Action Indications and EfficacySide Effects and Toxicology Drug-Drug interactions
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.
FIN 11 STUDY 11 years follow up of mortality in patients with schizophrenia. Sought to establish the long term contribution of antipsychotic drugs to mortality. 66,881 patients with schizophrenia compared to a total population of 5.2 million (Finland). Mortality data was linked to use of antipsychotic prescriptions using public registers.RESULTS Atypical antipsychotics were associated to lower mortality as compared to typical antipsychotics or to no medications at all. Clozapine had the lowest mortality rate.
What Have We Learned from Clozapine Which of the following dopamine receptor subtypes is of great psychopharmacological interest because of clozapine’s high affinity for this receptor?1. D12. D23. D34. D45. D5
A partial agonist can have a net effectof an agonist or an antagonist When the full agonist is absent, the partial agonist increases the frequency of the channel opening as compared to a resting state (acts as a net agonist). When the full agonist is present, the partial agonist decreases the frequency of the channel opening as compared to a resting state(acts as a net antagonist).
In the presence of an inverse agonist,an antagonist returns the channel to itsresting state
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
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 and ANC.
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.
Time frame of an adequateclozapine trial Carpenter vs. Meltzer : 3 months vs. 1 year According to Meltzer – late responders further benefit up to 1 year. In reality, what constitutes a reasonable trial? 6-12 weeks at adequate doses
What is an adequate dose ofclozapine? Good evidence for greater efficacy if Clozapine blood level is >350 ng/ml 350 – 450 ng/ml appears optimal. In case of poor/ no response, can titrate to a plasma level >450 ng/ml. Dose range 175 – 825 mg/day to achieve these levels across patients.
Treatment Resistant Schizophrenia In a pivotal study of Clozaril Kane J, Honigfeld G, Singer J et al. Clozapine for the treatment-resistant schizophrenic. A double blind comparison with chlorpromazine. Arch. Gen Psychiatry. 1988;45(9):789- 7896. At lest 3 periods of treatment in the preceding 5 years with neuroleptic agents from at least 2 different chemical classes at dosage equivalent to 1000 mg/day of chlorpromazine for 6 weeks, each without significant symptomatic relief, and no period of good functioning within the preceding 5 years.
Why is schizophrenia treatmentresistant? Neurodegeneration occurs during psychosis. Excitotoxicity Intracellular Calcium homeostasis
Intracellular Calcium Homeostasis Calcium is a very common signaling element and plays a critical role 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 damage by activating the cell death cascade (apoptosis). For this reason the neurons, developed diverse homeostatic mechanisms to regulate intracellular Calcium level very precisely. Thus extracellular Calcium level is approximately 2 mM, while the resting intracellular Calcium level is in the range of 100nM (20,000 times less).
Intracellular Calcium Homeostasis In order to keep tight control of the intracellular Calcium, the neuron developed Calcium pumps(to eliminate it), and Calcium proteins to carantine it . Thus it is estimated that Calcium ion can only diffuse 0.5 micrometers and is free for only 50 microseconds before encountering a Calcium binding protein to sequestrate it.
Why is Psychosis “bad for yourbrain”? During normal excitation, entry of small amounts of Calcium in the neuron is beneficial – it forms the basis of long term potentiation (memory). BUT Studies have shown that during psychotic episodes excessive amounts of Calcium enter the neurons, leading to the destruction of the organelles and the activation of cell death cascade (apoptosis). This process is called EXCITOTOXICITY
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
Hostile and Aggressive Behavior inSchizophrenia
Clozapine is of particular benefit to the patientswith treatment of refractory schizophrenia whodemonstrate hostile and aggressive behaviors A number of studies suggest that Clozapine may decrease hostility and aggression, compared with other agents. Citrome et al. (2001): in a study of 157 inpatients, Clozapine resulted in greater reduction in hostility item from the PANSS than both typical and atypical antipsychotics. Chengappa et al(2003) found significant reduction in the rates of seclusion and restraints in schizophrenia patients who received Clozapine during the first 3 years after its introduction on the market.
Schizophrenia Patients with HighRisk for Suicide
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.
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).
Maintenance Therapy inSchizophrenia Clozapine has largely been confined to patients with treatment resistant schizophrenia. As a result it was not studied in the traditional relapse prevention trials in which patients who are stable are randomly assigned to either Clozapine or a comparator drug. Nevertheless, there are substantial data supporting the long term effectiveness of Clozapine. Breier et al.(2000) evaluated the outcomes of 30 patients with schizophrenia who were treated with Clozapine for 1 year. Patients taking Clozapine experienced fewer relapses and rehospitalizations than they did in the year prior 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 other antipsychotics. Although Clozapine did not result in a greater likelihood of hospital discharge, patients who were treated with Clozapine had higher likelihood of remaining in the community after discharge.
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
Hematological Effects The side effects of Clozapine make it one of the most challenging medications to prescribe. The main factor that limits its use is the potential serious side effect of agranulocytosis (defined as a drop in absolute neutrphil count to levels below 500/cubic mm. In a review of morbidity and mortality of Clozapine treated patients done by Honigfeld et al. in 1998, over a 5 year period, 99,502 patients were registered through the Clozaril National Registry. Of these 2,931 developed leukopenia (WBC 3,500/cubicmm), and 382 patients developed agranulocytosis (ANC below 500/cubicmm). 12 cases of agranulocytosis were fatal. This study shows lower percentage of agranulocytosis than initially thought, leading to change in FDA guidelines in 2006.
Agranulocytosis The onset of agranulocytosis occurs most often during the first 6 months of treatment and is usually marked by a gradual fall in WBC count, often over several weeks. Thus patients must be monitored with weekly blood cell counts for the first 6 months of treatment and every 2 weeks thereafter. Dr. Schatzberg and his group believe in the allergic etiology of thrombocytopenia. This theory was not validated yet by other studies, but frequently agranulocytosis is preceded by eosinophilia . Also when a patient who once had agranulocytosis is re-challenged with Clozapine, the drop in WBC occurs sooner and is more severe, suggesting an allergic etiology.
Cardiac Effects In January 2002 Novartis reported that there had been 213 cases of myocarditis, 85% of which occurred at recommended dosages of Clozapine within the first 2 months of treatment. The presence of eosinophilia in many of the reported cases indicates that an immunoglobulin E mediated hypersensitivity reaction may be involved. In 2002 Novartis also reported 178 cases of Clozapine associated cardiomyopathy, 80% of which occurred in patients younger than 50. Almost 20% of these incidents resulted in death. The detection of cardiac toxicity is particularly challenging because its manifestations (tachycardia, fatigue and orthostatic hypotension) are frequently observed in Clozapine treated patients. Merril and Goff in 2005 conducted a thorough review of the literature examining reports from 1970-2004 of cardiac side effects in patients on Clozapine. They concluded that Clozapine is associated with a low risk (0.015%-0.188%) of potentially fatal myocarditis or cardiomyopathy.
Weight Gain In patients observed in various clinical trials, the average weight gain in 6 months period with Clozapine treatment was 6.9 Kg. Allison et al. (1999) performed a meta-analysis of weight gain data in in short-term trials of medications. The average weight gain observed with Clozapine was 4.45 Kg, which exceeded the weight gain observed with all the other medications in the study, including conventional agent Thioridazine(3.19 Kg), a medication known for its weight gain liability. Henderson (2001) observed patients in a Clozapine clinic for 5 years and noted weight gain occurring for up to 46 months in some patients.
Diabetes Numerous case reports have linked Clozapine with new onset diabetes. Henderson(2001) naturalistic study of 81 patients observed over a 5 year period, 36.6% of the patients developed diabetes. (The prevalence of diabetes in the US is estimated to be 7%, with another 7% of cases undiagnosed). Koller et al.( 2001)published the largest series of case reports submitted voluntarily to the FDA Med Watch Program. The report revealed that there were 2,424 new onset cases, 54 of which were cases of diabetic exacerbation and 80 of which were cases of diabetic ketoacidosis. 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 be independent of adiposity, instead reflecting the direct blockade of muscarinic(M3) receptors on the pancreatic beta cells.
Insulin Resistance / Elevated Triglycerides and Antipsychotics: Caused by Tissue Actions at an Unknown Receptor?atypicalinsulinadiposeliverskeletalmusclereceptor x
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.
Analyze This Could triglyceride elevations account for the beneficial psychiatric effect of these medications through stabilization of neuronal membranes? Kingsburry et al.(2001) showed correlations between elevations in triglyceride levels and changes in mood. Diebold et al( 1998) showed that increase in trigliceride levels was associated with decreased hostility. Spivak et al (1998) observed that patients taking Clozapine who developed increase in triglycerides also demonstrated decreases in aggression and suicidal behavior in comparison with people taking typical antipsychotics. Muldoon et al (1990) a cardiologist reviewed numerous randomized clinical trials that focused on reducing lipid levels for primary prevention of coronary artery disease. They concluded that the risk of death due to accidents, suicide, or violence was significantly higher in patients with reduced lipid levels.
Thought Provoking: To examine whether the medical consequences of obesity may offset the life saving benefits gained from Clozapine’s 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)
Seizures A well known risk of Clozapine treatment is the risk for seizures, which are thought to occur in 5%-10% of patients treated with this medication. Clozapine-associated seizures occur most often at doses greater than 600 mg /day. The relationship between Clozapine plasma levels and and seizures is inconsistent throughout the literature It is recommended obtaining a baseline EEG when initiating Clozapine treatment in patients who have a history of possible head injury, loss of consciousness, or other risk factors for seizures.
Constipation A truly problematic consequence of clozapine’s anticholinergic activity is its propensity to cause significant constipation. In institutional settings where patients have limited access to exercise and where monitoring of fluid intake is not performed, constipation from Clozapine can be serious or even fatal. The favored medical treatment is prophylaxis with sorbitol ( 3.3 % in plastic irrigation containers). High fiber diets, exercise and hydration are also very helpful.
Drug-Drug Interaction Clozapine is predominantly metabolized by cytochrome P450 1A2, although CYP 2D6 and CYP 3A3 also contribute to its metabolism. Smoking which induces CYP 1A2, lowers clozapine plasma level. Fluvoxamine(Luvox) is a potent inhibitor of CYP 1A2 for this reason it increases plasma levels of Clozapine. Inhibitors of CYP 2D6, such as Paroxetine and Fluoxetine can elevate Clozapine levels.