Skip to main content Accessibility help

Prospective longitudinal voxel-based morphometry study of major depressive disorder in young individuals at high familial risk

  • T. Nickson (a1), S. W. Y. Chan (a2), M. Papmeyer (a1) (a3), L. Romaniuk (a1), A. Macdonald (a1), T. Stewart (a1), S. Kielty (a1), S. M. Lawrie (a1), J. Hall (a1) (a4), J. E. Sussmann (a1), A. M. McIntosh (a1) (a5) and H. C. Whalley (a1)...



Previous neuroimaging studies indicate abnormalities in cortico-limbic circuitry in mood disorder. Here we employ prospective longitudinal voxel-based morphometry to examine the trajectory of these abnormalities during early stages of illness development.


Unaffected individuals (16–25 years) at high and low familial risk of mood disorder underwent structural brain imaging on two occasions 2 years apart. Further clinical assessment was conducted 2 years after the second scan (time 3). Clinical outcome data at time 3 was used to categorize individuals: (i) healthy controls (‘low risk’, n = 48); (ii) high-risk individuals who remained well (HR well, n = 53); and (iii) high-risk individuals who developed a major depressive disorder (HR MDD, n = 30). Groups were compared using longitudinal voxel-based morphometry. We also examined whether progress to illness was associated with changes in other potential risk markers (personality traits, symptoms scores and baseline measures of childhood trauma), and whether any changes in brain structure could be indexed using these measures.


Significant decreases in right amygdala grey matter were found in HR MDD v. controls (p = 0.001) and v. HR well (p = 0.005). This structural change was not related to measures of childhood trauma, symptom severity or measures of sub-diagnostic anxiety, neuroticism or extraversion, although cross-sectionally these measures significantly differentiated the groups at baseline.


These longitudinal findings implicate structural amygdala changes in the neurobiology of mood disorder. They also provide a potential biomarker for risk stratification capturing additional information beyond clinically ascertained measures.


Corresponding author

*Address for correspondence: Heather Whalley, Ph.D., Division of Psychiatry, University of Edinburgh, Royal Edinburgh Hospital, Morningside Park, Edinburgh EH10 5HF, UK. (Email:


Hide All
Alemany, S, Mas, A, Goldberg, X, Falcon, C, Fatjo-Vilas, M, Arias, B, Bargalló, N, Nenadic, I, Gastó, C, Fañanás, L (2013). Regional gray matter reductions are associated with genetic liability for anxiety and depression: an MRI twin study. Journal of Affective Disorders 149, 175181.
Almeida, JR, Versace, A, Mechelli, A, Hassel, S, Quevedo, K, Kupfer, DJ, Phillips, ML (2009). Abnormal amygdala–prefrontal effective connectivity to happy faces differentiates bipolar from major depression. Biological Psychiatry 66, 451459.
Amico, F, Meisenzahl, E, Koutsouleris, N, Reiser, M, Moller, HJ, Frodl, T (2011). Structural MRI correlates for vulnerability and resilience to major depressive disorder. Journal of Psychiatry and Neuroscience 36, 1522.
Arnone, D, McIntosh, AM, Ebmeier, KP, Munafo, MR, Anderson, IM (2012). Magnetic resonance imaging studies in unipolar depression: systematic review and meta-regression analyses. European Neuropsychopharmacology 22, 116.
Baare, WF, Vinberg, M, Knudsen, GM, Paulson, OB, Langkilde, AR, Jernigan, TL, Kessing, LV (2010). Hippocampal volume changes in healthy subjects at risk of unipolar depression. Journal of Psychiatric Research 44, 655662.
Bechdolf, A, Wood, SJ, Nelson, B, Velakoulis, D, Yucel, M, Takahashi, T, Yung, AR, Berk, M, Wong, MT, Pantelis, C, McGorry, PD (2012). Amygdala and insula volumes prior to illness onset in bipolar disorder: a magnetic resonance imaging study. Psychiatry Research 201, 3439.
Bernstein, DP, Fink, L (1988). Childhood Trauma Questionnaire: a Retrospective Self-report. The Psychological Corporation: San Antonio, TX.
Bitter, SM, Mills, NP, Adler, CM, Strakowski, SM, DelBello, MP (2011). Progression of amygdala volumetric abnormalities in adolescents after their first manic episode. Journal of the American Academy of Child and Adolescent Psychiatry 50, 10171026.
Boccardi, M, Almici, M, Bresciani, L, Caroli, A, Bonetti, M, Monchieri, S, Gennarelli, M, Frisoni, GB (2010). Clinical and medial temporal features in a family with mood disorders. Neuroscience Letters 468, 9397.
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.
Chan, SW, Goodwin, GM, Harmer, CJ (2007). Highly neurotic never-depressed students have negative biases in information processing. Psychological Medicine 37, 12811291.
Chen, MC, Hamilton, JP, Gotlib, IH (2010). Decreased hippocampal volume in healthy girls at risk of depression. Archives of General Psychiatry 67, 270276.
Desikan, RS, Ségonne, F, Fischl, B, Quinn, BT, Dickerson, BC, Blacker, D, Buckner, RL, Dale, AM, Maguire, RP, Hyman, BT, Albert, MS, Killiany, RJ (2006). An automated labeling system for subdividing the human cerebral cortex on MRI scans into gyral based regions of interest. NeuroImage 31, 968980.
Douaud, G, Smith, S, Jenkinson, M, Behrens, T, Johansen-Berg, H, Vickers, J, James, S, Voets, N, Watkins, K, Matthews, PM, James, A (2007). Anatomically related grey and white matter abnormalities in adolescent-onset schizophrenia. Brain 130, 23752386.
Drevets, WC (2003). Neuroimaging abnormalities in the amygdala in mood disorders. Annals of the New York Academy of Sciences 985, 420444.
Drevets, WC, Price, JL, Furey, ML (2008). Brain structural and functional abnormalities in mood disorders: implications for neurocircuitry models of depression. Brain Structure and Function 213, 93118.
Duffy, A, Alda, M, Hajek, T, Grof, P (2009). Early course of bipolar disorder in high-risk offspring: prospective study. British Journal of Psychiatry 195, 457458.
Duffy, A, Horrocks, J, Doucette, S, Keown-Stoneman, C, McCloskey, S, Grof, P (2014). The developmental trajectory of bipolar disorder. British Journal of Psychiatry 204, 122128.
Eker, C, Simsek, F, Yilmazer, EE, Kitis, O, Cinar, C, Eker, OD, Coburn, K, Gonul, AS (2014). Brain regions associated with risk and resistance for bipolar I disorder: a voxel-based MRI study of patients with bipolar disorder and their healthy siblings. Bipolar Disorders 16, 249261.
First, MB, Spitzer, RL, Gibbon, M, Williams, JB (2002). Structured Clinical Interview for DSM-IV-TR Axis I Disorders, Research Version, Patient Edition with Psychotic Screen. Biometrics Research, New York State Psychiatric Institute: New York.
Frodl, T, Meisenzahl, E, Zetzsche, T, Bottlender, R, Born, C, Groll, C, Jäger, M, Leinsinger, G, Hahn, K, Möller, HJ (2002). Enlargement of the amygdala in patients with a first episode of major depression. Biological Psychiatry 51, 708714.
Frodl, T, Meisenzahl, EM, Zetzsche, T, Born, C, Jager, M, Groll, C, Bottlender, R, Leinsinger, G, Möller, HJ (2003). Larger amygdala volumes in first depressive episode as compared to recurrent major depression and healthy control subjects. Biological Psychiatry 53, 338344.
Frodl, T, Moller, HJ, Meisenzahl, E (2008). Neuroimaging genetics: new perspectives in research on major depression? Acta Psychiatrica Scandinavica 118, 363372.
Good, CD, Johnsrude, IS, Ashburner, J, Henson, RN, Friston, KJ, Frackowiak, RS (2001). A voxel-based morphometric study of ageing in 465 normal adult human brains. NeuroImage 14, 2136.
Hajek, T, Kopecek, M, Kozeny, J, Gunde, E, Alda, M, Höschl, C (2009). Amygdala volumes in mood disorders – meta-analysis of magnetic resonance volumetry studies. Journal of Affective Disorders 115, 395410.
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.
Hamilton, M (1960). A rating scale for depression. Journal of Neurology, Neurosurgery and Psychiatry 23, 5662.
Heim, C, Nemeroff, CB (2001). The role of childhood trauma in the neurobiology of mood and anxiety disorders: preclinical and clinical studies. Biological Psychiatry 49, 10231039.
Hillegers, MH, Reichart, CG, Wals, M, Verhulst, FC, Ormel, J, Nolen, WA (2005). Five-year prospective outcome of psychopathology in the adolescent offspring of bipolar parents. Bipolar Disorders 7, 344350.
Hovens, JG, Wiersma, JE, Giltay, EJ, van Oppen, P, Spinhoven, P, Penninx, BW, Zitman, FG (2010). Childhood life events and childhood trauma in adult patients with depressive, anxiety and comorbid disorders vs. controls. Acta Psychiatrica Scandinavica 122, 6674.
Karchemskiy, A, Garrett, A, Howe, M, Adleman, N, Simeonova, DI, Alegria, D, Reiss, A, Chang, K (2011). Amygdalar, hippocampal, and thalamic volumes in youth at high risk for development of bipolar disorder. Psychiatry Research 194, 319325.
Kay, SR, Fiszbein, A, Opler, LA (1987). The Positive and Negative Syndrome Scale (PANSS) for schizophrenia. Schizophrenia Bulletin 13, 261276.
Kelley, R, Chang, KD, Garrett, A, Alegría, D, Thompson, P, Howe, M, Reiss, AL (2013). Deformations of amygdala morphology in familial pediatric bipolar disorder. Bipolar Disorders 15, 795802.
Kendler, KS, Gatz, M, Gardner, CO, Pedersen, NL (2006). Personality and major depression: a Swedish longitudinal, population-based twin study. Archives of General Psychiatry 63, 11131120.
LeDoux, JE (2000). Emotion circuits in the brain. Annual Review of Neuroscience 23, 155184.
Levesque, ML, Beauregard, M, Ottenhof, KW, Fortier, E, Tremblay, RE, Brendgen, M, Pérusse, D, Dionne, G, Robaey, P, Vitaro, F, Boivin, M, Booij, L (2011). Altered patterns of brain activity during transient sadness in children at familial risk for major depression. Journal of Affective Disorders 135, 410413.
Liu, Y, Blackwood, DH, Caesar, S, de Geus, EJ, Farmer, A, Ferreira, MA, Ferrier, IN, Fraser, C, Gordon-Smith, K, Green, EK, Grozeva, D, Gurling, HM, Hamshere, ML, Heutink, P, Holmans, PA, Hoogendijk, WJ, Hottenga, JJ, Jones, L, Jones, IR, Kirov, G, Lin, D, McGuffin, P, Moskvina, V, Nolen, WA, Perlis, RH, Posthuma, D, Scolnick, EM, Smit, AB, Smit, JH, Smoller, JW, St Clair, D, van Dyck, R, Verhage, M, Willemsen, G, Young, AH, Zandbelt, T, Boomsma, DI, Craddock, N, O'Donovan, MC, Owen, MJ, Penninx, BW, Purcell, S, Sklar, P, Sullivan, PF; Wellcome Trust Case–Control Consortium (2011). Meta-analysis of genome-wide association data of bipolar disorder and major depressive disorder. Molecular Psychiatry 16, 24.
MacMillan, HL, Fleming, JE, Streiner, DL, Lin, E, Boyle, MH, Jamieson, E, Duku, EK, Walsh, CA, Wong, MY, Beardslee, WR (2001). Childhood abuse and lifetime psychopathology in a community sample. American Journal of Psychiatry 158, 18781883.
Mannie, ZN, Filippini, N, Williams, C, Near, J, Mackay, CE, Cowen, PJ (2014). Structural and functional imaging of the hippocampus in young people at familial risk of depression. Psychological Medicine 44, 29392948.
Matthews, SC, Strigo, IA, Simmons, AN, Yang, TT, Paulus, MP (2008). Decreased functional coupling of the amygdala and supragenual cingulate is related to increased depression in unmedicated individuals with current major depressive disorder. Journal of Affective Disorder 111, 1320.
McCrae, RR, John, OP (1992). An introduction to the five-factor model and its applications. Journal of Personality 60, 175215.
McGuffin, P, Farmer, A, Harvey, I (1991). A polydiagnostic application of operational criteria in studies of psychotic illness. Development and reliability of the OPCRIT system. Archives of General Psychiatry 48, 764770.
McGuffin, P, Rijsdijk, F, Andrew, M, Sham, P, Katz, R, Cardno, A (2003). The heritability of bipolar affective disorder and the genetic relationship to unipolar depression. Archives of General Psychiatry 60, 497502.
Miskowiak, KW, Glerup, L, Vestbo, C, Harmer, CJ, Reinecke, A, Macoveanu, J, Siebner, HR, Kessing, LV, Vinberg, M (2015). Different neural and cognitive response to emotional faces in healthy monozygotic twins at risk of depression. Psychological Medicine 45, 14471458.
Nelson, HE (1982). National Adult Reading Test (NART): Test Manual. NFER-Nelson, Windsor.
Papmeyer, M, Giles, S, Sussmann, JE, Kielty, S, Stewart, T, Lawrie, SM, Whalley, HC, McIntosh, AMM (2015). Cortical thickness in individuals at high familial risk of mood disorders as they develop major depressive disorder. Biological Psychiatry 78, 58–66.
Peyrot, WJ, Milaneschi, Y, Abdellaoui, A, Sullivan, PF, Hottenga, JJ, Boomsma, DI, Penninx, BW (2014). Effect of polygenic risk scores on depression in childhood trauma. British Journal of Psychiatry 205, 113119.
Phillips, ML, Drevets, WC, Rauch, SL, Lane, R (2003). Neurobiology of emotion perception II: implications for major psychiatric disorders. Biological Psychiatry 54, 515528.
Rao, U, Chen, LA, Bidesi, AS, Shad, MU, Thomas, MA, Hammen, CL (2010). Hippocampal changes associated with early-life adversity and vulnerability to depression. Biological Psychiatry 67, 357364.
Romanczuk-Seiferth, N, Pohland, L, Mohnke, S, Garbusow, M, Erk, S, Erk, S, Haddad, L, Grimm, O, Tost, H, Meyer-Lindenberg, A, Walter, H, Wüstenberg, T (2014). Larger amygdala volume in first-degree relatives of patients with major depression. NeuroImage Clinical 5, 6268.
Sacher, J, Neumann, J, Funfstuck, T, Soliman, A, Villringer, A, Schroeter, ML (2012). Mapping the depressed brain: a meta-analysis of structural and functional alterations in major depressive disorder. Journal of Affective Disorders 140, 142148.
Saleh, K, Carballedo, A, Lisiecka, D, Fagan, AJ, Connolly, G, Boyle, G, Frodl, T (2012). Impact of family history and depression on amygdala volume. Psychiatry Research 203, 2430.
Savitz, J, Drevets, WC (2009). Bipolar and major depressive disorder: neuroimaging the developmental–degenerative divide. Neuroscience and Biobehavioural Reviews 33, 699771.
Schulze, TG, Akula, N, Breuer, R, Steele, J, Nalls, MA, Singleton, AB, Degenhardt, FA, Nöthen, MM, Cichon, S, Rietschel, M; Bipolar Genome Study, McMahon, FJ (2014). Molecular genetic overlap in bipolar disorder, schizophrenia, and major depressive disorder. World Journal of Biological Psychiatry 15, 200208.
Shih, RA, Belmonte, PL, Zandi, PP (2004). A review of the evidence from family, twin and adoption studies for a genetic contribution to adult psychiatric disorders. International Reviews of Psychiatry 16, 260283.
Smith, SM, Jenkinson, M, Woolrich, MW, Beckmann, CF, Behrens, TE, Johansen-Berg, H, Bannister, PR, De Luca, M, Drobnjak, I, Flitney, DE, Niazy, RK, Saunders, J, Vickers, J, Zhang, Y, De Stefano, N, Brady, JM, Matthews, PM (2004). Advances in functional and structural MR image analysis and implementation as FSL. NeuroImage 23 (Suppl. 1), S208S219.
Smith, SM, Nichols, TE (2009). Threshold-free cluster enhancement: addressing problems of smoothing, threshold dependence and localisation in cluster inference. NeuroImage 44, 8398.
Sprooten, E, Sussmann, JE, Clugston, A, Peel, A, McKirdy, J, Moorhead, TW, Anderson, S, Shand, AJ, Giles, S, Bastin, ME, Hall, J, Johnstone, EC, Lawrie, SM, McIntosh, AM (2011). White matter integrity in individuals at high genetic risk of bipolar disorder. Biological Psychiatry 70, 350356.
Swartz, JR, Williamson, DE, Hariri, AR (2014). Developmental change in amygdala reactivity during adolescence: effects of family history of depression and stressful life events. American Journal of Psychiatry 172, 276283.
Whalley, HC, Papmeyer, M, Sprooten, E, Romaniuk, L, Blackwood, DH, Glahn, DC, Hall, J, Lawrie, SM, Sussmann, J, McIntosh, AM (2012). The influence of polygenic risk for bipolar disorder on neural activation assessed using fMRI. Translational Psychiatry 2, e130.
Whalley, HC, Sussmann, JE, Chakirova, G, Mukerjee, P, Peel, A, McKirdy, J, Hall, J, Johnstone, EC, Lawrie, SM, McIntosh, AM (2011). The neural basis of familial risk and temperamental variation in individuals at high risk of bipolar disorder. Biological Psychiatry 70, 343349.
Whalley, HC, Sussmann, JE, Romaniuk, L, Stewart, T, Kielty, S, Lawrie, SM, Hall, J, McIntosh, AM (2015). Dysfunction of emotional brain systems in individuals at high risk of mood disorder with depression and predictive features prior to illness. Psychological Medicine 45, 12071218.
Whalley, HC, Sussmann, JE, Romaniuk, L, Stewart, T, Papmeyer, M, Sprooten, E, Hackett, S, Hall, J, Lawrie, SM, McIntosh, AM (2013). Prediction of depression in individuals at high familial risk of mood disorders using functional magnetic resonance imaging. PLOS ONE 8, e57357.
Whittle, S, Lichter, R, Dennison, M, Vijayakumar, N, Schwartz, O, Byrne, ML, Simmons, JG, Yücel, M, Pantelis, C, McGorry, P, Allen, NB (2015). Structural brain development and depression onset during adolescence: a prospective longitudinal study. American Journal of Psychiatry 171, 564571.
Young, RC, Biggs, JT, Ziegler, VE, Meyer, DA (1978). A rating scale for mania: reliability, validity and sensitivity. British Journal of Psychiatry 133, 429435.



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