Clozapine was the first atypical anti-psychotic available in the U.S.  It's biggest drawback is that it can cause an elimination of white blood cells (agranulocytosis) and death in a small percentage of patients if the medicine is not discontinued fairly quickly after white blood cell counts start to decline.  This can be prevent by getting blood tests every 1-2 weeks.  However, this is inconvenient and not welcomed by most patients.  

Clozapine also causes a fair number of side-effects including considerable weight gain in a fair number of patients.  Blood sugars should be monitored, especially in those at risk for diabetes.  Symptoms of diabetes are excessive thirst, excessive urination, excessive hunger, and tiredness.  

Clozapine is considered by a number of research reviews to be the most effective anti-psychotic, but there is some evidence that suggests that the differences may not be very significant. 

Clozapine (Clozaril) Appears to Increase Risk of Death: In a 10-year naturalistic study of 96 adults on clozapine, African American and Hispanic Americans had an markedly elevated risk of cardiovascular disease-related mortality (OR = 7.2, p = .09; OR = 11.3, p = .04, respectively) compared to European-Americans. The Kaplan-Meier estimate for new-onset diabetes mellitus was approximately 43% of all patients with Hispanic American (OR = 4.3, p = .027) and African American (OR = 11.5, p = .0001) with the worst elevations. BMI, total cholesterol level, and serum triglyceride level modestly increased the odds ratio for the development of diabetes mellitus. The authors conclude, "These results support the hypothesis that clozapine-treated patients appear to be at risk for death from cardiovascular disease secondary to clozapine-associated medical disorders such as obesity, diabetes, hypertension, and hyperlipidemia." Clozapine, Diabetes Mellitus, Hyperlipidemia, and Cardiovascular Risks and Mortality: Results of a 10-Year Naturalistic Study. Henderson DC, et al. MGH-Harvard. J Clin Psychiatry. 2005 Sep;66(9):1116-1121.

Added Risperidone No Help For Clozapine-Treated Schizophrenics: In an 8-week DB PC study of 68 schizophrenic patients on clozapine, the addition of 3 mg of risperidone made no statistically significant difference: 9 of 34 patients receiving placebo and 6 of 34 receiving risperidone responded to treatment. Clozapine Alone versus Clozapine and Risperidone with Refractory Schizophrenia. Honer WG, et al. University of British Columbia. N Engl J Med 2006 Feb 2;354(5):472-482. 

Risperidone Add-On to Clozapine Didn't Help Treatment Resistant Schizophrenics: In a 6-week DB PC study of 30 schizophrenic patients only partially responsive to clozapine after 32 months of treatment, adding risperidone up to 6 mg/day did not significantly improve symptoms or quality of life. A double-blind controlled study of adjunctive treatment with risperidone in schizophrenic patients partially responsive to clozapine: efficacy and safety. Anil Yagcioglu AE, Kivircik Akdede BB, et al. Hacettepe University , Ankara, Turkey. J Clin Psychiatry. 2005 Jan;66(1):63-72

Clozapine Equal to Olanzapine (Zyprexa) for Schizophrenia: In a DB randomized study of 114 patients with schizophrenia, there was no significant difference favoring olanzapine or clozapine. The lack of a marked correlation between PANSS and the subjective well-being measure SWN improvements indicates that patients and psychiatrists perceive treatment differently. Naber D, Riedel M, et al. Randomized double blind comparison of olanzapine vs. clozapine on subjective well-being and clinical outcome in patients with schizophrenia. Acta Psychiatr Scand 2005: 111: 106-115.  

Clozapine Better for Severe: Clozapine better than haldol in 422 refractory schizophrenia for both positive and negative symptoms (blunt affect, lack motivation, motor retardation) Am J Psychiatry 1/99 156:88-93. Also, H Lane, J Clin Psychiatry 1/99 60:36-40

Clozapine No Better as First Line Treatment: An open trial of 36 first time schizophrenics found clozapine no better than fluphenazine in a recent trial by the same authors. Only 32% stayed on clozapine for the year. 66% had responded by 13 weeks and none responded after that. Clozapine as a first treatment for schizophrenia. Woerner MG, Robinson DG, Alvir JM, Sheitman BB, Lieberman JA, Kane JM.

Clozapine May Not Be as Superior as Claimed: Ten trials were examined. Recent large-scale studies have not found a substantial advantage for clozapine, especially in terms of a clinically relevant effect. Meta-regression showed that shorter study duration, financial support from a drug company and higher baseline symptom score consistently predicted greater advantage of clozapine. The benefits of clozapine compared with conventional treatment may not be substantial. Clozapine v. conventional antipsychotic drugs for treatment-resistant schizophrenia: a re-examination. University College London. Moncrieff J. Br J Psychiatry. 2003 Aug;183:161-6

Clozapine Claimed More Cost-Effective for Some: VA study 423 pts found $2700 per pt per year lower cost with clozapine for refractory pts with high hosp usage (>30 days/yr) although study notes difficulty with cost estimates. Hosp Serv Res 12/98;33:1237

Olanzapine = Clozapine in DB: A Hungarian 147-patient, 18-week DB study of schizophrenic patients who had not improved on or tolerated another anti-psychotic found that 58% improved ("responded") while on olanzapine vs. 61% while on clozapine. Olanzapine versus clozapine in treatment-resistant or treatment-intolerant schizophrenia. Bitter I, Dossenbach MR, Brook S, Feldman PD, Metcalfe S, Gagiano CA, Furedi J, Bartko G, Janka Z, Banki CM, Kovacs G, Breier A. Prog Neuropsychopharmacol Biol Psychiatry. 2004 Jan;28(1):173-80

Anti-Cholinergic Drugs Soften Clozapine Abrupt Withdrawal: Of the 28 patients with schizophrenia who had been receiving clozapine and from whom it was abruptly withdrawn due to the withdrawal of the drug from the market in the summer of 1975, a rapid deterioration after clozapine withdrawal in almost half (46%). Patients receiving anticholinergic drugs (such as antiparkinsonians, tricyclic antidepressants and antipsychotics with anticholinergic properties) were significantly less likely to deteriorate than those not receiving these drugs (21% vs 71%, p = 0.008). Effect of Anticholinergics in Preventing Acute Deterioration in Patients Undergoing Abrupt Clozapine Withdrawal. Seppala N, et al. Harjavalta, Finland. CNS Drugs 2005;19(12):1049-1055.

Clozapine May Decrease Selenium: Venous blood from mood disorder (n = 36), schizophrenics treated with clozapine (n = 54), schizophrenics not treated with clozapine (n = 41) and a healthy control group (n = 56). Selenium concentrations in plasma and red cells were found to be significantly lower in schizophrenic patients treated with clozapine as compared with all other groups. Selenium is an essential antioxidant. Its deficiency has been implicated in myocarditis and cardiomyopathy. Low selenium concentrations in clozapine-treated patients may be important in the pathogenesis of life threatening cardiac side-effects associated with clozapine. Low blood selenium concentrations in schizophrenic patients on clozapine. Vaddadi KS, Soosai E, Vaddadi G. Br J Clin Pharmacol 2003 Mar;55(3):307-309

Clozapine Differs: Clozapine, like risperidone and olanzapine, preferentially blocks the 5-HT2 receptors. However, the D2 receptor occupancy of risperidone and olanzapine are around 80% at standard doses, similar to traditional anti-psychotics, compared to clozapine which plateaus at 60%. Shitij Kapur, U Toronto, Am J Psychiatry 2/99 156:286-293.

Clozapine Levels Higher for Women: The plasma levels were about one third higher in women. Also each year of age increased levels by 1% and each 1-mg daily dosage increase increased levels by 0.3%

Clozapine Might Be No Better as an Initial Treatment: 34 patients in a 4 year open trial, 66% responded, the same as a previous trial with fluphenazine. only 32% still on clozapine at 4 years. Clozapine as a first treatment for schizophrenia. Woerner MG, Robinson DG, Alvir JM, Sheitman BB, Lieberman JA, Kane JM. Long Island Jewish. Am J Psychiatry. 2003 Aug;160(8):1514-6. Ed: This open trial is a very poor quality study.

Clozapine Superior to Haldol for Positive Symptoms: 75 stable schizophrenics in a 10 wk DB. Buchana, U Maryland, Am J Psychiatry 155:751-760 ’98

Clozapine Better than Haldol Both Positive and Negative Symptoms: DB clozapine vs haldol 422 pt for 1 yr. Both pts with positive and negative symptoms improved equally and both positive and negative symptoms improved better with clozapine. Rosenheck, Yale, Am J Psych 1/99;156:88

Agranulocytosis More Common in Elderly: Says risk/benefit ratio higher in elderly with 5-10% suffering agranulocytosis. Aust NZ J Psych ’97;31:411

Clozapine Cardiomyopathy 0.3%: 8000 patient in Australia on clozapine 1993-9. Myocarditis in 15 (17-46yo) and dilated cardiomyopathy in 8 (22-52yo). Myocarditis 14-18 days after starting. 5 dead =IgE-mediated hypersensitivity allergic reaction. Dilated cardio 2-30 months after starting. 1 dead. Kilian, Lancet 99;354:1841

18 Fatal Venous Thromboembolisms: Mortality rate 27 times higher than general population. At least 1/2000 patients get thromoembolism. Epidem 97;8:671

Clozapine=Chlorpromazine Efficacy: A 12-wk DB VA study of 42 elderly patients with chronic schizophrenia found with doses up to 300mg/day for clozapine or 600 mg/day for chlorpromazine that improvement was equal as were the rates of side-effects. Evelyn Howanitz, VA New Jersey, J Clin Psychiatry 1/99, 60:41-4.

PPA Didn’t Help Weight Gain: 12-week, double-blind, randomized, placebo-controlled trial of PPA, 75 mg/day, in outpatients with treatment-refractory schizophrenia (DSM-IV) who were stable on clozapine treatment for at least 4 months and had gained > 10% of their baseline body weight since starting clozapine. : J Clin Psychiatry 2002 Apr;63(4):345-8

Clozapine Slightly Better than Olanzapine for Suicide Attempts, But Not Actual Suicides: 908 patients in 11 countries in a single blind 2 year study (only the raters were blinded, not the physicians or patients). 24% clozapine 300-900mg/day vs. 32% of olanzapine 10-20mg/day had suicide attempts (34 vs. 55) or hospitalizations (82 vs. 107) to prevent suicide. Novartis study. No difference in PANSS or CGI was found. Clozapine treatment for suicidality in schizophrenia: International Suicide Prevention Trial (InterSePT). Meltzer HY, Alphs L, Green AI, Altamura AC, Anand R, Bertoldi A, Bourgeois M, Chouinard G, Islam MZ, Kane J, Krishnan R, Lindenmayer JP, Potkin S; International Suicide Prevention Trial Study Group. Arch Gen Psychiatry. 2003 Jan;60(1):82-91. Steven Potkin, University of California, Irvine, an investigator in the study and paid by the manufacturer, hailed the committee’s vote. "The InterSePT study suggests that clozapine should be a first-line treatment consideration in acutely suicidal patients with schizophrenia regardless of their stage of illness.... Given the nearly 3 million patients in the United States with schizophrenia and schizoaffective disorder, and a 9 percent suicide rate, as many as 60,000 lives may be saved." Novartis Pharmaceuticals last month won the influential support of the Food and Drug Administration’s Psychopharmacological Drugs Advisory Committee (PDAC) by an 8-0 vote for the company’s application to label Clozaril (clozapine) "for the treatment of emergent suicidal behavior in patients with schizophrenia or schizoaffective disorder." (Ed: Potkin goes far beyond the evidence in puffing up clozapine, claiming it might save 60,000 lives.  In fact, while there were fewer clozapine suicide attempts in the study, five clozapine patients killed themselves vs. only three olanzapine patients! Based on this study, which raises more questions than answers, the FDA granted Novartis the right to promote its medicine as superior at preventing suicide). 

Clozapine Decreases Selenium in Schizophrenia: Study of 36 depressed, 56 clozapine, 56 other schiz, and normals. Selenium concentrations in plasma and red cells were found to be significantly lower in schizophrenic patients treated with clozapine as compared with all other groups. Selenium is an essential antioxidant. Its deficiency has been implicated in myocarditis and cardiomyopathy. Low blood selenium concentrations in schizophrenic patients on clozapine. Vaddadi KS, Soosai E, Vaddadi G. Br J Clin Pharmacol 2003 Mar;55(3):307-9

Adding Olanzapine to Clozapine Said to Help Two: Case report of two treatment resistant psychotics. Both improved 35% but didn’t recover. Annals Clin Psych 98;10:113. (Ed: Case reports like this are virtually worthless since observer bias and publication bias are unavoidable and great. The publisher of the Annals should be embarrassed. These studies have an impact on the clinical practices of many psychiatrists that only a drug manufacturer could love.)

Helped Some Olanzapine Failures: NIMH study 27 schizophrenics. 41% responders. Conley, Biol Psych U Maryland 99;46:73

Smokers Did Better on Clozapine: 70 schizophrenics, 79% of whom were smokers. 79% of the smokers v 21% non-smokers responded. Fewer cigs smoked after switch from traditional anti-psychotics to clozapine. McEvoy, Duke, Biol Psych 99;46:125

Atropine for Hypersalivation: 1 drop 1% solution atropine eye drops subligually HS gave immediate relief to 3 without side effects. One patinet needed an extra rx during night and same amount in a glass of water left at bedside. Antonello, J Psychiatry Neurosci 99;24:250

Blood Level Important, Fluvoxamine Can Reduce Pills: Six studies show a significantly higher response rate at clozapine plasma of 350-400 micro g/L. The absolute risk reduction is about 40%. An additional study found best results with plasma levels between 300 and 700 micro g/L. At the time of response 17 out of 19 responders showed clozapine concentrations above 350 micro g/L. The nine non-responders remained below this threshold throughout the rest of the year. These results favor an approach of raising the clozapine plasma level in treatment-refractory schizophrenic patients who do not respond to an initial low-to-medium dose treatment with clozapine. Some patients, especially young male smokers, will need dosages higher than 900 mg/day. Addition of low-dose fluvoxamine while closely monitoring clozapine levels can help decrease the high number of necessary pills. An adequate trial with clozapine should last at least 8 weeks on a plasma trough level above 350-400 micro g/L. Netherlands. What is an adequate trial with clozapine?: therapeutic drug monitoring and time to response in treatment-refractory schizophrenia. Schulte P. Clin Pharmacokinet. 2003;42(7):607-18