Inflammation has been implicated in depressive symptoms, but few studies use longitudinal designs with adolescents. Furthermore, the extant literature has yielded inconsistent results. Blood was collected from a community sample of 201 adolescents (109 female, age range = 12.3–20.0 years) and analyzed for inflammatory proteins. Up to five follow-up assessments of depressive symptoms were conducted. Multilevel modeling indicated that high C-reactive protein (CRP) but no other proinflammatory markers predicted depressive symptom increases. Three-way interactions between different inflammatory biomarkers, sex, and months to follow-up predicted change in depressive symptoms. Higher interleukin-6 predicted increased depressive symptoms at 13 to 31 months after baseline assessment of depression and inflammation for females. Higher tumor necrosis factor-α predicted increased depressive symptoms at < 1 month after baseline for males and 13 to 31 months after baseline for females. Higher interleukin-8 in males predicted lower depressive symptoms at 31 months after baseline. Exploratory post hoc analyses were used to examine these predictive associations for specific subsets of depressive symptoms. These findings are the first to support the predictive association of elevated CRP for depressive symptoms in a community adolescent sample and serve as preliminary evidence that the relationship between cytokines and later depressive symptoms differs by sex, time to follow-up, and the specific biomarker.
AcockA. C. (2014). A gentle introduction to Stata (4th ed.). College Station, TX: Stata Press.
2.
AlloyL. B.BlackS. K.YoungM. E.GoldsteinK. E.ShaperoB. G.StangeJ. P.. . . AbramsonL. Y. (2012). Cognitive vulnerabilities and depression versus other psychopathology symptoms and diagnoses in early adolescence. Journal of Clinical Child and Adolescent Psychology, 41, 539–60. doi:10.1080/15374416.2012.703123.
3.
American Psychiatric Association. (2013). Diagnostic and statistical manual of mental disorders (5th ed.). Arlington, VA: Author.
BalázsJ.MiklõsiM.KeresztényÁ.HovenC. W.CarliV.WassermanC.. . . WassermanD. (2013). Adolescent subthreshold-depression and anxiety: Psychopathology, functional impairment and increased suicide risk. Journal of Child Psychology and Psychiatry and Allied Disciplines, 54, 670–677. doi:10.1111/jcpp.12016
6.
BaldwinJ. R.ArseneaultL.CaspiA.FisherH. L.MoffittT. E.OdgersC. L.DaneseA. (2018). Childhood victimization and inflammation in young adulthood: A genetically sensitive cohort study. Brain, Behavior, and Immunity, 67, 211–217. doi:10.1016/j.bbi.2017.08.025
7.
BangY. R.ParkJ. H.KimS. H. (2015). Cut-off scores of the children’ s depression inventory for screening and rating severity in Korean adolescents. Psychiatry Investigation, 12, 23–28.
8.
BangasserD. A.EckS. R.SanchezE. O. (2019). Sex differences in stress reactivity in arousal and attention systems. Neuropsychopharmacology, 44, 129–139. doi:10.1038/s41386-018-0137-2
9.
BatesD.MaechlerM.BolkerB.WalkerS. (2015). Fitting linear mixed-effects models using lme4. Journal of Statistical Software, 67, 1–48. doi:10.18637/jss.v067.i01>.
10.
BlandJ. M.AltmanD. G. (1995). Multiple significance tests: The Bonferroni method. BMJ, 310(6973), 170.
11.
BleidornW.ArslanR. C.DenissenJ. J. A.RentfrowP. J.PotterJ.GebauerJ. E.GoslingS. D. (2016). Age and gender differences in self-esteem—A cross-cultural window. Journal of Personality and Social Psychology, 111, 396–410.
12.
BreenE. C.ReynoldsS. M.CoxC.JacobsonL. P.MagpantayL.MulderC. B.NorrisP. J. (2011). Multisite comparison of high-sensitivity multiplex cytokine assays. Clinical and Vaccine Immunology, 18, 1229–1242. doi:10.1128/CVI.05032-11
13.
CalderP. C. (2006). n-3 Polyunsaturated fatty acids, inflammation, and inflammatory diseases. The American Journal of Clinical Nutrition, 83, 1505–1519. doi:16841861
14.
CapuronL.MillerA. H. (2004). Cytokines and psychopathology: Lessons from interferon-α. Biological Psychiatry, 56, 819–824. doi:10.1016/j.biopsych.2004.02.009
15.
CartierA.CoteM.LemieuxI.PerusseL.TremblayA.BouchardC.DespresJ.-P. (2009). Sex differences in inflammatory markers: What is the contribution of visceral adiposity. The American Journal of Clinical Nutrition, 89, 1307–1314. doi:10.3945/ajcn.2008.27030.1
16.
CopelandW. E.ShanahanL.WorthmanC.AngoldA.CostelloE. J. (2012). Cumulative depression episodes predict later C-reactive protein levels: A prospective analysis. Biological Psychiatry, 71, 15–21. doi:10.1016/j.biopsych.2011.09.023
17.
CostelloE. J.ErkanliA.AngoldA. (2006). Is there an epidemic of child or adolescent depression?Journal of Child Psychology and Psychiatry and Allied Disciplines, 47, 1263–1271. doi:10.1111/j.1469-7610.2006.01682.x
18.
Couzin-FrankelJ. (2010). Inflammation bares a dark side. Science, 330, 1621. doi:10.1126/science.330.6011.1621
19.
DabitaoD.MargolickJ. B.LopezJ.BreamJ. H. (2011). Multiplex measurement of proinflammatory cytokines in human serum: Comparison of the Meso Scale Discovery electrochemiluminescence assay and the Cytometric Bead Array. Journal of Immunological Methods, 372, 71–77. doi:10.1038/jid.2014.371
20.
DantzerR.KelleyK. W. (2007). Twenty years of research on cytokine-induced sickness behavior. Brain Research, 21, 153–160. doi:10.1016/j.bbi.2006.09.006
21.
DantzerR.O’ConnorJ. C.FreundG. G.JohnsonR. W.KelleyK. W. (2008). From inflammation to sickness and depression: When the immune system subjugates the brain. Nature Reviews Neuroscience, 9, 46–57.
22.
DhabharF. S.BurkeH. M.EpelE. S.MellonS. H.RosserR.ReusV. I.WolkowitzO. M. (2009). Low serum IL-10 concentrations and loss of regulatory association between IL-6 and IL-10 in adults with major depression. Journal of Psychiatric Research, 43, 962–969. doi:10.1016/j.jpsychires.2009.05.010
23.
DowlatiY.HerrmannN.SwardfagerW.LiuH.ShamL.ReimE. K.LanctôtK. L. (2010). A Meta-analysis of cytokines in major depression. Biological Psychiatry, 67, 446–457. doi:10.1016/j.biopsych.2009.09.033
24.
DuivisH. E.KupperN.VermuntJ. K.PenninxB. W.BoschN. M.RieseH.de JongeP. (2015). Depression trajectories, inflammation, and lifestyle factors in adolescence: The Tracking Adolescents’ Individual Lives Survey. Health Psychology, 34, 1047–1057. doi:10.1037/hea0000210
25.
GarberJ.KeileyM. K.MartinN. C. (2002). Developmental trajectories of adolescents’ depressive symptoms: Predictors of change. Journal of Consulting and Clinical Psychology, 70, 79–95. doi:10.1037//0022-006X.70.1.79
26.
GilmanS. E.KawachiI.FitzmauriceG. M.BukaS. L. (2003). Socio-economic status, family disruption and residential stability in childhood: relation to onset, recurrence and remission of major depression. Psychological Medicine, 33, 1341–1355.
27.
GimenoD.KivimäkiM.BrunnerE. J.ElovainioM.De VogliR.SteptoeA.FerrieJ. E. (2009). Associations of C-reactive protein and interleukin-6 with cognitive symptoms of depression: 12-year follow-up of the Whitehall II study. Psychological Medicine, 39, 413–423. doi:10.1017/S0033291708003723
28.
GjerdeP. F.BlockJ.BlockJ. H. (1988). Depressive symptoms and personality during late adolescence: Gender differences in the externalization-internalization of symptom expression. Journal of Abnormal Psychology, 97, 475–486.
29.
GoodwinR. D.FergussonD. M.HorwoodL. J. (2004). Asthma and depressive and anxiety disorders among young persons in the community. Psychological Medicine, 34, 1465–74. doi:10.1017/S0033291704002739
30.
HankinB. L.AbramsonL. Y.MoffittT. E.SilvaP. A.McGeeR.AngellK. E. (1998). Development of depression from preadolescence to young adulthood: Emerging gender differences in a 10-year longitudinal study. Journal of Abnormal Psychology, 107, 128–140. doi:10.1037/0021-843X.107.1.128
31.
HarrisK. M.Gordon-LarsenP.ChantalaK.UdryJ. R. (2006). Longitudinal trends in race/ethnic disparities in leading health indicators from adolescence to young adulthood. Archives of Pediatrics and Adolescent Medicine, 160, 74–81.
32.
HartB. L. (1988). Biological basis of the behavior of sick animals. Neuroscience & Biobehavioral Reviews, 12, 123–137. doi:10.1016/S0149-7634(88)80004-6
33.
HowrenM. B.LamkinD. M.SulsJ. (2009). Associations of depression with C-reactive protein, IL-1, and IL-6: A meta-analysis. Psychosomatic Medicine, 71, 171–186. doi:10.1097/PSY.0b013e3181907c1b
34.
HuangC.DongN. (2014). Dimensionality of the Children’s Depression Inventory: Meta-analysis of pattern matrices. Journal of Child and Family Studies, 23, 1182–1192. doi:10.1007/s10826-013-9779-1
35.
IBM Corp. (2016). IBM SPSS Statistics for Windows (Version 23.0) [Software]. Armonk, NY: Author.
36.
IrwinM. R.ColeS. W. (2011). Reciprocal regulation of the neural and innate immune systems. Nature Reviews Immunology, 11, 625–635.
37.
JanewayC. A. (1989). Approaching the asymptote? Evolution and revolution in immunology. Journal of Immunology, 54(9), 1–13. Retrieved from http://www.jimmunol.org/content/191/9/4475
38.
KleinD.DoughertyL. R.OlinoT. M. (2005). Toward guidelines for evidence-based assessment of depression in children and adolescents. Journal of Clinical Child & Adolescent Psychology, 34, 412, 432. doi:10.1207/s15374424jccp3403
39.
KornsteinS. G.SchatzbergA. F.ThaseM. E.TonykersK. A.McColloughJ. P.KeitnerG. I.DavisS. M. (2000). Gender differences in chronic major and double depression. Journal of Affective Disorders, 60, 1–11.
KrishnadasR.HarrisonN. A. (2016). Depression phenotype, inflammation, and the brain: Implications for future research. Psychosomatic Medicine, 78, 384–388. doi:10.1097/PSY.0000000000000339
42.
KuznetsovaA.BrockhoffP.RHDC. (2017). lmerTest package: Tests in linear mixed effects models. Journal of Statsitcal Software, 82(13), 1–26. doi:10.18637/jss.v082.i13
43.
MalarkeyW. B.JarjouraD.KlattM. (2013). Workplace based mindfulness practice and inflammation: A randomized trial. Brain, Behavior, and Immunity, 27, 145–154. doi:10.1016/j.bbi.2012.10.009
44.
MartinL. A.NeighborsH. W.GriffithD. M. (2013). The experience of symptoms of depression in men vs women analysis of the National Comorbidity Survey replication. JAMA Psychiatry, 70, 1100–1106. doi:10.1001/jamapsychiatry.2013.1985
45.
MillerA. H.MaleticV.RaisonC. L. (2009). Inflammation and its discontents: The role of cytokines in the pathophysiology of major depression. Biological Psychiatry, 65, 732–741. doi:10.1016/j.biopsych.2008.11.029
46.
MillerG. E.CohenS.RitcheyA. K. (2002). Chronic psychological stress and the regulation of pro-inflammatory cytokines: A glucocorticoid-resistance model. Health Psychology, 21, 531–541 doi:10.1037//0278-6133.21.6.531
47.
MillerG. E.ColeS. W. (2012). Clustering of depression and inflammation in adolescents previously exposed to childhood adversity. Biological Psychiatry, 72, 34–40. doi:10.1016/j.biopsych.2012.02.034.CLUSTERING
48.
Nolen-HoeksemaS. (1987). Sex differences in unipolar depression: Evidence and theory. Psychological Bulletin, 101, 259–282. doi:10.1037/0033-2909.101.2.259
49.
O’BrienS. M.ScullyP.ScottL. V.DinanT. G. (2006). Cytokine profiles in bipolar affective disorder: Focus on acutely ill patients. Journal of Affective Disorders, 90, 263–267. doi:10.1016/j.jad.2005.11.015
50.
OhayonM. M.SchatzbergA. F. (2003). Using chronic pain to predict depressive morbidity in the general population. Archives of General Psychiatry, 60, 39–47. doi:10.1001/archpsyc.60.1.39
51.
PallaviP.SagarR.MehtaM.SharmaS.SubramaniumA.ShamshiF.MukhopadhyayA. K. (2015). Serum cytokines and anxiety in adolescent depression patients: Gender effect. Psychiatry Research, 229, 374–380. doi:10.1016/j.psychres.2015.06.036
52.
PanA.KeumN.OkerekeO. I.SunQ.KivimakiM.RubinR. R.HuF. B. (2012). Bidirectional association between depression and metabolic syndrome: A systematic review and meta-analysis of epidemiological studies. Diabetes Care, 35, 1171–1180. doi:10.2337/dc11-2055
53.
ParkerG.FletcherK.PatersonA.AndersonJ.HongM. (2014). Gender differences in depression severity and symptoms across depressive sub-types. Journal of Affective Disorders, 167, 351–357. doi:10.1016/j.jad.2014.06.018
54.
RaisonC. L.RutherfordR. E.WoolwineB. J.ShuoC.SchettlerP.DrakeD. F.MillerA. H. (2013). A randomized controlled trial of the tumor necrosis factor antagonist infliximab for treatment-resistant depression. JAMA Psychitary, 70, 31–41. doi:10.1001/2013.jamapsychiatry.4
55.
RosenkranzM. A.DavidsonR. J.MacCoonD. G.SheridanJ. F.KalinN. H.LutzA. (2013). A comparison of mindfulness-based stress reduction and an active control in modulation of neurogenic inflammation. Brain, Behavior, and Immunity, 27, 174–184. doi:10.1016/j.bbi.2012.10.013
56.
StewartJ. C.RandK. L.MuldoonM. F.KamarckT. W. (2009). A prospective evaluation of the directionality of the depression-inflammation relationship. Brain, Behavior, and Immunity, 23, 936–944. doi:10.1016/j.bbi.2009.04.011
57.
R Core Team. (2013). R: A language and environment for statistical computing. Vienna, Austria: R Foundation for Statistical Computing. Retrieved from http://www.r-project.org
58.
van den BiggelaarA. H. J.GusseklooJ.de CraenA. J. M.FrölichM.StekM. L.van der MastR. C.WestendorpR. G. J. (2007). Inflammation and interleukin-1 signaling network contribute to depressive symptoms but not cognitive decline in old age. Experimental Gerontology, 42, 693–701. doi:10.1016/j.exger.2007.01.011
59.
van LangN. D. J.FerdinandR. F.VerhulstF. C. (2007). Predictors of future depression in early and late adolescence. Journal of Affective Disorders, 97, 137–144. doi:10.1016/j.jad.2006.06.007
60.
WadeT. J.CairneyJ.PevalinD. J. (2002). Emergence of gender differences in depression during adolescence: National panel results from three countries. Journal of the American Academy of Child & Adolescent Psychiatry, 41(2), 190–198. doi:10.1097/00004583-200202000-00013
61.
WatkinsL. R.MaierS. F. (1999). Implications of immune-to-brain communication for sickness and pain. Proceedings of the National Academy of Sciences of the United States of America, 96, 7710–7713. doi:10.1073/pnas.96.14.7710
62.
WeissmanM. M.KeirmanG. L. (1977). Sex differences and the epidemiology of depression. Archives of General Psychiatry, 34, 98–111. doi:10.1001/archpsyc.1977.01770130100011
63.
WhooleyM. A. (2006). Depression and cardiovascular disease healing the broken-hearted. JAMA, 295, 2874–2881.
64.
ZalliA.JovanovaO.HoogendijkW. J. G.TiemeierH.CarvalhoL. A. (2016). Low-grade inflammation predicts persistence of depressive symptoms. Psychopharmacology, 233, 1669–1678. doi:10.1007/s00213-015-3919-9
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