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A systematic review of the effects of antipsychotic drugs on brain volume

Published online by Cambridge University Press:  20 January 2010

J. Moncrieff*
Affiliation:
Department of Mental Health Sciences, University College London, UK
J. Leo
Affiliation:
Department of Anatomy, Lincoln Memorial University, Harrogate, TN, USA
*
*Address for correspondence: Dr J. Moncrieff, Department of Mental Health Sciences, University College London, Charles Bell House, 67-73, Riding House Street, London, WIW7EJ, UK. (Email: j.moncrieff@ucl.ac.uk)
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Abstract

Background

People with schizophrenia are often found to have smaller brains and larger brain ventricles than normal, but the role of antipsychotic medication remains unclear.

Method

We conducted a systematic review of magnetic resonance imaging (MRI) studies. We included longitudinal studies of brain changes in patients taking antipsychotic drugs and we examined studies of antipsychotic-naive patients for comparison purposes.

Results

Fourteen out of 26 longitudinal studies showed a decline in global brain or grey-matter volume or an increase in ventricular or cerebrospinal fluid (CSF) volume during the course of drug treatment, including the largest studies conducted. The frontal lobe was most consistently affected, but overall changes were diffuse. One large study found different degrees of volume loss with different antipsychotics, and another found that volume changes were associated with taking medication compared with taking none. Analyses of linear associations between drug exposure and brain volume changes produced mixed results. Five out of 21 studies of patients who were drug naive, or had only minimal prior treatment, showed some differences from controls in volumes of interest. No global differences were reported in three studies of drug-naive patients with long-term illness. Studies of high-risk groups have not demonstrated differences from controls in global or lobar brain volumes.

Conclusions

Some evidence points towards the possibility that antipsychotic drugs reduce the volume of brain matter and increase ventricular or fluid volume. Antipsychotics may contribute to the genesis of some of the abnormalities usually attributed to schizophrenia.

Type
Review Article
Copyright
Copyright © Cambridge University Press 2010

Introduction

Neuroimaging and post-mortem studies suggest that the structure of the brain in people diagnosed with schizophrenia is subtly different from that of ‘healthy controls’. In particular, numerous studies have reported that the brains of people with schizophrenia or psychosis seem to be smaller and to have less grey matter and larger ventricles and cerebrospinal fluid (CSF) spaces than brains of healthy controls (Wright et al. Reference Wright, Rabe-Hesketh, Woodruff, David, Murray and Bullmore2000). Although most of the patients involved in such studies had a history of antipsychotic treatment, the role of drug treatment in producing these abnormalities has received little attention. As some studies with first-episode patients show abnormalities of brain volume, it has been assumed that drug treatment cannot be a causal factor. However, the majority of subjects in most of these studies had received antipsychotic drugs for several weeks, and the results of recent research suggest that drug treatment may induce detectable changes within a few weeks of treatment (Dazzan et al. Reference Dazzan, Morgan, Orr, Hutchinson, Chitnis, Suckling, Fearon, McGuire, Mallett, Jones, Leff and Murray2005; Lieberman et al. Reference Lieberman, Tollefson, Charles, Zipursky, Sharma, Kahn, Keefe, Green, Gur, McEvoy, Perkins, Hamer, Gu and Tohen2005; Schaufelberger et al. Reference Schaufelberger, Duran, Lappin, Scazufca, Amaro, Leite, de Castro, Murray, McGuire, Menezes and Busatto2007). Several studies and reviews have suggested that typical antipsychotics may induce enlargement of basal ganglia structures and that effects of typical and atypical antipsychotics may vary (Chakos et al. Reference Chakos, Lieberman, Alvir, Bilder and Ashtari1995; Scherk & Falkai, Reference Scherk and Falkai2006; Vita & De Peri, Reference Vita and De Peri2007; Navari & Dazzan, Reference Navari and Dazzan2009). It remains unclear, however, whether antipsychotic drugs per se affect global brain structure.

This study set out to examine data from imaging studies regarding the impact of antipsychotic drug treatment on global brain structures, particularly ventricular or CSF volume, whole-brain and grey-matter volume. We looked at longitudinal studies of people treated with antipsychotic drugs, to ascertain whether there was brain volume change during a period of drug treatment. We also examined studies of patients who underwent brain imaging when they were drug naive, or after minimal treatment, to ascertain whether brain volume differed from controls prior to drug treatment. We looked at research on subjects at ‘high risk’ of psychosis who later developed psychosis and who had not received medication at the time of their scan.

Method

We identified imaging studies of people diagnosed with psychosis or schizophrenia that contained data on the effects of antipsychotic drugs on overall brain volume, grey-matter volume, lobar volumes, CSF volume, and subcortical ventricular spaces. We included recent magnetic resonance imaging (MRI) studies of people who had been taking antipsychotic medication between scans that included a group of healthy controls, also studied longitudinally. We excluded studies examining only changes in brain density, cortical surface area, or thickness. A Medline search was conducted using the terms ‘longitudinal’ or ‘progressive’ combined with ‘MRI’ and ‘psychosis’ or ‘schizophrenia’. All longitudinal studies published between 1995 and April 2009 with follow-up longer than 6 months were included. These studies have usually been interpreted as indicating disease-related effects but, as many authors acknowledge, the studies cannot definitively distinguish between the effects of disease and the effects of treatment. Unlike other reviews, therefore, we considered that all studies that examine brain changes in drug-treated patients may constitute evidence of the role of drug treatment.

We searched Medline for all studies of brain structure in neuroleptic-naive patients published between 1995 and April 2009 using the terms ‘neuroleptic-naive’, ‘antipsychotic-naive’ or ‘drug-naive’ combined with ‘MRI’ and ‘psychosis’ or ‘schizophrenia’. We also examined research on people from ‘high-risk’ samples who have subsequently developed psychosis, identifying the studies from citations of other reviews.

We extracted data on numbers of patients and controls, duration of interscan interval where appropriate, and differences from controls in total CSF, ventricular volumes, whole-brain volume, cortical volume, grey-matter volume and regional lobar volumes, where these were recorded. We noted the results of any analysis that had been performed to assess the effects of drug treatment. In the common instances whereby a single study was reported in several different publications, we present findings from the last publication, and include previous findings only where they provide additional relevant information.

Results

Longitudinal studies

The search retrieved 279 articles. Many were not relevant because they reported functional MRI studies or receptor studies and many represented multiple publications of the same studies. Altogether, 26 longitudinal studies were identified that satisfied inclusion criteria. These studies involved a total of 767 patients experiencing a first episode of psychosis or schizophrenia and 360 patients with long-term illness (Table 1). The mean number of patients per study was 40 (range 10–161), and the average follow-up was around 34 months (range of 8 months to 10 years). Fourteen studies (58%) found that patients showed a greater reduction in whole-brain, cortical or grey-matter volume, or a greater increase in CSF or ventricular volumes compared with controls. Two further studies found effects in some patients (Nakamura et al. Reference Nakamura, Salisbury, Hirayasu, Bouix, Pohl, Yoshida, Koo, Shenton and McCarley2007; Reig et al. Reference Reig, Moreno, Moreno, Burdalo, Janssen, Parellada, Zabala, Desco and Arango2009).

Table 1. Longitudinal studies

CSF, Cerebrospinal fluid.

The largest study had a sample size of 161 patients, almost five times higher than the mean sample size of the other studies, which was 35. In this study, patients were randomized after a baseline scan to take haloperidol or olanzapine (Lieberman et al. Reference Lieberman, Tollefson, Charles, Zipursky, Sharma, Kahn, Keefe, Green, Gur, McEvoy, Perkins, Hamer, Gu and Tohen2005). The study revealed significant decline in grey matter in patients on haloperidol compared to controls after 12 weeks of treatment and reduced total brain volume after 1 year. Patients on olanzapine showed no effects at 12 weeks, but after 1 year they also showed reduced grey-matter volume, although this was not statistically significant after correcting for multiple comparisons. In addition, a subsidiary analysis of different brain areas after 1 year showed evidence of reduced volume in patients taking olanzapine, and also haloperidol, in frontal, occipital and parietal lobes (p⩽0.05). There were trend level reductions in total CSF volume in olanzapine-treated subjects compared with controls (p=0.07) (Lieberman et al. Reference Lieberman, Tollefson, Charles, Zipursky, Sharma, Kahn, Keefe, Green, Gur, McEvoy, Perkins, Hamer, Gu and Tohen2005) at 1 year, but no other differences between groups in changes in total CSF, lateral or third ventricle volume. The next largest study involved a sample of 96 patients with multiple episodes followed for 5 years. This study found statistically significant reductions in cerebral and grey-matter volume and greater expansion of the lateral and third ventricles in patients compared to controls. Analysis of different lobes revealed the same trends throughout the brain, except in the cerebellum (van Haren et al. Reference van Haren, Pol, Schnack, Cahn, Brans, Carati, Rais and Kahn2008). A study of 73 first-episode patients followed for a mean of 3 years also reported greater ventricular expansion in patients compared with controls and greater reduction in frontal lobe volume (Ho et al. Reference Ho, Andreasen, Nopoulos, Arndt, Magnotta and Flaum2003).

Studies that quantified the extent of the changes reported an increase in CSF or ventricular volumes of between 7.7% and 10.9% in adult patients over 1 year (Cahn et al. Reference Cahn, Hulshoff Pol, Lems, van Haren, Schnack, van der Linden, Schothorst, van Engeland and Kahn2002b; Ho et al. Reference Ho, Andreasen, Nopoulos, Arndt, Magnotta and Flaum2003) compared with a 1.4% decrease in controls (Ho et al. Reference Ho, Andreasen, Nopoulos, Arndt, Magnotta and Flaum2003). Over 10 years increases were 23% to 30.1% compared with increases of 0.6% to 5.1% in controls (Saijo et al. Reference Saijo, Abe, Someya, Sassa, Sudo, Suhara, Shuno, Asai and Okubo2001; DeLisi et al. Reference DeLisi, Sakuma, Maurizio, Relja and Hoff2004). Grey-matter, whole-brain or cerebral volume showed a decline of 1.2% to 2.9% per year in adult patients (DeLisi et al. Reference DeLisi, Sakuma, Tew, Kushner, Hoff and Grimson1997; Cahn et al. Reference Cahn, Hulshoff Pol, Lems, van Haren, Schnack, van der Linden, Schothorst, van Engeland and Kahn2002b; van Haren et al. Reference van Haren, Pol, Schnack, Cahn, Brans, Carati, Rais and Kahn2008) compared with 0.4% to 1% in controls (DeLisi et al. Reference DeLisi, Sakuma, Tew, Kushner, Hoff and Grimson1997). Over 5 years there was a 4.2–4.5% reduction in patients (van Haren et al. Reference van Haren, Pol, Schnack, Cahn, Brans, Carati, Rais and Kahn2008; Cahn et al. Reference Cahn, Rais, Stigter, van Haren, Caspers, Hulshoff Pol, Xu, Schnack and Kahn2009) and 2.5% in controls (van Haren et al. Reference van Haren, Pol, Schnack, Cahn, Brans, Carati, Rais and Kahn2008). A 10-year follow-up study of cerebral volume, however, found overall decreases of 5.5–5.9% in patients but changes in controls were similar (3.9–4.1%) (DeLisi et al. Reference DeLisi, Sakuma, Maurizio, Relja and Hoff2004).

Three studies found that changes were confined to the frontal lobe (Mathalon et al. Reference Mathalon, Sullivan, Lim and Pfefferbaum2001; Ho et al. Reference Ho, Andreasen, Nopoulos, Arndt, Magnotta and Flaum2003; Reig et al. Reference Reig, Moreno, Moreno, Burdalo, Janssen, Parellada, Zabala, Desco and Arango2009), which was the most consistently affected area across studies. Many studies, however, including the two largest, found diffuse changes across different regions (Sporn et al. Reference Sporn, Greenstein, Gogtay, Jeffries, Lenane, Gochman, Clasen, Blumenthal, Giedd and Rapoport2003; Lieberman et al. Reference Lieberman, Tollefson, Charles, Zipursky, Sharma, Kahn, Keefe, Green, Gur, McEvoy, Perkins, Hamer, Gu and Tohen2005; Whitford et al. Reference Whitford, Grieve, Farrow, Gomes, Brennan, Harris, Gordon and Williams2006; Theberge et al. Reference Theberge, Williamson, Aoyama, Drost, Manchanda, Malla, Northcott, Menon, Neufeld, Rajakumar, Pavlosky, Densmore, Schaefer and Williamson2007; van Haren et al. Reference van Haren, Pol, Schnack, Cahn, Brans, Carati, Rais and Kahn2008). Findings concerning the temporal lobe were contradictory, with some studies finding the greatest changes in this area (Sporn et al. Reference Sporn, Greenstein, Gogtay, Jeffries, Lenane, Gochman, Clasen, Blumenthal, Giedd and Rapoport2003; Whitford et al. Reference Whitford, Grieve, Farrow, Gomes, Brennan, Harris, Gordon and Williams2006; Nakamura et al. Reference Nakamura, Salisbury, Hirayasu, Bouix, Pohl, Yoshida, Koo, Shenton and McCarley2007) and some studies, which specifically examined the temporal lobe, finding no changes (DeLisi et al. Reference DeLisi, Sakuma, Tew, Kushner, Hoff and Grimson1997; Wood et al. Reference Wood, Velakoulis, Smith, Bond, Stuart, McGorry, Brewer, Bridle, Eritaia, Desmond, Singh, Copolov and Pantelis2001).

Two studies were set up to compare the effects of different drugs (Lieberman et al. Reference Lieberman, Tollefson, Charles, Zipursky, Sharma, Kahn, Keefe, Green, Gur, McEvoy, Perkins, Hamer, Gu and Tohen2005; Crespo-Facorro et al. Reference Crespo-Facorro, Roiz-Santianez, Perez-Iglesias, Pelayo-Teran, Rodriguez-Sanchez, Tordesillas-Gutierrez, Ramirez, Martinez, Gutierrez, de Lucas and Vazquez-Barquero2008) and one compared brain volumes between drug-treated and non-drug-treated patients (Dazzan et al. Reference Dazzan, Morgan, Reinders, Morgan, Fearon, Zanelli, Fisher, Jones, Murray, McGuire and Lappin2008). Some studies rescanned drug-naive patients after a period of drug treatment and several studies looked for linear associations between brain volume changes and quantitative aspects of drug treatment such as duration of exposure and dose.

The largest comparative randomized study suggested that different patterns of brain volume loss were associated with different drugs, as described above (Lieberman et al. Reference Lieberman, Tollefson, Charles, Zipursky, Sharma, Kahn, Keefe, Green, Gur, McEvoy, Perkins, Hamer, Gu and Tohen2005). By contrast, a smaller study found no differences in grey-matter volume changes between patients treated with either haloperidol, olanzapine or risperidone and controls. Changes in ventricle volumes were complex, with healthy controls and patients taking risperidone showing greater lateral ventricle volume increase than haloperidol-treated subjects (Crespo-Facorro et al. Reference Crespo-Facorro, Roiz-Santianez, Perez-Iglesias, Pelayo-Teran, Rodriguez-Sanchez, Tordesillas-Gutierrez, Ramirez, Martinez, Gutierrez, de Lucas and Vazquez-Barquero2008). The numbers of patients taking each drug were small, however, between 16 and 18, so differences are difficult to interpret.

Preliminary results of a 6-year follow-up of 44 first-episode patients also found an association between grey-matter changes, ventricular enlargement and being on drug treatment compared to being drug free (Dazzan et al. Reference Dazzan, Morgan, Reinders, Morgan, Fearon, Zanelli, Fisher, Jones, Murray, McGuire and Lappin2008).

Five studies started with mostly drug-naive patients, involving 120 patients in all. Two of these demonstrated reduction of grey matter after commencement of a period of drug treatment in patients compared with controls (Cahn et al. Reference Cahn, Hulshoff Pol, Lems, van Haren, Schnack, van der Linden, Schothorst, van Engeland and Kahn2002b; Theberge et al. Reference Theberge, Williamson, Aoyama, Drost, Manchanda, Malla, Northcott, Menon, Neufeld, Rajakumar, Pavlosky, Densmore, Schaefer and Williamson2007). One found some areas of increased grey matter after commencement of drug treatment, although a regression to the mean effect may have been present because the increase was strongly predicted by baseline volume (Spearman's R=0.62, p<0.001) (Molina et al. Reference Molina, Reig, Sanz, Palomo, Benito, Sanchez, Sarramea, Pascau and Desco2005). The others did not report any global or lobar volume changes (Keshavan et al. Reference Keshavan, Haas, Kahn, Aguilar, Dick, Schooler, Sweeney and Pettegrew1998a; Puri et al. Reference Puri, Hutton, Saeed, Oatridge, Hajnal, Duncan, Chapman, Barnes, Bydder and Joyce2001; MacMaster et al. Reference MacMaster, El Sheikh, Upadhyaya, Nutche, Rosenberg and Keshavan2007).

Several studies used correlation or regression analysis to test for a linear association between various estimates of exposure to antipsychotics and brain volume changes. Results were mainly negative. One study found an association between volume reductions and lifetime dose of antipsychotic medication (r=0.5, p=0.009) (Cahn et al. Reference Cahn, Hulshoff Pol, Lems, van Haren, Schnack, van der Linden, Schothorst, van Engeland and Kahn2002b). One study found an association between treatment duration and ventricle size but no effect for cortical or hippocampal volume (Lieberman et al. Reference Lieberman, Chakos, Wu, Alvir, Hoffman, Robinson and Bilder2001). Two studies found an association between current dose and some brain volume reductions, with one reporting correlations of 0.75 and 0.66 (p<0.001) between frontal and temporal lobe volume reduction and antipsychotic dose, but only among first-episode patients (Gur et al. Reference Gur, Cowell, Turetsky, Gallacher, Cannon, Bilker and Gur1998). The other found that reductions in areas of the frontal lobes were associated with antipsychotic dose in an exploratory analysis (Theberge et al. Reference Theberge, Williamson, Aoyama, Drost, Manchanda, Malla, Northcott, Menon, Neufeld, Rajakumar, Pavlosky, Densmore, Schaefer and Williamson2007). Other analyses were negative (Lieberman et al. Reference Lieberman, Chakos, Wu, Alvir, Hoffman, Robinson and Bilder2001; Puri et al. Reference Puri, Hutton, Saeed, Oatridge, Hajnal, Duncan, Chapman, Barnes, Bydder and Joyce2001; Saijo et al. Reference Saijo, Abe, Someya, Sassa, Sudo, Suhara, Shuno, Asai and Okubo2001; Ho et al. Reference Ho, Andreasen, Nopoulos, Arndt, Magnotta and Flaum2003; Sporn et al. Reference Sporn, Greenstein, Gogtay, Jeffries, Lenane, Gochman, Clasen, Blumenthal, Giedd and Rapoport2003; Nakamura et al. Reference Nakamura, Salisbury, Hirayasu, Bouix, Pohl, Yoshida, Koo, Shenton and McCarley2007; van Haren et al. Reference van Haren, Pol, Schnack, Cahn, Brans, Carati, Rais and Kahn2008; Reig et al. Reference Reig, Moreno, Moreno, Burdalo, Janssen, Parellada, Zabala, Desco and Arango2009; Takahashi et al. Reference Takahashi, Wood, Soulsby, McGorry, Tanino, Suzuki, Velakoulis and Pantelis2009a).

One research group attempted to control for the effects of drug treatment by comparing children with childhood-onset schizophrenia with those diagnosed with ‘transient psychosis and behavioural problems’ (Gogtay et al. Reference Gogtay, Sporn, Clasen, Nugent, Greenstein, Nicolson, Giedd, Lenane, Gochman, Evans and Rapoport2004). The authors found that the group with schizophrenia had greater loss of grey-matter volume than the comparison group, and they concluded that, as both groups had exposure to antipsychotics, their results confirmed the specificity of volume loss to schizophrenia. However, at baseline, the comparison group had a longer duration of illness, greater exposure to antipsychotics, and showed greater volume deficits than the children with schizophrenia. Over follow-up, the comparison group had less exposure to antipsychotics, with 32% not taking antipsychotics at the time of the second MRI. The volume changes over the follow-up period still left the comparison group with smaller volumes than controls in all areas, and smaller or comparable volumes to children with schizophrenia.

In addition to the large randomized comparative trial (Lieberman et al. Reference Lieberman, Tollefson, Charles, Zipursky, Sharma, Kahn, Keefe, Green, Gur, McEvoy, Perkins, Hamer, Gu and Tohen2005), one study of 96 long-term patients also found that a lesser degree of cerebral grey-matter loss was associated with a higher cumulative dose of olanzapine, although the association just failed to reach statistical significance (p=0.07) (van Haren et al. Reference van Haren, Pol, Schnack, Cahn, Brans, Carati, Rais and Kahn2008). However, another study did not report any differences after a switch from older antipsychotics to olanzapine, except for a reduction in thalamic volume, which had been increased at baseline (Khorram et al. Reference Khorram, Lang, Kopala, Vandorpe, Rui, Goghari, Smith and Honer2006; Panenka et al. Reference Panenka, Khorram, Barr, Smith, Lang, Kopala, Vandorpe and Honer2007). Other studies also found no difference in volume changes in patients taking typical and atypical antipsychotics (Cahn et al. Reference Cahn, Hulshoff Pol, Lems, van Haren, Schnack, van der Linden, Schothorst, van Engeland and Kahn2002b; Ho et al. Reference Ho, Andreasen, Nopoulos, Arndt, Magnotta and Flaum2003; Sporn et al. Reference Sporn, Greenstein, Gogtay, Jeffries, Lenane, Gochman, Clasen, Blumenthal, Giedd and Rapoport2003).

Drug-naive studies

Locating drug-naive studies was difficult as subjects in some studies that are presented as drug naive had taken antipsychotics for short periods, and some studies with drug-naive patients did not identify themselves as such. As some longitudinal and cross-sectional studies show possible changes after only short periods of treatment (Dazzan et al. Reference Dazzan, Morgan, Orr, Hutchinson, Chitnis, Suckling, Fearon, McGuire, Mallett, Jones, Leff and Murray2005; Lieberman et al. Reference Lieberman, Tollefson, Charles, Zipursky, Sharma, Kahn, Keefe, Green, Gur, McEvoy, Perkins, Hamer, Gu and Tohen2005), it was decided to include only studies in which patients had had ⩽4 weeks of antipsychotic treatment. Three studies that were presented as drug-naive studies were therefore excluded because patients had taken antipsychotic medication for a mean of around 5 weeks (Ettinger et al. Reference Ettinger, Chitnis, Kumari, Fannon, Sumich, O'Ceallaigh, Doku and Sharma2001; Moreno et al. Reference Moreno, Burdalo, Reig, Parellada, Zabala, Desco, Baca-Baldomero and Arango2005; Crespo-Facorro et al. Reference Crespo-Facorro, Roiz-Santianez, Perez-Iglesias, Pelayo-Teran, Rodriguez-Sanchez, Tordesillas-Gutierrez, Ramirez, Martinez, Gutierrez, de Lucas and Vazquez-Barquero2008). Two of these did not report any evidence of differences in total brain volume, ventricular volume or grey-matter volume (Ettinger et al. Reference Ettinger, Chitnis, Kumari, Fannon, Sumich, O'Ceallaigh, Doku and Sharma2001; Crespo-Facorro et al. Reference Crespo-Facorro, Roiz-Santianez, Perez-Iglesias, Pelayo-Teran, Rodriguez-Sanchez, Tordesillas-Gutierrez, Ramirez, Martinez, Gutierrez, de Lucas and Vazquez-Barquero2008). The third detected differences in total CSF and frontal lobe grey-matter volumes in males only, which may not have been detected had male and female patients been combined because female patients showed opposite trends (Moreno et al. Reference Moreno, Burdalo, Reig, Parellada, Zabala, Desco, Baca-Baldomero and Arango2005). One study that specified that patients had not had any ‘significant neuroleptic treatment’ was included (Bottmer et al. Reference Bottmer, Bachmann, Pantel, Essig, Amann, Schad, Magnotta and Schroder2005) because this was specified as less than 2 weeks of treatment in a previous paper (Bachmann et al. Reference Bachmann, Bottmer, Pantel, Schroder, Amann, Essig and Schad2004). Two other studies in which patients had had a mean or median of between 1 and 3 weeks of antipsychotic treatment were also included (Puri et al. Reference Puri, Hutton, Saeed, Oatridge, Hajnal, Duncan, Chapman, Barnes, Bydder and Joyce2001; Nakamura et al. Reference Nakamura, Salisbury, Hirayasu, Bouix, Pohl, Yoshida, Koo, Shenton and McCarley2007).

The Medline search produced 94 papers and 21 studies were identified that met inclusion criteria (Table 2). Other papers were not relevant or represented multiple publications. The studies included a total of 657 principally drug-naive patients. Most involved young people with a first psychotic episode prior to the commencement of medication. The majority of studies did not report any differences in volumes of whole brain, total grey matter or CSF spaces between patients and controls, including the largest study involving 68 patients.

Table 2. Imaging studies of brain structure in antipsychotic-naive patients

CSF, Cerebrospinal fluid, s.d., standard deviation.

Five out of 21 studies reported some differences between patients and controls in volumes of interest (Chua et al. Reference Chua, Cheung, Cheung, Tsang, Chen, Wong, Cheung, Yip, Tai, Suckling and McAlonan2007). One of these studies involved a sample of patients with first-episode schizophrenia and affective psychosis who had taken antipsychotic drugs for up to 24 weeks. Hence, drug use cannot be entirely excluded as a cause of the observed differences (Nakamura et al. Reference Nakamura, Salisbury, Hirayasu, Bouix, Pohl, Yoshida, Koo, Shenton and McCarley2007). Another study reported reductions in global grey-matter and CSF volume in an initial publication involving 18 subjects (Jayakumar et al. Reference Jayakumar, Venkatasubramanian, Gangadhar, Janakiramaiah and Keshavan2005), but did not report global differences in a larger sample of 51 patients (Venkatasubramanian et al. Reference Venkatasubramanian, Jayakumar, Gangadhar and Keshavan2008). A study from Hong Kong found no difference in absolute volumes, except for the right lateral ventricle, but did find differences in ratios of grey matter, white matter and CSF to whole-brain volume (Chua et al. Reference Chua, Cheung, Cheung, Tsang, Chen, Wong, Cheung, Yip, Tai, Suckling and McAlonan2007). Another study reported a difference in the third ventricle only (Cahn et al. Reference Cahn, Hulshoff Pol, Bongers, Schnack, Mandl, van Haren, Durston, Koning, van der Linden and Kahn2002a). One further study reported a trend level reduction in whole-brain volume (John et al. Reference John, Burgess, Yashavantha, Shakeel, Halahalli and Jain2009) and another reported that patients had smaller cerebellar volumes (Bottmer et al. Reference Bottmer, Bachmann, Pantel, Essig, Amann, Schad, Magnotta and Schroder2005).

One study involved 31 chronically ill, untreated patients in India. This study found no differences between patients and controls in the volume of both cerebral hemispheres, the ventricles and the caudate nuclei. A subgroup of patients without dyskinetic movements had a larger ventricle to hemisphere ratio on the right side (p=0.01) (McCreadie et al. Reference McCreadie, Thara, Padmavati, Srinivasan and Jaipurkar2002). Two other studies involved patients whose mean duration of illness was 4 to 5 years (Buchsbaum et al. Reference Buchsbaum, Someya, Teng, Abel, Chin, Najafi, Haier, Wu and Bunney1996; Ichimiya et al. Reference Ichimiya, Okubo, Suhara and Sudo2001). Neither of these studies reported any difference in global volumes. Hence, the only three studies of patients whose duration of illness is comparable to patients who have taken antipsychotic drug treatment for some time report no major differences in global cerebral, grey-matter, ventricular or CSF volumes.

Three studies of people considered to be at high risk for developing schizophrenia or psychosis due to genetic loading or subclinical symptoms have been conducted. None have reported any differences in global grey matter, whole-brain, lobar, CSF or ventricular volumes in high-risk patients as a whole, or in the subgroup who progress to psychosis compared to controls (Lawrie et al. Reference Lawrie, Whalley, Abukmeil, Kestelman, Donnelly, Miller, Best, Owens and Johnstone2001; Borgwardt et al. Reference Borgwardt, Riecher-Rossler, Dazzan, Chitnis, Aston, Drewe, Gschwandtner, Haller, Pfluger, Rechsteiner, D'Souza, Stieglitz, Radu and McGuire2007; Takahashi et al. Reference Takahashi, Wood, Yung, Phillips, Soulsby, McGorry, Tanino, Zhou, Suzuki, Velakoulis and Pantelis2009b, Reference Takahashi, Wood, Yung, Soulsby, McGorry, Suzuki, Kawasaki, Phillips, Velakoulis and Pantelisc). Longitudinal follow-up of the Australian cohort suggested reduction of the superior temporal gyrus and insular cortex, but most of the sample were treated with antipsychotics (Takahashi et al. Reference Takahashi, Wood, Yung, Phillips, Soulsby, McGorry, Tanino, Zhou, Suzuki, Velakoulis and Pantelis2009b, Reference Takahashi, Wood, Yung, Soulsby, McGorry, Suzuki, Kawasaki, Phillips, Velakoulis and Pantelisc). In the Scottish study, individuals in the high-risk group with psychotic symptoms showed greater right temporal lobe reduction than those who were unsymptomatic, but they did not differ from controls (Lawrie et al. Reference Lawrie, Whalley, Abukmeil, Kestelman, Miller, Best, Owens and Johnstone2002).

Discussion

The data presented here raise two important questions. First, does treatment with antipsychotic drugs cause a reduction in brain volume? Second, does antipsychotic drug treatment contribute to some of the features of brain structure that are usually attributed to schizophrenia, particularly reduced brain size and enlarged ventricles?

Some evidence suggests that there is progressive reduction of brain size and enlargement of brain spaces in people who are taking antipsychotic drugs. Fourteen studies found evidence of reduced brain or grey-matter volume or increased ventricular or CSF volume in patients compared with controls during a period of drug treatment. The two largest studies, one conducted in first-episode patients (Lieberman et al. Reference Lieberman, Tollefson, Charles, Zipursky, Sharma, Kahn, Keefe, Green, Gur, McEvoy, Perkins, Hamer, Gu and Tohen2005) and one in patients with long-term illness (van Haren et al. Reference van Haren, Pol, Schnack, Cahn, Brans, Carati, Rais and Kahn2008), both found global brain volume reductions, suggesting that some of the negative studies may have suffered from being underpowered. One of these studies found differential rates of volume reduction with different drugs (Lieberman et al. Reference Lieberman, Tollefson, Charles, Zipursky, Sharma, Kahn, Keefe, Green, Gur, McEvoy, Perkins, Hamer, Gu and Tohen2005).

Evidence from longitudinal studies has traditionally been interpreted as showing the progressive nature of the neuropathology of schizophrenia. The finding that some studies with first-episode patients showed the same patterns of volume loss was thought to demonstrate that drug treatment could not be responsible for the changes. However, authors of a systematic review of first-episode studies stress that antipsychotic drug effects cannot be discounted (Steen et al. Reference Steen, Mull, McClure, Hamer and Lieberman2006). Most studies of drug-naive patients examined here did not report or detect differences in total brain volume, global grey-matter volume or CSF volumes between patients and controls, including three studies of untreated patients with long-term illness. These results are particularly remarkable, given the difficulty of selecting a comparable control group in these studies. The results suggest that the brain changes found in some first-episode studies may also be attributable to drug treatment, especially because some studies suggest that structural changes may occur after only short periods of treatment (Lieberman et al. Reference Lieberman, Tollefson, Charles, Zipursky, Sharma, Kahn, Keefe, Green, Gur, McEvoy, Perkins, Hamer, Gu and Tohen2005).

The literature examined in this review is inconsistent, however, with almost half of the longitudinal studies failing to detect or report progressive changes, for example. We attempted to ascertain whether use of lower doses of medication might account for negative findings in some studies, but information on dose was scant and did not enable comparisons. The dose range of haloperidol in the negative comparative drug trial by Crespo-Facorro et al. (Reference Crespo-Facorro, Roiz-Santianez, Perez-Iglesias, Pelayo-Teran, Rodriguez-Sanchez, Tordesillas-Gutierrez, Ramirez, Martinez, Gutierrez, de Lucas and Vazquez-Barquero2008) was lower than the dose range for the larger trial (Lieberman et al. Reference Lieberman, Tollefson, Charles, Zipursky, Sharma, Kahn, Keefe, Green, Gur, McEvoy, Perkins, Hamer, Gu and Tohen2005), and the mean daily dose of haloperidol used was <5 mg, but no mean doses are given for the larger study.

Analyses of the relationship between the degree of exposure to antipsychotics and brain volume changes also gave mixed results, and only a minority of studies detected a linear association between measures of drug use and brain volume changes. However, this may partly reflect the difficulty of accurately ascertaining previous drug intake. In addition, the effects of drugs may be nonlinear in nature. If, for example, the impact of drug treatment occurs when a certain threshold of exposure is reached, which may vary between individuals, then it is unlikely that a linear association would be seen. Drug-induced effects may also vary as a function of the stage of exposure and age of recipients. One study found, for example, that the association between duration of illness and brain volume decrease was better described by a logarithmic than a linear function, with brain volume decreasing at a faster rate in the early years of illness than later on (Molina et al. Reference Molina, Sanz, Benito and Palomo2004). Studies that quantified the extent of brain volume loss also suggested that it was highest during the first year of follow-up. By contrast, however, there was little evidence in the studies examined here that changes varied between first-episode and long-term patients. Of the three studies that included both multiple-episode and first-episode patients, two found no differences in volume changes between the patient groups (Wood et al. Reference Wood, Velakoulis, Smith, Bond, Stuart, McGorry, Brewer, Bridle, Eritaia, Desmond, Singh, Copolov and Pantelis2001; Whitworth et al. Reference Whitworth, Kemmler, Honeder, Kremser, Felber, Hausmann, Walch, Wanko, Weiss, Stuppaeck and Fleischhacker2005) and only one found greater reductions of frontal and temporal lobe volumes in first-episode patients compared with long-term patients (Gur et al. Reference Gur, Cowell, Turetsky, Gallacher, Cannon, Bilker and Gur1998). Some authors have also suggested that brain volume changes may be exaggerated in children and adolescents compared to adults (Arango et al. Reference Arango, Moreno, Martinez, Parellada, Desco, Moreno, Fraguas, Gogtay, James and Rapoport2008).

Earlier research is sometimes thought to have ruled out drug-induced effects on brain volume. A cross-sectional study using computed tomography that included a small number of patients who had not received antipsychotic treatment found no association between categories of antipsychotic use and ventricular–brain ratio among long-term in-patients with schizophrenia. Nevertheless, the fact that an association between ventricular volume and involuntary movements was detected suggests that drug treatment may have played a contributory role (Owens et al. Reference Owens, Johnstone, Crow, Frith, Jagoe and Kreel1985). A previous review of drug-naive research suggested that differences in the brains of drug-naive patients with schizophrenia had been demonstrated (Torrey, Reference Torrey2002). However, this conclusion was based on pneumo-encephalography studies from the mid-twentieth century conducted on chronically institutionalized patients who had received many other types of drugs and physical treatments and two small computerized tomography studies from the 1980s that involved only 17 drug-naive patients in total (Schulz et al. Reference Schulz, Koller, Kishore, Hamer and Friedel1982; Weinberger et al. Reference Weinberger, DeLisi, Perman, Targum and Wyatt1982). Moreover, most of the drug-naive studies examined in the current paper were published subsequent to this review.

Other recent reviews have highlighted regional drug-induced effects and differences between typical and atypical antipsychotics (Scherk & Falkai, Reference Scherk and Falkai2006; Vita & De Peri, Reference Vita and De Peri2007; Navari & Dazzan, Reference Navari and Dazzan2009). One of these suggests that typical antipsychotics, but not atypicals, may reduce global grey-matter volume (Navari & Dazzan, Reference Navari and Dazzan2009), but this and other reviews place much weight on the results of the large randomized trial, funded by the manufacturers of olanzapine, which reported that haloperidol, but not olanzapine, was associated with reduced grey-matter volume at 1 year. Similar trends were apparent for olanzapine-treated subjects, however, both in global grey-matter volume and in several regional volumes (Lieberman et al. Reference Lieberman, Tollefson, Charles, Zipursky, Sharma, Kahn, Keefe, Green, Gur, McEvoy, Perkins, Hamer, Gu and Tohen2005). The authors of a review of structural changes in long-term patients suggested that drug treatment may even reverse underlying changes (Hulshoff Pol & Kahn, Reference Hulshoff Pol and Kahn2008), but this conclusion was based on a small number of studies and depended on the finding of a non-significant trend association between olanzapine dose and smaller brain volume loss in one study (van Haren et al. Reference van Haren, Pol, Schnack, Cahn, Brans, Carati, Rais and Kahn2008). The evidence on typicals and atypicals from the present review was inconsistent and overall it was not possible to conclude that they have differential effects.

Most post-mortem studies confirm that the brains of people who have received long-term treatment for schizophrenia are lighter, smaller and have larger ventricles than control brains (Harrison, Reference Harrison1999b). Studies of antipsychotic-treated rats conducted in the 1970s and 1980s found changes in neuronal density and volume attributable to antipsychotic drug treatment in the striatum but not in the cortex (Harrison, Reference Harrison1999a). However, a recent study of macaque monkeys treated with olanzapine or haloperidol for 18 months found an 8–11% reduction in mean fresh brain weight compared to controls (Dorph-Petersen et al. Reference Dorph-Petersen, Pierri, Perel, Sun, Sampson and Lewis2005). The deficit was present throughout the brain but was most significant in the frontal and parietal lobes.

Further evidence is provided by a recent meta-analysis of studies of people diagnosed with bipolar disorder, which found that antipsychotic use correlated with reduced grey-matter volume compared to controls across studies (Arnone et al. Reference Arnone, Cavanagh, Gerber, Lawrie, Ebmeier and McIntosh2009).

The mechanism by which antipsychotic drugs cause brain volume reduction, if they do, is uncertain, including whether changes are permanent or reversible. A small withdrawal study suggested that drug-induced volume changes are reversible over short periods of time, leading the authors to suggest that they represent physiological rather than permanent anatomical changes (McClure et al. Reference McClure, Phillips, Jazayerli, Barnett, Coppola and Weinberger2006). However, experimental neuropathological studies demonstrate that antipsychotics can cause neurotoxicity and apoptosis (Dean, Reference Dean2006). Human and animal brains demonstrate neuropathological effects such as gliosis in the brain stem and striatum (Harrison, Reference Harrison1999a), and some studies report more generalized gliosis (Bruton et al. Reference Bruton, Crow, Frith, Johnstone, Owens and Roberts1990; Selemon et al. Reference Selemon, Lidow and Goldman-Rakic1999).

The clinical significance of the structural changes is a further important question, and several longitudinal and cross-sectional studies find evidence of an association between impaired intellectual performance and brain volume changes (Sullivan et al. Reference Sullivan, Shear, Lim, Zipursky and Pfefferbaum1996; Gur et al. Reference Gur, Cowell, Turetsky, Gallacher, Cannon, Bilker and Gur1998, Reference Gur, Turetsky, Bilker and Gur1999; Ho et al. Reference Ho, Andreasen, Nopoulos, Arndt, Magnotta and Flaum2003). A recent study of patients with bipolar disorder found a significant correlation between IQ reduction and grey-matter density loss in the temporal lobe in patients and controls (Moorhead et al. Reference Moorhead, McKirdy, Sussmann, Hall, Lawrie, Johnstone and McIntosh2007). By contrast, DeLisi et al. (Reference DeLisi, Hoff, Schwartz, Shields, Halthore, Gupta, Henn and Anand1991) found no association between neurocognitive measures and brain volume loss.

This review is limited by the fact that few studies have been designed primarily to investigate the effects of drug treatment on brain structure. Existing studies are highly heterogeneous with respect to outcomes measured, sample size, length of follow-up and analysis of drug exposure, where this was conducted. Hence, it was not possible to conduct a meta-analysis of studies. The fact that many studies had small samples raises the possibility that they were underpowered to detect volume changes or effects of antipsychotic exposure. Studies of drug-naive patients may also have missed differences between patients and controls because of their small size. By contrast, studies may have selectively highlighted chance positive findings, especially where multiple tests were conducted.

Further studies that are specifically designed to investigate drug-induced effects on brain volume are needed. Randomized trials with drug-naive patients allocated to antipsychotic treatment and non-drug treatment and compared with well-matched healthy controls would be the ideal design. Although withholding drug treatment for a long period would be ethically problematic, it may be possible to do so for a few weeks. Given the importance of clarifying the impact of drug treatment, we suggest that such studies need to be conducted. Such studies would also clarify how rapidly drugs start to affect brain structure, which would aid the interpretation of imaging research in first-episode schizophrenia. Naturalistic comparisons between patients treated continuously and those who remain wholly or largely drug free would also be interesting, but factors such as illness course and severity may confound results. Further investigation is needed into the differential effects of different classes of antipsychotic drugs and of the impact on brain volume of incidental effects of schizophrenia such as use of illicit substances, institutionalization and poor physical health.

Conclusion

Overall, there seems to be enough evidence to suggest that antipsychotic drug treatment may play a role in reducing brain volume and increasing CSF or ventricular spaces. Further research is urgently required to clarify this possibility. The issue is clinically important as some studies suggest that there is a correlation between reduced brain volume and cognitive function. Although it remains possible that the underlying disease process also causes brain volume changes, we suggest that antipsychotic drug treatment may be responsible for some of the changes that are usually attributed to schizophrenia.

Declaration of Interest

No specific financial support was received for this study. J. M. is the co-chairperson of the Critical Psychiatry Network.

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Table 1. Longitudinal studies

Figure 1

Table 2. Imaging studies of brain structure in antipsychotic-naive patients