1. Action Indications and EfficacySide Effects and Toxicology Drug-Drug interactions

2. History of Clozapine Clozapine was first syntetised in 1958 in Switzerland and developed in Germany in 1960. By 1975 there were 13 cases of agranulocytosis reported in Finland and 8 of these patients died. Clozapine was taken off the European market (with the exception of Finland). In the US, Clozapine was approved in 1990 for treatment resistant schizophrenia. 3. FIN 11 STUDY 11 years follow up of mortality in patients withschizophrenia. Sought to establish the long term contribution ofantipsychotic drugs to mortality. 66,881 patients with schizophrenia compared to a totalpopulation of 5.2 million (Finland). Mortality data was linked to use of antipsychoticprescriptions using public registers.RESULTS Atypical antipsychotics were associated to lower mortalityas compared to typical antipsychotics or to no medicationsat all. Clozapine had the lowest mortality rate. 4. What Have We Learned from Clozapine Which of the following dopamine receptor subtypes isof great psychopharmacological interest because ofclozapines high affinity for this receptor?1. D12. D23. D34. D45. D5 5. Where in the World are D4receptors? 6. ClozapineXM1 M3H15HT2A 1 2 D1 D2 D3D4 7. Conventional antipsychotic: Clozapine occupies only 20-67% of D290% of striatal D2 receptorreceptors occupied 8. Clozaril thought us about partialagonists 9. A partial agonist can have a net effectof an agonist or an antagonist When the full agonist is absent, the partial agonistincreases the frequency of the channel opening ascompared to a resting state (acts as a net agonist). When the full agonist is present, the partial agonistdecreases the frequency of the channel opening ascompared to a resting state(acts as a net antagonist). 10. Action of an agonist 11. Action of an antagonist thechannel remains in its resting state 12. Antagonist can displace an agonist andreturn the channel to its resting state 13. Inverse agonists render thechannel inactive 14. In the presence of an inverse agonist,an antagonist returns the channel to itsresting state 15. Clozapine Indications and Efficacy Acute Schizophrenia and Schizoaffective disorder Treatment refractory schizophrenia Hostile and Aggressive Behavior in Schizophrenia Schizophrenia patients with high risk for suicide Schizophrenia with Comorbid Substance Abuse Maintenance Therapy in Schizophrenia 16. Prior to Initiation ofClozapineTreatment Need a baseline WBC count (3500/mm3) Need an Absolute Neutrophil Count (ANC) (2000/mm3) Clozaril Registry ensures monitoring of WBC andANC. 17. Initiation of Treatment Begin with one-half of a 25-mg tablet (12.5 mg) once or twice daily and then continue with daily dosage increments of 25-50 mg/day, if well tolerated, to achieve a target dose of 300-450 mg/day by the end of 2 weeks. 18. Time frame of an adequateclozapine trial Carpenter vs. Meltzer : 3 months vs. 1 yearAccording to Meltzer late responders furtherbenefit up to 1 year. In reality, what constitutes a reasonable trial? 6-12 weeks at adequate doses 19. What is an adequate dose ofclozapine? Good evidence for greater efficacy if Clozapineblood level is >350 ng/ml 350 450 ng/ml appears optimal. In case of poor/no response, can titrate to a plasma level >450ng/ml. Dose range 175 825 mg/day to achieve these levelsacross patients. 20. Treatment Resistant Schizophrenia In a pivotal study of Clozaril Kane J, Honigfeld G, Singer Jet al. Clozapine for the treatment-resistantschizophrenic. A double blind comparison withchlorpromazine. Arch. Gen Psychiatry. 1988;45(9):789-7896. At lest 3 periods of treatment in the preceding 5 yearswith neuroleptic agents from at least 2 differentchemical classes at dosage equivalent to 1000 mg/dayof chlorpromazine for 6 weeks, each withoutsignificant symptomatic relief, and no period of goodfunctioning within the preceding 5 years. 21. Why is schizophrenia treatmentresistant? Neurodegeneration occurs during psychosis. Excitotoxicity Intracellular Calcium homeostasis 22. Intracellular Calcium Homeostasis Calcium is a very common signaling element and plays a criticalrole in the CNS by regulating the activity of diverse enzymes,facilitating neurotransmitter release and long term potentiation(memory). Excessively high levels of Calcium in the neuron cause damageby activating the cell death cascade (apoptosis). For this reason the neurons, developed diverse homeostaticmechanisms to regulate intracellular Calcium level veryprecisely. Thus extracellular Calcium level is approximately 2 mM, whilethe resting intracellular Calcium level is in the range of 100nM(20,000 times less). 23. Intracellular Calcium Homeostasis In order to keep tight control of the intracellular Calcium, the neurondeveloped Calcium pumps(to eliminate it), and Calcium proteins to carantineit . Thus it is estimated that Calcium ion can only diffuse 0.5 micrometers andis free for only 50 microseconds before encountering a Calcium binding proteinto sequestrate it. 24. Why is Psychosis bad for yourbrain? During normal excitation, entry of small amounts of Calcium in theneuron is beneficial it forms the basis of long term potentiation(memory). BUT Studies have shown that during psychotic episodes excessive amountsof Calcium enter the neurons, leading to the destruction of theorganelles and the activation of cell death cascade (apoptosis). Thisprocess is called EXCITOTOXICITY 25. Other Indications- Show me theEvidence Hostile and Aggressive Behavior in Schizophrenia Schizophrenia patients with high risk for suicide Schizophrenia with Comorbid Substance Abuse Maintenance Therapy in Schizophrenia 26. Hostile and Aggressive Behavior inSchizophrenia 27. Clozapine is of particular benefit to the patientswith treatment of refractory schizophrenia whodemonstrate hostile and aggressive behaviors A number of studies suggest that Clozapine maydecrease hostility and aggression, compared withother agents. Citrome et al. (2001): in a study of 157 inpatients,Clozapine resulted in greater reduction in hostilityitem from the PANSS than both typical and atypicalantipsychotics. Chengappa et al(2003) found significant reduction inthe rates of seclusion and restraints in schizophreniapatients who received Clozapine during the first 3years after its introduction on the market. 28. Schizophrenia Patients with HighRisk for Suicide 29. Clozapine decreases suicidality Large epidemiological studies have found that mortality from suicide is reduced among individuals taking Clozapine (Reid et all 1988; Walker et all 1997; Meltzer and Okayali 1995). The most convincing study was a comparison of Clozapine and Olanzapine in 980 patients with schizophrenia who were considered at risk for suicide (Meltzer 2002). In this study Clozapine was more effective in reducing the risk of suicide. 30. Schizophrenia with ComorbidSubstance Abuse The effectiveness of Clozapine in patients with comorbid substance abuse has not been demonstrated in randomized clinical trials, there is some supporting evidence from naturalistic studies. Greene (2003) found that patients treated with Clozapine were more likely than those treated with Risperidone to abstain from alcohol and cannabis use. These findings were supported by other prospective studies (Brunette et al. 2006 and Drake et al 2000). 31. Maintenance Therapy inSchizophrenia Clozapine has largely been confined to patients with treatment resistantschizophrenia. As a result it was not studied in the traditional relapseprevention trials in which patients who are stable are randomly assigned toeither Clozapine or a comparator drug. Nevertheless, there are substantial data supporting the long term effectivenessof Clozapine. Breier et al.(2000) evaluated the outcomes of 30 patients with schizophreniawho were treated with Clozapine for 1 year. Patients taking Clozapineexperienced fewer relapses and rehospitalizations than they did in the yearprior to being on Clozapine. A study in the State hospitals in Connecticut, done by Essock et al. in 2000,compared patients who were on Clozapine to the patients maintained on otherantipsychotics. Although Clozapine did not result in a greater likelihood ofhospital discharge, patients who were treated with Clozapine had higherlikelihood of remaining in the community after discharge. 32. Side Effects and ToxicologyWhy not first line treatment? Even though it is very effective, Clozapine is not considered a first-line agent because it can lead to the potentially life-threatening side effect agranulocytosis. Weight increase and the concomitant risk of developing metabolic complications are greatest with clozapine 33. Hematological Effects The side effects of Clozapine make it one of the most challengingmedications to prescribe. The main factor that limits its use is the potential serious sideeffect of agranulocytosis (defined as a drop in absolute neutrphilcount to levels below 500/cubic mm. In a review of morbidity and mortality of Clozapine treatedpatients done by Honigfeld et al. in 1998, over a 5 year period,99,502 patients were registered through the Clozaril NationalRegistry. Of these 2,931 developed leukopenia (WBC3,500/cubicmm), and 382 patients developed agranulocytosis(ANC below 500/cubicmm). 12 cases of agranulocytosis werefatal. This study shows lower percentage of agranulocytosis thaninitially thought, leading to change in FDA guidelines in 2006. 34. Agranulocytosis The onset of agranulocytosis occurs most often during thefirst 6 months of treatment and is usually marked by agradual fall in WBC count, often over several weeks. Thus patients must be monitored with weekly blood cellcounts for the first 6 months of treatment and every 2weeks thereafter. Dr. Schatzberg and his group believe in the allergic etiologyof thrombocytopenia. This theory was not validated yet byother studies, but frequently agranulocytosis is precededby eosinophilia . Also when a patient who once hadagranulocytosis is re-challenged with Clozapine, the dropin WBC occurs sooner and is more severe, suggesting anallergic etiology. 35. Cardiovascular Adverse Effects Tachycardia caused by anticholinergic activity. Orthostatic hypotension alpha adrenergicblockade. Myocarditis Cardiomyopathy 36. Cardiac Effects In January 2002 Novartis reported that there had been 213 cases ofmyocarditis, 85% of which occurred at recommended dosages ofClozapine within the first 2 months of treatment. The presence ofeosinophilia in many of the reported cases indicates that animmunoglobulin E mediated hypersensitivity reaction may beinvolved. In 2002 Novartis also reported 178 cases of Clozapine associatedcardiomyopathy, 80% of which occurred in patients younger than 50.Almost 20% of these incidents resulted in death. The detection ofcardiac toxicity is particularly challenging because its manifestations(tachycardia, fatigue and orthostatic hypotension) are frequentlyobserved in Clozapine treated patients. Merril and Goff in 2005 conducted a thorough review of the literatureexamining reports from 1970-2004 of cardiac side effects in patients onClozapine. They concluded that Clozapine is associated with a low risk(0.015%-0.188%) of potentially fatal myocarditis or cardiomyopathy. 37. Weight Gain 38. Weight Gain In patients observed in various clinical trials, the average weightgain in 6 months period with Clozapine treatment was 6.9 Kg. Allison et al. (1999) performed a meta-analysis of weight gaindata in in short-term trials of medications. The average weightgain observed with Clozapine was 4.45 Kg, which exceeded theweight gain observed with all the other medications in the study,including conventional agent Thioridazine(3.19 Kg), amedication known for its weight gain liability. Henderson (2001) observed patients in a Clozapine clinic for 5years and noted weight gain occurring for up to 46 months insome patients. 39. Diabetes Numerous case reports have linked Clozapine with new onset diabetes. Henderson(2001) naturalistic study of 81 patients observed over a 5year period, 36.6% of the patients developed diabetes. (The prevalenceof diabetes in the US is estimated to be 7%, with another 7% of casesundiagnosed). Koller et al.( 2001)published the largest series of case reportssubmitted voluntarily to the FDA Med Watch Program. The reportrevealed that there were 2,424 new onset cases, 54 of which were casesof diabetic exacerbation and 80 of which were cases of diabeticketoacidosis. Newcomer(2006) concluded that antipsychotic medication-associated adiposity is the main culprit in the development of diabetes. Sasaki et al (2006) showed that the etiology of diabetes may beindependent of adiposity, instead reflecting the direct blockade ofmuscarinic(M3) receptors on the pancreatic beta cells. 40. Blocking M3 Cholinergic Receptors: Reduces InsulinRelease ACh presynaptic parasympathetic M3 fibers insulinpostsynapticcholinergicbeta cellsfibers SDA insulin 41. Insulin Resistance / Elevated Triglycerides andAntipsychotics: Caused by Tissue Actions at an Unknown Receptor?atypicalinsulinadiposeliverskeletalmusclereceptor x 42. Dyslipidemias Gaulin et al.(1999) compared 117 patients taking Clozapine with 45 taking Haloperidol. The study found significant increase in triglyceride levels for both men and women taking Clozapine a mean increase from 184.6 mg/dl to 273.4 mg/dl for men and 164.9 mg/dl to 223.3 mg/dl for women. More recently Mc Evoy et al.(2006) looked at the patients who received Clozapine in phase II of CATIE study and demonstrated greater elevations in both triglycerides and cholesterol as compared to the patients on Risperidone, Olanzapine or Quetiapine. 43. Analyze This Could triglyceride elevations account for the beneficial psychiatric effectof these medications through stabilization of neuronal membranes? Kingsburry et al.(2001) showed correlations between elevations intriglyceride levels and changes in mood. Diebold et al( 1998) showed that increase in trigliceride levels wasassociated with decreased hostility. Spivak et al (1998) observed that patients taking Clozapine who developedincrease in triglycerides also demonstrated decreases in aggression and suicidalbehavior in comparison with people taking typical antipsychotics. Muldoon et al (1990) a cardiologist reviewed numerous randomized clinicaltrials that focused on reducing lipid levels for primary prevention of coronaryartery disease. They concluded that the risk of death due to accidents, suicide,or violence was significantly higher in patients with reduced lipid levels. 44. Thought Provoking: To examine whether the medical consequences of obesity may offset the life saving benefits gained from Clozapines potentially decreased suicide rate, Fontaine et al(2001), using mathematical modeling, estimated that 492 suicide deaths per 100,000 schizophrenia patients would be prevented over 10 years with the use of Clozapine. This was compared with an estimated 416 additional deaths due to antipsychotic induced weight gain. Even though controversial, this mathematical model suggests that the lives saved by Clozapine may essentially be offset by the death associated with weight gain. These findings were confirmed by the FIN 11 study (published in 2010). Nature is subtle, but not malicious (Einstein) 45. Seizures A well known risk of Clozapine treatment is the risk for seizures,which are thought to occur in 5%-10% of patients treated withthis medication. Clozapine-associated seizures occur most often at doses greaterthan 600 mg /day. The relationship between Clozapine plasma levels and andseizures is inconsistent throughout the literature It is recommended obtaining a baseline EEG when initiatingClozapine treatment in patients who have a history of possiblehead injury, loss of consciousness, or other risk factors forseizures. 46. Constipation A truly problematic consequence of clozapinesanticholinergic activity is its propensity to cause significantconstipation. In institutional settings where patients have limited accessto exercise and where monitoring of fluid intake is notperformed, constipation from Clozapine can be serious oreven fatal. The favored medical treatment is prophylaxis with sorbitol( 3.3 % in plastic irrigation containers). High fiber diets, exercise and hydration are also veryhelpful. 47. Drug-Drug Interaction Clozapine is predominantly metabolized by cytochromeP450 1A2, although CYP 2D6 and CYP 3A3 also contributeto its metabolism. Smoking which induces CYP 1A2, lowers clozapine plasmalevel. Fluvoxamine(Luvox) is a potent inhibitor of CYP 1A2 forthis reason it increases plasma levels of Clozapine. Inhibitors of CYP 2D6, such as Paroxetine and Fluoxetinecan elevate Clozapine levels. 48. Thank youADONIS SFERA MD