Clozapine

From Wikipedia, the free encyclopedia
  (Redirected from Fazaclo odt)
Jump to: navigation, search
Not to be confused with clomifene, clonazepam (Klonopin), or clonidine.
Clozapine
Clozapine2DACS.svg
Clozapine3DanBS.gif
Systematic (IUPAC) name
8-Chloro-11-(4-methylpiperazin-1-yl)-5H-dibenzo[b,e][1,4]diazepine
Clinical data
Trade names Clozaril
AHFS/Drugs.com monograph
MedlinePlus a691001
Pregnancy cat.
Legal status
Routes Oral
Pharmacokinetic data
Bioavailability 60 to 70%
Metabolism Hepatic, by several CYP isozymes
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
Identifiers
CAS number 5786-21-0 YesY
ATC code N05AH02
PubChem CID 2818
IUPHAR ligand 38
DrugBank DB00363
ChemSpider 10442628 YesY
UNII J60AR2IKIC YesY
KEGG D00283 YesY
ChEBI CHEBI:3766 YesY
ChEMBL CHEMBL42 YesY
Chemical data
Formula C18H19ClN4 
Mol. mass 326.823 g/mol
Physical data
Melt. point 183 °C (361 °F)
Solubility in water 0.1889[1] mg/mL (20 °C)
 YesY (what is this?)  (verify)

Clozapine is an atypical antipsychotic medication used in the treatment of schizophrenia, and is also sometimes used off-label for the treatment of bipolar disorder. The first of the atypical antipsychotics to be developed, it was first introduced in Europe in 1971, but was voluntarily withdrawn by the manufacturer in 1975 after it was shown to cause agranulocytosis, a condition involving a dangerous decrease in the number of white blood cells, that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 effective in treating treatment-resistant schizophrenia[2] the United States Food and Drug Administration (FDA) approved the use of clozapine solely for that use, requiring regular white blood cell and absolute neutrophil counts.[3][4] The FDA also requires clozapine to carry five black box warnings for agranulocytosis, seizures, myocarditis, for "other adverse cardiovascular and respiratory effects", and for "increased mortality in elderly patients with dementia-related psychosis."[5] In 2002 the FDA approved clozapine for reducing the risk of suicidal behavior for patients with schizophrenia.

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.[6] 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.[7] Clozapine has numerous severe side effects including agranulocytosis, bowel infarction,[8] and seizures,[9] and has been associated with myocarditis[10] and diabetes[11] though those relationships have not been confirmed. Additionally, it also often causes less serious side effects such as hypersalivation and weight gain. It is on the World Health Organization's List of Essential Medicines, a list of the most important medication needed in a basic health system.[12]

Medical uses[edit]

Clozapine is an atypical antipsychotic drug primarily prescribed to patients who are unresponsive to or intolerant of conventional and other atypical neuroleptics.[13] It is used principally in treating treatment-resistant schizophrenia,[14] a term used for the failure of symptoms to respond satisfactorily to at least two different antipsychotics.[15] 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.[14] There is some evidence clozapine may reduce propensity for substance abuse in schizophrenic patients.[16]

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.[17]

A number of case reports indicate that clozapine can be an effective treatment for schizophrenia while at the same time diminishing some 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 does not produce Parkinsonian symptoms, even at high doses. This is in part because it binds relatively weakly to the D2 dopamine receptor, compared to most other antipsychotics.[18] Clozapine is not approved by the Food and Drug Administration (FDA) for the treatment of behavior problems in older adults with dementia.

Adverse effects[edit]

Clozapine may cause side effects; most are minor, although some are serious and potentially fatal. Common side effects include extreme constipation, bed-wetting, night-time drooling, muscle stiffness, sedation, tremors, orthostatic hypotension, hyperglycemia, and weight gain. The risk of developing extrapyramidal symptoms such as tardive dyskinesia is below that of 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.[19]

Clozapine also carries five black box warnings, including warnings for agranulocytosis, CNS depression, leukopenia, neutropenia, seizure disorder, bone marrow suppression, dementia, hypotension, myocarditis, orthostatic hypotension (with or without syncope) and seizures.[20] 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.[21]

Many male patients have experienced cessation of ejaculation during orgasm as a side effect of clozapine, though this is not documented in official drug guides.[22]

Agranulocytosis[edit]

Main article: 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;[23] the risk of developing it is highest about three months into treatment, and decreases substantially thereafter, to less than 0.01% after one year.[24]

It has been suggested that coadministration of clozapine with an antioxidant such as vitamin C can reduce the risk of agranulocytosis.[25]

Cardiac toxicity[edit]

A more recently identified and sometimes fatal side effect is that of myocarditis, which usually develops within the first month of commencement.[26] 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.[27] 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.[28]

Gastrointestinal hypomotility[edit]

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.[29][30]

Hypersalivation[edit]

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.[31]

Central nervous system[edit]

CNS 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.[32]

Urinary incontinence[edit]

Clozapine is linked to urinary incontinence[33] though its appearance may be under-recognized.[34]

Withdrawal effects[edit]

Abrupt withdrawal may lead to cholinergic 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.[35][36]

Weight gain and diabetes[edit]

In addition to hyperglycemia, significant weight gain is frequently experienced by patients treated with clozapine.[37] 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.[38] A study has established that olanzapine 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).[39]

Research has indicated that clozapine may cause a deficiency of selenium.[40]

Interactions[edit]

Fluvoxamine inhibits the metabolism of clozapine leading to significantly increased blood levels of clozapine.[41]

Chemistry[edit]

Clozapine is a dibenzodiazepine that is structurally related to loxapine. It is slightly soluble in water, soluble in acetone, and highly soluble in chloroform. Its solubility in water is 188.9 mg/L (25 °C).[1] Its manufacturer, Novartis, claims a solubility of <0.01% in water (<100 mg/L).[42]

Dibenzo-1,4-diazepines such as clozapine may be synthesised by various methods, including the Bischler–Napieralski reaction and intramolecular condensation in the presence of a dehydrating agent as depicted below:[43]

Clozapine Production.png

Several patents have been granted.[44][45][46]

Mechanism of action[edit]

Clozapine is classified as an atypical antipsychotic drug because it binds to serotonin as well as dopamine receptors.[47]

Clozapine is a partial antagonist [48] at the 5-HT1A subunit of the serotonin receptor, putatively improving depression, anxiety, and the negative cognitive symptoms associated with schizophrenia.[49]

A direct interaction of clozapine with the GABAB receptor has also been shown.[50] GABAB receptor-deficient mice exhibit increased extracellular dopamine levels and altered locomotor behaviour equivalent to that in schizophrenia animal models.[51] GABAB receptor agonists and positive allosteric modulators reduce the locomotor changes in these models.[52]

Clozapine induces the release of glutamate and D-serine, an agonist at the glycine site of the NMDA receptor, from astrocytes,[53] and reduces the expression of astrocytic glutamate transporters. These are direct effects that are also present in astrocyte cell cultures not containing neurons. Clozapine prevents impaired NMDA receptor expression caused by NMDA receptor antagonists.[54]

Binding Affinity (Ki [nM]) towards cloned human receptors unless otherwise specified[55]

Receptor/Transporter Protein Clozapine Norclozapine
SERT 1624 316.6
NET 3168 493.9
DAT >10000 >10000
5-HT1A 123.7 13.9
5-HT1B 519 406.8
5-HT1D 1356 476.2
5-HT2A 5.35 10.9
5-HT2B 8.37 2.8
5-HT2C 9.44 11.9
5-HT3 241 272.2
5-HT5A 3857 350.6
5-HT6 13.49 11.6
5-HT7 17.95 60.1
D1 266.25 14.3
D2 157 101.4
D3 269.08 193.5
D4 26.36 63.94
D5 255.33 283.6
α1A 1.62 104.8
α1B 7 85.2
α2A 37 137.6
α2B 26.5 95.1
α2C 6 117.7
β1 5000 6239
β2 1650 4725
M1 6.17 67.6
M2 36.67 414.5
M3 19.25 95.7
M4 15.33 169.9
M5 15.5 35.4
H1 1.13 3.4
H2 153 345.1
H3 >10000 >10000
H4 665 1028
δ-opioid 1000 (Mouse receptor) 127.9
μ-opioid 1000 (Rat receptor) >10000
κ-opioid 1000 (Guinea pig receptor) >10000
σ1 5000 (Guinea pig receptor) >10000
σ2 - >10000

Pharmacokinetics[edit]

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 isoenzyme 1A2 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.[56]

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.[57] 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.[56]

History[edit]

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.[58] In 1975, after reports of agranulocytosis leading to death in some clozapine-treated patients, clozapine was voluntarily withdrawn by the manufacturer.[59] 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.[60] In 2005 FDA approved criteria to allow reduced blood monitoring frequency.[61]

Marketing[edit]

As of 2014, three pharmaceutical companies market this drug: Novartis Pharmaceuticals (manufacturer), Mylan Laboratories and Teva Pharmaceuticals (market generic clozapine).[62] The drug is manufactured by Sun Pharmaceuticals in India.

See also[edit]

References[edit]

  1. ^ a b Hopfinger 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.
  2. ^ 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 Psychiatry 45 (9): 789–796. doi:10.1001/archpsyc.1988.01800330013001. PMID 3046553. 
  3. ^ "From Clozapine Package Insert: Frequency of Monitoring based on Stage of Therapy or Results from WBC Count and ANC Monitoring Tests" (pdf). TEVA Clozapine Patient Registry. Retrieved 2012-08-18. 
  4. ^ Wallis C & Willwerth J (July 6, 1992). "Awakenings Schizophrenia a New Drug Brings Patients Back to Life". Time. Retrieved 2008-10-09. 
  5. ^ "Clozaril (Clozapine) drug description - FDA approved labeling for prescription drugs and medications at RxList". Rxlist.com. Retrieved 2008-10-09. 
  6. ^ National Institute of Mental Health. "What medications are used to treat schizophrenia?". Retrieved 2012-08-18. 
  7. ^ "From Clozapine Package Insert: Frequency of Monitoring based on Stage of Therapy or Results from WBC Count and ANC Monitoring Tests" (pdf). TEVA Clozapine Patient Registry. Retrieved 2012-08-18. 
  8. ^ Townsend, G.; Curtis, D. (2006). "Case report: Rapidly fatal bowel ischaemia on clozapine treatment". BMC Psychiatry 6: 43. doi:10.1186/1471-244X-6-43. PMC 1621059. PMID 17052340.  edit
  9. ^ Devinsky, O.; Honigfeld, G.; Patin, J. (1991). "Clozapine-related seizures". Neurology 41 (3): 369–371. doi:10.1212/wnl.41.3.369. PMID 2006003.  edit
  10. ^ 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 safety 7 (1): 55–62. doi:10.2174/157488612800492681. PMID 22663959.  edit
  11. ^ 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 medicine 157 (7): 498–511. doi:10.7326/0003-4819-157-7-201210020-00525. PMID 22893011.  edit
  12. ^ "WHO Model List of EssentialMedicines". World Health Organization. October 2013. Retrieved 22 April 2014. 
  13. ^ MIMS Ireland. April 2007.
  14. ^ a b Wahlbeck K, Cheine MV, Essali A (2007). "Clozapine versus typical neuroleptic medication for schizophrenia". In Wahlbeck, Kristian. The Cochrane Database of Systematic Reviews (John Wiley and Sons, Ltd.) (2): CD000059. doi:10.1002/14651858.CD000059. ISSN 1464-780X. PMID 10796289. 
  15. ^ Meltzer HY (1997). "Treatment-resistant schizophrenia--the role of clozapine". Current Medical Research and Opinion 14 (1): 1–20. doi:10.1185/03007999709113338. PMID 9524789. 
  16. ^ Lee M, Dickson RA, Campbell M, Oliphant J, Gretton H, Dalby JT.. Clozapine and substance abuse in patients with schizophrenia. Canadian Journal of Psychiatry. 1998;43:855–856.
  17. ^ P03-358 Clozapine may be the answer: a case report of elevated serum creatine kinase in the absence of NMS. A. Mohandas, N. Talwar, A. James Langdon Hospital, Devon Partnership NHS Trust, Dawlish, UK
  18. ^ "How would you treat someone who has both schizophrenia and Parkinson's disease?". 
  19. ^ "Clozapine". 
  20. ^ http://www.clinicalpharmacology-ip.com/Forms/Monograph/monograph.aspx?cpnum=142&sec=monadve
  21. ^ "Clozapine". 
  22. ^ Baggaley, M. (2008). "Sexual dysfunction in schizophrenia: Focus on recent evidence". Human Psychopharmacology: Clinical and Experimental 23 (3): 201–209. doi:10.1002/hup.924. PMID 18338766.  edit
  23. ^ Baldessarini, Ross J.; Frank I. Tarazi (2006). "Pharmacotherapy of Psychosis and Maa". In Laurence Brunton, John Lazo, Keith Parker (eds.). Goodman & Gilman's The Pharmacological Basis of Therapeutics (11th ed.). New York: McGraw-Hill. ISBN 978-0-07-142280-2. OCLC 150149056. 
  24. ^ Alvir JM, Lieberman JA, Safferman AZ, Schwimmer JL, Schaaf JA (1993). "Clozapine-induced agranulocytosis. Incidence and risk factors in the United States". N Engl J Med 329 (3): 162–7. doi:10.1056/NEJM199307153290303. PMID 8515788.  Free full text with registration
  25. ^ Hsyuanyu Y., Dunford H.B. (1999). "Oxidation of Clozapine and Ascorbate by Myeloperoxidase.". Archives of Biochemistry and Biophysics 368 (2): 412–420. doi:10.1006/abbi.1999.1328. PMID 10441395. 
  26. ^ 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 Safety 30 (1): 47–57. doi:10.2165/00002018-200730010-00005. PMID 17194170. 
  27. ^ 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 Psych 45: 458–465. doi:10.3109/00048674.2011.572852. 
  28. ^ 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 Res 141: 173–8. doi:10.1016/j.schres.2012.08.018. 
  29. ^ Palmer SE, McLean RM, Ellis PM, Harrison-Woolrych M (2008). "Life-threatening clozapine-induced gastrointestinal hypomotility: an analysis of 102 cases". Journal of Clinical Psychiatry 69 (5): 759–768. doi:10.4088/JCP.v69n0509. PMID 18452342. 
  30. ^ Townsend G, Curtis D (2006). "Case report: rapidly fatal bowel ischaemia on clozapine treatment". BMC Psychiatry 6: 43. doi:10.1186/1471-244X-6-43. PMC 1621059. PMID 17052340. 
  31. ^ http://www.medscape.com/viewarticle/409612_2
  32. ^ rxlist.com / Clozapine side effects
  33. ^ Raja, M. (2011). "Clozapine safety, 35 years later". Current drug safety 6 (3): 164–184. doi:10.2174/157488611797579230. PMID 22122392.  edit
  34. ^ Barnes, T. R. E.; Drake, M. J.; Paton, C. (2012). "Nocturnal enuresis with antipsychotic medication". The British Journal of Psychiatry 200 (1): 7–9. doi:10.1192/bjp.bp.111.095737. PMID 22215862.  edit
  35. ^ 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 Psychiatry 59 (9): 472–7. doi:10.4088/JCP.v59n0906. PMID 9771818. 
  36. ^ Szafrański, T.; Gmurkowski, K. (1999). "[Clozapine withdrawal. A review]". Psychiatr Pol 33 (1): 51–67. PMID 10786215. 
  37. ^ Wirshing DA, Wirshing WC, Kysar L, Berisford MA (1999). "Novel antipsychotics: comparison of weight gain liabilities". Journal of Clinical Psychology 60 (6): 358–63. doi:10.4088/JCP.v60n0602. PMID 10401912. 
  38. ^ Nasrallah HA (January 2008). "Atypical antipsychotic-induced metabolic side effects: insights from receptor-binding profiles". Mol. Psychiatry 13 (1): 27–35. doi:10.1038/sj.mp.4002066. PMID 17848919. 
  39. ^ Albaugh, V. L.; Vary, T. C.; Ilkayeva, O.; Wenner, B. R.; Maresca, K. P.; Joyal, J. L.; Breazeale, S.; Elich, T. D.; Lang, C. H.; Lynch, C. J. (2010). "Atypical Antipsychotics Rapidly and Inappropriately Switch Peripheral Fuel Utilization to Lipids, Impairing Metabolic Flexibility in Rodents". Schizophrenia Bulletin 38 (1): 153–166. doi:10.1093/schbul/sbq053. PMC 3245588. PMID 20494946.  edit
  40. ^ Vaddadi KS, Soosai E, Vaddadi G (2003). "Low blood selenium concentrations in schizophrenic patients on clozapine". British Journal of Clinical Pharmacology 55 (3): 307–9. doi:10.1046/j.1365-2125.2003.01773.x. PMC 1884212. PMID 12630982. 
  41. ^ 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 Pharmacokinet 33 (6): 454–71. doi:10.2165/00003088-199733060-00004. PMID 9435993. 
  42. ^ Novartis Pharmaceuticals (April 2006). "Prescribing Information" (PDF). Novartis Pharmaceuticals. p. 36. Retrieved 2007-06-29. 
  43. ^ Hunziker, F.; Fischer, E.; Schmutz, J. (1967). "11-Amino-5H-dibenzo[b, e]-1, 4-diazepine. 10. Mitteilung über siebengliedrige Heterocyclen". Helvetica Chimica Acta 50 (6): 1588. doi:10.1002/hlca.19670500618.  edit
  44. ^ S.A.A. Wander, FR 1334944  (1963)
  45. ^ F. Hunziker, J. Schmutz, U.S. Patent 3,539,573 (1970)
  46. ^ S.A.A. Wander, GB 980853  (1961)
  47. ^ Naheed M, Green B. (2001). "Focus on clozapine". Curr Med Res Opin 17 (3): 223–9. doi:10.1185/0300799039117069. PMID 11900316. 
  48. ^ http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=2818
  49. ^ Robinson DS (2007). "CNS Receptor Partial Agonists: A New Approach to Drug Discovery". Primary Psychiatry 14 (8): 22–24. 
  50. ^ 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. PMID 21753741. 
  51. ^ 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. PMID 16606363. 
  52. ^ 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. PMC 3130949. PMID 21371011. 
  53. ^ 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. PMC 3372736. PMID 21880034. 
  54. ^ 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. PMC 3079418. PMID 21326193. 
  55. ^ 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.
  56. ^ a b Rostami-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 Psychopharmacol 24 (1): 70–8. doi:10.1097/01.jcp.0000106221.36344.4d. PMID 14709950. 
  57. ^ 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 Psychiatry 60 (1): 36–40. doi:10.4088/JCP.v60n0108. PMID 10074876. 
  58. ^ Crilly, John (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. PMID 17580753. 
  59. ^ Healy, David (2004). The Creation of Psychopharmacology. Cambridge: Harvard University Press. pp. 238–42. ISBN 0-674-01599-1. 
  60. ^ "Supplemental NDA Approval Letter for Clozaril, NDA 19-758 / S-047". United States Food and Drug Administration. December 18, 2002. Archived from the original on November 23, 1012. Retrieved November 23, 2012. 
  61. ^ http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2005/019758s054ltr.pdf
  62. ^ Wyatt RJ; Chew RH (2005). Wyatt's Practical Psychiatric Practice: Forms And Protocols For Clinical Use. American Psychiatric Association. pp. 39. ISBN 978-1-58562-109-5. 

Additional reading[edit]

  • 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[edit]