Skip to main content
    • Aa
    • Aa

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

  • S. Navari (a1) (a2) and P. Dazzan (a1)

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?


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.


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.


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.

Corresponding author
*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, London SE 8AF, UK. (Email:
Hide All
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, 311317.
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, 10021010.
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, 456457.
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, 14301436.
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, 2631.
Christensen J, Holcomb J, Garver DL (2004). State-related changes in cerebral white matter may underlie psychosis exacerbation. Psychiatry Research 130, 7178.
Cohen J (1992). A power primer. Psychiatric Bulletin 112, 115119.
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, 712720.
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, 12001204.
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, 765774.
Dazzan P, Murray RM (1999). Schizophrenia is (not simply) a neurodevelopmental disorder. Epidemiologia e Psichiatria Sociale 8, 235241.
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, 174189.
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, 135144.
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, 16491661.
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, 418428.
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, 258261.
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, 564566.
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, 21092112.
Garver DL, Holcomb JA, Christensen JD (2005). Cerebral cortical gray expansion associated with two second-generation antipsychotics. Biological Psychiatry 58, 6266.
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, 8994.
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, 145152.
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, 761768.
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, 17111717.
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, 10631069.
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, 137142.
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, 585594.
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, 354366.
Keshavan MS, Bagwell WW, Haas GL, Sweeney JA, Schooler NR, Pettegrew JW (1994). Changes in caudate volume with neuroleptic treatment. Lancet 344, 1434.
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, 20052007.
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, 625631.
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, 18291836.
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, 110120.
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, 487499.
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, 361370.
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, 111117.
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, 148157.
McCarley RW, Wible CG, Frumin M, Hirayasu Y, Levitt JJ, Fischer IA, Shenton ME (1999). MRI anatomy of schizophrenia. Biological Psychiatry 45, 10991119.
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, 121132.
Millan MJ (2005). N-Methyl-D-aspartate receptors as a target for improved antipsychotic agents: novel insights and clinical perspectives. Psychopharmacology (Berlin) 179, 3053.
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, 230240.
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, 704715.
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, 550559.
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, 3240.
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, 1319.
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, 869875.
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, 125131.
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, 281288.
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, 82368246.
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, 141150.
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, 4754.
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, 644646.
Scherk H, Falkai P (2006). Effects of antipsychotics on brain structure. Current Opinion in Psychiatry 19, 145150.
Seeman P (2002). Atypical antipsychotics: mechanism of action. Canadian Journal of Psychiatry 47, 2738.
Seeman P (2005). An update of fast-off dopamine D2 atypical antipsychotics. American Journal of Psychiatry 162, 19841985.
Shenton ME, Dickey CC, Frumin M, McCarley RW (2001). A review of MRI findings in schizophrenia. Schizophrenia Research 49, 152.
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, 235243.
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, 185188.
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, 8589.
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, 9941005.
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, 1165011655.
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, 133141.
Wang HD, Dunnavant FD, Jarman T, Deutch AY (2004). Effects of antipsychotic drugs on neurogenesis in the forebrain of the adult rat. Neuropsychopharmacology 29, 12301238.
Weinberger DR, McClure RK (2002). Neurotoxicity, neuroplasticity, and magnetic resonance imaging morphometry: what is happening in the schizophrenic brain? Archives of General Psychiatry 59, 553558.
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, 215222.
Zipursky RB, Zhang-Wong J, Lambe EK, Bean G, Beiser M (1998). MRI correlates of treatment response in first episode psychosis. Schizophrenia Research 30, 8190.
Recommend this journal

Email your librarian or administrator to recommend adding this journal to your organisation's collection.

Psychological Medicine
  • ISSN: 0033-2917
  • EISSN: 1469-8978
  • URL: /core/journals/psychological-medicine
Please enter your name
Please enter a valid email address
Who would you like to send this to? *


Type Description Title
Supplementary Materials

Navari supplementary material

 PDF (61 KB)
61 KB


Altmetric attention score

Full text views

Total number of HTML views: 16
Total number of PDF views: 76 *
Loading metrics...

Abstract views

Total abstract views: 423 *
Loading metrics...

* Views captured on Cambridge Core between September 2016 - 20th October 2017. This data will be updated every 24 hours.