Clozapine: A Clinical Review of Adverse Effects and Management

Clozapine (Clozaril^®) is a novel and unique prototype atypical, tricyclic, dibenzodiazepine-derivative, antipsychotic agent. It has been proven effective and significantly superior to placebo, as well as to conventional neuroleptics, in several placebo-controlled, double-blind studies in treatment-resistant schizophrenia. It has also been found to produce an incidence of extrapyramidal symptoms (EPS) as low as that found with placebo. Approximately 30–60% of all schizophrenic patients who fail to respond to typical antipsychotics may respond to clozapine. It was the first major advance that marked a turning point in the treatment of schizophrenia and other psychotic disorders since the introduction of the typical antipsychotic agents, i.e., chlorpromazine and haloperidol in the 1950s and 1960s, respectively. After its introduction in clinical studies in the United States in the early 1970s, it was withdrawn in 1974, and was not approved for clinical use in the United States until February 1990, because of the risk of agranulocytosis. Its novel pharmacological profile, lack of propensity to cause EPS in both short- and long-term uses, lack of effects on serum prolactin, and ameliorative effects on tardive dyskinesia have resulted in the expansion of its use from refractory schizophrenia to schizoaffective disorders, affective disorders, some neurological disorders, aggression, as well as psychosis in patients with dementia and parkinsonism. This review covers the history, pharmacology, management of side effects, and fetal and neonatal effects of clozapine.     

Rehospitalization Risk with Second-Generation and Depot Antipsychotics

Decreasing hospital admissions is important for improving outcomes for people with schizophrenia. Second-generation antipsychotics (SGAs) are better tolerated for long-term therapy than traditional medications and may contribute to a lower rehospitalization risk, but have not been compared to depot forms with regard to long-term outcomes. This study evaluates the risk of readmission in patients discharged from six State of Maryland inpatient mental health facilities between Jan. 1, 1997 and Dec. 31, 1997 on clozapine (N = 41), risperidone (N = 149), and olanzapine (N = 103). These patients were compared with those discharged from the two largest state facilities during the same time period on fluphenazine decanoate (N = 59) or haloperidol decanoate (N = 59). One-year readmission risk (measured by Kaplan–Meier survival analysis with Holm's adjustment for multiple comparison on Log Rank tests) were 10% for clozapine, 12% for risperidone, and 13% for olanzapine. These risks were not significantly lower than the readmission risk for fluphenazine decanoate (21%) but were significantly lower than haloperidol decanoate (35%) for all three SGAs. Demographic and clinical variables did not predict readmission for any of the medications. In patients with similar demographic and clinical characteristics, 1-year risk of readmission for patients treated with SGAs were at least comparable to the 1-year risk for patients receiving fluphenazine decanoate and lower than the risk for patients treated with haloperidol decanoate. SGAs may provide better long-term prognoses and outcomes for patients with schizophrenia.     

A Case with Neutropenia Related with the Use of Various Atypical Antipsychotics

Herein, we report here a case of a 21-year-old patient with a conduct disorder, who had neutropenia associated with treatment with 4 different antipsychotics (olanzapine, quetiapine, risperidone, and aripiprazole) on a sequential basis. This case supports the hypothesis that patients who developed antipsychotic-induced neutropenia on one medication are more likely to develop neutropenia when taking other antipsychotics. Based on this finding, we may suggest that the number of white blood cell and neutrophil counts in patients with a history of antipsychotic-induced neutropenia needs to be carefully monitored during antipsychotic treatment.     

State of the Art of Drug Treatment of Schizophrenia and the Future Position of the Novel/Atypical Antipsychotics

Summary: Neuroleptic medication is the most important part of the treatment regimen for schizophrenic patients. The efficacy of neuroleptics in the acute and long-term treatment of schizophrenia is very well proven and the effect size is comparatively high. After more than 40 years of clinical practice with the classical neuroleptics, several more or less generally accepted rules for the management of drug treatment in schizophrenia have been established. The paper aims to describe these standards, discussing, among other things, developments which have appeared in the last 10 to 20 years, e.g. the tendency to a lower daily dose during acute treatment and the tendency to alternative strategies during long-term treatment. The paper especially also takes into consideration the benefits of the novel/atypical antipsychotics as compared to the classical neuroleptics, which will change the current treatment standards under several aspects — a change which is already ongoing. The novel/atypical antipsychotics will be much better accepted by patients, thus leading to increased compliance, will be associated with a better quality of life and will possibly change the long-term outcome of schizophrenic patients in a very important manner. It should be considered that the so-called novel/atypical neuroleptics do not constitute a homogeneous group but are a group of individual drugs, each with their own advantages and disadvantages. As was the situation with the classical neuroleptics, the physician also has to choose the most adequate drug under consideration of the risk/benefit profile of each drug in relation to the disposition of the individual patient.     

Phenomenology of and Risk Factors for New-Onset Diabetes Mellitus and Diabetic Ketoacidosis Associated with Atypical Antipsychotics: An Analysis of 45 Published Cases

Case reports and small retrospective studies suggest that atypical antipsychotic agents may be associated with new-onset Type II diabetes mellitus (DM) or diabetic ketoacidosis (DKA); however, these reports often provide limited or no information on demographic variables such as age, gender, ethnicity, relationship to weight gain, and time course. We analyzed 45 published cases of new-onset DM or DKA for which followed initiation of atypical antipsychotic treatment. Of the 45 patients, 20 had received clozapine, 19 olanzapine, 3 quetiapine, and 3 risperidone. Eighty-seven percent patients were male, and 47% African American. Forty-two percent of these patients presented as DKA, and 50% manifested no weight gain at time of presentation with DM or DKA, although 84% were overweight before antipsychotic therapy. Eighty-four percent presented within 6 months and 59% within 3 months of commencing atypical antipsychotics. The DKA cohort had significantly younger age, less overweight at baseline, and higher proportion of women than did those with DM alone, without significant differences in distribution of ethnicity, weight gain, family history of DM, or duration of exposure to atypical agents. Clinicians should be aware of the potential risks of new-onset DM and DKA in patients taking atypical antipsychotics, and utilize appropriate clinical and laboratory monitoring to prevent serious adverse events.     

Correlates of subjective well-being in schizophrenic patients treated with atypical antipsychotics

Objective

A growing body of research indicates that a low subjective well-being (SW) may be predictive of non-adherence and less favourable outcome. This study examined baseline variables and variables in the course of treatment hypothesised to be associated with later SW.

Methods

Sixty-three inpatients with schizophreniform disorder or schizophrenia were randomly assigned to treatment with various atypical antipsychotics after a wash-out phase of 2 days. Subjects were evaluated with a protocol that examined psychopathology (Positive and Negative Symptom Scale, PANSS), side effects (Scandinavian Society of Pharmacology, UKU), and subjective well-being (Subjective Well-being under Neuroleptic treatment, SWN) at baseline and endpoint (mean duration of treatment 39.9 days). Two-thirds of subjects were multiple episode schizophrenic inpatients pre-treated with antipsychotics.

Results

Multiple regression analyses revealed that the PANSS negative score, neurological side effects, and SWN at baseline, as well as change of the PANSS positive score between baseline and endpoint, were associated independently with SW at endpoint (R²=0.55 after exclusion of two subjects).

Conclusions

Patients with low SW, severe negative symptoms, and neurological side effects, all at baseline, as well as those without improvement or deterioration of positive symptoms are at risk of low SW later in treatment and, most likely, of non-adherence.     

Extrapyramidal symptoms in substance abusers with and without schizophrenia and in nonabusing patients with schizophrenia

Extrapyramidal symptoms (EPS) such as parkinsonism, dystonia, dyskinesia, and akathisia are conditions of impaired motor function, which are associated with chronic antipsychotic treatment in schizophrenia. In addition, EPS is often exacerbated by psychoactive substance (PAS) abuse, which is frequently observed in this population. Few studies, however, have investigated the contribution of PAS abuse on EPS in PAS‐abusers without comorbid psychosis. This study compared the occurrence of EPS in outpatient schizophrenia patients with (DD group; n= 36) and without PAS abuse (SCZ group; n = 41) as well as in nonschizophrenia PAS abusers undergoing detoxification [substance use disorder (SUD) group; n = 38]. Psychiatric symptoms were measured using the Positive and Negative Syndrome Scale and the Calgary Depression Scale for schizophrenia. Extrapyramidal symptoms were evaluated with the Extrapyramidal Symptoms Rating Scale and the Barnes Akathisia Scale. SUD diagnoses were complemented with urine drug screenings. We found that DD patients exhibited significantly more parkinsonism than SCZ patients. Our subanalyses revealed that cocaine and alcohol abuse/dependence was responsible for the increase in parkinsonism in DD patients. Additionally, we found that SUD individuals exhibited significantly more akathisia than SCZ patients. In these latter individuals, subanalyses revealed that alcohol and cannabis abuse/dependence was responsible for the increase in akathisia. Our results suggest that PAS abuse is a contributor to EPS in individuals with and without schizophrenia. © 2010 Movement Disorder Society.     

Atypical Antipsychotics Rapidly and Inappropriately Switch Peripheral Fuel Utilization to Lipids,Impairing Metabolic Flexibility in Rodents

Patients taking atypical antipsychotics are frequented by serious metabolic (eg, hyperglycemia, obesity, and diabetes) and cardiac effects. Surprisingly, chronic treatment also appears to lower free fatty acids (FFAs). This finding is paradoxical because insulin resistance is typically associated with elevated not lower FFAs. How atypical antipsychotics bring about these converse changes in plasma glucose and FFAs is unknown. Chronic treatment with olanzapine, a prototypical, side effect prone atypical antipsychotic, lowered FFA in Sprague–Dawley rats. Olanzapine also lowered plasma FFA acutely, concomitantly impairing in vivo lipolysis and robustly elevating whole-body lipid oxidation. Increased lipid oxidation was evident from accelerated losses of triglycerides after food deprivation or lipid challenge, elevated FFA uptake into most peripheral tissues (∼2-fold) except heart, rises in long-chain 3-hydroxylated acyl-carnitines observed in diabetes, and rapid suppression of the respiratory exchange ratio (RER) during the dark cycle. Normal rises in RER following refeeding, a sign of metabolic flexibility, were severely blunted by olanzapine. Increased lipid oxidation in muscle could be explained by ∼50% lower concentrations of the negative cytoplasmic regulator of carnitine palmitoyltransferase I, malonyl-CoA. This was associated with loss of anapleurotic metabolites and citric acid cycle precursors of malonyl-CoA synthesis rather than adenosine monophosphate-activated kinase activation or direct ACC1/2 inhibition. The ability of antipsychotics to lower dark cycle RER in mice corresponded to their propensities to cause metabolic side effects. Our studies indicate that lipocentric mechanisms or altered intermediary metabolism could underlie the FFA lowering and hyperglycemia (Randle cycle) as well as some of the other side effects of atypical antipsychotics, thereby suggesting strategies for alleviating them.     

Subjective response and attitudes toward antipsychotic drug therapy during the initial treatment period: a prospective follow-up study in patients with schizophrenia

Objective: In this prospective study, patients with schizophrenia were followed up for 3 months to investigate the impact of sociodemographic factors, psychopathology, change in psychopathology and side effects on subjective response and attitudes toward antipsychotics during the initial treatment period. Method: We investigated 42 patients starting treatment with a new‐generation antipsychotic. Next to the registration of demographic data various rating scales were used: the Positive and Negative Syndrome Scale (PANSS), the Udvalg for Kliniske Undersogelser (UKU) Side Effect Rating Scale and the Drug Attitude Inventory (DAI). Results: Two patients experienced a first episode of the illness and were neuroleptic naïve, and 40 had suffered from at least one prior episode of schizophrenia. Longer duration of illness as well as the amelioration of psychopathological symptoms had a positive impact on subjective response to treatment. Correlations between antipsychotic‐induced side effects and drug attitude tended to be weak. Conclusion: Our results emphasize the necessity of improving psychopathological symptoms during the initial treatment period to improve attitudes toward and compliance with treatment.     

Aripiprazole in the acute treatment of male patients with schizophrenia: effectiveness, acceptability, and risks in the inner-city hospital setting

Aripiprazole, a novel atypical antipsychotic that acts as a partial agonist at the dopamine D₂ receptors, has been reported to be effective in the treatment of chronic schizophrenia. However, the risks and benefits of using aripiprazole in the acute hospital setting to treat severe psychotic disorders are unclear. This naturalistic study assessed the effectiveness of aripiprazole monotherapy in a group of actively psychotic male patients (n = 10) with schizophrenia who were admitted to an inner-city acute psychiatric unit. Most patients (n = 7) responded to aripiprazole treatment, which was well tolerated and significantly ameliorated psychotic symptoms after 2–3 weeks. Patients who responded to it could be safely discharged on aripiprazole monotherapy. Side effects observed were mostly mild and transient, and included extrapyramidal symptoms (n = 1) and neutropenia (n = 1). Aripiprazole also remarkably attenuated dyskinetic movements in 1 patient with severe tardive dyskinesia, thereby suggesting that it may be useful in the treatment of other disorders that are also associated with dopamine dysfunction. Results showed that aripiprazole can be safely and effectively employed in the hospital setting to treat severely psychotic patients with schizophrenia, but further studies are required to establish the full range of adverse reactions and therapeutic indications associated with its use.     

The METEOR study of diabetes and other metabolic disorders in patients with schizophrenia treated with antipsychotic drugs. I. Methodology

Patients with schizophrenia present a two‐ to three‐fold higher prevalence of diabetes, of metabolic syndrome and of cardiovascular morbidity. The reason for this increased prevalence may involve intrinsic vulnerability, lifestyle factors and iatrogenic effects of antipsychotic drugs. The objective of this multinational, cross‐sectional, pharmacoepidemiological study was to determine the prevalence of diabetes, lipid disorders, obesity, hypertension and the metabolic syndrome in patients with schizophrenia treated with antipsychotic drugs. Particular attention was taken to acquire data on a wide a range as possible of demographic, clinical and lifestyle variables that may influence the risk of metabolic disorders, which were taken into account in the calculation of prevalence data by propensity scoring. The study included 2270 subjects from 16 European countries, predominantly from Central and Eastern Europe. The proportion of subjects presenting the pathologies of interest was relatively high, ranging from 28% for glycaemic disorders to 70% for lipid disorders. Copyright © 2010 John Wiley & Sons, Ltd.     

Olanzapine in the treatment of depression with psychotic features: A prospective open-label study

Objective. Depression with psychotic features is a severe subtype of major depression associated with the presence of delusions, hallucinations and specific neurobiological features. Despite clinical consensus and guideline recommendations, data comparing the efficacy of combining antipsychotics with antidepressants compared to antidepressants alone remain inconclusive. The aim of the study was to investigate effectiveness and tolerability of the atypical antipsychotic olanzapine in acute depression with psychotic features. Methods. Seventeen inpatients with major depressive disorder with psychosis (MDDp) were treated with a combination of an antidepressant and olanzapine for 6 weeks in a prospective open-label study. Depressive and psychotic symptoms, extrapyramidal and general side effects were assessed every 2 weeks. Sixteen patients were eligible for final analysis. Results. The Brief Psychiatric Rating Scale (BPRS) showed a 30% symptom reduction after week 2, a 45% symptom reduction after week 4 and no considerable improvement thereafter. Depressive symptoms (Bech–Rafaelsen Melancholia Scale, BRMS) receded by 37% after week 2 and 50% after week 4. No extrapyramidal side effects occurred. Conclusion. Olanzapine is effective and tolerable in combination with an antidepressant in an MDDp inpatient sample. The results concur with data supporting good efficacy in negative and depressive symptoms of patients with schizophrenic and schizoaffective diseases.     

Hospital vs. outreach treatment of patients with mental retardation and psychiatric disorders: a controlled study

The aim of this study was to investigate the effectiveness of specialized hospital treatment vs. outreach treatment of patients with mental retardation and serious mental illness. A total of 50 patients were randomly assigned to either the hospital treatment (n=25) or the outreach treatment group (n=25). The outcome measures included psychiatric symptoms, family burden, costs and hospital admissions. At most observation points (up to 28 weeks) and at all endpoints the two groups were equivalent with regard to psychiatric symptoms. The burden on carers did not increase significantly during the outreach treatment. Treatment costs were lower for the outreach treatment. Of the 25 patients who received outreach treatment, four had to be admitted to the specialized hospital. Aggressive behaviour, social competence and number of previous psychiatric hospitalizations were found to be predictors of treatment outcome. It is concluded that outreach treatment represents an effective and efficient alternative to hospital treatment for patients with mental retardation and psychiatric disorders.     

Psychiatric disorders in adults diagnosed as children with atypical autism. A case control study

Summary. The prevalence and types of psychiatric disorders were studied in a clinical sample of 89 individuals with atypical autism (AA) first seen as children, and 258 matched controls from the general population using data from the nationwide Danish Psychiatric Central Register. The average observation time was 36.9 years, and mean age at follow-up 45.3 years. A total of 61 persons with AA (68.5%) had been in contact with psychiatric hospitals during the follow-up period, compared with 10.9% in the comparison group. A whole range of significantly elevated psychiatric disorders was found, so AA is not seen to be associated with any specific mental disorder. Schizophrenia spectrum disorders were the most commonly associated psychiatric disorders, diagnosed at least one time in 34.8% of the AA cases. Our findings underscore that it is important for clinicians working in adult psychiatric services to be aware that AA and a wide range of psychiatric disorders often co-exist. Correspondence: Svend Erik Mouridsen, Department of Child and Adolescent Psychiatry, Bispebjerg University Hospital, 2400 Copenhagen, Denmark     

Psychiatric disorders and behavioral problems in children with velocardiofacial syndrome: usefulness as phenotypic indicators of schizophrenia risk.

BACKGROUND: Velocardiofacial syndrome (VCFS), a genetic deletion condition with numerous cognitive sequelae, is associated with a high rate of psychiatric disorders in childhood. More recently, VCFS has been identified as a high-risk factor for developing adult onset schizophrenia. However, it has never been demonstrated that the childhood psychiatric disorders found in children with VCFS differ from those found in children with a similar degree of cognitive impairment. Identification of a specific behavioral (psychiatric) phenotype in childhood VCFS offers the potential for elucidating the symptomatic precursors of adult onset schizophrenia. METHODS: Twenty-eight children with VCFS and 29 age- and cognitively matched control subjects received a standardized assessment of childhood psychiatric disorders and behaviors measured by the Child Behavior Checklist (CBCL). Findings from the two groups were compared. RESULTS: The rates and types of psychiatric disorder and behavior problems in VCFS and cognitively matched control subjects were very high, but showed no significant differences. CONCLUSIONS: Psychopathology in children with VCFS may not differ from that found in cognitively matched control subjects. Another explanation is that subtle phenotypic differences in behavior found in VCFS can not be observed using standard symptom inventories. The high rate of psychopathology in children with VCFS is not a useful phenotypic indicator of high risk for adult onset schizophrenia.     

Neuroleptic-potentiating effect of alpha-methyl-p-tyrosine compared with haloperidol and placebo in a double-blind cross-over trial.

The hypothesis that schizophrenia results from overactive dopaminergic influences suggests that reducing dopamine synthesis may increase the clinical effects of dopamine receptor blocking neuroleptic drugs. The neuroleptic potentiating role of alpha-methyl-paratyrosine (AMPT), a tyrosine hydroxylase inhibitor, was compared with haloperidol and placebo in a double-blind cross-over trial. Both AMPT and haloperidol increased the anti-schizophrenic effect of neuroleptic treatment in reduced dose compared with placebo (P less than 0.05), though two patients relapsed during the AMPT period. Both drugs slightly increased extrapyramidal symptoms, but the effect was greater with haloperidol. The limited antipsychotic effect and the potential for aggravating neurological symptoms suggest that the combination of AMPT and neuroleptics does not offer a superior advantage to treating schizophrenia. AMPT, however, may still be used as a research tool in elucidating pathogenetic mechanisms.     

Psychiatric and neuropsychiatric adverse events associated with deep brain stimulation: A meta-analysis of ten years' experience.

Deep brain stimulation (DBS) has been approved by the FDA for use in the treatment of Parkinson's disease, essential tremor, and dystonia. Case reports and case series have reported significant psychiatric side effects in some individuals. The goal of this meta-analysis is to characterize the risks and benefits of DBS and to assess its possible use within the psychiatric setting. A search was conducted on PubMed, EBSCO, and PsycInfo in January 2006 that covered the time period 1 Jan 1996-30 Dec 2005. All identified articles were reviewed and those describing adverse events were further examined with a structured instrument. The initial searches yielded 2667 citations; 808 articles met inclusion criteria for the meta-analysis; 98.2% of studies that specifically assessed motor function reported some level of improvement. Most reported side effects were device or procedure related (e.g., infection and lead fracture). The prevalence of depression was 2-4%, mania 0.9-1.7%, emotional changes 0.1-0.2%, and the prevalence of suicidal ideation/suicide attempt was 0.3-0.7%. The completed suicide rate was 0.16-0.32%. In conclusion, DBS is an effective treatment for Parkinson's disease, dystonia, and essential tremor, and case reports suggest that major depression and OCD may also respond to DBS. Reported rates of depression, cognitive impairment, mania, and behavior change are low, but there is a high rate of suicide in patients treated with DBS, particularly with thalamic and GPi stimulation. Because of the high suicide rate, patients should be prescreened for suicide risk prior to DBS surgery. Additionally, patients should be monitored closely for suicidal behavior post-operatively.     

A combined analysis of double-blind studies with risperidone vs. placebo and other antipsychotic agents: factors associated with extrapyramidal symptoms

Combined data from double-blind risperidone studies were used to analyse the severity of extrapyramidal symptoms (EPS) associated with treatment in patients with chronic schizophrenia. Factors associated with maximum EPS severity were increasing risperidone dose (< or = 8 mg/day was similar to placebo), lower baseline EPS scores, and longer duration of psychotic symptoms, particularly in older patients. EPS severity was significantly greater in patients receiving haloperidol or other antipsychotics than in those receiving risperidone (4 to 8 mg/day) or placebo. Antiparkinsonian medications were required by significantly fewer patients treated with risperidone (4 to 8 mg/day) than by patients treated with haloperidol or other antipsychotics. Combined efficacy data showed that 4 to 8 mg/day was also the most efficacious dose range; there was no increase in efficacy with doses over 4 mg/day. Based on these data and post-marketing experience, 4 mg/day is an appropriate initial target dose for most patients with schizophrenia. Higher doses may be appropriate for patients with chronic illness, and lower doses may be appropriate for patients with a first psychotic episode or for elderly patients.