Skip to main content Accessibility help

No progression of the alterations in the cortical thickness of individuals with schizophrenia-spectrum disorder: a three-year longitudinal magnetic resonance imaging study of first-episode patients

  • R. Roiz-Santiáñez (a1) (a2), V. Ortiz-García de la Foz (a1) (a2), R. Ayesa-Arriola (a1) (a2), D. Tordesillas-Gutiérrez (a2) (a3), R. Jorge (a4), N. Varela-Gómez (a1) (a2), P. Suárez-Pinilla (a1) (a2), A. Córdova-Palomera (a2) (a5), J. M. Navasa-Melado (a6) and B. Crespo-Facorro (a1) (a2)...



Cortical thickness measurement offers an index of brain development processes. In healthy individuals, cortical thickness is reduced with increasing age and is related to cognitive decline. Cortical thinning has been reported in schizophrenia. Whether cortical thickness changes differently over time in patients and its impact on outcome remain unanswered.


Data were examined from 109 patients and 76 healthy controls drawn from the Santander Longitudinal Study of first-episode schizophrenia for whom adequate structural magnetic resonance imaging (MRI) data were available (n = 555 scans). Clinical and cognitive assessments and MRIs were acquired at three regular time points during a 3-year follow-up period. We investigated likely progressive cortical thickness changes in schizophrenia during the first 3 years after initiating antipsychotic treatment. The effects of cortical thickness changes on cognitive and clinical variables were also examined along with the impact of potential confounding factors.


There were significant diagnoses × scan time interaction main effects for total cortical thickness (F 1,309.1 = 4.60, p = 0.033) and frontal cortical thickness (F 1,310.6 = 5.30, p = 0.022), reflecting a lesser thinning over time in patients. Clinical and cognitive outcome was not associated with progressive cortical changes during the early years of the illness.


Cortical thickness abnormalities do not unswervingly progress, at least throughout the first years of the illness. Previous studies have suggested that modifiable factors may partly account for cortical thickness abnormalities. Therefore, the importance of implementing practical actions that may modify those factors and improve them over the course of the illness should be highlighted.


Corresponding author

* Address for correspondence: R. Roiz-Santiáñez, Ph.D., Unidad Investigación Psiquiatría, Hospital Universitario Marqués de Valdecilla, Avda. Valdecilla s/n, 39008, Santander, Spain. (Email:


Hide All
Agartz, I, Okuguwa, G, Nordstrom, M, Greitz, D, Magnotta, V, Sedvall, G (2001). Reliability and reproducibility of brain tissue volumetry from segmented MR scans. European Archives of Psychiatry and Clinical Neuroscience 251, 255261.
Alexander, GE, Chen, K, Aschenbrenner, M, Merkley, TL, Santerre-Lemmon, LE, Shamy, JL, Skaggs, WE, Buonocore, MH, Rapp, PR, Barnes, CA (2008). Age-related regional network of magnetic resonance imaging gray matter in the rhesus macaque. Journal of Neuroscience 28, 27102718.
Andreasen, NC (1983). The Scale for the Assessment of Negative Symptoms (SANS). University of Iowa: Iowa City.
Andreasen, NC (1984). The Scale for the Assessment of Positive Symptoms (SAPS). University of Iowa: Iowa City.
Andreasen, NC, Flaum, M, Arndt, S (1992). The Comprehensive Assessment of Symptoms and History (CASH). An instrument for assessing diagnosis and psychopathology. Archives of General Psychiatry 49, 615623.
Andreasen, NC, Liu, D, Ziebell, S, Vora, A, Ho, BC (2013). Relapse duration, treatment intensity, and brain tissue loss in schizophrenia: a prospective longitudinal MRI study. American Journal of Psychiatry 170, 609615.
Ayesa-Arriola, R, Perez-Iglesias, R, Rodriguez-Sanchez, JM, Pardo-Garcia, G, Tabares-Seisdedos, R, Ayuso-Mateos, JL, Vazquez-Barquero, JL, Crespo-Facorro, B (2013). Predictors of neurocognitive impairment at 3 years after a first episode non-affective psychosis. Progress in Neuro-Psychopharmacology and Biological Psychiatry 43C, 2328.
Blix, E, Perski, A, Berglund, H, Savic, I (2013). Long-term occupational stress is associated with regional reductions in brain tissue volumes. PLOS ONE 8, e64065.
Cobia, DJ, Csernansky, JG, Wang, L (2011). Cortical thickness in neuropsychologically near-normal schizophrenia. Schizophrenia Research 133, 6876.
Cobia, DJ, Smith, MJ, Wang, L, Csernansky, JG (2012). Longitudinal progression of frontal and temporal lobe changes in schizophrenia. Schizophrenia Research 139, 16.
Crespo-Facorro, B, Perez-Iglesias, R, Mata, I, Martinez-Garcia, O, Ortiz, V, Pelayo-Teran, JM, Valdizan, E, Vazquez-Barquero, JL (2012). Long-term (3-year) effectiveness of haloperidol, risperidone and olanzapine: results of a randomized, flexible-dose, open-label comparison in first-episode nonaffective psychosis. Psychopharmacology (Berlin) 219, 225233.
Crespo-Facorro, B, Roiz-Santianez, R, Perez-Iglesias, R, Rodriguez-Sanchez, JM, Mata, I, Tordesillas-Gutierrez, D, Sanchez, E, Tabares-Seisdedos, R, Andreasen, N, Magnotta, V, Vazquez-Barquero, JL (2011). Global and regional cortical thinning in first-episode psychosis patients: relationships with clinical and cognitive features. Psychological Medicine 41, 14491460.
Crespo-Facorro, B, Roiz-Santianez, R, Perez-Iglesias, R, Tordesillas-Gutierrez, D, Mata, I, Rodriguez-Sanchez, JM, de Lucas, EM, Vazquez-Barquero, JL (2009). Specific brain structural abnormalities in first-episode schizophrenia. A comparative study with patients with schizophreniform disorder, non-schizophrenic non-affective psychoses and healthy volunteers. Schizophrenia Research 115, 191201.
DeLisi, LE (2008). The concept of progressive brain change in schizophrenia: implications for understanding schizophrenia. Schizophrenia Bulletin 34, 312321.
Eggert, LD, Sommer, J, Jansen, A, Kircher, T, Konrad, C (2012). Accuracy and reliability of automated gray matter segmentation pathways on real and simulated structural magnetic resonance images of the human brain. PLOS ONE 7, e45081.
Ehrlich, S, Brauns, S, Yendiki, A, Ho, BC, Calhoun, V, Schulz, SC, Gollub, RL, Sponheim, SR (2012). Associations of cortical thickness and cognition in patients with schizophrenia and healthy controls. Schizophrenia Bulletin 38, 10501062.
Engvig, A, Fjell, AM, Westlye, LT, Moberget, T, Sundseth, O, Larsen, VA, Walhovd, KB (2010). Effects of memory training on cortical thickness in the elderly. NeuroImage 52, 16671676.
First, MB, Spitzer, RL, Gibbon, M, Williams, J (2001). Structured Clinical Interview for DSM-IV-TR Axis I Disorders – Non-Patient Edition. New York State Psychiatric Institute: New York.
Fjell, AM, Walhovd, KB (2010). Structural brain changes in aging: courses, causes and cognitive consequences. Reviews in the Neurosciences 21, 187221.
Goghari, VM, Smith, GN, Honer, WG, Kopala, LC, Thornton, AE, Su, W, Macewan, GW, Lang, DJ (2013). Effects of eight weeks of atypical antipsychotic treatment on middle frontal thickness in drug-naive first-episode psychosis patients. Schizophrenia Research 149, 149155.
Grube, BS, Bilder, RM, Goldman, RS (1998). Meta-analysis of symptom factors in schizophrenia. Schizophrenia Research 31, 113120.
Haier, RJ, Karama, S, Leyba, L, Jung, RE (2009). MRI assessment of cortical thickness and functional activity changes in adolescent girls following three months of practice on a visual–spatial task. BMC Research Notes 2, 174.
Harris, G, Andreasen, NC, Cizadlo, T, Bailey, JM, Bockholt, HJ, Magnotta, VA, Arndt, S (1999). Improving tissue classification in MRI: a three-dimensional multispectral discriminant analysis method with automated training class selection. Journal of Computer Assisted Tomography 23, 144154.
Ho, BC, Alicata, D, Ward, J, Moser, DJ, O'Leary, DS, Arndt, S, Andreasen, NC (2003). Untreated initial psychosis: relation to cognitive deficits and brain morphology in first-episode schizophrenia. American Journal of Psychiatry 160, 142148.
Horacek, J, Bubenikova-Valesova, V, Kopecek, M, Palenicek, T, Dockery, C, Mohr, P, Hoschl, C (2006). Mechanism of action of atypical antipsychotic drugs and the neurobiology of schizophrenia. CNS Drugs 20, 389409.
Janca, A, Kastrup, M, Katschnig, H, Lopez-Ibor, JJ Jr, Mezzich, JE, Sartorius, N (1996). The World Health Organization Short Disability Assessment Schedule (WHO DAS-S): a tool for the assessment of difficulties in selected areas of functioning of patients with mental disorders. Social Psychiatry and Psychiatric Epidemiology 31, 349354.
Keshavan, MS, Haas, GL, Kahn, CE, Aguilar, E, Dick, EL, Schooler, NR, Sweeney, JA, Pettegrew, JW (1998). Superior temporal gyrus and the course of early schizophrenia: progressive, static, or reversible? Journal of Psychiatric Research 32, 161167.
Kubota, M, Miyata, J, Yoshida, H, Hirao, K, Fujiwara, H, Kawada, R, Fujimoto, S, Tanaka, Y, Sasamoto, A, Sawamoto, N, Fukuyama, H, Murai, T (2011). Age-related cortical thinning in schizophrenia. Schizophrenia Research 125, 2129.
Kuperberg, GR, Broome, MR, McGuire, PK, David, AS, Eddy, M, Ozawa, F, Goff, D, West, WC, Williams, SC, van der Kouwe, AJ, Salat, DH, Dale, AM, Fischl, B (2003). Regionally localized thinning of the cerebral cortex in schizophrenia. Archives of General Psychiatry 60, 878888.
Lamont, AJ, Mortby, ME, Anstey, KJ, Sachdev, PS, Cherbuin, N (2014). Using sulcal and gyral measures of brain structure to investigate benefits of an active lifestyle. NeuroImage 91, 353359.
Magnotta, VA, Harris, G, Andreasen, NC, O'Leary, DS, Yuh, WT, Heckel, D (2002). Structural MR image processing using the BRAINS2 toolbox. Computerized Medical Imaging and Graphics 26, 251264.
Malla, AK, Bodnar, M, Joober, R, Lepage, M (2011). Duration of untreated psychosis is associated with orbital-frontal grey matter volume reductions in first episode psychosis. Schizophrenia Research 125, 1320.
Menezes, NM, Arenovich, T, Zipursky, RB (2006). A systematic review of longitudinal outcome studies of first-episode psychosis. Psychological Medicine 36, 13491362.
Mondelli, V, Pariante, CM, Navari, S, Aas, M, D'Albenzio, A, Di Forti, M, Handley, R, Hepgul, N, Marques, TR, Taylor, H, Papadopoulos, AS, Aitchison, KJ, Murray, RM, Dazzan, P (2010). Higher cortisol levels are associated with smaller left hippocampal volume in first-episode psychosis. Schizophrenia Research 119, 7578.
Mosconi, L, Murray, J, Tsui, WH, Li, Y, Davies, M, Williams, S, Pirraglia, E, Spector, N, Osorio, RS, Glodzik, L, McHugh, P, de Leon, MJ (2014). Mediterranean diet and magnetic resonance imaging-assessed brain atrophy in cognitively normal individuals at risk for Alzheimer's disease. Journal of Prevention of Alzheimer's Disease 1, 2332.
Mueser, KT, McGurk, SR (2004). Schizophrenia. Lancet 363, 20632072.
Narr, KL, Bilder, RM, Toga, AW, Woods, RP, Rex, DE, Szeszko, PR, Robinson, D, Sevy, S, Gunduz-Bruce, H, Wang, YP, DeLuca, H, Thompson, PM (2005). Mapping cortical thickness and gray matter concentration in first episode schizophrenia. Cerebral Cortex 15, 708719.
Nesvag, R, Bergmann, O, Rimol, LM, Lange, EH, Haukvik, UK, Hartberg, CB, Fagerberg, T, Soderman, E, Jonsson, EG, Agartz, I (2012). A 5-year follow-up study of brain cortical and subcortical abnormalities in a schizophrenia cohort. Schizophrenia Research 142, 209216.
Nesvag, R, Lawyer, G, Varnas, K, Fjell, AM, Walhovd, KB, Frigessi, A, Jonsson, EG, Agartz, I (2008). Regional thinning of the cerebral cortex in schizophrenia: effects of diagnosis, age and antipsychotic medication. Schizophrenia Research 98, 1628.
Okugawa, G, Takase, K, Nobuhara, K, Yoshida, T, Minami, T, Tamagaki, C, Magnotta, VA, Andreasen, NC, Kinoshita, T (2003). Inter- and intraoperator reliability of brain tissue measures using magnetic resonance imaging. European Archives of Psychiatry and Clinical Neuroscience 253, 301306.
Overall, JE, Gorman, DR (1962). The Brief Psychiatric Rating Scale. Psychological Reports 10, 799812.
Pelayo-Teran, JM, Perez-Iglesias, R, Ramirez-Bonilla, M, Gonzalez-Blanch, C, Martinez-Garcia, O, Pardo-Garcia, G, Rodriguez-Sanchez, JM, Roiz-Santianez, R, Tordesillas-Gutierrez, D, Mata, I, Vazquez-Barquero, JL, Crespo-Facorro, B (2008). Epidemiological factors associated with treated incidence of first-episode non-affective psychosis in Cantabria: insights from the Clinical Programme on Early Phases of Psychosis. Early Intervention Psychiatry 2, 178187.
Peters, A, Kemper, T (2012). A review of the structural alterations in the cerebral hemispheres of the aging rhesus monkey. Neurobiology of Aging 33, 23572372.
Rodríguez-Sánchez, JM, Ayesa-Arriola, R, Pérez-Iglesias, R, Periañez, JA, Martinez-Garcia, O, Gomez-Ruiz, E, Tabares-Seisdedos, R, Crespo-Facorro, B (2013). Course of cognitive deficits in first episode of non-affective psychosis: a 3-year follow-up study. Schizophrenia Research 150, 121128.
Roiz-Santianez, R, Ayesa-Arriola, R, Tordesillas-Gutierrez, D, Ortiz-Garcia de la Foz, V, Perez-Iglesias, R, Pazos, A, Sanchez, E, Crespo-Facorro, B (2014). Three-year longitudinal population-based volumetric MRI study in first-episode schizophrenia spectrum patients. Psychological Medicine 44, 15911604.
Roiz-Santianez, R, Tordesillas-Gutierrez, D, Ortiz-Garcia de la Foz, V, Ayesa-Arriola, R, Gutierrez, A, Tabares-Seisdedos, R, Vazquez-Barquero, JL, Crespo-Facorro, B (2012). Effect of antipsychotic drugs on cortical thickness. A randomized controlled one-year follow-up study of haloperidol, risperidone and olanzapine. Schizophrenia Research 141, 2228.
Savic, I (2013). Structural changes of the brain in relation to occupational stress. Cerebral Cortex. Published online 18 December 2013. doi:10.1093/cercor/bht348.
Schaufelberger, MS, Lappin, JM, Duran, FL, Rosa, PG, Uchida, RR, Santos, LC, Murray, RM, McGuire, PK, Scazufca, M, Menezes, PR, Busatto, GF (2011). Lack of progression of brain abnormalities in first-episode psychosis: a longitudinal magnetic resonance imaging study. Psychological Medicine 41, 16771689.
Schneider, CE, White, T, Hass, J, Geisler, D, Wallace, SR, Roessner, V, Holt, DJ, Calhoun, VD, Gollub, RL, Ehrlich, S (2014). Smoking status as a potential confounder in the study of brain structure in schizophrenia. Journal of Psychiatric Research 50, 8491.
Sizonenko, SV, Babiloni, C, Sijben, JW, Walhovd, KB (2013). Brain imaging and human nutrition: which measures to use in intervention studies? Advances in Nutrition 4, 554556.
Steen, RG, Mull, C, McClure, R, Hamer, RM, Lieberman, JA (2006). Brain volume in first-episode schizophrenia: systematic review and meta-analysis of magnetic resonance imaging studies. British Journal of Psychiatry 188, 510518.
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 Sciences 98, 1165011655.
Tuladhar, AM, Reid, AT, Shumskaya, E, de Laat, KF, van Norden, AG, van Dijk, EJ, Norris, DG, de Leeuw, FE (2015). Relationship between white matter hyperintensities, cortical thickness, and cognition. Stroke 46, 425432.
Van Haren, NE, Cahn, W, Hulshoff Pol, HE, Kahn, RS (2013). Confounders of excessive brain volume loss in schizophrenia. Neuroscience and Biobehavioral Reviews 37, 24182423.
Van Haren, NE, Schnack, HG, Cahn, W, van den Heuvel, MP, Lepage, C, Collins, L, Evans, AC, Hulshoff Pol, HE, Kahn, RS (2011). Changes in cortical thickness during the course of illness in schizophrenia. Archives of General Psychiatry 68, 871880.
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. Published online 16 February 2015. doi:10.1016/j.biopsych.2015.02.008.
Zipursky, RB, Reilly, TJ, Murray, RM (2013). The myth of schizophrenia as a progressive brain disease. Schizophrenia Bulletin 39, 13631372.
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

Roiz-Santiáñez supplementary material
Tables S1-S4

 Word (32 KB)
32 KB


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