Clozapine

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Clozapine chemical structure Clozapine
8-chloro-11-(4-methyl-1-piperazinyl)- 5H-dibenzo(b,e)(1,4)diazepine IUPAC name
CAS number 5786-21-0	ATC code N05AH02
PubChem 2818	DrugBank APRD00470
Chemical formula	{{{chemical_formula}}}
Molecular weight	326.823 g/mol
Bioavailability	60 to 70%
Metabolism	Hepatic, by several CYP isozymes
Elimination half-life	6 to 26 hours (mean value 14.2 hours in steady state conditions)
Excretion	80% in metabolized state: 30% biliary and 50% renal
Pregnancy category	B
Legal status	Prescription only, special restrictions imposed in many countries
Routes of administration	Oral

Clozapine (sold as Clozaril, Leponex, Fazaclo, Froidir; Gen-Clozapine in Canada, Klozapol in Poland) 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 leukopenia, 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1975, after reports of agranulocytosis leading to death in some clozapine-treated patients, clozapine was voluntarily withdrawn by the manufacturer.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, a term generally 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.

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, results have been inconclusive regarding its actual efficacy in treating those conditions.

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.^{[How to reference and link to summary or text]}

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^{[How to reference and link to summary or text]}.

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; 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 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. Cardiomyopathy is another potentially fatal cardiac condition which may arise less acutely.

Central nervous system

Psychotic symptoms can worsen while under influence and following the discontinuation especially after long-term use.

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, 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 suggests that clozapine may be more likely to cause adverse metabolic effects than some of the other atypical antipsychotics.^{[How to reference and link to summary or text]} Research has indicated that clozapine may cause a deficiency of selenium.

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 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 solubility of <0.01% in water

Pharmacology

Clozapine is classified as an atypical antipsychotic drug because its profile of binding to serotonergic as well as dopamine 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 D₁, D₂, D₃ and D₅ receptors, and has a high affinity for the D₄ 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 is also partial agonists at the 5-HT1A receptor, putatively improving depression, anxiety, and negative/cognitive symptoms.

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 affect 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.

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. 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.

See also

• DHA-clozapine

References

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. DOI:10.1177/0957154X07070335

External links

• Clozaril - Novartis
• Clozapine
• US Clozaril Package Insert (PDF)
• Clozaril Registry Website