Changes in Cortical Volume with Olanzapine in ...

Original Paper 1

Phpsy/522/17.5.2007/Macmillan

Changes in Cortical Volume with Olanzapine in Chronic Schizophrenia

Author

V. Molina1, S. Reig2, J. Sanz3, T. Palomo3, C. Benito4, J. Sánchez2, J. Pascau2, M. Desco2

Affiliation

1

Department of Psychiatry, Hospital Clínico Universitario, Salamanca, Spain Department of Experimental Medicine, Hospital Gregorio Marañón, Madrid, Spain 3 Department of Psychiatry, Hospital Doce de Octubre, Madrid, Spain 4 Department of Neuroradiology, Hospital Gregorio Marañón, Madrid, Spain 2

Abstract &

Key words 䉴䊏䊉䉴䊏䊉䉴䊏䊉

Introduction: Atypical antipsychotics can affect cortical volume differently from traditional drugs. The study of the outcome of grey matter deficits in schizophrenia with olanzapine may be of particular interest in this context. Methods: In this study, we evaluated the changes in the volume of gray matter in the cortex of 11 schizophrenic patients treated with olanzapine and in 11 healthy controls after three years of follow-up. After MR imaging, acquisition data were processed with a volumetric quantification method based on the Talairach atlas. The

Introduction &

received revised accepted

25. 9. 2006 16. 4. 2007 17. 4. 2007

Bibliography DOI 10.1055/s-2007-981479 Pharmacopsychiatry 2007; 40:1–6 © Georg Thieme Verlag KG Stuttgart · New York ISSN 0176-3679 Correspondence V. Molina, MD, PhD Department of Psychiatry Hospital Clínico Universitario P S. Vicente 58-182 Salamanca 37007·Spain Tel.: 䊏䊏䊏 Fax: + 34/923/291 383 [email protected]

Atypical antipsychotics can have a significant effect on the structural alterations of the cortex in schizophrenia. Recent results suggest that the influence of certain atypical antipsychotics can compensate, albeit partially, existing structural deficits [25] and increase the volume of total gray matter (GM) [9]. Divergent results have been reported on the effects of typical and atypical drugs on GM volume in both cross-sectional [7] and longitudinal [19, 21] studies. The respective effects of olanzapine, risperidone and clozapine on cortical volume may be different from each other. One longitudinal study using olanzapine and haloperidol during follow-up reported that patients receiving olanzapine did not show the progression of total GM deficit observed in the group treated with haloperidol [19]. Nevertheless, another longitudinal study using risperidone and clozapine over two years of follow-up found significant increases in the GM of the cerebral cortex [25]. The latter study reports an association between the quantification of GM at baseline, and its increase after treatment with risperidone and clozapine. There

longitudinal change of volumetric data was corrected for differences in overall brain size. Results: Patients showed greater reduction than controls in cortical volume in the frontal and parietal regions during follow-up. No relationship was observed between clinical and volumetric changes. Conclusion: Our data suggest that the profile of action of olanzapine on the cortical volume of chronically ill patients may be similar to that of typical antipsychotics. Other explanations, however, cannot be completely discarded for that outcome with our data.

has also been a report of a significant increase in total GM at four weeks of follow-up after therapy with risperidone and ziprasidone in a sample of 13 cases [9]. Such different patterns across the atypicals suggest the convenience of studying their effects on brain structure separately. Our objective was to complete our previous study [25] by examining the possible longitudinal changes in the volume of patients treated with olanzapine, in those cortical structures reported as relevant for schizophrenia. Olanzapine is a good therapeutic option in schizophrenia patients [18]. We obtained magnetic resonance (MR) images both before and after therapy with olanzapine in patients suffering from schizophrenia in order to perform a volumetric analysis after a minimum two-year follow-up. In most cases the baseline MR study was acquired after chronic treatment with typical drugs.

Material and Methods & Patients The study population was initially composed of 19 patients (11 men/8 women), of whom only 11

Molina V et al. Changes in Cortical Volume with Olanzapine … Pharmacopsychiatry 2007; 40: 1–6

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Table 1


MRI acquisition and processing MRI protocol

Demographic and clinical values

Age Male:female Parental socioeconomic status Education Duration Positive (pre-post) Negative (pre-post) General (pre-post)

Patients

Controls

41.0 (11.3) 6:5 2.4 (0.9) 11.8 (7.9) 12.3 (7.8) 21.5 (8.7)–16.8 (8.8)* 24.8 (7.2)–22.2 (8.4)* 40.8 (10.9)–36.7 (11.1)*

29.8 (6.2)** 5:6 2.5 (0.9) 13.9 (6.3) – – – –

*

Significant change (p < 0.05) in pre-post treatment values (Wilcoxon test)

**

Significant differences between groups (p < 0.005, Mann-Whitney test)

(5 women/6 men) could be evaluated longitudinally. They received olanzapine during follow-up (mean dose 15.4 sd 9.5 mg/d). In six of the eight patients who did not complete the follow-up, therapy was switched for clinical reasons (exacerbation or insufficient response) before the end of follow-up, and the two remaining patients were lost to follow-up during this period. All the patients had previously been diagnosed with schizophrenia and 3 had received risperidone during the previous year (doses of 4 – 6 mg/d). The remainder had been receiving treatment during this period with typical drugs (7 haloperidol at doses of 5 to 10 mg/d, 1 pimocide, 4 mg/d). In five cases patients did not comply with the treatment prior to their inclusion. The study used 11 healthy controls (5 men and 6 women) who were also studied longitudinally using MRI. All patients and controls were righthanded. Patients were clinically evaluated on enrolment and at the end of follow-up using the PANSS [16]. In all cases, the diagnosis was confirmed using a semi-structured interview (SCID, patient version) and information from families and clinical staff. Scores were calculated for the positive, negative and general dimensions, as well as for the total dimension, and the change in weight was recorded between the first and second MR. Data on clinical and demographic characteristics on enrolment are shown in 䊉䉴 Table 1. Healthy controls had a below-college educational level in order to properly match them with the patient group. No differences in parental socio-economic status [13] were detected between groups. The inclusion criteria were non-residual schizophrenia, with recent clinical exacerbation justifying a switch in therapy, and the absence of a recent history of substance abuse (ruled out by urine analysis). Exclusion criteria for both patients and controls were: neurological illness, MRI findings judged clinically relevant by a radiologist blind to diagnosis, history of cranial trauma with loss of consciousness, substance dependence during the last 3 years (except for caffeine or nicotine), substance abuse during the last 6 months (a urine analysis on enrolment was used to rule out current consumption), antecedents of axis I psychiatric processes or treatment (except schizophrenia in the case of patients), or any current treatment having known CNS action in addition to neuroleptics and benzodiazepines for insomnia. After receiving full information, the patients and their relatives signed an informed consent form. The Ethics Committee of our hospital approved the study.

Baseline MRI was performed immediately before initiating olanzapine, and the second study after a follow-up period, which was similar both for controls (mean = 29 sd = 14.3. months) and patients (mean = 38, sd = 15.0 months). Magnetic resonance imaging studies were acquired on a Philips Gyroscan 1.5-T scanner using a T1-weighted 3D gradient echo sequence with the following parameters: matrix size 256 × 256, voxel size 1 × 1 × 3.5 mm (FOV 256 mm), flip angle 30 ˚ , repetition time 16 ms, echo time 4.6 ms. T2-weighted sequences were also acquired to obtain the intracranial volume mask, verification of CSF segmentations and for other clinical purposes (Turbo-Spin Echo, turbo factor 15, echo time 120 ms, matrix size 256 × 256, voxel size 1 × 1 × 3.5 mm).

Segmentation and ROI definition MRI processing and volumetric quantification have been described in detail elsewhere [8, 26]. Briefly, to obtain volume measurements of the main brain lobes, we used a method for semi-automated segmentation of the brain based on the Talairach reference system similar to the method described [1, 14]. This method has also been used in similar studies measuring longitudinal volume changes in brain regions [12] and involves a two-step procedure. First, the MRI was edited to remove skull and extracranial tissue using the T2-weighted image, and an initial segmentation of cerebral tissues into gray matter (GM), white matter (WM), and cerebrospinal fluid (CSF) was made using the edited intracranial volume of the T1weighted image. In a second stage, we applied the Talairach reference system [36] to define ROIs and to obtain volume data. Tissue segmentation was performed using an automated method included in the SPM2 (Statistical Parametric Mapping) program [2] and provides a cluster analysis with a modified mixture model and a priori information about the likelihood of each MRI voxel being one of four tissue types: GM, WM, CSF, and “other tissues”. The a priori information consists of anatomic templates that represent an ‘average’ brain and provide information about the spatial distribution of the different brain tissues. The algorithm also removes the effect of radiofrequency field inhomogeneities [3]. This segmentation was checked for inconsistencies and manually corrected whenever necessary by an experienced radiologist blind to the diagnosis. After tissue segmentation, we applied the Talairach proportional reference system [36] to define ROIs and to obtain volume data. The Talairach grid is built on the edited brain MRI by manually selecting the position of the AC and PC points and a third point in the mid-sagittal plane. The coordinates of these points serve to calculate the transformation (rigid translation) required to comply with the Talairach space. Thus, our software application automatically finds the outer limits of the scalp edited MRI in Talairach space, and the 3D grid is built. At the end of this process, the brain is subdivided into the 1056 box cells of the Talairach proportional grid system. The Talairach proportional grid is built for each edited MRI without any scaling or warping, thus fully maintaining the volume and geometry of the brain images. The validity of the Talairach-based procedure as a suitable automated segmentation tool in schizophrenia research has been proven elsewhere [1, 14]. In our study, all manual procedures were performed by a single operator, thus avoiding any potential inter-rater variability. Reliability of the method was assessed by repeating the entire segmentation procedure in a sample of five


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quantitative measurement of atrophy and vice versa. The regression parameters used for this transformation were obtained from a previous study [26].

Statistical analysis and sources of error

Fig. 1 Individual changes in each structure by group (left patients, right controls).

randomly selected cases. The intra-class correlation coefficient (ICC) ranged from 0.95 – 0.99 for regional GM measurements, and from 0.89 – 0.99 for CSF data. Again, all manual procedures were performed by a single operator to avoid any potential interrater variability. Repeatability of the tissue segmentation procedure was 99 % for total volumes of GM and WM [5, 10]. In addition to total volumes of GM, the analysis included the frontal, temporal, parietal and occipital lobes, as well as the lateral ventricles, defined using the boundaries described previously for the Talairach method [1]. ROIs were measured bilaterally, adding the left and right sides together. Intracranial volume (ICV) was calculated by adding total GM, WM, and CSF for each brain (including the cerebellum). All steps of MRI processing were performed using locally developed software, incorporating a variety of image processing and quantification tools [8] 䊉䉴 Fig. 1.

Data analysis Gross change in volume The longitudinal change in volume was measured as the difference between the initial and final volume of each ROI. To avoid bias due to overall differences in brain size, instead of absolute volume change values we used the proportion with respect to total volume. Furthermore, to control for possible calibration differences in the MRI equipment used for the two scans, we calculated the correction factor as the quotient of the initial (baseline) and final intracranial volume (ICV) (E_ICV = ICV1/ ICV2), assuming that the total ICV should be equal in both scans [20]. Thus, for each ROI, the magnitude of the relative change in volume between the baseline (Vol1) and final (Vol2) MRI was calculated as follows: Longitudinal change = [((Vol2 × E_ICV) Vol1)/Vol1] × 100

Measurement of baseline volume deviation To evaluate the hypothesis of the existence of a relationship between the degree of initial volume alteration and the magnitude of longitudinal change, we converted the volume values to directly indicate a condition of atrophy/hypertrophy in each region as compared to healthy subjects, independently of factors such as age and ICV. Since age and total cranial size are known to affect regional cerebral volumes, their effect was removed by using the residuals from the regression models obtained from a group of healthy individuals (n = 45) following Pfefferbaum’s procedure [28]. After this correction, volume variables were expressed as deviations from the expected volumes in healthy individuals of the same age as the patient. Thus, negative residuals represent a

Changes in the three symptom dimensions were studied using Wilcoxon tests for paired samples, comparing the scores before and after the treatment period. To test the significance of the differences in the longitudinal change in each ROI between the patient group and the controls we used a non-parametric Mann-Whitney test. Because there were differences between patients and controls as regards age and time between scans, we explored group differences between patients and controls in ANCOVA models of rank transformed volume data (thus equivalent to non-parametric tests), and using age and follow-up period as covariates. Results showed that none of these two covariates or their interactions with the group factor showed significant effects. Thus, to avoid loosing more degrees of freedom, we decided to use a simple model of group differences in the Mann-Whitney test without any covariate. Among other sources of error with the potential to affect our results, we found that gender did not affect the measurement of longitudinal changes, since there were no significant differences between men and women in the Mann-Whitney test. Nor did we find any significant relationship between longitudinal changes in weight or volume using a Spearman correlation. Moreover, illness duration before the basal scan was also unrelated with volume changes in the patient group (42 < rho < 0.24, p = ns). To discard an age effect on our transformed volumes, we calculated the correlation coefficients between the cortical changes observed and age in the total sample (patients plus controls). These coefficients were not significant for any of the volume variables. (0.26 < r < 33, p = ns). We used Spearman’s rho test to calculate the significance of the association between volume and clinical changes. In this case, we used the rank-transformed percent of change in the positive, negative, general and total subscales of the PANSS between baseline and post-olanzapine conditions. Another Spearman’s rho test was used to calculate the significance of the relation between baseline volume deviations and volume changes Statistical analyses were performed using the SPSS software package (version 11).

Results & Therapy with olanzapine led to a statistically significant, but quantitatively slight, clinical improvement in the three dimensions (䊉䉴 Table 1). Patients showed a significant increase in weight between studies (mean = 4.9 kg, SD = 6.2, p = 0.01). At baseline, patients showed no significant differences in GM volume with respect to the controls in any of the structures analyzed (䊉䉴 Table 2). With regard to longitudinal change (䊉䉴 Table 2), patients showed a greater loss of frontal (U = 26, z = 2.26, p = 0.023) and parietal (U = 28, z = 2.13, p = 0.034) GM than controls. Total and occipital GM, as well as ventricular volume did not reveal significant differences between groups. There was no significant relationship between the changes in volume and baseline deviation (atrophy or hypertrophy), nor


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Table 2


Baseline measures (absolute value) and percentage change (adjusting for the effect of ICC on volume change between scans) in patients and controls Controls

Intracranial volume Total GM Frontal Parietal Occipital Temporal Ventricles **

Patients

Baseline

Change

Baseline

Change

1460.9 (131.1) 799.7 (73.4) 154.8 (17.7) 117.3 (17.2) 68.4 (9.3) 148.1 (8.4) 22.1 (9.1)

1425.8 (132.3) − 0.5 (2.5) − 0.1 (4.2) − 3.3 (3.6) − 1.8 (5.7) − 1.3 (3.3) − 2.2 (9.8)

1494.2 (186.0) 769.2 (84.3) 142.8 (16.5) 114.0 (9.6) 68.4(9.4) 141.8 (16.2) 24.9 (12.8)

1463.4 (167.9) − 2.0 (3.2) − 5.3 (5.3)** − 7.0 (4.1)** − 0.1 (6.6) 2.6 (5.2)* 3.5 (13.4)

p < 0.05

*

p < 0.10 Mann-Whitney U test

were significant relationships detected between longitudinal changes and clinical changes. In order to rule out a possible influence of atypical treatment on the GM volumes observed, the comparison between controls and patients was repeated, but only including those patients not receiving atypical drugs or who had never received them (n = 7). The result was similar to the comparison with the group as a whole: patients also showed a greater loss of frontal and parietal GM than the controls.

Discussion & In this sample, patients treated with olanzapine did not show the increase in cortical volume reported in other studies with risperidone, ziprasidone and clozapine [9, 25]. This different outcome may be explained by two factors that are not mutually exclusive. First, different atypical drugs could have different effects on cortical volume. Second, the absence of a significant baseline volume deficit with respect to the controls in the present sample. In our earlier study [25], the patients who received risperidone and clozapine had a significant GM deficit with respect to the controls, and a relationship between the changes in GM and the initial deficit was observed. After therapy with olanzapine, patients in the present sample showed some loss in the volume of GM in comparison with the healthy controls. In this sense, the effect of treatment with olanzapine on cortical volume seems similar to that of typical antipsychotics, since longitudinal studies with typical drugs have shown a similar rate of reduction [11, 20]. Their respective effects on brain volumes could be directly compared in patients switching from a typical drug to olanzapine. Our results are different from those found by Lieberman et al. [19] in a sample of first episodes. This group showed the absence of changes in total and regional GM in a wide sample treated with olanzapine, whereas in another group of patients receiving haloperidol, reductions in GM were observed. The differences in the population studied (chronically ill patients in our case) could explain these discrepancies, and suggest a greater protective effect on the loss of volume observed at the onset of the disease. Our results do not rule out the possibility that olanzapine could have positive structural effects on other, smaller regions relevant for schizophrenia, such as the hippocampus or the superior temporal gyrus. This possibility is suggested by a certain gain in GM in the temporal lobe in our study and in that of Lieberman et al. [19] Furthermore, Keshavan et al. [17] showed how treatment (without specifying whether this was typical or atypical) induced a regression in the volume deficit in the superior temporal gyrus.

Moreover, in a recent study, Dazzan et al. [7] reported an excess of GM in the thalamus which correlated with the current dose of olanzapine compared with neuroleptic-naïve patients. Risperidone has been found to increase NAA concentrations in the thalamus [35], another region where olanzapine could hypothetically have a potentially beneficial effect. The absence of increase in cortical volume with olanzapine in our group agrees with the absence of significant metabolic changes in a group of patients studied using PET before and after therapy [22]. In this study, patients partially overlapped with those in the present sample. Nevertheless, those patients who showed increases in cortical GM volume with risperidone and clozapine in our previous study [25] also showed significant changes in activity in the same regions where changes in volume were observed. Specifically, in open-eye PET studies, both groups showed increases in occipital activity coinciding with the region which showed the most prominent changes in volume [23, 24]. Regarding the cause of volume changes, we can only speculate. The magnitude of the observed changes probably implies that its bases are non-neuronal, and may include both the effects of the withdrawal of previous treatment as well as those directly related to olanzapine. Although a loss in the volume of GM may be normal in the course of untreated schizophrenia [27], there are data that suggest that such a volume loss may be unrelated to a neurodegenerative effect, since there is no neuronal deficit in this disease [31, 32]. Furthermore, the reversibility of GM deficits with some atypical drugs [25], together with their magnitude, point to a different mechanism. An alternative explanation could relate the changes in volume to changes in glial cells. A glial deficit, supported by specific neuropathological evidence [15, 29, 34, 37], could be reversible with some atypical drugs, according to primate data reported by [30], who found glial proliferation with neuroleptics. In any case, we must stress that we cannot fully explain the functional significance of the changes in volume which may be induced by atypical drugs. One limitation of our study is that the patients were older than the controls. This may have affected the greater loss of volume in the former. However, no correlation was observed between age and the volume changes observed. On the other hand, the magnitude of the change cannot be explained in this age range according to studies on volume change in controls [4, 6, 33]. Moreover, the patients who received clozapine in our earlier study showed increases in volume [25], despite the fact that they were older than those studied in the present study. The main methodological limitation of our longitudinal measurements is that they are based only on two data points: basal and follow-up. Considering the large variability of brain volume measurements, together with the known changes due to age (which may differ in patients and controls), our estimation of


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longitudinal changes should be taken with caution. Our results should be confirmed in a larger sample, including several scans for each subject. However, taking into account the difficulties involved in obtaining repeated scans from a sample of patients such as those studied here, we believe that our sample makes a significant starting point for further studies. Another obvious limitation of our study is the absence of a group treated with typical antipsychotics, although our objective was not to compare the effects of both types of drugs but rather the change in GM with olanzapine compared with that of the healthy controls. Finally, a large number of patients were excluded from the study due to their poor response. Therefore, we do not know the outcome of the cortical parameters in this group. In conclusion, it may be affirmed that the changes in cortical volume in non-resistant chronic schizophrenic patients show characteristics similar to those observed with typical drugs. This effect was different from that observed with clozapine in therapy-resistant patients and those taking risperidone at the time of their first episodes. However, our results do not rule out a different effect in other regions which are relevant for schizophrenia, such as the limbic system, the thalamus or the basal ganglia.

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Supported in part by grants from the “Fondo de Investigaciones Sanitarias” (02/3095, 02/1178, Red Temática IM3), “Ministerio de Ciencia y Tecnología” TIC (2001-3697-C03-03), Lilly Pharmaceuticals and “Fundación La Caixa” (99/042-00).

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References 1 Andreasen NC, Rajarethinam R, Cizadlo T, Arndt S, Swayze VW 2nd, Flashman LA, O’Leary DS, Ehrhardt JC, Yuh WT. Automatic atlas-based volume estimation of human brain regions from MR images. J Comput Assist Tomogr 1996; 20: 98–106 2 Ashburner J, Friston KJ. Multimodal image coregistration and partitioning a unified framework. Neuroimage 1997; 6: 209–217 3 Ashburner J, Friston KJ. Voxel-based morphometry the methods. Neuroimage 2000; 11: 805–821 4 Bartzokis G, Beckson M, Lu PH, Nuechterlein KH, Edwards N, Mintz J. Age-related changes in frontal and temporal lobe volumes in men: a magnetic resonance imaging study. Arch Gen Psychiatry 2001; 58: 461–465 5 Chard DT, Parker GJ, Griffin CM, Thompson AJ, Miller DH. The reproducibility and sensitivity of brain tissue volume measurements derived from an SPM-based segmentation methodology. J Magn Reson Imaging 2002; 15: 259–567 6 Coffey CE, Wilkinson WE, Parashos IA, Soady SA, Sullivan RJ, Patterson LJ, Figiel GS, Webb MC, Spritzer CE, Djang WT. Quantitative cerebral anatomy of the aging human brain: a cross-sectional study using magnetic resonance imaging. Neurology 1992; 42: 527–536 7 Dazzan P, Morgan KD, Orr K, Hutchinson G, Chitnis X, Suckling J, Fearon P, McGuire PK, Mallett RM, Jones PB, Leff J, Murray RM. Different effects of typical and atypical antipsychotics on grey matter in first episode psychosis: the AESOP study. Neuropsychopharmacology 2005; 30: 765–774 8 Desco M, Pascau J, Reig S, Gispert JD, Santos A, Benito B, Molina V, Garcia-Barreno P. Multimodality image quantification using Talairach grid. Proc SPIE Medical Imaging 2001; 4422: 1385–1392 9 Garver DL, Holcomb JA, Christensen JD. Cerebral cortical gray expansion associated with two second-generation antipsychotics. Biol Psychiatry 2005; 58: 62–66 10 Gispert JD, Reig S, Pascau J, Vaquero JJ, Desco M. Repeatability of brain tissue volume quantification using magnetic resonance images. 10th Annual Meeting of the Organization for Human Brain Mapping, Budapest, Hungary. Neuroimage 2004; 22 (suppl 1) 11 Gur RE, Cowell P, Turetsky BI, Gallacher F, Cannon T, Bilker W, Gur RC. A follow-up magnetic resonance imaging study of schizophrenia.

23

24

25

26

27

28

29

30

31

32

Relationship of neuroanatomical changes to clinical and neurobehavioral measures. Arch Gen Psychiatry 1998; 55: 145–152 Ho BC, Andreasen NC, Nopoulos P, Arndt S, Magnotta V, Flaum M. Progressive structural brain abnormalities and their relationship to clinical outcome: a longitudinal magnetic resonance imaging study early in schizophrenia. Arch Gen Psychiatry 2003; 60: 585–594 Hollingshead A, Frederick R. Social stratification and psychiatric disorders. Am Soc Rev 1953; 18: 163–189 Kates WR, Warsofsky IS, Patwardhan A, Abrams MT, Liu AM, Naidu S, Kaufmann WE, Reiss AL. Automated Talairach atlas-based parcellation and measurement of cerebral lobes in children. Psychiatry Res 1999; 91: 11–30 Katsel P, Davis KL, Haroutunian V. Variations in myelin and oligodendrocyte-related gene expression across multiple brain regions in schizophrenia: A gene ontology study. Schizophr Res 2005; 79: 157–173 Kay SR, Fiszbein A, Opler LA. The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr Bull 1987; 13: 261–276 Keshavan MS, Haas GL, Kahn CE, Aguilar E, Dick EL, Schooler NR, Sweeney JA, Pettegrew JW. Superior temporal gyrus and the course of early schizophrenia: progressive, static, or reversible? J Psychiatr Res 1998; 32: 161–167 Lambert M, Conus P, Schimmelmann BG, Eide P, Ward J, Yuen H, Schacht M, Edwards J, Naber D, McGorry PD. Comparison of olanzapine and risperidone in 367 first-episode patients with non-affective or affective psychosis: results of an open retrospective medical record study. Pharmacopsychiatry 2005; 38: 206–213 Lieberman JA, Tollefson GD, Charles C, Zipursky R, Sharma T, Kahn RS, Keefe RS, Green AI, Gur RE, McEvoy J, Perkins D, Hamer RM, Gu H, Tohen M. Antipsychotic drug effects on brain morphology in first-episode psychosis. Arch Gen Psychiatry 2005; 62: 361–370 Mathalon DH, Sullivan EV, Lim KO, Pfefferbaum A. Progressive brain volume changes and the clinical course of schizophrenia in men: a longitudinal magnetic resonance imaging study. Arch Gen Psychiatry 2001; 58: 148–157 McCormick L, Decker L, Nopoulos P, Ho BC, Andreasen N. Effects of atypical and typical neuroleptics on anterior cingulate volume in schizophrenia. Schizophr Res 2005; 80: 73–84 Molina V, Gispert JD, Reig S, Pascau J, Palomo T, Martínez R, Desco M. Olanzapine-induced cerebral metabolic changes. Relation to symptom changes in schizophrenia. Int Clin Psychopharmacol 2005; 20: 13–18 Molina V, Gispert JD, Reig S, Sanz J, Pascau J, Santos A, Desco M, Palomo T. Cerebral metabolic changes induced by clozapine in schizophrenia. Psychopharmacology 2005; 178: 17–26 Molina V, Gispert JD, Reig S, Sanz J, Pascau J, Santos A, Palomo T, Desco M. Cerebral metabolism and risperidone treatment in schizophrenia. Schizophrenia Res 2003; 60: 1–7 Molina V, Reig S, Sanz J, Palomo T, Benito C, Sánchez J, Sarramea F, Pascau J, Desco M. Increase in gray matter volume and decrease in white matter volume in the cerebral cortex during treatment with atypical neuroleptics in schizophrenia. Schizophrenia Res 2005; 80: 61–71 Molina V, Reig S, Sarramea F, Sanz J, F.Artaloytia J, Luque R, Aragüés M, Pascau J, Benito C, Palomo T, Desco M. Anatomical and functional brain variables associated to clozapine response in treatment-resistant schizophrenia. Psychiatry Res:Neuroimaging 2003; 124: 153–161 Pantelis C, Velakoulis D, McGorry PD, Wood SJ, Suckling J, Phillips LJ, Yung AR, Bullmore ET, Brewer W, Soulsby B, Desmond P, McGuire PK. Neuroanatomical abnormalities before and after onset of psychosis: a cross-sectional and longitudinal MRI comparison. Lancet 2003; 361: 281–288 Pfefferbaum A, Lim KO, Zipursky RB, Mathalon DH, Rosenbloom MJ, Lane B, Ha CN, Sullivan EV. Brain gray and white matter volume loss accelerates with aging in chronic alcoholics: a quantitative MRI study. Alcohol Clin Exp Res 1992; 16: 1078–1089 Rajkowska G, Miguel-Hidalgo JJ, Makkos Z, Meltzer H, Overholser J, Stockmeier C. Layer-specific reductions in GFAP-reactive astroglia in the dorsolateral prefrontal cortex in schizophrenia. Schizophr Res 2002; 57: 127–138 Selemon LD, Lidow MS. Goldman-Rakic PS Increased volume and glial density in primate prefrontal cortex associated with chronic antipsychotic drug exposure. Biol Psychiatry 1999; 46: 161–172 Selemon LD, Rajkowska G. Goldman-Rakic PS Abnormally high neuronal density in the schizophrenic cortex. A morphometric analysis of prefrontal area 9 and occipital area 17. Arch Gen Psychiatry 1995; 52: 805–818 ; discussion: 819-820 Selemon LD, Rajkowska G. Goldman-Rakic PS Elevated neuronal density in prefrontal area 46 in brains from schizophrenic patients: appli-


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cation of a three-dimensional, stereologic counting method. J Comp Neurol 1998; 392: 402–412 33 Sowell ER, Peterson BS, Thompson PM, Welcome SE, Henkenius AL, Toga AW. Mapping cortical change across the human life span. Nat Neurosci 2003; 6: 309–315 34 Stark AK, Uylings HB, Sanz-Arigita E, Pakkenberg B. Glial cell loss in the anterior cingulate cortex, a subregion of the prefrontal cortex, in subjects with schizophrenia. Am J Psychiatry 2004; 161: 882–888 35 Szulc A, Galinska B, Tarasow E, Dzienis W, Kubas B, Konarzewska B, Walecki J, Alathiaki AS, Czernikiewicz A. The effect of risperidone on metabolite measures in the frontal lobe, temporal lobe, and thalamus

in schizophrenic patients. A proton magnetic resonance spectroscopy (1 H MRS). Pharmacopsychiatry 2005; 38: 214–219 36 Talairach J, Tournoux P. Co-planar Stereotaxic Atlas of the Human Brain. Thieme Medical, Stuttgart, New York, 1988 37 Uranova NA, Vostrikov VM, Orlovskaya DD, Rachmanova VI. Oligodendroglial density in the prefrontal cortex in schizophrenia and mood disorders: a study from the Stanley Neuropathology Consortium. Schizophr Res 2004; 67: 269–275

Author! please check figure citation.Thankyou
