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Brain grey matter abnormalities in medication-free patients with major depressive disorder: a meta-analysis

  • Y.-J. Zhao (a1), M.-Y. Du (a1), X.-Q. Huang (a1), S. Lui (a1), Z.-Q. Chen (a1), J. Liu (a1), Y. Luo (a1), X.-L. Wang (a1), G. J. Kemp (a2) and Q.-Y. Gong (a1)...



Because cerebral morphological abnormalities in major depressive disorder (MDD) may be modulated by antidepressant treatment, inclusion of medicated patients may have biased previous meta-analyses of voxel-based morphometry (VBM) studies. A meta-analysis of VBM studies on medication-free MDD patients should be able to distinguish the morphological features of the disease itself from those of treatment.


A systematic search was conducted for the relevant studies. Effect-size signed differential mapping was applied to analyse the grey matter differences between all medication-free MDD patients and healthy controls. Meta-regression was used to explore the effects of demographics and clinical characteristics.


A total of 14 datasets comprising 400 medication-free MDD patients and 424 healthy controls met the inclusion criteria. The pooled meta-analysis and subgroup meta-analyses showed robustly reduced grey matter in prefrontal and limbic regions in MDD. Increased right thalamus volume was only seen in first-episode medication-naive patients, and increased grey matter in the bilateral anterior cingulate cortex only in medication wash-out patients. In meta-regression analyses the percentage of female patients in each study was negatively correlated with reduced grey matter in the right hippocampus.


By excluding interference from medication effects, the present study identified grey matter reduction in the prefrontal–limbic network in MDD. The subgroup meta-analysis results suggest that an increased right thalamus volume might be a trait directly related to MDD, while an increased anterior cingulate cortex volume might be an effect of medication. The meta-regression results perhaps reveal the structural underpinning of the sex differences in epidemiological and clinical aspects of MDD.

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The online version of this article is published within an Open Access environment subject to the conditions of the Creative Commons Attribution licence .

Corresponding author

* Address for correspondence: Q.-Y. Gong, M.D., Huaxi MR Research Center (HMRRC), Department of Radiology, West China Hospital of Sichuan University, No. 37 Guo Xue Xiang Chengdu, 610041, People's Republic of China. (Email:


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Arnone, D, McKie, S, Elliott, R, Juhasz, G, Thomas, EJ, Downey, D, Williams, S, Deakin, JF, Anderson, IM (2012). State-dependent changes in hippocampal grey matter in depression. Molecular Psychiatry 6, 12651272.
Ashburner, J, Friston, KJ (2001). Why voxel-based morphometry should be used. NeuroImage 14, 12381243.
Banasr, M, Soumier, A, Hery, M, Mocaer, E, Daszuta, A (2006). Agomelatine, a new antidepressant, induces regional changes in hippocampal neurogenesis. Biological Psychiatry 59, 10871096.
Blease, C (2011). Deception as treatment: the case of depression. Journal of Medical Ethics 37, 1316.
Bora, E, Fornito, A, Pantelis, C, Yucel, M (2012). Gray matter abnormalities in major depressive disorder: a meta-analysis of voxel based morphometry studies. Journal of Affective Disorders 138, 918.
Bora, E, Fornito, A, Radua, J, Walterfang, M, Seal, M, Wood, SJ, Yucel, M, Velakoulis, D, Pantelis, C (2011). Neuroanatomical abnormalities in schizophrenia: a multimodal voxelwise meta-analysis and meta-regression analysis. Schizophrenia Research 127, 4657.
Brambilla, P, Nicoletti, MA, Harenski, K, Sassi, RB, Mallinger, AG, Frank, E, Kupfer, DJ, Keshavan, MS, Soares, JC (2002). Anatomical MRI study of subgenual prefrontal cortex in bipolar and unipolar subjects. Neuropsychopharmacology 27, 792799.
Chang, K, Karchemskiy, A, Barnea-Goraly, N, Garrett, A, Simeonova, DI, Reiss, A (2005). Reduced amygdalar gray matter volume in familial pediatric bipolar disorder. Journal of the American Academy of Child and Adolescent Psychiatry 44, 565573.
Cheng, YQ, Xu, J, Chai, P, Li, HJ, Luo, CR, Yang, T, Li, L, Shan, BC, Xu, XF, Xu, L (2010). Brain volume alteration and the correlations with the clinical characteristics in drug-naïve first-episode MDD patients: a voxel-based morphometry study. Neuroscience Letters 480, 3034.
Cotter, D, Mackay, D, Chana, G, Beasley, C, Landau, S, Everall, IP (2002). Reduced neuronal size and glial cell density in area 9 of the dorsolateral prefrontal cortex in subjects with major depressive disorder. Cerebral Cortex 12, 386394.
Czeh, B, Michaelis, T, Watanabe, T, Frahm, J, de Biurrun, G, van Kampen, M, Bartolomucci, A, Fuchs, E (2001). Stress-induced changes in cerebral metabolites, hippocampal volume, and cell proliferation are prevented by antidepressant treatment with tianeptine. Proceedings of the National Academy of Sciences USA 98, 1279612801.
Davies, RR, Scahill, V, Graham, A, Williams, G, Graham, K, Hodges, J (2009). Development of an MRI rating scale for multiple brain regions: comparison with volumetrics and with voxel-based morphometry. Neuroradiology 51, 491503.
Du, MY, Wu, QZ, Yue, Q, Li, J, Liao, Y, Kuang, WH, Huang, XQ, Chan, RC, Mechelli, A, Gong, QY (2012). Voxelwise meta-analysis of gray matter reduction in major depressive disorder. Progress in Neuro-Psychopharmacology and Biological Psychiatry 36, 1116.
Duman, RS, Monteggia, LM (2006). A neurotrophic model for stress-related mood disorders. Biological Psychiatry 59, 11161127.
Fang, J, Jin, Z, Wang, Y, Li, K, Kong, J, Nixon, EE, Zeng, Y, Ren, Y, Tong, H, Wang, P, Hui, KK (2009). The salient characteristics of the central effects of acupuncture needling: limbic–paralimbic–neocortical network modulation. Human Brain Mapping 30, 11961206.
Fossati, P (2012). Neural correlates of emotion processing: from emotional to social brain. European Neuropsychopharmacology 22, S487-S491.
Frodl, T, Meisenzahl, EM, Zetzsche, T, Born, C, Groll, C, Jager, M, Leinsinger, G, Bottlender, R, Hahn, K, Moller, HJ (2002). Hippocampal changes in patients with a first episode of major depression. American Journal of Psychiatry 159, 11121118.
Frodl, TS, Koutsouleris, N, Bottlender, R, Born, C, Jager, M, Scupin, I, Reiser, M, Moller, HJ, Meisenzahl, EM (2008). Depression-related variation in brain morphology over 3 years: effects of stress? Archives of General Psychiatry 65, 11561165.
Hamilton, JP, Siemer, M, Gotlib, IH (2008). Amygdala volume in major depressive disorder: a meta-analysis of magnetic resonance imaging studies. Molecular Psychiatry 13, 9931000.
Hasler, G (2010). Pathophysiology of depression: do we have any solid evidence of interest to clinicians? World Psychiatry 9, 155161.
Jia, Z, Huang, X, Wu, Q, Zhang, T, Lui, S, Zhang, J, Amatya, N, Kuang, W, Chan, RC, Kemp, GJ, Mechelli, A, Gong, Q (2010). High-field magnetic resonance imaging of suicidality in patients with major depressive disorder. American Journal of Psychiatry 167, 13811390.
Kempton, MJ, Salvador, Z, Munafo, MR, Geddes, JR, Simmons, A, Frangou, S, Williams, SC (2011). Structural neuroimaging studies in major depressive disorder. Meta-analysis and comparison with bipolar disorder. Archives of General Psychiatry 68, 675690.
Kessler, RC, Chiu, WT, Demler, O, Merikangas, KR, Walters, EE (2005). Prevalence, severity, and comorbidity of 12-month DSM-IV disorders in the National Comorbidity Survey Replication. Archives of General Psychiatry 62, 617627.
Koenigs, M, Grafman, J (2009). The functional neuroanatomy of depression: distinct roles for ventromedial and dorsolateral prefrontal cortex. Behavioural Brain Research 201, 239243.
Kronmuller, KT, Schroder, J, Kohler, S, Gotz, B, Victor, D, Unger, J, Giesel, F, Magnotta, V, Mundt, C, Essig, M, Pantel, J (2009). Hippocampal volume in first episode and recurrent depression. Psychiatry Research 174, 6266.
Lai, CH (2013). Gray matter volume in major depressive disorder: a meta-analysis of voxel-based morphometry studies. Psychiatry Research 211, 3746.
Lai, CH, Hsu, YY, Wu, YT (2010). First episode drug-naïve major depressive disorder with panic disorder: gray matter deficits in limbic and default network structures. European Neuropsychopharmacology 20, 676682.
Lavretsky, H, Roybal, DJ, Ballmaier, M, Toga, AW, Kumar, A (2005). Antidepressant exposure may protect against decrement in frontal gray matter volumes in geriatric depression. Journal of Clinical Psychiatry 66, 964967.
Levesque, J, Eugene, F, Joanette, Y, Paquette, V, Mensour, B, Beaudoin, G, Leroux, JM, Bourgouin, P, Beauregard, M (2003). Neural circuitry underlying voluntary suppression of sadness. Biological Psychiatry 53, 502510.
Ma, C, Ding, J, Li, J, Guo, W, Long, Z, Liu, F, Gao, Q, Zeng, L, Zhao, J, Chen, H (2012). Resting-state functional connectivity bias of middle temporal gyrus and caudate with altered gray matter volume in major depression. PLOS ONE 7, 24.
MacMaster, FP, Mirza, Y, Szeszko, PR, Kmiecik, LE, Easter, PC, Taormina, SP, Lynch, M, Rose, M, Moore, GJ, Rosenberg, DR (2008). Amygdala and hippocampal volumes in familial early onset major depressive disorder. Biological Psychiatry 63, 385390.
MacQueen, GM, Campbell, S, McEwen, BS, Macdonald, K, Amano, S, Joffe, RT, Nahmias, C, Young, LT (2003). Course of illness, hippocampal function, and hippocampal volume in major depression. Proceedings of the National Academy of Sciences USA 100, 13871392.
Marcus, SM, Young, EA, Kerber, KB, Kornstein, S, Farabaugh, AH, Mitchell, J, Wisniewski, SR, Balasubramani, GK, Trivedi, MH, Rush, AJ (2005). Gender differences in depression: findings from the STAR*D study. Journal of Affective Disorders 87, 141150.
Mathers, C, Fat, DM, Boerma, J (2008). The Global Burden of Disease: 2004 Update. World Health Organization: Geneva.
Matsuo, K, Glahn, DC, Peluso, MA, Hatch, JP, Monkul, ES, Najt, P, Sanches, M, Zamarripa, F, Li, J, Lancaster, JL, Fox, PT, Gao, JH, Soares, JC (2007). Prefrontal hyperactivation during working memory task in untreated individuals with major depressive disorder. Molecular Psychiatry 12, 158166.
Nakao, T, Radua, J, Rubia, K, Mataix-Cols, D (2011). Gray matter volume abnormalities in ADHD: voxel-based meta-analysis exploring the effects of age and stimulant medication. American Journal of Psychiatry 168, 11541163.
Neumeister, A, Wood, S, Bonne, O, Nugent, AC, Luckenbaugh, DA, Young, T, Bain, EE, Charney, DS, Drevets, WC (2005). Reduced hippocampal volume in unmedicated, remitted patients with major depression versus control subjects. Biological Psychiatry 57, 935937.
Ochsner, KN, Ray, RD, Cooper, JC, Robertson, ER, Chopra, S, Gabrieli, JD, Gross, JJ (2004). For better or for worse: neural systems supporting the cognitive down- and up-regulation of negative emotion. NeuroImage 23, 483499.
Palaniyappan, L, Balain, V, Radua, J, Liddle, PF (2012). Structural correlates of auditory hallucinations in schizophrenia: a meta-analysis. Schizophrenia Research 137, 169173.
Phan, KL, Fitzgerald, DA, Nathan, PJ, Moore, GJ, Uhde, TW, Tancer, ME (2005). Neural substrates for voluntary suppression of negative affect: a functional magnetic resonance imaging study. Biological Psychiatry 57, 210219.
Post, RM, Weiss, SR, Smith, M, Rosen, J, Frye, M (1995). Stress, conditioning, and the temporal aspects of affective disorders. Annals of the New York Academy of Sciences 771, 677696.
Price, JL, Drevets, WC (2010). Neurocircuitry of mood disorders. Neuropsychopharmacology 35, 192216.
Radua, J, Borgwardt, S, Crescini, A, Mataix-Cols, D, Meyer-Lindenberg, A, McGuire, PK, Fusar-Poli, P (2012 a). Multimodal meta-analysis of structural and functional brain changes in first episode psychosis and the effects of antipsychotic medication. Neuroscience and Biobehavioral Reviews 36, 23252333.
Radua, J, Mataix-Cols, D (2009). Voxel-wise meta-analysis of grey matter changes in obsessive–compulsive disorder. British Journal of Psychiatry 195, 393402.
Radua, J, Mataix-Cols, D, Phillips, ML, El-Hage, W, Kronhaus, DM, Cardoner, N, Surguladze, S (2012 b). A new meta-analytic method for neuroimaging studies that combines reported peak coordinates and statistical parametric maps. European Psychiatry 27, 605611.
Radua, J, Via, E, Catani, M, Mataix-Cols, D (2011). Voxel-based meta-analysis of regional white-matter volume differences in autism spectrum disorder versus healthy controls. Psychological Medicine 41, 15391550.
Rajkowska, G (2000). Postmortem studies in mood disorders indicate altered numbers of neurons and glial cells. Biological Psychiatry 48, 766777.
Rajkowska, G, Miguel-Hidalgo, JJ, Wei, J, Dilley, G, Pittman, SD, Meltzer, HY, Overholser, JC, Roth, BL, Stockmeier, CA (1999). Morphometric evidence for neuronal and glial prefrontal cell pathology in major depression. Biological Psychiatry 45, 10851098.
Rizvi, SJ, Kennedy, SH (2012). Emerging drugs for major depressive disorder: an update. Expert Opinion on Emerging Drugs 17, 285295.
Roeloffs, CA, Fink, A, Unutzer, J, Tang, L, Wells, KB (2001). Problematic substance use, depressive symptoms, and gender in primary care. Psychiatric Services 52, 12511253.
Salvadore, G, Nugent, AC, Lemaitre, H, Luckenbaugh, DA, Tinsley, R, Cannon, DM, Neumeister, A, Zarate, CA Jr, Drevets, WC (2011). Prefrontal cortical abnormalities in currently depressed versus currently remitted patients with major depressive disorder. NeuroImage 54, 26432651.
Savitz, J, Nugent, AC, Bogers, W, Liu, A, Sills, R, Luckenbaugh, DA, Bain, EE, Price, JL, Zarate, C, Manji, HK, Cannon, DM, Marrett, S, Charney, DS, Drevets, WC (2010). Amygdala volume in depressed patients with bipolar disorder assessed using high resolution 3 T MRI: the impact of medication. NeuroImage 49, 29662976.
Scheuerecker, J, Meisenzahl, EM, Koutsouleris, N, Roesner, M, Schopf, V, Linn, J, Wiesmann, M, Bruckmann, H, Moller, HJ, Frodl, T (2010). Orbitofrontal volume reductions during emotion recognition in patients with major depression. Journal of Psychiatry and Neuroscience 35, 311320.
Smith, R, Chen, K, Baxter, L, Fort, C, Lane, RD (2013). Antidepressant effects of sertraline associated with volume increases in dorsolateral prefrontal cortex. Journal of Affective Disorders 146, 414419.
Steffens, DC, Byrum, CE, McQuoid, DR, Greenberg, DL, Payne, ME, Blitchington, TF, MacFall, JR, Krishnan, KR (2000). Hippocampal volume in geriatric depression. Biological Psychiatry 48, 301309.
Tang, Y, Wang, F, Xie, G, Liu, J, Li, L, Su, L, Liu, Y, Hu, X, He, Z, Blumberg, HP (2007). Reduced ventral anterior cingulate and amygdala volumes in medication-naïve females with major depressive disorder: a voxel-based morphometric magnetic resonance imaging study. Psychiatry Research 156, 8386.
Vakili, K, Pillay, SS, Lafer, B, Fava, M, Renshaw, PF, Bonello-Cintron, CM, Yurgelun-Todd, DA (2000). Hippocampal volume in primary unipolar major depression: a magnetic resonance imaging study. Biological Psychiatry 47, 10871090.
Wagner, G, Koch, K, Schachtzabel, C, Reichenbach, JR, Sauer, H, Schlösser, RG (2008). Enhanced rostral anterior cingulate cortex activation during cognitive control is related to orbitofrontal volume reduction in unipolar depression. Journal of Psychiatry and Neuroscience 33, 199208.
Walter, H, Wolf, RC, Spitzer, M, Vasic, N (2007). Increased left prefrontal activation in patients with unipolar depression: an event-related, parametric, performance-controlled fMRI study. Journal of Affective Disorders 101, 175185.
Zhang, X, Yao, S, Zhu, X, Wang, X, Zhong, M (2012). Gray matter volume abnormalities in individuals with cognitive vulnerability to depression: a voxel-based morphometry study. Journal of Affective Disorders 136, 443452.
Zou, K, Deng, W, Li, T, Zhang, B, Jiang, L, Huang, C, Sun, X (2010). Changes of brain morphometry in first-episode, drug-naive, non-late-life adult patients with major depression: an optimized voxel-based morphometry study. Biological Psychiatry 67, 186188.


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Brain grey matter abnormalities in medication-free patients with major depressive disorder: a meta-analysis

  • Y.-J. Zhao (a1), M.-Y. Du (a1), X.-Q. Huang (a1), S. Lui (a1), Z.-Q. Chen (a1), J. Liu (a1), Y. Luo (a1), X.-L. Wang (a1), G. J. Kemp (a2) and Q.-Y. Gong (a1)...


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