Skip to main content Accessibility help

Brain volume changes over the first year of treatment in schizophrenia: relationships to antipsychotic treatment

  • R. Emsley (a1), L. Asmal (a1), S. du Plessis (a1), B. Chiliza (a1), L. Phahladira (a1) and S. Kilian (a1)...



Progressive brain volume reductions have been described in schizophrenia, and an association with antipsychotic exposure has been reported.


We compared percentage changes in grey and white matter volume from baseline to month 12 in 23 previously antipsychotic-naïve patients with a first episode of schizophrenia or schizophreniform disorder who were treated with the lowest effective dose of flupenthixol decanoate depot formulation, with 53 matched healthy individuals. Total antipsychotic dose was precisely calculated and its relationship with brain volume changes investigated. Relationships between volumetric changes and treatment were further investigated in terms of treatment response (changes in psychopathology and functionality) and treatment-related adverse-events (extrapyramidal symptoms and weight gain).


Excessive cortical volume reductions were observed in patients [−4.6 (6.6)%] v. controls [−1.12 (4.0)%] (p = 0.009), with no significant group differences for changes in subcortical grey matter and white matter volumes. In a multiple regression model, the only significant predictor of cortical volume change was total antipsychotic dose received (p = 0.04). Cortical volume change was not significantly associated with the changes in psychopathology, functionality, extrapyramidal symptoms and body mass index or age, gender and duration of untreated psychosis.


Brain volume reductions associated with antipsychotic treatment are not restricted to poor outcome patients and occur even with the lowest effective dose of antipsychotic. The lack of an association with poor treatment response or treatment-related adverse effects counts against cortical volume reductions reflecting neurotoxicity, at least in the short term. On the other hand, the volume reductions were not linked to the therapeutic benefits of antipsychotics.


Corresponding author

*Address for correspondence: R. Emsley, Department of Psychiatry, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg Campus, 8000, Cape Town, South Africa. (Email:


Hide All
Al-Amin, MM, Nasir Uddin, MM, Mahmud, RH (2013). Effects of antipsychotics on the inflammatory response system of patients with schizophrenia in peripheral blood mononuclear cell cultures. Clinical Psychopharmacology and Neuroscience 11, 144151.
American Psychiatric Association (1994). Diagnostic and Statistical Manual of Mental Disorders. DSM IV, 4th edn. American Psychaitric Association Washington: DC.
Andreasen, NC, Carpenter, WT Jr., Kane, JM, Lasser, RA, Marder, SR, Weinberger, DR (2005). Remission in schizophrenia: proposed criteria and rationale for consensus. American Journal of Psychiatry 162, 441449.
Andreasen, NC, Nopoulos, P, Magnotta, V, Pierson, R, Ziebell, S, Ho, BC (2011). Progressive brain change in schizophrenia: a prospective longitudinal study of first-episode schizophrenia. Biological Psychiatry 70, 672679.
Brissos, S, Veguilla, MR, Taylor, D, Balanza-Martinez, V (2014). The role of long-acting injectable antipsychotics in schizophrenia: a critical appraisal. Therapeutic Advances in Psychopharmacology 4, 198219.
Chouinard, G, Margolese, HC (2005). Manual for the Extrapyramidal Symptom Rating Scale (ESRS). Schizophrenia Research 76(2-3), 247–65.
Coldham, EL, Addington, J, Addington, D (2002). Medication adherence of individuals with a first episode of psychosis. Acta Psychiatrica Scandinavica 106, 286290.
Dale, AM, Fischl, B, Sereno, MI (1999). Cortical surface-based analysis. I. Segmentation and surface reconstruction. Neuroimage 9, 179194.
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 AESOP study. Neuropsychopharmacology 30, 765774.
de Wit, H (2010). Flupenthixol. In Encyclopedia of Psychopharmacology (ed. Stolerman, I. P.), pp. 538539. Springer: Berlin.
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.
Ebdrup, BH, Norbak, H, Borgwardt, S, Glenthoj, B (2013). Volumetric changes in the basal ganglia after antipsychotic monotherapy: a systematic review. Current Medicinal Chemistry 20, 438447.
Emsley, R, Asmal, L, Chiliza, B, du Plessis, S, Carr, J, Kidd, M, Malhotra, AK, Vink, M, Kahn, RS (2015). Changes in brain regions associated with food-intake regulation, body mass and metabolic profiles during acute antipsychotic treatment in first-episode schizophrenia. Psychiatry Research 233, 186193.
First, MB, Spitzer, RLGM, Williams, LBW (1994). Structured Clinical Interview for DSM-IV Axis I Disorders, Patient edn (SCID-P). New York State Psychiatric Institute, Biometrics Research: New York.
Fischl, B, Sereno, MI, Dale, AM (1999). Cortical surface-based analysis. II: inflation, flattening, and a surface-based coordinate system. Neuroimage 9, 195207.
Fusar-Poli, P, Smieskova, R, Kempton, MJ, Ho, BC, Andreasen, NC, Borgwardt, S (2013). Progressive brain changes in schizophrenia related to antipsychotic treatment? A meta-analysis of longitudinal MRI studies. Neuroscience and Biobehavioral Reviews 37, 16801691.
Gardner, DM, Murphy, AL, O'Donnell, H, Centorrino, F, Baldessarini, RJ (2010). International consensus study of antipsychotic dosing. American Journal of Psychiatry 167, 686693.
Gattaz, WF, Diehl, A, Geuppert, MS, Hubrich, P, Schmitt, A, Linde, I, Maras, A, Dittmann, RW (2004). Olanzapine versus flupenthixol in the treatment of inpatients with schizophrenia: a randomized double-blind trial. Pharmacopsychiatry 37, 279285.
Geddes, J, Freemantle, N, Harrison, P, Bebbington, P (2000). Atypical antipsychotics in the treatment of schizophrenia: systematic overview and meta-regression analysis. British Medical Journal 321, 13711376.
Goff, DC (2011). Antipsychotics and the shrinking brain. Psychaitric Times (
Graeber, MB, Li, W, Rodriguez, ML (2011). Role of microglia in CNS inflammation. FEBS Letters 585, 37983805.
Guo, JY, Huhtaniska, S, Miettunen, J, Jaaskelainen, E, Kiviniemi, V, Nikkinen, J, Moilanen, J, Haapea, M, Maki, P, Jones, PB, Veijola, J, Isohanni, M, Murray, GK (2015). Longitudinal regional brain volume loss in schizophrenia: relationship to antipsychotic medication and change in social function. Schizophrenia Research 168, 297304.
Haijma, SV, Van Haren, N, Cahn, W, Koolschijn, PC, Hulshoff Pol, HE, Kahn, RS (2013). Brain volumes in schizophrenia: a meta-analysis in over 18 000 subjects. Schizophrenia Bulletin 39, 11291138.
Haukvik, UK, Hartberg, CB, Nerland, S, Jorgensen, KN, Lange, EH, Simonsen, C, Nesvag, R, Dale, AM, Andreassen, OA, Melle, I, Agartz, I (2016). No progressive brain changes during a 1-year follow-up of patients with first-episode psychosis. Psychological Medicine 46, 589598.
Ho, BC, Andreasen, NC, Dawson, JD, Wassink, TH (2007). Association between brain-derived neurotrophic factor Val66Met gene polymorphism and progressive brain volume changes in schizophrenia. American Journal of Psychiatry 164, 18901899.
Ho, BC, Andreasen, NC, Ziebell, S, Pierson, R, Magnotta, V (2011). Long-term antipsychotic treatment and brain volumes: a longitudinal study of first-episode schizophrenia. Archives of General Psychiatry 68, 128137.
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.
International Conference on Harmonization (1996). ICH Harmonised Tripartite Guidelines for Good Clinical Practice. Brookwood Medical Publications Ltd: Surrey.
Kapur, S, Arenovich, T, Agid, O, Zipursky, R, Lindborg, S, Jones, B (2005). Evidence for onset of antipsychotic effects within the first 24 h of treatment. American Journal of Psychiatry 162, 939946.
Kay, SR, Fizbein, A, Opler, LA (1987). The Positive and Negative Syndrome Scale (PANSS) for Schizophrenia. Schizophrenia Bulletin 13, 261267.
Kempton, MJ, Stahl, D, Williams, SC, DeLisi, LE (2010). Progressive lateral ventricular enlargement in schizophrenia: a meta-analysis of longitudinal MRI studies. Schizophrenia Research 120, 5462.
Leucht, S, Corves, C, Arbter, D, Engel, RR, Li, C, Davis, JM (2009). Second-generation versus first-generation antipsychotic drugs for schizophrenia: a meta-analysis. Lancet 373, 3141.
Lewis, DA (2011). Antipsychotic medications and brain volume: do we have cause for concern? Archives of General Psychiatry 68, 126127.
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.
Medic, N, Ziauddeen, H, Ersche, KD, Farooqi, IS, Bullmore, ET, Nathan, PJ, Ronan, L, Fletcher, PC (2016). Increased body mass index is associated with specific regional alterations in brain structure. International Journal of Obesity (London) 40, 11771182.
Navari, S, Dazzan, P (2009). Do antipsychotic drugs affect brain structure? A systematic and critical review of MRI findings. Psychological Medicine 39, 17631777.
Olabi, B, Ellison-Wright, I, McIntosh, AM, Wood, SJ, Bullmore, E, Lawrie, SM (2011). Are there progressive brain changes in schizophrenia? A meta-analysis of structural magnetic resonance imaging studies. Biological Psychiatry 70, 8896.
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, 281–8.
Roiz-Santianez, R, Suarez-Pinilla, P, Crespo-Facorro, B (2015). Brain structural effects of antipsychotic treatment in schizophrenia: a systematic review. Current Neuropharmacol. 13, 422434.
Sarro, S, Pomarol-Clotet, E, Canales-Rodriguez, EJ, Salvador, R, Gomar, JJ, Ortiz-Gil, J, Landin-Romero, R, Vila-Rodriguez, F, Blanch, J, McKenna, PJ (2013). Structural brain changes associated with tardive dyskinesia in schizophrenia. British Journal of Psychiatry 203, 5157.
Shen, X, Xia, J, Adams, CE (2012). Flupenthixol versus placebo for schizophrenia. Cochrane Database Systematic Revue 11, CD009777.
Smieskova, R, Fusar-Poli, P, Allen, P, Bendfeldt, K, Stieglitz, RD, Drewe, J, Radue, EW, McGuire, PK, Riecher-Rossler, A, Borgwardt, SJ (2009). The effects of antipsychotics on the brain: what have we learnt from structural imaging of schizophrenia? – a systematic review. Current Pharmaceutical Design 15, 25352549.
Strassnig, M, Miewald, J, Keshavan, M, Ganguli, R (2007). Weight gain in newly diagnosed first-episode psychosis patients and healthy comparisons: one-year analysis. Schizophrenia Research 93, 9098.
Tost, H, Braus, DF, Hakimi, S, Ruf, M, Vollmert, C, Hohn, F, Meyer-Lindenberg, A (2010). Acute D2 receptor blockade induces rapid, reversible remodeling in human cortical-striatal circuits. Nature Neuroscience 13, 920922.
Veijola, J, Guo, JY, Moilanen, JS, Jaaskelainen, E, Miettunen, J, Kyllonen, M, Haapea, M, Huhtaniska, S, Alaraisanen, A, Maki, P, Kiviniemi, V, Nikkinen, J, Starck, T, Remes, JJ, Tanskanen, P, Tervonen, O, Wink, AM, Kehagia, A, Suckling, J, Kobayashi, H, Barnett, JH, Barnes, A, Koponen, HJ, Jones, PB, Isohanni, M, Murray, GK (2014). Longitudinal changes in total brain volume in schizophrenia: relation to symptom severity, cognition and antipsychotic medication. PLoS ONE 9, e101689.
Vita, A, De Peri, L, Deste, G, Barlati, S, Sacchetti, E (2015). 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. Biological Psychiatry 78, 403412.
Zatorre, RJ, Fields, RD, Johansen-Berg, H (2012). Plasticity in gray and white: neuroimaging changes in brain structure during learning. Nature Neuroscience 15, 528536.
Zipursky, RB, Reilly, TJ, Murray, RM (2013). The myth of schizophrenia as a progressive brain disease. Schizophrenia Bulletin 39, 13631372.



Altmetric attention score

Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed