necrosis. Monitoring of bowel function is recommended, as untreated cases are occasionally fatal.
Hypersalivation
HypersalivationHypersalivation is excessive production of saliva. It has also been defined as increased amount of saliva in the mouth, which may also be caused by decreased clearance of saliva....
(drooling or 'wet pillow syndrome') is seen in up to 30% of patients on clozapine.While clozapine is a muscarinic antagonist at the
M1The muscarinic acetylcholine receptor M1, also known as the cholinergic receptor, muscarinic 1, is a muscarinic receptor.This receptor is found mediating slow EPSP at the ganglion in the postganglionic nerve, is common in exocrine glands and in the CNS.It is predominantly found bound to G proteins...
,
M2The muscarinic acetylcholine receptor M2, also known as the cholinergic receptor, muscarinic 2, is a muscarinic acetylcholine receptor.-Heart:...
,
M3The muscarinic acetylcholine receptor M3, also known as the cholinergic receptor, muscarinic 3, is a muscarinic acetylcholine receptor. It is encoded by the human gene CHRM3....
, and
M5The human muscarinic acetylcholine receptor M5 which is encoded by the gene is a member of the G protein-coupled receptor superfamily of integral membrane proteins. Binding of the endogenous ligand acetylcholine to the M5 receptor triggers a number of cellular responses such as adenylate cyclase...
receptors, clozapine is a full agonist at the
M4The muscarinic acetylcholine receptor M4, also known as the cholinergic receptor, muscarinic 4 , is a protein that, in humans, is encoded by the CHRM4 gene.-Function:...
subset. Because M4 is highly expressed in the
salivary glandThe salivary glands in mammals are exocrine glands, glands with ducts, that produce saliva. They also secrete amylase, an enzyme that breaks down starch into maltose...
, its M4 agonist activity is thought to be responsible for the hypersalivaiton.
Central Nervous System
Central Nervous System side effects include drowsiness, vertigo, headache, tremor, syncope, sleep disturbances, nightmares, restlessness, akinesia, agitation, seizures, rigidity, akathisia, confusion, fatigue, insomnia, hyperkinesia, weakness, lethargy, ataxia, slurred speech, depression, myoclonic jerks, and anxiety. Rarely seen are delusions, hallucinations, delirium, amnesia, libido increase or decrease, paranoia and irritability, abnormal EEG, worsening of psychosis, paresthesia, status epilepticus, and obsessive compulsive symptoms.Similar to other antipsychotics Clozapine rarely has been known to cause Neuroleptic Malignant syndrome.
Withdrawal effects
Abrupt withdrawal may lead to
cholinergicThe word choline generally refers to the various quaternary ammonium salts containing the N,N,N-trimethylethanolammonium cation. Found in most animal tissues, choline is a primary component of the neurotransmitter acetylcholine and functions with inositol as a basic constituent of lecithin...
rebound effects, severe movement disorders as well as severe psychotic decompensation. It has been recommended that patients, families, and caregivers are aware of the symptoms and risks of abrupt withdrawal of clozapine. When discontinuing clozapine, gradual dose reduction is recommended to reduce the intensity of withdrawal effects.
Weight gain and diabetes
The FDA requires the manufacturers of all atypical antipsychotics to include a warning about the risk of hyperglycemia and diabetes with these medications. Indeed, there are case reports of clozapine-induced hyperglycemia and diabetes. In addition, there are also case reports of clozapine-induced diabetic
ketoacidosisKetoacidosis is a metabolic state associated with high concentrations of ketone bodies, formed by the breakdown of fatty acids and the deamination of amino acids. The two common ketones produced in humans are acetoacetic acid and β-hydroxybutyrate....
. There is data showing that clozapine can decrease insulin sensitivity. Clozapine should be used with caution in patients who are diagnosed with diabetes or in patients at risk for developing diabetes. All patients receiving clozapine should have their fasting blood glucose monitored.
In addition to
hyperglycemiaHyperglycemia or Hyperglycæmia, or high blood sugar, is a condition in which an excessive amount of glucose circulates in the blood plasma. This is generally a glucose level higher than 13.5mmol/l , but symptoms may not start to become noticeable until even higher values such as 15-20 mmol/l...
, significant weight gain is frequently experienced by patients treated with clozapine. Impaired glucose metabolism and obesity have been shown to be constituents of the metabolic syndrome and may increase the risk of cardiovascular disease. The data suggest that clozapine may be more likely to cause adverse metabolic effects than some of the other atypical antipsychotics. A study has established that
olanzapineOlanzapine is an atypical antipsychotic, approved by the FDA for the treatment of schizophrenia and bipolar disorder...
and clozapine disturb the metabolism by making the body take preferentially its energy from fat (instead of privileging carbohydrates). Levels of carbohydrates remaining high, the body develops insulin resistance (causing diabetes).
Research has indicated that clozapine may cause a deficiency of
seleniumSelenium is a chemical element with atomic number 34, chemical symbol Se, and an atomic mass of 78.96. It is a nonmetal, whose properties are intermediate between those of adjacent chalcogen elements sulfur and tellurium...
.
Contraindications
Clozapine is contraindicated in individuals with uncontrolled
epilepsyEpilepsy is a common chronic neurological disorder characterized by seizures. These seizures are transient signs and/or symptoms of abnormal, excessive or hypersynchronous neuronal activity in the brain.About 50 million people worldwide have epilepsy, and nearly two out of every three new cases...
,
myeloproliferative diseaseThe myeloproliferative diseases are a group of diseases of the bone marrow in which excess cells are produced. They are related to, and may evolve into, myelodysplastic syndrome and acute myeloid leukemia, although the myeloproliferative diseases on the whole have a much better prognosis than...
, or
agranulocytosisGranulopenia, also known as Agranulosis or Agranulocytosis, is an acute condition involving a severe and dangerous leukopenia , most commonly of neutrophils causing a neutropenia in the circulating blood. It represents a severe lack of one major class of infection-fighting white blood cells...
with prior clozapine treatment.
Many other (relative) contraindications (e.g. preexisting cardiovascular or liver damage, epilepsy) also exist.
Interactions
FluvoxamineFluvoxamine is an antidepressant which functions as a selective serotonin reuptake inhibitor . Fluvoxamine was first approved by the U.S. Food and Drug Administration in 1993 for the treatment of obsessive compulsive disorder . Fluvoxamine CR is approved to treat social anxiety disorder...
inhibits the metabolism of clozapine leading to significantly increased blood levels of clozapine.
Chemistry
Clozapine is a dibenzodiazepine, that is structurally related to
loxapineLoxapine is a typical antipsychotic medication, used primarily in the treatment of schizophrenia. It is a member of the dibenzoxazepine class and as a dibenzazepine derivative, it is structurally related to clozapine...
. It is slightly soluble in water, soluble in
acetoneAcetone is the organic compound with the formula 2CO, a colorless, mobile, flammable liquid, the simplest example of the ketones.Acetone is miscible with water and serves as an important solvent in its own right, typically as the solvent of choice for cleaning purposes in the laboratory...
, and very soluble in
chloroformChloroform is an organic compound with formula CHCl3. It is one of the four chloromethanes. The colorless, sweet-smelling, dense liquid is a trihalomethane, and is considered somewhat hazardous...
. Its solubility in water is 188.9 mg/L (25 C). The manufacturer Novartis claim a solubility of <0.01% in water.
- S.A.A. Wander, (1963).
- F. Hunziker, J. Schmutz, (1970).
- S.A.A. Wander, (1961).
Mechanism of action
Clozapine is classified as an
atypical antipsychoticThe atypical antipsychotics are a group of antipsychotic tranquilizing drugs used to treat psychiatric conditions. Some atypical antipsychotics are FDA approved for use in the treatment of schizophrenia...
drug because its profile of binding to serotonergic as well as
dopamineDopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...
receptors; its effects on various dopamine mediated behaviors also differ from those exhibited by more typical antipsychotics. In particular, clozapine interferes to a lower extent with the binding of dopamine at D
1, D
2, D
3 and D
5 receptors, and has a high affinity for the D
4 receptor, but it does not induce
catalepsyCatalepsy is also a term used by hypnotists to refer to the state of making a hypnotised subject's arm, leg or back rigid. "Arm catalepsy" is often a pre-hypnotic test performed prior to an induction into a full trance.-Causes:...
nor inhibit
apomorphineApomorphine is a non-selective dopamine agonist which activates both D1-like and D2-like receptors, with some preference for the latter subtypes. It is historically a morphine decomposition product by boiling with concentrated acid, hence the -morphine suffix...
-induced stereotypy in animal models as is seen with
'conventional' neurolepticsTypical antipsychotics are a class of antipsychotic drugs first developed in the 1950s and used to treat psychosis...
. This evidence suggests clozapine is preferentially more active at limbic than at striatal dopamine receptors and may explain the relative freedom of clozapine from
extrapyramidalExtrapyramidal can refer to:* Extrapyramidal system* Extrapyramidal symptoms...
side effects together with strong
anticholinergicAn anticholinergic agent is a substance that blocks the neurotransmitter acetylcholine in the central and the peripheral nervous system. An example of an anticholinergic is dicycloverine, and the classic example is atropine....
activity.
Several metabolites of Clozapine exhibit binding profiles similar to Clozapine. N-Desmethylclozapine may contribute significantly to the atypical effects of Clozapine treatment. N-desmethylclozapine acts as an agonist and/or partial agonist at D
2, D
3, δ-opioid, M
1, M
2, M
3, M
4, M
5 receptors, and an antagonist/inverse agonist at 5-HT
2A and 5-HT
2C receptors.
Clozapine is also a partial agonist at the 5-HT
1A receptor, putatively improving depression, anxiety, and the negative cognitive symptoms.
Clozapine also is a strong antagonist at different subtypes of
adrenergicThe adrenergic receptors are a class of metabotropic G protein-coupled receptors that are targets of the catecholamines, especially noradrenaline and adrenaline ....
,
cholinergicMuscarinic receptors, or mAChRs, are acetylcholine receptors that form G protein-coupled in the plasma membranes of certain neurons and other cells...
and
histaminergicThe histamine receptors are a class of G protein-coupled receptors with histamine as their endogenous ligand.There are four known histamine receptors:*H1 receptor*H2 receptor*H3 receptor*H4 receptor-Comparison:...
receptors, the last two being predominantly responsible for its side effect profile.
It has approximately the same potency as
chlorpromazineChlorpromazine is a typical antipsychotic...
.
Pharmacokinetics
The absorption of clozapine is almost complete, but the oral
bioavailabilityIn pharmacology, bioavailability is a subcategory of absorption and is used to describe the fraction of an administered dose of unchanged drug that reaches the systemic circulation, one of the principal pharmacokinetic properties of drugs. By definition, when a medication is administered...
is only 60 to 70% due to first-pass metabolism. The time to peak concentration after oral dosing is about 2.5 hours, and food does not appear to affect the bioavailability of clozapine.
The elimination half-life of clozapine is about 14 hours at
steady stateA system in a steady state has numerous properties that are unchanging in time. This implies that for any property p of the system, the partial derivative with respect to time is zero:...
conditions (varying with daily dose).
Clozapine is extensively metabolized in the liver, via the cytochrome P450 system, to
polarIn chemistry, polarity refers to a separation of electric charge leading to a molecule or its chemical groups having an electric dipole or multipole moment. Polar molecules interact through dipole–dipole intermolecular forces and hydrogen bonds. Molecular polarity is dependent on the difference in...
metabolites suitable for elimination in the urine and faeces. The major metabolite,
norclozapine (
desmethylDemethylation is the chemical process resulting in the removal a of methyl group from a molecule.A common way of demethylation is the replacement of a methyl group by a hydrogen atom, resulting in a net loss of one carbon and two hydrogen atoms....
-clozapine), is pharmacologically active. The cytochrome P450 isoenzyme
1A2Cytochrome P450 1A2 , a member of the cytochrome P450 mixed-function oxidase system, is involved in the metabolism of xenobiotics in the body...
is primarily responsible for clozapine metabolism, but 2C,
2D6Cytochrome P450 2D6 , a member of the cytochrome P450 mixed-function oxidase system, is one of the most important enzymes involved in the metabolism of xenobiotics in the body. Also, many substances are bioactivated by CYP2D6 to form their active compounds...
,
2E1Cytochrome P450 2E1 , a member of the cytochrome P450 mixed-function oxidase system, is involved in the metabolism of xenobiotics in the body. In humans, the CYP2E1 enzyme is encoded by the CYP2E1 gene...
and
3A3/4Cytochrome P450 3A4 , a member of the cytochrome P450 mixed-function oxidase system, is one of the most important enzymes involved in the metabolism of xenobiotics in the body. CYP3A4 is involved in the oxidation of the largest range of substrates of all the CYPs. As a result, CYP3A4 is present in...
appear to play roles as well. Agents that
induceEnzyme induction is a process in which a molecule induces the expression of an enzyme.Enzyme inhibition can refer to* the inhibition of the expression of the enzyme by another molecule...
(e.g., cigarette smoke) or
inhibitAn enzyme inhibitor is a molecule that binds to enzymes and decreases their activity. Since blocking an enzyme's activity can kill a pathogen or correct a metabolic imbalance, many drugs are enzyme inhibitors. They are also used as herbicides and pesticides...
(e.g.,
theophyllineTheophylline, also known as dimethylxanthine, is a methylxanthine drug used in therapy for respiratory diseases such as COPD and asthma under a variety of brand names. Because of its numerous side-effects, the drug is now rarely administered for clinical use. As a member of the xanthine family, it...
,
ciprofloxacinCiprofloxacin is a synthetic chemotherapeutic antibiotic of the fluoroquinolone drug class.It is a second-generation fluoroquinolone antibacterial. It kills bacteria by interfering with the enzymes that cause DNA to rewind after being copied, which stops synthesis of DNA and of...
,
fluvoxamineFluvoxamine is an antidepressant which functions as a selective serotonin reuptake inhibitor . Fluvoxamine was first approved by the U.S. Food and Drug Administration in 1993 for the treatment of obsessive compulsive disorder . Fluvoxamine CR is approved to treat social anxiety disorder...
) CYP1A2 may increase or decrease, respectively, the metabolism of clozapine. For example, the induction of metabolism caused by smoking means that smokers require up to double the dose of clozapine compared with non-smokers to achieve an equivalent plasma concentration.
Clozapine and norclozapine plasma levels may also be monitored, though they show a significant degree of variation and are higher in women and increase with age. Monitoring of plasma levels of clozapine and norclozapine has been shown to be useful in assessment of compliance, metabolic status, prevention of toxicity, and in dose optimization.
Dosage
Due to risk of serious side effects, clozapine treatment is commenced at a very low dose usually 12.5 mg once or twice on the first day and increased slowly until a therapeutic dose is reached. In severely ill and/or younger patients higher doses may be needed, while in the elderly much lower doses may be sufficient. Once the patient is stabilized and the maintenance dose has been determined, the greater part or all of the daily dose may be given at bedtime. This will ameliorate daytime sedation and orthostatic problems; most people benefit from the sedation to get to sleep anyway. Furthermore, compliance on medication taken more frequently than once daily drops off dramatically.
Norclozapine - the primary metabolite of clozapine, which accumulates to, on average, 70% or so of the clozapine concentration in plasma at steady-state (their sample, i.e., pre-dose, ideally in the morning). However, there is substantial variation in the clozapine:norclozapine concentration ratio between individuals.
A steady-state plasma clozapine concentration of 0.35 to 0.6 mg/L (NB. - quoted values may vary slightly) should produce a clinical response in most patients.
History
Clozapine was developed by
SandozFounded in 2003, Sandoz presently is the generic drug subsidiary of Novartis, a multinational pharmaceutical company. The company develops, manufactures and markets generic drugs as well as pharmaceutical and biotechnological active ingredients....
in 1961, and trials took place in 1972, when it was released in Switzerland and Austria as Leponex. Two years later it was released in West Germany, and Finland in 1975. Early testing was performed in the United States around the same time. In 1975, after reports of
agranulocytosisGranulopenia, also known as Agranulosis or Agranulocytosis, is an acute condition involving a severe and dangerous leukopenia , most commonly of neutrophils causing a neutropenia in the circulating blood. It represents a severe lack of one major class of infection-fighting white blood cells...
leading to death in some clozapine-treated patients, clozapine was voluntarily withdrawn by the manufacturer. Clozapine fell out of favor for more than a decade. However, when studies demonstrated that clozapine was more effective against treatment-resistant
schizophreniaSchizophrenia is a mental disorder characterized by a disintegration of thought processes and of emotional responsiveness. It most commonly manifests itself as auditory hallucinations, paranoid or bizarre delusions, or disorganized speech and thinking, and it is accompanied by significant social...
than other antipsychotics, the FDA and health authorities in most other countries approved its use only for treatment-resistant schizophrenia, and required regular hematological monitoring to detect granulocytopenia, before
agranulocytosisGranulopenia, also known as Agranulosis or Agranulocytosis, is an acute condition involving a severe and dangerous leukopenia , most commonly of neutrophils causing a neutropenia in the circulating blood. It represents a severe lack of one major class of infection-fighting white blood cells...
develops. In December 2002, clozapine was also approved for reducing the risk of suicide in schizophrenic or schizoaffective patients judged to be at chronic risk for suicidal behavior. In 2005 FDA approved criteria to allow reduced blood monitoring frequency.
External links