0
Get Alert
Please Wait... Processing your request... Please Wait.
You must sign in to sign-up for alerts.

Please confirm that your email address is correct, so you can successfully receive this alert.

Articles   |    
Structural Brain Development and Depression Onset During Adolescence: A Prospective Longitudinal Study
Sarah Whittle, Ph.D.; Renee Lichter, Ph.D.; Meg Dennison, Ph.D.; Nandita Vijayakumar, B.Sc.; Orli Schwartz, Ph.D.; Michelle L. Byrne, Ph.D.; Julian G. Simmons, Ph.D.; Murat Yücel, Ph.D.; Christos Pantelis, M.D., M.R.C.Psych.; Patrick McGorry, M.D., Ph.D.; Nicholas B. Allen, Ph.D.
Am J Psychiatry 2014;171:564-571. doi:10.1176/appi.ajp.2013.13070920
View Author and Article Information

Prof. McGorry has received research grant funding from Janssen-Cilag and AstraZeneca and honoraria from Janssen, Lundbeck, Roche, and Servier. The other authors report no financial relationships with commercial interests.

Supported by grants from the Colonial Foundation, the National Health and Medical Research Council (NHMRC; program grant 350241), and the Australian Research Council (discovery grant DP0878136). Dr. Whittle is supported by an NHMRC Career Development Fellowship (ID: 1007716). Dr. Dennison was supported by an Australian Postgraduate Award. Dr. Lichter was supported by a Fay Marles Scholarship. Prof. Yücel is supported by an NHMRC Fellowship (ID: 1021973). Prof. Pantelis is supported by a NHMRC Senior Principal Research Fellowship (ID: 628386). Ms. Vijayakumar is supported by a Melbourne International Research Scholarship.

From the Melbourne Neuropsychiatry Centre (Department of Psychiatry), Orygen Youth Health Research Centre (Centre for Youth Mental Health), and the Melbourne School of Psychological Sciences, University of Melbourne, Parkville, Australia; and the Monash Clinical and Imaging Neuroscience Laboratory, School of Psychology and Psychiatry, Monash University, Clayton, Australia.

Presented at the sixth biennial conference of the International Society for Affective Disorders, London, April 18–20, 2012.

Address correspondence to Prof. Allen (nba@unimelb.edu.au).

Copyright © 2014 by the American Psychiatric Association

Received July 14, 2013; Revised November 17, 2013; Revised December 21, 2013; Accepted December 30, 2013.

Abstract

Objective  The authors sought to investigate whether the structural development of limbic, striatal, and prefrontal regions that are critically implicated in the pathophysiology of depression is associated with adolescent-onset depression.

Method  In a longitudinal design, a risk-enriched community sample of 86 adolescents (41 of them female) who had no history of depressive disorders participated in neuroimaging assessments conducted during early (age 12) and mid-adolescence (age 16). Onset of depressive disorders was assessed for the period spanning early to late adolescence (ages 12 to 18). Thirty participants experienced a first episode of a depressive disorder during the follow-up period. The authors assessed whether onset of depressive disorder was associated with structural change in limbic, striatal, and prefrontal cortical regions from early to mid-adolescence.

Results  Volumetric change in the hippocampus, amygdala, and putamen from early to mid-adolescence was associated with the onset of depression during adolescence. Attenuated growth of the hippocampus and attenuated reduction in putamen volume over time were associated with the onset of depression. Sex moderated the association between amygdala growth and depression such that exaggerated growth and attenuated growth of the amygdala were associated with depression in females and males, respectively. Across time, smaller nucleus accumbens volume was associated with depression in females only.

Conclusions  These findings suggest that alterations in the developmental trajectories of limbic and striatal regions during adolescence may represent a neurobiological manifestation of a risk factor for the development of depression during this critical period and thus may provide clues as to etiological mechanisms of this disorder.

Abstract Teaser
Figures in this Article

Your Session has timed out. Please sign back in to continue.
Sign In Your Session has timed out. Please sign back in to continue.
Sign In to Access Full Content
 
Username
Password
Sign in via Athens (What is this?)
Athens is a service for single sign-on which enables access to all of an institution's subscriptions on- or off-site.
Not a subscriber?

Subscribe Now/Learn More

PsychiatryOnline subscription options offer access to the DSM-5 library, books, journals, CME, and patient resources. This all-in-one virtual library provides psychiatrists and mental health professionals with key resources for diagnosis, treatment, research, and professional development.

Need more help? PsychiatryOnline Customer Service may be reached by emailing PsychiatryOnline@psych.org or by calling 800-368-5777 (in the U.S.) or 703-907-7322 (outside the U.S.).

FIGURE 1. Group-by-Time Interaction of Selected Brain Volumes in Participants in a Longitudinal Study of Brain Development and Depression Onset During Adolescencea

a Values on the y-axis represent estimated volumes (corrected for whole brain volume and averaged across left and right hemispheres) accounting for covariates (baseline depressive and anxiety symptoms, socioeconomic status, time between imaging assessments, Tanner stage). Error bars indicate standard deviation.

Anchor for Jump
TABLE 1.Participation Across the Four Waves in a Longitudinal Study of Structural Brain Development and Depression Onset During Adolescence
Table Footer Note

a All participants who completed MRI assessments also completed the interview assessments.

Table Footer Note

b Only 117 of these participants also completed an MRI scan at wave 1 and were thus eligible for inclusion in this study. Fifteen MRI scans from the 117 longitudinal pairs of scans were discarded because of poor quality.

Table Footer Note

c Eighty-six of these participants completed MRI scans at waves 1 and 3 (and had usable MRI data).

Anchor for Jump
TABLE 2.Diagnostic and Treatment Data for Participants in a Longitudinal Study of Structural Brain Development and Depression Onset During Adolescence
Table Footer Note

a This disorder was included because it has been suggested to be a closely related, although moderate, form of major depressive disorder (44). Note that excluding these cases from the analyses weakened some results (significant results for the amygdala and putamen dropped to trend level, with p values <0.1).

Table Footer Note

b Not necessarily concurrent with depressive episodes.

Table Footer Note

c Behavioral or substance use disorder.

Table Footer Note

d Note that there were no effects of treatment (treated=11, untreated=19) on any region volume or thickness measure.

Anchor for Jump
TABLE 3.Demographic and Clinical Characteristics of Participants in a Longitudinal Study of Structural Brain Development and Depression Onset During Adolescence
Table Footer Note

a Socioeconomic status was estimated using the Australian National University Four (ANU4) Scale, which ranges from 0 to 100, with higher values indicating higher socioeconomic status. Depressive symptoms were measured using the Center for Epidemiological Studies Depression Scale. Anxiety symptoms were measured using the Beck Anxiety Inventory. Externalizing symptoms were measured using the Child Behavior Checklist (parent report). Tanner stage was assessed with the Pubertal Development Scale.

Table Footer Note

b Significant difference between depression and comparison groups.

Table Footer Note

c Significant difference among males between depression and comparison groups.

Table Footer Note

d Significant difference among females between depression and comparison groups.

Anchor for Jump
TABLE 4.Significant Main or Interaction Effects of Group, Time, Sex, and Hemisphere on Estimates of Volume or Thickness of Regions of Interesta
Table Footer Note

a Only significant main and interaction effects are reported. Depressive and anxiety symptoms at wave 1, socioeconomic status, time between imaging assessments, and Tanner stage were used as covariates in all analyses.

+

References

Hankin  BL;  Abramson  LY;  Moffitt  TE;  Silva  PA;  McGee  R;  Angell  KE:  Development of depression from preadolescence to young adulthood: emerging gender differences in a 10-year longitudinal study.  J Abnorm Psychol 1998; 107:128–140
[CrossRef] | [PubMed]
 
Harrington  R;  Vostanis  P:  Longitudinal perspectives and affective disorder in children and adolescents, in  The Depressed Child and Adolescent: Developmental and Clinical Perspectives . Edited by Goodyer  IM.  New York,  Cambridge University Press, 1995, pp 311–342
 
Bora  E;  Harrison  BJ;  Davey  CG;  Yücel  M;  Pantelis  C:  Meta-analysis of volumetric abnormalities in cortico-striatal-pallidal-thalamic circuits in major depressive disorder.  Psychol Med 2012; 42:671–681
[CrossRef] | [PubMed]
 
Kempton  MJ;  Salvador  Z;  Munafò  MR;  Geddes  JR;  Simmons  A;  Frangou  S;  Williams  SC:  Structural neuroimaging studies in major depressive disorder: meta-analysis and comparison with bipolar disorder.  Arch Gen Psychiatry 2011; 68:675–690
[CrossRef] | [PubMed]
 
Bora  E;  Fornito  A;  Pantelis  C;  Yücel  M:  Gray matter abnormalities in major depressive disorder: a meta-analysis of voxel based morphometry studies.  J Affect Disord 2012; 138:9–18
[CrossRef] | [PubMed]
 
Hulvershorn  LA;  Cullen  K;  Anand  A:  Toward dysfunctional connectivity: a review of neuroimaging findings in pediatric major depressive disorder.  Brain Imaging Behav 2011; 5:307–328
[CrossRef] | [PubMed]
 
Munn  MA;  Alexopoulos  J;  Nishino  T;  Babb  CM;  Flake  LA;  Singer  T;  Ratnanather  JT;  Huang  H;  Todd  RD;  Miller  MI;  Botteron  KN:  Amygdala volume analysis in female twins with major depression.  Biol Psychiatry 2007; 62:415–422
[CrossRef] | [PubMed]
 
Shad  MU;  Muddasani  S;  Rao  U:  Gray matter differences between healthy and depressed adolescents: a voxel-based morphometry study.  J Child Adolesc Psychopharmacol 2012; 22:190–197
[CrossRef] | [PubMed]
 
Matsuo  K;  Rosenberg  DR;  Easter  PC;  MacMaster  FP;  Chen  HH;  Nicoletti  M;  Caetano  SC;  Hatch  JP;  Soares  JC:  Striatal volume abnormalities in treatment-naïve patients diagnosed with pediatric major depressive disorder.  J Child Adolesc Psychopharmacol 2008; 18:121–131
[CrossRef] | [PubMed]
 
Peterson  BS;  Warner  V;  Bansal  R;  Zhu  H;  Hao  X;  Liu  J;  Durkin  K;  Adams  PB;  Wickramaratne  P;  Weissman  MM:  Cortical thinning in persons at increased familial risk for major depression.  Proc Natl Acad Sci USA 2009; 106:6273–6278
[CrossRef] | [PubMed]
 
Ostby  Y;  Tamnes  CK;  Fjell  AM;  Westlye  LT;  Due-Tønnessen  P;  Walhovd  KB:  Heterogeneity in subcortical brain development: a structural magnetic resonance imaging study of brain maturation from 8 to 30 years.  J Neurosci 2009; 29:11772–11782
[CrossRef] | [PubMed]
 
Andersen  SL;  Teicher  MH:  Stress, sensitive periods, and maturational events in adolescent depression.  Trends Neurosci 2008; 31:183–191
[CrossRef] | [PubMed]
 
Ducharme  S;  Albaugh  MD;  Hudziak  JJ;  Botteron  KN;  Nguyen  T-V;  Truong  C;  Evans  AC;  Karama  S; for the Brain Development Cooperative Group:  Anxious/depressed symptoms are linked to right ventromedial prefrontal cortical thickness maturation in healthy children and young adults.  Cereb Cortex  (Epub ahead of print, June 7, 2013)
 
Ellis LK, Rothbart MK (eds): Revision of the Early Adolescent Temperament Questionnaire. Presented at the 2001 Biennial Meeting of the Society for Research in Child Development, Minneapolis (http://www.bowdoin.edu/~sputnam/rothbart-temperament-questionnaires/pdf/lesa-ellis-srcd-poster-reprint.pdf)
 
Kaufman  J;  Birmaher  B;  Brent  D;  Rao  U;  Flynn  C;  Moreci  P;  Williamson  D;  Ryan  N:  Schedule for Affective Disorders and Schizophrenia for School-Age Children–Present and Lifetime Version (K-SADS-PL): initial reliability and validity data.  J Am Acad Child Adolesc Psychiatry 1997; 36:980–988
[CrossRef] | [PubMed]
 
Radloff  LS:  The CES-D Scale: a self-report depression scale for research in the general population.  Appl Psychol Meas 1977; 1:385–401
[CrossRef]
 
Beck  AT;  Epstein  N;  Brown  G;  Steer  RA:  An inventory for measuring clinical anxiety: psychometric properties.  J Consult Clin Psychol 1988; 56:893–897
[CrossRef] | [PubMed]
 
Achenbach  TM:  Manual for the Youth Self-Report and 1991 Profiles .  Burlington,  University of Vermont, Department of Psychiatry, 1991
 
Wechsler  D:  Wechsler Intelligence Scale for Children , 4th ed.  San Antonio, Tex,  Harcourt Assessment, 2003
 
Oldfield  RC:  The assessment and analysis of handedness: the Edinburgh inventory.  Neuropsychologia 1971; 9:97–113
[CrossRef] | [PubMed]
 
Petersen  AC;  Crockett  L;  Richards  M;  Boxer  A:  A self-report measure of pubertal status: reliability, validity, and initial norms.  J Youth Adolesc 1988; 17:117–133
[CrossRef] | [PubMed]
 
Jones  FL;  McMillan  J:  Scoring occupational categories for social research: a review of current practice, with Australian examples.  Work Employ Soc 2001; 15:539–563
[CrossRef]
 
Han  X;  Jovicich  J;  Salat  D;  van der Kouwe  A;  Quinn  B;  Czanner  S;  Busa  E;  Pacheco  J;  Albert  M;  Killiany  R;  Maguire  P;  Rosas  D;  Makris  N;  Dale  A;  Dickerson  B;  Fischl  B:  Reliability of MRI-derived measurements of human cerebral cortical thickness: the effects of field strength, scanner upgrade, and manufacturer.  Neuroimage 2006; 32:180–194
[CrossRef] | [PubMed]
 
Ghosh  SS;  Kakunoori  S;  Augustinack  J;  Nieto-Castanon  A;  Kovelman  I;  Gaab  N;  Christodoulou  JA;  Triantafyllou  C;  Gabrieli  JD;  Fischl  B:  Evaluating the validity of volume-based and surface-based brain image registration for developmental cognitive neuroscience studies in children 4 to 11 years of age.  Neuroimage 2010; 53:85–93
[CrossRef] | [PubMed]
 
Free  SL;  Bergin  PS;  Fish  DR;  Cook  MJ;  Shorvon  SD;  Stevens  JM:  Methods for normalization of hippocampal volumes measured with MR.  AJNR Am J Neuroradiol 1995; 16:637–643
[PubMed]
 
Rao  U;  Chen  LA;  Bidesi  AS;  Shad  MU;  Thomas  MA;  Hammen  CL:  Hippocampal changes associated with early-life adversity and vulnerability to depression.  Biol Psychiatry 2010; 67:357–364
[CrossRef] | [PubMed]
 
Caetano  SC;  Fonseca  M;  Hatch  JP;  Olvera  RL;  Nicoletti  M;  Hunter  K;  Lafer  B;  Pliszka  SR;  Soares  JC:  Medial temporal lobe abnormalities in pediatric unipolar depression.  Neurosci Lett 2007; 427:142–147
[CrossRef] | [PubMed]
 
Dedovic  K;  Duchesne  A;  Andrews  J;  Engert  V;  Pruessner  JC:  The brain and the stress axis: the neural correlates of cortisol regulation in response to stress.  Neuroimage 2009; 47:864–871
[CrossRef] | [PubMed]
 
Phelps  EA:  Human emotion and memory: interactions of the amygdala and hippocampal complex.  Curr Opin Neurobiol 2004; 14:198–202
[CrossRef] | [PubMed]
 
Duman  RS;  Monteggia  LM:  A neurotrophic model for stress-related mood disorders.  Biol Psychiatry 2006; 59:1116–1127
[CrossRef] | [PubMed]
 
Rudolph  KD;  Hammen  C;  Burge  D;  Lindberg  N;  Herzberg  D;  Daley  SE:  Toward an interpersonal life-stress model of depression: the developmental context of stress generation.  Dev Psychopathol 2000; 12:215–234
[CrossRef] | [PubMed]
 
Whittle  S;  Dennison  M;  Vijayakumar  N;  Simmons  JG;  Yücel  M;  Lubman  DI;  Pantelis  C;  Allen  NB:  Childhood maltreatment and psychopathology affect brain development during adolescence.  J Am Acad Child Adolesc Psychiatry 2013; 52:940–952.e1
[CrossRef] | [PubMed]
 
Charney  DS;  Manji  HK:  Life stress, genes, and depression: multiple pathways lead to increased risk and new opportunities for intervention.  Sci STKE 2004; 2004:re5
[PubMed]
 
Giedd  JN;  Castellanos  FX;  Rajapakse  JC;  Vaituzis  AC;  Rapoport  JL:  Sexual dimorphism of the developing human brain.  Prog Neuropsychopharmacol Biol Psychiatry 1997; 21:1185–1201
[CrossRef] | [PubMed]
 
Ziabreva  I;  Poeggel  G;  Schnabel  R;  Braun  K:  Separation-induced receptor changes in the hippocampus and amygdala of Octodon degus: influence of maternal vocalizations.  J Neurosci 2003; 23:5329–5336
[PubMed]
 
Pezawas  L;  Meyer-Lindenberg  A;  Drabant  EM;  Verchinski  BA;  Munoz  KE;  Kolachana  BS;  Egan  MF;  Mattay  VS;  Hariri  AR;  Weinberger  DR:  5-HTTLPR polymorphism impacts human cingulate-amygdala interactions: a genetic susceptibility mechanism for depression.  Nat Neurosci 2005; 8:828–834
[CrossRef] | [PubMed]
 
Parashos  IA;  Tupler  LA;  Blitchington  T;  Krishnan  KR:  Magnetic-resonance morphometry in patients with major depression.  Psychiatry Res 1998; 84:7–15
[CrossRef] | [PubMed]
 
Sowell  ER;  Thompson  PM;  Holmes  CJ;  Jernigan  TL;  Toga  AW:  In vivo evidence for post-adolescent brain maturation in frontal and striatal regions.  Nat Neurosci 1999; 2:859–861
[CrossRef] | [PubMed]
 
Tarazi  FI;  Baldessarini  RJ:  Comparative postnatal development of dopamine D(1), D(2), and D(4) receptors in rat forebrain.  Int J Dev Neurosci 2000; 18:29–37
[CrossRef] | [PubMed]
 
Wacker  J;  Dillon  DG;  Pizzagalli  DA:  The role of the nucleus accumbens and rostral anterior cingulate cortex in anhedonia: integration of resting EEG, fMRI, and volumetric techniques.  Neuroimage 2009; 46:327–337
[CrossRef] | [PubMed]
 
Chambers  RA;  Taylor  JR;  Potenza  MN:  Developmental neurocircuitry of motivation in adolescence: a critical period of addiction vulnerability.  Am J Psychiatry 2003; 160:1041–1052
[CrossRef] | [PubMed]
 
Munro  CA;  McCaul  ME;  Wong  DF;  Oswald  LM;  Zhou  Y;  Brasic  J;  Kuwabara  H;  Kumar  A;  Alexander  M;  Ye  W;  Wand  GS:  Sex differences in striatal dopamine release in healthy adults.  Biol Psychiatry 2006; 59:966–974
[CrossRef] | [PubMed]
 
Morey  RA;  Selgrade  ES;  Wagner  HR  2nd;  Huettel  SA;  Wang  L;  McCarthy  G:  Scan-rescan reliability of subcortical brain volumes derived from automated segmentation.  Hum Brain Mapp 2010; 31:1751–1762
[PubMed]
 
Casey  P;  Maracy  M;  Kelly  BD;  Lehtinen  V;  Ayuso-Mateos  JL;  Dalgard  OS;  Dowrick  C:  Can adjustment disorder and depressive episode be distinguished? Results from ODIN.  J Affect Disord 2006; 92:291–297
[CrossRef] | [PubMed]
 
References Container
+
+

Self-Assessment Quiz

Did you know? You can add a subscription now to earn CME Credits!

1.
In which brain regions was an attenuation of the normative pattern of change associated with adolescent depression onset in males?
2.
For which brain regions did results suggest that abnormalities in structure might predate the onset of depression, and thus reflect a neurobiological manifestation of a vulnerability factor?
3.
What can explain the sex differences found in the association between amygdala development and adolescent depression onset?
Submit a Comments
Please read the other comments before you post yours. Contributors must reveal any conflict of interest.
Comments are moderated and will appear on the site at the discertion of APA editorial staff.

* = Required Field
(if multiple authors, separate names by comma)
Example: John Doe



Web of Science® Times Cited: 1

Related Content
See Also...
Articles
Books
The American Psychiatric Publishing Textbook of Psychopharmacology, 4th Edition > Chapter 45.  >
The American Psychiatric Publishing Textbook of Psychopharmacology, 4th Edition > Chapter 52.  >
The American Psychiatric Publishing Textbook of Psychopharmacology, 4th Edition > Chapter 52.  >
DSM-5™ Clinical Cases > Chapter 2.  >
DSM-5™ Clinical Cases > Chapter 16.  >
Topic Collections
Psychiatric News
APA Guidelines