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Do antipsychotic drugs affect brain structure? A systematic and critical review of MRI findings

Published online by Cambridge University Press:  02 April 2009

S. Navari  and
P. Dazzan
S. Navari*
Affiliation:
Division of Psychological Medicine and Psychiatry, Institute of Psychiatry, King's College London, UK Section of Psychiatry, Department of Psychiatry, Neurobiology, Pharmacology and Biotechnology, University of Pisa, Italy
P. Dazzan
Affiliation:
Division of Psychological Medicine and Psychiatry, Institute of Psychiatry, King's College London, UK
*
*Address for correspondence: S. Navari, M.D., Ph.D., Psychiatrist and Research Associate, Division of Psychological Medicine and Psychiatry, PO Box 63, Institute of Psychiatry, De Crespigny Park, LondonSE 8AF, UK. (Email: [email protected])
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Abstract

Background

The potential effects of antipsychotic drugs on brain structure represent a key factor in understanding neuroanatomical changes in psychosis. This review addresses two issues: (1) do antipsychotic medications induce changes in total or regional human brain volumes and (2) do such effects depend on antipsychotic type?

Method

A systematic review of studies reporting structural brain magnetic resonance imaging (MRI) measures: (1) directly in association with antipsychotic use; and (2) in patients receiving lifetime treatment with antipsychotics in comparison with drug-naive patients or healthy controls. We searched Medline and EMBASE databases using the medical subject heading terms: ‘antipsychotics’ AND ‘brain’ AND (MRI NOT functional). The search included studies published up to 31 January 2007. Wherever possible, we reported the effect size of the difference observed.

Results

Thirty-three studies met our inclusion criteria. The results suggest that antipsychotics act regionally rather than globally on the brain. These volumetric changes are of a greater magnitude in association with typical than with atypical antipsychotic use. Indeed, there is evidence of a specific effect of antipsychotic type on the basal ganglia, with typicals specifically increasing the volume of these structures. Differential effects of antipsychotic type may also be present on the thalamus and the cortex, but data on these and other brain areas are more equivocal.

Conclusions

Antipsychotic treatment potentially contributes to the brain structural changes observed in psychosis. Future research should take into account these potential effects, and use adequate sample sizes, to allow improved interpretation of neuroimaging findings in these disorders.

Keywords

Antipsychotic drugsbrainMRIpsychosis
Type
Review Article
Information
Psychological Medicine , Volume 39 , Issue 11 , November 2009 , pp. 1763 - 1777
Copyright
Copyright © Cambridge University Press 2009

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References

Angelucci, F, Aloe, L, Iannitelli, A, Gruber, SH, Mathe, AA (2005). Effect of chronic olanzapine treatment on nerve growth factor and brain-derived neurotrophic factor in the rat brain. European Neuropsychopharmacology 15, 311–317.CrossRefGoogle ScholarPubMed
Cahn, W, Hulshoff Pol, HE, Lems, EB, van Haren, NE, Schnack, HG, van der Linden, JA, Schothorst, PF, van Engeland, H, Kahn, RS (2002). Brain volume changes in first-episode schizophrenia: a 1-year follow-up study. Archives of General Psychiatry 59, 1002–1010.CrossRefGoogle ScholarPubMed
Chakos, MH, Lieberman, JA, Alvir, J, Bilder, R, Ashtari, M (1995). Caudate nuclei volumes in schizophrenic patients treated with typical antipsychotics or clozapine. Lancet 345, 456–457.CrossRefGoogle ScholarPubMed
Chakos, MH, Lieberman, JA, Bilder, RM, Borenstein, M, Lerner, G, Bogerts, B, Wu, H, Kinon, B, Ashtari, M (1994). Increase in caudate nuclei volumes of first-episode schizophrenic patients taking antipsychotic drugs. American Journal of Psychiatry 151, 1430–1436.Google ScholarPubMed
Chakos, MH, Schobel, SA, Gu, H, Gerig, G, Bradford, D, Charles, C, Lieberman, JA (2005). Duration of illness and treatment effects on hippocampal volume in male patients with schizophrenia. British Journal of Psychiatry 186, 26–31.CrossRefGoogle ScholarPubMed
Christensen, J, Holcomb, J, Garver, DL (2004). State-related changes in cerebral white matter may underlie psychosis exacerbation. Psychiatry Research 130, 71–78.CrossRefGoogle ScholarPubMed
Cohen, J (1992). A power primer. Psychiatric Bulletin 112, 115–119.Google ScholarPubMed
Corson, PW, Nopoulos, P, Andreasen, NC, Heckel, D, Arndt, S (1999 a). Caudate size in first-episode neuroleptic-naive schizophrenic patients measured using an artificial neural network. Biological Psychiatry 46, 712–720.CrossRefGoogle ScholarPubMed
Corson, PW, Nopoulos, P, Miller, DD, Arndt, S, Andreasen, NC (1999 b). Change in basal ganglia volume over 2 years in patients with schizophrenia: typical versus atypical neuroleptics. American Journal of Psychiatry 156, 1200–1204.CrossRefGoogle ScholarPubMed
Dazzan, P, Morgan, KD, Orr, K, Hutchinson, G, Chitnis, X, Suckling, J, Fearon, P, McGuire, PK, Mallett, RM, Jones, PB, Leff, J, Murray, RM (2005). Different effects of typical and atypical antipsychotics on grey matter in first episode psychosis: the ÆSOP study. Neuropsychopharmacology 30, 765–774.CrossRefGoogle ScholarPubMed
Dazzan, P, Murray, RM (1999). Schizophrenia is (not simply) a neurodevelopmental disorder. Epidemiologia e Psichiatria Sociale 8, 235–241.CrossRefGoogle ScholarPubMed
Dean, CE (2006). Antipsychotic-associated neuronal changes in the brain: toxic, therapeutic, or irrelevant to the long-term outcome of schizophrenia? Progress in Neuropsychopharmacology and Biological Psychiatry 30, 174–189.CrossRefGoogle ScholarPubMed
Deicken, RF, Eliaz, Y, Chosiad, L, Feiwell, R, Rogers, L (2002). Magnetic resonance imaging of the thalamus in male patients with schizophrenia. Schizophrenia Research 58, 135–144.CrossRefGoogle ScholarPubMed
Dorph-Petersen, KA, Pierri, JN, Perel, JM, Sun, Z, Sampson, AR, Lewis, DA (2005). 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 30, 1649–1661.CrossRefGoogle ScholarPubMed
Duncan, GE, Zorn, S, Lieberman, JA (1999). Mechanisms of typical and atypical antipsychotic drug action in relation to dopamine and NMDA receptor hypofunction hypotheses of schizophrenia. Molecular Psychiatry 4, 418–428.CrossRefGoogle ScholarPubMed
Farde, L, Hall, H, Ehrin, E, Sedvall, G (1986). Quantitative analysis of D2 dopamine receptor binding in the living human brain by PET. Science 231, 258–261.CrossRefGoogle ScholarPubMed
Frazier, JA, Giedd, JN, Kaysen, D, Albus, K, Hamburger, S, Alaghband-Rad, J, Lenane, MC, McKenna, K, Breier, A, Rapoport, JL (1996). Childhood-onset schizophrenia: brain MRI rescan after 2 years of clozapine maintenance treatment. American Journal of Psychiatry 153, 564–566.Google ScholarPubMed
Fumagalli, F, Molteni, R, Bedogni, F, Pennarelli, M, Perez, J, Racagni, G, Riva, MA (2004). Quetiapine regulates FGF-2 and BDNF expression in the hippocampus of animals treated with MK-801. Neuroreport 15, 2109–2112.CrossRefGoogle ScholarPubMed
Garver, DL, Holcomb, JA, Christensen, JD (2005). Cerebral cortical gray expansion associated with two second-generation antipsychotics. Biological Psychiatry 58, 62–66.CrossRefGoogle ScholarPubMed
Girgis, RR, Diwadkar, VA, Nutche, JJ, Sweeney, JA, Keshavan, MS, Hardan, AY (2006). Risperidone in first-episode psychosis: a longitudinal, exploratory voxel-based morphometric study. Schizophrenia Research 82, 89–94.CrossRefGoogle ScholarPubMed
Gur, RE, Cowell, P, Turetsky, BI, Gallacher, F, Cannon, T, Bilker, W, Gur, RC (1998 a). A follow-up magnetic resonance imaging study of schizophrenia. Relationship of neuroanatomical changes to clinical and neurobehavioral measures. Archives of General Psychiatry 55, 145–152.CrossRefGoogle ScholarPubMed
Gur, RE, Cowell, PE, Latshaw, A, Turetsky, BI, Grossman, RI, Arnold, SE, Bilker, WB, Gur, RC (2000). Reduced dorsal and orbital prefrontal gray matter volumes in schizophrenia. Archives of General Psychiatry 57, 761–768.CrossRefGoogle ScholarPubMed
Gur, RE, Maany, V, Mozley, PD, Swanson, C, Bilker, W, Gur, RC (1998 b). Subcortical MRI volumes in neuroleptic-naive and treated patients with schizophrenia. American Journal of Psychiatry 155, 1711–1717.CrossRefGoogle ScholarPubMed
Halim, ND, Weickert, CS, McClintock, BW, Weinberger, DR, Lipska, BK (2004). Effects of chronic haloperidol and clozapine treatment on neurogenesis in the adult rat hippocampus. Neuropsychopharmacology 29, 1063–1069.CrossRefGoogle ScholarPubMed
Heitmiller, DR, Nopoulos, PC, Andreasen, NC (2004). Changes in caudate volume after exposure to atypical neuroleptics in patients with schizophrenia may be sex-dependent. Schizophrenia Research 66, 137–142.CrossRefGoogle ScholarPubMed
Ho, BC, Andreasen, NC, Nopoulos, P, Arndt, S, Magnotta, V, Flaum, M (2003). Progressive structural brain abnormalities and their relationship to clinical outcome: a longitudinal magnetic resonance imaging study early in schizophrenia. Archives of General Psychiatry 60, 585–594.CrossRefGoogle ScholarPubMed
Hulshoff Pol, HE, Kahn, RS (2008). What happens after the first episode? A review of progressive brain changes in chronically ill patients with schizophrenia. Schizophrenia Bulletin 34, 354–366.CrossRefGoogle ScholarPubMed
Keshavan, MS, Bagwell, WW, Haas, GL, Sweeney, JA, Schooler, NR, Pettegrew, JW (1994). Changes in caudate volume with neuroleptic treatment. Lancet 344, 1434.CrossRefGoogle ScholarPubMed
Khorram, B, Lang, DJ, Kopala, LC, Vandorpe, RA, Rui, Q, Goghari, VM, Smith, GN, Honer, WG (2006). Reduced thalamic volume in patients with chronic schizophrenia after switching from typical antipsychotic medications to olanzapine. American Journal of Psychiatry 163, 2005–2007.CrossRefGoogle ScholarPubMed
Lang, DJ, Kopala, LC, Vandorpe, RA, Rui, Q, Smith, GN, Goghari, VM, Honer, WG (2001). An MRI study of basal ganglia volumes in first-episode schizophrenia patients treated with risperidone. American Journal of Psychiatry 158, 625–631.CrossRefGoogle ScholarPubMed
Lang, DJ, Kopala, LC, Vandorpe, RA, Rui, Q, Smith, GN, Goghari, VM, Lapointe, JS, Honer, WG (2004). Reduced basal ganglia volumes after switching to olanzapine in chronically treated patients with schizophrenia. American Journal of Psychiatry 161, 1829–1836.CrossRefGoogle ScholarPubMed
Lawrie, SM, Abukmeil, SS (1998). Brain abnormality in schizophrenia. A systematic and quantitative review of volumetric magnetic resonance imaging studies. British Journal of Psychiatry 172, 110–120.CrossRefGoogle ScholarPubMed
Lieberman, J, Chakos, M, Wu, H, Alvir, J, Hoffman, E, Robinson, D, Bilder, R (2001). Longitudinal study of brain morphology in first episode schizophrenia. Biological Psychiatry 49, 487–499.CrossRefGoogle ScholarPubMed
Lieberman, JA, Tollefson, GD, Charles, C, Zipursky, R, Sharma, T, Kahn, RS, Keefe, RS, Green, AI, Gur, RE, McEvoy, J, Perkins, D, Hamer, RM, Gu, H, Tohen, M (2005). Antipsychotic drug effects on brain morphology in first-episode psychosis. Archives of General Psychiatry 62, 361–370.CrossRefGoogle ScholarPubMed
Massana, G, Salgado-Pineda, P, Dunque, C, Perez, M, Baeza, I, Pons, A, Massana, J, Navarro, V, Blanch, J, Morer, A, Mercader, JM, Bernardo, M (2005). Volume changes in gray matter in first-episode neuroleptic-naive schizophrenic patients treated with risperidone. Journal of Clinical Psychopharmacology 25, 111–117.CrossRefGoogle ScholarPubMed
Mathalon, DH, Sullivan, EV, Lim, KO, Pfefferbaum, A (2001). Progressive brain volume changes and the clinical course of schizophrenia in men: a longitudinal magnetic resonance imaging study. Archives of General Psychiatry 58, 148–157.CrossRefGoogle Scholar
McCarley, RW, Wible, CG, Frumin, M, Hirayasu, Y, Levitt, JJ, Fischer, IA, Shenton, ME (1999). MRI anatomy of schizophrenia. Biological Psychiatry 45, 1099–1119.CrossRefGoogle ScholarPubMed
McClure, RK, Phillips, I, Jazayerli, R, Barnett, A, Coppola, R, Weinberger, DR (2006). Regional change in brain morphometry in schizophrenia associated with antipsychotic treatment. Psychiatry Research 148, 121–132.CrossRefGoogle ScholarPubMed
Millan, MJ (2005). N-Methyl-D-aspartate receptors as a target for improved antipsychotic agents: novel insights and clinical perspectives. Psychopharmacology (Berlin) 179, 30–53.CrossRefGoogle ScholarPubMed
Miller, DD, Andreasen, NC, O'Leary, DS, Rezai, K, Watkins, GL, Ponto, LL, Hichwa, RD (1997 a). Effect of antipsychotics on regional cerebral blood flow measured with positron emission tomography. Neuropsychopharmacology 17, 230–240.CrossRefGoogle ScholarPubMed
Miller, DD, Andreasen, NC, O'Leary, DS, Watkins, GL, Boles Ponto, LL, Hichwa, RD (2001). Comparison of the effects of risperidone and haloperidol on regional cerebral blood flow in schizophrenia. Biological Psychiatry 49, 704–715.CrossRefGoogle ScholarPubMed
Miller, DD, Rezai, K, Alliger, R, Andreasen, NC (1997 b). The effect of antipsychotic medication on relative cerebral blood perfusion in schizophrenia: assessment with technetium-99m hexamethyl-propyleneamine oxime single photon emission computed tomography. Biological Psychiatry 41, 550–559.CrossRefGoogle ScholarPubMed
Narr, KL, Toga, AW, Szeszko, P, Thompson, PM, Woods, RP, Robinson, D, Sevy, S, Wang, Y, Schrock, K, Bilder, RM (2005). Cortical thinning in cingulate and occipital cortices in first episode schizophrenia. Biological Psychiatry 58, 32–40.CrossRefGoogle ScholarPubMed
Nopoulos, PC, Ceilley, JW, Gailis, EA, Andreasen, NC (2001). An MRI study of midbrain morphology in patients with schizophrenia: relationship to psychosis, neuroleptics, and cerebellar neural circuitry. Biological Psychiatry 49, 13–19.CrossRefGoogle ScholarPubMed
Nyberg, S, Eriksson, B, Oxenstierna, G, Halldin, C, Farde, L (1999). Suggested minimal effective dose of risperidone based on PET-measured D2 and 5-HT2A receptor occupancy in schizophrenic patients. American Journal of Psychiatry 156, 869–875.CrossRefGoogle ScholarPubMed
Oosthuizen, P, Emsley, R, Jadri Turner, H, Keyter, N (2004). A randomized, controlled comparison of the efficacy and tolerability of low and high doses of haloperidol in the treatment of first-episode psychosis. International Journal of Neuropsychopharmacology 7, 125–131.CrossRefGoogle ScholarPubMed
Pantelis, C, Velakoulis, D, McGorry, PD, Wood, SJ, Suckling, J, Phillips, LJ, Yung, AR, Bullmore, ET, Brewer, W, Soulsby, B, Desmond, P, McGuire, PK (2003). Neuroanatomical abnormalities before and after onset of psychosis: a cross-sectional and longitudinal MRI comparison. Lancet 361, 281–288.CrossRefGoogle ScholarPubMed
Post, A, Holsboer, F, Behl, C (1998). Induction of NF-kappaB activity during haloperidol-induced oxidative toxicity in clonal hippocampal cells: suppression of NF-kappaB and neuroprotection by antioxidants. Journal of Neuroscience 18, 8236–8246.CrossRefGoogle ScholarPubMed
Puri, BK, Hutton, SB, Saeed, N, Oatridge, A, Hajnal, JV, Duncan, L, Chapman, MJ, Barnes, TR, Bydder, GM, Joyce, EM (2001). A serial longitudinal quantitative MRI study of cerebral changes in first-episode schizophrenia using image segmentation and subvoxel registration. Psychiatry Research 106, 141–150.CrossRefGoogle ScholarPubMed
Scheepers, FE, de Wied, CC, Hulshoff Pol, HE, van de Flier, W, van der Linden, JA, Kahn, RS (2001 a). The effect of clozapine on caudate nucleus volume in schizophrenic patients previously treated with typical antipsychotics. Neuropsychopharmacology 24, 47–54.CrossRefGoogle ScholarPubMed
Scheepers, FE, Gispen de Wied, CC, Hulshoff Pol, HE, Kahn, RS (2001 b). Effect of clozapine on caudate nucleus volume in relation to symptoms of schizophrenia. American Journal of Psychiatry 158, 644–646.CrossRefGoogle ScholarPubMed
Scherk, H, Falkai, P (2006). Effects of antipsychotics on brain structure. Current Opinion in Psychiatry 19, 145–150.CrossRefGoogle ScholarPubMed
Seeman, P (2002). Atypical antipsychotics: mechanism of action. Canadian Journal of Psychiatry 47, 27–38.CrossRefGoogle ScholarPubMed
Seeman, P (2005). An update of fast-off dopamine D2 atypical antipsychotics. American Journal of Psychiatry 162, 1984–1985.CrossRefGoogle ScholarPubMed
Shenton, ME, Dickey, CC, Frumin, M, McCarley, RW (2001). A review of MRI findings in schizophrenia. Schizophrenia Research 49, 1–52.CrossRefGoogle ScholarPubMed
Shihabuddin, L, Buchsbaum, MS, Hazlett, EA, Haznedar, MM, Harvey, PD, Newman, A, Schnur, DB, Spiegel-Cohen, J, Wei, T, Machac, J, Knesaurek, K, Vallabhajosula, S, Biren, MA, Ciaravolo, TM, Luu-Hsia, C (1998). Dorsal striatal size, shape, and metabolic rate in never-medicated and previously medicated schizophrenics performing a verbal learning task. Archives of General Psychiatry 55, 235–243.CrossRefGoogle ScholarPubMed
Tauscher-Wisniewski, S, Tauscher, J, Logan, J, Christensen, BK, Mikulis, DJ, Zipursky, RB (2002). Caudate volume changes in first episode psychosis parallel the effects of normal aging: a 5-year follow-up study. Schizophrenia Research 58, 185–188.CrossRefGoogle ScholarPubMed
Taylor, S, Christensen, JD, Holcomb, JM, Garver, DL (2005). Volume increases in striatum associated with positive symptom reduction in schizophrenia: a preliminary observation. Psychiatry Research 140, 85–89.CrossRefGoogle ScholarPubMed
Thompson, PM, Hayashi, KM, de Zubicaray, G, Janke, AL, Rose, SE, Semple, J, Herman, D, Hong, MS, Dittmer, SS, Doddrell, DM, Toga, AW (2003). Dynamics of gray matter loss in Alzheimer's disease. Journal of Neuroscience 23, 994–1005.CrossRefGoogle ScholarPubMed
Thompson, PM, Vidal, C, Giedd, JN, Gochman, P, Blumenthal, J, Nicolson, R, Toga, AW, Rapoport, JL (2001). Mapping adolescent brain change reveals dynamic wave of accelerated gray matter loss in very early-onset schizophrenia. Proceedings of the National Academy of USA 98, 11650–11655.CrossRefGoogle ScholarPubMed
Velakoulis, D, Pantelis, C, McGorry, PD, Dudgeon, P, Brewer, W, Cook, M, Desmond, P, Bridle, N, Tierney, P, Murrie, V, Singh, B, Copolov, D (1999). Hippocampal volume in first-episode psychoses and chronic schizophrenia: a high-resolution magnetic resonance imaging study. Archives of General Psychiatry 56, 133–141.CrossRefGoogle ScholarPubMed
Wang, HD, Dunnavant, FD, Jarman, T, Deutch, AY (2004). Effects of antipsychotic drugs on neurogenesis in the forebrain of the adult rat. Neuropsychopharmacology 29, 1230–1238.CrossRefGoogle ScholarPubMed
Weinberger, DR, McClure, RK (2002). Neurotoxicity, neuroplasticity, and magnetic resonance imaging morphometry: what is happening in the schizophrenic brain? Archives of General Psychiatry 59, 553–558.CrossRefGoogle ScholarPubMed
Wright, AM, Bempong, J, Kirby, ML, Barlow, RL, Bloomquist, JR (1998). Effects of haloperidol metabolites on neurotransmitter uptake and release: possible role in neurotoxicity and tardive dyskinesia. Brain Research 788, 215–222.CrossRefGoogle ScholarPubMed
Zipursky, RB, Zhang-Wong, J, Lambe, EK, Bean, G, Beiser, M (1998). MRI correlates of treatment response in first episode psychosis. Schizophrenia Research 30, 81–90.CrossRefGoogle ScholarPubMed
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