0
Original Article |

Antipsychotic Drug Effects on Brain Morphology in First-Episode Psychosis FREE

Jeffrey A. Lieberman, MD; Gary D. Tollefson, MD, PhD; Cecil Charles, PhD; Robert Zipursky, MD; Tonmoy Sharma, MD; Rene S. Kahn, MD, PhD; Richard S. E. Keefe, PhD; Alan I. Green, MD; Raquel E. Gur, MD, PhD; Joseph McEvoy, MD; Diana Perkins, MD, MPH; Robert M. Hamer, PhD; Hongbin Gu, PhD; Mauricio Tohen, MD, DrPH; HGDH Study Group
[+] Author Affiliations

Author Affiliations: Departments of Psychiatry, University of North Carolina School of Medicine, Chapel Hill (Drs Lieberman, Perkins, Hamer, and Gu); University of Utrecht Medical School, Utrecht, the Netherlands (Dr Kahn); Duke University School of Medicine, Durham, NC (Drs Keefe and McEvoy); Dartmouth Medical School, Hanover, NH (Dr Green); University of Pennsylvania School of Medicine, Philadelphia (Dr Gur); Harvard Medical School, Boston, Mass (Dr Tohen); Lilly Research Laboratories, Indianapolis, Ind (Drs Tollefson and Tohen); Department of Radiology, Duke University School of Medicine (Dr Charles); University of Toronto Faculty of Medicine, Toronto, Ontario (Dr Zipursky); and Clinical Neuroscience Research Centre, Kent, England (Dr Sharma). Dr Lieberman is now with the Department of Psychiatry, College of Physicians and Surgeons, Columbia University, and New York State Psychiatric Institute, New York.


Arch Gen Psychiatry. 2005;62(4):361-370. doi:10.1001/archpsyc.62.4.361.
Text Size: A A A
Published online

Background  Pathomorphologic brain changes occurring as early as first-episode schizophrenia have been extensively described. Longitudinal studies have demonstrated that these changes may be progressive and associated with clinical outcome. This raises the possibility that antipsychotics might alter such pathomorphologic progression in early-stage schizophrenia.

Objective  To test a priori hypotheses that olanzapine-treated patients have less change over time in whole brain gray matter volumes and lateral ventricle volumes than haloperidol-treated patients and that gray matter and lateral ventricle volume changes are associated with changes in psychopathology and neurocognition.

Design  Longitudinal, randomized, controlled, multisite, double-blind study. Patients treated and followed up for up to 104 weeks. Neurocognitive and magnetic resonance imaging (MRI) assessments performed at weeks 0 (baseline), 12, 24, 52, and 104. Mixed-models analyses with time-dependent covariates evaluated treatment effects on MRI end points and explored relationships between MRI, psychopathologic, and neurocognitive outcomes.

Setting  Fourteen academic medical centers (United States, 11; Canada, 1; Netherlands, 1; England, 1).

Participants  Patients with first-episode psychosis (DSM-IV) and healthy volunteers.

Interventions  Random allocation to a conventional antipsychotic, haloperidol (2-20 mg/d), or an atypical antipsychotic, olanzapine (5-20 mg/d).

Main Outcome Measures  Brain volume changes assessed by MRI.

Results  Of 263 randomized patients, 161 had baseline and at least 1 postbaseline MRI evaluation. Haloperidol-treated patients exhibited significant decreases in gray matter volume, whereas olanzapine-treated patients did not. A matched sample of healthy volunteers (n = 58) examined contemporaneously showed no change in gray matter volume.

Conclusions  Patients with first-episode psychosis exhibited a significant between-treatment difference in MRI volume changes. Haloperidol was associated with significant reductions in gray matter volume, whereas olanzapine was not. Post hoc analyses suggested that treatment effects on brain volume and psychopathology of schizophrenia may be associated. The differential treatment effects on brain morphology could be due to haloperidol-associated toxicity or greater therapeutic effects of olanzapine.

Figures in this Article

Structural brain abnormalities have been extensively and consistently described in patients with schizophrenia.13 This pathomorphologic finding has been most commonly demonstrated as brain volume differences involving the ventricular system and cortical and subcortical gray matter regions in patients with schizophrenia compared with matched healthy volunteers. Longitudinal studies using high-resolution magnetic resonance imaging (MRI) to examine brain structure have found that MRI volume (hereafter referred to simply as “volume”) changes were progressive over time and related to the illness course and treatment outcome of patients with first-episode,49 chronic,10,11 and childhood-onset12,13 schizophrenia. These findings suggest that although schizophrenia may arise from a neurodevelopmental diathesis, its pathophysiology may be progressive after the onset of illness.14,15 They also raise the question of what role medication may have in mitigating schizophrenia-associated pathomorphologic changes or, alternatively, contributing to such changes. Preclinical studies have suggested the possibility of specific atypical antipsychotic drugs having pharmacologic properties that could produce neurotrophic, neurogenetic, or neuroprotective effects.1622

We addressed these questions in a controlled trial of first-episode psychosis, in which patients were randomized to either a conventional antipsychotic (haloperidol) or an atypical antipsychotic (olanzapine). We hypothesized that (1) olanzapine-treated patients would have less change over time in whole brain gray matter (WBGM) volumes and lateral ventricle volumes than haloperidol-treated patients; (2) decreases in gray matter volumes and increases in lateral ventricle volumes over time would be associated with less improvement on measures of psychopathology and neurocognitive functioning; and (3) caudate nuclei volumes would be differentially affected by treatment, increasing in response to haloperidol and with little or no change in response to olanzapine.

This longitudinal study was conducted from March 1, 1997, to July 31, 2001, at 14 academic medical centers (11 in the United States, 1 in Canada, 1 in the Netherlands, and 1 in England).

PATIENTS

Patients who presented to clinical services (inpatient, emergency, and outpatient) for evaluation and treatment of psychotic symptoms were enrolled in the study if they met the following inclusion and exclusion criteria: age 16 to 40 years; onset of psychotic symptoms before age 35 years; diagnosis of schizophrenia, schizophreniform, or schizoaffective disorder according to DSM-IV criteria (as assessed with the Structured Clinical Interview for DSM-IV, Research Version23); previous antipsychotic drug treatment of more than 16 cumulative weeks, or treatment with clozapine at any time in the patient’s lifetime; no current substance dependence (except caffeine and nicotine) by DSM-IV within 1 month before study entry; no current indication of serious suicidal risk; female subjects not pregnant or nursing; premorbid IQ of 70 or more; no requirement of concurrent treatment with anticonvulsants, benzodiazepines (except as allowed for agitation and control of extrapyramidal symptoms), antidepressants, psychostimulants, or other antipsychotic drugs at study entry; and no contraindication for neuroimaging per current regulations from the local regulatory agency (eg, metal prostheses). Each patient (or a patient’s authorized legal representative) had to understand the nature of the study and sign an informed consent document. Each site’s institutional review board approved the study.

STUDY DESIGN AND PROCEDURES

Patients were randomized to double-blind treatment with olanzapine, 5 to 20 mg/d, or haloperidol, 2 to 20 mg/d, for up to 104 weeks. Permitted concomitant medications included chloral hydrate, 500 to 2000 mg/d; lorazepam, 1 to 8 mg/d; or diazepam, 5 to 40 mg/d, for the management of agitation, general behavior disturbances, and/or insomnia. Concomitant medications were allowed only for a cumulative duration of no more than 21 days.

If clinically important extrapyramidal symptoms emerged, anticholinergic medication (benztropine mesylate or biperiden, up to 6 mg/d; propranolol hydrochloride, 10-80 mg/d; or procyclidine hydrochloride [oral or intramuscular administration of 5-10 mg, 2-3 times daily, up to 30 mg/d]) was also permitted. Antidepressants (except fluoxetine hydrochloride) and/or mood stabilizers were not allowed in the first 12 weeks of the study but could be added if clinically indicated thereafter.

EFFICACY ASSESSMENTS

Patients were assessed by MRI at weeks 0 (baseline), 12, 24, 52, and 104. Patients who dropped out were assessed by MRI until the point at which they dropped out. A very small number of subjects (12) missed a scheduled MRI assessment but did not drop out and were assessed at the next scheduled MRI assessment. All MRI studies were performed with a 1.5-T MRI system. Six of the 8 imaging sites used Signa scanners (General Electric Co, Milwaukee, Wis), and 2 sites used a Gyroscan scanner (Philips Medical Systems, Best, the Netherlands). Two imaging centers studied subjects from more than 1 clinical site. Each subject laid supine with his or her head situated in the head holder for the radiofrequency coil. Two image-intensity standards were placed on either side of the subject’s head. The imaging protocol included 3-dimensional T1-weighted, inversion recovery–prepared spoiled gradient-recalled acquisition in steady state images (0.94 × 0.94 × 1.50 mm, axial direction) and contiguous proton density and T2-weighted fast spin-echo images (0.94 × 0.94 × 3.00 mm, axial slicing direction). Quality-control scans were performed twice a month on each MRI system with standardized imaging phantoms. The imaging component of the study was centrally coordinated (by one of us [C.C.] at Duke Imaging and Analysis Laboratory, Durham, NC) and included site training, MRI system monitoring, and centralized data analysis. The coordinating center remained blinded throughout the trial. Every data set was processed by means of an automated, atlas-based, multichannel brain-tissue segmentation program that generates detailed maps of gray matter, white matter, and cerebrospinal fluid.24 This processing includes a bias-field correction that adjusts for intensity in homogeneities in the data sets. On the basis of Talairach coordinates, a 3-dimensional brain atlas was divided into 16 discrete boxes (parcellated volumes) for regional measurements. The image sets were aligned to the atlas before the automated, atlas-based, multichannel segmentation was applied. Volumes of gray and white matter and cerebrospinal fluid were extracted from each of the 16 parcellated volumes. Anatomically guided combinations of these volumes approximate the frontal, temporal, parietal, and occipital lobes. A rater-guided connectivity-based masking method was used to separate the lateral ventricles from voxel-based cerebrospinal fluid segmentation. Caudate volumes were obtained with manual outlining. Rigorous standardization and quality-control procedures were used, and reliability of measurements across sites was established and maintained throughout the study.25

Psychopathology and neurocognitive outcomes were the other primary assessments of efficacy. Psychopathology was assessed by the 30-item Positive and Negative Syndrome Scale (PANSS)26 (1-7 severity score) and Clinical Global Impressions–Severity27 scale (1-7 score). Neurocognitive function was assessed by a neuropsychological test battery that evaluated attention, verbal fluency, verbal learning and memory, working memory, visuomotor processing, and motor speed. (Complete methods for this clinical trial, including psychopathology and neurocognitive assessments, have been previously described.28,29)

HEALTHY VOLUNTEERS

Fifty-eight healthy volunteers matched to the patients’ demographic characteristics were ascertained from respondents to advertisements at 4 of the 14 study sites (University of North Carolina, Chapel Hill; University of Toronto, Toronto, Ontario; Harvard Medical School, Boston, Mass; and Institute of Psychiatry, Maudsley Hospital, London, England). Volunteers were screened for medical and psychiatric history in face-to-face interviews and underwent a physical examination and laboratory testing to rule out medical or psychiatric conditions.

STATISTICAL METHODS

Two analysis populations were used to analyze the MRI data: the intent-to-treat (ITT) population (all randomized patients who received at least a baseline scan) and a modified ITT (MITT) population (that subset of the ITT population who received the baseline MRI and at least 1 postbaseline MRI during follow-up period under experimental treatment). The primary analysis used this MITT population, since it was only possible to estimate changes in subjects with baseline and at least 1 postbaseline MRI assessment. To ensure that our findings were not an artifact of the MITT population, we repeated the primary analyses including the subjects who received baseline scans only, carrying forward observations for these patients. This was a conservative sensitivity analysis, because carrying forward baseline observations for subjects with no postbaseline measurements created in both treatment groups a cohort of subjects for whom MRI measures did not change over time, thus minimizing the differences between the means over time. The primary analysis of the MITT population is the analysis presented.

All analyses were conducted with SAS 8.2 (SAS Institute Inc, Cary, NC). We used random-coefficient mixed models to compare the 2 treatments regarding changes over time (baseline to weeks 12, 24, 52, and 104) in the volumes of 7 primary MRI regions of interest (ROIs): whole brain, WBGM, whole brain white matter, whole brain fluid, lateral ventricles, third ventricle, and caudate nucleus. A Bonferroni-corrected α of .05/7 = .00714 was used to control for multiple comparisons. This model fitted separate intercepts, linear slopes, and quadratic slopes for the 2 treatments over the 5 time points. We considered covariates such as investigator, treatment × investigator interaction, sex, duration of illness, and intracranial volume. We eliminated sex as a covariate because sex-specific volume differences could be explained by intracranial volume if necessary. We used WBGM as the response variable for which we refined the model and eliminated covariates, one by one, since they either were nonsignificant or did not appreciably alter the treatment effects, and the resulting final model contained as predictors only drug treatment (olanzapine or haloperidol) and duration of illness. Having arrived at the set of predictors, we fit the same simple and straightforward model to the 7 primary ROIs, as we believed it would be inappropriate to select potentially different individual sets of covariates for each ROI. From the full model, we eliminated all covariates except duration of illness, one by one, since each either was not significantly related to response or did not appreciably alter the treatment effects. The final random-coefficient, mixed-growth-curve model used baseline-to-observation point as the response variable (with separate intercepts, linear slopes, and quadratic slopes for each therapy), using duration of illness as a covariate. The same model was fit to the secondary ROIs (frontal, temporal, parietal, and occipital gray matter volumes). As a secondary analysis to place these effects in context, we obtained volumes on healthy controls on 3 occasions (baseline, week 12, and week 52) and did a similar mixed-model analysis, although the duration-of-illness covariate was omitted because the controls were healthy.

To examine the associations between the changes in morphologic variables, psychopathology variables, and neurocognitive functioning in response to treatment, we used repeated-measure mixed-model analysis with observed cases at each time point. (All variables were selected from a priori hypotheses including MRI variables [WBGM, lateral ventricular], psychopathology variables [PANSS total, positive, and negative subscales], and the first principal component derived from the cognitive battery.) Changes in PANSS scores at follow-ups were modeled as repeated measures, whereas the concurrent MRI changes and interaction between therapy and MRI changes were modeled as time-dependent covariates. Other non–time-dependent covariates included baseline PANSS score, age, sex, investigator, and therapy. The same modeling approach was applied to the neurocognitive variable.

Demographic information and baseline volumes were presented as descriptive statistics. Categorical data were evaluated by Fisher exact and χ2 tests. All hypothesis tests were performed with a 2-sided α = .05.

For this study, the protocol-designated primary analysis consisted of comparisons between haloperidol and olanzapine on changes from baseline for the 7 primary ROIs. All other analyses were designated as secondary or exploratory, and findings resulting from those analyses should be considered to be suggestive of hypotheses for future studies.

Figure 1 presents the patient flowchart. Of the 263 patients randomized (ITT), 239 had baseline MRI, and 161 (MITT) received a baseline and at least 1 follow-up MRI measure. The demographic and clinical characteristics of the MITT sample are given in Table 1. The ITT and MITT samples did not differ significantly with respect to demographic and clinical characteristics. Among the MITT patients, the treatment groups differed significantly on duration of illness; this difference was used as a covariate in further MRI analyses.

Place holder to copy figure label and caption
Figure 1.

Flowchart of patient sample ascertained and assessed. MR indicates magnetic resonance.

Graphic Jump Location
Table Graphic Jump LocationTable 1. Demographic and Clinical Characteristics of 161 Patients (MITT Sample) and 62 Normal Controls
TREATMENT RESPONSE: MRI

Table 2 and Table 3 contain results for the ROI-specific volume changes (by treatment group) from baseline to each time point. The final model for all ROIs was based on effect, covariate, and covariance structure selection used with WBGM.

Table Graphic Jump LocationTable 2. Changes in MRI Volumes for Primary Regions of Interest by Treatment Group (Baseline to Weeks 12, 24, 52, and 104)
Table Graphic Jump LocationTable 3. Changes in MRI Volumes for Secondary Regions of Interest by Treatment Group (Baseline to Weeks 12, 24, 52, and 104)

Using a .00714 significance level, corrected analyses of the primary ROIs demonstrated a significant difference in WBGM volume change between the 2 treatment groups at weeks 12 and 24 (Table 2). Figure 2 shows the WBGM mean changes for weeks 12, 24, 52, and 104. The olanzapine group appeared to largely retain WBGM, whereas the haloperidol group appeared to lose gray matter over time. Most of the decline in the haloperidol group appeared to occur during the first 12 weeks. Although the magnitude of the differences between the groups remained reasonably constant over time, significance was lost at the later time points because the standard error of the estimates increased as a result of increasing patient dropouts. Although no consistent treatment effects met the multiplicity-corrected α = .00714 for the other ROIs, increases in lateral ventricle and caudate nucleus volumes reached uncorrected significance levels of .05 at weeks 24, 52, and 104 (Table 2). To understand whether the gray matter was changing differentially, we examined frontal, temporal, parietal, and occipital gray matter changes (Table 3). For frontal gray matter, a significant difference occurred between the therapies at weeks 12 and 24 (using the same multiplicity-corrected α = .00714). When not correcting for multiple comparisons (α = .05), significant differences were seen for temporal gray matter (weeks 24 and 52) and parietal gray matter (weeks 12 and 24).

Place holder to copy figure label and caption
Figure 2.

Mean changes in whole brain gray matter volumes by treatment group (from baseline to weeks 12, 24, 52, and 104) and healthy control group (from baseline to weeks 12 and 52). Hal indicates haloperidol; Olz, olanzapine; Con, controls; and limit lines, standard error.

Graphic Jump Location

Caudate nucleus volumes increased in the haloperidol-treated patients compared with the olanzapine group, the differences reaching significance (α = .05) at weeks 24, 52, and 104 (Table 2).

PATIENTS AND HEALTHY VOLUNTEERS: MRI

A random-coefficient mixed model was fit for data from both the patient groups and the control group. Figure 2 displays WBGM volume changes from baseline to weeks 12 and 52 for patients and controls. Using the same multiplicity-corrected α = .00714, haloperidol-treated patients exhibited significant decreases in WBGM compared with controls at weeks 12 (P = .005) and 52 (P<.001), whereas olanzapine-treated patients did not. Using α = .05, we secondarily examined gray volume in individual lobes and found significant differences for frontal gray between the haloperidol and control groups at weeks 12 (P<.001) and 52 (P<.001). A similar pattern of significant differences in temporal and parietal gray matter volumes was seen at week 52 (P = .03 and P = .002, respectively).

SENSITIVITY ANALYSES

Data from 239 patients with baseline, but no follow-up, MRIs were used for these analyses. (At all time points in both the ITT and MITT samples, more haloperidol-treated patients than olanzapine-treated patients dropped out.) By week 104, 29 olanzapine-treated patients and 14 haloperidol-treated patients remained in the MITT sample (P = .01; Fisher exact test). (Since the proportion of patients who dropped out was larger in the haloperidol group than in the olanzapine group, this greater number of baseline observations carried forward would have resulted in a smaller change in the haloperidol group. In fact, the opposite happened: there was still little or no change in the olanzapine group, with change in the haloperidol group.) The results of this analysis were similar to those of the primary MITT analysis. In this secondary analysis, the groups differed significantly, with haloperidol-treated patients showing greater reductions than olanzapine-treated patients in WBGM at weeks 12 (mean [SE]: −3.42 cm3 [1.18 cm3] vs 1.24 cm3 [1.17 cm3]; P = .008), 24 (−4.26 cm3 [1.11 cm3] vs −0.04 cm3 [1.17 cm3]; P = .01), 52 (−5.41 cm3 [1.20 cm3] vs −1.75 cm3 [1.30 cm3]; P = .004), and 104 (−4.47 cm3 [1.23 cm3] vs −0.25 cm3 [1.34 cm3]; P = .01); and in frontal gray matter specifically at weeks 12 (−2.89 cm3 [0.70 cm3] vs 0.17 cm3 [0.77 cm3]; P = .004), 24 (−3.20 cm3 [0.66 cm3] vs −0.76 cm3 [0.71 cm3]; P = .01), and 104 (−3.24 cm3 [0.73 cm3] vs −1.06 cm3 [0.81 cm3]; P = .047). Other sensitivity analysis results were also consistent with the results found in the MITT sample.

BRAIN MORPHOLOGY AND CLINICAL RESPONSE

There were significant associations between changes in PANSS scores and lateral ventricular volumes (PANSS total: F1,207 = 4.76, P = .03; PANSS negative: F1,208 = 7.74, P = .006). Greater improvements in PANSS total and negative scores were associated with less lateral ventricular volume increase for the olanzapine group. For olanzapine-treated patients, each 1-cm3 increase in lateral ventricular volume was associated with 0.8-point reduction in improvement on PANSS total subscale (SE = 0.3, F1,207 = 5.86, P = .01, effect size g = 0.36, small to moderate association) and 0.3-point reduction in improvement on PANSS negative (SE = 0.1, F1,208 = 7.02, P = .01, g = 0.37, small to moderate association). Similar associations were not significant for the haloperidol group. We also found group differences in associations between changes in neurocognitive functioning and changes in gray matter volumes (WBGM: F1,133 = 2.69, P = .10; parietal gray: F1,133 = 5.24, P = .02; frontal gray: F1,133 = 5.71, P = .02). For haloperidol-treated patients, less improvement in neurocognitive functioning was associated with greater decrease in gray matter volumes. This association was moderate (F1,133 = 6.92, P = .01, g = 0.46) for the WBGM volume and greatest for the frontal and parietal lobes (F1,133 = 11.56, P = .001, g = 0.59 and F1,133 = 9.54, P = .003, g = 0.54, respectively). Similar associations were not significant for the olanzapine group.

These results are consistent with previous studies in first-episode schizophrenia that reported changes in gray matter volume over time.46,8,9 They also replicate findings of caudate volume increases associated with conventional antipsychotics but not atypical drugs.30,31 The principal new finding of this study is the significant difference in the course and magnitude of these changes between patients treated with haloperidol, a conventional antipsychotic, and olanzapine, an atypical antipsychotic. Specifically, olanzapine was associated with less such change in brain volume observed during and in the aftermath of the first psychotic episode. These differences in volume change were highlighted by the comparison with healthy volunteers, which showed no significant reductions in gray matter volume and a trajectory similar to that of the olanzapine group.

These results are also consistent with previous studies that included first-episode patients with schizophrenia who predominantly received conventional antipsychotics.46,8

To our knowledge, the relative absence of such volume changes in olanzapine-treated patients has not been previously reported. The mean ± SE maximum WBGM volume loss was −12.80 ± 2.51 cm3, or −1.9%, for the haloperidol group and −3.70 ± 1.72 cm3, or −0.5%, for the olanzapine group (Table 2). This magnitude of WBGM volume loss was less than that seen in elderly patients with Alzheimer disease (−5.03% per year) followed up over a similar timeframe32 and comparable with the magnitude of change observed in previous schizophrenia studies.8,9,13 The mean ± SE maximum WBGM volume decreases in our haloperidol-treated patients were predominantly seen in the frontal (−7.56 ± 2.04 cm3, or −2.4%), parietal (−3.65 ± 2.09 cm3, or −2.9%), and temporal (−1.33 ± 2.56 cm3, or −1.1%) lobes, whereas little change was seen in the occipital lobes (Table 3). These results conform to the ROIs that have been implicated in the theoretical models of the pathophysiology of schizophrenia33 and in previous postmortem34 and in vivo imaging studies13 and also are consistent with the cortical regions showing volume reductions in previous first-episode schizophrenia studies.8,9,13

While it appeared that most of the volume change occurred in the first 12 weeks of treatment, it is not clear whether progressive loss of gray matter was an acute phenomenon associated with the active phase of the illness and manifest symptoms, or, alternatively, the result of attrition in the extended follow-up phase of the study. A potential limitation of the high attrition rate is that the retained subset of patients may not be representative of the entire sample. However, a comparison of the baseline characteristics between the patients who completed 24, 52, and 104 weeks of the study and all patients who were randomized showed no meaningful differences. Moreover, a sensitivity analysis of 239 patients with at least baseline MRI, carrying forward observations (including baseline) when patients dropped out without obtaining follow-up MRIs, produced the same pattern of results, suggesting that the findings are not due to the particular pattern or differential nature of the attrition.

There are several possible explanations for the differences in the observed brain volume changes in the haloperidol- and olanzapine-treated patients. Although it is possible that these changes could be due to an artifact inherent in the image acquisition or analysis process, we do not believe that this was the case, as we could neither identify nor think of one that could produce this effect. Moreover, an artifactual process would presumably be random and not systematically affect only patients in one treatment group or the other. A second possibility is that treatments are not affecting brain structure per se but may alter blood flow and metabolism in the brain.3538 This possibility cannot be ruled out by the methods used for data acquisition in this study. A third explanation is a possible toxic effect of haloperidol that has been suggested to potentially induce oxidative stress and excitatory neurotoxicity.3941 In addition, caudate enlargement is known to be due to treatment effects of conventional drugs causing ultrastructural changes in striatal neurons4244 and alterations of dendritic morphology in cortical neurons.45,46 However, in this study a relatively low dose of haloperidol was used (which may have accounted for the delayed and modest caudate volume enlargement that was seen), and there was no correlation between dose and brain volume change. An alternative interpretation of the brain volume changes observed in this study is that they reflect the underlying pathophysiology and progressive nature of schizophrenia.14,15 Accordingly, if the changes in brain volume (that we and other investigators have found) reflect the pathological progression associated with schizophrenia, it is possible that olanzapine could have ameliorated this process, whereas haloperidol did not. Antipsychotic drugs have been suggested to have effects on neuroplasticity including synaptic remodeling and neurogenesis.47 Specific atypical antipsychotic drugs (particularly clozapine and olanzapine) have been reported to have various actions that could enhance cellular resilience and ameliorate the pathophysiology of schizophrenia. These include the antagonism of the effects of N-methyl-D-aspartate receptor antagonists,16,48 increased expression of trophic factors,1719 and stimulation of neurogenesis.2022 Consequently, these various actions of specific atypical antipsychotic drugs could be seen as ameliorating pathophysiologic effects on cell processes and synapses or enhancing their ability to withstand such insults. In this context, Wang and Deutch49 recently reported that olanzapine treatment prevented decreases in the spine density of basilar dendrites on layers II/III and V of prefrontal cortex pyramidal neurons in rats in which lesions of cortical dopamine innervation were created by injection of 6-hydroxydopamine into the ventral tegmental area.

A consistent finding of postmortem studies in schizophrenia has been the decrease in cortical neuropil relative to tissue from control subjects.50 These neuropathology findings are consistent with the gray matter volume reduction seen in MRI studies. Thus, subtle disease-associated loss of cell processes may be observed morphometrically as changes in gray matter volume.

The associations between greater decrease in WBGM volume and less improvement in neurocognitive functioning, and greater improvements on PANSS total and negative subscales with less increase in lateral ventricular volume indicate that treatment effects on brain volume and the behavioral pathology of the illness may be associated. These clinical and volumetric associations are also consistent with some4,6,9,13 but not all5 previous studies. Although these results must be confirmed, they suggest that a significant difference exists between a typical antipsychotic (haloperidol) and an atypical agent (olanzapine) that is due to either a safety or efficacy advantage and reflected by a differential pattern of brain volume change and clinical response. Future clinical studies should attempt to verify whether the early stage of psychosis is associated with brain volume changes and whether antipsychotics can neurobiologically alter the course of the disease.

Correspondence: Jeffrey A. Lieberman, MD, New York State Psychiatric Institute, 1051 Riverside Dr, Unit 4, New York, NY 10032 (jlieberman@pi.cpmc.columbia.edu).

Submitted for Publication: June 1, 2004; final revision received August 20, 2004; accepted September 9, 2004.

Funding/Support: This work was supported by Lilly Research Laboratories, Indianapolis, Ind; Public Health Service grants MH00537 and MH33127 from the National Institute of Mental Health, National Institutes of Health, Bethesda, Md; the University of North Carolina Mental Health and Neuroscience Clinical Research Center, Chapel Hill; grants MH52376 (Dr Lieberman) and MH62157 (Dr Green) from the National Institute of Mental Health; the North Carolina Foundation of Hope, Raleigh; and the National Alliance for Research on Schizophrenia and Depression (NARSAD) Foundation, Great Neck, NY.

Previous Presentation: This study was presented at the Society for Neuroscience; November 10, 2003; New Orleans, La; and the 42nd Annual Meeting of the American College of Neuropsychopharmacology; December 10, 2003; San Juan, Puerto Rico.

Acknowledgment: We thank Svetlana Dominguez and Janice Linn for their editorial assistance.

Box Section Ref ID

The HGDH Study Group

The term HGDH is a naming convention used by the sponsor and has no significance. The HGDH study group consisted of the following people who participated in the design and execution of the study: Jeffrey A. Lieberman, MD, and Diana Perkins, MD, MPH, Department of Psychiatry, University of North Carolina School of Medicine, Chapel Hill; Charles B. Nemeroff, MD, PhD, Department of Psychiatry, Emory University School of Medicine, Atlanta, Ga; Franca Centorrino, MD, and Bruce Cohen, MD, PhD, McLean Hospital, Harvard Medical School, Belmont, Mass; Gary D. Tollefson, MD, PhD, Todd Sanger, PhD, and Mauricio Tohen, MD, DrPH, Lilly Research Laboratories, Indianapolis, Ind; Joseph P. McEvoy, MD, Cecil Charles, PhD, and Richard S. E. Keefe, PhD, John Umstead Hospital, Duke University Health System, Durham, NC; John Kuldau, MD, Department of Psychiatry, University of Florida, Gainesville; Alan I. Green, MD, Massachusetts Mental Health Center, Harvard Medical School, Boston; Anthony J. Rothschild, MD, and Jayendra K. Patel, MD, Department of Psychiatry, University of Massachusetts Medical Center, Worcester; Raquel E. Gur, MD, PhD, Department of Psychiatry, University of Pennsylvania Medical Center, Philadelphia; Robert B. Zipursky, MD, and Zafiris J. Daskalakis, MD, FRCPC, Department of Psychiatry, University of Toronto Faculty of Medicine, Toronto, Ontario; Stephen M. Strakowski, MD, Department of Psychiatry, University of Cincinnati, Cincinnati, Ohio; Ira Glick, MD, Department of Psychiatry, Stanford University School of Medicine, Stanford, Calif; John De Quardo, MD, Department of Psychiatry, University of Michigan Medical Center, Ann Arbor; Rene S. Kahn, MD, PhD, University Hospital Utrecht, Utrecht, the Netherlands; Tonmoy Sharma, MD, Clinical Neuroscience Research Centre, Kent, England; and Robin Murray, MD, DSc, Institute of Psychiatry, London, England.

McCarley  RWWible  CGFrumin  MHirayasu  YLevitt  JJFischer  IAShenton  ME MRI anatomy of schizophrenia. Biol Psychiatry 1999;451099- 1119
PubMed
Shenton  MEDickey  CCFrumin  MMcCarley  RW A review of MRI findings in schizophrenia. Schizophr Res 2001;491- 52
PubMed
Lawrie  SMAbukmeil  SS Brain abnormality in schizophrenia: a systematic and quantitative review of volumetric magnetic resonance imaging studies. Br J Psychiatry 1998;172110- 120
PubMed
DeLisi  LESakuma  MTew  WKushner  MHoff  ALGrimson  R Schizophrenia as a chronic active brain process: a study of progressive brain structural change subsequent to the onset of schizophrenia. Psychiatry Res 1997;74129- 140
PubMed
Gur  RECowell  PTuretsky  BIGallacher  FCannon  TBilker  WGur  RC A follow-up magnetic resonance imaging study of schizophrenia: relationship of neuroanatomical changes to clinical and neurobehavioral measures. Arch Gen Psychiatry 1998;55145- 152
PubMed
Lieberman  JChakos  MWu  HAlvir  JHoffman  ERobinson  DBilder  R Longitudinal study of brain morphology in first episode schizophrenia. Biol Psychiatry 2001;49487- 499
PubMed
Wood  SJVelakoulis  DSmith  DJBond  DStuart  GWMcGorry  PDBrewer  WJBridle  NEritaia  JDesmond  PSingh  BCopolov  DPantelis  C A longitudinal study of hippocampal volume in first episode psychosis and chronic schizophrenia. Schizophr Res 2001;5237- 46
PubMed
Cahn  WPol  HELems  EBvan Haren  NESchnack  HGvan der Linden  JASchothorst  PFvan Engeland  HKahn  RS Brain volume changes in first-episode schizophrenia: a 1-year follow-up study. Arch Gen Psychiatry 2002;591002- 1010
PubMed
Ho  BCAndreasen  NCNopoulos  PArndt  SMagnotta  VFlaum  M Progressive structural brain abnormalities and their relationship to clinical outcome: a longitudinal magnetic resonance imaging study early in schizophrenia. Arch Gen Psychiatry 2003;60585- 594
PubMed
Davis  KLBuchsbaum  MSShihabuddin  LSpiegel-Cohen  JMetzger  MFrecska  EKeefe  RSPowchik  P Ventricular enlargement in poor-outcome schizophrenia. Biol Psychiatry 1998;43783- 793
PubMed
Mathalon  DHSullivan  EVLim  KOPfefferbaum  A Progressive brain volume changes and the clinical course of schizophrenia in men: a longitudinal magnetic resonance imaging study. Arch Gen Psychiatry 2001;58148- 157
PubMed
Rapoport  JLGiedd  JNBlumenthal  JHamburger  SJeffries  NFernandez  TNicolson  RBedwell  JLenane  MZijdenbos  APaus  TEvans  A Progressive cortical change during adolescence in childhood-onset schizophrenia: a longitudinal magnetic resonance imaging study. Arch Gen Psychiatry 1999;56649- 654
PubMed
Gogtay  NSporn  AClasen  LSGreenstein  DGiedd  JNLenane  MGochman  PAZijdenbos  ARapoport  JL Structural brain MRI abnormalities in healthy siblings of patients with childhood-onset schizophrenia. Am J Psychiatry 2003;160569- 571
PubMed
Woods  BT Is schizophrenia a progressive neurodevelopmental disorder? toward a unitary pathogenetic mechanism. Am J Psychiatry 1998;1551661- 1670
PubMed
Lieberman  JA Is schizophrenia a neurodegenerative disorder? a clinical and pathophysiological perspective. Biol Psychiatry 1999;46729- 739
PubMed
Duncan  GEMiyamoto  SLeipzig  JNLieberman  JA Comparison of the effects of clozapine, risperidone, and olanzapine on ketamine-induced alterations in regional brain metabolism. J Pharmacol Exp Ther 2000;2938- 14
PubMed
Fumagalli  FMolteni  RRoceri  MBedogni  FSantero  RFossati  CGennarelli  MRacagni  GRiva  MA Effect of antipsychotic drugs on brain-derived neurotrophic factor expression under reduced N-methyl-D-aspartate receptor activity. J Neurosci Res 2003;72622- 628
PubMed
Bai  OChlan-Fourney  JBowen  RKeegan  DLi  XM Expression of brain-derived neurotrophic factor mRNA in rat hippocampus after treatment with antipsychotic drugs. J Neurosci Res 2003;71127- 131
PubMed
Marx  CEVanDoren  MJDuncan  GELieberman  JAMorrow  AL Olanzapine and clozapine increase the GABAergic neuroactive steroid allopregnanolone in rodents. Neuropsychopharmacology 2003;281- 13
PubMed
Wakade  CGMahadik  SPWaller  JLChiu  FC Atypical neuroleptics stimulate neurogenesis in adult rat brain. J Neurosci Res 2002;6972- 79
PubMed
Halim  NDWeickert  CSMcClintock  BWWeinberger  DRLipska  BK Effects of chronic haloperidol and clozapine treatment on neurogenesis in the adult rat hippocampus. Neuropsychopharmacology 2004;291063- 1069
PubMed
Wang  HDDunnavant  FDJarman  TDeutch  AY Effects of antipsychotic drugs on neurogenesis in the forebrain of the adult rat. Neuropsychopharmacology 2004;291230- 1238
PubMed
First  MBSpitzer  RLGibbon  MWilliams  JBW Structured Clinical Interview for DSM-IV-TR Axis I Disorders, Research Version, Non-patient Edition (SCID-I/NP).  New YorkBiometrics Research New York State Psychiatric Institute November2002;
Van Leemput  KMaes  FVandermeulen  DSuetens  P Automated model-based tissue classification of MR images of the brain. IEEE Trans Med Imaging 1999;18897- 908
PubMed
Styner  MACharles  HCPark  JGerig  G Multisite validation of image analysis methods: assessing intra- and intersite variability. Sonka  MFitzpatrick  JMeds.Medical Imaging 2002: Image Processing. Vol 4684. Bellingham, Wash International Society for Optical Engineering2002;278- 286
Kay  SRFiszbein  AOpler  LA The Positive and Negative Syndrome Scale (PANSS) for schizophrenia. Schizophr Bull 1987;13261- 276
PubMed
 Guy W. ECDEU Assessment Manual for Psychopharmacology, Revised. Rockville, Md US Dept of Health, Education and Welfare, National Institute of Mental Health1976;Publication (ADM) 76-338
Lieberman  JATollefson  GTohen  MGreen  AIGur  REKahn  RMcEvoy  JPerkins  DSharma  TZipursky  RWei  HHamer  RM Comparative efficacy and safety of atypical and conventional antipsychotic drugs in first-episode psychosis: a randomized, double-blind trial of olanzapine versus haloperidol. Am J Psychiatry 2003;1601396- 1404
PubMed
Keefe  RSSeidman  LJChristensen  BKHamer  RMSharma  TSitskoorn  MMLewine  RRYurgelun-Todd  DAGur  RCTohen  MTollefson  GDSanger  TMLieberman  JA Comparative effect of atypical and conventional antipsychotic drugs on neurocognition in first-episode psychosis: a randomized, double-blind trial of olanzapine versus low doses of haloperidol. Am J Psychiatry 2004;161985- 995
PubMed
Chakos  MHLieberman  JAAlvir  JBilder  RAshtari  M Caudate nuclei volumes in schizophrenic patients treated with typical antipsychotics or clozapine. Lancet 1995;345456- 457
PubMed
Corson  PWNopoulos  PMiller  DDArndt  SAndreasen  NC Change in basal ganglia volume over 2 years in patients with schizophrenia: typical versus atypical neuroleptics. Am J Psychiatry 1999;1561200- 1204
PubMed
Thompson  PMHayashi  KMde Zubicaray  GJanke  ALRose  SESemple  JHerman  DHong  MSDittmer  SSDoddrell  DMToga  AW Dynamics of gray matter loss in Alzheimer’s disease. J Neurosci 2003;23994- 1005
PubMed
Lewis  DALieberman  JA Catching up on schizophrenia: natural history and neurobiology. Neuron 2000;28325- 334
PubMed
Harrison  PJ The neuropathology of schizophrenia: a critical review of the data and their interpretation. Brain 1999;122593- 624
PubMed
Miller  DDAndreasen  NCO’Leary  DSRezai  KWatkins  GLPonto  LLHichwa  RD Effect of antipsychotics on regional cerebral blood flow measured with positron emission tomography. Neuropsychopharmacology 1997;17230- 240
PubMed
Lahti  ACHolcomb  HHWeiler  MAMedoff  DRFrey  KNHardin  MTamminga  CA Clozapine but not haloperidol reestablishes normal task-activated rCBF patterns in schizophrenia within the anterior cingulate cortex. Neuropsychopharmacology 2004;29171- 178
PubMed
Molina  VGispert  JDReig  SSanz  JPascau  JSantos  APalomo  TDesco  M Cerebral metabolism and risperidone treatment in schizophrenia. Schizophr Res 2003;601- 7
PubMed
Cohen  RMNordahl  TESemple  WEPickar  D The brain metabolic patterns of clozapine- and fluphenazine-treated female patients with schizophrenia: evidence of a sex effect. Neuropsychopharmacology 1999;21632- 640
PubMed
Post  AHolsboer  FBehl  C Induction of NF-kappaB activity during haloperidol-induced oxidative toxicity in clonal hippocampal cells: suppression of NF-κB and neuroprotection by antioxidants. J Neurosci 1998;188236- 8246
PubMed
Wright  AMBempong  JKirby  MLBarlow  RLBloomquist  JR Effects of haloperidol metabolites on neurotransmitter uptake and release: possible role in neurotoxicity and tardive dyskinesia. Brain Res 1998;788215- 222
PubMed
Goff  DCTsai  GBeal  MFCoyle  JT Tardive dyskinesia and substrates of energy metabolism in CSF. Am J Psychiatry 1995;1521730- 1736
PubMed
Chakos  MHShirakawa  OLieberman  JLee  HBilder  RTamminga  CA Striatal enlargement in rats chronically treated with neuroleptic. Biol Psychiatry 1998;44675- 684
PubMed
Benes  FMPaskevich  PADavidson  JDomesick  VB The effects of haloperidol on synaptic patterns in the rat striatum. Brain Res 1985;329265- 273
PubMed
Meshul  CKJanowsky  ACasey  DEStallbaumer  RKTaylor  B Effect of haloperidol and clozapine on the density of “perforated” synapses in caudate, nucleus accumbens, and medial prefrontal cortex. Psychopharmacology (Berl) 1992;10645- 52
PubMed
Lidow  MSSong  ZMCastner  SAAllen  PBGreengard  PGoldman-Rakic  PS Antipsychotic treatment induces alterations in dendrite- and spine-associated proteins in dopamine-rich areas of the primate cerebral cortex. Biol Psychiatry 2001;491- 12
PubMed
Selemon  LDLidow  MSGoldman-Rakic  PS Increased volume and glial density in primate prefrontal cortex associated with chronic antipsychotic drug exposure. Biol Psychiatry 1999;46161- 172
PubMed
Konradi  CHeckers  S Antipsychotic drugs and neuroplasticity: insights into the treatment and neurobiology of schizophrenia. Biol Psychiatry 2001;50729- 742
PubMed
Olney  JWFarber  NB Glutamate receptor dysfunction and schizophrenia. Arch Gen Psychiatry 1995;52998- 1007
PubMed
Wang  HDDeutch  AY Olanzapine reverses dopamine depletion-induced dendritic spine loss in prefrontal cortical pyramidal neurons.  Paper presented at: 34th Annual Meeting of Society for Neuroscience October 24, 2004 San Diego, Calif
Selemon  LDGoldman-Rakic  PS The reduced neuropil hypothesis: a circuit based model of schizophrenia. Biol Psychiatry 1999;4517- 25
PubMed

Figures

Place holder to copy figure label and caption
Figure 1.

Flowchart of patient sample ascertained and assessed. MR indicates magnetic resonance.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Mean changes in whole brain gray matter volumes by treatment group (from baseline to weeks 12, 24, 52, and 104) and healthy control group (from baseline to weeks 12 and 52). Hal indicates haloperidol; Olz, olanzapine; Con, controls; and limit lines, standard error.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1. Demographic and Clinical Characteristics of 161 Patients (MITT Sample) and 62 Normal Controls
Table Graphic Jump LocationTable 2. Changes in MRI Volumes for Primary Regions of Interest by Treatment Group (Baseline to Weeks 12, 24, 52, and 104)
Table Graphic Jump LocationTable 3. Changes in MRI Volumes for Secondary Regions of Interest by Treatment Group (Baseline to Weeks 12, 24, 52, and 104)

References

McCarley  RWWible  CGFrumin  MHirayasu  YLevitt  JJFischer  IAShenton  ME MRI anatomy of schizophrenia. Biol Psychiatry 1999;451099- 1119
PubMed
Shenton  MEDickey  CCFrumin  MMcCarley  RW A review of MRI findings in schizophrenia. Schizophr Res 2001;491- 52
PubMed
Lawrie  SMAbukmeil  SS Brain abnormality in schizophrenia: a systematic and quantitative review of volumetric magnetic resonance imaging studies. Br J Psychiatry 1998;172110- 120
PubMed
DeLisi  LESakuma  MTew  WKushner  MHoff  ALGrimson  R Schizophrenia as a chronic active brain process: a study of progressive brain structural change subsequent to the onset of schizophrenia. Psychiatry Res 1997;74129- 140
PubMed
Gur  RECowell  PTuretsky  BIGallacher  FCannon  TBilker  WGur  RC A follow-up magnetic resonance imaging study of schizophrenia: relationship of neuroanatomical changes to clinical and neurobehavioral measures. Arch Gen Psychiatry 1998;55145- 152
PubMed
Lieberman  JChakos  MWu  HAlvir  JHoffman  ERobinson  DBilder  R Longitudinal study of brain morphology in first episode schizophrenia. Biol Psychiatry 2001;49487- 499
PubMed
Wood  SJVelakoulis  DSmith  DJBond  DStuart  GWMcGorry  PDBrewer  WJBridle  NEritaia  JDesmond  PSingh  BCopolov  DPantelis  C A longitudinal study of hippocampal volume in first episode psychosis and chronic schizophrenia. Schizophr Res 2001;5237- 46
PubMed
Cahn  WPol  HELems  EBvan Haren  NESchnack  HGvan der Linden  JASchothorst  PFvan Engeland  HKahn  RS Brain volume changes in first-episode schizophrenia: a 1-year follow-up study. Arch Gen Psychiatry 2002;591002- 1010
PubMed
Ho  BCAndreasen  NCNopoulos  PArndt  SMagnotta  VFlaum  M Progressive structural brain abnormalities and their relationship to clinical outcome: a longitudinal magnetic resonance imaging study early in schizophrenia. Arch Gen Psychiatry 2003;60585- 594
PubMed
Davis  KLBuchsbaum  MSShihabuddin  LSpiegel-Cohen  JMetzger  MFrecska  EKeefe  RSPowchik  P Ventricular enlargement in poor-outcome schizophrenia. Biol Psychiatry 1998;43783- 793
PubMed
Mathalon  DHSullivan  EVLim  KOPfefferbaum  A Progressive brain volume changes and the clinical course of schizophrenia in men: a longitudinal magnetic resonance imaging study. Arch Gen Psychiatry 2001;58148- 157
PubMed
Rapoport  JLGiedd  JNBlumenthal  JHamburger  SJeffries  NFernandez  TNicolson  RBedwell  JLenane  MZijdenbos  APaus  TEvans  A Progressive cortical change during adolescence in childhood-onset schizophrenia: a longitudinal magnetic resonance imaging study. Arch Gen Psychiatry 1999;56649- 654
PubMed
Gogtay  NSporn  AClasen  LSGreenstein  DGiedd  JNLenane  MGochman  PAZijdenbos  ARapoport  JL Structural brain MRI abnormalities in healthy siblings of patients with childhood-onset schizophrenia. Am J Psychiatry 2003;160569- 571
PubMed
Woods  BT Is schizophrenia a progressive neurodevelopmental disorder? toward a unitary pathogenetic mechanism. Am J Psychiatry 1998;1551661- 1670
PubMed
Lieberman  JA Is schizophrenia a neurodegenerative disorder? a clinical and pathophysiological perspective. Biol Psychiatry 1999;46729- 739
PubMed
Duncan  GEMiyamoto  SLeipzig  JNLieberman  JA Comparison of the effects of clozapine, risperidone, and olanzapine on ketamine-induced alterations in regional brain metabolism. J Pharmacol Exp Ther 2000;2938- 14
PubMed
Fumagalli  FMolteni  RRoceri  MBedogni  FSantero  RFossati  CGennarelli  MRacagni  GRiva  MA Effect of antipsychotic drugs on brain-derived neurotrophic factor expression under reduced N-methyl-D-aspartate receptor activity. J Neurosci Res 2003;72622- 628
PubMed
Bai  OChlan-Fourney  JBowen  RKeegan  DLi  XM Expression of brain-derived neurotrophic factor mRNA in rat hippocampus after treatment with antipsychotic drugs. J Neurosci Res 2003;71127- 131
PubMed
Marx  CEVanDoren  MJDuncan  GELieberman  JAMorrow  AL Olanzapine and clozapine increase the GABAergic neuroactive steroid allopregnanolone in rodents. Neuropsychopharmacology 2003;281- 13
PubMed
Wakade  CGMahadik  SPWaller  JLChiu  FC Atypical neuroleptics stimulate neurogenesis in adult rat brain. J Neurosci Res 2002;6972- 79
PubMed
Halim  NDWeickert  CSMcClintock  BWWeinberger  DRLipska  BK Effects of chronic haloperidol and clozapine treatment on neurogenesis in the adult rat hippocampus. Neuropsychopharmacology 2004;291063- 1069
PubMed
Wang  HDDunnavant  FDJarman  TDeutch  AY Effects of antipsychotic drugs on neurogenesis in the forebrain of the adult rat. Neuropsychopharmacology 2004;291230- 1238
PubMed
First  MBSpitzer  RLGibbon  MWilliams  JBW Structured Clinical Interview for DSM-IV-TR Axis I Disorders, Research Version, Non-patient Edition (SCID-I/NP).  New YorkBiometrics Research New York State Psychiatric Institute November2002;
Van Leemput  KMaes  FVandermeulen  DSuetens  P Automated model-based tissue classification of MR images of the brain. IEEE Trans Med Imaging 1999;18897- 908
PubMed
Styner  MACharles  HCPark  JGerig  G Multisite validation of image analysis methods: assessing intra- and intersite variability. Sonka  MFitzpatrick  JMeds.Medical Imaging 2002: Image Processing. Vol 4684. Bellingham, Wash International Society for Optical Engineering2002;278- 286
Kay  SRFiszbein  AOpler  LA The Positive and Negative Syndrome Scale (PANSS) for schizophrenia. Schizophr Bull 1987;13261- 276
PubMed
 Guy W. ECDEU Assessment Manual for Psychopharmacology, Revised. Rockville, Md US Dept of Health, Education and Welfare, National Institute of Mental Health1976;Publication (ADM) 76-338
Lieberman  JATollefson  GTohen  MGreen  AIGur  REKahn  RMcEvoy  JPerkins  DSharma  TZipursky  RWei  HHamer  RM Comparative efficacy and safety of atypical and conventional antipsychotic drugs in first-episode psychosis: a randomized, double-blind trial of olanzapine versus haloperidol. Am J Psychiatry 2003;1601396- 1404
PubMed
Keefe  RSSeidman  LJChristensen  BKHamer  RMSharma  TSitskoorn  MMLewine  RRYurgelun-Todd  DAGur  RCTohen  MTollefson  GDSanger  TMLieberman  JA Comparative effect of atypical and conventional antipsychotic drugs on neurocognition in first-episode psychosis: a randomized, double-blind trial of olanzapine versus low doses of haloperidol. Am J Psychiatry 2004;161985- 995
PubMed
Chakos  MHLieberman  JAAlvir  JBilder  RAshtari  M Caudate nuclei volumes in schizophrenic patients treated with typical antipsychotics or clozapine. Lancet 1995;345456- 457
PubMed
Corson  PWNopoulos  PMiller  DDArndt  SAndreasen  NC Change in basal ganglia volume over 2 years in patients with schizophrenia: typical versus atypical neuroleptics. Am J Psychiatry 1999;1561200- 1204
PubMed
Thompson  PMHayashi  KMde Zubicaray  GJanke  ALRose  SESemple  JHerman  DHong  MSDittmer  SSDoddrell  DMToga  AW Dynamics of gray matter loss in Alzheimer’s disease. J Neurosci 2003;23994- 1005
PubMed
Lewis  DALieberman  JA Catching up on schizophrenia: natural history and neurobiology. Neuron 2000;28325- 334
PubMed
Harrison  PJ The neuropathology of schizophrenia: a critical review of the data and their interpretation. Brain 1999;122593- 624
PubMed
Miller  DDAndreasen  NCO’Leary  DSRezai  KWatkins  GLPonto  LLHichwa  RD Effect of antipsychotics on regional cerebral blood flow measured with positron emission tomography. Neuropsychopharmacology 1997;17230- 240
PubMed
Lahti  ACHolcomb  HHWeiler  MAMedoff  DRFrey  KNHardin  MTamminga  CA Clozapine but not haloperidol reestablishes normal task-activated rCBF patterns in schizophrenia within the anterior cingulate cortex. Neuropsychopharmacology 2004;29171- 178
PubMed
Molina  VGispert  JDReig  SSanz  JPascau  JSantos  APalomo  TDesco  M Cerebral metabolism and risperidone treatment in schizophrenia. Schizophr Res 2003;601- 7
PubMed
Cohen  RMNordahl  TESemple  WEPickar  D The brain metabolic patterns of clozapine- and fluphenazine-treated female patients with schizophrenia: evidence of a sex effect. Neuropsychopharmacology 1999;21632- 640
PubMed
Post  AHolsboer  FBehl  C Induction of NF-kappaB activity during haloperidol-induced oxidative toxicity in clonal hippocampal cells: suppression of NF-κB and neuroprotection by antioxidants. J Neurosci 1998;188236- 8246
PubMed
Wright  AMBempong  JKirby  MLBarlow  RLBloomquist  JR Effects of haloperidol metabolites on neurotransmitter uptake and release: possible role in neurotoxicity and tardive dyskinesia. Brain Res 1998;788215- 222
PubMed
Goff  DCTsai  GBeal  MFCoyle  JT Tardive dyskinesia and substrates of energy metabolism in CSF. Am J Psychiatry 1995;1521730- 1736
PubMed
Chakos  MHShirakawa  OLieberman  JLee  HBilder  RTamminga  CA Striatal enlargement in rats chronically treated with neuroleptic. Biol Psychiatry 1998;44675- 684
PubMed
Benes  FMPaskevich  PADavidson  JDomesick  VB The effects of haloperidol on synaptic patterns in the rat striatum. Brain Res 1985;329265- 273
PubMed
Meshul  CKJanowsky  ACasey  DEStallbaumer  RKTaylor  B Effect of haloperidol and clozapine on the density of “perforated” synapses in caudate, nucleus accumbens, and medial prefrontal cortex. Psychopharmacology (Berl) 1992;10645- 52
PubMed
Lidow  MSSong  ZMCastner  SAAllen  PBGreengard  PGoldman-Rakic  PS Antipsychotic treatment induces alterations in dendrite- and spine-associated proteins in dopamine-rich areas of the primate cerebral cortex. Biol Psychiatry 2001;491- 12
PubMed
Selemon  LDLidow  MSGoldman-Rakic  PS Increased volume and glial density in primate prefrontal cortex associated with chronic antipsychotic drug exposure. Biol Psychiatry 1999;46161- 172
PubMed
Konradi  CHeckers  S Antipsychotic drugs and neuroplasticity: insights into the treatment and neurobiology of schizophrenia. Biol Psychiatry 2001;50729- 742
PubMed
Olney  JWFarber  NB Glutamate receptor dysfunction and schizophrenia. Arch Gen Psychiatry 1995;52998- 1007
PubMed
Wang  HDDeutch  AY Olanzapine reverses dopamine depletion-induced dendritic spine loss in prefrontal cortical pyramidal neurons.  Paper presented at: 34th Annual Meeting of Society for Neuroscience October 24, 2004 San Diego, Calif
Selemon  LDGoldman-Rakic  PS The reduced neuropil hypothesis: a circuit based model of schizophrenia. Biol Psychiatry 1999;4517- 25
PubMed

Correspondence

CME
Meets CME requirements for:
Browse CME for all U.S. States
Accreditation Information
The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
Commitment to Change (optional):
Indicate what change(s) you will implement in your practice, if any, based on this CME course.
Your quiz results:
The filled radio buttons indicate your responses. The preferred responses are highlighted
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.
NOTE:
Citing articles are presented as examples only. In non-demo SCM6 implementation, integration with CrossRef’s "Cited By" API will populate this tab (http://www.crossref.org/citedby.html).
Submit a Comment

Multimedia

Some tools below are only available to our subscribers or users with an online account.

Related Content

Customize your page view by dragging & repositioning the boxes below.

Articles Related By Topic
Related Topics
PubMed Articles
JAMAevidence.com