Advertisement

The Effect of Antipsychotic Treatment on Cortical Gray Matter Changes in Schizophrenia: Does the Class Matter? A Meta-analysis and Meta-regression of Longitudinal Magnetic Resonance Imaging Studies

Published:February 16, 2015DOI:https://doi.org/10.1016/j.biopsych.2015.02.008

      Abstract

      Background

      Deficits in cortical gray matter (GM) have been found in patients with schizophrenia, with evidence of progression over time. The aim of this study was to determine the role of potential moderators of such changes, in particular of the amount and type of antipsychotic medication intake.

      Methods

      Longitudinal magnetic resonance imaging studies comparing changes in the volume of cortical GM over time between patients with schizophrenia and healthy control subjects published between January 1, 1983, and March 31, 2014, were analyzed. Hedges’ g was calculated for each study and volume changes from baseline to follow-up were analyzed. Meta-regression statistics were applied to investigate the role of potential moderators of the effect sizes.

      Results

      Eighteen studies involving 1155 patients with schizophrenia and 911 healthy control subjects were included. Over time, patients with schizophrenia showed a significantly higher loss of total cortical GM volume. This was related to cumulative antipsychotic intake during the interval between scans in the whole study sample. Subgroup meta-analyses of studies on patients treated with second-generation antipsychotics and first-generation antipsychotics revealed a different and contrasting moderating role of medication intake on cortical GM changes: more progressive GM loss correlated with higher mean daily antipsychotic intake in patients treated with at least one first-generation antipsychotic and less progressive GM loss with higher mean daily antipsychotic intake in patients treated only with second-generation antipsychotics.

      Conclusions

      These findings add useful information to the controversial debate on the brain structural effects of antipsychotic medication and may have both clinical relevance and theoretical implications.

      Keywords

      The presence of structural brain abnormalities in schizophrenia has been well established (
      • Wright I.C.
      • Rabe-Hesketh S.
      • Woodruff P.W.R.
      • David A.S.
      • Murray R.M.
      • Bullmore E.T.
      Meta-analysis of regional brain volumes in schizophrenia.
      ,
      • Honea R.
      • Crow T.J.
      • Passingham D.
      • Mackay C.E.
      Regional deficits in brain volume in schizophrenia: A meta-analysis of voxel-based morphometry studies.
      ,
      • Haijma S.V.
      • Van Haren N.
      • Cahn W.
      • Koolschijn P.C.
      • Hulshoff Pol H.E.
      • Kahn R.S.
      Brain volumes in schizophrenia: A meta-analysis in over 18 000 subjects.
      ,
      • Shepherd A.M.
      • Matheson S.L.
      • Laurens K.R.
      • Carr V.J.
      • Green M.J.
      Systematic meta-analysis of insula volume in schizophrenia.
      ,
      • Glahn D.C.
      • Laird A.R.
      • Ellison-Wright I.
      • Thelen S.M.
      • Robinson J.L.
      • Lancaster J.L.
      • et al.
      Meta-analysis of gray matter anomalies in schizophrenia: Application of anatomic likelihood estimation and network analysis.
      ). Reductions in whole-brain and gray matter (GM) volume, primarily in the frontal and temporal lobes, and enlargement of the lateral ventricles are among the most replicated findings (
      • Wright I.C.
      • Rabe-Hesketh S.
      • Woodruff P.W.R.
      • David A.S.
      • Murray R.M.
      • Bullmore E.T.
      Meta-analysis of regional brain volumes in schizophrenia.
      ,
      • Haijma S.V.
      • Van Haren N.
      • Cahn W.
      • Koolschijn P.C.
      • Hulshoff Pol H.E.
      • Kahn R.S.
      Brain volumes in schizophrenia: A meta-analysis in over 18 000 subjects.
      ,
      • Glahn D.C.
      • Laird A.R.
      • Ellison-Wright I.
      • Thelen S.M.
      • Robinson J.L.
      • Lancaster J.L.
      • et al.
      Meta-analysis of gray matter anomalies in schizophrenia: Application of anatomic likelihood estimation and network analysis.
      ). These abnormalities are largely evident from the first episode of schizophrenia (
      • Vita A.
      • De Peri L.
      • Silenzi C.
      • Dieci M.
      Brain morphology in first-episode schizophrenia: A meta-analysis of quantitative magnetic resonance imaging studies.
      ) and are detectable before illness onset in prodromal/high-risk individuals (
      • Pantelis C.
      • Yücel M.
      • Wood S.J.
      • Velakoulis D.
      • Sun D.
      • Berger G.
      • et al.
      Structural brain imaging evidence for multiple pathological processes at different stages of brain development in schizophrenia.
      ). Longitudinal magnetic resonance imaging (MRI) studies have shown that these brain volume abnormalities in schizophrenia are progressive, with evidence that whole-brain and cortical GM volumes decrease and lateral ventricle volumes increase over time both in first-episode and chronic schizophrenia (
      • Kempton M.J.
      • Stahl D.
      • Williams S.C.
      • DeLisi L.E.
      Progressive lateral ventricular enlargement in schizophrenia: A meta-analysis of longitudinal MRI studies.
      ,
      • Olabi B.
      • Ellison-Wright I.
      • McIntosh A.M.
      • Wood S.J.
      • Bullmore E.
      • Lawrie S.M.
      Are there progressive brain changes in schizophrenia? A meta-analysis of structural magnetic resonance imaging studies.
      ,
      • Vita A.
      • De Peri L.
      • Deste G.
      • Sacchetti E.
      Progressive loss of cortical gray matter in schizophrenia: A meta-analysis and meta-regression of longitudinal MRI studies.
      ,
      • Fusar-Poli P.
      • Smieskova R.
      • Kempton M.J.
      • Ho B.C.
      • Andreasen N.C.
      • Borgwardt S.
      Progressive brain changes in schizophrenia related to antipsychotic treatment? A meta-analysis of longitudinal MRI studies.
      ). The nature of the pathophysiologic process underlying such progressive brain changes is still largely a matter of speculation. Genetic factors (
      • Sharma T.
      • Lancaster E.
      • Lee D.
      • Lewis S.
      • Sigmundsson T.
      • Takei N.
      • et al.
      Brain changes in schizophrenia. Volumetric MRI study of families multiply affected with schizophrenia--the Maudsley family study 5.
      ,
      • Baare W.F.
      • van Oel C.J.
      • Hulshoff Pol H.E.
      • Schnack H.G.
      • Durston S.
      • Sitskoorn M.M.
      • Kahn R.S.
      Volumes of brain structures in twins discordant for schizophrenia.
      ,
      • Cannon T.D.
      • Thompson P.M.
      • van Erp T.G.
      • Toga A.W.
      • Poutanen V.P.
      • Huttunen M.
      • et al.
      Cortex mapping reveals regionally specific patterns of genetic and disease-specific gray-matter deficits in twins discordant for schizophrenia.
      ,
      • Brans R.G.
      • van Haren N.E.
      • van Baal G.C.
      • Schnack H.G.
      • Kahn R.S.
      • Hulshoff Pol H.E.
      Heritability of changes in brain volume over time in twin pairs discordant for schizophrenia.
      ,
      • van Haren N.E.
      • Rijsdijk F.
      • Schnack H.G.
      • Picchioni M.M.
      • Toulopoulou T.
      • Weisbrod M.
      • et al.
      The genetic and environmental determinants of the association between brain abnormalities and schizophrenia: The schizophrenia twins and relatives consortium.
      ), symptom severity (
      • Lieberman J.A.
      • Tollefson G.D.
      • Charles C.
      • Zipursky R.
      • Sharma T.
      • Kahn R.S.
      • et al.
      HGDH Study Group. Antipsychotic drug effects on brain morphology in first-episode psychosis.
      ,
      • van Haren N.E.
      • Hulshoff Pol H.E.
      • Schnack H.G.
      • Cahn W.
      • Brans R.
      • Carati I.
      • et al.
      Progressive brain volume loss in schizophrenia over the course of the illness: Evidence of maturational abnormalities in early adulthood.
      ,
      • Ho B.C.
      • Andreasen N.C.
      • Ziebell S.
      • Pierson R.
      • Magnotta V.
      Long-term antipsychotic treatment and brain volumes: A longitudinal study of first-episode schizophrenia.
      ,
      • Arango C.
      • Rapado-Castro M.
      • Reig S.
      • Castro-Fornieles J.
      • González-Pinto A.
      • Otero S.
      • et al.
      Progressive brain changes in children and adolescents with first-episode psychosis.
      ), duration of relapses (
      • Andreasen N.C.
      • Liu D.
      • Ziebell S.
      • Vora A.
      • Ho B.C.
      Relapse duration, treatment intensity, and brain tissue loss in schizophrenia: A prospective longitudinal MRI study.
      ) or number of weeks hospitalized (
      • Lieberman J.
      • Chakos M.
      • Wu H.
      • Alvir J.
      • Hoffman E.
      • Robinson D.
      • Bilder R.
      Longitudinal study of brain morphology in first episode schizophrenia.
      ), and poorer social functioning (
      • van Haren N.E.
      • Hulshoff Pol H.E.
      • Schnack H.G.
      • Cahn W.
      • Brans R.
      • Carati I.
      • et al.
      Progressive brain volume loss in schizophrenia over the course of the illness: Evidence of maturational abnormalities in early adulthood.
      ,
      • Lieberman J.
      • Chakos M.
      • Wu H.
      • Alvir J.
      • Hoffman E.
      • Robinson D.
      • Bilder R.
      Longitudinal study of brain morphology in first episode schizophrenia.
      ,
      • Cahn W.
      • Hulshoff Pol H.E.
      • Lems E.B.
      • van Haren N.E.
      • Schnack H.G.
      • van der Linden J.A.
      • et al.
      Brain volume changes in first-episode schizophrenia: A 1-year follow-up study.
      ) have been associated with larger decreases in brain volume or increases in lateral ventricular volume.
      The role played by antipsychotic treatment on the pathophysiologic trajectory of brain abnormalities in schizophrenia is currently a matter of lively debate. The findings from the largest meta-analysis of cross-sectional studies on schizophrenia performed to date (
      • Haijma S.V.
      • Van Haren N.
      • Cahn W.
      • Koolschijn P.C.
      • Hulshoff Pol H.E.
      • Kahn R.S.
      Brain volumes in schizophrenia: A meta-analysis in over 18 000 subjects.
      ) indicate that the reduction in whole-brain GM volume is associated with the dose of antipsychotics taken at the time of scanning. A longitudinal MRI investigation of a large cohort of patients from the first episode of schizophrenia followed for up to 14 years (Iowa Longitudinal Study) showed that decreases in whole-brain and GM volumes were associated with higher exposure to antipsychotics (
      • Ho B.C.
      • Andreasen N.C.
      • Ziebell S.
      • Pierson R.
      • Magnotta V.
      Long-term antipsychotic treatment and brain volumes: A longitudinal study of first-episode schizophrenia.
      ,
      • Andreasen N.C.
      • Liu D.
      • Ziebell S.
      • Vora A.
      • Ho B.C.
      Relapse duration, treatment intensity, and brain tissue loss in schizophrenia: A prospective longitudinal MRI study.
      ). A meta-analysis of longitudinal MRI studies showed a correlation between cumulative antipsychotic intake during the interscan follow-up period and the decrease in whole-brain GM volume (
      • Fusar-Poli P.
      • Smieskova R.
      • Kempton M.J.
      • Ho B.C.
      • Andreasen N.C.
      • Borgwardt S.
      Progressive brain changes in schizophrenia related to antipsychotic treatment? A meta-analysis of longitudinal MRI studies.
      ). However, these studies and meta-analysis did not analyze the potential impact of first-generation antipsychotics (FGAs) and second-generation antipsychotics (SGAs) on progressive loss of brain tissue.
      In fact, the relationship between antipsychotic treatment and loss of cortical GM in schizophrenia and the potential differential effect of SGAs versus FGAs on such loss is a topic of crucial clinical and heuristic interest. A number of studies have reported different impacts of SGAs versus FGAs on changes in brain volume in schizophrenia, especially GM, with SGAs being putatively associated with a lesser decrease in longitudinal GM volume than FGAs (
      • Lieberman J.A.
      • Tollefson G.D.
      • Charles C.
      • Zipursky R.
      • Sharma T.
      • Kahn R.S.
      • et al.
      HGDH Study Group. Antipsychotic drug effects on brain morphology in first-episode psychosis.
      ,
      • Garver D.L.
      • Holcomb J.A.
      • Christensen J.D.
      Cerebral cortical gray expansion associated with two second-generation antipsychotics.
      ,
      • van Haren N.E.
      • Hulshoff Pol H.E.
      • Schnack H.G.
      • Cahn W.
      • Mandl R.C.
      • Collins D.L.
      • et al.
      Focal gray matter changes in schizophrenia across the course of the illness: A 5-year follow-up study.
      ), although a study performed in first-episode patients over 1 year of treatment concluded that low doses of haloperidol, risperidone, or olanzapine may have similar effects on the overall change in GM volume (
      • Crespo-Facorro B.
      • Roiz-Santiáñez R.
      • Pérez-Iglesias R.
      • Pelayo-Terán J.M.
      • Rodríguez-Sánchez J.M.
      • Tordesillas-Gutiérrez D.
      • et al.
      Effect of antipsychotic drugs on brain morphometry. A randomized controlled one-year follow-up study of haloperidol, risperidone and olanzapine.
      ). Qualitative reviews addressing the topic of brain changes in schizophrenia in relation to antipsychotic treatment have yielded inconclusive results (
      • Vita A.
      • De Peri L.
      The effects of antipsychotic treatment on cerebral structure and function in schizophrenia.
      ,
      • Navari S.
      • Dazzan P.
      Do antipsychotic drugs affect brain structure? A systematic and critical review of MRI findings.
      ,
      • Smieskova R.
      • Fusar-Poli P.
      • Allen P.
      • Bendfeldt K.
      • Stieglitz R.D.
      • Drewe J.
      • et al.
      The effects of antipsychotics on the brain: What have we learnt from structural imaging of schizophrenia?--a systematic review.
      ,
      • Moncrieff J.
      • Leo J.
      A systematic review of the effects of antipsychotic drugs on brain volume.
      ). A recent quantitative review of longitudinal cortical GM changes in schizophrenia (
      • Vita A.
      • De Peri L.
      • Deste G.
      • Sacchetti E.
      Progressive loss of cortical gray matter in schizophrenia: A meta-analysis and meta-regression of longitudinal MRI studies.
      ) suggested that treatment with SGAs may be associated with less progressive loss of GM, but a very rough index of intake of different classes of antipsychotics (the percentage of patients using SGAs in each study included in the review) was used.
      In this article, we report the results of a meta-analysis of MRI longitudinal studies analyzing cortical GM volume in schizophrenia specifically aimed at investigating: 1) the influence of antipsychotic medications on changes in GM volume over time; 2) the possible different impact of SGAs versus FGAs on such changes; and 3) the influence of other potential moderators of longitudinal changes in cortical brain volumes (
      • Van Haren N.E.
      • Cahn W.
      • Hulshoff Pol H.E.
      • Kahn R.S.
      Confounders of excessive brain volume loss in schizophrenia.
      ).

      Methods and Materials

       Data Sources

      We conducted a systematic literature search via the MEDLINE/PubMed (National Library of Medicine at the National Institutes of Health, Bethesda, Maryland; http://www-ncbi-nlm-nih-gov.proxy.unibs.it/pubmed) and EMBASE (Elsevier, Amsterdam, Netherlands; http://www.embase.com.proxy.unibs.it) databases for MRI studies investigating longitudinal cortical GM volume changes and the role of antipsychotic drugs on such changes in samples of patients with schizophrenia. We used the following keywords to generate a list of potentially useful studies: ([Magnetic Resonance Imaging] OR [MRI]) AND [schizophrenia] AND ([antipsychotics] OR [neuroleptics]) AND ([longitudinal] OR ([progressive]). The search was performed through March 31, 2014. All the reference lists within the selected studies, as well as the list of studies included in previous meta-analyses on similar topics, were reviewed to check for additional references.

       Study Selection

      Studies were included if they met the following criteria: 1) were reported in an original paper published in a peer-reviewed journal; 2) included subjects with a DSM-IV-TR, DSM-IV, DSM-III-R, or ICD-10 diagnosis of schizophrenia; 3) used longitudinal analysis of regions of interest (ROIs) of GM volume on MRI in a group of patients with schizophrenia and a group of healthy control subjects; and 4) reported the cumulative dose or the mean daily dose (MDD) of antipsychotic medication administered during the follow-up period or the same information was provided by the authors of the study. In fact, when studies did not report the data required to compute the antipsychotic dose, we contacted the respective authors to collect the individual data (cumulative or MDD of antipsychotic medication administered during the follow-up period) and avoid biases in the literature search. If no response was received from the authors, that study was excluded from the meta-analysis. Longitudinal MRI studies conducted on patients diagnosed as being in an at-risk mental state for schizophrenia or during transition to psychosis were not considered for the present meta-analysis. Studies that used voxel-based morphometry, deformation-based morphometry, or tensor-based morphometry, which cannot be included in a traditional meta-analysis, were also excluded.
      Studies performed using ROI MRI were considered if they reported quantitative measurements of changes in cortical GM volume over time in terms of means and SD or as a variable that could be lead back to such values (e.g., SE values). When repeat studies by the same research group were available and the patients included in one study were included in a subsequent study, only the most recent or larger study was included. An exception to this was longitudinal studies with multiple subsequent follow-up evaluations that reported both GM volume and pharmacologic regimens of patients at each follow-up time point. In this case, even if the findings were derived from the same cohort of patients, all the follow-up intervals were included in the analysis and considered as if they were derived from independent studies. Moreover, in the case of studies that reported separately brain volumes for subgroups of patients treated with different pharmacologic treatments, we entered the results as if they were from separate studies. This technique was adopted by previous meta-analyses (
      • Kempton M.J.
      • Stahl D.
      • Williams S.C.
      • DeLisi L.E.
      Progressive lateral ventricular enlargement in schizophrenia: A meta-analysis of longitudinal MRI studies.
      ,
      • Steen R.G.
      • Mull C.
      • McClure R.
      • Hamer R.M.
      • Lieberman J.A.
      Brain volume in first-episode schizophrenia: Systematic review and meta-analysis of magnetic resonance imaging studies.
      ).
      Brain regions were included when investigated in at least 10 independent study samples.

       Data Recorded in the Database

      The variables recorded from each article included in the meta-analysis were sample size, year of publication, mean age of participants, type of antipsychotic treatment, dose of antipsychotic at baseline and follow-up MRI scan or MDD or cumulative dose of antipsychotics during the follow-up, brain volume (baseline and follow-up means ± SD or baseline to follow-up volume mean difference ± SD), duration of follow-up (months), duration of illness at baseline MRI scan (weeks), number (or percentage) of substance abusers in the study sample, number of Tesla of MRI scanner, overall cognitive functioning (IQ), duration of untreated psychosis (DUP), and change in severity of psychotic symptoms during the follow-up (Supplement 1). The antipsychotic intake was recorded both as cumulative exposure to antipsychotics during the interscan interval and as the MDD of antipsychotics. We used the Antipsychotic Dose Conversion Table equivalency to 100 mg of chlorpromazine (
      • Ho B.C.
      • Andreasen N.C.
      • Ziebell S.
      • Pierson R.
      • Magnotta V.
      Long-term antipsychotic treatment and brain volumes: A longitudinal study of first-episode schizophrenia.
      ) to convert all antipsychotic doses into chlorpromazine equivalents (CPZ-Eq) (Supplement 1).

       Meta-Analytical Methods and Data Analyses

      Meta-analyses were carried out using the Comprehensive Meta-Analysis software, version 2 (Biostat Inc., Englewood, New Jersey). Effect sizes (ES) were calculated for each study included in the meta-analyses. As a measure of ES, Hedges’ g was adopted and computed by subtracting the follow-up from the baseline mean volume (or using the mean volume change from baseline), divided by the standard deviation, and weighted for sample size (
      • Hedges L.V.
      • Holkin I.
      Statistical Methods for Meta-Analysis.
      ). The 95% interval around the composite ES was also calculated (
      • Hedges L.V.
      • Holkin I.
      Statistical Methods for Meta-Analysis.
      ). The Q statistic was used to determine between-group (patients vs. control subjects) differences. Egger’s test of publication bias was used to assess whether there was a tendency for selective publication of studies based on the direction of their results (
      • Egger M.
      • Davey Smith G.
      • Schneider M.
      • Minder C
      Bias in meta-analysis detected by a simple, graphical test.
      ).

       Meta-regression Analyses

      Meta-regression analyses were conducted to test the influence of the following potential moderators of ES: cumulative exposure to antipsychotic medication during the interscan interval (as CPZ-Eq); MDD of antipsychotics during the interscan interval (MDD CPZ-Eq); patient’s age at baseline MRI scan; duration of illness at baseline; duration of MRI follow-up; change in severity of psychotic symptoms during the follow-up; and percentage of substance abusers in the study sample. Due to co-linearity between the highly correlated variables age and duration of illness, the latter was not included in the meta-regressions. The number of Tesla of MRI scanner was not included in the meta-regression analyses since all studies but one (
      • Ebdrup B.H.
      • Skimminge A.
      • Rasmussen H.
      • Aggernaes B.
      • Oranje B.
      • Lublin H.
      • et al.
      Progressive striatal and hippocampal volume loss in initially antipsychotic-naive, first-episode schizophrenia patients treated with quetiapine: Relationship to dose and symptoms.
      ) were performed with 1.5 Tesla MRI scanner. Meta-regressions were performed when at least 10 independent studies were available for the outcome of interest. Thus, the potential moderating impact on GM changes of such variables as patient’s IQ [reported only in three studies (
      • Arango C.
      • Rapado-Castro M.
      • Reig S.
      • Castro-Fornieles J.
      • González-Pinto A.
      • Otero S.
      • et al.
      Progressive brain changes in children and adolescents with first-episode psychosis.
      ,
      • Sporn A.L.
      • Greenstein D.K.
      • Gogtay N.
      • Jeffries N.O.
      • Lenane M.
      • Gochman P.
      • et al.
      Progressive brain volume loss during adolescence in childhood-onset schizophrenia.
      ,
      • Lappin J.M.
      • Morgan C.
      • Chalavi S.
      • Morgan K.D.
      • Reinders A.A.
      • Fearon P.
      • et al.
      Bilateral hippocampal increase following first-episode psychosis is associated with good clinical, functional and cognitive outcomes.
      )] or DUP [reported only in three studies (
      • Crespo-Facorro B.
      • Roiz-Santiáñez R.
      • Pérez-Iglesias R.
      • Pelayo-Terán J.M.
      • Rodríguez-Sánchez J.M.
      • Tordesillas-Gutiérrez D.
      • et al.
      Effect of antipsychotic drugs on brain morphometry. A randomized controlled one-year follow-up study of haloperidol, risperidone and olanzapine.
      ,
      • Molina V.
      • Reig S.
      • Sanz J.
      • Palomo T.
      • Benito C.
      • Sánchez J.
      • et al.
      Increase in gray matter and decrease in white matter volumes in the cortex during treatment with atypical neuroleptics in schizophrenia.
      ,
      • Roiz-Santiáñez R.
      • Ayesa-Arriola R.
      • Tordesillas-Gutiérrez D.
      • Ortiz-García de la Foz V.
      • Pérez-Iglesias R.
      • Pazos A.
      • et al.
      Three-year longitudinal population-based volumetric MRI study in first-episode schizophrenia spectrum patients.
      )] was not considered.

       Subgroup Meta-analyses

      To address the issue of a potential different impact of SGAs and FGAs on progressive loss of cortical GM, a supplementary set of meta-analyses was conducted. On the one hand, we selected from the database those studies that investigated brain morphology longitudinally in patients treated exclusively with SGAs. A separate analysis was also performed for those studies that investigated patients treated with FGAs or that included mixed antipsychotic treatments (both FGAs and SGAs) during the interscan interval. Mixed treatment means that both FGAs and SGAs were used within the patient sample, with the exception of one study (
      • van Haren N.E.
      • Hulshoff Pol H.E.
      • Schnack H.G.
      • Cahn W.
      • Brans R.
      • Carati I.
      • et al.
      Progressive brain volume loss in schizophrenia over the course of the illness: Evidence of maturational abnormalities in early adulthood.
      ) where a subgroup of patients was treated with both FGAs and SGAs polypharmacy. This was a heterogeneous group with respect to the relative amount of different types of antipsychotics administered, with a mean percentage of patients treated with SGAs of 43.6 ± 30.4%. Since considerably fewer studies were available on patients treated with SGAs only or with FGAs or mixed treatments, brain regions were included in the analyses when studied in at least five independent studies. Due to insufficient data, it was not conducted as a subgroup meta-analysis for studies including patients treated exclusively with FGAs [three studies available (
      • Lieberman J.A.
      • Tollefson G.D.
      • Charles C.
      • Zipursky R.
      • Sharma T.
      • Kahn R.S.
      • et al.
      HGDH Study Group. Antipsychotic drug effects on brain morphology in first-episode psychosis.
      ,
      • Garver D.L.
      • Holcomb J.A.
      • Christensen J.D.
      Cerebral cortical gray expansion associated with two second-generation antipsychotics.
      ,
      • Crespo-Facorro B.
      • Roiz-Santiáñez R.
      • Pérez-Iglesias R.
      • Pelayo-Terán J.M.
      • Rodríguez-Sánchez J.M.
      • Tordesillas-Gutiérrez D.
      • et al.
      Effect of antipsychotic drugs on brain morphometry. A randomized controlled one-year follow-up study of haloperidol, risperidone and olanzapine.
      )].

      Results

       Results of the Systematic Search

      The selection procedure, according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (
      • Moher D.
      • Liberati A.
      • Tetzlaff J.
      • Altman D.G.
      PRISMA Group
      Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement.
      ), is shown in Figure 1.
      Figure thumbnail gr1
      Figure 1Study selection procedure (Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines). MRI, magnetic resonance imaging; ROI, region of interest.
      The final database comprised 18 original independent studies suitable for analysis (Table 1) and published between 2002 and March 2014. Moreover, four studies (
      • Lieberman J.A.
      • Tollefson G.D.
      • Charles C.
      • Zipursky R.
      • Sharma T.
      • Kahn R.S.
      • et al.
      HGDH Study Group. Antipsychotic drug effects on brain morphology in first-episode psychosis.
      ,
      • Garver D.L.
      • Holcomb J.A.
      • Christensen J.D.
      Cerebral cortical gray expansion associated with two second-generation antipsychotics.
      ,
      • Crespo-Facorro B.
      • Roiz-Santiáñez R.
      • Pérez-Iglesias R.
      • Pelayo-Terán J.M.
      • Rodríguez-Sánchez J.M.
      • Tordesillas-Gutiérrez D.
      • et al.
      Effect of antipsychotic drugs on brain morphometry. A randomized controlled one-year follow-up study of haloperidol, risperidone and olanzapine.
      ,
      • Molina V.
      • Reig S.
      • Sanz J.
      • Palomo T.
      • Benito C.
      • Sánchez J.
      • et al.
      Increase in gray matter and decrease in white matter volumes in the cortex during treatment with atypical neuroleptics in schizophrenia.
      ) reported brain volumes of subgroups of patients in relation to different pharmacologic treatments (two or three arms). In these cases, as reported in Methods and Materials, we entered their results as if they were from separate studies. The same criterion was adopted for two studies (
      • Ho B.C.
      • Andreasen N.C.
      • Ziebell S.
      • Pierson R.
      • Magnotta V.
      Long-term antipsychotic treatment and brain volumes: A longitudinal study of first-episode schizophrenia.
      ,
      • Roiz-Santiáñez R.
      • Ayesa-Arriola R.
      • Tordesillas-Gutiérrez D.
      • Ortiz-García de la Foz V.
      • Pérez-Iglesias R.
      • Pazos A.
      • et al.
      Three-year longitudinal population-based volumetric MRI study in first-episode schizophrenia spectrum patients.
      ) with multiple follow-up evaluations and reporting GM volume at each follow-up time point and for which antipsychotic intake between each follow-up period was derivable. Thus, a number of independent samples of patients higher than the number of original studies were analyzed. The overall sample consisted of 1155 patients with schizophrenia and 911 healthy control subjects. The following cerebral regions (GM) for which at least 10 studies were available were included in the analyses: whole brain (n = 26), frontal lobe (n = 15), temporal lobe (n = 14), and parietal lobe (n = 14).
      Table 1Description of the Studies Included in the Meta-Analysis
      Author (Year) (Reference)Follow-up Duration, Months ± SD (Range)Type of AntipsychoticMDD (mg CPZ-Eq)Cumulative Antipsychotic Intake (mg CPZ-Eq)Substance Abuse: Y/NM/F RatioMean Age
      PatientsControl SubjectsPatientsControl Subjects
      Cahn et al. (2002) (
      • Cahn W.
      • Hulshoff Pol H.E.
      • Lems E.B.
      • van Haren N.E.
      • Schnack H.G.
      • van der Linden J.A.
      • et al.
      Brain volume changes in first-episode schizophrenia: A 1-year follow-up study.
      )
      12.85 ± 1.15Mixed (FGAs or SGAs or FGAs + SGAs)159.5762391.87
      Data reported in the original paper.
      N29/530/626.224.5
      Ho et al. (2003) (
      • Ho B.C.
      • Andreasen N.C.
      • 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.
      )
      40.68 ± 19.20Mixed (FGAs or SGAs)462.20
      Data reported in the original paper.
      556117.10
      Data reported in the original paper.
      NR53/2015/824.526.9
      Sporn et al. (2003) (
      • Sporn A.L.
      • Greenstein D.K.
      • Gogtay N.
      • Jeffries N.O.
      • Lenane M.
      • Gochman P.
      • et al.
      Progressive brain volume loss during adolescence in childhood-onset schizophrenia.
      )
      40.80 ± 19.20Mixed (SGAs or FGAs + SGAs)384.26
      Data derived from previous published reviews.
      470180.54
      Data derived from previous published reviews.
      N24/3927/4315.014.8
      Lieberman et al. (2005) (
      • Lieberman J.A.
      • Tollefson G.D.
      • Charles C.
      • Zipursky R.
      • Sharma T.
      • Kahn R.S.
      • et al.
      HGDH Study Group. Antipsychotic drug effects on brain morphology in first-episode psychosis.
      )
      12.00FGAs (n = 79, HAL)597.82
      Data reported in the original paper.
      218204.30N136/2540/2223.825.3
      NRSGAs (n = 82, OLA)263.15
      Data reported in the original paper.
      96049.75
      Molina et al. (2005) (
      • Molina V.
      • Reig S.
      • Sanz J.
      • Palomo T.
      • Benito C.
      • Sánchez J.
      • et al.
      Increase in gray matter and decrease in white matter volumes in the cortex during treatment with atypical neuroleptics in schizophrenia.
      )
      25.60 ± 9.90 (naive)SGAs (n = 17, RIS)378.78
      Data reported in the original paper.
      294943.36N20/296/1131.0 (naïve)28.4
      28.70 ± 11.80 (chronic)SGAs (n = 12,CLO)310.18
      Data reported in the original paper.
      270774.2125.6 (chronic)
      Garver et al. (2005) (
      • Garver D.L.
      • Holcomb J.A.
      • Christensen J.D.
      Cerebral cortical gray expansion associated with two second-generation antipsychotics.
      )
      1.0FGAs (n = 6, HAL)380.43
      Data reported in the original paper.
      10652.04N13/65/233.029.0
      SGAs (n = 7, RIS)237.62
      Data reported in the original paper.
      6653.36
      SGAs (n = 6, ZIP)303.03
      Data reported in the original paper.
      8484.84
      Molina et al. (2007) (
      • Molina V.
      • Reig S.
      • Sanz J.
      • Palomo T.
      • Benito C.
      • Sánchez J.
      • et al.
      Changes in cortical volume with olanzapine in chronic schizophrenia.
      )
      38.00 ± 15.00SGAs (OLA)324.21
      Data reported in the original paper.
      374731.64N6/55/641.029.8
      van Haren et al. (2008) (
      • van Haren N.E.
      • Hulshoff Pol H.E.
      • Schnack H.G.
      • Cahn W.
      • Brans R.
      • Carati I.
      • et al.
      Progressive brain volume loss in schizophrenia over the course of the illness: Evidence of maturational abnormalities in early adulthood.
      )
      57.96 ± 6.60Mixed (FGAs or SGAs or FGAs + SGAs)338.68
      Data derived from previous published reviews.
      611656.08
      Data derived from previous published reviews.
      NR70/2676/3732.235.2
      Crespo-Facorro et al. (2008) (
      • Crespo-Facorro B.
      • Roiz-Santiáñez R.
      • Pérez-Iglesias R.
      • Pelayo-Terán J.M.
      • Rodríguez-Sánchez J.M.
      • Tordesillas-Gutiérrez D.
      • et al.
      Effect of antipsychotic drugs on brain morphometry. A randomized controlled one-year follow-up study of haloperidol, risperidone and olanzapine.
      )
      12.05 ± 1.06FGAs (n = 18, HAL)244.09
      Data reported in the original paper.
      89464.07Y11/1826/1229.7
      12.03 ± 1.24SGAs (n = 16, RIS)183.65
      Data reported in the original paper.
      67199.8313/1624.9
      12.07 ± 1.02SGAs (n = 18, OLA)289.02
      Data reported in the original paper.
      106107.6713/1828.0
      Reig et al. (2009) (
      • Reig S.
      • Moreno C.
      • Moreno D.
      • Burdalo M.
      • Janssen J.
      • Parellada M.
      • et al.
      Progression of brain volume changes in adolescent onset psychosis.
      )
      24.20 ± 1.00Mixed (SGAs)223.71
      Data provided by the authors on request.
      88318.19
      Data provided by the authors on request.
      N16/521/1315.715.2
      Takahashi et al. (2010) (
      • Takahashi T.
      • Suzuki M.
      • Zhou S.Y.
      • Tanino R.
      • Nakamura K.
      • Kawasaki Y.
      • et al.
      A follow-up MRI study of the superior temporal subregions in schizotypal disorder and first-episode schizophrenia.
      )
      32.40 ± 7.20Mixed (FGAs or SGAs or FGAs + SGAs)415.76
      Data reported in the original paper.
      439755.43
      Data reported in the original paper.
      N12/611/923.123.2
      Takahashi et al. (2010) (
      • Takahashi T.
      • Wood S.J.
      • Kawasaki Y.
      • Suzuki M.
      • Velakoulis D.
      • Pantelis
      Lack of progressive gray matter reduction of the superior temporal subregions in chronic schizophrenia.
      )
      28.80 ± 12.00Mixed (FGAs or SGAs)559.25
      Data reported in the original paper.
      489903N10/112/532.730.2
      Boonstra et al. (2011) (
      • Boonstra G.
      • van Haren N.E.
      • Schnack H.G.
      • Cahn W.
      • Burger H.
      • Boersma M.
      • et al.
      Brain volume changes after withdrawal of atypical antipsychotics in patients with first-episode schizophrenia.
      )
      12.10 ± 1.20Mixed (SGAs)183.69
      Data reported in the original paper.
      67605.57
      Data reported in the original paper.
      Y12/415/528.827.9
      Andreasen et al. (2011) (
      • Andreasen N.C.
      • Nopoulos P.
      • Magnotta V.
      • Pierson R.
      • Ziebell S.
      • Ho B.C.
      Progressive brain change in schizophrenia: A prospective longitudinal study of first-episode schizophrenia.
      , data derived also from
      • Ho B.C.
      • Andreasen N.C.
      • Ziebell S.
      • Pierson R.
      • Magnotta V.
      Long-term antipsychotic treatment and brain volumes: A longitudinal study of first-episode schizophrenia.
      )
      86.4 ± 45.40Mixed297.10
      Data reported in the original paper.
      (1st follow-up)
      332915.40Y148/5466/5924.529.6
      393.90
      Data reported in the original paper.
      (2nd follow-up)
      475890.28
      479.40
      Data reported in the original paper.
      (3rd follow-up)
      680676.09
      Ebdrup et al. (2011) (
      • Ebdrup B.H.
      • Skimminge A.
      • Rasmussen H.
      • Aggernaes B.
      • Oranje B.
      • Lublin H.
      • et al.
      Progressive striatal and hippocampal volume loss in initially antipsychotic-naive, first-episode schizophrenia patients treated with quetiapine: Relationship to dose and symptoms.
      )
      7.30 ± 1.00SGA (QUE)379.15
      Data reported in the original paper.
      84324.05Y15/721/726.228.4
      Arango et al. (2012) (
      • Arango C.
      • Rapado-Castro M.
      • Reig S.
      • Castro-Fornieles J.
      • González-Pinto A.
      • Otero S.
      • et al.
      Progressive brain changes in children and adolescents with first-episode psychosis.
      )
      26.20 ± 3.00Mixed (FGAs or SGAs)211.86168840.00
      Data reported in the original paper.
      N18/723/4715.515.3
      Roiz-Santiáñez et al. (2013) (
      • Roiz-Santiáñez R.
      • Ayesa-Arriola R.
      • Tordesillas-Gutiérrez D.
      • Ortiz-García de la Foz V.
      • Pérez-Iglesias R.
      • Pazos A.
      • et al.
      Three-year longitudinal population-based volumetric MRI study in first-episode schizophrenia spectrum patients.
      )
      36.70 (34.50–44.90)Mixed (FGAs or SGAs)266.43297420.00
      Data reported in the original paper.
      Y66/10947/7629.427.8
      Lappin et al. (2013) (
      • Lappin J.M.
      • Morgan C.
      • Chalavi S.
      • Morgan K.D.
      • Reinders A.A.
      • Fearon P.
      • et al.
      Bilateral hippocampal increase following first-episode psychosis is associated with good clinical, functional and cognitive outcomes.
      )
      72.10 ± 12.00Mixed (FGAs or SGAs)343
      Data provided by the authors on request.
      751170
      Data provided by the authors on request.
      Y15/2014/3225.329.8
      CLO, clozapine; F, female; FGAs, first generation antipsychotics; HAL, haloperidol; M, male; N, no; NR, not reported; SGAs, second-generation antipsychotics; OLA, olanzapina; QUE, quetiapine; RIS, riperidone; Y, yes; ZIP, ziprasidone.
      a Data reported in the original paper.
      b Data derived from previous published reviews.
      c Data provided by the authors on request.

       Results of the Overall Meta-analysis

      Changes in GM volume over time in patients with schizophrenia and healthy control subjects are presented in Table 2. To limit the risk of type 1 errors arising from multiple comparisons, we used the Bonferroni correction (p settled at .00625 [.05/8]).
      Table 2Summary of the Meta-analyses
      Brain RegionNumber of StudiesGroupsNumber of Patients or Control SubjectsEffect Size (95% CI)Effect Size: p ValueHeterogeneity (Between- Groups Comparison)Egger Test: p Value
      Qp Value
      Whole-Brain GM26CTRL883−.10 (−.17 to −.02).006
      Statistically significant after correction for multiple comparisons (p = .00625).
      5.62.018.348
      SCZ1102−.24 (−.33 to −.15)<.001
      Statistically significant after correction for multiple comparisons (p = .00625).
      Frontal Lobe GM15CTRL542−.11 (−.27 to .04).163.43.511.193
      SCZ891−.18 (−.33 to −.03).013
      Temporal Lobe GM14CTRL519−.02 (−.17 to .07).574.44.503.460
      SCZ818−.08 (−.18 to .02).149
      Parietal Lobe GM14CTRL519−.18 (−.32 to −.04).008.05.816.390
      SCZ818−.21 (−.32 to −.09)<.001
      Statistically significant after correction for multiple comparisons (p = .00625).
      CI, confidence interval; CTRL, control subject; GM, gray matter; SCZ, schizophrenia. Bold text indicates statistically significant values.
      a Statistically significant after correction for multiple comparisons (p = .00625).

       Subgroup Meta-analyses

      In the subgroup of studies analyzing patients treated with FGAs or mixed antipsychotic treatment (FGAs and SGAs), a statistically significant decrease in volume of whole-brain, frontal, temporal, and parietal lobe GM was found (Table S1 in Supplement 1). These changes in GM volume persisted after correction for multiple comparisons.
      In the subgroup of patients treated only with SGAs, no decrease in whole-brain and parietal lobe GM volume was found. For frontal and temporal lobes, there was even an increase, although not statistically significant, in GM volume during the follow-up period (Table S2 in Supplement 1).

       Meta-regression Analyses

      A meta-regression analysis of potential moderators of the ES was performed for whole-brain GM, i.e., the cerebral region for which a statistically significant between-group heterogeneity (patients vs. control subjects) in cortical volume changes was demonstrated in the whole study sample (Table 2). The mean values of the moderators investigated are reported in Supplement 1. For computing statistical significance, the Bonferroni correction for multiple comparisons was applied (statistical significance settled at p = .0083 [.05/6]). The results of meta-regressions are reported in Table 3.
      Table 3Meta-regression of Gray Matter Volume Changes Over Time in Patients with Schizophrenia: Treatment, Clinical, and Study Variables
      Mean Daily Dose of Antipsychotics (CPZ-Eq)Cumulative Exposure to Antipsychotics (CPZ-Eq)Age of PatientsSeverity of Psychotic SymptomsSubstance AbuseInterscan Interval
      Whole-Brain GM (Entire Sample)
      Z−2.19−2.631.13.29.17−2.20
      p.028.008
      Statistically significant after correction for multiple comparisons (p = .0083). Bold text indicates statistically significant values.
      .255.770.866.027
      Whole-Brain GM (FGAs + SGAs)
      Z−2.88−2.31.88.05−2.01−1.51
      p.003
      Statistically significant after correction for multiple comparisons (p = .0083). Bold text indicates statistically significant values.
      .020.373.958.044.128
      Whole-Brain GM (Only SGAs)
      Z2.95.781.111.73−1.03−.38
      p.003
      Statistically significant after correction for multiple comparisons (p = .0083). Bold text indicates statistically significant values.
      .439.267.083.299.701
      CPZ-Eq, chlorpromazine equivalents; FGAs, first-generation antipsychotics; GM, gray matter; SGAs, second-generation antipsychotics.
      a Statistically significant after correction for multiple comparisons (p = .0083). Bold text indicates statistically significant values.
      In all the studies analyzed, the ES of the within-subjects difference in whole-brain GM was affected by the moderator cumulative exposure to antipsychotics (the greater the exposure to antipsychotics during the interscan interval, the greater the reduction in GM volume). Also, in the studies including patients treated with FGAs, the ES of whole-brain GM change was negatively affected by the cumulative exposure to antipsychotics and MDD of antipsychotics, the latter correlation persisting after correction for multiple comparisons. On the other hand, in the subgroup of studies including patients treated only with SGAs, no significant correlation emerged between whole-brain GM volume change and cumulative exposure to antipsychotics during the interscan interval. ES was even positively moderated by the MDD of antipsychotic—the higher the MDD of antipsychotics during the follow-up, the lower the reduction in GM volume, a significance persisting after correction for multiple comparisons.
      The meta-regressions of time-corrected antipsychotic treatment (MDD) on whole-brain GM changes are represented in Figure 2.
      Figure thumbnail gr2
      Figure 2Meta-regression analyses. GM volume changes and mean daily dose (MDD) of antipsychotic medication administered to patients during the interscan interval: (A) in the whole sample (Z = −2.19, p = .028); (B) in the subgroup of patients treated with first-generation antipsychotics or mixed treatment (second-generation antipsychotics [SGAs] + first-generation antipsychotics) (Z = −2.88, p = .003); and (C) in the studies including patients treated exclusively with SGAs (Z = 2.95, p = .003). The size of the circles reflects the sample size of the study. (C) The colors indicate the different SGAs used as follows: red: clozapine; green: olanzapine; pink: quetiapine; yellow: risperidone; blue: ziprasidone; black: more atypicals (risperidone or olanzapine or quetiapine); brown: more atypicals (risperidone or olanzapine or quetiapine or ziprasidone or aripiprazole or clozapine); violet: more atypicals (risperidone or olanzapine or quetiapine or clozapine). CPZ-Eq, chlorpromazine equivalents.

      Discussion

      This meta-analysis investigated longitudinal changes of cortical GM in schizophrenia and specifically addressed the issue of the impact of the amount and type of antipsychotic medication intake on progressive change of GM volumes.
      No previous quantitative review tried to analyze separately the effects of FGAs and SGAs on cortical GM changes. In fact, the meta-analysis by Fusar-Poli et al. (
      • Fusar-Poli P.
      • Smieskova R.
      • Kempton M.J.
      • Ho B.C.
      • Andreasen N.C.
      • Borgwardt S.
      Progressive brain changes in schizophrenia related to antipsychotic treatment? A meta-analysis of longitudinal MRI studies.
      ) reached the conclusion that antipsychotics in general may have a detrimental effect on brain structure but did not differentiate the effects of FGAs and SGAs; the other, by our group (
      • Vita A.
      • De Peri L.
      • Deste G.
      • Sacchetti E.
      Progressive loss of cortical gray matter in schizophrenia: A meta-analysis and meta-regression of longitudinal MRI studies.
      ), suggested a possible different effect of FGAs and SGAs but used a very rough index of intake of different classes of antipsychotics (percentage of patients using SGAs in each study included), limited the analysis to a subgroup of studies, and did not analyze the effect of cumulative exposure to or mean daily dose of different classes of antipsychotics on GM changes.
      One main finding of the present meta-analysis is that longitudinal changes in whole-brain cortical GM volume in schizophrenia are related to exposure to antipsychotic medication during the MRI follow-up. The effect sizes detected were small to moderate, but the consistency of the findings are strengthened by the results of the statistics for within-group heterogeneity and those for publication bias, both nonsignificant for all cortical regions. A significant between-group (patients vs. control subjects) difference in GM volume loss was demonstrated, however, only for whole-brain GM, with higher volume reduction in patients.
      The meta-regression analyses showed that both the cumulative exposure and the MDD of antipsychotics were associated with greater whole-brain cortical GM decreases in the entire patient sample, although the latter regression did not maintain statistical significance after applying a conservative correction for multiple comparisons. Other variables, such as illness severity, age, substance use, and duration of follow-up, were not significant moderators of longitudinal GM changes.
      However, a different impact of SGAs and FGAs on cortical GM changes in schizophrenia based on the amount of antipsychotic intake during the MRI follow-up interval did emerge. In fact, whole-brain GM volume reduction was inversely correlated with exposure to antipsychotic treatment only in patients treated with FGAs or mixed treatments; on the other hand, in the sample of studies including patients treated only with SGAs, the cumulative exposure to antipsychotics did not correlate with GM volume changes over time and was not associated with cortical tissue loss. The different impact of SGAs versus FGAs on longitudinal cortical GM changes became even more evident when considering the MDD of antipsychotic intake during the follow-up period. In this case, a robustly significant negative correlation emerged for patients who were administered FGAs or mixed treatments, while a reversed, statistically highly significant, positive correlation was detected in studies including patients treated only with SGAs—the higher the MDD of antipsychotics taken, the lower the reduction of whole brain GM volume over time. It is worth noting that MDD corrects the cumulative intake of antipsychotics for the different durations of follow-up between the study groups (although not statistically significant in our analysis) and may reflect, more than the cumulative dose of antipsychotics taken, the patient’s continuous level of exposure to drug treatment. It may also indicate whether the drug is prescribed at therapeutic, subtherapeutic, or even excessive dose and may be considered an indicator of the degree of probability of a given drug to exert its biological effects on the patient’s brain. It could be argued that it may be also an indirect index of severity of patient’s psychopathology, since a higher daily dose of antipsychotics is expected to be prescribed in more severe illness. Although we could not explore directly this possibility, we analyzed a variable that may be considered a proxy of such psychopathological severity, i.e., the change over the follow-up period of different scales of symptom severity, an approach already used by other authors (
      • Fusar-Poli P.
      • Smieskova R.
      • Kempton M.J.
      • Ho B.C.
      • Andreasen N.C.
      • Borgwardt S.
      Progressive brain changes in schizophrenia related to antipsychotic treatment? A meta-analysis of longitudinal MRI studies.
      ). The latter resulted, however, totally unrelated to the ES of GM volume changes, so excluding that the effect of antipsychotic intake on brain morphology could be entirely mediated by the clinical severity of the disease during the follow-up. Rather, it could be inferred that the higher the MDD, the more evident is the divergent effect of different categories of antipsychotics on cerebral GM. Nor could these differences be attributable to different duration of follow-up in the groups of patients, since the meta-regressions of interscan interval on cortical GM changes were not significant both in the mixed and the pure SGA groups.
      On the whole, our results indicate that the putative contributory role of antipsychotic treatment in reducing the volume of cortical GM in schizophrenia cannot be generalized and appears to be less evident for SGAs, which seem to be associated with less loss of brain tissue. The evidence of a different impact of SGAs on brain tissue over time is reinforced by the absence of any progressive decrease in whole-brain GM observed in this subgroup of patients with respect to healthy control subjects (between-group comparison: Q = .002; p = .965), at variance with what was observed for the whole patient sample.
      Obviously, only studies directly comparing GM changes in patients randomly assigned to FGAs or SGAs for the same period of time could give a definitive answer to the question raised by the results of our analysis. At present, only three ROI MRI studies (
      • Lieberman J.A.
      • Tollefson G.D.
      • Charles C.
      • Zipursky R.
      • Sharma T.
      • Kahn R.S.
      • et al.
      HGDH Study Group. Antipsychotic drug effects on brain morphology in first-episode psychosis.
      ,
      • Garver D.L.
      • Holcomb J.A.
      • Christensen J.D.
      Cerebral cortical gray expansion associated with two second-generation antipsychotics.
      ,
      • Crespo-Facorro B.
      • Roiz-Santiáñez R.
      • Pérez-Iglesias R.
      • Pelayo-Terán J.M.
      • Rodríguez-Sánchez J.M.
      • Tordesillas-Gutiérrez D.
      • et al.
      Effect of antipsychotic drugs on brain morphometry. A randomized controlled one-year follow-up study of haloperidol, risperidone and olanzapine.
      ) had such design and demonstrated less GM volume loss (or even increase) in patients treated with SGAs as compared with those treated with FGAs. A description of these studies and a subgroup meta-analysis on their results is reported in Supplement 1.
      Any interpretation of the main result of this meta-analysis, i.e., a different moderating effect of SGAs taken alone and of FGAs or mixed treatment on cortical GM tissue loss in schizophrenia, are speculative at this time. It has been hypothesized that SGAs may have a neuroprotective effect, either increasing the expression of neurotrophic factors (
      • Angelucci F.
      • Aloe L.
      • Iannitelli A.
      • Gruber S.H.
      • Mathe A.A.
      Effect of chronic olanzapine treatment on nerve growth factor and brain-derived neurotrophic factor in the rat brain.
      ) or stimulating neurogenesis (
      • Halim N.D.
      • Weickert C.S.
      • McClintock B.W.
      • Weinberger D.R.
      • Lipska B.K.
      Effects of chronic haloperidol and clozapine treatment on neurogenesis in the adult rat hippocampus.
      ) or interacting with and increasing the activity of N-methyl-D-aspartate glutamate receptors (
      • Millan M.J.
      N-Methyl-D-aspartate receptors as a target for improved antipsychotic agents: Novel insights and clinical perspectives.
      ). Conversely, the excessive reduction in cortical GM observed in patients treated with FGAs may be attributable to a direct neurotoxic effect secondary to oxidative stress and/or excitotoxic phenomena, which have been well documented in animals treated with haloperidol (
      • Post A.
      • Holsboer F.
      • Behl C.
      Induction of NF-kappaB activity during haloperidol induced oxidative toxicity in clonal hippocampal cells: Suppression of NF-kappaB and neuroprotection by antioxidants.
      ,
      • Wright A.M.
      • Bempong J.
      • Kirby M.L.
      • Barlow R.L.
      • Bloomquist J.R.
      Effects of haloperidol metabolites on neurotransmitter uptake and release: Possible role in neurotoxicity and tardive dyskinesia.
      ,
      • Goff D.C.
      • Tsai G.
      • Beal M.F.
      • Coyle J.T.
      Tardive dyskinesia and substrates of energy metabolism in CSF.
      ,
      • Raudenska M.
      • Gumulec J.
      • Babula P.
      • Stracina T.
      • Sztalmachova M.
      • Polanska H.
      • et al.
      Haloperidol cytotoxicity and its relation to oxidative stress.
      ,
      • Dorph-Petersen K.-A.
      • Pierri J.N.
      • Perel J.M.
      • Sun Z.
      • Sampson A.R.
      • Lewis D.A.
      The influence of chronic exposure to antipsychotic medications on brain size before and after tissue fixation: A comparison of haloperidol and olanzapine in macaque monkeys.
      ). It may also indicate a hypothetical lower capacity of FGAs to interfere with the natural pathophysiologic trajectory of the disease, which may also be reflected in the different impact on cerebral blood flow and metabolism of FGAs versus SGAs (
      • Miller D.D.
      • Andreasen N.C.
      • O’Leary D.S.
      • Rezai K.
      • Watkins G.L.
      • Ponto L.L.
      • Hichwa R.D.
      Effect of antipsychotics on regional cerebral blood flow measured with positron emission tomography.
      ,
      • Lahti A.C.
      • Holcomb H.H.
      • Weiler M.A.
      • Medoff D.R.
      • Frey K.N.
      • Hardin M.
      • Tamminga C.A.
      Clozapine but not haloperidol reestablishes normal task-activated rCBF patterns in schizophrenia within the anterior cingulate cortex.
      ,
      • Molina V.
      • Gispert J.D.
      • Reig S.
      • Sanz J.
      • Pascau J.
      • Santos A.
      • et al.
      Cerebral metabolism and risperidone treatment in schizophrenia.
      ,
      • Handley R.
      • Zelaya F.O.
      • Reinders A.A.
      • Marques T.R.
      • Mehta M.A.
      • O’Gorman R.
      • et al.
      Acute effects of single-dose aripiprazole and haloperidol on resting cerebral blood flow (rCBF) in the human brain.
      ,
      • Ertugrul A.
      • Volkan-Salanci B.
      • Basar K.
      • Karli Oguz K.
      • Demir B.
      • Ergun E.L.
      • et al.
      The effect of clozapine on regional cerebral blood flow and brain metabolite ratios in schizophrenia: Relationship with treatment response.
      ,
      • Dean C.E.
      Antipsychotic-associated neuronal changes in the brain: Toxic, therapeutic, or irrelevant to the long-term outcome of schizophrenia?.
      ,
      • Harrison P.J.
      Neurochemical alterations in schizophrenia affecting the putative receptor targets of atypical antipsychotics. Focus on dopamine (D1, D3, D4) and 5-HT2a receptors.
      ). It is not even possible to exclude that the metabolic effects and weight gain related to the treatment with some SGAs (
      • Letourneau G.
      • Bentaleb L.A.
      • Stip B.
      • Luck D.
      • Stip E.
      Relationships between brain structure and metabolic changes in schizophrenia patients treated with olanzapine: A voxel-based morphometric study.
      ) may have had a role in mediating such relationship between higher SGA dose and less GM loss, an hypothesis warranting further exploration. Given the limited number of studies, it was not possible to investigate whether different SGA compounds had different effects on GM volume. The qualitative inspection of the degree of correlation between daily drug exposure to individual compounds and changes in GM volume (Figure 2) suggests that more favorable effects on cortical structures could apply to the whole class of SGAs. The most marked positive effect on GM volume over the follow-up was detected in a study including only patients treated with clozapine, an SGA for which there is much evidence, although not univocal, of neurogenesis or neurotrophic effects in animal models (
      • Roiz-Santiáñez R.
      • Ayesa-Arriola R.
      • Tordesillas-Gutiérrez D.
      • Ortiz-García de la Foz V.
      • Pérez-Iglesias R.
      • Pazos A.
      • et al.
      Three-year longitudinal population-based volumetric MRI study in first-episode schizophrenia spectrum patients.
      ,
      • Maeda K.
      • Sugino H.
      • Hirose T.
      • Kitagawa H.
      • Nagai T.
      • Mizoguchi H.
      • et al.
      Clozapine prevents a decrease in neurogenesis in mice repeatedly treated with phencyclidine.
      ,
      • Agius M.
      • Nandra K.S.
      Do atypical antipsychotics promote neurogenesis as a class effect?.
      ,
      • Parikh V.
      • Khan M.M.
      • Terry A.
      • Mahadik S.P.
      Differential effects of typical and atypical antipsychotics on nerve growth factor and choline acetyltransferase expression in the cortex and nucleus basalis of rats.
      ).
      This study has several limitations. First, common to all meta-analyses, a complete control of the validity and quality of the primary studies was not possible. Second, our analysis was limited to the variables reported in the original studies. Few studies reported the amount of the individual antipsychotic drugs taken between scans, and we could obtain these data from the authors in a minority of cases. We relied on the cumulative dosage or MDD of different classes of antipsychotics taken but could not investigate the effect of each drug on brain morphology. Similarly, insufficient data were available to conduct an analysis of brain volumes for male or female subjects separately [only one study available (
      • Reig S.
      • Moreno C.
      • Moreno D.
      • Burdalo M.
      • Janssen J.
      • Parellada M.
      • et al.
      Progression of brain volume changes in adolescent onset psychosis.
      )] or a meta-regression with IQ or DUP or other potential moderators of GM changes that should be the object of future research. Third, insufficient information was available to analyze separately patients treated with FGAs and SGAs in the studies including both treatments. Even in the case of detailed information reported in the article or provided by the authors about the number of patients treated with each class of antipsychotics and the amount of treatment given, it was impossible to link such medication intake with the individual MRI data in the follow-up. Fourth, there is little empirical foundation for converting SGA doses in CPZ-Eq; however, this is the conversion more frequently used and that allows direct comparison with previous analyses. Moreover, even different methods of dose conversion (
      • Leucht S.
      • Samara M.
      • Heres S.
      • Patel M.X.
      • Woods S.W.
      • Davis J.M.
      Dose equivalents for second-generation antipsychotics: The minimum effective dose method.
      ) may present problems of applicability to SGAs and FGAs. In any case, also applying an olanzapine equivalent conversion (
      • Leucht S.
      • Samara M.
      • Heres S.
      • Patel M.X.
      • Woods S.W.
      • Davis J.M.
      Dose equivalents for second-generation antipsychotics: The minimum effective dose method.
      ), we confirmed that in the group of studies including patients treated only with SGAs, the cumulative dose of antipsychotics taken was not a significant moderator of cortical GM change (Z = −.0905, p > .05), so excluding that our results might be an artifact of the CPZ-Eq conversion. Finally, the relationship between antipsychotic exposure and change in GM volume could be not linear and so might be better captured by more sophisticated and complex data analysis procedures.
      In conclusion, there is evidence to suggest that antipsychotic treatment may have a contributory role in reducing the volume of cortical GM in schizophrenia, but this effect cannot be generalized and appears to be far less evident for SGAs, which results in being associated with less loss of brain tissue. More longitudinal studies specifically designed to directly test the hypothesis of a different effect on regional brain volumes of FGAs and SGAs, conducted with adequate methodology on samples allowing sufficient statistical power, are warranted. Whether different drugs may have varying effects on brain structure or whether their effects on the brain vary as a function of the patient’s age and stage of illness or may occur only when a certain threshold of exposure (daily dose or cumulative dose) is reached will also require specifically designed studies. Clarification of these issues will have crucial importance in the clinical management of schizophrenia and will allow a better understanding of the mechanisms underlying the progression of structural brain abnormalities in schizophrenia and the effects of antipsychotic medication on such progression.

      Acknowledgments and Disclosures

      Funding for this study was partially provided by an unrestricted Grant from the Lombardia Region (project 153).
      We thank all the authors of published papers who provided additional information on their database, particularly on antipsychotic drug type and dosage, during the magnetic resonance imaging follow-up study.
      Professor Vita has received funding for advisory board membership and sponsored lectures from AstraZeneca Pharmaceuticals, Eli Lilly, Janssen-Cilag, Lundbeck, Pfizer, Sanofi, Servier, and Stroder. He is not a shareholder in any of these corporations.
      Professor Sacchetti has received funding for research, advisory board membership, and sponsored lectures from Angelini, AstraZeneca Pharmaceuticals, Bristol-Myers Squibb, Dainippon Sumitomo Pharma, Eli Lilly, Glaxo SmithKline, Janssen-Cilag, Lundbeck, Pfizer, Rottapharm, Servier, and Stroder. He is not a shareholder in any of these corporations.
      Dr. Barlati, Dr. De Peri, and Dr. Deste report no biomedical financial interests or potential conflicts of interest.

      Appendix A. Supplementary Materials

      References

        • Wright I.C.
        • Rabe-Hesketh S.
        • Woodruff P.W.R.
        • David A.S.
        • Murray R.M.
        • Bullmore E.T.
        Meta-analysis of regional brain volumes in schizophrenia.
        Am J Psychiatry. 2000; 157: 16-25
        • Honea R.
        • Crow T.J.
        • Passingham D.
        • Mackay C.E.
        Regional deficits in brain volume in schizophrenia: A meta-analysis of voxel-based morphometry studies.
        Am J Psychiatry. 2005; 162: 2233-2245
        • Haijma S.V.
        • Van Haren N.
        • Cahn W.
        • Koolschijn P.C.
        • Hulshoff Pol H.E.
        • Kahn R.S.
        Brain volumes in schizophrenia: A meta-analysis in over 18 000 subjects.
        Schizophr Bull. 2013; 39: 1129-1138
        • Shepherd A.M.
        • Matheson S.L.
        • Laurens K.R.
        • Carr V.J.
        • Green M.J.
        Systematic meta-analysis of insula volume in schizophrenia.
        Biol Psychiatry. 2012; 72: 775-784
        • Glahn D.C.
        • Laird A.R.
        • Ellison-Wright I.
        • Thelen S.M.
        • Robinson J.L.
        • Lancaster J.L.
        • et al.
        Meta-analysis of gray matter anomalies in schizophrenia: Application of anatomic likelihood estimation and network analysis.
        Biol Psychiatry. 2008; 64: 774-781
        • Vita A.
        • De Peri L.
        • Silenzi C.
        • Dieci M.
        Brain morphology in first-episode schizophrenia: A meta-analysis of quantitative magnetic resonance imaging studies.
        Schizophr Res. 2006; 82: 75-88
        • Pantelis C.
        • Yücel M.
        • Wood S.J.
        • Velakoulis D.
        • Sun D.
        • Berger G.
        • et al.
        Structural brain imaging evidence for multiple pathological processes at different stages of brain development in schizophrenia.
        Schizophr Bull. 2005; 31: 672-696
        • Kempton M.J.
        • Stahl D.
        • Williams S.C.
        • DeLisi L.E.
        Progressive lateral ventricular enlargement in schizophrenia: A meta-analysis of longitudinal MRI studies.
        Schizophr Res. 2010; 120: 54-62
        • Olabi B.
        • Ellison-Wright I.
        • McIntosh A.M.
        • Wood S.J.
        • Bullmore E.
        • Lawrie S.M.
        Are there progressive brain changes in schizophrenia? A meta-analysis of structural magnetic resonance imaging studies.
        Biol Psychiatry. 2011; 70: 88-96
        • Vita A.
        • De Peri L.
        • Deste G.
        • Sacchetti E.
        Progressive loss of cortical gray matter in schizophrenia: A meta-analysis and meta-regression of longitudinal MRI studies.
        Transl Psychiatry. 2012; 2: e190
        • Fusar-Poli P.
        • Smieskova R.
        • Kempton M.J.
        • Ho B.C.
        • Andreasen N.C.
        • Borgwardt S.
        Progressive brain changes in schizophrenia related to antipsychotic treatment? A meta-analysis of longitudinal MRI studies.
        Neurosci Biobehav Rev. 2013; 37: 1680-1691
        • Sharma T.
        • Lancaster E.
        • Lee D.
        • Lewis S.
        • Sigmundsson T.
        • Takei N.
        • et al.
        Brain changes in schizophrenia. Volumetric MRI study of families multiply affected with schizophrenia--the Maudsley family study 5.
        Br J Psychiatry. 1998; 173: 132-138
        • Baare W.F.
        • van Oel C.J.
        • Hulshoff Pol H.E.
        • Schnack H.G.
        • Durston S.
        • Sitskoorn M.M.
        • Kahn R.S.
        Volumes of brain structures in twins discordant for schizophrenia.
        Arch Gen Psychiatry. 2001; 58: 33-40
        • Cannon T.D.
        • Thompson P.M.
        • van Erp T.G.
        • Toga A.W.
        • Poutanen V.P.
        • Huttunen M.
        • et al.
        Cortex mapping reveals regionally specific patterns of genetic and disease-specific gray-matter deficits in twins discordant for schizophrenia.
        Proc Natl Acad Sci U S A. 2002; 99: 3228-3233
        • Brans R.G.
        • van Haren N.E.
        • van Baal G.C.
        • Schnack H.G.
        • Kahn R.S.
        • Hulshoff Pol H.E.
        Heritability of changes in brain volume over time in twin pairs discordant for schizophrenia.
        Arch Gen Psychiatry. 2008; 65: 1259-1268
        • van Haren N.E.
        • Rijsdijk F.
        • Schnack H.G.
        • Picchioni M.M.
        • Toulopoulou T.
        • Weisbrod M.
        • et al.
        The genetic and environmental determinants of the association between brain abnormalities and schizophrenia: The schizophrenia twins and relatives consortium.
        Biol Psychiatry. 2012; 71: 915-921
        • Lieberman J.A.
        • Tollefson G.D.
        • Charles C.
        • Zipursky R.
        • Sharma T.
        • Kahn R.S.
        • et al.
        HGDH Study Group. Antipsychotic drug effects on brain morphology in first-episode psychosis.
        Arch Gen Psychiatry. 2005; 62: 361-370
        • van Haren N.E.
        • Hulshoff Pol H.E.
        • Schnack H.G.
        • Cahn W.
        • Brans R.
        • Carati I.
        • et al.
        Progressive brain volume loss in schizophrenia over the course of the illness: Evidence of maturational abnormalities in early adulthood.
        Biol Psychiatry. 2008; 63: 106-113
        • Ho B.C.
        • Andreasen N.C.
        • Ziebell S.
        • Pierson R.
        • Magnotta V.
        Long-term antipsychotic treatment and brain volumes: A longitudinal study of first-episode schizophrenia.
        Arch Gen Psychiatry. 2011; 68: 128-137
        • Arango C.
        • Rapado-Castro M.
        • Reig S.
        • Castro-Fornieles J.
        • González-Pinto A.
        • Otero S.
        • et al.
        Progressive brain changes in children and adolescents with first-episode psychosis.
        Arch Gen Psychiatry. 2012; 69: 16-26
        • Andreasen N.C.
        • Liu D.
        • Ziebell S.
        • Vora A.
        • Ho B.C.
        Relapse duration, treatment intensity, and brain tissue loss in schizophrenia: A prospective longitudinal MRI study.
        Am J Psychiatry. 2013; 170: 609-615
        • Lieberman J.
        • Chakos M.
        • Wu H.
        • Alvir J.
        • Hoffman E.
        • Robinson D.
        • Bilder R.
        Longitudinal study of brain morphology in first episode schizophrenia.
        Biol Psychiatry. 2001; 49: 487-499
        • Cahn W.
        • Hulshoff Pol H.E.
        • Lems E.B.
        • van Haren N.E.
        • Schnack H.G.
        • van der Linden J.A.
        • et al.
        Brain volume changes in first-episode schizophrenia: A 1-year follow-up study.
        Arch Gen Psychiatry. 2002; 59: 1002-1010
        • Garver D.L.
        • Holcomb J.A.
        • Christensen J.D.
        Cerebral cortical gray expansion associated with two second-generation antipsychotics.
        Biol Psychiatry. 2005; 58: 62-66
        • van Haren N.E.
        • Hulshoff Pol H.E.
        • Schnack H.G.
        • Cahn W.
        • Mandl R.C.
        • Collins D.L.
        • et al.
        Focal gray matter changes in schizophrenia across the course of the illness: A 5-year follow-up study.
        Neuropsychopharmacology. 2007; 32: 2057-2066
        • Crespo-Facorro B.
        • Roiz-Santiáñez R.
        • Pérez-Iglesias R.
        • Pelayo-Terán J.M.
        • Rodríguez-Sánchez J.M.
        • Tordesillas-Gutiérrez D.
        • et al.
        Effect of antipsychotic drugs on brain morphometry. A randomized controlled one-year follow-up study of haloperidol, risperidone and olanzapine.
        Prog Neuropsychopharmacol Biol Psychiatry. 2008; 32: 1936-1943
        • Vita A.
        • De Peri L.
        The effects of antipsychotic treatment on cerebral structure and function in schizophrenia.
        Int Rev Psychiatry. 2007; 19: 429-436
        • Navari S.
        • Dazzan P.
        Do antipsychotic drugs affect brain structure? A systematic and critical review of MRI findings.
        Psychol Med. 2009; 39: 1763-1777
        • Smieskova R.
        • Fusar-Poli P.
        • Allen P.
        • Bendfeldt K.
        • Stieglitz R.D.
        • Drewe J.
        • et al.
        The effects of antipsychotics on the brain: What have we learnt from structural imaging of schizophrenia?--a systematic review.
        Curr Pharm Des. 2009; 15: 2535-2549
        • Moncrieff J.
        • Leo J.
        A systematic review of the effects of antipsychotic drugs on brain volume.
        Psychol Med. 2010; 40: 1409-1422
        • Van Haren N.E.
        • Cahn W.
        • Hulshoff Pol H.E.
        • Kahn R.S.
        Confounders of excessive brain volume loss in schizophrenia.
        Neurosci Biobehav Rev. 2013; 37: 2418-2423
        • Steen R.G.
        • Mull C.
        • McClure R.
        • Hamer R.M.
        • Lieberman J.A.
        Brain volume in first-episode schizophrenia: Systematic review and meta-analysis of magnetic resonance imaging studies.
        Br J Psychiatry. 2006; 188: 510-518
        • Hedges L.V.
        • Holkin I.
        Statistical Methods for Meta-Analysis.
        Academic Press, New York1985
        • Egger M.
        • Davey Smith G.
        • Schneider M.
        • Minder C
        Bias in meta-analysis detected by a simple, graphical test.
        BMJ. 1997; 315: 629-634
        • Ebdrup B.H.
        • Skimminge A.
        • Rasmussen H.
        • Aggernaes B.
        • Oranje B.
        • Lublin H.
        • et al.
        Progressive striatal and hippocampal volume loss in initially antipsychotic-naive, first-episode schizophrenia patients treated with quetiapine: Relationship to dose and symptoms.
        Int J Neuropsychopharmacol. 2011; 14: 69-82
        • Sporn A.L.
        • Greenstein D.K.
        • Gogtay N.
        • Jeffries N.O.
        • Lenane M.
        • Gochman P.
        • et al.
        Progressive brain volume loss during adolescence in childhood-onset schizophrenia.
        Am J Psychiatry. 2003; 160: 2181-2189
        • Lappin J.M.
        • Morgan C.
        • Chalavi S.
        • Morgan K.D.
        • Reinders A.A.
        • Fearon P.
        • et al.
        Bilateral hippocampal increase following first-episode psychosis is associated with good clinical, functional and cognitive outcomes.
        Psychol Med. 2014; 44: 1279-1291
        • Molina V.
        • Reig S.
        • Sanz J.
        • Palomo T.
        • Benito C.
        • Sánchez J.
        • et al.
        Increase in gray matter and decrease in white matter volumes in the cortex during treatment with atypical neuroleptics in schizophrenia.
        Schizophr Res. 2005; 80: 61-71
        • Roiz-Santiáñez R.
        • Ayesa-Arriola R.
        • Tordesillas-Gutiérrez D.
        • Ortiz-García de la Foz V.
        • Pérez-Iglesias R.
        • Pazos A.
        • et al.
        Three-year longitudinal population-based volumetric MRI study in first-episode schizophrenia spectrum patients.
        Psychol Med. 2013; 44: 1591-1604
        • Moher D.
        • Liberati A.
        • Tetzlaff J.
        • Altman D.G.
        • PRISMA Group
        Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement.
        J Clin Epidemiol. 2009; 62: 1006-1012
        • Angelucci F.
        • Aloe L.
        • Iannitelli A.
        • Gruber S.H.
        • Mathe A.A.
        Effect of chronic olanzapine treatment on nerve growth factor and brain-derived neurotrophic factor in the rat brain.
        Eur Neuropsychopharmacol. 2005; 15: 311-317
        • Halim N.D.
        • Weickert C.S.
        • McClintock B.W.
        • Weinberger D.R.
        • Lipska B.K.
        Effects of chronic haloperidol and clozapine treatment on neurogenesis in the adult rat hippocampus.
        Neuropsychopharmacology. 2004; 29: 1063-1069
        • Millan M.J.
        N-Methyl-D-aspartate receptors as a target for improved antipsychotic agents: Novel insights and clinical perspectives.
        Psychopharmacology (Berl). 2005; 179: 30-53
        • Post A.
        • Holsboer F.
        • Behl C.
        Induction of NF-kappaB activity during haloperidol induced oxidative toxicity in clonal hippocampal cells: Suppression of NF-kappaB and neuroprotection by antioxidants.
        J Neurosci. 1998; 18: 8236-8246
        • Wright A.M.
        • Bempong J.
        • Kirby M.L.
        • Barlow R.L.
        • Bloomquist J.R.
        Effects of haloperidol metabolites on neurotransmitter uptake and release: Possible role in neurotoxicity and tardive dyskinesia.
        Brain Res. 1998; 788: 215-222
        • Goff D.C.
        • Tsai G.
        • Beal M.F.
        • Coyle J.T.
        Tardive dyskinesia and substrates of energy metabolism in CSF.
        Am J Psychiatry. 1995; 152: 1730-1736
        • Raudenska M.
        • Gumulec J.
        • Babula P.
        • Stracina T.
        • Sztalmachova M.
        • Polanska H.
        • et al.
        Haloperidol cytotoxicity and its relation to oxidative stress.
        Mini Rev Med Chem. 2013; 13: 1993-1998
        • Dorph-Petersen K.-A.
        • Pierri J.N.
        • Perel J.M.
        • Sun Z.
        • Sampson A.R.
        • Lewis D.A.
        The influence of chronic exposure to antipsychotic medications on brain size before and after tissue fixation: A comparison of haloperidol and olanzapine in macaque monkeys.
        Neuropsychopharmacology. 2005; 30: 1649-1661
        • Miller D.D.
        • Andreasen N.C.
        • O’Leary D.S.
        • Rezai K.
        • Watkins G.L.
        • Ponto L.L.
        • Hichwa R.D.
        Effect of antipsychotics on regional cerebral blood flow measured with positron emission tomography.
        Neuropsychopharmacology. 1997; 17: 230-240
        • Lahti A.C.
        • Holcomb H.H.
        • Weiler M.A.
        • Medoff D.R.
        • Frey K.N.
        • Hardin M.
        • Tamminga C.A.
        Clozapine but not haloperidol reestablishes normal task-activated rCBF patterns in schizophrenia within the anterior cingulate cortex.
        Neuropsychopharmacology. 2004; 29: 171-178
        • Molina V.
        • Gispert J.D.
        • Reig S.
        • Sanz J.
        • Pascau J.
        • Santos A.
        • et al.
        Cerebral metabolism and risperidone treatment in schizophrenia.
        Schizophr Res. 2003; 60: 1-7
        • Handley R.
        • Zelaya F.O.
        • Reinders A.A.
        • Marques T.R.
        • Mehta M.A.
        • O’Gorman R.
        • et al.
        Acute effects of single-dose aripiprazole and haloperidol on resting cerebral blood flow (rCBF) in the human brain.
        Hum Brain Mapp. 2013; 34: 272-282
        • Ertugrul A.
        • Volkan-Salanci B.
        • Basar K.
        • Karli Oguz K.
        • Demir B.
        • Ergun E.L.
        • et al.
        The effect of clozapine on regional cerebral blood flow and brain metabolite ratios in schizophrenia: Relationship with treatment response.
        Psychiatry Res. 2009; 174: 121-129
        • Dean C.E.
        Antipsychotic-associated neuronal changes in the brain: Toxic, therapeutic, or irrelevant to the long-term outcome of schizophrenia?.
        Prog Neuropsychopharmacol Biol Psychiatry. 2006; 30: 174-189
        • Harrison P.J.
        Neurochemical alterations in schizophrenia affecting the putative receptor targets of atypical antipsychotics. Focus on dopamine (D1, D3, D4) and 5-HT2a receptors.
        Br J Psychiatry Suppl. 1999; 38: 12-22
        • Letourneau G.
        • Bentaleb L.A.
        • Stip B.
        • Luck D.
        • Stip E.
        Relationships between brain structure and metabolic changes in schizophrenia patients treated with olanzapine: A voxel-based morphometric study.
        Schizophr Res Treatment. 2011; 2011: 862350
        • Maeda K.
        • Sugino H.
        • Hirose T.
        • Kitagawa H.
        • Nagai T.
        • Mizoguchi H.
        • et al.
        Clozapine prevents a decrease in neurogenesis in mice repeatedly treated with phencyclidine.
        J Pharmacol Sci. 2007; 103: 299-308
        • Agius M.
        • Nandra K.S.
        Do atypical antipsychotics promote neurogenesis as a class effect?.
        Psychiatr Danub. 2012; 24: S191-S193
        • Parikh V.
        • Khan M.M.
        • Terry A.
        • Mahadik S.P.
        Differential effects of typical and atypical antipsychotics on nerve growth factor and choline acetyltransferase expression in the cortex and nucleus basalis of rats.
        J Psychiatr Res. 2004; 38: 521-529
        • Reig S.
        • Moreno C.
        • Moreno D.
        • Burdalo M.
        • Janssen J.
        • Parellada M.
        • et al.
        Progression of brain volume changes in adolescent onset psychosis.
        Schizophr Bull. 2009; 35: 233-243
        • Leucht S.
        • Samara M.
        • Heres S.
        • Patel M.X.
        • Woods S.W.
        • Davis J.M.
        Dose equivalents for second-generation antipsychotics: The minimum effective dose method.
        Schizophr Bull. 2014; 40: 314-326
        • Ho B.C.
        • Andreasen N.C.
        • 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
        • Molina V.
        • Reig S.
        • Sanz J.
        • Palomo T.
        • Benito C.
        • Sánchez J.
        • et al.
        Changes in cortical volume with olanzapine in chronic schizophrenia.
        Pharmacopsychiatry. 2007; 40: 135-139
        • Takahashi T.
        • Suzuki M.
        • Zhou S.Y.
        • Tanino R.
        • Nakamura K.
        • Kawasaki Y.
        • et al.
        A follow-up MRI study of the superior temporal subregions in schizotypal disorder and first-episode schizophrenia.
        Schizophr Res. 2010; 119: 65-74
        • Takahashi T.
        • Wood S.J.
        • Kawasaki Y.
        • Suzuki M.
        • Velakoulis D.
        • Pantelis
        Lack of progressive gray matter reduction of the superior temporal subregions in chronic schizophrenia.
        Schizophr Res. 2010; 117: 101-102
        • Boonstra G.
        • van Haren N.E.
        • Schnack H.G.
        • Cahn W.
        • Burger H.
        • Boersma M.
        • et al.
        Brain volume changes after withdrawal of atypical antipsychotics in patients with first-episode schizophrenia.
        J Clin Psychopharmacol. 2011; 31: 146-153
        • Andreasen N.C.
        • Nopoulos P.
        • Magnotta V.
        • Pierson R.
        • Ziebell S.
        • Ho B.C.
        Progressive brain change in schizophrenia: A prospective longitudinal study of first-episode schizophrenia.
        Biol Psychiatry. 2011; 70: 672-679