'Clozapine' (sold as 'Clozaril', 'Leponex', 'Fazaclo'; 'Gen-Clozapine' in Canada) was the first of the
atypical antipsychotics to be developed. It was approved by the United States
Food and Drug Administration (FDA) in 1989 and is the only FDA-approved medication indicated for treatment-resistant
schizophrenia and for reducing the risk of
suicidal behaviour in patients with schizophrenia.
Clozapine has been shown to be superior in efficacy in treating schizophrenia. Were it not for its
side effects it would be first line treatment; however the rare but potentially lethal side effects of
agranulocytosis and
myocarditis relegate it to third-line use. Furthermore it may rarely lower seizure threshold, cause hepatic dysfunction, weight gain and be associated with
type II diabetes. More common side effects are predominantly
anticholinergic in nature, with dry mouth, sedation and constipation. It is also a strong antagonist at different subtypes of
adrenergic,
cholinergic,
histaminergic and
serotonergic receptors.
Safer use of clozapine requires weekly
blood monitoring for around five months followed by four weekly testing thereafter.
Echocardiograms are recommended every 6 months to exclude cardiac damage.
History
Clozapine was developed by
Sandoz in
1961, and introduced in
Europe ten years later. In
1975, after reports of
agranulocytosis leading to death in some clozapine-treated patients, clozapine was voluntarily withdrawn by the manufacturer.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
schizophrenia 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
agranulocytosis develops. In December of 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.
Indications
Clozapine is used principally in treating treatment-resistant schizophrenia,
[ Clozapine versus typical neuroleptic medication for schizophrenia, Wahlbeck K, Cheine MV, Essali A, , , The Cochrane Database of Systematic Reviews, ] a term generally used for the failure of symptoms to respond satisfactorily to at least two different antipsychotics;
[1] 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.
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
olanzapine.
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.
Off-label and investigational drug use
★ Treatment of psychosis in L-Dopa treated patients (25 to 50 mg at bedtime is often sufficient); this indication is currently approved in Switzerland
★ Treatment of psychotic symptoms occurring in patients with
dementia of the Lewy-body-type
★ Treatment of otherwise resistant acute episodes of
mania
★ Treatment of intractable chronic
insomnia, if all other measures have failed
★ Treatment of
schizoid personality disorder
Though much research has been done evaluating the benefit of clozapine in treating the aforementioned conditions, it is too early to come to a conclusive result. If you contemplate clozapine as drug for these conditions, weigh carefully benefits and risks and inform the patients fully, if possible, about the advantages and risks of clozapine treatment, before a joint decision is made. If the patient is not able to make own decisions, parents or guardians or the competent court must give their consent...
Contraindications
Clozapine is
contraindicated in individuals with uncontrolled
epilepsy,
myeloproliferative disease, or
agranulocytosis with prior clozapine treatment.
Many other (relative) contraindications (e.g. preexisting cardiovascular or liver damage, epilepsy) also exist.
Adverse effects
The use of clozapine is associated with a fair number of side effects, many minor though some serious and potentially fatal: the more common include
constipation,
drooling,
muscle stiffness,
sedation,
tremors,
orthostasis,
hyperglycemia, and
weight gain. The risks of
extrapyramidal symptoms such as
tardive dyskinesia 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 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
male patients have experienced ceasure of
ejaculation during
orgasm as a side effect of Clozapine though this is not documented in official drug guides.
Agranulocytosis
Clozapine carries a
black box warning for drug-induced
agranulocytosis. Without monitoring, agranulocytosis occurs in about 1% of patients who take clozapine during the first few months of treatment;
[2] the risk of developing it is highest about three months into treatment, and decreases substantially thereafter, to less than 0.01% after one year.
[3] Patients who have experienced agranulocytosis with prior treatment of clozapine should not receive it again. Clozapine also carries black box warnings for
seizures,
myocarditis, and "other adverse
cardiovascular and
respiratory effects." Lowering of the
seizure threshold 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 hypotension and other adverse cardiovascular side effects.
Cardiac toxicity
A more recently identified and sometimes fatal side effect is that of
myocarditis which usually develops within the first month of commencement and presents with signs of
cardiac failure and cardiac arrhythmias.
[4] Cardiomyopathy is another potentially fatal cardiac condition which may arise less acutely.
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; additionally, there are case reports of clozapine-induced diabetic
ketoacidosis. 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
hyperglycemia, weight gain may be 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 suggests that clozapine may be more likely to cause adverse metabolic effects than some of the other atypical antipsychotics. Research has indicated that clozapine may cause a deficiency of
selenium.
[5]
In 2007, a pharmacogenetic test was introduced to measure the probability of developing agranulocytosis.
[6][7] 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
SNPs of the
HLA-DQB1 gene.
Chemistry
It is insoluble in water, soluble in
acetone, very well soluble in
chloroform.
Its solubility in water is 11.8 mg/L (25 C)
The manufacturer Novartis claim a soluability of <0.01% in water
[8]
Pharmacology
Clozapine is classified as an
atypical antipsychotic drug because its profile of binding to
serotonergic as well as
dopamine receptors;
[ Focus on clozapine, Naheed M, Green B., , , , 2001 ] 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
catalepsy nor inhibit
apomorphine-induced
stereotypy in animal models as is seen with
'conventional' neuroleptics. This evidence suggests clozapine is preferentially more active at limbic than at striatal dopamine receptors and may explain the relative freedom of clozapine from
extrapyramidal side effects together with strong
anticholinergic activity.
Clozapine also is a strong antagonist at different subtypes of
adrenergic,
cholinergic and
histaminergic receptors, the last two being predominantly responsible for its side effect profile.
It has approximately the same potency as
chlorpromazine.
Pharmacokinetics
The absorption of clozapine is almost complete, but the oral
bioavailability 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 effect the bioavailability of clozapine.
The
elimination half-life of clozapine is about 14 hours at
steady state conditions (varying with daily dose).
Clozapine is extensively metabolized in the liver, via the
cytochrome P450 system, to
polar metabolites suitable for elimination in the urine and faeces. The major metabolite, ''norclozapine'' (
desmethyl-clozapine), is pharmacologically active. The cytochrome P450
isoenzyme 1A2 is primarily responsible for clozapine metabolism, but 2C,
2D6,
2E1 and
3A3/4 appear to play roles as well. Agents which
induce (e.g. cigarette smoke) or
inhibit (e.g.
theophylline,
ciprofloxacin,
fluvoxamine) CYP1A2 may increase or decrease, respectively, the metabolism of clozapine.
Monitoring
In the USA, patients who take clozapine are required to have a
blood cell count every week, for the first six months of therapy. 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.
If the number of white blood-cells drops notably, one should consult with a
hematologist. If you are using clozapine and have a
sore throat, or
fever, then you should inform your
doctor.
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.
[9]
More recently, a regular six-monthly
echocardiogram is also recommended to detect
myocarditis.
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 rechallenge with clozapine in patients with a history of clozapine-induced agranulocytosis and to detect
leukopenic events among patients taking clozapine. In other countries (e.g. in Europe), restrictions have been eased.
Dosage
Due to risk of serious side effects, clozapine treatment is commenced at a very low dose (25 mg daily) and increased slowly until a therapeutic dose (300–600 mg daily) is reached.
[10] In severely ill and/or younger patients up to 900 mg may be needed. In the elderly, much lower doses may be sufficient (25 to 100 mg). 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.
Undocumented side-effects
Known to cause inability to
ejaculate while
orgasming in some
male patients.
See also
★
DHA-clozapine
References
Notes
1. Treatment-resistant schizophrenia--the role of clozapine., Meltzer HY, , , Current Medical Research and Opinion,
2. Goodman & Gilman's The Pharmacological Basis of Therapeutics, , Ross J., Baldessarini, McGraw-Hill, 2006,
3. Clozapine-induced agranulocytosis. Incidence and risk factors in the United States, Alvir JM, Lieberman JA, Safferman AZ, Schwimmer JL, Schaaf JA, , , N Engl J Med, 1993 Free full text with registration
4. Clozapine-associated myocarditis, Haas SJ, Hill R, Krum H, , , Drug Safety,
5. Low blood selenium concentrations in schizophrenic patients on clozapine, Vaddadi KS, Soosai E, Vaddadi G, , , British journal of clinical pharmacology, 2003
6. PGxPredict:CLOZAPINE - a page about the agranulocytosis risk test.
7. Clinical Data Launches Pharmacogenetic Test for Clozapine-Induced Agranulocytosis on Schedule - press release at the Forbes site.
8.
9. Effects of gender and age on plasma levels of clozapine and its metabolites: analyzed by critical statistics, Lane HY, Chang YC, Chang WH, Lin SK, Tseng YT, Jann MW., , , J Clin Psychiatry, 1999
10. Clozaril Dosing Guide Novartis Pharmaceuticals
Sources
★ Benkert, Hippius: Kompendium der Psychiatrischen Pharmakotherapie (German), 4th. ed., Springer Verlag
★ B. Bandelow, S. Bleich, and S. Kropp: Handbuch Psychopharmaka (German), 2nd. ed. Hogrefe
★ Crilly JF (2007) ''The history of clozapine and its emergence in the US Market: A review and Analysis.'' History of Psychiatry, 18(1): 39-60.
External links
★
Clozaril -
Novartis
★
Clozapine
★
US Clozaril Package Insert (PDF)
★
Clozaril Registry Website
العربية
中国
Français
Deutsch
Ελληνική
हिन्दी
Italiano
日本語
Português
Русский
Español
