Jeffrey A. Lieberman

Prevalence of the metabolic syndrome in patients with schizophrenia: baseline results from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) schizophrenia trial and comparison with national estimates from NHANES III.

UNLABELLED One important risk factor for cardiovascular disease is the metabolic syndrome (MS), yet limited data exist on its prevalence in US patients with schizophrenia. METHODS Using baseline data from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Schizophrenia Trial, assessment of MS prevalence was performed based on National Cholesterol Education Program (NCEP) criteria, and also using a fasting glucose threshold of 100 mg/dl (AHA). Subjects with sufficient anthropometric data, data on use of antihypertensives, hypoglycemic medications or insulin, and fasting glucose and lipid values >8 h from last meal were included in the analysis. Comparative analyses were performed using a randomly selected sample from NHANES III matched 1:1 on the basis of age, gender and race/ethnicity. RESULTS Of 1460 CATIE baseline subjects, 689 met analysis criteria. MS prevalence was 40.9% and 42.7%, respectively using the NCEP and AHA derived criteria. In females it was 51.6% and 54.2% using the NCEP and AHA criteria, compared to 36.0% (p = .0002) and 36.6% (p = .0003), respectively for males. 73.4% of all females (including nonfasting subjects) met the waist circumference criterion compared to 36.6% of males. In a logistic regression model with age, race and ethnicity as covariates, CATIE males were 138% more likely to have MS than the NHANES matched sample, and CATIE females 251% more likely than their NHANES counterparts. Even when controlling for differences in body mass index, CATIE males were still 85% more likely to have MS than the NHANES male sample, and CATIE females 137% more likely to have MS than females in NHANES. CONCLUSIONS The metabolic syndrome is highly prevalent in US schizophrenia patients and represents an enormous source of cardiovascular risk, especially for women. Clinical attention must be given to monitoring for this syndrome, and minimizing metabolic risks associated with antipsychotic treatment.

Clozapine-induced agranulocytosis. Incidence and risk factors in the United States.

BACKGROUND Clozapine is an atypical antipsychotic agent that is more effective than standard neuroleptic drugs in the treatment of patients with refractory schizophrenia. Unlike classic neuroleptic agents, clozapine is not associated with the development of acute extrapyramidal symptoms or tardive dyskinesia. The main factor limiting its use is the risk of potentially fatal agranulocytosis, estimated to occur in 1 to 2 percent of treated patients. After clozapine was approved by the Food and Drug Administration, it became available for marketing in the United States in February 1990 only as part of a special surveillance system (the Clozaril Patient Management System, or CPMS), in which a weekly white-cell count was required for the patient to receive a supply of the drug. METHODS We evaluated the CPMS data for February 1990 through April 1991 by survival analysis to determine the incidence of agranulocytosis and the effects of potential risk factors such as age and sex. Data were available for 11,555 patients who received clozapine during the period after marketing began. RESULTS Agranulocytosis developed in 73 patients, resulting in death from infectious complications in 2 patients. Episodes of agranulocytosis occurred in 61 patients within three months after they began treatment. The cumulative incidence of this side effect was 0.80 percent (95 percent confidence interval, 0.61 to 0.99) at 1 year and 0.91 percent (95 percent confidence interval, 0.62 to 1.20) at 1 1/2 years. The risk of agranulocytosis increased with age and was higher among women. CONCLUSIONS The occurrence of agranulocytosis is a substantial hazard of the administration of clozapine, but this hazard can be reduced by monitoring the white-cell count. The increasing risk of agranulocytosis with age and the reduced incidence after the first six months of treatment provide additional guidelines for the prescription and monitoring of clozapine treatment in the future.

Catching Up on Schizophrenia: Natural History and Neurobiology

These research findings provide new opportunities and new challenges to understanding and treating schizophrenia. Certainly, a major challenge is to determine the genetic susceptibilities and pathogenetic mechanisms that can produce the complex clinical phenotype of schizophrenia. The identification of pathways of dysfunction, such as thalamo-prefrontal circuitry or the connections linking other cortical, subcortical, and cerebellar regions implicated in schizophrenia, permits studies of the relationships among the various alterations in a circuit and the elucidation of a putative endophenotype. For example, does a given abnormality represent a primary brain disturbance due to a causal factor of the disorder, or does it reflect a downstream pathologic consequence of the primary brain disturbance or an adaptive response that attempts to normalize the function of the circuit?Answers to these types of questions may create new opportunities for research at the intersection between systems level investigations and genetic approaches. Current views hold that schizophrenia is probably a consequence of multiple interacting genes; individually, these genes may have relatively little independent influence, and they may not all be involved in every individual who meets diagnostic criteria for the illness. Thus, assessment of the patterns of altered gene expression in the affected brain circuits of subjects with schizophrenia (using cDNA microarray technology or related techniques), and comparison of the chromosomal locations of these genes with regions implicated in schizophrenia through linkage studies (Pulver 2000xSearch for schizophrenia vulnerability genes. Pulver, A.E. Biol. Psychiatry. 2000; 47: 221–230Abstract | Full Text | Full Text PDF | PubMed | Scopus (99)See all ReferencesPulver 2000), may provide convergent approaches to the identification of specific vulnerability genes. For example, a recent study of gene expression profiling in the dorsal PFC of subjects with schizophrenia revealed that, of over 250 gene groups, the group of genes encoding proteins involved in the regulation of presynaptic function were most consistently altered (Mirnics et al. 2000xMolecular characterization of schizophrenia viewed by microarray analysis of gene expression in prefrontal cortex. Mirnics, K., Middleton, F.A., Marquez, A., Lewis, D.A., and Levitt, P. Neuron. 2000; 28: 33–67Abstract | Full Text | Full Text PDFSee all ReferencesMirnics et al. 2000). Although the subjects with schizophrenia appeared to share a common abnormality in the control of synaptic transmission, the specific combinations of genes involved in presynaptic function that showed reduced expression differed among them. Interestingly, a number of the chromosomal loci that have been implicated in schizophrenia contain genes encoding proteins related to presynaptic function (Mirnics et al. 2000xMolecular characterization of schizophrenia viewed by microarray analysis of gene expression in prefrontal cortex. Mirnics, K., Middleton, F.A., Marquez, A., Lewis, D.A., and Levitt, P. Neuron. 2000; 28: 33–67Abstract | Full Text | Full Text PDFSee all ReferencesMirnics et al. 2000).Recent research suggests that the heterogeneous phenotype of schizophrenia may be the result of multiple pathophysiological processes occurring at different stages of the illness (Lieberman 1999xIs schizophrenia a neurodegenerative disorder?. Lieberman, J.A. Biol. Psychiatry. 1999; 46: 729–739Abstract | Full Text | Full Text PDF | PubMed | Scopus (296)See all ReferencesLieberman 1999). These can be further characterized using multiple investigative approaches including in vivo neuroimaging, genetics, molecular neuropathology, and the development of animal models. Although animal models can only approximate the complex clinical phenotype of schizophrenia, they are essential to understand the molecular and cellular mechanisms that underlie the pathogenesis and pathophysiology of schizophrenia and can be used to test predictions from direct investigations of the illness. For example, conditional knockouts can be used to assess the consequences, at different stages of development, of the deficient expression of genes observed in subjects with schizophrenia. Therapeutic strategies based on this knowledge offer the promise of more effective interventions (including secondary and tertiary prevention), reduced morbidity, and better outcomes for patients.Thus, it should be apparent that although great progress has been made in catching up on schizophrenia, much remains to be done.‡To whom correspondence should be addressed (e-mail: lewisda@msx.upmc.edu [D. A. L.], jlieberman@css.unc.edu [J. A. L.]).

Microduplications of 16p11.2 are associated with schizophrenia.

Recurrent microdeletions and microduplications of a 600-kb genomic region of chromosome 16p11.2 have been implicated in childhood-onset developmental disorders. We report the association of 16p11.2 microduplications with schizophrenia in two large cohorts. The microduplication was detected in 12/1,906 (0.63%) cases and 1/3,971 (0.03%) controls (P = 1.2 × 10−5, OR = 25.8) from the initial cohort, and in 9/2,645 (0.34%) cases and 1/2,420 (0.04%) controls (P = 0.022, OR = 8.3) of the replication cohort. The 16p11.2 microduplication was associated with a 14.5-fold increased risk of schizophrenia (95% CI (3.3, 62)) in the combined sample. A meta-analysis of datasets for multiple psychiatric disorders showed a significant association of the microduplication with schizophrenia (P = 4.8 × 10−7), bipolar disorder (P = 0.017) and autism (P = 1.9 × 10−7). In contrast, the reciprocal microdeletion was associated only with autism and developmental disorders (P = 2.3 × 10−13). Head circumference was larger in patients with the microdeletion than in patients with the microduplication (P = 0.0007).

Low rates of treatment for hypertension, dyslipidemia and diabetes in schizophrenia: Data from the CATIE schizophrenia trial sample at baseline

UNLABELLED Persons diagnosed with schizophrenia have higher morbidity and mortality rates from cardiovascular disease, yet often have limited access to appropriate primary care screening or treatment. Metabolic disorders such as diabetes, hyperlipidemia and hypertension are highly prevalent in populations with schizophrenia, exceeding 50% in some studies; however, there have been few published studies on treatment rates among schizophrenia patients screened for these disorders. METHODS Using the baseline data from subjects (N=1460) recruited into the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) schizophrenia study, we examined the point prevalence of diabetes, hyperlipidemia and hypertension treatment at the time of enrollment for the entire cohort and those with fasting laboratory values obtained 8 or more hours since last meal. RESULTS Rates of non-treatment ranged from 30.2% for diabetes, to 62.4% for hypertension, and 88.0% for dyslipidemia. Nonwhite men were more likely to be treated for DM and dyslipidemia than nonwhite women. CONCLUSIONS These data indicate the high likelihood that metabolic disorders are untreated in patients with schizophrenia, with particularly high rates of non-treatment for hypertension and dyslipidemia. Nonwhite women may be especially vulnerable to undertreatment of dyslipidemia and diabetes compared to nonwhite men. The findings here support the need for increased attention to basic monitoring and treatment of cardiovascular risk factors in this vulnerable and often underserved psychiatric population.

Longitudinal study of brain morphology in first episode schizophrenia

BACKGROUND Beginning with Kraepelin, schizophrenia has been viewed as a progressive disorder. Although numerous studies of the longitudinal course of schizophrenia have demonstrated the clinical deterioration that occurs predominantly in the early stages of the illness, the pathophysiology of this clinical phenomenon has not been established. This aspect of the illness may be of critical importance to understanding the pathogenesis of schizophrenia and determining preventive therapeutic strategies. Abnormalities in brain morphology have been consistently described in schizophrenia, but it is not known when in the natural history of the illness they arise and whether they are progressive. Previous studies of brain morphology have been inconclusive, in part because of the variability of methods for image acquisition and analysis, assessment of patients already at chronic stages of their illness with extensive prior treatment exposure, and inadequate periods of follow-up. METHODS To address these questions we examined 107 patients in their first episode of schizophrenia or schizoaffective disorder and 20 healthy volunteers using high resolution magnetic resonance imaging (MRI) and clinical assessments of psychopathology and treatment outcome for periods of up to 6 years. Fifty-one patients and 13 control subjects had MRIs after at least 12 months of follow-up. RESULTS Results confirm the findings of ventricular enlargement and anterior hippocampal volume reductions in first episode schizophrenia patients that have been previously reported. In addition, we found changes in selected structures over time in relation to treatment outcome, including increases in ventricular volume that were associated with poor outcome patients. Contrary to our hypothesis, there were no significant reductions in cortical and hippocampal volumes over time. CONCLUSIONS The finding of progressive ventricular enlargement in patients with poor outcome schizophrenia is consistent with the hypothesis that persistent positive and negative symptoms result in progressive brain changes in the form of ventricular enlargement, possibly due to neurodegeneration rather than the confounding effects of treatment. Future studies of first episodes of schizophrenia should utilize higher resolution imaging techniques that compare clinically well characterized patients with and without poor outcome and recurrent symptoms to control subjects who are well matched to patients for age and gender. There is also a need to control for treatment effects of typical antipsychotic medication on brain structure.

The early stages of schizophrenia: Speculations on pathogenesis, pathophysiology, and therapeutic approaches

Schizophrenia is commonly considered a neurodevelopmental disorder that is associated with significant morbidity; however, unlike other neurodevelopmental disorders, the symptoms of schizophrenia often do not manifest for decades. In most patients, the formal onset of schizophrenia is preceded by prodromal symptoms, including positive symptoms, mood symptoms, cognitive symptoms, and social withdrawal. The proximal events that trigger the formal onset of schizophrenia are not clear but may include developmental biological events and environmental interactions or stressors. Treatment with antipsychotic drugs clearly ameliorates psychotic symptoms, and maintenance therapy may prevent the occurrence of relapse. The use of atypical antipsychotic agents may additionally ameliorate the pathophysiology of schizophrenia and prevent disease progression. Moreover, if treated properly early in the course of illness, many patients can experience a significant remission of their symptoms and are capable of a high level of recovery following the initial episode. Because the clinical deterioration that occurs in schizophrenia may actually begin in the prepsychotic phase, early identification and intervention may favorably alter the course and outcome of schizophrenia.

Is schizophrenia a neurodegenerative disorder? a clinical and neurobiological perspective

The history of psychiatric research is filled with widely accepted etiologic and pathophysiologic theories that eventually were proven wrong. The prevailing pathophysiologic theories of schizophrenia have emphasized the role of abnormal neurodevelopment in determining the onset and course of the illness. Relatively little attention has been paid to the role of neurodegenerative processes despite the clinical course of the illness and the fact that most patients experience varying degrees of behavioral and cognitive deterioration. This is partially due to the absence of clear histologic evidence of neurodegeneration, but may also be due to the narrow traditional conception of neurodegeneration that is generally employed. This article suggests that the rejection of a role for neurodegeneration in the pathophysiology of schizophrenia is unproven and may be premature. A wholly neurodevelopmental perspective of the illness imbues the illness with a pessimistic inevitability and therapeutic nihilism that may be unwarranted. This article reviews selectively a diverse body of evidence that is consistent with the hypothesis that schizophrenia involves a limited neurodegenerative process reflected by the psychotic symptoms and that is most active in the early stages of the illness. The evidence for this hypothesis comes from studies of premorbid status, illness course, symptomatology and treatment effects as well as neuroimaging and postmortem findings. Recent results from the latter interpreted in the context of molecular neurobiology suggest new pathophysiologic models.

Baseline neurocognitive deficits in the CATIE schizophrenia trial

Neurocognition is moderately to severely impaired in patients with schizophrenia. However, the factor structure of the various neurocognitive deficits, the relationship with symptoms and other variables, and the minimum amount of testing required to determine an adequate composite score has not been determined in typical patients with schizophrenia. An ‘all-comer’ approach to cognition is needed, as provided by the baseline assessment of an unprecedented number of patients in the CATIE (Clinical Antipsychotic Trials of Intervention Effectiveness) schizophrenia trial. From academic sites and treatment providers representative of the community, 1493 patients with chronic schizophrenia were entered into the study, including those with medical comorbidity and substance abuse. Eleven neurocognitive tests were administered, resulting in 24 individual scores reduced to nine neurocognitive outcome measures, five domain scores and a composite score. Despite minimal screening procedures, 91.2% of patients provided meaningful neurocognitive data. Exploratory principal components analysis yielded one factor accounting for 45% of the test variance. Confirmatory factor analysis showed that a single-factor model comprised of five domain scores was the best fit. The correlations among the factors were medium to high, and scores on individual factors were very highly correlated with the single composite score. Neurocognitive deficits were modestly correlated with negative symptom severity (r=0.13–0.27), but correlations with positive symptom severity were near zero (r<0.08). Even in an ‘all-comer’ clinical trial, neurocognitive deficits can be assessed in the overwhelming majority of patients, and the severity of impairment is similar to meta-analytic estimates. Multiple analyses suggested that a broad cognitive deficit characterizes this sample. These deficits are modestly related to negative symptoms and essentially independent of positive symptom severity.

Double-blind comparison of first- and second-generation antipsychotics in early-onset schizophrenia and schizo-affective disorder: findings from the treatment of early-onset schizophrenia spectrum disorders (TEOSS) study

OBJECTIVE Atypical (second-generation) antipsychotics are considered standard treatment for children and adolescents with early-onset schizophrenia and schizoaffective disorder. However, the superiority of second-generation antipsychotics over first-generation antipsychotics has not been demonstrated. This study compared the efficacy and safety of two second-generation antipsychotics (olanzapine and risperidone) with a first-generation antipsychotic (molindone) in the treatment of early-onset schizophrenia and schizoaffective disorder. METHOD This double-blind multisite trial randomly assigned pediatric patients with early-onset schizophrenia and schizoaffective disorder to treatment with either olanzapine (2.5-20 mg/day), risperidone (0.5-6 mg/day), or molindone (10-140 mg/day, plus 1 mg/day of benztropine) for 8 weeks. The primary outcome was response to treatment, defined as a Clinical Global Impression (CGI) improvement score of 1 or 2 and >or=20% reduction in Positive and Negative Syndrome Scale (PANSS) total score after 8 weeks of treatment. RESULTS In total, 119 youth were randomly assigned to treatment. Of these subjects, 116 received at least one dose of treatment and thus were available for analysis. No significant differences were found among treatment groups in response rates (molindone: 50%; olanzapine: 34%; risperidone: 46%) or magnitude of symptom reduction. Olanzapine and risperidone were associated with significantly greater weight gain. Olanzapine showed the greatest risk of weight gain and significant increases in fasting cholesterol, low density lipoprotein, insulin, and liver transaminase levels. Molindone led to more self-reports of akathisia. CONCLUSIONS Risperidone and olanzapine did not demonstrate superior efficacy over molindone for treating early-onset schizophrenia and schizoaffective disorder. Adverse effects were frequent but differed among medications. The results question the nearly exclusive use of second-generation antipsychotics to treat early-onset schizophrenia and schizoaffective disorder. The safety findings related to weight gain and metabolic problems raise important public health concerns, given the widespread use of second-generation antipsychotics in youth for nonpsychotic disorders.