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Cerebral Cortical Gray Expansion Associated with Two Second-Generation Antipsychotics
Cerebral Cortical Gray Expansion Associated with Two Second-Generation Antipsychotics David L. Garver, Jennifer A. Holcomb, and James D. Christensen Background: Second-generation antipsychotics (SGAs) differ from first-generation antipsychotics (FGAs) with respect to induction of less extrapyramidal morbidity, partially reducing negative symptoms, and causing modest improvement in neurocognitive functioning in patients with schizophrenia. SGAs demonstrate 5-HT2a antagonism. Differential effects of SGAs and FGAs on cortical gray volumes are explored herein. Methods: Cerebral cortical gray was examined volumetrically in 19 patients with schizophrenia before and following 28 days of treatment with two SGAs (risperidone and ziprasidone; n ⫽ 13) or a FGA (haloperidol; n ⫽ 6). Seven (untreated) control subjects were also assessed at a similar interval. Results: During treatment with the SGAs risperidone and ziprasidone, cerebral cortical gray of 13 patients with schizophrenia expanded 20.6 ⫾ 11.4 cc (p ⬍ .0005). Six patients receiving the FGA haloperidol, as well as 7 control subjects, showed no change in cortical gray volumes (p ⫽ .983 and p ⫽ .932, respectively) at the time of reassessment. Conclusions: Volumetric increase of cerebral cortical gray occurred early in the course of treatment with the SGAs ziprasidone and risperidone, but not with the FGA haloperidol. Such cortical gray expansion may be relevant to the reported enhanced neurocognition and quality of life associated with SGA treatment. Key Words: Atypical antipsychotics, cortical gray, magnetic resonance imaging, neurocognition, neurotrophins, schizophrenia
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umerous investigators have reported volumetric reduction of cortical gray matter in patients with schizophrenia. Serial magnetic resonance imaging (MRI) studies have shown successive waves of excessive loss of cortical gray matter during adolescence in early-onset schizophrenias (Thompson et al 2001). Such excessive loss continues during early adult stages of schizophrenia (Mathalon et al 2001). Postmortem studies have confirmed thinning of gray matter and increased neuronal density, reflective of loss of neuropil (Selemon and Goldman-Rakic 1999). Metabolic activities of gray matter in frontal, temporal, and cingulate cortices have been reported to be deficient in patients with schizophrenia (Carter et al 2001; Davidson and Heinrichs 2003). Second-generation antipsychotics (SGAs), in contrast to firstgeneration antipsychotics (FGAs), show high affinity to serotonin 2a (5-HT2a) receptors as well as to dopamine-2 (D2) receptors (Altar et al 1986). Increased release of neurotrophic factors including brain-derived nerve growth factor (BDNF; ChlanFourney et al 2002; Toyooka et al 2002) and nerve growth factor (NGF; Parikh et al 2003a; Terry et al 2003) are reportedly induced by SGAs, but not by FGAs. Such induction may be a down-stream effect associated with such 5-HT2a blockade. Neurotrophic factors are necessary for maintenance of dendritic structure (Gorski et al 2003). Axonal and dendritic sprouting are facilitated by such neurotrophic factors (Stahl 2000). High-affinity 5HT2a binding and blockade therefore may be relevant not only to reduction of extrapyramidal symptoms, but may also be relevant to cortical functions, such as neurocognition. Indeed, SGAs have demonstrated modest neurocognitive improvement across a host
From the Department of Psychiatry and Behavioral Science (DLG, JAH, JDC) and Department of Radiology (JDC), University of Louisville School of Medicine, Louisville, Kentucky. Address reprint requests to David L. Garver, M.D., 3 East Mill Place, Louisville, KY 40222; E-mail: [email protected]. Received August 19, 2004; revised January 31, 2005; accepted February 7, 2005.
0006-3223/05/$30.00 doi:10.1016/j.biopsych.2005.02.008
of neurocognitive domains (Bilder et al 2002; Harvey et al 2001; Meltzer and McGurk 1999; Purdon et al 2000). This investigation focuses on the pathologically atrophied cortical gray volumes of patients with schizophrenia. It contrasts the subacute effects of two SGAs (risperidone and ziprasidone) with that of the classic FGA (haloperidol).
Methods and Materials Subjects Nineteen patients (aged 33 ⫾ 12; 13 men and 6 women) with recent emergence or exacerbation of psychosis were admitted to inpatient services at the University of Louisville Hospital. Each had been free of antipsychotic medication for at least 2 months before admission. Previously treated patients had been noncompliant with antipsychotic medications. Based on an assessment using the Comprehensive Assessment of Symptoms and History (Andreasen 1985), each patient met DSM-IV criteria for schizophrenia. Exclusion criteria included a history of head injury, mental retardation, substance dependence, or medical or neurologic impairment. All patients tested negative for substances of abuse at the time of hospital admission and had by history never been dependent. The protocol was approved by the Internal Review Board (IRB) of the University of Louisville. Each of the 18 patients provided written informed consent in accordance of IRB requirements for serial volumetric magnetic resonance (MR) studies and treatment with an antipsychotic in hospital for a period of at least 4 weeks. Seven control subjects (aged 29 ⫾ 9; 5 men and 2 women) were recruited from the student body and staff. Each was without history of mental or neurologic disease and were drawn from the university and surrounding communities. All denied previous history of substance use, and each tested negative for current illegal drug use. Each also provided written consent for serial MR studies. Schedule of Assessments At drug-free baseline, MR volumetric imaging and psychosis ratings according to the Schedule for Assessment of Positive Symptoms (SAPS) and the Schedule for Assessment of Negative Symptoms (SANS; Andreasen 1984a, 1984b) were undertaken in both patients and control subjects. Following baseline studies, BIOL PSYCHIATRY 2005;58:62– 66 © 2005 Society of Biological Psychiatry
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D.L. Garver et al the first seven patients with schizophrenia began antipsychotic treatment with assignment to 4 mg risperidone daily. The seven normal control subjects received no medication. The subsequent 12 study patients with schizophrenia received random assignment to 7 mg haloperidol daily or 60 mg ziprasidone twice daily with meals. Patients receiving haloperidol (FGA) were aged 32.2 ⫾ 14.8 years; 67% were men, and 50% were first-episode patients. Patients receiving risperidone or ziprasidone (SGAs) were aged 31.6 ⫾ 10.2 years; 69% were men, and 54% were first-episode patients. All patients had weekly psychosis (SAPS) assessments in hospital for a period of 4 weeks. Continued hospitalization ensured medication compliance and prevented use of other psychoactive drugs between assessments. Four weeks into treatment and following symptom reevaluation (SAPS and SANS), patients were again assessed with MR volumetrics. Control subjects underwent similar serial MR assessments to assess reliability of methods and for contrasts with patients receiving SGAs and FGA.
Magnetic Resonance Imaging Volumetric Assessments Following baseline assessments of psychosis, brain images were obtained using a 1.5-T clinical MR imaging (MRI) scanner (Siemens Medical Systems, Erlanger, Germany). T1-weighted images were acquired using the MP-RAGE pulse sequence (Mugler and Brookeman 1990). Co-localized T2- and densityweighted images were acquired using the turbo spin-echo pulse sequence (Engleheard et al 1994). Each three-dimensional (3D) image consisted of 2-mm contiguous sagittal slices covering the entire head with in-plane resolution of 1 mm ⫻ 1 mm. Data were interpolated to 1-mm cubic volume elements (voxels), corrected for detector spatial variance and intensity normalized to correct for intersubject and interscan intensity variations (Christensen 2003). Image spatial coregistration was performed using Automatic Image Registration software (Woods et al 1998) with spatial transformations confined to 3D rigid body motion, as described previously by this laboratory (Christensen et al 2004). A probabilistic neural network (Masters 1995) was used to classify the brain into gray matter (GM), white matter (WM), and cerebrospinal fluid (CSF) using three normal control and three schizophrenic subjects who were members of the two study groups. This network built class probability estimate functions using Gaussian kernels with independent line-widths in the three dimensions of the input parameters: the intensities of the T1-, T2and density-weighted images. Network output was the probability of membership in each of the three classes (GM, WM and CSF). Accuracy of class assignment was 95%, 97%, and 98% for GM, WM, and CSF, respectively. The result was a set of three, 3D images, one for each tissue type (GM, WM, and CSF), with image intensities representing the voxel-by-voxel tissue volume fractions (Christensen et al 2004). Gray matter volume for each scan was estimated from the sum of voxels representing the GM volume fraction. Reported GM volume reflects total cerebral cortical volume (excluding subcortical gray, i.e., thalamus, hypothalamus, caudate–putamen, brainstem, cerebellar peduncles, and cerebellum). Regional brain volume calculations were performed using a revised digital version of Talairach and Tournoux’s (1988) stereotaxic to classify each point in the brain as belonging to one of the following six brain regions: frontal, parietal, temporal, occipital, subcortical, and cerebellum, using a parcellation scheme similar in principle to that of Andreasen et al (1996).
Data Analysis Blind test–retest (two scans and volumetric assessments performed within 20 ⫾ 19 [SD] days) in the seven control subjects assessed the reliability of cerebral GM volume assessments. The coefficient of variation (CV) of these within-subject, test–retest assessments was 1.30% ⫾ .93%. Changes of GM volumes within SGA and FGA patients during the period of treatment, and at test–retest for the control subjects were assessed by paired t test, as were associated changes in CSF and WM. Between-group statistical comparisons were based on patient data that had been corrected for differences in intracranial volume (ICV) (GM/[WM ⫹ GM ⫹ CSF volume]) and used unpaired t tests or Mann–Whitney assessments. Change in cortical gray volumes in patients receiving risperidone or ziprasidone (SGA patients) was contrasted to changes found in haloperidol-treated patients (FGA patients) and control subjects using one-way analysis of variance (ANOVA) with Tukey Honest Significant Difference (HSD)– corrected post hoc contrasts. Relationships between change in cerebral gray volume and change in SAPS and SANS were assessed using Pearson correlations. All data are presented as mean ⫾ SD.
Results ICV of Patients and Control Subjects The ICVs did not differ between the 19 patients and 7 control subjects (1355.1 ⫾ 176.1 cc [range 890.4 –1576.6 cc] vs. 1404.4 ⫾ 161.6 cc [range 1183.4 –1595.3 cc], respectively [t ⫽ .646, df ⫽ 24, p ⫽ .524]); however, cortical gray volume at baseline was 495.5 ⫾ 55.8 cc [range 414.8 –594.5 cc] in patients and 537.3 ⫾ 62.83 cc [range 444.9 – 643.2 cc] in control subjects (t ⫽ 1.644, df ⫽ 24, p ⫽ .113). Cortical Gray Volume: Changes with SGA Treatment The 13 patients receiving treatment with the SGAs demonstrated a significant increase of cortical gray volume of 20.6 ⫾ 11.4 cc (paired t ⫽ 6.493, df ⫽ 12, p ⬍ .0005) (Table 1). The six patients receiving the FGA and the test–retest assessments within the seven normal control subjects demonstrated no significant change in cortical gray volumes (–.167 ⫾ 18.282 cc [t ⫽ .022, df ⫽ 5, p ⫽ .983] and –.429 ⫾ 12.827 cc [t ⫽ .088, df ⫽ 6, p ⫽ .932], respectively). Contrasting ICV-corrected cortical gray changes among the three groups of subjects resulted in a highly significant difference between volume changes in SGA patients versus both FGA and control subjects [ANOVA: F ⫽ 7.813(2,23), p ⫽ .003] with Tukey HSD adjustment for multiple comparisons showing SGA patients versus control subjects (p ⫽ .008) and SGA patients versus the FGA haloperidol (p ⫽ .012; Figure 1). In the 13 patients treated with SGA, the increase of cortical gray was diffuse, not limited to one or more regions. Frontal gray expanded by 7.5 ⫾ 8.8 cc (paired t ⫽ 3.075, df ⫽ 12, p ⫽ .010), parietal gray expanded by 4.7 ⫾ 3.4 cc (paired t ⫽ 4.981, df ⫽ 12, p ⬍.0005), occipital gray expanded by 3.4 ⫾ 2.5 cc (paired t ⫽ 4.860, df ⫽ 12, p ⬍.0005), and temporal gray, by 4.9 ⫾ 2.8 cc (paired t ⫽ 6.391, df ⫽ 12, p ⬍ .0005; Figure 2). There were no significant changes in the six patients treated with FGA in frontal (p ⫽ .834), parietal (p ⫽ .890), occipital (p ⫽ .472), or temporal (p ⫽ .224) gray areas. At baseline and relative to ICVs, there was an excess of CSF in patients as compared with control subjects (t ⫽ 2.248, df ⫽ 24, p ⫽ .034). Patients receiving SGAs showed cortical gray expansion accompanied by 11.5 ⫾ 16.4 cc reduction of CSF (paired t ⫽ 2.524, df ⫽ 12, p ⫽ .027) as well as a 10.2 ⫾ 12.2 cc reduction of WM volumes (paired t ⫽ 3.014, df ⫽ 12, p ⫽ .011). In contrast, www.sobp.org/journal
64 BIOL PSYCHIATRY 2005;58:62– 66
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Table 1. Change in Serial Cerebral Gray Volume with Antipsychotic Treatments Baseline
1 Month of Treatment
Change
Significance (Paired t Test)
Control (n ⫽ 7)
537.3 ⫾ 62.8 cc
536.9 ⫾ 53.6 cc test–retest (no treatment)
⫺0.43 ⫾ 12.83 cca,c
p ⫽ .932
Patients (n ⫽ 19) FGA: Haloperidol (n ⫽ 6) SGAs: Ziprasidone (n ⫽ 6) Risperidone (n ⫽ 7)
513.0 ⫾ 74.3 487.4 ⫾ 46.3 466.7 ⫾ 44.4 505.1 ⫾ 43.0
⫺0.17 ⫾ 18.28 ccb,d ⫹20.6 ⫾ 11.4 cca,b ⫹15.3 ⫾ 10.7 ccd ⫹25.1 ⫾ 10.7 ccc
p p p p
Subjects
cc cc cc cc
512.8 ⫾ 77.8 508.0 ⫾ 51.3 482.1 ⫾ 48.3 530.2 ⫾ 45.6
cc cc cc cc
⫽ ⬍ ⫽ ⫽
.983 .0005 .017 .001
FGA, first-generation antipsychotic; SGA, second generation antipsychotic. Change in cerebral gray volumes (mean cc ⫾ SD) in control subjects and patients treated with an FGA, haloperidol, or SGAs, ziprasidone or risperidone, for 28 days. Control subjects and risperidone-treated patients were assessed during the same period; haloperidol- and ziprasidone-treated patients were assessed during the subsequent study period. Differences in change in ICV-corrected cortical gray volume during treatments and compared with repeat examination in control subjects (analysis of variance F ⫽ 7.813, df ⫽ 2,23, p ⫽ .003) with Tukey Honest Significant Difference adjustment for multiple comparisons. a SGAs versus control, p ⫽ .008. b SGAs versus FGA, p ⫽ .012. c Risperidone versus controls (unpaired t ⫽ 3.647, df ⫽ 12, p ⫽ .003). d Haloperidol versus ziprasidone (unpaired t ⫽ 1.993, df ⫽ 10, p ⫽ .074).
patients treated with the FGA, who failed to showed cortical gray expansion, demonstrated a trend toward further increased CSF (7.3 ⫾ 8.4 cc) during haloperidol treatment (t ⫽ 2.124, df ⫽ 5, p ⫽ .087) and a quantitative, but not significant, decrease in WM volume (– 8.5 ⫾ 17.3 cc [t ⫽ 1.201, df ⫽ 5, p ⫽ .284]). The 13 patients receiving the SGAs (ziprasidone and risperidone) had a reduction of psychosis (SAPS) scores from 44.9 ⫾ 24.4 to 15.3 ⫾ 15.5 during the 28 days of treatment; the 6 FGA patients had a SAPS reduction from 47.0 ⫾ 18.1 to 17.5 ⫾ 18.6. Change in SAPS during treatment was virtually identical between the SGA- and FGA-treated patients (29.6 ⫾ 22.9 vs. 29.5 ⫾ 16.9 cc [t ⫽ .011, df ⫽ 17, p ⫽ .991]). Change in cerebral GM was unrelated to change in psychotic symptoms (SAPS) in the 19 patients (rp ⫽ –.160, p ⫽ .513). Similarly, there was no significant
Figure 1. Change (mean ⫾ SE) in cerebral gray matter in control subjects during test–retest assessments (n ⫽ 7) and in patients with schizophrenia during the first 28 days of treatment with a first-generation antipsychotic (haloperidol, n ⫽ 6) or second-generation antipsychotics (risperidone, n ⫽ 7; ziprasidone, n ⫽ 6). Differences in change of gray matter volumes between SGA-treated patients and control subjects (p ⫽ .043) and between SGAtreated patients and FGA-treated patients (p ⫽ .020).
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relationship between changes in negative symptoms (SANS) and changes in cortical gray volumes (rp ⫽ .117, p ⫽ .634) as SANS scores fell from 45.7 ⫾ 22.7 to 18.5 ⫾ 15.5 in SGA patients, and from 34.3 ⫾ 10.6 to 23.2 ⫾ 13.4 in FGA-treated patients. The seven patients treated with the SGA risperidone demonstrated a 25.1 ⫾ 10.7 cc increase of cortical gray volume with treatment (paired t ⫽ 6.187, df ⫽ 6, p ⫽ .001), whereas the six ziprasidone-treated patients showed an increase of 15.3 ⫾ 10.71 cc (t ⫽ 3.513, df ⫽ 5, p ⫽ .017). There was no significant difference between the effects of risperidone and ziprasidone on change in cortical gray volume (t ⫽ .966, df ⫽ 11, p ⫽ .341). The six patients treated with the FGA haloperidol failed to show any
Figure 2. Coronal images (before and after 4 weeks of treatment) through frontal and temporal lobes, demonstrating diffuse increase in cortical gray and reduction of cerebrospinal fluid in a patient with schizophrenia treated with a second-generation antipsychotic.
D.L. Garver et al change in cortical gray volume (–.16 ⫾ 18.28 cc; paired t ⫽ .022, df ⫽ 5, p ⫽ .983).
Discussion Despite virtually identical ICVs, this group of 18 patients with schizophrenia demonstrated a decrement in cortical GM, an increase of WM signal, and an increase of CSF volume at baseline, compared with control subjects. The increase in WM during psychosis exacerbation and its reduction during remission of psychosis is consistent with a previous report of reduction of WM volumes associated with antipsychotic effects of dopamine-2 blocking agents (Christensen et al 2004). An excess of CSF in patients with schizophrenia and a paucity of cortical GM is consistent with the characteristic retraction– atrophy of the brain from the time of closure of cranial sutures in infancy to the period of adult schizophrenia, as reported previously by Woods et al (1996), a process documented by Thompson et al (2001). Such reduction–atrophy of cerebral volume in patients with schizophrenia has been suggested to be a consequence of loss of neuropile and loss of axonal and dendritic arborization and their synaptic connections rather than a loss of neurons themselves (Selemon and Goldman-Rakic 1999). Cellular integrity, including maintenance of full arborization of dendritic networks, axonal sprouting, and synaptic maintenance, is dependent on a critical balance of apoptotic– degenerative and protective factors. Although negative findings are also reported in some cohorts, there are multiple reports of alterations (predominantly deficits) of several neurotrophic factors in patients with schizophrenia: BDNF (Durany et al 2001; Toyooka et al 2002; Weickert CS et al 2003), neurotrophin-3 (NT-3; Hattori et al 2002; Jonsson et al 1997), and NGF (Miyatake et al 2002; Parikh et al 2003a). Although FGAs were reported to have little effect on deficient plasma NGF in schizophrenia patients, treatment with three SGAs (clozapine, olanzapine, and risperidone) increased NGF levels (Parikh et al 2003a). There is some evidence that neurotrophin synthesis and release induced by SGAs may be associated with 5-HT2a blockade. In animal studies, the selective 5-HT2a receptor blocker ritanserin significantly increased hippocampal BDNF mRNA expression, whereas FGAs did not; downregulation of hippocampal BDNF mRNA expression induced by FGAs, presumably through D2 blockade, was also significantly antagonized by the two SGAs, risperidone and clozapine, both of which block 5-HT2a receptors (Chlan-Fourney et al 2002). 5-HT2a receptor blockade, a common characteristic of the SGAs, may be the first step in facilitating the synthesis and release of several trophic factors that are known to play a crucial role in growth, maintenance, and function of a variety of brain neurons both during development and in adult life (Aloe et al 2000). Such effects of SGAs, by signaling multiple modification of regulatory sites that ultimately increase synthesis and release of neurotrophic factors following initial 5-HT2a blockade may be responsible for the increased dendritic arborization, axonal branching, and synaptogenesis associated with healthy neuronal function. Such neuropile expansion is not inconsistent with the observations of increased cortical GM seen with subacute administration of these SGAs, but not FGAs. There are other factors also at work that may provide alternate or additional explanations for abnormalities of cortical GM and subsequent repair following treatment with SGAs. Free radical (oxidative) challenges to the integrity of neuronal membranes
BIOL PSYCHIATRY 2005;58:62– 66 65 have also been suggested as potentially responsible for neuronal impairment. Abnormalities in antioxidant defense systems and excessive oxidative damage have been suggested as relevant to the pathology of schizophrenia (Cadet and Kahler 1994; Mahadik and Mukherjee 1996; Reddy and Yao 1996). The SGAs antagonize free radical oxidation in schizophrenia (Dakhale et al 2004) and upregulate gene expression of protective dismutase in cell cultures (Bai et al 2002); animal studies showed that FGAs increase markers of lipid peroxidation in brain, whereas SGAs, presumably through 5-HT2a antagonism, neutralize the effect of D2 blockade in inducing oxidative stress (Parikh et al 2003b). Remotely, there is also the possibility that the volumetric change related to these SGAs is simply a side effect of risperidone and ziprasidone, analogous to gingival hypertrophy with phenytoin treatment. Although we have not herein demonstrated an association of cortical gray enhancement and improvement of neurocognitive function and quality of life, there is evidence in the literature for modest neurocognitive effects of SGAs in contrast with the effects of FGAs (Bilder et al 2002; Harvey et al 2001; Meltzer and McGurk 1999; Purdon et al 2000). This study did not utilize a fully randomized design because the initial part of the study contrasted control subjects at test–retest to patients before and during risperidone treatment; only the second part of the study (haloperidol vs. ziprasidone) utilized randomized design. Further studies are needed to assess the more chronic effects of risperidone and ziprasidone on cortical gray volumes, as well as the relationship between changes in cortical gray volumes and the reported neurocognitive changes with these SGAs. The subacute and long-term effects of other SGAs (i.e., clozapine, olanzapine, quetiapine, and aripiprazole) need be assessed to determine whether such cortical gray expansion, like reported effects on neurocognition, is a class-effect of 5-HT2a blockade associated with all SGAs. This study was funded in part by a VA Merit award to DLG and grants from Pfizer, Inc. (to DLG) and the Stanley Research Foundation (to JDC). Aloe L, Iannitelli A, Angelucci, Bersani G, Fiore M (2000): Studies in animal models and humans suggesting a role of nerve growth factor in schizophrenia-like disorders. Behav Pharmacol 11:235–242. Altar CA, Wasley AM, Neale RF, Stone GA (1986): Typical and atypical antipsychotics occupancy of D2 and S2 receptors: An autoradiographic analysis in rat brain. Brain Res Bull 16:517–525. Andreasen NC (1984a): The Scale for the Assessment of Positive Symptoms in Schizophrenia (SAPS). Iowa City: University of Iowa Press. Andreasen NC (1984b): The Scale for the Assessment of Negative Symptoms in Schizophrenia (SANS). Iowa City: University of Iowa Press. Andreasen NC (1985): The Comprehensive Assessment of Symptoms and History (CASH). Iowa City: University of Iowa Press. Andreasen NC, Rajarethinam R, Cizadlo T, Arndt S, Swayze VW, Flashman LA, et al (1996): Automatic atlas-based volume estimation of human brain regions from MR images. J Comp Assist Tomogr 20:98 –106. Bai O, Wei Z, Lu W, Bowen R, Kegan D, Li XM (2002): Protective effects of atypical antipsychotic drugs on PC12 cells after serum withdrawal. J Neurosci Res 69:278 –283. Bilder RM, Goldman R, Volavka J, Czobor P, Hoptman M, Scheitman B, et al (2002): Neurocognitive effects of clozapine, olanzapine, risperidone, and haloperidol in patients with chronic schizophrenia or schizoaffective disorder. Am J Psychiatry 159:1018 –1028. Cadet JL, Kahler LA (1994): Free radical mechanisms in schizophrenia and tardive dyskinesia. Neurosci Biobehav Rev 18:457– 467. Carter CS, MacDonald AW III, Ross LL, Stenger VA (2001): Anterior cingulate cortex activity and impaired self-monitoring of performance in patients
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D.L. Garver et al Miyatake R, Furukawa A, Suwaki H (2002): Identification of a novel variant of the human NR2B gene promotor region and its possible association with schizophrenia. Mol Psychiatry 7:1101–1106. Mugler JP, Brookeman JR (1990): Three-dimensional magnetization-prepared rapid gradient-echo imaging (3D MP RAGE). Magn Reson Med 15:152–157. Parikh V, Evans DR, Khan MM, Mahadik SP (2003a): Nerve growth factor in never-medicated first episode psychotic and medicated chronic schizophrenic patients: Possible implications for treatment outcome. Schizophr Res 60:117–123. Parikh V, Kahn MM, Mahadik SP (2003b): Differential effects of antipsychotics on expression of antioxidant enzymes and membrane lipid peroxidation in rat brain. J Psychiatr Res 37:43–51. Purdon SE, Jones BD, Stip E, Labelle A, Addington D, David S, et al (2000): Neuropsychological change in early phase schizophrenia during 12 months of treatment with olanzapine, risperidone, or haloperidol. Arch Gen Psychiatry 57:249 –258. Reddy R, Yao J (1996). Free radical pathology in schizophrenia: A review. Prostaglandins Leukot Essent Fatty Acids 55:33– 43. Stahl SM (2000): Chemical neurotransmission as the mediator of disease actions. In: Essential Psychopharmacology: Neuroscientific Basis and Practical Applications, 3rd ed. Cambridge, UK: Cambridge University Press, 99 –133. Selemon LD, Goldman-Rakic PS (1999): The reduced neuropile hypothesis: A circuit-based model of schizophrenia. Biol Psychiatry 45:17–25. Talairach J, Tournoux P (1998): Co-Planar Stereotaxic Atlas of the Human Brain. Stuttgart: Tieme. Terry AV Jr, Hill WD, Parikh V, Waller JL, Evans DR, Mahadik SP (2003): Differential effects of haloperidol, risperidone, and clozapine exposure on cholinergic markers and spatial learning performance in rats. Neuropsychopharmacology 28:300 –309. Thompson PM, Vidal C, Giedd JN, Gochman P, Blumenthal J, Nicolson R, et al (2001): Mapping adolescent brain change reveals dynamic wave of accelerated gray matter loss in very early-onset schizophrenia. Proc Natl Acad Sci U S A 98:11650 –11655. Toyooka K, Asama K, Wantanbe Y, Muratake T, Takahashi M, Someya T, Nawa H (2002): Decreased levels of brain-derived neurotrophic factor in serum of chronic schizophrenic patients. Psychiat Res 110:249 –257. Weickert CS, Hyde TM, Lipska BK, Herman MM, Weinberger DR, Kleinman JE (2003): Reduced brain-derived neurotrophic factor in prefrontal cortex of patients with schizophrenia. Mol Psychiatry 8:592– 610. Woods BT, Yurgelun-Todd D, Goldstein JM, Seidman LJ, Tsuang MT (1996): MRI brain abnormalities in chronic schizophrenia: One process or more? Biol Psychiatry 40:585–596. Woods RP, Grafton ST, Holmes CJ, Cherry SR, Mazziotta JC (1998): Automated image registration: I. General methods and intrasubject, intramodality validation. J Comp Assist Tomogr 22:139 –152.
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umerous investigators have reported volumetric reduction of cortical gray matter in patients with schizophrenia. Serial magnetic resonance imaging (MRI) studies have shown successive waves of excessive loss of cortical gray matter during adolescence in early-onset schizophrenias (Thompson et al 2001). Such excessive loss continues during early adult stages of schizophrenia (Mathalon et al 2001). Postmortem studies have confirmed thinning of gray matter and increased neuronal density, reflective of loss of neuropil (Selemon and Goldman-Rakic 1999). Metabolic activities of gray matter in frontal, temporal, and cingulate cortices have been reported to be deficient in patients with schizophrenia (Carter et al 2001; Davidson and Heinrichs 2003). Second-generation antipsychotics (SGAs), in contrast to firstgeneration antipsychotics (FGAs), show high affinity to serotonin 2a (5-HT2a) receptors as well as to dopamine-2 (D2) receptors (Altar et al 1986). Increased release of neurotrophic factors including brain-derived nerve growth factor (BDNF; ChlanFourney et al 2002; Toyooka et al 2002) and nerve growth factor (NGF; Parikh et al 2003a; Terry et al 2003) are reportedly induced by SGAs, but not by FGAs. Such induction may be a down-stream effect associated with such 5-HT2a blockade. Neurotrophic factors are necessary for maintenance of dendritic structure (Gorski et al 2003). Axonal and dendritic sprouting are facilitated by such neurotrophic factors (Stahl 2000). High-affinity 5HT2a binding and blockade therefore may be relevant not only to reduction of extrapyramidal symptoms, but may also be relevant to cortical functions, such as neurocognition. Indeed, SGAs have demonstrated modest neurocognitive improvement across a host
From the Department of Psychiatry and Behavioral Science (DLG, JAH, JDC) and Department of Radiology (JDC), University of Louisville School of Medicine, Louisville, Kentucky. Address reprint requests to David L. Garver, M.D., 3 East Mill Place, Louisville, KY 40222; E-mail: [email protected]. Received August 19, 2004; revised January 31, 2005; accepted February 7, 2005.
0006-3223/05/$30.00 doi:10.1016/j.biopsych.2005.02.008
of neurocognitive domains (Bilder et al 2002; Harvey et al 2001; Meltzer and McGurk 1999; Purdon et al 2000). This investigation focuses on the pathologically atrophied cortical gray volumes of patients with schizophrenia. It contrasts the subacute effects of two SGAs (risperidone and ziprasidone) with that of the classic FGA (haloperidol).
Methods and Materials Subjects Nineteen patients (aged 33 ⫾ 12; 13 men and 6 women) with recent emergence or exacerbation of psychosis were admitted to inpatient services at the University of Louisville Hospital. Each had been free of antipsychotic medication for at least 2 months before admission. Previously treated patients had been noncompliant with antipsychotic medications. Based on an assessment using the Comprehensive Assessment of Symptoms and History (Andreasen 1985), each patient met DSM-IV criteria for schizophrenia. Exclusion criteria included a history of head injury, mental retardation, substance dependence, or medical or neurologic impairment. All patients tested negative for substances of abuse at the time of hospital admission and had by history never been dependent. The protocol was approved by the Internal Review Board (IRB) of the University of Louisville. Each of the 18 patients provided written informed consent in accordance of IRB requirements for serial volumetric magnetic resonance (MR) studies and treatment with an antipsychotic in hospital for a period of at least 4 weeks. Seven control subjects (aged 29 ⫾ 9; 5 men and 2 women) were recruited from the student body and staff. Each was without history of mental or neurologic disease and were drawn from the university and surrounding communities. All denied previous history of substance use, and each tested negative for current illegal drug use. Each also provided written consent for serial MR studies. Schedule of Assessments At drug-free baseline, MR volumetric imaging and psychosis ratings according to the Schedule for Assessment of Positive Symptoms (SAPS) and the Schedule for Assessment of Negative Symptoms (SANS; Andreasen 1984a, 1984b) were undertaken in both patients and control subjects. Following baseline studies, BIOL PSYCHIATRY 2005;58:62– 66 © 2005 Society of Biological Psychiatry
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D.L. Garver et al the first seven patients with schizophrenia began antipsychotic treatment with assignment to 4 mg risperidone daily. The seven normal control subjects received no medication. The subsequent 12 study patients with schizophrenia received random assignment to 7 mg haloperidol daily or 60 mg ziprasidone twice daily with meals. Patients receiving haloperidol (FGA) were aged 32.2 ⫾ 14.8 years; 67% were men, and 50% were first-episode patients. Patients receiving risperidone or ziprasidone (SGAs) were aged 31.6 ⫾ 10.2 years; 69% were men, and 54% were first-episode patients. All patients had weekly psychosis (SAPS) assessments in hospital for a period of 4 weeks. Continued hospitalization ensured medication compliance and prevented use of other psychoactive drugs between assessments. Four weeks into treatment and following symptom reevaluation (SAPS and SANS), patients were again assessed with MR volumetrics. Control subjects underwent similar serial MR assessments to assess reliability of methods and for contrasts with patients receiving SGAs and FGA.
Magnetic Resonance Imaging Volumetric Assessments Following baseline assessments of psychosis, brain images were obtained using a 1.5-T clinical MR imaging (MRI) scanner (Siemens Medical Systems, Erlanger, Germany). T1-weighted images were acquired using the MP-RAGE pulse sequence (Mugler and Brookeman 1990). Co-localized T2- and densityweighted images were acquired using the turbo spin-echo pulse sequence (Engleheard et al 1994). Each three-dimensional (3D) image consisted of 2-mm contiguous sagittal slices covering the entire head with in-plane resolution of 1 mm ⫻ 1 mm. Data were interpolated to 1-mm cubic volume elements (voxels), corrected for detector spatial variance and intensity normalized to correct for intersubject and interscan intensity variations (Christensen 2003). Image spatial coregistration was performed using Automatic Image Registration software (Woods et al 1998) with spatial transformations confined to 3D rigid body motion, as described previously by this laboratory (Christensen et al 2004). A probabilistic neural network (Masters 1995) was used to classify the brain into gray matter (GM), white matter (WM), and cerebrospinal fluid (CSF) using three normal control and three schizophrenic subjects who were members of the two study groups. This network built class probability estimate functions using Gaussian kernels with independent line-widths in the three dimensions of the input parameters: the intensities of the T1-, T2and density-weighted images. Network output was the probability of membership in each of the three classes (GM, WM and CSF). Accuracy of class assignment was 95%, 97%, and 98% for GM, WM, and CSF, respectively. The result was a set of three, 3D images, one for each tissue type (GM, WM, and CSF), with image intensities representing the voxel-by-voxel tissue volume fractions (Christensen et al 2004). Gray matter volume for each scan was estimated from the sum of voxels representing the GM volume fraction. Reported GM volume reflects total cerebral cortical volume (excluding subcortical gray, i.e., thalamus, hypothalamus, caudate–putamen, brainstem, cerebellar peduncles, and cerebellum). Regional brain volume calculations were performed using a revised digital version of Talairach and Tournoux’s (1988) stereotaxic to classify each point in the brain as belonging to one of the following six brain regions: frontal, parietal, temporal, occipital, subcortical, and cerebellum, using a parcellation scheme similar in principle to that of Andreasen et al (1996).
Data Analysis Blind test–retest (two scans and volumetric assessments performed within 20 ⫾ 19 [SD] days) in the seven control subjects assessed the reliability of cerebral GM volume assessments. The coefficient of variation (CV) of these within-subject, test–retest assessments was 1.30% ⫾ .93%. Changes of GM volumes within SGA and FGA patients during the period of treatment, and at test–retest for the control subjects were assessed by paired t test, as were associated changes in CSF and WM. Between-group statistical comparisons were based on patient data that had been corrected for differences in intracranial volume (ICV) (GM/[WM ⫹ GM ⫹ CSF volume]) and used unpaired t tests or Mann–Whitney assessments. Change in cortical gray volumes in patients receiving risperidone or ziprasidone (SGA patients) was contrasted to changes found in haloperidol-treated patients (FGA patients) and control subjects using one-way analysis of variance (ANOVA) with Tukey Honest Significant Difference (HSD)– corrected post hoc contrasts. Relationships between change in cerebral gray volume and change in SAPS and SANS were assessed using Pearson correlations. All data are presented as mean ⫾ SD.
Results ICV of Patients and Control Subjects The ICVs did not differ between the 19 patients and 7 control subjects (1355.1 ⫾ 176.1 cc [range 890.4 –1576.6 cc] vs. 1404.4 ⫾ 161.6 cc [range 1183.4 –1595.3 cc], respectively [t ⫽ .646, df ⫽ 24, p ⫽ .524]); however, cortical gray volume at baseline was 495.5 ⫾ 55.8 cc [range 414.8 –594.5 cc] in patients and 537.3 ⫾ 62.83 cc [range 444.9 – 643.2 cc] in control subjects (t ⫽ 1.644, df ⫽ 24, p ⫽ .113). Cortical Gray Volume: Changes with SGA Treatment The 13 patients receiving treatment with the SGAs demonstrated a significant increase of cortical gray volume of 20.6 ⫾ 11.4 cc (paired t ⫽ 6.493, df ⫽ 12, p ⬍ .0005) (Table 1). The six patients receiving the FGA and the test–retest assessments within the seven normal control subjects demonstrated no significant change in cortical gray volumes (–.167 ⫾ 18.282 cc [t ⫽ .022, df ⫽ 5, p ⫽ .983] and –.429 ⫾ 12.827 cc [t ⫽ .088, df ⫽ 6, p ⫽ .932], respectively). Contrasting ICV-corrected cortical gray changes among the three groups of subjects resulted in a highly significant difference between volume changes in SGA patients versus both FGA and control subjects [ANOVA: F ⫽ 7.813(2,23), p ⫽ .003] with Tukey HSD adjustment for multiple comparisons showing SGA patients versus control subjects (p ⫽ .008) and SGA patients versus the FGA haloperidol (p ⫽ .012; Figure 1). In the 13 patients treated with SGA, the increase of cortical gray was diffuse, not limited to one or more regions. Frontal gray expanded by 7.5 ⫾ 8.8 cc (paired t ⫽ 3.075, df ⫽ 12, p ⫽ .010), parietal gray expanded by 4.7 ⫾ 3.4 cc (paired t ⫽ 4.981, df ⫽ 12, p ⬍.0005), occipital gray expanded by 3.4 ⫾ 2.5 cc (paired t ⫽ 4.860, df ⫽ 12, p ⬍.0005), and temporal gray, by 4.9 ⫾ 2.8 cc (paired t ⫽ 6.391, df ⫽ 12, p ⬍ .0005; Figure 2). There were no significant changes in the six patients treated with FGA in frontal (p ⫽ .834), parietal (p ⫽ .890), occipital (p ⫽ .472), or temporal (p ⫽ .224) gray areas. At baseline and relative to ICVs, there was an excess of CSF in patients as compared with control subjects (t ⫽ 2.248, df ⫽ 24, p ⫽ .034). Patients receiving SGAs showed cortical gray expansion accompanied by 11.5 ⫾ 16.4 cc reduction of CSF (paired t ⫽ 2.524, df ⫽ 12, p ⫽ .027) as well as a 10.2 ⫾ 12.2 cc reduction of WM volumes (paired t ⫽ 3.014, df ⫽ 12, p ⫽ .011). In contrast, www.sobp.org/journal
64 BIOL PSYCHIATRY 2005;58:62– 66
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Table 1. Change in Serial Cerebral Gray Volume with Antipsychotic Treatments Baseline
1 Month of Treatment
Change
Significance (Paired t Test)
Control (n ⫽ 7)
537.3 ⫾ 62.8 cc
536.9 ⫾ 53.6 cc test–retest (no treatment)
⫺0.43 ⫾ 12.83 cca,c
p ⫽ .932
Patients (n ⫽ 19) FGA: Haloperidol (n ⫽ 6) SGAs: Ziprasidone (n ⫽ 6) Risperidone (n ⫽ 7)
513.0 ⫾ 74.3 487.4 ⫾ 46.3 466.7 ⫾ 44.4 505.1 ⫾ 43.0
⫺0.17 ⫾ 18.28 ccb,d ⫹20.6 ⫾ 11.4 cca,b ⫹15.3 ⫾ 10.7 ccd ⫹25.1 ⫾ 10.7 ccc
p p p p
Subjects
cc cc cc cc
512.8 ⫾ 77.8 508.0 ⫾ 51.3 482.1 ⫾ 48.3 530.2 ⫾ 45.6
cc cc cc cc
⫽ ⬍ ⫽ ⫽
.983 .0005 .017 .001
FGA, first-generation antipsychotic; SGA, second generation antipsychotic. Change in cerebral gray volumes (mean cc ⫾ SD) in control subjects and patients treated with an FGA, haloperidol, or SGAs, ziprasidone or risperidone, for 28 days. Control subjects and risperidone-treated patients were assessed during the same period; haloperidol- and ziprasidone-treated patients were assessed during the subsequent study period. Differences in change in ICV-corrected cortical gray volume during treatments and compared with repeat examination in control subjects (analysis of variance F ⫽ 7.813, df ⫽ 2,23, p ⫽ .003) with Tukey Honest Significant Difference adjustment for multiple comparisons. a SGAs versus control, p ⫽ .008. b SGAs versus FGA, p ⫽ .012. c Risperidone versus controls (unpaired t ⫽ 3.647, df ⫽ 12, p ⫽ .003). d Haloperidol versus ziprasidone (unpaired t ⫽ 1.993, df ⫽ 10, p ⫽ .074).
patients treated with the FGA, who failed to showed cortical gray expansion, demonstrated a trend toward further increased CSF (7.3 ⫾ 8.4 cc) during haloperidol treatment (t ⫽ 2.124, df ⫽ 5, p ⫽ .087) and a quantitative, but not significant, decrease in WM volume (– 8.5 ⫾ 17.3 cc [t ⫽ 1.201, df ⫽ 5, p ⫽ .284]). The 13 patients receiving the SGAs (ziprasidone and risperidone) had a reduction of psychosis (SAPS) scores from 44.9 ⫾ 24.4 to 15.3 ⫾ 15.5 during the 28 days of treatment; the 6 FGA patients had a SAPS reduction from 47.0 ⫾ 18.1 to 17.5 ⫾ 18.6. Change in SAPS during treatment was virtually identical between the SGA- and FGA-treated patients (29.6 ⫾ 22.9 vs. 29.5 ⫾ 16.9 cc [t ⫽ .011, df ⫽ 17, p ⫽ .991]). Change in cerebral GM was unrelated to change in psychotic symptoms (SAPS) in the 19 patients (rp ⫽ –.160, p ⫽ .513). Similarly, there was no significant
Figure 1. Change (mean ⫾ SE) in cerebral gray matter in control subjects during test–retest assessments (n ⫽ 7) and in patients with schizophrenia during the first 28 days of treatment with a first-generation antipsychotic (haloperidol, n ⫽ 6) or second-generation antipsychotics (risperidone, n ⫽ 7; ziprasidone, n ⫽ 6). Differences in change of gray matter volumes between SGA-treated patients and control subjects (p ⫽ .043) and between SGAtreated patients and FGA-treated patients (p ⫽ .020).
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relationship between changes in negative symptoms (SANS) and changes in cortical gray volumes (rp ⫽ .117, p ⫽ .634) as SANS scores fell from 45.7 ⫾ 22.7 to 18.5 ⫾ 15.5 in SGA patients, and from 34.3 ⫾ 10.6 to 23.2 ⫾ 13.4 in FGA-treated patients. The seven patients treated with the SGA risperidone demonstrated a 25.1 ⫾ 10.7 cc increase of cortical gray volume with treatment (paired t ⫽ 6.187, df ⫽ 6, p ⫽ .001), whereas the six ziprasidone-treated patients showed an increase of 15.3 ⫾ 10.71 cc (t ⫽ 3.513, df ⫽ 5, p ⫽ .017). There was no significant difference between the effects of risperidone and ziprasidone on change in cortical gray volume (t ⫽ .966, df ⫽ 11, p ⫽ .341). The six patients treated with the FGA haloperidol failed to show any
Figure 2. Coronal images (before and after 4 weeks of treatment) through frontal and temporal lobes, demonstrating diffuse increase in cortical gray and reduction of cerebrospinal fluid in a patient with schizophrenia treated with a second-generation antipsychotic.
D.L. Garver et al change in cortical gray volume (–.16 ⫾ 18.28 cc; paired t ⫽ .022, df ⫽ 5, p ⫽ .983).
Discussion Despite virtually identical ICVs, this group of 18 patients with schizophrenia demonstrated a decrement in cortical GM, an increase of WM signal, and an increase of CSF volume at baseline, compared with control subjects. The increase in WM during psychosis exacerbation and its reduction during remission of psychosis is consistent with a previous report of reduction of WM volumes associated with antipsychotic effects of dopamine-2 blocking agents (Christensen et al 2004). An excess of CSF in patients with schizophrenia and a paucity of cortical GM is consistent with the characteristic retraction– atrophy of the brain from the time of closure of cranial sutures in infancy to the period of adult schizophrenia, as reported previously by Woods et al (1996), a process documented by Thompson et al (2001). Such reduction–atrophy of cerebral volume in patients with schizophrenia has been suggested to be a consequence of loss of neuropile and loss of axonal and dendritic arborization and their synaptic connections rather than a loss of neurons themselves (Selemon and Goldman-Rakic 1999). Cellular integrity, including maintenance of full arborization of dendritic networks, axonal sprouting, and synaptic maintenance, is dependent on a critical balance of apoptotic– degenerative and protective factors. Although negative findings are also reported in some cohorts, there are multiple reports of alterations (predominantly deficits) of several neurotrophic factors in patients with schizophrenia: BDNF (Durany et al 2001; Toyooka et al 2002; Weickert CS et al 2003), neurotrophin-3 (NT-3; Hattori et al 2002; Jonsson et al 1997), and NGF (Miyatake et al 2002; Parikh et al 2003a). Although FGAs were reported to have little effect on deficient plasma NGF in schizophrenia patients, treatment with three SGAs (clozapine, olanzapine, and risperidone) increased NGF levels (Parikh et al 2003a). There is some evidence that neurotrophin synthesis and release induced by SGAs may be associated with 5-HT2a blockade. In animal studies, the selective 5-HT2a receptor blocker ritanserin significantly increased hippocampal BDNF mRNA expression, whereas FGAs did not; downregulation of hippocampal BDNF mRNA expression induced by FGAs, presumably through D2 blockade, was also significantly antagonized by the two SGAs, risperidone and clozapine, both of which block 5-HT2a receptors (Chlan-Fourney et al 2002). 5-HT2a receptor blockade, a common characteristic of the SGAs, may be the first step in facilitating the synthesis and release of several trophic factors that are known to play a crucial role in growth, maintenance, and function of a variety of brain neurons both during development and in adult life (Aloe et al 2000). Such effects of SGAs, by signaling multiple modification of regulatory sites that ultimately increase synthesis and release of neurotrophic factors following initial 5-HT2a blockade may be responsible for the increased dendritic arborization, axonal branching, and synaptogenesis associated with healthy neuronal function. Such neuropile expansion is not inconsistent with the observations of increased cortical GM seen with subacute administration of these SGAs, but not FGAs. There are other factors also at work that may provide alternate or additional explanations for abnormalities of cortical GM and subsequent repair following treatment with SGAs. Free radical (oxidative) challenges to the integrity of neuronal membranes
BIOL PSYCHIATRY 2005;58:62– 66 65 have also been suggested as potentially responsible for neuronal impairment. Abnormalities in antioxidant defense systems and excessive oxidative damage have been suggested as relevant to the pathology of schizophrenia (Cadet and Kahler 1994; Mahadik and Mukherjee 1996; Reddy and Yao 1996). The SGAs antagonize free radical oxidation in schizophrenia (Dakhale et al 2004) and upregulate gene expression of protective dismutase in cell cultures (Bai et al 2002); animal studies showed that FGAs increase markers of lipid peroxidation in brain, whereas SGAs, presumably through 5-HT2a antagonism, neutralize the effect of D2 blockade in inducing oxidative stress (Parikh et al 2003b). Remotely, there is also the possibility that the volumetric change related to these SGAs is simply a side effect of risperidone and ziprasidone, analogous to gingival hypertrophy with phenytoin treatment. Although we have not herein demonstrated an association of cortical gray enhancement and improvement of neurocognitive function and quality of life, there is evidence in the literature for modest neurocognitive effects of SGAs in contrast with the effects of FGAs (Bilder et al 2002; Harvey et al 2001; Meltzer and McGurk 1999; Purdon et al 2000). This study did not utilize a fully randomized design because the initial part of the study contrasted control subjects at test–retest to patients before and during risperidone treatment; only the second part of the study (haloperidol vs. ziprasidone) utilized randomized design. Further studies are needed to assess the more chronic effects of risperidone and ziprasidone on cortical gray volumes, as well as the relationship between changes in cortical gray volumes and the reported neurocognitive changes with these SGAs. The subacute and long-term effects of other SGAs (i.e., clozapine, olanzapine, quetiapine, and aripiprazole) need be assessed to determine whether such cortical gray expansion, like reported effects on neurocognition, is a class-effect of 5-HT2a blockade associated with all SGAs. This study was funded in part by a VA Merit award to DLG and grants from Pfizer, Inc. (to DLG) and the Stanley Research Foundation (to JDC). Aloe L, Iannitelli A, Angelucci, Bersani G, Fiore M (2000): Studies in animal models and humans suggesting a role of nerve growth factor in schizophrenia-like disorders. Behav Pharmacol 11:235–242. Altar CA, Wasley AM, Neale RF, Stone GA (1986): Typical and atypical antipsychotics occupancy of D2 and S2 receptors: An autoradiographic analysis in rat brain. Brain Res Bull 16:517–525. Andreasen NC (1984a): The Scale for the Assessment of Positive Symptoms in Schizophrenia (SAPS). Iowa City: University of Iowa Press. Andreasen NC (1984b): The Scale for the Assessment of Negative Symptoms in Schizophrenia (SANS). Iowa City: University of Iowa Press. Andreasen NC (1985): The Comprehensive Assessment of Symptoms and History (CASH). Iowa City: University of Iowa Press. Andreasen NC, Rajarethinam R, Cizadlo T, Arndt S, Swayze VW, Flashman LA, et al (1996): Automatic atlas-based volume estimation of human brain regions from MR images. J Comp Assist Tomogr 20:98 –106. Bai O, Wei Z, Lu W, Bowen R, Kegan D, Li XM (2002): Protective effects of atypical antipsychotic drugs on PC12 cells after serum withdrawal. J Neurosci Res 69:278 –283. Bilder RM, Goldman R, Volavka J, Czobor P, Hoptman M, Scheitman B, et al (2002): Neurocognitive effects of clozapine, olanzapine, risperidone, and haloperidol in patients with chronic schizophrenia or schizoaffective disorder. Am J Psychiatry 159:1018 –1028. Cadet JL, Kahler LA (1994): Free radical mechanisms in schizophrenia and tardive dyskinesia. Neurosci Biobehav Rev 18:457– 467. Carter CS, MacDonald AW III, Ross LL, Stenger VA (2001): Anterior cingulate cortex activity and impaired self-monitoring of performance in patients
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