Hostname: page-component-78c5997874-j824f Total loading time: 0 Render date: 2024-11-14T19:21:14.395Z Has data issue: false hasContentIssue false
  • English
  • Français

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

Published online by Cambridge University Press:  28 March 2017

R. Emsley ,
L. Asmal ,
S. du Plessis ,
B. Chiliza ,
L. Phahladira  and
S. Kilian
R. Emsley*
Affiliation:
Department of Psychiatry, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
L. Asmal
Affiliation:
Department of Psychiatry, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
S. du Plessis
Affiliation:
Department of Psychiatry, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
B. Chiliza
Affiliation:
Department of Psychiatry, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
L. Phahladira
Affiliation:
Department of Psychiatry, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
S. Kilian
Affiliation:
Department of Psychiatry, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
*
*Address for correspondence: R. Emsley, Department of Psychiatry, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg Campus, 8000, Cape Town, South Africa. (Email: [email protected])
Get access Rights & Permissions [Opens in a new window]

Abstract

Background

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

Methods

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).

Results

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.

Conclusions

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.

Keywords

Brain-volumecortex-volumeschizophreniaantipsychoticflupenthixoldose-response
Type
Original Articles
Information
Psychological Medicine , Volume 47 , Issue 12 , September 2017 , pp. 2187 - 2196
Copyright
Copyright © Cambridge University Press 2017 

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

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, 144–151.Google Scholar
American Psychiatric Association (1994). Diagnostic and Statistical Manual of Mental Disorders. DSM IV, 4th edn. American Psychaitric Association Washington: DC.Google Scholar
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, 441–449.CrossRefGoogle ScholarPubMed
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, 672–679.CrossRefGoogle ScholarPubMed
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, 198–219.Google Scholar
Chouinard, G, Margolese, HC (2005). Manual for the Extrapyramidal Symptom Rating Scale (ESRS). Schizophrenia Research 76(2-3), 247–65.Google Scholar
Coldham, EL, Addington, J, Addington, D (2002). Medication adherence of individuals with a first episode of psychosis. Acta Psychiatrica Scandinavica 106, 286–290.Google Scholar
Dale, AM, Fischl, B, Sereno, MI (1999). Cortical surface-based analysis. I. Segmentation and surface reconstruction. Neuroimage 9, 179–194.Google Scholar
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, 765–774.Google Scholar
de Wit, H (2010). Flupenthixol. In Encyclopedia of Psychopharmacology (ed. Stolerman, I. P.), pp. 538–539. Springer: Berlin.Google Scholar
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
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, 438–447.Google Scholar
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, 186–193.Google Scholar
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.Google Scholar
Fischl, B, Sereno, MI, Dale, AM (1999). Cortical surface-based analysis. II: inflation, flattening, and a surface-based coordinate system. Neuroimage 9, 195–207.Google Scholar
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, 1680–1691.Google Scholar
Gardner, DM, Murphy, AL, O'Donnell, H, Centorrino, F, Baldessarini, RJ (2010). International consensus study of antipsychotic dosing. American Journal of Psychiatry 167, 686–693.CrossRefGoogle ScholarPubMed
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, 279–285.Google Scholar
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, 1371–1376.Google Scholar
Goff, DC (2011). Antipsychotics and the shrinking brain. Psychaitric Times (http://www.psychiatrictimes.com/display/article/10168/1854683)Google Scholar
Graeber, MB, Li, W, Rodriguez, ML (2011). Role of microglia in CNS inflammation. FEBS Letters 585, 3798–3805.Google Scholar
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, 297–304.Google Scholar
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, 1129–1138.Google Scholar
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, 589–598.CrossRefGoogle ScholarPubMed
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, 1890–1899.Google Scholar
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, 128–137.Google Scholar
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.Google Scholar
International Conference on Harmonization (1996). ICH Harmonised Tripartite Guidelines for Good Clinical Practice. Brookwood Medical Publications Ltd: Surrey.Google Scholar
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, 939–946.Google Scholar
Kay, SR, Fizbein, A, Opler, LA (1987). The Positive and Negative Syndrome Scale (PANSS) for Schizophrenia. Schizophrenia Bulletin 13, 261–267.Google Scholar
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, 54–62.Google Scholar
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, 31–41.Google Scholar
Lewis, DA (2011). Antipsychotic medications and brain volume: do we have cause for concern? Archives of General Psychiatry 68, 126–127.Google Scholar
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.Google Scholar
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, 1177–1182.Google Scholar
Navari, S, Dazzan, P (2009). Do antipsychotic drugs affect brain structure? A systematic and critical review of MRI findings. Psychological Medicine 39, 1763–1777.Google Scholar
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, 88–96.Google Scholar
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.Google Scholar
Roiz-Santianez, R, Suarez-Pinilla, P, Crespo-Facorro, B (2015). Brain structural effects of antipsychotic treatment in schizophrenia: a systematic review. Current Neuropharmacol. 13, 422–434.CrossRefGoogle ScholarPubMed
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, 51–57.Google Scholar
Shen, X, Xia, J, Adams, CE (2012). Flupenthixol versus placebo for schizophrenia. Cochrane Database Systematic Revue 11, CD009777.Google Scholar
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, 2535–2549.CrossRefGoogle ScholarPubMed
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, 90–98.Google Scholar
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, 920–922.Google Scholar
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.Google Scholar
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, 403–412.CrossRefGoogle Scholar
Zatorre, RJ, Fields, RD, Johansen-Berg, H (2012). Plasticity in gray and white: neuroimaging changes in brain structure during learning. Nature Neuroscience 15, 528–536.Google Scholar
Zipursky, RB, Reilly, TJ, Murray, RM (2013). The myth of schizophrenia as a progressive brain disease. Schizophrenia Bulletin 39, 1363–1372.Google Scholar