clozapine: balancing safety with superior antipsychotic ... · clozapine is often referred to as...

Clozapine is often referred to as the gold standard for the treatment of schizophrenia and yet has also been described as the most underutilized treatment for schizophrenia supported by solid evidence-based medicine. In 2008, it was used to treat only 4.4% of patients with schizophrenia in the U.S., which is ~10–20% of those with approved indications for clozapine for which there is no alternative of equal efficacy. Its use is much higher in Scandinavian countries and China. The primary indications for clozapine are: 1) treatment-resistant schizophrenia or schizoaffective disorder, defined as persistent moderate to severe delusions or hallucinations despite two or more clinical trials with other antipsychotic drugs; and, 2) patients with schizophrenia or schizoaffective disorder who are at high risk for suicide. Concerns over a number of safety considerations are responsible for much of the underutilization of clozapine: 1) agranulocytosis; 2) metabolic side effects; and, 3) myocarditis. These side effects can be detected, prevented, minimized and treated, but there will be a very small number of fatalities. Nevertheless, clozapine has been found in two large epidemiologic stud-ies to have the lowest mortality of any antipsychotic drug, mainly due to its very large effect to reduce the risk for sui-cide. Other reasons for limited use of clozapine include the extra effort entailed in monitoring white blood cell counts to detect granulocytopenia or agranulocytosis and, possibly, minimal efforts to market it now that it is largely generic. Awareness of the benefits and risks of clozapine is essential for increasing the use of this lifesaving agent.

Comprehensive Reviews

Clozapine: Balancing Safety with Superior Antipsychotic Efficacy

1Professor of Psychiatry and Behavioral Sciences, Feinberg School of Medicine

Address for correspondence: Dr. Herbert Y. Meltzer, Professor of Psychiatry and Behavioral Sciences, Northwestern Feinberg School of Medicine, Ward Building-12-104, 303 East Chicago Avenue, Chicago, IL 60611Phone: 312-503-0309; Fax: 313-503-0486; E-mail: [email protected]

Submitted: June 28, 2011; Revised: June 12, 2012; Accepted: June 16, 2012

Herbert Y. Meltzer 1

Key Words: Schizophrenia, Clozapine, Treatment Resistant, Suicide, Agranulocytosis, Metabolic Side Effects, Myocarditis

Abstract

Introduction The primary aim of this article is to provide information about the efficacy and safety of clozapine for the treatment of schizophrenia to enable clinicians, patients, their families, and other stakeholders to make informed decisions as to

when and how to use clozapine, a drug generally considered the most effective, and at the same time, the most dangerous treatment for schizophrenia and schizoaffective disorder. Mainly because of perceived dangerousness, many clinicians avoid prescribing clozapine even for those indications where there is no good alternative for patients with schizophrenia or schizoaffective disorder: 1) treatment resistance; 2) high risk of suicide; and, 3) inability to tolerate other antipsy-chotic drugs because of motor side effects, including mod-erate–severe tardive dyskinesia. Thus, although conservative estimates of the percentages of patients with schizophrenia who are treatment resistant (~30%) and who have survived a serious suicide attempt (~10%) suggest that at least 35–40% (as the two groups partially overlap) should be treated with clozapine, the latest available data in the U.S. (2008) show

134 • Clinical Schizophrenia & Related Psychoses October 2012

that clozapine has a 4.4% market share (IMS, 2010). The U.S. lags behind many other countries in the use of clozapine, especially Scandinavian and other European countries, and China. This state of affairs has been singled out as the pre-eminent example of the lack of use of evidence-based medi-cine in the treatment of schizophrenia. Horvitz-Lennon et al. noted that the FDA issuance of the indication for clozap-ine for use in patients deemed at high risk for suicide had no impact on the prescription of clozapine, despite the inten-sive marketing efforts made by Novartis, the company who funded the key research on clozapine and suicide, to educate providers and facilitate access to management tools to pre-scribe clozapine for this new indication (1).

Clozapine: A Brief History A brief historical review is useful to understand the rea-sons for this low utilization of clozapine and to point the way to a possible increase in its use. There have been two semi-nal and transformational discoveries in the pharmacologic treatment of schizophrenia. The first was the discovery of chlorpromazine, serendipitously, in 1952 in Paris by Laborit, Delay and Deniker, who were the first to observe that this compound, which had been expected to be no more than a highly sedative antihistamine to relieve agitation, controlled delusions and hallucinations, and was, thus, the first anti-psychotic drug (2). Little matter then, at least initially, that during ongoing treatment, many of the patients manifested a variety of motor side effects, including parkinsonism, dys-tonias, opisthotonus, akathisia, most likely a few cases of neuroleptic malignant syndrome (NMS) which were prob-ably misdiagnosed as “lethal catatonia,” and eventually many cases of tardive dyskinesia or tardive dystonia. This would be especially true in elderly and post-menopausal patients. Other pharmaceutical companies sought to find other drugs

which were equally effective as antipsychotics but more tol-erable. Numerous drugs with a similar mechanism of action, which was quickly discovered to be a blockade of dopamine D2 receptors, were identified but, like chlorpromazine, they too produced motor side effects. This led to the expectation that the “typical” antipsychotic drug should produce motor side effects at clinically effective doses. The motor side ef-fects gave these drugs a class name, neuroleptics, but they are also referred to as typical or first-generation antipsychot-ics. The prior concern with tardive dyskinesia as a result of neuroleptic treatment is diminished to some extent now that it is so rarely seen because of the introduction of, and near ubiquitous use of, atypical antipsychotic drugs. This may be one reason why clozapine use is not as prevalent as it should be. However, in 1956, only a few years after the discovery of chlorpromazine, a drug was synthesized and characterized by Hunziker, Schmutz and Stille from the Wander Laborato-ries in Berne, Switzerland, which showed that antipsychotic efficacy and motor side effects could be dissociated. That drug was clozapine. In animal models, it did not cause cata-lepsy, an immobilized state which was shown to predict mo-tor side effects with chlorpromazine and its congeners. Clo-zapine produced no motor side effects at doses in which it was effective. Indeed, it was eventually found to be tolerable in patients with Lewy Body Dementia and the L-DOPA-in-duced psychosis of Parkinson’s disease, who became totally immobilized when even the smallest doses of a neuroleptic able to control psychotic symptoms was administered. Thus, clozapine was atypical and, like chlorpromazine, became the progenitor of, and eventually the clue to, discovering the pharmacologic properties needed to produce other atypical antipsychotic drugs. This article will refer to these two types of antipsychotic drugs as typical and atypical antipsychotic

Herbert Y. Meltzer

Clinical Schizophrenia & Related Psychoses October 2012 • 135

Clinical ImplicationsDespite the risk of agranulocytosis, metabolic side effects, and a variety of cardiovascular problems, including myocardi-tis, the specific advantages of clozapine with regard to efficacy can still make it a prudent choice for as many as 30–40% of patients with schizophrenia or schizoaffective disorder. The following advantages are well established: 1) superiority for positive symptoms in treatment-resistant patients; 2) lower risk for suicide; 3) lower risk for tardive dyskinesia and suppression of established tardive dyskinesia; 4) improvement in cognition contributing to better work and social func-tion; 5) higher quality of life and longer time to discontinuation; and, 6) decreased relapse. On the other hand, there are serious risks: 1) agranulocytosis; 2) insulin resistance with increased risk of type II diabetes, weight gain, and various vascular complications; and, 3) myocarditis. There are also other unpleasant side effects, such as hypersalivation and increased risk of seizures. The results from the U.S. (47) and Finnish (50, 67) epidemiologic studies suggest that none of the potentially life threatening risks, as managed in the “real world,” have enough of an impact to negate the advantages which come from clozapine. Whether this will remain true after even longer term use of clozapine cannot be known for sure. However, clozapine has been available for twenty years in the U.S. now, and there is no evidence that mortality in the clozapine patients who have been taking it for this extended period is increasing. The success of clozapine in terms of time to discontinuation and fewer relapses than almost any other drug suggests that once patients get started on clozap-ine, their subjective experience is sufficiently favorable that they prefer it to other treatments.

pharmacology Algorithm (IPAP, www.IPAP.org), and the Schizophrenia Patient Outcomes Research Team (PORT) (15). With the exception of supplemental ECT and, as will be discussed, high doses of other atypical antipsychotic drugs, there is little disagreement that clozapine is the treatment of choice once a patient with schizophrenia or schizoaffective disorder has failed two trials of adequate duration and dos-age of other antipsychotic drugs. About 10% of first-episode patients fulfill this definition after a year of treatment (16), while another ~20% do so after years of responding ad-equately to other antipsychotic drugs (17, 18).

Other benefits for clozapine that have to be consid-ered to evaluate its benefit-to-risk ratio for specific patients include, in order of importance and identifying the initial reports of efficacy: 1) reducing the risk for suicide (19); 2) improvement in some domains of cognition (20); and, 3) blocking L-DOPA-induced psychosis in patients with Par-kinson’s disease without worsening motor symptoms (21). On the other hand, the early safety issues with clozapine, which included major motor seizures, pulmonary embo-lism, and tachycardia, have been expanded as evidence for metabolic side effects, including type II diabetes mellitus and major weight gain for some patients (22, 23), myocardi-tis, cardiomyopathy and sudden death (24, 25) has accumu-lated.

Evaluating the Benefits of Clozapine

Efficacy in Treatment-Resistant Schizophrenia As mentioned in the Introduction, the first indication of the superiority of clozapine over other antipsychotic drugs in patients with schizophrenia was the advantages for posi-tive and negative symptoms in treatment-resistant patients who participated in the six-week, double-blind, randomized U.S. Clozaril trial (11). Three issues that need to be clearly delineated to make the decision to recommend clozapine over other treatments, including other atypical antipsychotic

Clozapine: Balancing Safety


drugs. Since clozapine does not cause catalepsy, it is incor-rect to call it a neuroleptic. Clozapine usage spread throughout Europe and, inter-estingly, to China, where it became almost the only antipsy-chotic drug used once China substituted western antipsy-chotic drugs for traditional medicines (3). Clozapine testing in the U.S. was just beginning when a cluster of elderly and infirm patients in Finland developed agranulocytosis, lead-ing to eight deaths in a small geographic region (4, 5). No such clustering of deaths has been reported since, in Fin-land or anywhere else. The ensuing investigation rejected the conclusion that clozapine was the cause of these deaths, at least through an agranulocytosis mechanism (6). Neverthe-less, these deaths led to its withdrawal from general use in all countries where it had been marketed. Subsequently, many patients who had been stabilized on clozapine relapsed se-verely shortly after its abrupt withdrawal (7). It was reintro-duced on a very restricted basis with weekly monitoring of the white blood count so as to detect agranulocytosis within days of its emergence. Clozapine would probably not have been reintroduced were it not for observations that it appeared to be more ef-fective to control the symptoms of severe tardive dyskinesia and to improve psychotic symptoms in patients with tardive dyskinesia than other antipsychotic drugs (8-10). The poten-tial of clozapine to treat schizophrenia with minimal risk of causing tardive dyskinesia was the main motivation for the willingness of Sandoz (now Novartis) and the U.S. FDA to permit a trial in patients who had failed to respond to other antipsychotic drugs or who had intolerable motor side ef-fects, including tardive dyskinesia. Thus, the issue that is the subject of this article, balancing risk and benefit, is the main reason why clozapine was given any chance for approval in the U.S. The result was the U.S. Clozaril® study, intended to determine if clozapine was more effective in patients who had failed to respond to at least three other antipsychotic drugs. The clear superiority of clozapine over chlorproma-zine in a six-week trial, in the relatively small sample of 268 patients who were treatment resistant by history and failed to respond to haloperidol at doses ≥60 mg/day for up to six weeks, led to the approval of clozapine for use in treatment-resistant and neuroleptic-intolerant patients with weekly monitoring of the white blood cell count on an indefinite basis (11). Approval by the FDA led to its eventual approval in all Western countries, but it was not until 2009 that it was approved in Japan. Worldwide experience since its U.S. ap-proval has confirmed the greater efficacy of clozapine over not only typical but also other atypical antipsychotic drugs, at least at conventional doses in treatment-resistant pa-tients (12, 13). Clozapine is the recommended treatment for treatment-resistant schizophrenia by the Texas Medical Al-gorithm Project (14), the web-based International Psycho-

With the exception of supplemental ECT and, as will be discussed, high doses of other atypical

antipsychotic drugs, there is little disagreement that clozapine is the treatment of choice once a patient with schizophrenia or schizoaffective

disorder has failed two trials of adequate duration and dosage of other

antipsychotic drugs.

drugs such as olanzapine and risperidone, for treatment-re-sistant patients are: 1) the definition of treatment resistance, which includes which symptoms of schizophrenia are to be targeted; 2) the dose of clozapine to be used during a trial; and, 3) duration of the trial. The definition of treatment-resistant schizophrenia which is appropriate for consideration whether or not to be-gin a clozapine trial is: the subgroup of poor (or functionally impaired) outcome schizophrenia which has persistent posi-tive symptoms of at least moderate severity after two or more trials of other antipsychotic drugs, typical or atypical. Ap-proximately 30% of patients with schizophrenia meet these criteria for treatment resistance (12, 26). There is no evi-dence that this percentage has diminished since the substi-tution of atypical for typical antipsychotic drugs as first-line treatment, as these two classes of drugs are equal in efficacy for the treatment of positive symptoms in nontreatment-resistant patients and, at ordinary doses, the atypicals are no better than typical antipsychotic drugs in treatment-resistant patients (27, 28; see Meltzer [29] for further discussion). Not all schizophrenia patients with poor outcome have severe positive symptoms, and those that do not are not as likely to have a superior response to clozapine as those who do (have persistent positive symptoms). The proportion with poor outcome is estimated to be upwards of 50% (30). The causes of poor outcome in those with minimal to moderate positive symptoms, assuming they have been compliant with treatment, may be severe, persistent negative symptoms, cognitive impairment, substance abuse, inadequate psy-chosocial treatment and economic support, both of which may be exacerbated in difficult economic conditions such as those affecting the U.S. and other countries since 2008 (12). While clozapine may be more effective for negative symp-toms than other treatments, especially to the extent that the negative symptoms are secondary to positive symptoms and those positive symptoms respond to clozapine, the benefits to be expected in such patients and, hence, the efficacy-to-safety ratio, may be less than those with moderate-to-severe positive symptoms (11, 12, 31). Clozapine has been shown to have advantages over other atypical antipsychotic drugs for overall psychopathology, including general symptoms, in poor-outcome patients (32), but this effect is weaker than that for positive symptoms. Thus, it is the subset of poor outcome patients who have persistent moderate-to-severe positive symptoms, along with those who are highly suicidal, whether or not they have moderate-to-severe positive symp-toms, for which a trial of clozapine is most clearly justified. Dosage of clozapine in treatment-resistant patients with schizophrenia is usually between 300–600 mg/day (11, 12). Both lower and higher doses may be sufficient or necessary to achieve efficacy and tolerability. Nontreatment-resistant

patients usually respond at doses of 150–400 mg/day (see [29] for discussion). The latter corresponds to doses of ris-peridone of 4–6 mg/day and olanzapine 10–20 mg/day. There is some evidence that at higher doses of olanzapine (e.g., 25–45 mg/day or higher) positive symptoms in treat-ment-resistant patients with schizophrenia or schizoaf-fective disorder will respond as well as to higher doses of clozapine. At six months, both high-dose olanzapine and clozapine improved multiple measures of psychopathology with no significant difference between them, but the im-provement in Global Assessment of Functioning score was significantly greater with clozapine (p=0.01). There were no significant differences in motor side effects, but weight gain was significantly greater with high-dose olanzapine (p=0.05; [33]). There are few trials with higher doses of other atypical antipsychotic drugs to compare with clozapine in the higher dose range. We are currently engaged in a trial of long-acting risperidone at a dose of 100 mg/day in comparison with a 50 mg dose of the injectable risperidone. More such trials are needed with other atypical antipsychotic drugs to inves-tigate the possibility that clozapine is more effective than other atypicals because its low motor side effect profile per-sists throughout a very wide dose range. There is no question that high dosages of typical antipsychotic drugs do not im-prove their efficacy for treatment-resistant patients. A recent report showing that ziprasidone, at ordinary doses, showed comparable efficacy to clozapine in treatment-resistant pa-tients requires independent replication (34). Partly because the U.S. Clozaril trial (11) was of short duration—six weeks—and was sufficient to show advantage for clozapine over chlorpromazine, it has been assumed by some that this is a sufficient duration for all trials with clo-zapine. Other comparative studies have produced similar results (31, 35-38). However, there is considerable evidence that improvement in positive symptoms with clozapine for individual patients may require up to six months of treat-ment, and that some patients will show no advantage to clo-zapine during the first three months of treatment, or even longer, and yet have a marked response. Clozapine differs from typical antipsychotic drugs in this regard. The evidence for this comes from open trials (39, 40), retrospective studies (41), and the double-blind trial which compared clozapine and high-dose olanzapine previously mentioned (33). Sig-nificant improvement in measures such as relapse and social function, even after more prolonged treatment with clo-zapine, has been reported by Joffe et al. (41). A longer time period of a trial with clozapine does increase the risk for agranulocytosis, which peaks within the first six months, but given the limited treatment options for treatment-resistant patients it would appear that it is prudent to recommend the longer trial rather than failing to identify all or nearly all

Herbert Y. Meltzer


patients who are responders. However, others have sug-gested that trials of clozapine should last no more than 3–4 months (42, 43).

Suicide Reduction with Clozapine: Impact on Overall Mortality Suicide is the major contributor to premature death among patients with schizophrenia (44). Overall, approxi-mately 30–50% of patients with schizophrenia attempt sui-cide, while 5% actually die from suicide, a fivefold greater rate than the lifetime risk for suicide in the general popu-lation of the U.S. (45, 46). There is now extensive evidence of various types that clozapine markedly reduces suicidal behavior in patients with schizophrenia and schizoaffective disorder, regardless of treatment-resistance status. The first evidence for this effect of clozapine was a two-year mirror image study of 88 patients with treatment-resistant schizo-phrenia which showed an 85% decrease in attempts follow-ing switching to clozapine (19). An epidemiologic study of 67,000 cases of clozapine-treated patients in the U.S. between 1989 and 1996, adjusted for age, sex, and race, found that all-cause mortality was lower during the period of clozap-ine use than during nonuse. The longevity-enhancing effect of clozapine was mainly the result of a dramatic decrease in suicide in clozapine users (47). This was confirmed in a sub-sequent mirror image study from Europe (48). These studies could not rule out the possibility that more frequent clinic visits during clozapine treatment may have accounted for the advantage. To address this issue, a multicenter, random-ized, international, two-year follow-up study—the Interna-tional Suicide Prevention Trial (InterSePT)—was conducted to compare the risk for suicidal behavior in patients at high risk for suicide who were randomized to clozapine or olan-zapine (49). Patients randomized to clozapine attempted suicide significantly less than those in the olanzapine group (p=0.03). This led to clozapine being approved by the FDA

for the indication of suicide reduction but, as noted in the Introduction, this had no discernable impact on the use of clozapine for this purpose. Clearly, some knowledgeable physicians are making their patients aware of this treatment option, but many fewer than need to. A second major epidemiologic study confirmed that clozapine markedly reduces all-cause mortality compared to all other antipsychotic drugs and that a major contribut-ing factor is the reduction in death by suicide (50). Using national record-based data on medication prescription and deaths in 66,881 patients with a schizophrenia-related diag-nosis from 1996 to 2006, it was found that the lowest risk for overall mortality was present in patients treated with clo-zapine. Compared to the reference treatment, perphenazine, the risk was reduced 26% (relative risk=0.74, confidence interval=0.60 to 0.91, p=0.0045). Clozapine was superior to all other antipsychotic drugs in reducing death due to sui-cide as well (p<0.0001). The risk of death from suicide on clozapine, adjusted for risk factors, was 0.34, compared to 1.0 for perphenazine and 1.58 for quetiapine. No other drug had a lower risk for suicide than any other. As will be dis-cussed, there was no offsetting increase in mortality due to ischemic heart disease with clozapine. Tiihonen et al. (50) recommended a reconsideration of clozapine as a first-line treatment based upon their data and other available data supporting the efficacy of clozapine for reducing suicide. This conclusion was challenged by De Hert et al. (51) but none of the issues raised could possibly change the overall findings. For example, they raise the possibility that because the lower mortality rate was highly likely to be driven by the ability to reduce the risk for suicide, a conclusion they ac-cept, that there is a survivor bias in the overall mortality rate, on the assumption that patients early in their course made a suicide attempt and were prescribed clozapine and remained on it, noting that discontinuation from clozapine is less fre-quent than other drugs. However, there are no data available which indicate the proportion of patients who are treated with clozapine in Finland which is due to a prior suicide at-tempt. Treatment resistance would be much more common as a reason for prescribing clozapine. It can be estimated from the effects of clozapine on sui-cide attempts and the proportion of attempters who com-plete suicide that at least one-third of the approximately 5,000 patients per year with schizophrenia or schizoaffective disorder who commit suicide in the U.S. would not do so had they been treated with clozapine. This requires treat-ing survivors of serious previous suicide attempts with clo-zapine, and initiating clozapine treatment in those patients whose well known other risk factors indicate a high risk for suicide (e.g., hopelessness, substance abuse, family history of suicide and insight) (44).

It can be estimated from the effects of clozapine on suicide attempts and the

proportion of attempters who complete suicide that at least one-third of the

approximately 5,000 patients per year with schizophrenia or schizoaffective disorder

who commit suicide in the U.S. would not do so had they been treated with clozapine.



Clozapine Advantages in Cognition and Broad Outcome Measures Improvementinpositiveandnegativesymptoms,gen-eralpsychopathology,cognition,suicidality/mood,andfew-erextrapyramidalsideeffects(EPS)contributetoclozapinehavingbroaderadvantagesthatmostprobablyrepresenttheintegratedsumoftheseeffects.Theseincludeimprovementinworkandsocialfunction,qualityoflife,lowerrelapserateandrehospitalization.Muchofthisdependsuponimprove-ment in cognitive function. Clozapine has been reliablyshown to improve some domains of cognition in schizo-phrenia.Theseincludeverbalfluency,declarativememory,attention,andspeededmentalfunctions(20,52-54). Some have claimed that this is simply a practice ef-fect(55)orthattypicalantipsychoticdrugsareaseffective(56).Wehavefoundthatverbalfluencyin25%ofpatientstreatedwithclozapineimprovedatleastonestandarddevia-tion,whichisunlikelytobeapracticeeffect.Improvementofthismagnitudewasnotobservedinpatientstreatedwithtypical antipsychotic drugs (Meltzer and Sumiyoshi, to besubmitted).Aswithimprovement inpositivesymptoms, itmay take up to six months for improvement in cognitionto become evident and maximal (20). There is abundantevidenceforthefailureoftypicalantipsychoticdrugstoim-provecognition(seeMeltzerandMcGurk[22]forreview).The reasons for these discrepancies in views on clozapineandotheratypicalsoncognitiongobeyondthescopeofthisarticletodiscussindetail.Itisimportanttonotethatpre-clinicalstudiesoftheeffectsoftypicalandatypicaldrugsoncertain models of cognitive impairment, such as impairednovel object recognition due to subchronic phencyclidine(PCP) administration in rodents, have demonstrated thatatypicals can reverse the deficit due to PCP while typicalantipsychoticsareineffective(57).Theimportanceofcogni-tiveimprovementtofunctionaloutcomeinschizophreniaissufficientlywellestablishedtowarrantutilizingthepossiblebenefits conveyed by clozapine over typical antipsychoticdrugsintheconsiderationofwhetherornottotreatapa-tientwithit. Improvementinmeasuresofqualityoflifealsoreflectsadvantages of clozapine over typical antipsychotic drugs(58,59).IntheEuropeanSchizophreniaOutpatientsHealthOutcomes (EU-SOHO) study, a three-year observationalstudyofoutcomesassociatedwithantipsychotic treatmentforschizophrenia inanoutpatientsettinginvolvingatotalof9,340patients,olanzapineandclozapinewereassociatedwithimportanthealth-relatedqualityoflifebenefitsatend-point,mostofwhichoccurredduring thefirst sixmonths(60).Otherbroadoutcomemeasuresof clinical andphar-macoeconomic importance inwhichclozapine isadvanta-

geousincludetimetodiscontinuationandfewerhospitaliza-tions(38,58,61). Improvement in cognition and psychopathology intreatment-resistant patients after more prolonged treat-ment with clozapine can lead to functional improvementin30–50%ofpatients,which isacomponentofqualityoflife measures (41, 62-65). Functional improvement, whichincludes return to employment and continuing educationatanappropriatepremorbidlevel,hasbeenrelatedmoretoimprovementincognitionthantoimprovementinpositivesymptoms(64,65)andrequireslongerperiodsoftimeandpsychosocial support. Short-term trials with clozapine aregenerallyinsufficientindurationtoachievesignificantfunc-tionalimprovement(66).Clozapinecanfacilitateimprove-mentinsocialfunctionofpatientswithtreatment-resistantschizophrenia,particularlywhencombinedwithappropri-ate support from clinicians who can facilitate finding andkeepingjobsorreturningtoschool(62,63). Relapse requiring rehospitalization is another highlyrelevantclinicaloutcomeinschizophreniawhereclozapinehasbeenfoundtobesuperiortoothertreatments.Relapseprevention is easily shown to translate into cost effective-ness, reduced burden on relatives, and functional benefitstopatients.Anationwidecohortof2,230consecutiveadultshospitalizedinFinlandforthefirsttimebecauseofschizo-phreniaorschizoaffectivedisorderbetween1995and2001found that initial use of clozapine (adjusted relative risk0.17, 95% confidence interval 0.10 to 0.29), perphenazinedepot(0.24,0.13to0.47),andolanzapine(0.35,0.18to0.71)were associated with the lowest rates of discontinuationforanyreasonwhencomparedwithoralhaloperidol (67).During an average follow-up of 3.6 years, 4,640 cases ofrehospitalization were recorded. Current use of perphen-azine depot (0.32, 0.22 to 0.49), olanzapine (0.54, 0.41 to0.71),andclozapine(0.64,0.48to0.85)wereassociatedwiththelowestriskofrehospitalization(67).ACochranemeta-analysisofclozapinefoundfewerrelapsesinpatientstreatedwithclozapinethanthosetreatedwithtypicalantipsychoticdrugs(n=1,303,relativerisk0.62,confidenceinterval0.5to0.8 [31]).Wehavereportedan89.6%reduction inrelapseinaone-yearmirrorimagestudyin57treatment-resistantschizophreniapatientsintheU.S.(63).Similarbenefitswereobservedoverafive-yearperiodofclozapinetreatmentinalargeKoreancohort(68).Lowerrelapsewasalsonotedinahead-to-headcomparisonofrisperidoneandclozapine(69). In summary, the advantages of clozapine which haveemergedfromcontrolledclinicaltrialshavebeenborneoutinclinicalpracticeandintheoftenremarkableimprovementnotedinpatientswhohavefailedpreviousattemptsattreat-ment.

Herbert Y. Meltzer

Clinical Schizophrenia & Related PsychosesOctober2012•139

Evaluating the Risk of Clozapine

Agranulocytosis The risk of developing granulocytopenia or agranulocy-tosis during clozapine treatment is between 0.7–1.0% (70). Most cases occur between six weeks and six months. The chance in the second six months of treatment is 0.70/1,000 patient-years and, after the first year, 0.39/1,000 patient-years (71). Mandatory monitoring of white blood cells or neutrophils permits early detection of granulocytopenia and cessation of clozapine before full agranulocytosis occurs. As a result, very few cases of full agranulocytosis occur any more. Data from the U.S. clozapine registry covering the first five years of use showed that, with monitoring, there were 382 cases of agranulocytosis in 99,502 patients (0.38%) and 12 deaths (0.01%). If agranulocytosis occurs, treatment with granulocyte colony-stimulating factor is effective to restore normal white blood cell levels in most cases, before infec-tions develop. Treatment with antibiotics is usually effective in those cases, so the mortality due to agranulocytosis is in the range of 1/10,000. Given the mortality from other causes of patients with clozapine, and the limited choices open to patients who are treatment resistant or highly suicidal, it would seem to be a relatively easy decision to balance the benefits from clozapine against this small risk of fatality. According to Schulte, even with no monitoring of clozap-ine after six months, the mortality due to agranulocytosis is comparable to other drugs with no monitoring (e.g., mian-serin or phenylbutazone) and with life in general. While it is a real risk, it is not so great a risk that it overrides the benefit for those patients who respond poorly to other antipsychotic drugs. With appropriate monitoring, the rate of fatal agranu-locytosis should be in the range of 1 per 10,000 patients. This has to be compared with the reduced risk of suicide. Both the epidemiologic studies noted above demonstrate that mortality in schizophrenia is significantly less with clozap-

Between 4–8% of African Americans and people of Middle Eastern origin have

chronically low white blood cell counts (e.g., 2,500–3,500), with absolute neutrophil

counts of 1,300–1,700 (72). These individuals are not at any greater risk for

agranulocytosis than are those with typical white cell counts of 4,500–8,000.

ine than any other antipsychotic drug. Between 4–8% of Af-rican Americans and people of Middle Eastern origin have chronically low white blood cell counts (e.g., 2,500–3,500), with absolute neutrophil counts of 1,300–1,700 (72). These individuals are not at any greater risk for agranulocytosis than are those with typical white cell counts of 4,500–8,000. It is important not to deny such patients a trial of clozapine or to stop clozapine when it might be chanced upon by an-other clinician.

Metabolic Side Effects of Clozapine Clozapine and olanzapine are comparable to one anoth-er in risk of causing marked weight gain, glucose dysregula-tion leading in some cases to type II diabetes mellitus and diabetic ketoacidosis, and lipid increases (23, 73, 74). These metabolic changes result from insulin resistance (75). Afri-can Americans and Hispanic people may be at greater risk than Caucasians (22). Both olanzapine and clozapine are more likely to produce these changes than any other atypi-cal or typical antipsychotic drug and, for this reason, would be avoided compared to those which are atypical but which produce infrequent and mild insulin resistance (e.g., ziprasi-done and aripiprazole) (74). However, it is important to re-call that factors such as life style, including diet, and intrinsic vulnerability to metabolic problems present in schizophrenia may minimize the differences between clozapine and other antipsychotic treatments with regard to adverse metabolic consequences (76). For some patients who develop type II diabetes, it will be a particularly difficult decision to con-tinue clozapine as long-term renal, peripheral vascular, and ocular side effects may be such that patients will prefer not to risk their development. Those patients with the most adverse metabolic effects of clozapine should be counseled about the need for diet and exercise. However, an interesting feature of weight gain with clozapine is that weight gain with clo-zapine predicts clinical response (77, 78). Thus, because of increased efficacy, the decision to stop clozapine treatment may be more complicated. In addition, relapse following termination of clozapine treatment may be rapid and severe (79). Therefore, treatments to counteract the metabolic side effects of clozapine may be of particular interest. Metformin treatment has been found to be useful to reduce a wide range of the adverse metabolic effects of clozapine (80). There is extensive investigation of genetic markers for the risk for developing metabolic syndrome. It is possible that these will become sufficiently sensitive to allow identification of those patients most like to develop metabolic effects (81), and enable consideration of the value of the trial relative to this added risk or permitting some preventive actions such as diet and exercise.



Motor Side Effects and Tardive Dyskinesia Thedifferencebetweenclozapineandneurolepticdrugssuchashaloperidolandperphenazinewithregardtomotorsideeffectsinrodentsandhumanswasthebasisforthesec-ondstageintheevolutionofantipsychoticdrugtreatmentdiscussedintheIntroduction.AsnotedintheIntroduction,thehighprevalenceoftardivedyskinesiaintheU.S.inthe1980s(26),clearlytheresultofneurolepticdrugtreatment,ledtotherevivalofclozapineafterithadbeenbannedduetoitsriskforagranulocytosis.AccordingtoKaneetal.(26),tardive dyskinesia developed in about 5% of patients witheachyearofcumulativeneurolepticexposure.Theincidenceinolderindividualsismarkedlyhigher.Whilethishighratemayhavebeenduetothehighdosesthatwerecommoninthatera,thereisnoindicationthatlowerdosesofneurolep-ticswhengiven forprolongedperiodsproduceratescom-parable to theatypicalantipsychoticdrugs(82).Clozapineclearly has a lower likelihood to cause tardive dyskinesiathantypicalneurolepticsandisamongtheleastlikelyoftheatypicals to cause tardive dyskinesia (82). Thus, clozapineshould be considered for patients with severe tardive dys-kinesiaandgivenextraconsiderationasatreatmentinpa-tientswhoshowsignsofdevelopingtardivedyskinesiaandwho require continuingantipsychoticdrug treatment.Thelowermortalityratewithclozapine(50)plustheemergingtardivedyskinesiaprovidesmorerationaleforusingclozap-ineeveninnontreatmentresistantandnonsuicidalpatients. Themotorsideeffectsofneurolepticsareanestablishedfactor in noncompliance with antipsychotic drug treat-ment and relapse (83). The near complete absence of mo-tor side effects contributes to the low rate of discontinua-tion with clozapine. The desire to find other antipsychoticdrugswhichwereasfreeofmotorsideeffectsasclozapinebutdidnotcauseagranulocytosisorhavesomeoftheothersideeffectsspecifictoclozapine,suchashypersalivationandmajormotorseizure,stimulatedthedevelopmentofrisperi-done,olanzapine,quetiapine,andsubsequentatypicalanti-psychoticdrugs.Becausesomepatientswithclozapinehavespecialvulnerabilitytodevelopmotorsideeffects,veryrarecases of tardive dyskinesia and NMS have been reported.Long-termclozapineusageastheprimary,ifnotonly,anti-psychoticdrugisneededtoevaluateitsriskforcausingtar-divedyskinesia.AstudyfromChinaof101patientswhore-ceivedclozapineasaprimaryantipsychoticdrugsincetheirfirstepisode,withameanfollowupof12±6years,showedaprevalenceoftardivedyskinesiaof3.96%.Thetardivedyski-nesiawasmildandorolingualinnature(84). Clozapine is tolerable in patients who have had NMSfrompriorantipsychoticdrugsbutcanalsorarelybeapre-cipitating factor, usually in patients with concurrent treat-

mentwithmoodstabilizersorwithahistoryofNMSfromother drugs (85). The greater tolerability of clozapine inpatientswithParkinson’sdiseasewhorequireantipsychoticdrugtreatmentbecauseofthedevelopmentofpsychosisfol-lowingL-DOPAcomparedtoallotherantipsychotics,withtheexceptionofquetiapine,providesstrongevidencethatitandquetiapinehave the least likelihoodofcausing tardivedyskinesia of all antipsychotic drugs (86). It also can sup-presstardivedyskinesia(9,87).Otheratypicalantipsychot-icscandosoaswell,butclozapinemaybemoreeffectiveinsomepatients(82).Thus,forpatientswhoexperiencemotorsideeffectssufficientlyonotherantipsychoticdrugsthat itisafactorintheiradherencetotreatmentorleadstomotorside effects such as dystonias or NMS, clozapine’s benefitswouldjustifytheincreasedriskofagranulocytosis.

Clozapine and Cardiovascular Risk Clozapineisassociatedwithalow(0.015%to0.188%)riskofpotentiallyfatalmyocarditisorcardiomyopathy(88).A higher rate of suspected myocarditis (0.7% and 1.2%)wasidentifiedinAustralia.Theconditiondevelopedwithina median 17 days (mean 171.7 days, ±530.9 days) and 12(10.3%)died.Theoutcomewasunknownintherest.Clo-zapineisnotassociatedwithprolongationoftheQTcinter-valorsuddendeathduetotorsadesdepointes(89).

Optimizing the Benefits of Clozapine A few considerations on how best to administer clo-zapine will be mentioned here. The importance of initialtitration, dosage and adequate duration of treatment, andavoidance of additional add-on antipsychotic drugs untilmonotherapyhasbeen triedare importantgeneralprinci-ples.Itiscriticalattheoutsetoftreatmentwithclozapinetoeducatepatientsandsignificantothersastowhyatrialwithclozapine has been suggested, whether it be for treatmentresistance or suicide risk reduction, how evidence has ac-cumulatedthatfortherightpatientbenefitsoutweighrisks,howtheriskwillbeminimizedwithwhitebloodcellmoni-toring,whatwillhappenif thewhitecount fallsbelowthethresholds for granulocytopenia and agranulocytosis, andthewiderangeofannoyingsideeffects,includingsedation,

Thus, clozapine should be considered for patients with severe tardive dyskinesia and given extra consideration as a treatment in

patients who show signs of developing tardive dyskinesia and who require

continuing antipsychotic drug treatment.

Herbert Y. Meltzer

Clinical Schizophrenia & Related PsychosesOctober2012•141

hypersalivation, tachycardia, weight gain, lipid changes, myoclonic jerks and seizures. This group of side effects can generally be effectively managed, although the weight gain less so. They should rarely be the cause for discontinuation in patients who require clozapine because of treatment re-sistance or suicide. A discussion of reduction in any current extrapyramidal side effects and reduced risk of tardive dys-kinesia, the necessity for compliance and not stopping the medication in order to avoid a relapse, should also be part of this discussion. Achieving adequate plasma levels of clozapine (≥350 ng/ml), which may require periodic measurement at the early phase of treatment and utilization of doses up to 900 mg/day, will enhance the benefit-to-risk ratio. If the pa-tient is on another antipsychotic drug when clozapine is initiated, it should be discontinued shortly after adequate dosage has been achieved. Monotherapy trials should last for six months whenever possible. As discussed above, for some patients a second antipsychotic drug may sometimes be effective. There is controversy about the value of adding risperidone (90, 91). Some selective serotonin reuptake in-hibitors, including paroxetine and fluoxetine (but especially fluvoxamine), impair the metabolism of clozapine so that reducing the dose of clozapine is usually appropriate. Sertra-line and citalopram do not interfere with the metabolism of clozapine (92). Valproic acid may also increase plasma levels of clozapine, warranting reducing the dosage (92). Smoking leads to induction of cytochrome P450 CYP1A2 which will lead to lower plasma clozapine levels. Conversely, smoking cessation may markedly elevate clozapine plasma levels (93). Plasma levels of clozapine should be monitored for at least 3–6 months after smoking cessation and dosage adjustments made as needed. Patients receiving clozapine will need psy-chosocial treatment to maximize the benefits from the im-provement in psychosis, negative symptoms and cognitive impairment which may emerge in the months after starting clozapine. Family and group therapy, cognitive behavioral treatment, supportive employment, and activity therapy have all been used with considerable success to enhance im-provement with clozapine.

Conclusions Despite the risk of agranulocytosis, metabolic side ef-fects, and a variety of cardiovascular problems, including myocarditis, the specific advantages of clozapine with regard to efficacy can still make it a prudent choice for as many as 30–40% of patients with schizophrenia or schizoaffective disorder. The following advantages are well established: 1) superiority for positive symptoms in treatment-resistant patients; 2) lower risk for suicide; 3) lower risk for tardive dyskinesia and suppression of established tardive dyskine-

sia; 4) improvement in cognition contributing to better work and social function; 5) higher quality of life and longer time to discontinuation; and, 6) decreased relapse. On the other hand, there are serious risks: 1) agranulocytosis; 2) insulin resistance with increased risk of type II diabetes, weight gain, and various vascular complications; and, 3) myocar-ditis. There are also other unpleasant side effects, such as hypersalivation and increased risk of seizures. The results from the U.S. (47) and Finnish (50, 67) epidemiologic stud-ies suggest that none of the potentially life threatening risks, as managed in the “real world,” have enough of an impact to negate the advantages which come from clozapine. Whether this will remain true after even longer term use of clozap-ine cannot be known for sure. However, clozapine has been available for twenty years in the U.S. now, and there is no evi-dence that mortality in the clozapine patients who have been taking it for this extended period is increasing. The success of clozapine in terms of time to discontinuation and fewer relapses than almost any other drug suggests that once pa-tients get started on clozapine, their subjective experience is sufficiently favorable that they prefer it to other treatments.

Disclosures HY Meltzer has been a consultant or grantee of Sandoz, Novartis, Azur, Teva, ACADIA, BioLineRx, BioVail, Cepha-lon, Dainippon Sumitomo, Eli Lilly, EnVivo, Janssen, Merck, Pfizer, Roche, and Schering-Plough.

ReferencesHorvitz-Lennon M, Donohue JM, Domino ME, Normand SL. Improving quality and diffusing best practices: the case of schizophrenia. Health Aff (Millwood) 2009;28(3):701-712.

Healy D. The creation of psychopharmacology. Cambridge (MA); Harvard Uni-versity Press: 2004.

Tang YL, Mao PX, Jiang F, Chen Q, Wang CY, Cai ZJ, et al. Clozapine in China. Pharmacopsychiatry 2008;41(1):1-9.

Idänpään-Heikkilä J, Alhava E, Olkinuora M, Palva I. Clozapine and agranulocy-tosis. Lancet 1975;2(7935):611.

Idänpään-Heikkilä J, Alhava E, Olkinuora M, Palva IP. Agranulocytosis during treatment with clozapine. Eur J Clin Pharmacol 1977;11(3):193-198.

Amsler HA, Teerenhovi L, Barth E, Harjula K, Vuopio P. Agranulocytosis in pa-tients treated with clozapine. A study of the Finnish epidemic. Acta Psychiatr Scand 1977;56(4):241-248.

Ekblom B, Eriksson K, Lindström LH. Supersensitivity psychosis in schizo-phrenic patients after sudden clozapine withdrawal. Psychopharmacology (Berl) 1984;83(3):293-294.

Simpson GM, Lee JH, Shrivastava RK. Clozapine in tardive dyskinesia. Psycho-pharmacology (Berl) 1978;56(1):75-80.

Meltzer HY, Luchins DJ. Effect of clozapine in severe tardive dyskinesia: a case report. J Clin Psychopharmacol 1984;4(5):286-287.

Singer JM. Clozapine and tardive dyskinesia. Arch Gen Psychiatry 1983;40(3):347-348.

Kane J, Honigfeld G, Singer J, Meltzer H. Clozapine for the treatment-resistant schizophrenic. A double-blind comparison with chlorpromazine. Arch Gen Psy-chiatry 1988;45(9):789-796.

1.

2.

3.

4.

5.

6.

7.

8.

9.

10.

11.



Meltzer HY. Treatment-resistant schizophrenia--the role of clozapine. Curr Med Res Opin 1997;14(1):1-20.

Leucht S, Corves C, Arbter D, Engel RR, Li C, Davis JM. Second-generation versus first-generation antipsychotic drugs for schizophrenia: a meta-analysis. Lancet 2009;373(9657):31-41.

Moore TA, Buchanan RW, Buckley PF, Chiles JA, Conley RR, Crismon ML, et al. The Texas Medication Algorithm Project antipsychotic algorithm for schizo-phrenia: 2006 update. J Clin Psychiatry 2007;68(11):1751-1762.

Lehman AF, Kreyenbuhl J, Buchanan RW, Dickerson FB, Dixon LB, Goldberg R, et al. Schizophr Bull 2004;30(2):193-217.

Robinson DG, Woerner MG, Alvir JM, Geisler S, Koreen A, Sheitman B, et al. Predictors of treatment response from a first episode of schizophrenia or schizoaffective disorder. Am J Psychiatry 1999;156(4):544-549.

Meltzer HY, Lee M, Cola P. The evolution of treatment resistance: biological im-plications. J Clin Psychopharmacology 1998;18:5S-11S.

Lieberman JA, Sheitman B, Chakos M, Robinson D, Schooler N, Keith S. The development of treatment resistance in patients with schizophrenia: a clinical and pathophysiologic perspective. J Clin Psychopharmacol 1998;18(2 Suppl 1):20S-24S.

Meltzer HY, Okayli G. Reduction of suicidality during clozapine treatment of neuroleptic-resistant schizophrenia: impact on risk-benefit assessment. Am J Psychiatry 1995;152(2):183-190.

Hagger C, Buckley P, Kenny JT, Friedman L, Ubogy D, Meltzer HY. Improve-ment in cognitive functions and psychiatric symptoms in treatment-refractory schizophrenic patients receiving clozapine. Biol Psychiatry 1993;34(10):702-712.

Scholz E, Dichgans J. Treatment of drug-induced exogenous psychosis in par-kinsonism with clozapine and fluperlapine. Eur Arch Psychiatry Neurol Sci 1985;235(1):60-64.

Henderson DC. Clozapine: diabetes mellitus, weight gain, and lipid abnormali-ties. J Clin Psychiatry 2001;62(Suppl 23):39-44.

Allison DB, Mentore JL, Heo M, Chandler LP, Cappelleri JC, Infante MC, et al. Antipsychotic-induced weight gain: a comprehensive research synthesis. Am J Psychiatry 1999; 156(11):1686-1696.

Kilian JG, Kerr K, Lawrence C, Celermajer DS. Myocarditis and cardiomyopathy associated with clozapine. Lancet 1999;354(9193):1841-1845.

La Grenade L, Graham D, Trontell A. Myocarditis and cardiomyopathy associ-ated with clozapine use in the United States. N Engl J Med 2001;345(3):224-225.

Kane JM, Woerner M, Lieberman J. Epidemiological aspects of tardive dyskine-sia. Encephale 1988;14 Spec No:191-194.

Lee MA, Thompson P, Meltzer HY. Effects of clozapine on cognitive function in schizophrenia. J Clin Psychiatry 1994;55:82-87.

Lieberman JA, Stroup TS, McEvoy JP, Swartz MS, Rosenheck RA, Perkins DO, et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med 2005;353(12):1209-1223.

Meltzer HY, Bobo WV, Lee MA, Cola P, Jayathilake K. A randomized trial comparing clozapine and typical neuroleptic drugs in non-treatment-resistant schizophrenia. Psychiatry Res 2010;177(3):286-293.

Hegarty JD, Baldessarini RJ, Tohen M, Waternaux C, Oepen G. One hundred years of schizophrenia: a meta-analysis of the outcome literature. Am J Psychia-try 1994;151(10):1409-1416.

Essali A, Al-Haj Haasan N, Li C, Rathbone J. Clozapine versus typical neuroleptic medication for schizophrenia. Cochrane Database Syst Rev 2009;(1):CD000059.

Lewis SW, Barnes TR, Davies L, Murray RM, Dunn G, Hayhurst KP, et al. Ran-domized controlled trial of effect of prescription of clozapine versus other sec-ond-generation antipsychotic drugs in resistant schizophrenia. Schizophr Bull 2006;32(4):715-723.

Meltzer HY, Bobo WV, Roy A, Jayathilake K, Chen Y, Ertugrul A, et al. A randomized, double-blind comparison of clozapine and high-dose olan-zapine in treatment-resistant patients with schizophrenia. J Clin Psychiatry 2008;69(2):274-285.

Sacchetti E, Galluzzo A, Valsecchi P, Romeo F, Gorini B, Warrington L; INITI-ATE Study Group. Ziprasidone vs clozapine in schizophrenia patients refrac-

tory to multiple antipsychotic treatments: the MOZART study. Schizophr Res 2009;110(1-3):80-89.

Buchanan RW, Breier A, Kirkpatrick B, Ball P, Carpenter WT Jr. Positive and negative symptom response to clozapine in schizophrenic patients with and without the deficit syndrome. Am J Psychiatry 1998;155:751-760.

Breier AF, Malhotra AK, Su TP, Pinals DA, Elman I, Adler CM, et al. Clozapine and risperidone in chronic schizophrenia: effects on symptoms, parkinsonian side effects, and neuroendocrine response. Am J Psychiatry 1999;156(2):294-298.

Volavka J, Czobor P, Sheitman B, Lindenmayer JP, Citrome L, McEvoy JP, et al. Clozapine, olanzapine, risperidone, and haloperidol in the treatment of pa-tients with chronic schizophrenia and schizoaffective disorder. Am J Psychiatry 2002;159(2):255-262.

McEvoy JP, Lieberman JA, Stroup TS, Davis SM, Meltzer HY, Rosenheck RA, et al.; CATIE Investigators. Effectiveness of clozapine versus olanzapine, quetiap-ine, and risperidone in patients with chronic schizophrenia who did not respond to prior atypical antipsychotic treatment. Am J Psychiatry 2006;163(4):600-610.

Meltzer HY, Matsubara S, Lee JC. Classification of typical and atypical antipsy-chotic drugs on the basis of dopamine D1, D2, and serotonin2 pKi values. J Phar-macol Exp Ther 1989;251:238-246.

Lieberman JA, Kane JM, Johns CA. Clozapine: guidelines for clinical manage-ment. J Clin Psychiatry 1989;50(9):329-338.

Joffe G, Venäläinen E, Tupala J, Hiltunen O, Wahlbeck K, Gädeke R, et al. The ef-fect of clozapine on the course of illness in chronic schizophrenia: focus on treat-ment outcome in out-patients. Int Clin Psychopharmacol 1996;11(4):265-272.

Safferman A, Lieberman JA, Kane JM, Szymanski S, Kinon B. Update on the clinical efficacy and side effects of clozapine. Schizophr Bull 1991;17(2):247-261.

Carpenter WT Jr, Conley RR, Buchanan RW, Breier A, Tamminga CA. Patient response and resource management: another view of clozapine treatment of schizophrenia. Am J Psychiatry 1995;152(6):827-832.

Meltzer HY. Suicide in schizophrenia, clozapine and adoption of evidence-based medicine. J Clin Psychiatry 2005;66:530-533.

Asnis GM, Friedman TA, Sanderson WC, Kaplan ML, van Praag HM, Harkavy-Friedman JM. Suicidal behaviors in adult psychiatric outpatients, I: Description and prevalence. Am J Psychiatry 1993;150(1):108-112.

Palmer BA, Pankratz VS, Bostwick JM. The lifetime risk of suicide in schizophre-nia: a reexamination. Arch Gen Psychiatry 2005;62(3):247-253.

Walker AM, Lanza LL, Arellano F, Rothman KJ. Mortality in current and former users of clozapine. Epidemiology 1997;8(6):671-677.

Modestin J, Dal Pian D, Agarwalla P. Clozapine diminishes suicidal behavior. J Clin Psychiatry 2005;66(4):534-538.

Meltzer HY, Alphs L, Green AI, Altamura AC, Anand R, Bertoldi A, et al.; Inter-national Suicide Prevention Trial Study Group. Clozapine treatment for suicidal-ity in schizophrenia: International Suicide Prevention Trial (InterSePT). Arch Gen Psychiatry 2003;60(1):82-91

Tiihonen J, Lönnqvist J, Wahlbeck K, Klaukka T, Niskanen L, Tanskanen A, et al. 11-year follow-up of mortality in patients with schizophrenia: a population-based cohort study (FIN11 study). Lancet 2009;374(9690):620-627.

De Hert M, Correll CU, Cohen D. Do antipsychotic medications reduce or increase mortality in schizophrenia? A critical appraisal of the FIN-11 study. Schizophr Res 2010;117(1):68-74.

Meltzer HY, McGurk SR. The effect of clozapine, risperidone and olanzapine on cognitive function in schizophrenia. Schizophr Bull 1999;25:233-255.

McGurk SR. The effects of clozapine on cognitive functioning in schizophrenia. J Clin Psychiatry 1999;60(Suppl 12):24-29.

Woodward ND, Purdon SE, Meltzer HY, Zald DH. A meta-analysis of neuro-psychological change to clozapine, olanzapine, quetiapine, and risperidone in schizophrenia. Int J Neuropsychopharm 2005;8:457-472.

Goldberg TE, Keefe RS, Goldman RS, Robinson DG, Harvey PD. Circumstances under which practice does not make perfect: a review of the practice effect litera-ture in schizophrenia and its relevance to clinical treatment studies. Neuropsy-chopharmacology 2010;35(5):1053-1062.

Keefe RSE, Bilder RM, Davis SM, Harvey PD, Palmer BW, Gold JM, et al.; for the

12.

13.

14.

15.

16.

17.

18.

19.

20.

21.

22.

23.

24.

25.

26.

27.

28.

29.

30.

31.

32.

33.

34.

35.

36.

37.

38.

39.

40.

41.

42.

43.

44.

45.

46.

47.

48.

49.

50.

51.

52.

53.

54.

55.

56.

Herbert Y. Meltzer


CATIE investigators and the neurocognitive working group. Neurocognitive effects of antipsychotic medications in patients with chronic schizophrenia in the CATIE trial. Arch Gen Psychiatry 2007;64:633-647.

Snigdha S, Horiguchi M, Huang M, Li Z, Shahid M, Neill JC, et al. Attenu-ation of phencyclidine-induced object recognition deficits by the combi-nation of atypical antipsychotic drugs and pimavanserin (ACP 103), a 5-hydroxytryptamine(2A) receptor inverse agonist. J Pharm Exp Thera 2010;332(2):622-631.

Meltzer HY, Burnett S, Bastani B, Ramirez LF. Effect of six months of clozapine treatment on the quality of life of chronic schizophrenic patients. Hosp Comm Psychiatry 1990;41:892-897.

Meltzer, HY. Quality of life in schizophrenia: importance for psychopharma-cology research and practice. Quality of Life Newsletter 1994;9:8-9.

Alonso J, Croudace T, Brown J, Gasquet I, Knapp MR, Suárez D, et al. Health-related quality of life (HRQL) and continuous antipsychotic treatment: 3-year results from the Schizophrenia Health Outcomes (SOHO) study. Value Health 2009;12(4):536-543.

Rosenheck R, Cramer J, Xu W, Thomas J, Henderson W, Frisman L, et al. A comparison of clozapine and haloperidol in hospitalized patients with refrac-tory schizophrenia. Department of Veterans Affairs Cooperative Study Group on Clozapine in Refractory Schizophrenia. N Engl J Med 1997;337(12):809-815.

Lindström LH. The effect of long-term treatment with clozapine in schizophre-nia: a retrospective study in 96 patients treated with clozapine for up to 13 years. Acta Psychiatr Scand 1988;77(5):524-529.

Meltzer HY, Alphs LD, Bastani B, Ramirez LF, Kwon K. Clinical efficacy of clo-zapine in the treatment of schizophrenia. Pharmacopsychiatry 1991;24(2):44-45.

Manschreck TC, Redmond DA, Candela SF, Maher BA. Effects of clozapine on psychiatric symptoms, cognition, and functional outcome in schizophrenia. J Neuropsychiatry Clin Neurosci 1999;11(4):481-489.

Kaneda Y, Jayathilak K, Meltzer HY. Determinants of work outcome in schizo-phrenia and schizoaffective disorder: role of cognitive function. Psychiatry Res 2009;169(2):178-179.

Wahlbeck K, Cheine M, Essali A, Adams C. Evidence of clozapine’s effective-ness in schizophrenia: a systematic review and meta-analysis of randomized trials. Am J Psychiatry 1999;156(7):990-999.

Tiihonen J, Wahlbeck K, Lönnqvist J, Klaukka T, Ioannidis JP, Volavka J, et al. Effectiveness of antipsychotic treatments in a nationwide cohort of patients in community care after first hospitalisation due to schizophrenia and schizoaf-fective disorder: observational follow up. BMJ 2006;333(7561):224-227.

Ahn YM, Chang JS, Kim Y, Lee KY, Kim JH, Kim SC, et al. Reduction in hospi-tal stay of chronic schizophrenic patients after long-term clozapine treatment. Int Clin Psychopharmacol 2005;20(3):157-161.

Conley RR, Love RC, Kelly DL, Bartko JJ. Rehospitalization rates of patients recently discharged on a regimen of risperidone or clozapine. Am J Psychiatry 1999;156(6):863-868.

Honigfeld G, Arellano F, Sethi J, Bianchini A, Schein J. Reducing clozapine-re-lated morbidity and mortality: 5 years of experience with the Clozaril National Registry. J Clin Psychiatry 1998;59(Suppl 3):3-7.

Schulte PF. Risk of clozapine-associated agranulocytosis and mandatory white blood cell monitoring. Ann Pharmacother 2006;40(4):683-688.

Kelly DL, Kreyenbuhl J, Dixon L, Love RC, Medoff D, Conley RR. Clozapine underutilization and discontinuation in African Americans due to leucopenia. Schizophr Bull 2007;33(5):1221-1224.

Liebzeit KA, Markowitz JS, Caley CF. New onset diabetes and atypical antipsy-chotics. Eur Neuropsychopharmacol 2001;11(1):25-32.

Meyer JM, Koro CE. The effects of antipsychotic therapy on serum lipids: a

comprehensive review. Schizophr Res 2004;70(1):1-17.Avram AM, Patel V, Taylor HC, Kirwan JP, Kalhan S. Euglycemic clamp study in clozapine-induced diabetic ketoacidosis. Ann Pharmacother 2001;35(11):1381-1387.

Lund BC, Perry PJ, Brooks JM, Arndt S. Euglycemic clamp study in clozap-ine-induced diabetic ketoacidosis. Clozapine use in patients with schizo-phrenia and the risk of diabetes, hyperlipidemia, and hypertension: a claims-based approach. Arch Gen Psychiatry 2001;58(12):1172-1176.

Leadbetter R, Shutty M, Pavalonis D, Vieweg V, Higgins P, Downs M. Clozap-ine-induced weight gain: prevalence and clinical relevance. Am J Psychiatry 1992;149(1):68-72.

Meltzer HY, Perry E, Jayathilake K. Clozapine-induced weight gain predicts improvement in psychopathology. Schizophr Res 2003;59:19-27.

Meltzer HY, Lee MA, Ranjan R, Mason ED, Cola PA. Relapse following clo-zapine withdrawal: effect of cyproheptadine plus neuroleptic. Psychophar-macology 1996;124:176-187.

Carrizo E, Fernández V, Connell L, Sandia I, Prieto D, Mogollón J, et al. Ex-tended release metformin for metabolic control assistance during prolonged clozapine administration: a 14- week, double-blind, parallel-group, placebo-controlled study. Schizophr Res 2009;113(1):19-26.

Mulder H, Cohen D, Scheffer H, Gispen-de Wied C, Arends J, Wilmink FW, et al. HTR2C gene polymorphisms and the metabolic syndrome in patients with schizophrenia: a replication study. J Clin Psychopharmacol 2009;29(1):16-20.

Margolese HC, Chouinard G, Kolivakis TT, Beauclair L, Miller R, Annable L. Tardive dyskinesia in the era of typical and atypical antipsychotics. Part 2: Incidence and management strategies in patients with schizophrenia. Can J Psychiatry 2005;50:703-714.

Lambert M, Conus P, Eide P, Mass R, Karow A, Moritz S, et al. Impact of present and past antipsychotic side effects on attitude toward typical antipsy-chotic treatment and adherence. Eur Psychiatry 2004;19(7):415-422.

Li CR, Chung YC, Park TW, Yang JC, Kim KW, Lee KH, et al. Clozapine-in-duced tardive dyskinesia in schizophrenic patients taking clozapine as a first-line antipsychotic drug. World J Biol Psychiatry 2009;10(4 Pt 3):919-924.

Miller DD, Sharafuddin MJ, Kathol RG. A case of clozapine-induced neuro-leptic malignant syndrome. J Clin Psychiatry 1991;52(3):99-101.

Fernandez HH, Trieschmann ME, Friedman JH. Treatment of psychosis in Parkinson’s disease: safety considerations. Drug Saf 2003;26(9):643-659.

Small JG, Milstein V, Marhenke JD, Hall DD, Kellams JJ. Treatment outcome with clozapine in tardive dyskinesia, neuroleptic sensitivity, and treatment-resistant psychosis. J Clin Psychiatry 1987;48(7):263-267.

Merrill DB, Dec GW, Goff DC. Adverse cardiac effects associated with clo-zapine. J Clin Psychopharmacol 2005;25(1):32-41.

Warner B, Hoffmann P. Investigation of the potential of clozapine to cause torsade de pointes. Adverse Drug React Toxicol Rev 2002;21(4):189-203.

Yağcioğlu AEA, Akdede BBK, Turgut TI, Tümüklü M, Kâzim Y, Alptekin K, et al. A double-blind controlled study adjunctive treatment with risperidone in schizophrenic patients partially responsive to clozapine: efficacy and safe-ty. J Clin Psychiatry 2005;66:63-72.

Weiner E, Conley RR, Ball MP, Feldman S, Gold JM, Kelly DL, et al. Adjunc-tive risperidone for partially responsive people with schizophrenia treated with clozapine. Neuropsychopharmacology 2010;35(11):2274-2283.

Urichuk L, Prior TI, Dursun S, Baker G. Metabolism of atypical antipsychot-ics: involvement of cytochrome p450 enzymes and relevance for drug-drug interactions. Curr Drug Metab 2008;9(5):410-418.

Cormac I, Brown A, Creasey S, Ferriter M, Huckstep B. A retrospective evaluation of the impact of total smoking cessation on psychiatric inpatients taking clozapine. Acta Psychiatr Scand 2010;121(5):393-397.

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