Miranda Chakos

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.

Valmet: A New Validation Tool for Assessing and Improving 3D Object Segmentation

Extracting 3D structures from volumetric images like MRI or CT is becoming a routine process for diagnosis based on quantitation, for radiotherapy planning, for surgical planning and image-guided intervention, for studying neurodevelopmental and neurodegenerative aspects of brain diseases, and for clinical drug trials. Key issues for segmenting anatomical objects from 3D medical images are validity and reliability. We have developed VALMET, a new tool for validation and comparison of object segmentation. New features not available in commercial and public-domain image processing packages are the choice between different metrics to describe differences between segmentations and the use of graphical overlay and 3D display for visual assessment of the locality and magnitude of segmentation variability. Input to the tool are an original 3D image (MRI, CT, ultrasound), and a series of segmentations either generated by several human raters and/or by automatic methods (machine). Quantitative evaluation includes intra-class correlation of resulting volumes and four different shape distance metrics, a) percentage overlap of segmented structures (R intersect S)/(R union S), b) probabilistic overlap measure for non-binary segmentations, c) mean/median absolute distances between object surfaces, and maximum (Hausdorff) distance. All these measures are calculated for arbitrarily selected 2D cross-sections and full 3D segmentations. Segmentation results are overlaid onto the original image data for visual comparison. A 3D graphical display of the segmented organ is color-coded depending on the selected metric for measuring segmentation difference. The new tool is in routine use for intra- and inter-rater reliability studies and for testing novel automatic machine-segmentation versus a gold standard established by human experts. Preliminary studies showed that the new tool could significantly improve intra- and inter-rater reliability of hippocampus segmentation to achieve intra-class correlation coefficients significantly higher than published elsewhere.

The Clinical Antipsychotic Trials Of Intervention Effectiveness (CATIE) Schizophrenia Trial: clinical comparison of subgroups with and without the metabolic syndrome.

UNLABELLED The metabolic syndrome (MS) is highly prevalent among patients with schizophrenia (current estimates 35-40%), yet no data exist on the correlation of this diagnosis with illness severity, neurocognitive or quality of life measures in this population. METHODS Using baseline data from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Schizophrenia Trial, assignment of MS status was performed using an updated definition derived from the National Cholesterol Education Program (NCEP) criteria. Those with and without MS were compared on the basis of primary and secondary variables of interest from baseline data encompassing psychiatric, neurocognitive and quality of life measures. RESULTS Of 1460 subjects enrolled at baseline, MS status could be reliably assigned for 1231 subjects, with a prevalence of 35.8% using the NCEP derived criteria. After adjustment for age, gender, race, ethnicity and site variance, those with MS rated themselves significantly lower on physical health by SF-12 (p < .001), and scored higher on somatic preoccupation (PANSS item G1) (p = .03). There were no significant differences between the two cohorts on measures of symptom severity, depression, quality of life, neurocognition, or self-rated mental health. Neither years of antipsychotic exposure nor alcohol usage were significant predictors of MS status when adjusted for age, gender, race, and ethnicity. CONCLUSIONS The metabolic syndrome is highly prevalent in this large cohort of schizophrenia patients and is strongly associated with a poor self-rating of physical health and increased somatic preoccupation. These results underscore the need for mental health practitioners to take an active role in the health monitoring of patients with schizophrenia to minimize the impact of medical comorbidity on long-term mortality and on daily functioning. Outcomes data from CATIE will provide important information on the metabolic and clinical impact of antipsychotic treatment for those subjects with MS and other medical comorbidities.

Extrapyramidal side-effects of antipsychotics in a randomised trial

BACKGROUND There are claims that second-generation antipsychotics produce fewer extrapyramidal side-effects (EPS) compared with first-generation drugs. AIMS To compare the incidence of treatment-emergent EPS between second-generation antipsychotics and perphenazine in people with schizophrenia. METHOD Incidence analyses integrated data from standardised rating scales and documented use of concomitant medication or treatment discontinuation for EPS events. Mixed model analyses of change in rating scales from baseline were also conducted. RESULTS There were no significant differences in incidence or change in rating scales for parkinsonism, dystonia, akathisia or tardive dyskinesia when comparing second-generation antipsychotics with perphenazine or comparing between second-generation antipsychotics. Secondary analyses revealed greater rates of concomitant antiparkinsonism medication among individuals on risperidone and lower rates among individuals on quetiapine, and lower rates of discontinuation because of parkinsonism among people on quetiapine and ziprasidone. There was a trend for a greater likelihood of concomitant medication for akathisia among individuals on risperidone and perphenazine. CONCLUSIONS The incidence of treatment-emergent EPS and change in EPS ratings indicated that there are no significant differences between second-generation antipsychotics and perphenazine or between second-generation antipsychotics in people with schizophrenia.

Antipsychotic-induced weight gain and therapeutic response: A differential association

This study investigated the association between antipsychotic-induced weight gain and therapeutic response to haloperidol and three commonly used atypical neuroleptic medications in schizophrenia and schizoaffective disorder. The subjects were 151 patients enrolled in a double-blind experiment with a duration of 14 weeks comparing the therapeutic efficacy of haloperidol (n = 36), clozapine (n = 38), olanzapine (n = 38), and risperidone (n = 39). Absolute and relative (%) gain in body weight and body mass index (BMI) was determined for the entire duration of the double-blind treatment period; therapeutic response was assessed by the total score and the individual subscales of the Positive and Negative Symptom Scale. Compared with the pretreatment baseline, results indicated that for olanzapine and clozapine, therapeutic response was closely related to an absolute and relative gain in weight and to a gain in BMI. No association between weight gain and therapeutic response was found for risperidone and haloperidol. These findings suggest that patients who are likely to have the maximal benefits of olanzapine or clozapine treatment for symptom alleviation are at the highest risk of a clinically significant increase in weight gain.

Clinical correlates of tardive dyskinesia in schizophrenia: Baseline data from the CATIE schizophrenia trial

OBJECTIVE To examine the clinical characteristics of individuals with schizophrenia that develop tardive dyskinesia (TD) associated with antipsychotic treatment. METHODS Baseline data on 1460 patients with schizophrenia were collected as part of the Clinical Antipsychotic Trials of Intervention Effectiveness schizophrenia study. Subjects who met Schooler-Kane criteria for probable TD were compared to those without TD. Multiple regression analyses were used to examine the relationship between TD and clinical variables. RESULTS 212 subjects met the Schooler-Kane criteria for probable TD and 1098 had no history or current evidence of TD. Subjects with TD were older, had a longer duration of receiving antipsychotic medication, and were more likely to have been receiving a conventional antipsychotic and an anticholinergic agent. After controlling for important baseline covariates, diabetes mellitus (DM) and hypertension did not predict TD, whereas substance abuse significantly predicted TD. Differences in cognitive functioning were not significantly different after controlling for baseline covariates. The TD subjects also had higher ratings of psychopathology, EPSE, and akathisia. CONCLUSION Our results confirm the established relationships between the presence of TD and age, duration of treatment with antipsychotics, treatment with a conventional antipsychotic, treatment with anticholinergics, the presence of EPS and akathisia, and substance abuse. Subjects with TD had higher ratings of psychopathology as measured by the PANSS. We found no support for DM or hypertension increasing the risk of TD, or for TD being associated with cognitive impairment.

Striatal enlargement in rats chronically treated with neuroleptic

BACKGROUND Striatal enlargement with chronic neuroleptic treatment in schizophrenic patients has been reported by several investigators. Longitudinal magnetic resonance imaging studies of patients suggest that changes in striatal volume may be caused by treatment with antipsychotic medication. METHODS We have examined the effects of chronic neuroleptic treatment on postmortem striatal volume in the laboratory rat and have examined the relationship between striatal volume and vacuous chewing movements (VCMs). Autoradiographs of 50 rats treated with haloperidol (1.5 mg/kg/day) or drug free for varying durations of time (1-12 months) were utilized in this analysis. RESULTS Chronic treatment with neuroleptics (1 month or greater) was associated with larger striatal volumes. The increase in striatal volume was present at 1 month of treatment and was sustained to 12 months of treatment. Rats that developed the high-VCM syndrome had larger striatal volumes than both drug-free and low-VCM rats, while low-VCM rats had larger striatal volumes than drug-free rats. CONCLUSIONS These data suggest that chronic neuroleptic treatment is the cause of striatal enlargement in the laboratory rat, and that this enlargement is most prominent in rats that have the high-VCM syndrome.

The development of treatment resistance in patients with schizophrenia: A clinical and pathophysiologic perspective

&NA; The pathophysiologic process and clinical factors that contribute to the development of treatment resistance in schizophrenia are not well defined. This article describes data indicating that treatment resistance may evolve over the course of the patients’ illness and maturational development. Data from multiepisode patients suggest that early effective intervention with clozapine can prevent treatment resistance. Early identification of patients with signs of treatment resistance is vital. Treatments must be effective and prevent relapse. At the first indication that a patient may be developing resistance (e.g., the emergence of extrapyramidal symptoms or increases in negative symptomatology) or may not be complying with treatment, clozapine therapy should be considered.

Treatment outcomes of patients with tardive dyskinesia and chronic schizophrenia

OBJECTIVE We compared the response to antipsychotic treatment between patients with and without tardive dyskinesia (TD) and examined the course of TD. METHOD This analysis compared 200 patients with DSM-IV-defined schizophrenia and TD and 997 patients without TD, all of whom were randomly assigned to receive one of 4 second-generation antipsychotics. The primary clinical outcome measure was time to all-cause treatment discontinuation, and the primary measure for evaluating the course of TD was change from baseline in Abnormal Involuntary Movement Scale (AIMS) score. Kaplan-Meier survival analysis and Cox proportional hazards regression models were used to compare treatment discontinuation between groups. Changes in Positive and Negative Syndrome Scale (PANSS) and neurocognitive scores were compared using mixed models and analysis of variance. Treatment differences between drugs in AIMS scores and all-cause discontinuation were examined for those with TD at baseline. Percentages of patients meeting criteria for TD postbaseline or showing changes in AIMS scores were evaluated with χ(2) tests. Data were collected from January 2001 to December 2004. RESULTS Time to treatment discontinuation for any cause was not significantly different between the TD and non-TD groups (χ(2)(1) = 0.11, P = .743). Changes in PANSS scores were not significantly different (F(1,974) = 0.82, P = .366), but patients with TD showed less improvement in neurocognitive scores (F(1,359) = 6.53, P = .011). Among patients with TD, there were no significant differences between drugs in the decline in AIMS scores (F(3,151) = 0.32, P = .811); 55% met criteria for TD at 2 consecutive visits postbaseline, 76% met criteria for TD at some or all postbaseline visits, 24% did not meet criteria for TD at any subsequent visit, 32% showed a ≥ 50% decrease in AIMS score, and 7% showed a ≥ 50% increase in AIMS score. CONCLUSIONS Schizophrenia patients with and without TD were similar in time to discontinuation of treatment for any cause and improvement in psychopathology, but differed in neurocognitive response. There were no significant differences between treatments in the course of TD, with most patients showing either persistence of or fluctuation in observable symptoms. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00014001.