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Risk Markers Are Not One Size Fits All

      Identifying risk markers for depression has long been an elusive goal in psychiatric research. These efforts have been undertaken using a variety of methods investigating environmental, genetic, physiological, and neural candidate markers (
      • Gray J.P.
      • Müller V.I.
      • Eickhoff S.B.
      • Fox P.T.
      Multimodal abnormalities of brain structure and function in major depressive disorder: A meta-analysis of neuroimaging studies.
      ,
      • LeMoult J.
      • Humphreys K.L.
      • Tracy A.
      • Hoffmeister J.A.
      • Ip E.
      • Gotlib I.H.
      Meta-analysis: Exposure to early life stress and risk for depression in childhood and adolescence.
      ,
      • Mazurka R.
      • Wynne-Edwards K.E.
      • Harkness K.L.
      Sex differences in the cortisol response to the trier social stress test in depressed and nondepressed adolescents.
      ,
      • Wray N.R.
      • Ripke S.
      • Mattheisen M.
      • Trzaskowski M.
      • Byrne E.M.
      • Abdellaoui A.
      • et al.
      Genome-wide association analyses identify 44 risk variants and refine the genetic architecture of major depression.
      ). The search for useful and valid risk markers for depression has been plagued by small sample sizes, inconsistent effects, and likely overestimated effect sizes. Even large consortia formed to overcome issues of low statistical power in this endeavor have yet to identify large and replicable effects when seeking neural markers of depression. Illustrative of this point, the ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis) consortium reported only a small effect of reduced hippocampal volumes in patients with depression compared with those without depression when combining cohorts from around the world (
      • Schmaal L.
      • Veltman D.J.
      • Van Erp T.G.M.
      • Smann P.G.
      • Frodl T.
      • Jahanshad N.
      • et al.
      Subcortical brain alterations in major depressive disorder: Findings from the ENIGMA Major Depressive Disorder working group.
      ). The clinical utility of such small, cross-sectional effects is likely limited, suggesting that new approaches to the search for risk markers of depression are needed.
      SEE CORRESPONDING ARTICLE ON PAGE 932
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