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Original Article |

A Follow-up Magnetic Resonance Imaging Study of Schizophrenia:  Relationship of Neuroanatomical Changes to Clinical and Neurobehavioral Measures FREE

Raquel E. Gur, MD, PhD; Patricia Cowell, PhD; Bruce I. Turetsky, MD; Fiona Gallacher, MS; Tyrone Cannon, PhD; Warren Bilker, PhD; Ruben C. Gur, PhD
[+] Author Affiliations

From the Mental Health Clinical Research Center, Neuropsychiatry Section, Department of Psychiatry, University of Pennsylvania School of Medicine, Philadelphia.


Arch Gen Psychiatry. 1998;55(2):145-152. doi:10.1001/archpsyc.55.2.145.
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Published online

Background  Cross-sectional neuroanatomical studies have reported abnormalities in schizophrenia that relate to disease variables. Longitudinal neuroimaging investigations that integrate anatomical, clinical, and neurobehavioral measures may help clarify the pathogenesis of schizophrenia.

Methods  Magnetic resonance brain imaging and neurobehavioral studies were conducted at baseline and after 30.63±12.92 months (mean±SD) in 40 patients with schizophrenia (23 men and 17 women) and 17 healthy controls (13 men and 4 women). The schizophrenia group included 20 first-episode and 20 previously treated subjects. Volumes of whole-brain, cerebrospinal fluid, and frontal and temporal lobes were measured. The severity of negative and positive symptoms was assessed, medications were monitored, and neurobehavioral functioning in 8 domains was evaluated.

Results  Both first-episode and previously treated patients had smaller brains and frontal and temporal lobes than controls at intake. Longitudinally, reduction in frontal lobe volume was found only in patients, whereas temporal lobe reduction was also seen in controls. The association between volume reduction and symptom changes differed between patient groups, but volume reduction was associated with decline in some neurobehavioral functions in both groups. Exploratory analysis suggested that neuroleptic dose is correlated with changes in all 3 domains.

Conclusions  The existence of neuroanatomical and neurobehavioral abnormalities in patients with first-episode schizophrenia indicates that the brain dysfunction occurred before clinical presentation. However, there is also evidence of progression, in which anatomical changes may affect some clinical and neurobehavioral features of the illness in some patients.

Figures in this Article

CROSS-SECTIONAL computed tomographic1 and magnetic resonance imaging (MRI)26 studies have reported decreased brain volume in schizophrenia, affecting frontal2,3 and temporal46 regions. Abnormalities in patients with first-episode (FE) schizophrenia support a neurodevelopmental hypothesis because brain dysfunction precedes clinical presentation. However, a longitudinal design is necessary to examine the progressive deterioration suggested by the neurodegenerative hypothesis.

Computed tomographic follow-up studies reported no changes in neuroanatomy711 or increased cerebrospinal fluid (CSF) in some patients.12,13 These studies had small samples of patients with chronic illness and limited scanning and measurement procedures. An MRI follow-up scan (at 1-2 years) of 13 FE patients and 8 controls14 found no ventricular changes. DeLisi et al15 found no consistent change in ventricular size in 16 FE patients and 5 controls 2 years after intake. Decreased right temporal lobe volume was found in FE patients, but did not persist in a larger sample.16 A report on 20 of these patients and 5 controls who underwent rescanning during the next 4 years noted decreases in whole-brain (WB) volume and enlargement in left ventricular volume in FE patients.17 The limited number of longitudinal MRI studies leaves unresolved the question of progression and precludes the distinction of disease-related changes from those associated with normal aging.1821

We have applied a reliable and validated MRI method for measuring brain volume,22 yielding parameters related to sex differences and aging18,19 and to clinical features in schizophrenia.2327 We reported an age-related reduction in frontal and temporal lobe volumes in healthy men, and lower frontal and temporal lobe volumes in patients with schizophrenia. Temporal lobe volume correlated with impairment in memory and severity of negative symptoms. These were observed in FE patients, but the cross-sectional design is inadequate for establishing progression. The purpose of this prospective study was to assess changes in MRI parameters and relate them to clinical and neurobehavioral measures. Two hypotheses were tested. Patients with schizophrenia show a decline in frontal and temporal lobe volume that exceeds the age-related decline observed in controls. The degree of decline is correlated with worsening of negative symptoms, improvement of positive symptoms, and deteriorating neuropsychological performance. We also examined the association of medication dose with neuroanatomical changes.

SUBJECTS

Forty patients (20 FE and 20 previously treated [PT]; 24 inpatients, 16 outpatients) and 17 healthy controls (Table 1), whose intake data has been previously reported, participated in the longitudinal MRI study.18,19,2327 Two women were excluded because of movement during the MRI procedure. Subjects had the same clinical, neurobehavioral, and neuroanatomical measures at intake and follow-up.

Table Graphic Jump LocationTable 1. Demographic and Clinical Characteristics*

Patients had a DSM-IV diagnosis of schizophrenia that had been established by measures detailed earlier.28,29 Healthy controls underwent standard evaluations.30,31 Subjects had no disorder that might affect brain function. Informed consent was obtained prior to participation.

PROCEDURES

Studies were conducted at intake and a mean±SD of 29.8±12.2 (range, 12-63) and 32.6±14.7 (range, 15-68) months later for patients and controls, respectively. The range of follow-up, while similar in both groups, varied across subjects. The MRI follow-up was planned for about 2 years after intake. However, logistics produced variability in scheduling unrelated to clinical status. Outpatient follow-up, with ratings at 6-month intervals, permitted assessment of the course of illness and ensured the absence of any new pathological process that might affect brain function. Patients with schizophreniform disorder met criteria for schizophrenia at follow-up.

At intake, FE patients were neuroleptic-naive, and PT patients had not received neuroleptics for at least 2 weeks.25 Therapeutic interventions were clinically based, starting with typical neuroleptics and introducing atypical ones as indicated (Table 1). The medication record was updated between intake and follow-up using information from patients, caregivers, and medical records. Compliance was assessed by monitoring ingestion, supply, and visits, but not blood levels. Average daily dose was quantified as chlorpromazine-equivalent milligrams per kilogram of body weight units.32

MRI MEASUREMENTS
Acquisition

Scans were acquired on the same, daily calibrated Signa 1.5-tesla scanner (General Electric, Milwaukee, Wis) with uniform protocol and software. Scanning was over the same epoch, with no relationship between scan date and volume estimates. Transaxial images were obtained in planes parallel to the orbitomeatal line. A multiecho acquisition sequence (TR=3000, TE=30, 80 milliseconds) was used, and slices were 5 mm thick without gaps.

Volumetric Measures

A segmentation algorithm22 used proton densities and T2-weighted values of pixels within operator-defined regions of interest, and volumetric calculations in milliliters were performed for WB, CSF, and the frontal and temporal lobes. Brains were realigned in 3 dimensions and resliced along the anterior commissure/posterior commissure axis to correct for head tilt.19 The borders of the frontal and temporal lobes were drawn by 2 investigators using standardized reliable (intraclass correlation >0.85) procedures.19,26 The scans were blinded and mixed.

CLINICAL RATINGS

Assessments were conducted by trained investigators with established (intraclass correlation >0.85) procedures.25,29 Ratings included the Scales for Assessment of Negative Symptoms (SANS)33 and Positive Symptoms (SAPS).34

NEUROBEHAVIORAL TESTING

The neuropsychological battery examined 8 domains. The tests are established and procedures for administration and scoring have been published.3538

DATA ANALYSIS

None of the distributions differed significantly from normal and there were no outliers. The hypothesis testing requires several analyses, raising the issue of multiple comparison correction. As recommended,3941 we refrained from such corrections in planned analyses or when decomposing a significant higher order interaction. We applied a conservative Bonferroni correction for the exploratory analyses on medication effects.

The focus was MRI changes and their ability to predict clinical and neurobehavioral changes. We tested the hypothesis of higher rate of reduction of brain volume in patients compared with controls by examining changes between evaluations (intake and follow-up) in MRI volumes. We then examined whether changes differed for subgroups of patients (FE and PT). We have reported clinical scale changes42 and follow-up neuropsychological measures.43 Therefore, these analyses were considered corollary, aiming to ensure that this subsample shows the same effects.

The repeated volumes for WB, CSF (ventricular and sulcal), and frontal and temporal lobes were the dependent measures in repeated-measures multiple analyses of variance (MANOVAs), with diagnosis (controls vs patients) as a grouping factor and session (intake vs follow-up) as a within-group (repeated-measures) factor. Significance was tested using the Hotelling-Lawley Trace statistic. The hypothesis of greater reduction in patients would be supported by a group × session interaction and subsequent demonstration with planned univariate contrasts that the reduction is greater in patients than controls. Subgroups (FE, PT, men, and women) were contrasted in subsequent analyses with the same design. For the clinical scales analyses were performed on the SANS and SAPS subscales, and for the neuropsychological evaluations scores were grouped into the 8 functions.38

The second hypothesis posits correlations between volume reduction and clinical and neurobehavioral changes. Change rates were calculated for MRI, clinical, and neurobehavioral measures as follow-up measures minus intake measures. To control for initial values (regression to the mean), these scores were corrected to the intake measure using linear regressions and divided by the intermeasure interval for an index of change per month. The neuroanatomical predictors of clinical and neurobehavioral change were determined by regression analyses, entering clinical and neuropsychological change scores as dependent measures to be predicted from change in WB compared with CSF volumes and temporal compared with frontal lobe volumes. For significant volume predictors, sequential regressions added duration of illness and age as regressors (in all cases the volume measures remained significant predictors). Repeated analysis without the interscan interval as divisor likewise did not diminish effects. Regarding directionality, the second hypothesis postulates that volume reduction is associated with worsening of (or less improvement in) negative symptoms and deterioration of neuropsychological performance related to affected regions (eg, executive functions and attention with frontal lobe reduction, and memory with temporal lobe reduction). Medication effects were examined by correlating the daily neuroleptic dose for the period between intake and follow-up with the change scores.

MAGNETIC RESONANCE IMAGING
WB and CSF Volumes

Mean±SD volume estimates (in milliliters) for WB at intake were 1201.2±131.0, 1100.8±121.9, and 1079.4±121.3 for controls, FE patients, and PT patients, respectively. Volumes from the 2 sessions were highly intercorrelated for controls (0.98, 0.91, 0.85, 0.93 for WB, CSF, frontal lobe, and temporal lobe, respectively) and patients (0.94, 0.87, 0.76, and 0.82) (P<.001). The diagnosis × session × hemisphere MANOVA for WB showed a significant main effect for diagnosis (F[1,53] = 9.64; P=.003), patients having lower volumes than controls. No other main effect or interaction was significant. No effects or interactions were significant for CSF. The MANOVAs comparing FE patients with PT patients showed no main effects or interactions.

Frontal and Temporal Lobe Volumes

The diagnosis × session × hemisphere MANOVA for frontal lobe volumes showed main effects for diagnosis (F[1,53]= 5.67, P=.02), patients having lower volumes than controls, and hemisphere (T=0.31, F[1,53]= 16.51, P<.001), higher volumes on the right. There was a diagnosis × session × hemisphere interaction (T=0.13, F[1,53]=6.71, P=.01). Decomposition of this interaction indicated that the reduction in patients was more pronounced in the left (4.2% reduction) than the right hemisphere (2.8% reduction).

The same analysis for temporal lobe yielded significant main effects for diagnosis (F[1, 53]=6.94, P=.01, patients had lower volumes), session (T=0.52, F[1,53]=27.61, P<.001, lower volume for follow-up), and hemisphere (T=0.08, F[1,53]=4.14, P=.05, higher values in the right). There was also a diagnosis × session interaction (T=0.08, F[1,53]=4.19, P=.04), reflecting less volume reduction in patients (3.4% and 2.8% reduction for the left and right hemispheres, respectively) than controls (7.5% and 7.2%, respectively).

The MANOVAs comparing FE with PT patients on frontal lobe volumes showed a group × session interaction (T=0.17, F[2,52]=4.31, P=.02), and a group × session × hemisphere interaction (T=0.13, F[2,52]=3.34, P=.04). This reflected more pronounced left hemispheric reduction in FE than in PT patients (Figure 1). For temporal lobe volume, there was a group × session interaction (T=0.12, F[2,52]= 3.24, P=.05). First-episode patients showed greater bilateral tissue reduction (Figure 1).

Place holder to copy figure label and caption
Figure 1.

Frontal and temporal hemispheric volumes at the 2 testing times. NC indicates normal controls; FE, first-episode patients; and PT, previously treated patients.

Graphic Jump Location
CLINICAL RATINGS

The intake severity ratings on the SANS and SAPS, respectively, were 2.7±1.1 and 2.4±0.7 for FE patients and 2.8±1.0 and 2.2±0.8 for PT patients. The corresponding follow-up ratings were 1.9±1.2 and 1.0±0.9 for FE patients and 1.9±1.1 and 1.6±1.0 for PT patients. The session × clinical subscale ANOVA showed main effects of session for both SANS (F[1,37]=15.37, P<.001) and SAPS (F[1,37]= 27.31, P<.001), indicating improvement of negative and positive symptoms. With the FE vs PT grouping there were no differences for SANS. For SAPS there was a group × session interaction (F[1,36]=4.46, P=.04), FE patients showing more improvement (Table 2).

Table Graphic Jump LocationTable 2. Mean (SD) Symptom Ratings for First-Episode (FE) and Previously Treated (PT) Patients at Intake and Follow-up*
NEUROBEHAVIORAL TESTING

The diagnosis × session × function ANOVA showed main effects of diagnosis (F[1,52]=22.33, P<.001; patients performing overall worse), function (F[7,364]=3.62, P=.001), and a function × diagnosis interaction (F[7,364]=6.65, P<.001), reflecting selective deficits in abstraction, attention, and verbal memory. Analyses contrasting FE with PT patients showed no effects. Thus, the neuropsychological measures were relatively stable over time and severity and pattern of deficit was similar in patient subgroups.

ASSOCIATIONS AMONG CHANGE INDEXES
MRI and Clinical Changes

For FE patients, reduced frontal and temporal volumes was correlated with less improvement in negative and some positive symptoms, and better improvement in delusions and thought disorder. For PT patients, volume reductions were correlated with greater improvement across most symptoms (Figure 2).Regression analyses entering change in frontal and temporal volumes as predictors of clinical change showed rate of temporal lobe reduction as the main unique predictor of clinical improvement. For FE patients, a lack of correlation between volume and clinical change was a unique predictor of improvement in negative symptoms. For positive symptoms, rate of temporal volume reduction predicted improvement rate in thought disorder (β=.10, P=.007 [because the β weights are in "natural units," for every milliliter of temporal lobe tissue lost per month we expect a clinical improvement of .1 per month in thought disorder rating]). For the PT group, temporal lobe reduction predicted improved affective flattening (β=.19, P=.001) and avolition (β=.16, P=.02). These predictors remained significant when age or duration of illness were added to the model.

Place holder to copy figure label and caption
Figure 2.

Correlations between brain volume change and clinical change. Frontal and temporal lobe brain tissue volumes are presented for first-episode and previously treated patients. Clinical change was measured by the Scale for the Assessment of Negative Symptoms subscales (AF indicates affective flattening or blunting; AL, alogia; AV, avolition-apathy; AN, anhedonia-asociality; and AT, attention) and by the Scale for the Assessment of Positive Symptoms subscales (HA indicates hallucinations; DE, delusions; BI, bizarre behavior; and TH, positive formal thought disorder). Since clinical improvement is reflected in lower severity ratings at follow-up, lower (and more negative) change scores (follow-up minus intake) reflect more improvement. For volumetric change measures, lower values reflect more tissue loss. Therefore, positive correlations indicate that higher rates of tissue loss are associated with higher rates of clinical improvement, whereas negative correlations indicate that tissue loss is associated with clinical worsening for that symptom.

Graphic Jump Location
MRI and Neurobehavioral Changes

For controls there were modest correlations between reduced WB volume and decline in performance, significant for attention and verbal memory (r=0.49 and 0.53, respectively; df= 14, P<.05). The correlations for WB and CSF changes in FE and PT patients showed reciprocity between reduced WB volume and increased CSF volume associated with decline in performance. This was evident for verbal memory, where rate of reduction in WB volume was associated with worsening of performance in both FE (r=0.35, P<.05) and PT groups (r=0.62, P<.01); the opposite correlations were observed for CSF (r=−0.21, P=.38 and r=−0.55, P<.01, for FE and PT patients, respectively). The frontal and temporal volume changes showed positive correlations, less volume reduction being associated with less neuropsychological decline. The exception was a negative correlation between temporal lobe reduction and verbal functioning in the PT group (Figure 3).

Place holder to copy figure label and caption
Figure 3.

Correlations between brain volume and neurobehavioral change. Frontal and temporal lobe brain tissue volumes are presented for first-episode and previously treated patients. The neurobehavioral domains include abstraction and flexibility (ABF), attention (ATT), verbal memory (VME), spatial memory (SME), verbal abilities (VER), spatial abilities (SPA), sensory (SEN), and motor (MOT). Positive correlations indicate less tissue loss associated with less neurobehavioral deterioration and negative correlations indicate less tissue loss associated with more deterioration (or, conversely, more tissue loss associated with less neurobehavioral deterioration).

Graphic Jump Location

Regression analyses showed that rate of temporal lobe reduction predicted worsening performance on language tests in controls (β=−.05, P=.02). In FE patients, the rate of frontal lobe reduction predicted decline in abstraction-flexibility and language (β=.19, P=.02, and β=.09, P=.03, respectively). Neither frontal nor temporal lobe changes uniquely predicted neuropsychological changes for the PT group.

CORRELATIONS OF CHANGE INDEXES WITH MEDICATION DOSE

For FE patients, higher medication dose was associated with greater reduction in frontal and temporal volume (r=−0.75 and −0.66, respectively; P<.001). The corresponding correlations for PT patients were nil (0.03 and 0.16). For FE patients, higher dose was also associated with less improvement in affect (r=0.38), alogia (r=0.38), and avolition (r=0.40) (all P<.05) and in the positive symptom of bizarre behavior (r=0.66, P<.01), but with better improvement in delusions (r=−0.35) and thought disorder (r=−0.46) (both P<.05). These correlations were negligible in PT patients except for hallucinations (r=0.50, P<.05), higher dose being associated with less improvement. The correlations between neuroleptic dose and change in neuropsychological measures were generally negative for FE patients, higher dose being associated with relative worsening of neuropsychological functioning. These reached significance for abstraction-flexibility (r=−0.45), spatial memory (r=−0.53), and verbal (r=−0.53) and spatial (r=−0.41) abilities. The corresponding correlations for PT patients were not significant.

We also examined whether correlations between volume change and clinical change were mediated by dose. The partial correlations between volume and symptom change (neuroleptic dose partialled out) did not change significance. For example, the correlation between volume reduction in temporal lobe and improvement in thought disorder in the FE group was r=0.77, and partialling out the dose resulted in a partial correlation rvol ×symptom.dose=0.71, both P<.01. Another potential source of variability is compliance with the medication regimen. This was quantified as the number of months in which medication was taken during the follow-up period (Table 1). No correlation was found between this measure and the average daily dosage of medication (r=0.14, P=.41) nor was the correlation significant when the measure of months receiving medication was divided by the length of follow-up (r=−0.01, P=.95). Thus, it does not appear that less compliant patients were given higher doses. We performed regression analyses predicting regional brain volume change based on neuroleptic dose after controlling for compliance. The dose effects remained significant for both frontal (P<.001) and temporal (P=.005) volumes in FE patients, with no compliance or dose effects for the PT group.

An ANOVA on clinical change scores showed better improvement in women across positive and negative symptoms (F[1,37]=5.39, P=.02). The ANOVA on the volume measures showed only a main effect of sex (F[1,37]= 5.93, P=.02), men having higher brain volumes than women. Similarly for both frontal and temporal lobes, only main effects of sex were observed (F[1,37]=4.79, P=.04 and F[1,37]=6.03, P=.02, respectively). On the neurobehavioral measures there were no sex differences in performance or change scores.

As in cross-sectional neuroanatomical studies,25,26 our intake measures show that patients had lower WB and frontal and temporal lobe volumes. Also consistent with earlier reports, the volumes were similar in FE and PT patients. Clinically, the patients' presentation was comparable to that observed in larger samples.42,43 The neuropsychological profile was also similar to that reported in schizophrenia, showing differential deficits in abstraction, attention, and verbal memory3538 and no differences between FE and PT patients.36 These consistencies suggest that this subsample resembles both the larger sample and samples from other centers regarding the main dependent measures.

Our longitudinal clinical and neurobehavioral results are also consistent with earlier studies. Both groups of patients showed the expected clinical improvement associated with treatment, as in our larger sample42 and other samples.4446 Also corresponding with follow-up studies, improvement was more pronounced for positive symptoms, particularly hallucinations and delusions, than for negative symptoms. This was more evident in FE than in PT patients. Regarding neurobehavioral measures, the neuropsychological profile remained relatively stable in patients and controls.4749 This stability is noticeable against a background of improvement in symptoms for patients, suggesting that neurobehavioral deficits are present at the onset of illness and do not change systematically over time. These consistencies with earlier reports justify some confidence in this sample's representativeness and the validity of our clinical and neuropsychological parameters.

The longitudinal neuroanatomical findings are harder to place in the context of earlier reports because of the paucity of such research and the lack of consistent findings in the literature. Direct comparison of longitudinal with cross-sectional studies is problematic because intersubject variability in the latter is likely to cause an underestimate of individual change rates. Our study found reductions in the volumes of both frontal and temporal lobes in patients, but there was also a temporal lobe volume reduction in controls. Reduction in controls could be consistent with cross-sectional studies indicating age-related decline.1821 The rate of decrease is difficult to estimate from cross-sectional studies, may vary across the lifespan,50 and is more pronounced for men,19 who made up the majority of our controls. Our ability to detect subtle changes (4%-9%) may reflect the power of the within-subjects design and the reliability of the measures.19,26 However, without sufficient longitudinal data available, this finding should be interpreted with caution and replicated. The more pronounced reduction in frontal and temporal lobes in FE than in PT patients may suggest that neuroanatomical changes are more evident early in psychosis. The lack of difference between patient groups at intake may reflect sample variability, since this contrast is cross-sectional. Thus, the expectation of greater volume decline in patients than controls was not supported for the temporal lobe, but for the frontal lobe the FE group shows volume reduction not observed in controls or in PT patients.

Correlations between volume change and clinical and neurobehavioral changes have not been examined before. Our findings generally support an association between brain and behavioral changes. Some results, however, were not predicted and may appear counterintuitive.We attempted to control statistically for initial values, age, illness duration, and medication dose. A higher rate of reduction in frontal and temporal lobe volumes was associated with less improvement in negative symptoms and hallucinations in FE patients, but in both groups it was associated with greater improvement in other positive symptoms. The association between lower brain volumes and a greater severity of symptoms has been reported in cross-sectional studies.5,6,26 The association between volume reduction and improvement in some positive symptoms is new, and hence tentative and requiring replication. An association in schizophrenia between improvement in positive symptoms and reduced volume in regions with presumed neuropathological characteristics has not been established. Such effects are reported in irritative lesions, where symptomatic improvement is associated with suppression or removal of diseased tissue. Volume reductions have been interpreted as atrophy, reflecting neurodegeneration or neural injury, yet postmortem studies in schizophrenia do not show astrocytosis51,52 but possibly reduced cell size.53 Neuroleptics may contribute to further reduction in neuronal density, as suggested in animal studies,54 but there is also evidence that neuroleptics may increase neuronal size in specific regions.55

Neurobehaviorally, in both healthy subjects and patients we found positive correlations between volume change and neuropsychological change, volume reduction being associated with decreased performance. While there are no earlier longitudinal studies for comparison, these results are consistent with studies showing a correlation between brain volume and neurocognitive measures.38 Note that no significant overall change in cognitive performance occurred for patients, but those with temporal volume reduction also had greater reduction in neurocognitive performance.

Medication effects, in this naturalistic treatment setting, are tentative and in need of verification with controlled therapeutic interventions. In exploratory evaluation, we found that for FE patients a greater rate of reduction in frontal and temporal lobe volumes was associated with improvement of delusions and thought disorder and higher neuroleptic dose. These changes were concomitant with less improvement in affective flattening and alogia. However, neuroleptic dose alone does not account for the correlations between reduced temporal lobe volume and clinical improvement. The anatomical changes remained significant predictors of clinical improvement when medication dose was partialled out and when age or duration of illness were included in the regression analysis. The change values were corrected for initial severity, making less plausible the alternative explanation that the initially sicker patients received higher doses and also had an accelerated process of neuroanatomical and neurobehavioral deterioration. Medication regimens were individualized and related to treatment response. However, the effects were also maintained when controlling for compliance, and this militates against the possibility that the less compliant patients were given higher doses and represent a subgroup with neurodegenerative features. Still, we can not establish causality without systematic manipulation of medication and dose.

There are several limitations to this study. While the sample has adequate power for testing hypotheses on global measures of anatomical, clinical, and neurobehavioral changes, larger samples are needed to probe with confidence more detailed and specific low-magnitude correlations. Another limitation is the choice of a follow-up interval determined by time rather than symptom severity. This design was chosen to permit some variability in the outcome measures while maintaining a standard interval. However, as presented in Table 2, patients were moderately symptomatic at intake and had mild symptoms or remission of symptoms at follow-up. The findings regarding medications are also tentative because data on medication prior to admission for PT patients is retrospective, and the choice of medication and dose during follow-up were clinically determined. Targeted sampling may permit comparison of informative groups of patients treated with specific medications. There is no evidence that neuroleptic treatment is associated with neuropathological changes in postmortem studies of schizophrenia.56

Our results do not contradict the neurodevelopmental hypothesis, which stipulates an early insult and presence of abnormalities at clinical presentation. However, we found evidence for continued structural changes in some patients. They showed reduction in frontal lobe volume within the limited age and interscan time interval, but for the temporal lobe, healthy subjects also showed volume reduction. This underscores the need to examine effects of normal aging to put in perspective findings in schizophrenia, where aging operates on compromised neural substrates undergoing concomitant disease- and treatment-related changes. In FE patients, we are perhaps documenting the psychotic process at a virulent phase and possibly for this reason we obtain associations between rate of reduction in brain volume and clinical improvement in positive symptoms. In PT patients, these associations are more general. The time course of these changes can be established by more frequent measurements in early phases of illness. The role of neuroleptics can be elucidated through controlled medication regimens. Such studies may help explain why negative symptoms, the manifestations of core pathological processes57 emanating perhaps from neurodevelopmental aberrations,58,59 are resistant to treatment with typical neuroleptics, whereas positive symptoms, which reflect lack of inhibition,60 improve. The psychotic process may itself induce neurotoxic effects with consequent structural changes.60

Accepted for publication February 19, 1997.

This research was supported by grants MH-42191, MH-43880, MH-01336, MH-19112 and MO1RR0040 from the National Institute of Health, Rockville, Md, and by the EJLB Foundation, Montreal, Quebec.

We thank Ross J. Baldessarini, MD, for critical review, and Larry Muenz, PhD, for statistical input.

Reprints: Raquel E. Gur, MD, PhD, Neuropsychiatry, University of Pennsylvania, 10th Floor, Gates Building, Philadelphia, PA 19104.

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DeLisi  LEStritzke  PRiordan  HHolan  VBoccio  AKushner  MMcClelland  JVan Eyl  OAnand  A The timing of brain morphological changes in schizophrenia and their relationship to clinical outcome. Biol Psychiatry. 1992;31241- 254
DeLisi  LETew  WXie  SHoff  ALSakuma  MKushner  MLee  GShedlack  KSmith  AMGrimson  R A prospective follow-up study of brain morphology and cognition in first-episode schizophrenic patients: preliminary findings. Biol Psychiatry. 1995;38349- 360
Gur  RCMozley  PDResnick  SMGottlieb  GEKohn  MZimmerman  RHerman  GAtlas  SGrossman  RBerretta  DErwin  RGur  RE Gender differences in age effect on brain atrophy measured by magnetic resonance imaging. Proc Natl Acad Sci U S A. 1991;882845- 2849
Cowell  PETuretsky  BTGur  RCGrossman  RIShtasel  DLGur  RE Sex differences in aging of the human frontal and temporal lobe. J Neurosci. 1994;144748- 4755
Coffey  CWilkinson  WParashos  ISoady  SSullivan  RPatterson  LFigiel  GWebb  MSpritzer  CDjang  W Quantitative cerebral anatomy of the aging human brain: a cross-sectional study using magnetic resonance imaging. Neurology. 1992;42527- 536
Condon  BGrant  RHadley  DLawrence  A Brain and intracranial cavity volumes: in vivo determination by MRI. Acta Neurol Scand. 1988;78387- 393
Kohn  MITanna  NKHerman  GTResnick  SMMozley  PDGur  REAlavi  AZimmerman  RAGur  RC Analysis of brain and CSF volumes from magnetic resonance imaging: methodology, reliability and validation. Radiology. 1991;178115- 122
Gur  REMozley  PDResnick  SMShtasel  DKohn  MZimmerman  RHerman  GAtlas  SGrossman  RErwin  RGur  RC Magnetic resonance imaging in schizophrenia, I: volumetric analysis of brain and cerebrospinal fluid. Arch Gen Psychiatry. 1991;48407- 412
Mozley  PDGur  REShtasel  DLResnick  SMRichards  JKohn  MGrossman  RHerman  GGur  RC Magnetic resonance imaging in schizophrenia, II: relationship to clinical measures. Schizophr Res. 1994;12195- 203
Gur  REMozley  PDShtasel  DLCannon  TDGallacher  FTuretsky  BGrossman  RGur  RC Clinical subtypes of schizophrenia differ in brain and cerebrospinal fluid volume. Am J Psychiatry. 1994;151343- 350
Turetsky  BTCowell  PEGur  RCGrossman  RIShtasel  DLGur  RE Frontal and temporal lobe brain volumes in schizophrenia: relationship to symptomatology and clinical subtype. Arch Gen Psychiatry. 1995;521061- 1070
Cowell  PEKostianovsky  DJGur  RCTuretsky  BIGur  RE Sex differences in neuroanatomical and clinical correlations in schizophrenia. Am J Psychiatry. 1996;153799- 805
Spitzer  RLWilliams  JBWGibbon  M Structured Clinical Interview for DSM-III-R, Patient Version (SCID-P).  New York, NY New York State Psychiatric Institute1986;
Gur  REMozley  DResnick  SMLevick  SErwin  RSaykin  AJGur  RC Relations among clinical scales in schizophrenia: overlap and subtypes. Am J Psychiatry. 1991;148472- 478
Spitzer  RLWilliams  JBWGibbon  M Structured Clinical Interview for DSM-III-R: Non-Patient Version (SCID-NP).  New York, NY New York State Psychiatric Institute1989;
Shtasel  DLGur  REMozley  PDRichards  JTaleff  MMHeimberg  CGallacher  FGur  RC Volunteers for biomedical research: recruitment and screening of normal controls. Arch Gen Psychiatry. 1991;481022- 1025
Kaplan  HISadock  BI Synopsis of Psychiatry. 6th ed.  Baltimore, Md Williams & Wilkins1992;639
Andreasen  NC The Scale for the Assessment of Negative Symptoms (SANS).  Iowa City, Iowa The University of Iowa1984;
Andreasen  NC The Scale for the Assessment of Positive Symptoms (SAPS).  Iowa City, Iowa The University of Iowa1984;
Saykin  AJGur  RCGur  REMozley  DMozley  LHResnick  SMKester  DBStafiniak  P Neuropsychological function in schizophrenia: selective impairment in memory and learning. Arch Gen Psychiatry. 1991;48618- 624
Saykin  AJShtasel  DLGur  REKester  DBMozley  LHStafiniak  PGur  RC Neuropsychological deficits in neuroleptic-naive, first-episode schizophrenic patients. Arch Gen Psychiatry. 1994;51124- 131
Saykin  AJGur  RCGur  REShtasel  DLFlannery  KAMozley  LHMalamut  BLWatson  BMozley  PD Normative neuropsychological test performance: effects of age, education, gender and ethnicity. Appl Neuropsychol. 1995;279- 88
Kareken  DAGur  RCMozley  PDMozley  LHSaykin  AJShtasel  DLGur  RE Cognitive functioning and neuroanatomic volume measures in schizophrenia. Neuropsychology. 1995;9211- 219
Rothman  KJ No adjustments are needed for multiple comparisons. Epidemiology. 1990;143- 46
Miettinen  OS Theoretical Epidemiology.  New York, NY John Wiley & Sons1985;114- 116
Walker  AM Reporting the results of epidemiologic studies. Am J Public Health. 1986;76556- 558
Szymanski  SCannon  TDGallacher  FErwin  RGur  RE The course of treatment response in first-episode and chronic schizophrenia. Am J Psychiatry. 1996;153519- 525
Shtasel  DLGur  REGallacher  FHeimberg  CCannon  TDGur  RC Phenomenology and functioning in first episode schizophrenia. Schizophr Bull. 1992;18449- 462
Ram  RBromet  EGEaton  WWPato  CSchwartz  JE The natural course of schizophrenia: a review of first admission studies. Schizophr Bull. 1992;18185- 207
Eatpm  WWThara  RFederman  BMelton  BLiang  K Structure and course of positive and negative symptoms in schizophrenia. Arch Gen Psychiatry. 1995;52127- 134
Lieberman  JAAlvir  JAWoerner  MDegreef  GBilder  RAshtari  MBogarts  BMayerhoff  DGeisler  SLoebel  ALevy  DLHinrichsen  GSzymanski  SChakos  MKoreen  ABorenstein  MKane  J Prospective study of psychobiology in first-episode schizophrenia at Hillside Hospital. Schizophr Bull. 1992;18351- 371
Nopoulos  PFlashman  LFlaum  MArndt  SAndreasen  N Stability of cognitive functioning early in the course of schizophrenia. Schizophr Res. 1994;1429- 37
Goldberg  TEHyde  TMKleinman  JEWeinberger  DR Course of schizophrenia: neuropsychological evidence for a static encephalopathy. Schizophr Bull. 1993;19797- 804
Bilder  RMLipschutz-Broch  LReiter  GGeisler  SHMayerhoff  DILieberman  JA Intellectual deficits in first-episode schizophrenia: evidence for progressive deterioration. Schizophr Bull. 1992;18437- 448
Jernigan  TLTrauner  DAHesselink  JRTallal  PA Maturation of human cerebrum observed in vivo during adolescence. Brain. 1991;1142037- 2049
Shapiro  RM Regional neuropathology in schizophrenia: where are we? where are we going? Schizophr Res. 1993;10187- 239
Arnold  SEFranz  BRTrojanowski  JQMoberg  PJGur  RE Glial fibrillary acidic protein–immunoreactive astrocytosis in elderly patients with schizophrenia and dementia. Acta Neuropathol. 1996;91269- 277
Arnold  SEFranz  BRGur  RCGur  REShapiro  RMMoberg  PJTrojanowski  JQ Smaller neuron size in schizophrenia in hippocampal subfields that mediate cortical-hippocampal interactions. Am J Psychiatry. 1995;152738- 748
Jeste  DVLohr  JBManley  M Study of neuropathological changes in the striatum following 4, 8 and 12 months of treatment with fluphenazine in rats. Psychopharmacology. 1992;106154- 160
Benes  FMPaskevich  PADomesick  V Haloperidol-induced plasticity of axon terminals in rat substantia nigra. Science. 1983;221969- 971
Baldessarini  RJHegarty  JDBird  EDBenes  FM Meta-analysis of postmortem studies of Alzheimer's disease–like neuropathology in schizophrenia. Am J Psychiatry. 1997;154861- 863
Carpenter  WTHeinrichs  DWWagman  AMI Deficit and nondeficit forms of schizophrenia: the concept. Am J Psychiatry. 1988;145578- 583
Weinberger  DR Implications of normal brain development for the pathogenesis of schizophrenia. Arch Gen Psychiatry. 1987;44660- 669
Wyatt  RJ Neurodevelopmental abnormalities and schizophrenia: a family affair. Arch Gen Psychiatry. 1996;5311- 15
Olney  JWFarber  NB Glutamate receptor dysfunction and schizophrenia. Arch Gen Psychiatry. 1995;52998- 1007

Figures

Place holder to copy figure label and caption
Figure 1.

Frontal and temporal hemispheric volumes at the 2 testing times. NC indicates normal controls; FE, first-episode patients; and PT, previously treated patients.

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

Correlations between brain volume change and clinical change. Frontal and temporal lobe brain tissue volumes are presented for first-episode and previously treated patients. Clinical change was measured by the Scale for the Assessment of Negative Symptoms subscales (AF indicates affective flattening or blunting; AL, alogia; AV, avolition-apathy; AN, anhedonia-asociality; and AT, attention) and by the Scale for the Assessment of Positive Symptoms subscales (HA indicates hallucinations; DE, delusions; BI, bizarre behavior; and TH, positive formal thought disorder). Since clinical improvement is reflected in lower severity ratings at follow-up, lower (and more negative) change scores (follow-up minus intake) reflect more improvement. For volumetric change measures, lower values reflect more tissue loss. Therefore, positive correlations indicate that higher rates of tissue loss are associated with higher rates of clinical improvement, whereas negative correlations indicate that tissue loss is associated with clinical worsening for that symptom.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 3.

Correlations between brain volume and neurobehavioral change. Frontal and temporal lobe brain tissue volumes are presented for first-episode and previously treated patients. The neurobehavioral domains include abstraction and flexibility (ABF), attention (ATT), verbal memory (VME), spatial memory (SME), verbal abilities (VER), spatial abilities (SPA), sensory (SEN), and motor (MOT). Positive correlations indicate less tissue loss associated with less neurobehavioral deterioration and negative correlations indicate less tissue loss associated with more deterioration (or, conversely, more tissue loss associated with less neurobehavioral deterioration).

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1. Demographic and Clinical Characteristics*
Table Graphic Jump LocationTable 2. Mean (SD) Symptom Ratings for First-Episode (FE) and Previously Treated (PT) Patients at Intake and Follow-up*

References

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DeLisi  LEHoff  ALSchwartz  JEShields  GWHalthore  SNGupta  SMHenn  FAAnand  AK Brain morphology in first-episode schizophrenic-like psychotic patients: a quantitative magnetic resonance imaging study. Biol Psychiatry. 1991;29159- 175
DeLisi  LEStritzke  PRiordan  HHolan  VBoccio  AKushner  MMcClelland  JVan Eyl  OAnand  A The timing of brain morphological changes in schizophrenia and their relationship to clinical outcome. Biol Psychiatry. 1992;31241- 254
DeLisi  LETew  WXie  SHoff  ALSakuma  MKushner  MLee  GShedlack  KSmith  AMGrimson  R A prospective follow-up study of brain morphology and cognition in first-episode schizophrenic patients: preliminary findings. Biol Psychiatry. 1995;38349- 360
Gur  RCMozley  PDResnick  SMGottlieb  GEKohn  MZimmerman  RHerman  GAtlas  SGrossman  RBerretta  DErwin  RGur  RE Gender differences in age effect on brain atrophy measured by magnetic resonance imaging. Proc Natl Acad Sci U S A. 1991;882845- 2849
Cowell  PETuretsky  BTGur  RCGrossman  RIShtasel  DLGur  RE Sex differences in aging of the human frontal and temporal lobe. J Neurosci. 1994;144748- 4755
Coffey  CWilkinson  WParashos  ISoady  SSullivan  RPatterson  LFigiel  GWebb  MSpritzer  CDjang  W Quantitative cerebral anatomy of the aging human brain: a cross-sectional study using magnetic resonance imaging. Neurology. 1992;42527- 536
Condon  BGrant  RHadley  DLawrence  A Brain and intracranial cavity volumes: in vivo determination by MRI. Acta Neurol Scand. 1988;78387- 393
Kohn  MITanna  NKHerman  GTResnick  SMMozley  PDGur  REAlavi  AZimmerman  RAGur  RC Analysis of brain and CSF volumes from magnetic resonance imaging: methodology, reliability and validation. Radiology. 1991;178115- 122
Gur  REMozley  PDResnick  SMShtasel  DKohn  MZimmerman  RHerman  GAtlas  SGrossman  RErwin  RGur  RC Magnetic resonance imaging in schizophrenia, I: volumetric analysis of brain and cerebrospinal fluid. Arch Gen Psychiatry. 1991;48407- 412
Mozley  PDGur  REShtasel  DLResnick  SMRichards  JKohn  MGrossman  RHerman  GGur  RC Magnetic resonance imaging in schizophrenia, II: relationship to clinical measures. Schizophr Res. 1994;12195- 203
Gur  REMozley  PDShtasel  DLCannon  TDGallacher  FTuretsky  BGrossman  RGur  RC Clinical subtypes of schizophrenia differ in brain and cerebrospinal fluid volume. Am J Psychiatry. 1994;151343- 350
Turetsky  BTCowell  PEGur  RCGrossman  RIShtasel  DLGur  RE Frontal and temporal lobe brain volumes in schizophrenia: relationship to symptomatology and clinical subtype. Arch Gen Psychiatry. 1995;521061- 1070
Cowell  PEKostianovsky  DJGur  RCTuretsky  BIGur  RE Sex differences in neuroanatomical and clinical correlations in schizophrenia. Am J Psychiatry. 1996;153799- 805
Spitzer  RLWilliams  JBWGibbon  M Structured Clinical Interview for DSM-III-R, Patient Version (SCID-P).  New York, NY New York State Psychiatric Institute1986;
Gur  REMozley  DResnick  SMLevick  SErwin  RSaykin  AJGur  RC Relations among clinical scales in schizophrenia: overlap and subtypes. Am J Psychiatry. 1991;148472- 478
Spitzer  RLWilliams  JBWGibbon  M Structured Clinical Interview for DSM-III-R: Non-Patient Version (SCID-NP).  New York, NY New York State Psychiatric Institute1989;
Shtasel  DLGur  REMozley  PDRichards  JTaleff  MMHeimberg  CGallacher  FGur  RC Volunteers for biomedical research: recruitment and screening of normal controls. Arch Gen Psychiatry. 1991;481022- 1025
Kaplan  HISadock  BI Synopsis of Psychiatry. 6th ed.  Baltimore, Md Williams & Wilkins1992;639
Andreasen  NC The Scale for the Assessment of Negative Symptoms (SANS).  Iowa City, Iowa The University of Iowa1984;
Andreasen  NC The Scale for the Assessment of Positive Symptoms (SAPS).  Iowa City, Iowa The University of Iowa1984;
Saykin  AJGur  RCGur  REMozley  DMozley  LHResnick  SMKester  DBStafiniak  P Neuropsychological function in schizophrenia: selective impairment in memory and learning. Arch Gen Psychiatry. 1991;48618- 624
Saykin  AJShtasel  DLGur  REKester  DBMozley  LHStafiniak  PGur  RC Neuropsychological deficits in neuroleptic-naive, first-episode schizophrenic patients. Arch Gen Psychiatry. 1994;51124- 131
Saykin  AJGur  RCGur  REShtasel  DLFlannery  KAMozley  LHMalamut  BLWatson  BMozley  PD Normative neuropsychological test performance: effects of age, education, gender and ethnicity. Appl Neuropsychol. 1995;279- 88
Kareken  DAGur  RCMozley  PDMozley  LHSaykin  AJShtasel  DLGur  RE Cognitive functioning and neuroanatomic volume measures in schizophrenia. Neuropsychology. 1995;9211- 219
Rothman  KJ No adjustments are needed for multiple comparisons. Epidemiology. 1990;143- 46
Miettinen  OS Theoretical Epidemiology.  New York, NY John Wiley & Sons1985;114- 116
Walker  AM Reporting the results of epidemiologic studies. Am J Public Health. 1986;76556- 558
Szymanski  SCannon  TDGallacher  FErwin  RGur  RE The course of treatment response in first-episode and chronic schizophrenia. Am J Psychiatry. 1996;153519- 525
Shtasel  DLGur  REGallacher  FHeimberg  CCannon  TDGur  RC Phenomenology and functioning in first episode schizophrenia. Schizophr Bull. 1992;18449- 462
Ram  RBromet  EGEaton  WWPato  CSchwartz  JE The natural course of schizophrenia: a review of first admission studies. Schizophr Bull. 1992;18185- 207
Eatpm  WWThara  RFederman  BMelton  BLiang  K Structure and course of positive and negative symptoms in schizophrenia. Arch Gen Psychiatry. 1995;52127- 134
Lieberman  JAAlvir  JAWoerner  MDegreef  GBilder  RAshtari  MBogarts  BMayerhoff  DGeisler  SLoebel  ALevy  DLHinrichsen  GSzymanski  SChakos  MKoreen  ABorenstein  MKane  J Prospective study of psychobiology in first-episode schizophrenia at Hillside Hospital. Schizophr Bull. 1992;18351- 371
Nopoulos  PFlashman  LFlaum  MArndt  SAndreasen  N Stability of cognitive functioning early in the course of schizophrenia. Schizophr Res. 1994;1429- 37
Goldberg  TEHyde  TMKleinman  JEWeinberger  DR Course of schizophrenia: neuropsychological evidence for a static encephalopathy. Schizophr Bull. 1993;19797- 804
Bilder  RMLipschutz-Broch  LReiter  GGeisler  SHMayerhoff  DILieberman  JA Intellectual deficits in first-episode schizophrenia: evidence for progressive deterioration. Schizophr Bull. 1992;18437- 448
Jernigan  TLTrauner  DAHesselink  JRTallal  PA Maturation of human cerebrum observed in vivo during adolescence. Brain. 1991;1142037- 2049
Shapiro  RM Regional neuropathology in schizophrenia: where are we? where are we going? Schizophr Res. 1993;10187- 239
Arnold  SEFranz  BRTrojanowski  JQMoberg  PJGur  RE Glial fibrillary acidic protein–immunoreactive astrocytosis in elderly patients with schizophrenia and dementia. Acta Neuropathol. 1996;91269- 277
Arnold  SEFranz  BRGur  RCGur  REShapiro  RMMoberg  PJTrojanowski  JQ Smaller neuron size in schizophrenia in hippocampal subfields that mediate cortical-hippocampal interactions. Am J Psychiatry. 1995;152738- 748
Jeste  DVLohr  JBManley  M Study of neuropathological changes in the striatum following 4, 8 and 12 months of treatment with fluphenazine in rats. Psychopharmacology. 1992;106154- 160
Benes  FMPaskevich  PADomesick  V Haloperidol-induced plasticity of axon terminals in rat substantia nigra. Science. 1983;221969- 971
Baldessarini  RJHegarty  JDBird  EDBenes  FM Meta-analysis of postmortem studies of Alzheimer's disease–like neuropathology in schizophrenia. Am J Psychiatry. 1997;154861- 863
Carpenter  WTHeinrichs  DWWagman  AMI Deficit and nondeficit forms of schizophrenia: the concept. Am J Psychiatry. 1988;145578- 583
Weinberger  DR Implications of normal brain development for the pathogenesis of schizophrenia. Arch Gen Psychiatry. 1987;44660- 669
Wyatt  RJ Neurodevelopmental abnormalities and schizophrenia: a family affair. Arch Gen Psychiatry. 1996;5311- 15
Olney  JWFarber  NB Glutamate receptor dysfunction and schizophrenia. Arch Gen Psychiatry. 1995;52998- 1007

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