Clozapine is usually used only 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 four-week monitoring. Clozapine has numerous severe side effects including agranulocytosis, bowel infarction, and seizures, and has been associated with myocarditis and diabetes though those relationships have not been confirmed. Additionally, it also often causes less serious side effects such as hypersalivation and weight gain.
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 has been shown to be more effective in reducing symptoms of schizophrenia than the older typical antipsychotics, with more pronounced 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.
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.
There are a number of case reports in the literature that indicate that the atypical antipsychotic medication clozapine can be an effective treatment for the psychosis associated with schizophrenia, while at the same time helping to improve the physical symptoms associated with Parkinson's, such as the tremor and dyskinesia. Unlike typical antipsychotics, such as haloperidol, and some atypical antipsychotics, such as risperidone, clozapine is relatively unique in its lack of producing Parkinsonian-like symptoms, even at high doses. This is in part because clozapine binds relatively weakly to the D2 dopamine receptor compared to most other antipsychotics.
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.
It has been suggested that coadministration of clozapine with an antioxidant such as vitamin C can reduce the risk of agranulocytosis.
A more recently identified and sometimes fatal side effect is that of myocarditis, which usually develops within the first month of commencement. First manifestations of illness are fever which may be accompanied by symptoms associated with upper respiratory tract, gastrointestinal or urinary tract infection. Typically C-reactive protein (CRP) increases with the onset of fever and rises in the cardiac enzyme, troponin, occur up to 5 days later. Monitoring guidelines advise checking CRP and troponin at baseline and weekly for the first 4 weeks after clozapine initiation and observing the patient for signs and symptoms of illness. Signs of cardiac failure are less common and may develop with the rise in troponin. A recent case-control study found that the risk of clozapine-induced myocarditis is increased with increasing rate of clozapine dose titration, increasing age and concomitant sodium valproate.
While clozapine is a muscarinic antagonist at the M1, M2, M3, and M5 receptors, clozapine is a full agonist at the M4 subset. Because M4 is highly expressed in the salivary gland, its M4 agonist activity is thought to be responsible for the hypersalivation.
Abrupt withdrawal may lead to cholinergicrebound 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.
Research has indicated that clozapine may cause a deficiency of selenium.
Fluvoxamine inhibits the metabolism of clozapine leading to significantly increased blood levels of clozapine.
Clozapine is a dibenzodiazepine, that is structurally related to loxapine. It is slightly soluble in water, soluble in acetone, and very soluble in chloroform. Its solubility in water is 188.9 mg/L (25 C). The manufacturer Novartis claims a solubility of <0.01% in water.
Clozapine is also a partial agonist at the 5-HT1A receptor, putatively improving depression, anxiety, and the negative cognitive symptoms.
A direct interaction of clozapine with the GABAB receptor has been shown. GABAB receptor deficient mice exhibit increased extracellular dopamine levels and altered locomotor behaviour equivalent to that in schizophrenia animal models. GABAB receptor agonists and positive allosteric modulators reduce the locomotor changes in these models.
Norclozapine (N-desmethylclozapine), clozapine's chief active metabolite
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 feces. The major metabolite, norclozapine (desmethyl-clozapine), is pharmacologically active. The cytochrome P450 isoenzyme1A2 is primarily responsible for clozapine metabolism, but 2C, 2D6, 2E1 and 3A3/4 appear to play roles as well. Agents that induce (e.g., cigarette smoke) or inhibit (e.g., theophylline, ciprofloxacin, fluvoxamine) 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.
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. 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.
Clozapine was developed by Sandoz 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 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 2002, clozapine was approved in the US 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.
In 2005 three pharmaceutical companies marketed this drug: Novartis Pharmaceuticals (manufacturer), Mylan Laboratories and Ivax Pharmaceuticals (market generic clozapine). The drug is manufactured by Sun Pharmaceuticals in India.
^ abHopfinger A, Esposito EX, Llinas A, Glen RC, Goodman JM.. Findings of the Challenge To Predict Aqueous Solubility. Journal of Chemical Information and Modeling. 2009;49:1-5.
^Kane, J; Honigfeld G, Singer J, Meltzer H (September 1988). "Clozapine for the treatment-resistant schizophrenic: a double-blind comparison versus chlorpromazine/benztropine". Archives of General Psychiatry45 (9): 789–796. doi:10.1001/archpsyc.1988.01800330013001. PMID3046553.Cite uses deprecated parameters (help)
^De Berardis, D.; Serroni, N.; Campanella, D.; Olivieri, L.; Ferri, F.; Carano, A.; Cavuto, M.; Martinotti, G.; Cicconetti, A.; Piersanti, M.; Saverio Moschetta, F.; Di Giannantonio, M. (2012). "Update on the adverse effects of clozapine: Focus on myocarditis". Current drug safety7 (1): 55–62. doi:10.2174/157488612800492681. PMID22663959. edit
^Hartling, L.; Abou-Setta, A. M.; Dursun, S.; Mousavi, S. S.; Pasichnyk, D.; Newton, A. S. (2012). "Antipsychotics in Adults with Schizophrenia: Comparative Effectiveness of First-Generation Versus Second-Generation Medications: A Systematic Review and Meta-analysis". Annals of internal medicine157 (7): 498–511. doi:10.7326/0003-4819-157-7-201210020-00525. PMID22893011. edit
^Haas SJ, Hill R, Krum H (2007). "Clozapine-associated myocarditis: a review of 116 cases of suspected myocarditis associated with the use of clozapine in Australia during 1993-2003". Drug Safety30 (1): 47–57. doi:10.2165/00002018-200730010-00005. PMID17194170.
^Ronaldson KJ, Taylor AJ, Fitzgerald PB, Topliss DJ, McNeil JJ. (2011). "A new monitoring protocol for clozapine-induced myocarditis based on an analysis of 75 cases and 94 controls.". Aust NZ J Psych45: 458–465. doi:10.3109/00048674.2011.572852.
^Ronaldson KJ, Fitzgerald PB, Taylor DJ, Topliss DJ, Wolfe R, McNeil JJ. (2012). "Rapid clozapine dose titration and concomitant sodium valproate increase the risk of myocarditis with clozapine: A case-control study.". Schizophr Res141: 173–8. doi:10.1016/j.schres.2012.08.018.
^Palmer SE, McLean RM, Ellis PM, Harrison-Woolrych M (2008). "Life-threatening clozapine-induced gastrointestinal hypomotility: an analysis of 102 cases". Journal of Clinical Psychiatry69 (5): 759–768. doi:10.4088/JCP.v69n0509. PMID18452342.
^Ahmed, S.; Chengappa, KN.; Naidu, VR.; Baker, RW.; Parepally, H.; Schooler, NR. (Sep 1998). "Clozapine withdrawal-emergent dystonias and dyskinesias: a case series". J Clin Psychiatry59 (9): 472–7. doi:10.4088/JCP.v59n0906. PMID9771818.
^Szafrański, T.; Gmurkowski, K. (1999). "[Clozapine withdrawal. A review]". Psychiatr Pol33 (1): 51–67. PMID10786215.
^Wirshing DA, Wirshing WC, Kysar L, Berisford MA (1999). "Novel antipsychotics: comparison of weight gain liabilities". Journal of Clinical Psychology60 (6): 358–63. doi:10.4088/JCP.v60n0602. PMID10401912.
^Nasrallah HA (January 2008). "Atypical antipsychotic-induced metabolic side effects: insights from receptor-binding profiles". Mol. Psychiatry13 (1): 27–35. doi:10.1038/sj.mp.4002066. PMID17848919.
^Sproule B. A., Naranjo C. A., Brenmer K. E., Hassan P. C. (December 1997). "Selective serotonin reuptake inhibitors and CNS drug interactions. A critical review of the evidence". Clin Pharmacokinet33 (6): 454–71. doi:10.2165/00003088-199733060-00004. PMID9435993.
^Wu Y, Blichowski M, Daskalakis ZJ, Wu Z, Liu CC, Cortez MA, Snead OC 3rd. (2011). "Evidence that clozapine directly interacts on the GABAB receptor.". Neuroreport.22 (13): 637–41. doi:10.1097/WNR.0b013e328349739b. PMID21753741.
^Vacher CM, Gassmann M, Desrayaud S, Challet E, Bradaia A, Hoyer D, Waldmeier P, Kaupmann K, Pévet P, Bettler B. (2006). "Hyperdopaminergia and altered locomotor activity in GABAB1-deficient mice.". J Neurochem.97 (4): 979–91. doi:10.1111/j.1471-4159.2006.03806.x. PMID16606363.
^Wierońska JM, Kusek M, Tokarski K, Wabno J, Froestl W, Pilc A. (2011). "The GABA B receptor agonist CGP44532 and the positive modulator GS39783 reverse some behavioural changes related to positive syndromes of psychosis in mice.". Br J Pharmacol.163 (5): 1034–47. doi:10.1111/j.1476-5381.2011.01301.x. PMID21371011.
^Tanahashi S, Yamamura S, Nakagawa M, Motomura E, Okada M. (2012). "Clozapine, but not haloperidol, enhances glial D-serine and L-glutamate release in rat frontal cortex and primary cultured astrocytes.". Br J Pharmacol.165 (5): 1543–55. doi:10.1111/j.1476-5381.2011.01638.x. PMID21880034.
^Xi D, Li YC, Snyder MA, Gao RY, Adelman AE, Zhang W, Shumsky JS, Gao WJ. (2011). "Group II metabotropic glutamate receptor agonist ameliorates MK801-induced dysfunction of NMDA receptors via the Akt/GSK-3β pathway in adult rat prefrontal cortex.". Neuropsychopharmacology.36 (6): 1260–74. doi:10.1038/npp.2011.12. PMID21326193.
^Roth, BL; Driscol, J. "PDSP Ki Database". Psychoactive Drug Screening Program (PDSP). University of North Carolina at Chapel Hill and the United States National Institute of Mental Health. Retrieved 2013-10-10 from http://pdsp.med.unc.edu/pdsp.php.
^ abRostami-Hodjegan A, Amin AM, Spencer EP, Lennard MS, Tucker GT, Flanagan RJ (2004). "Influence of dose, cigarette smoking, age, sex, and metabolic activity on plasma clozapine concentrations: a predictive model and nomograms to aid clozapine dose adjustment and to assess compliance in individual patients". J Clin Psychopharmacol24 (1): 70–8. doi:10.1097/01.jcp.0000106221.36344.4d. PMID14709950.
^Lane HY, Chang YC, Chang WH, Lin SK, Tseng YT, Jann MW. (January 1999). "Effects of gender and age on plasma levels of clozapine and its metabolites: analyzed by critical statistics". J Clin Psychiatry60 (1): 36–40. doi:10.4088/JCP.v60n0108. PMID10074876.|accessdate= requires |url= (help)