Clozapine Utilization Research Articles

Clozapine: a review of clinical practice guidelines and prescribing trends.

BackgroundClozapine effectiveness in the treatment of refractory schizophrenia has been sustained by published evidence in the last two decades, despite the introduction of safer options.DiscussionCurrent clinical practice guidelines have strongly recommended the use of clozapine in treatment-resistant schizophrenia, but prescribing trends do not appear to have followed such recommendations. Clozapine is still underutilized especially in patients at risk of suicide. It seems that physicians are hesitant in prescribing clozapine due to concerns about serious adverse effects. Recent reports have highlighted the need to inform health professionals about the benefits of treating patients with clozapine and have voiced concerns about the underutilization of clozapine especially in patients at risk of suicide.SummaryGuidelines and prescribing patterns reported in various countries worldwide are discussed. Suggestions on how to optimize clozapine utilization have been published but more efforts are needed to properly inform and support prescribers’ practices.

Antipsychotic Prescribing Pathways, Polypharmacy, and Clozapine Use in Treatment of Schizophrenia

To ensure optimal care for patients with schizophrenia, antipsychotic medications must be appropriately prescribed and used. Therefore, the primary objectives of this study were to identify and describe pathways for antipsychotic prescribing, assess the consistency of observed pathways with treatment guidelines, and describe variability across facilities. Data from Veterans Affairs administrative data sets from fiscal year (FY) 2003 to FY 2007 were gathered for analysis in this retrospective cohort study of antipsychotic prescribing pathways among 13 facilities across two regional networks. Patients with a new episode of care for schizophrenia or schizoaffective disorder in FY 2005 were identified, and antipsychotic prescribing history was obtained for two years before and after the index diagnosis. Demographic characteristics and distribution of comorbidities were assessed. Median medical center rates of polypharmacy were calculated and compared with Fisher's exact test. Of 1,923 patients with a new episode of schizophrenia care, 1,003 (52%) had complete data on prescribing pathways. A majority (74%) of patients were prescribed antipsychotic monotherapy, and 19% received antipsychotic polypharmacy. Of patients receiving antipsychotic polypharmacy, 65% began polypharmacy within 90 days of starting any antipsychotic treatment. There was a fourfold difference in polypharmacy across facilities. Antipsychotic polypharmacy was not associated with geographic location or medical center patient volume. Clozapine utilization was low (0%-2%). Retrospective examination of longitudinal prescribing patterns identified multiple antipsychotic prescribing pathways. Although most patients received guideline-concordant care, antipsychotic polypharmacy was commonly used as initial treatment, and there was substantial variability among facilities. Study findings suggest the utility of secondary data to assess treatment adaptation or switching for practical clinical trials.

Clozapine is underutilized.

I read the piece by Wang and Li[1] with great interest. The issues surrounding the use of clozapine in China and the United States provide an interesting contrast. Wang and Li suggest that clozapine is over-utilized in China both as a first-line treatment and (in low doses) to augment other antipsychotic agents. The situation in the United States is that clozapine is grossly underutilized as a treatment for patients with refractory schizophrenia and clinically significant suicidality. Despite the evidence that 25-40% of patients with schizophrenia would be candidates for clozapine based on labeled indications, approximately 5% of patients with schizophrenia are receiving it. Clozapine was approved by the Food and Drug Administration in the United States in 1989 following a large-scale clinical trial we conducted in 1988[2] demonstrating clozapine's superiority over chlorpromazine in carefully selected treatment refractory patients who had undergone a prospective trial of high dose haloperidol in order to confirm their lack of response. Over the subsequent two decades clozapine's superiority has been confirmed in several government-funded studies.[3]–[5] Despite the introduction of other so called ‘atypical’ or second generation antipsychotics, no other compound—even those with similar chemical structures—has consistently replicated clozapine's effects. Although clozapine has been shown to be superior in patients who have failed on other medications, there is no evidence that clozapine is superior as a first-line medication. At the same time, however, it is possible that waiting until a patient fails adequate trials of three different medications is too conservative an approach; these patients may be waiting too long to try an effective treatment. Unfortunately, there is insufficient research to establish the optimum point in an individual's treatment history to introduce clozapine. It is certainly possible that the introduction of clozapine after one fully adequate failed trial of an antipsychotic medication (with confirmed adherence and therapeutic blood levels) would be sufficient. If this proved true it would be particularly valuable in the first episode of illness or in the first years after onset of illness as it would increase the likelihood of a timely treatment response. Clozapine's use has been somewhat constrained by the requirement for weekly blood monitoring in order to detect the presence of agranulocytosis. The risk of true agranulocytosis appears to have declined since the early years of clozapine use, and new methods for managing this condition has reduced fatality rates enormously. Nevertheless, the management of clozapine's side effects continues to be a challenge. Though progress is being made in identifying individuals at high risk for agranulocytosis[6] this still remains an obstacle for some physicians and patients. The risk of metabolic side effects is also very real and needs to be considered in any management plan. The appropriate or optimum dosing of clozapine also remains a challenge. Dosage patterns vary considerably from country to country. Though some studies provide guidance regarding therapeutic blood levels it is likely that there are ethnic differences in these relationships as well. Clearly, as suggested by Wang and Li,[1] more research is necessary to achieve the goals of personalized medicine in the use of a drug like clozapine, where both the potential rewards and risks are higher than usual. Some clinicians and policy makers attribute the underutilization of clozapine to its side effect profile and, therefore, patient resistance to its use. However, it is often the case that physicians project their own concerns about the possible serious side effects of clozapine onto patients and make assumptions about patients' desires without an appropriate process of shared decision-making. Moreover, many physicians in the United States and in China appear more comfortable with antipsychotic drug polypharmacy than with clozapine monotherapy, despite the fact that polypharmacy has not been adequately established as an appropriate strategy for the treatment of refractory patients. The fact that clozapine utilization varies as much as it does from country to country underscores the variety of factors that contribute to its use. Many clinicians are inadequately informed about the evidence base for the use of clozapine and about the strategies necessary for managing its potential adverse effects. Further training about clozapine is necessary. But there is also a need for research on implementation. How can the field of psychiatry better succeed at promulgating the use of evidence-based practices?

A user’ guide to clozapine

In this issue of Acta Psychiatrica Scandinavica, Jimmi Nielsen et al. (1) provide a timely guide to optimizing clozapine treatment for the practicing psychiatrist. The review provides a summary of treatment recommendations as well as relevant strategies to reduce side effects and increase the likelihood of response. At the same time the authors emphasize the need to personalize treatment and engage in shared decision-making with the patient. The decision to use clozapine is not made lightly by either patient or physician, and it is particularly important that once this step is taken that everything possible be done to maximize the likelihood of its success. For the vast majority of appropriate patients it is their last hope for the kind of improvement that they and their loved ones hope for. Despite important advances in genetics and neuroscience the treatment of schizophrenia continues to rely very heavily on the use of antipsychotic drugs, hopefully combined with an appropriate array of psychosocial and vocational therapies. After a concerted effort on the part of the pharmaceutical industry drawing on years of basic research in industry and academia we are still relying on a paradigm that was developed decades ago. Clozapine remains the most efficacious antipsychotic drug when other medications produce partial or no response (2). It has also proven to be of value in reducing suicidality and aggressive behavior. Yet it is sobering to realize that clozapine was developed almost half a century ago. A number of so-called ‘atypical’ or second-generation antipsychotics were developed and modeled to some extent on what were thought to be neurochemical mechanisms which might account for clozapine’s unique properties. However, none of these medications have succeeded in replicating clozapine’s unique profile. Given this, it is imperative that we take full potential advantage of clozapine for the large population of patients who might benefit from it. Toward that end having a comprehensive understanding of how to best use clozapine is critical. Unfortunately, clozapine remains strikingly underutilized in many clinical settings across a broad range of countries around world. This has been particularly striking in the US. To some extent over the past fifteen years the introduction of other second-generation drugs gave practitioners some hope that alternatives which were easier to use might be equally efficacious. Unfortunately, that has not proven to be the case. Yet, many practitioners still do not turn to clozapine when they should. Hopefully, the availability of systematic reviews such as Nielsen’s will help by providing a readily, available resource for the busy clinician. At the same time, the review highlights areas where data are lacking and should help to stimulate further research to address unanswered questions. Examples of such questions would include: should clozapine be introduced after only one, or at most two, well-documented failures, rather than three; are there better predictors (e.g. pharmacogenetic, proteomic, neuroimaging) for who is most likely to benefit from a trial of clozapine and who is most likely to suffer from serious adverse effects; what strategies should be employed when clozapine fails; are there adjunctive pharmacotherapeutic strategies to enhance clozapine’s overall effectiveness. Although most treatment guidelines suggest that clozapine should be the preferred medication after inadequate response to two or three trials of antipsychotics Taylor et al. (3) found that patients who had been treated with clozapine had received an average of over five adequate trials (defined as treatment for at least 6 weeks with what would be considered a therapeutic dose). They also reported that the utilization of clozapine was delayed for an average of 5 years longer than should have been the case if the guidelines had been followed. Many clinicians site the inconvenience of the required blood monitoring due to the risk of agranulocytosis. Hodge and Jespersen (4) examined whether this posed as great a problem for patients as doctors thought it would. They reported that 19% of patients indicated that they felt inconvenienced by the blood monitoring, while in contrast 52% of the clinicians felt that their patients would be inconvenienced. There is no question that clozapine presents special challenges. It is associated with a significantly higher risk of agranulocytosis than other drugs and the risk of metabolic complications is also very high. There are other side effects as well. However, if an adequate therapeutic trial is given then an assessment can be made regarding benefits and risks. Until we and the patient have the opportunity to see how much benefit actually results from clozapine, it is difficult to make a personalized decision. One of the most important questions that remains for us is what can we do to increase the appropriate utilization of this treatment. The biggest obstacle appears not to be patient refusal, but physician reluctance. It is hoped that the work of Nielsen and others will help to remedy this situation.

Treatment dilemma in comorbidity of schizophrenia and idiopathic Parkinson's disease

Extrapyramidal symptoms are frequently found in patients with schizophrenia. Most are attributed as drug-induced parkinsonism, but comorbidity of idiopathic Parkinson's disease is also possible. We report a 59-year-old male with a diagnosis of schizophrenia for 32 years. Progressive hand tremor was noted from age 53; and then masked face, bradykinesia, dysphagia, sialorrhea; and unsteady shuffling gait became markedly exacerbated, even after discontinuing all antipsychotics for 6 months. The diagnosis of idiopathic Parkinson's disease was confirmed by Tc99m TRODAT SPECT. The dilemma of psychopharmacological treatment to control both disorders was encountered. Based on the review of treatment for Parkinson's disease psychosis (PDP), the recommended treatments suggest the utilization of quetiapine, clozapine, or aripiprazole. However, monotherapy with each of the three atypical antipsychotics failed due to poor efficacy or worsening of parkinsonism symptoms. After a 2-month cautious titration, a combination of quetiapine 50 mg/day and clozapine 37.5 mg/day finally achieved satisfactory efficacy. This case report illustrates the dilemma of treating a patient with schizophrenia and comorbid idiopathic Parkinson's disease, which differed from PDP and required more clinical data for a proper treatment recommendation.

Clozapine: A friend estranged?

Sir, Fact one: clozapine has proven superiority in partial or non-responsive schizophrenia and is the only evidence-based medication for treatment resistant schizophrenia.[1] Fact two: the incidence of the most feared side effect – Agranulocytosis, is as low as 0.38% and falls to 0.08% after 1 year of treatment.[2] Fact three: Clozapine has been shown to reduce suicidal behavior in comparison with Olanzapine.[3] Fact four: Only 14% of all patients who deserve clozapine are prescribed clozapine.[4] In the face of these facts, the continuing under utilization of clozapine is difficult to explain and numerous patients undergo multiple trials of other antipsychotics and live more than a decade with disability before clozapine is considered. One, therefore, needs to look beyond drug and response characteristics to make sense of these inconsistencies. The attitude of psychiatrists toward clozapine may be of special relevance. A recent study on the attitudes of practicing psychiatrists towards clozapine[5] brings up surprising results with 64% psychiatrists opting to combine two antipsychotics rather than opt for clozapine, in spite of several treatment guidelines clearly recommending otherwise. Clozapine's use obviously mandates strict blood monitoring, and is accompanied by side effects quite unique to this drug, which may perhaps be seen as barriers against its more frequent use by psychiatrists. Alongside, there is perhaps an element of therapeutic nihilism that creeps in if clozapine is viewed as the last resort medication-the proverbial panic button. However, an interesting study comparing the attitudes of patients and prescribers toward clozapine[6] revealed that patients were happier and more satisfied with clozapine and were less troubled by the repeated blood tests and side effects than their prescribers believed them to be. A recent article[2] elegantly investigated clozapine's current status and if it can be promoted to become a second line medication for schizophrenia. The authors recommend that clozapine should be considered at the same stage as other atypical antipsychotics, and not as a “special” drug for resistant cases. A necessary prerequisite for that to happen would be the removal of the associated misperceptions with clozapine and a gradual and thorough ‘demystification’ of the drug, so that clinicians would be much more comfortable using it. The risk of agranulocytosis though real, needs to be put in perspective. Carbamazepine, another commonly used drug in patients with psychiatric disorders, has a 1-2% risk of life-threatening hematological complications like aplastic anemia and agranulocytosis. Thus, studies are needed to explore the role of clozapine as a second line agent vis-a-vis other antipsychotics to guide rational and effective use of all available antipsychotics. Schizophrenia is a difficult condition to manage, its natural course pockmarked with multiple relapses, incomplete recovery and limited therapeutic options. It would perhaps do us good not to estrange the occasional friend we chance upon.

Utilization and Costs of Antipsychotic Agents: A Canadian Population-Based Study, 1996–2006

This study evaluated the prescribing patterns and costs for antipsychotic agents in the population of the Canadian province of Manitoba over the past decade. A population-based study of antipsychotic utilization and costs was conducted on data collected from the administrative databases of the Manitoba Population Health Data Repository and the Statistics Canada census between index years 1996 and 2006 (April 1, 1995, through March 31, 2006). The total annual number of antipsychotic prescriptions dispensed in Manitoba increased by 227% between 1996 and 2006, and the prevalence of antipsychotic users increased by 62% over the same time interval. The fastest-growing segment of antipsychotic users in Manitoba appears to be young males, who increased from .16% in 1996 to .88% in 2006. The highest numbers of prescriptions were reported for schizophrenia, dementia, and conduct disorder. Annual expenditures for antipsychotics increased from $1.7 million in 1996 to $22.0 million in 2006 (expenditures are in Canadian dollars). The cost of second-generation agents reached 80% of total antipsychotic expenditures in 2006; risperidone was the most prescribed agent in all age groups of patients. The per-patient annual cost of antipsychotic pharmacotherapy increased by approximately 680% between 1996 and 2006 in Manitoba. The number of antipsychotic prescriptions and the prevalence of users of antipsychotic medications increased significantly in Manitoba over the study period, despite a steady-state population of approximately 1.2 million. Incremental costs relative to the use of antipsychotic medications can be explained by the market penetration of the second-generation agents and their expanded use in the treatment of various diagnoses.

Clozapine Utilization and Outcomes by Race in a Public Mental Health System: 1994-2000

This study aimed to assess racial differences in clozapine prescribing, dosing, symptom presentation and response, and hospitalization status. This study extends previous studies of clozapine by examining patient- and treatment-related factors that may help explain or eliminate reasons for differential prescribing. Clozapine records for 373 white and African American patients with schizophrenia or schizoaffective disorder treated between March 1, 1994, and December 31, 2000, in inpatient mental health facilities in the state of Maryland were examined. Records for this study were derived from 3 state of Maryland databases: the Clozapine Authorization and Monitoring Program, the State of Maryland Antipsychotic Database, and the Health Maintenance Information System Database. A total of 10.3% of African Americans (150/1458) with schizophrenia received clozapine treatment compared with 15.3% of whites (223/1453) (chi2 = 16.74, df = 1, p < .001) during inpatient treatment in the public mental health system in Maryland. Clozapine doses were lower in African Americans relative to whites (385.3 +/- 200.6 vs. 447.3 +/- 230.3 mg/day) (t = -2.66, df = 366, p = .008). At the time of clozapine initiation, whites had more activating symptoms as measured by the Brief Psychiatric Rating Scale (BPRS) (t = -3.98, df = 301, p < .0001); however, African Americans had significantly greater improvements in BPRS total symptoms (F = 4.80, df = 301, p = .03) and in anxiety/ depressive symptoms during 1 year of treatment with clozapine (F = 10.04, df = 303, p = .002). The estimated rate of hospital discharge was not significantly different for African Americans compared to whites prescribed clozapine (log-rank chi2 = 0.523, df = 1, p = .470); however, African Americans were more likely than whites to discontinue clozapine during hospitalization (log-rank chi2 = 4.19, df = 1, p = .041). Our data suggest underutilization of clozapine in African American populations. This racial disparity in clozapine treatment is of special concern because of the favorable outcomes associated with clozapine in treatment-resistant schizophrenia and in the specific benefits observed in African American patients. More research is needed to determine why disparities with clozapine treatment occur and why African Americans may be discontinued from clozapine at a higher rate, despite potential indicators of equal or greater effectiveness among African Americans compared with whites.

Trends in consumption of psychiatric drugs in Serbia and Montenegro 2000–2004

To investigate the trends in psychiatric drugs utilization in Serbia and Montenegro over the 5-years period (2000-2004). The wholesale data issued by the manufacturers or distributors were used. Also, the lists of drugs used from the Institute of Mental Health (institution which provides primary, secondary and tertiary psychiatric care) were used to corroborate the wholesale data. The utilization of drugs in general population was calculated using ATC/DDD methodology, and was expressed in Defined Daily Doses (DDD) per 1000 inhabitants per day. The utilization of drugs in the Institute of Mental Health was calculated from the hospital pharmacy records and was expressed as the number of DDDs per 100 bed-days. The statistics was performed using standard statistical methods. The general consumption of psychiatric drugs in Serbia and Montenegro significantly increased during the 2000-2004 period (from 45.1 DDD/1000 inhabitants/day in 2000 to 69.1 DDD/1000 inhour/day in 2004). The general utilization of anxiolytic/hypnotic drugs surged significantly, but the inhospital use remained rather stable. The most prominent changes were noted in the utilization of antidepressants, which doubled in that period, both in general and inhospital settings. Among antipsychotics in general population, there is a significant increase in the utilization of clozapine. In inhospital setting, there is a significant increase of total utilization of antipsychotic drugs, but this is also mainly on the account of atypicals. The total consumption of psychiatric drugs significantly increased. The utilization of anxiolytic/hypnotic drugs in 2004 reached 60 DDDs/1000 inhabitants/day, which is in collision with the trend in developed countries. It is necessary to form national guidelines for prescribing anxiolytic/hypnotic drugs, in order to rationalize their use. More favourable is the antidepressant (SSRIs in particular) and atypical antipsychotic drugs utilization increase.

Guidelines for the use of clozapine in individuals with developmental disabilities

Clozapine is the most effective antipsychotic medication currently in use, but there has been a paucity of well-controlled research on its efficacy with people with developmental disabilities. We present a set of guidelines to ensure proper utilization of clozapine in individuals with developmental disabilities, because it can offer them therapeutic advantages similar to those observed in people with schizophrenia. We provide recommendations regarding the use of clozapine that are based on three main sources: literature and published professional practice guidelines regarding the use of clozapine in individuals who do not have developmental disabilities, the limited literature on the use of clozapine in individuals who have developmental disabilities, and our own clinical experience. The first part of the guidelines contains an overview of necessary practical knowledge regarding side effects, dose and blood level considerations, and interactions with other medications, diet and tobacco smoking. In the second part, we offer procedures for selecting individuals for clozapine therapy based on proper indications and contraindications for treatment. We also include requirements regarding informed consent, dosage and special laboratory and clinical monitoring.

Health care costs of therapy-refractory schizophrenic patients treated with clozapine: a study in a community psychiatric service in Italy.

This study evaluates the utilization of clozapine in the treatment of therapy-refractory schizophrenia in terms both of patterns of care and of health care costs in a community psychiatric service in Italy. Data covering the year prior to commencing clozapine and the year following the initiation of the therapy were collected. Clinical outcome was assessed by means of the Clinical Global Impression (CGI) and Global Assessment of Functioning (GAF) scales. Cost analysis followed a two-step procedure: (i) to record all health care services provided to patients and (ii) to assign a monetary value to each service. Three of the 15 patients enrolled in the study dropped out before the end of the 12-month period of therapy. Considering the 12 patients on clozapine treatment for at least 1 year, clinical improvements are associated with a substantial modification of the pattern of care. While patients in the pre-clozapine period were mainly managed in hospital settings, patients on clozapine were prevalently placed in the community and participated in intensive rehabilitative programmes. The higher costs of drug therapy and community services in the post-clozapine period were more than offset by the lower costs of acute hospital care.

Tardive dyskinesia, clozapine, and treatment response

1. 1. Tardive Dyskinesia (TD) can be a serious consequence of the use of antipsychotic medications to treat psychotic illness. There is evidence to suggest that the atypical antipsychotic, clozapine, is less likely to cause, and may even ameliorate TD. 2. 2. The authors reviewed their experience regarding clozapine and TD among patients in their Clozapine Clinic, and summarize some of the recent clinical literature in this area. 3. 3. Retrospective review of chart records for 13 patients was carried out. Comparisons of TD and symptom rating scales were made: 1) between groups (with and without TD) at baseline; 2) between individuals (self as own control) in the TD group at baseline and at the end of the follow-up period. 4. 4. Subjects with and without TD at baseline had a significant decrease in psychiatric symptoms over the course of treatment. 5. 5. In those with TD at baseline, mean Abnormal Involuntary Movement Scale (AIMS) score decreased by 85% over 10.3 ± 5.5 (mean ± S.D.) months at a dose of 358 ± 196 mg/day of clozapine. 6. 6. The data, and the recently published clinical literature on clozapine and TD, continue to support the striking utility of clozapine for chronically psychotic patients, and particularly those with TD.

Neuroleptic reduction and/or cessation and neuroleptics as specific treatments for tardive dyskinesia.

Since the 1950s neuroleptic medication has been extensively used to treat people with chronic mental illnesses, such as schizophrenia. These drugs, however, have been also associated with a wide range of adverse effects, including movement disorders such as tardive dyskinesia (TD). Various strategies have been examined to reduce a person's cumulative exposure to neuroleptics. These studies include dose reduction, intermittent dosing strategies, such as drug holidays, and neuroleptic cessation. To determine whether, for those people with both schizophrenia (or other chronic mental illnesses) and tardive dyskinesia (TD), a reduction or cessation of neuroleptic drugs was associated with reduction in TD symptoms. A secondary objective was to determine whether the use of specific neuroleptics for similar groups of people could be a treatment for already established TD. Electronic searches of Biological Abstracts (1982-1997), Cochrane Schizophrenia Group's Register of trials (1997), EMBASE (1980-1997), LILACS (1982-1996), MEDLINE (1966-1997), PsycLIT (1974-1997), and SCISEARCH (1997) were undertaken. References of all identified studies were searched for further trial citations. Principal authors of trials were contacted. Reports were included if they assessed the treatment of neuroleptic-induced tardive dyskinesia in people with schizophrenia or other chronic mental illnesses and already established TD, who had been randomly allocated to (a) neuroleptic cessation (placebo or no intervention) versus neuroleptic maintenance; b. neuroleptic reduction (including intermittent strategies) versus neuroleptic maintenance; or c. specific neuroleptics for the treatment of TD versus placebo or no intervention. The reviewers extracted the data independently and the Odds Ratio (95% CI) or the average difference (95% CI) were estimated. The reviewers assumed that people who dropped out had no improvement. Two trials were able to be included in this review. Sixty two were excluded and 16 are awaiting assessment. Seven trials are still pending classification. No randomised controlled trial-derived data were available to clarify the role of neuroleptics as treatments for TD. This includes the atypical antipsychotics including clozapine. Despite neuroleptic cessation being a frequently first-line recommendation, there were no RCT-derived data to support this. Two studies ( approximately approximately Cookson 1987 approximately approximately , approximately approximately Kane 1983 approximately approximately ) found a reduction in TD associated with neuroleptic reduction. The lack of evidence to support the efficacy of neuroleptic cessation as a treatment for TD, combined with the accumulating evidence of an increased risk of relapse should antipsychotic drugs be reduced, makes this intervention a hazardous treatment for TD. Dose reduction may offer some benefit as a treatment for TD compared to standard levels of neuroleptic use. There is a need to evaluate the utility of clozapine and the 'atypical' antipsychotics as treatments for established TD.

Clinical utility of clozapine in 16 patients with neurological disease

Patients who develop psychosis or agitated behavior secondary to neurological disorders present a therapeutic dilemma. The authors review clinical efficacy and side effect profiles of clozapine in a cohort of 16 patients with various neurobehavioral disorders. One-third showed a marked decrease in symptoms while on clozapine. However, one-quarter developed an acute confusional state; of these, all had diffuse slowing on their baseline EEG prior to starting the drug.

Clozapine plasma levels and convulsions

Two patients receiving clozapine developed grand mal seizures. The plasma levels in one of the patients at the time of the seizure were approximately 100% higher than on 12 previous occasions. This finding led to the conclusion and the patient's admission that she had taken an overdose. Plasma levels in the other patient exceeded the range the authors had noted in previous studies. The authors emphasize the usefulness of plasma level monitoring in relation to safety, drug defaulting, and side effects.