Objective: To identify clinical and central features that differentiate ADHD youth with and without familial risk for bipolar I disorder (BD). Methods: Psychostimulant-free ADHD youth (10–18 years) with and without a first-degree relative with BD and healthy controls were enrolled. Bilateral ventrolateral prefrontal cortex (VLPFC) proton magnetic resonance spectroscopy (1H MRS) scans and a range of symptom ratings were performed. Results: A total of n = 145 youth were enrolled. ADHD youth with a family history of BD exhibited greater manic and depressive symptom severity, ADHD hyperactivity/impulsive symptom severity, and higher parent-reported ratings of dysregulation compared with ADHD youth without a BD family history. Although VLPFC metabolite levels did not differ across groups, choline levels in the left VLPFC correlated with different symptom ratings. Conclusion: Symptom profiles including more severe mood and externalizing symptoms, but not VLPFC neurochemistry, differentiate psychostimulant-free ADHD youth with and without a family history of BD.
AchenbachT. M.RescorlaL. A. (2001). Manual for the ASEBA school-age forms & profiles. University of Vermont, Research Center for Children, Youth, & Families.
2.
AokiY.InokuchiR.SuwaH.AokiA. (2013). Age-related change of neurochemical abnormality in attention-deficit hyperactivity disorder: A meta-analysis. Neuroscience & Biobehavioral Reviews, 37, 1692–1701. https://doi.org/10.1016/j.neubiorev.2013.04.019
3.
AxelsonD.GoldsteinB.GoldsteinT.MonkK.YuH.HickeyM. B.SakolskyD.DilerR.HafemanD.MerrankoJ.IyengarS.BrentD.KupferD.BirmaherB. (2015). Diagnostic precursors to bipolar disorder in offspring of parents with bipolar disorder: A longitudinal study. American Journal of Psychiatry, 172, 638–646. https://doi.org/10.1176/appi.ajp.2014.14010035
4.
BechdolfA.RatheeshA.CottonS. M.NelsonB.ChanenA. M.BettsJ.BingmannT.YungA. R.BerkM.McGorryP. D. (2014). The predictive validity of bipolar at-risk (prodromal) criteria in help-seeking adolescents and young adults: A prospective study. Bipolar Disorders, 16, 493–504. https://doi.org/10.1111/bdi.12205
5.
BenamorL. (2014). (1)H-Magnetic resonance spectroscopy study of stimulant medication effect on brain metabolites in French Canadian children with attention deficit hyperactivity disorder. Neuropsychiatric Disease and Treatment, 10, 47–54. https://doi.org/10.2147/NDT.S52338
6.
BerbothS.MorawetzC. (2021). Amygdala-prefrontal connectivity during emotion regulation: A meta-analysis of psychophysiological interactions. Neuropsychologia, 153, 107767. https://doi.org/10.1016/j.neuropsychologia.2021.107767
7.
BiedermanJ.PettyC. R.MonuteauxM. C.EvansM.ParcellT.FaraoneS. V.WozniakJ. (2009). The child behavior checklist-pediatric bipolar disorder profile predicts a subsequent diagnosis of bipolar disorder and associated impairments in ADHD youth growing up: A longitudinal analysis. Journal of Clinical Psychiatry, 70, 732–740. https://doi.org/10.4088/JCP.08m04821
8.
BrancatiG. E.PerugiG.MiloneA.MasiG.SessoG. (2021). Development of bipolar disorder in patients with attention-deficit/hyperactivity disorder: A systematic review and meta-analysis of prospective studies. Journal of Affective Disorders, 293, 186–196. https://doi.org/10.1016/j.jad.2021.06.033
9.
CaetanoS. C.OlveraR. L.HatchJ. P.SanchesM.ChenH. H.NicolettiM.StanleyJ. A.FonsecaM.HunterK.LaferB.PliszkaS. R.SoaresJ. C. (2011). Lower N-acetyl-aspartate levels in prefrontal cortices in pediatric bipolar disorder: A ¹H magnetic resonance spectroscopy study. Journal of the American Academy of Child & Adolescent Psychiatry, 50, 85–94. https://doi.org/10.1016/j.jaac.2010.10.007
10.
CarreyN.MacMasterF. P.FogelJ.SparkesS.WaschbuschD.SullivanS.SchmidtM. (2003). Metabolite changes resulting from treatment in children with ADHD: A 1H-MRS study. Clinical Neuropharmacology, 26, 218–221. https://doi.org/10.1097/00002826-200307000-00013
11.
CastilloM.KwockL.Courvoisie.H.HooperS. R. (2000). Proton MR spectroscopy in children with bipolar affective disorder: Preliminary observations. American Journal of Neuroradiology, 21, 832–838.
12.
ChangK.AdlemanN.DienesK.Barnea-GoralyN.ReissA.KetterT. (2003). Decreased N-acetylaspartate in children with familial bipolar disorder. Biological Psychiatry, 53, 1059–1065. https://doi.org/10.1016/s0006-3223(02)01744-4
13.
CrovitzH. F.ZenerK. (1962). A group-test for assessing hand- and eye-dominance. American Journal of Psychology, 75, 271–276.
14.
DavanzoP.YueK.ThomasM. A.BelinT.MintzJ.VenkatramanT. N.SantoroE.BarnettS.McCrackenJ. (2003). Proton magnetic resonance spectroscopy of bipolar disorder versus intermittent explosive disorder in children and adolescents. American Journal of Psychiatry, 160, 1442–1452. https://doi.org/10.1176/appi.ajp.160.8.1442
DoerflerL. A.ConnorD. F.ToscanoP. F. (2011). Aggression, ADHD symptoms, and dysphoria in children and adolescents diagnosed with bipolar disorder and ADHD. Journal of Affective Disorders, 131, 312–319. https://doi.org/10.1016/j.jad.2010.11.029
17.
DonfrancescoR.Di TraniM.AndriolaE.LeoneD.TorrioliM. G.PassarelliF.DelBelloM. P. (2017). Bipolar disorder in children with ADHD: A clinical sample study. Journal of Attention Disorders, 21, 715–720. https://doi.org/10.1177/1087054714539999
18.
DonfrancescoR.MianoS.MartinesF.FerranteL.MelegariM. G.MasiG. (2011). Bipolar disorder co-morbidity in children with attention deficit hyperactivity disorder. Psychiatry Research, 186, 333–337. https://doi.org/10.1016/j.psychres.2010.07.008
19.
DukeP.LittI.GrossR. (1980). Adolescents’ self-assessment of sexual maturation. Pediatrics, 66, 918–920.
20.
FaeddaG. L.BaldessariniR. J.MarangoniC.BechdolfA.BerkM.BirmaherB.ConusP.DelBelloM. P.DuffyA. C.HillegersM. H. J.PfennigA.PostR. M.PreisigM.RatheeshA.SalvatoreP.TohenM.VázquezG. H.VietaE.YathamL. N.. . . CorrellC. U. (2019). An international society of bipolar disorders task force report: Precursors and prodromes of bipolar disorder. Bipolar Disorders, 21, 720–740. https://doi.org/10.1111/bdi.12831
21.
FaraoneS. V.BiedermanJ.MenninD.RussellR.TsuangM. T. (1998). Familial subtypes of attention deficit hyperactivity disorder: A 4-year follow-up study of children from antisocial-ADHD families. Journal of Child Psychology and Psychiatry, 39, 1045–1053.
22.
FaraoneS. V.BiedermanJ.WozniakJ.MundyE.MenninD.O’DonnellD. (1997). Is comorbidity with ADHD a marker for juvenile-onset mania?Journal of the American Academy of Child & Adolescent Psychiatry, 36, 1046–1055. https://doi.org/10.1097/00004583-199708000-00012
23.
FarlesD. E.YalcinI.HarderD.HeiligensteinJ. H. (2001). Validation of the ADHD Rating Scale as a clinician administered and scored instrument. Journal of Attention Disorders, 5, 39–47.
24.
FirstM. B.SpitzerR. L.GibbonM.WilliamsJ. B. (1996). Structured clinical interview for DSM-IV axis I disorders (SCID-IV). New York State.
25.
GussewA.ErdtelM.HiepeP.RzannyR.ReichenbachJ. R. (2012). Absolute quantitation of brain metabolites with respect to heterogeneous tissue compositions in (1)H-MR spectroscopic volumes. Magnetic Resonance Materials in Physics, Biology and Medicine, 25, 321–333. https://doi.org/10.1007/s10334-012-0305-z
26.
GuyW. (1970). ECDEU assessment manual for psychopharmacology (Rev. 12-1–12-6). National Institute of Mental Health.
27.
HartE. L.LaheyB. B.LoeberR.ApplegateB.FrickP. J. (1995). Developmental change in attention-deficit hyperactivity disorder in boys: A four-year longitudinal study. Journal of Abnormal Child Psychology, 23, 729–749. https://doi.org/10.1007/BF01447474
28.
HollingsheadA. B. (1975). Four factor index of social status. Yale University Department of Sociology.
29.
HusarovaV.BittsanskyM.OndrejkaI.DobrotaD. (2014). Prefrontal grey and white matter neurometabolite changes after atomoxetine and methylphenidate in children with attention deficit/hyperactivity disorder: A (1)H magnetic resonance spectroscopy study. Psychiatry Research, 222, 75–83. https://doi.org/10.1016/j.pscychresns.2014.03.003
30.
KaufmanJ.BirmaherB.BrentD.RaoU.FlynnC.MoreciP.WilliamsonDRyanN. (1997). Schedule for affective disorders and schizophrenia for school-age children-present and lifetime version (K-SADS-PL): Initial reliability and validity data. Journal of the American Academy of Child & Adolescent Psychiatry, 36, 980–988. https://doi.org/10.1097/00004583-199707000-00021
31.
KimJ. W.YuH.RyanN. D.AxelsonD. A.GoldsteinB. I.GoldsteinT. R.DilerR. S.MonkK.HickeyM. B.SakolskyD. J.MerrankoJ. A.BirmaherB. (2015). Longitudinal trajectories of ADHD symptomatology in offspring of parents with bipolar disorder and community controls. Journal of Clinical Psychiatry, 76, 599–606. https://doi.org/10.4088/JCP.14m09095
32.
KowatchR. A.YoungstromE. A.DanielyanA.FindlingR. L. (2005). Review and meta-analysis of the phenomenology and clinical characteristics of mania in children and adolescents. Bipolar Disorders, 7, 483–496. https://doi.org/10.1111/j.1399-5618.2005.00261.x
33.
KronenbergG.EndeG.AlmB.DeuschleM.HeuserI.Colla.M. (2008). Increased NAA and reduced choline levels in the anterior cingulum following chronic methylphenidate. A spectroscopic test-retest study in adult ADHD. European Archives of Psychiatry and Clinical Neuroscience, 258, 446–450. https://doi.org/10.1007/s00406-008-0810-2
34.
LauP.HawesD. J.HuntC.FranklandA.RobertsG.MitchellP. B. (2018). Prevalence of psychopathology in bipolar high-risk offspring and siblings: A meta-analysis. European Child & Adolescent Psychiatry, 27, 823–837. https://doi.org/10.1007/s00787-017-1050-7
35.
MasiG.PerugiG.ToniC.MillepiediS.MucciM.BertiniN.PfannerC. (2006). Attention-deficit hyperactivity disorder: Bipolar comorbidity in children and adolescents. Bipolar Disorders, 8, 373–381. https://doi.org/10.1111/j.1399-5618.2006.00342.x
36.
MaxwellE. (1999). Family interview for genetics studies. National Institutes of Mental Health.
37.
McGorryP.KeshavanM.GoldstoneS.AmmingerP.AllottK.BerkM.LavoieS.PantelisC.YungA.WoodS.HickieI. (2014). Biomarkers and clinical staging in psychiatry. World Psychiatry, 13, 211–223. https://doi.org/10.1002/wps.20144
38.
McNamaraR. K.NandagopalJ. J.StrakowskiS. M.DelBelloM. P. (2010). Preventative strategies for early-onset bipolar disorder: Towards a clinical staging model. CNS Drugs, 24, 983–996. https://doi.org/10.2165/11539700-000000000-00000
39.
MickE.BiedermanJ.PandinaG.FaraoneS. V. (2003). A preliminary meta-analysis of the child behavior checklist in pediatric bipolar disorder. Biological Psychiatry, 53, 1021–1027. https://doi.org/10.1016/s0006-3223(03)00234-8
40.
MooreC. M.BiedermanJ.WozniakJ.MickE.AleardiM.WardropM.DoughertyM.HarpoldT.HammernessP.RandallE.RenshawP. F. (2006). Differences in brain chemistry in children and adolescents with attention deficit hyperactivity disorder with and without comorbid bipolar disorder: A proton magnetic resonance spectroscopy study. American Journal of Psychiatry, 163, 316–318. https://doi.org/10.1176/appi.ajp.163.2.316
41.
MortensenP. B.PedersenC. B.MelbyeM.MorsO.EwaldH. (2003). Individual and familial risk factors for bipolar affective disorders in Denmark. Archives of General Psychiatry, 60, 1209–1215. https://doi.org/10.1001/archpsyc.60.12.1209
42.
NeryF. G.WeberW. A.BlomT. J.WelgeJ.PatinoL. R.StrawnJ. R.ChuW. J.AdlerC. M.KomoroskiR. A.StrakowskiS. M.DelBelloM. P. (2019). Longitudinal proton spectroscopy study of the prefrontal cortex in youth at risk for bipolar disorder before and after their first mood episode. Bipolar Disorders, 21, 330–341. https://doi.org/10.1111/bdi.12770
43.
OlveraR. L.CaetanoS. C.FonsecaM.NicolettiM.StanleyJ. A.ChenH. H.HatchJ. P.HunterK.PliszkaS. R.SoaresJ. C. (2007). Low levels of N-acetyl aspartate in the left dorsolateral prefrontal cortex of pediatric bipolar patients. Journal of Child and Adolescent Psychopharmacology, 17, 461–473. https://doi.org/10.1089/cap.2007.0102
44.
PerlisR. H.DennehyE. B.MiklowitzD. J.DelbelloM. P.OstacherM.CalabreseJ. R.AmetranoR. M.WisniewskiS. R.BowdenC. L.ThaseM. E.NierenbergA. A.SachsG. (2009). Retrospective age at onset of bipolar disorder and outcome during two-year follow-up: Results from the STEP-BD study. Bipolar Disorders, 11, 391–400. https://doi.org/10.1111/j.1399-5618.2009.00686.x
45.
PerlisR. H.MiyaharaS.MarangellL. B.WisniewskiS. R.OstacherM.DelBelloM. P.NierenbergA. A., & STEP-BD Investigators. (2004). Long-term implications of early onset in bipolar disorder: Data from the first 1000 participants in the systematic treatment enhancement program for bipolar disorder (STEP-BD). Biological Psychiatry, 55, 875–881. https://doi.org/10.1016/j.biopsych.2004.01.022.
46.
PerlovE.PhilipsenA.MatthiesS.DrielingT.MaierS.BublE.HesslingerB.BuechertM.HenningJ.EbertD.Tebartz Van ElstL. (2009). Spectroscopic findings in attention-deficit/hyperactivity disorder: Review and meta-analysis. World Journal of Biological Psychiatry, 10, 355–365. https://doi.org/10.1080/15622970802176032
47.
PoznanskiE. O.CookS. C.CarrollB. J. (1979). A depression rating scale for children. Pediatrics, 64, 442–450.
48.
PoznanskiE. O.CookS. C.CarrollB. J.CorzoH. (1983). Use of the Children’s Depression Rating Scale in an inpatient psychiatric population. Journal of Clinical Psychiatry, 44, 200–203.
49.
PropperL.SandstromA.RempelS.Howes VallisE.AbidiS.BagnellA.LovasD.AldaM.PavlovaB.UherR. (2021). Attention-deficit/hyperactivity disorder and other neurodevelopmental disorders in offspring of parents with depression and bipolar disorder. Psychological Medicine, 18, 1–8. https://doi.org/10.1017/S0033291721001951
50.
ProvencherS. W. (1993). Estimation of metabolite concentrations from localized in vivo proton NMR spectra. Magnetic Resonance in Medicine, 30, 672–679. https://doi.org/10.1002/mrm.1910300604
51.
SassiR. B.StanleyJ. A.AxelsonD.BrambillaP.NicolettiM. A.KeshavanM. S.RamosR. T.RyanN.BirmaherB.SoaresJ. C. (2005). Reduced NAA levels in the dorsolateral prefrontal cortex of young bipolar patients. American Journal of Psychiatry, 162, 2109–2115. https://doi.org/10.1176/appi.ajp.162.11.2109
52.
SerranoE.EzpeletaL.Castro-FornielesJ. (2013). Comorbidity and phenomenology of bipolar disorder in children with ADHD. Journal of Attention Disorders, 17, 330–338. https://doi.org/10.1177/1087054711427553
53.
ShafferD.GouldM. S.BrasicJ.AmbrosiniP.FisherP.BirdH.AluwahliaS. (1983). A Children’s Global Assessment Scale (CGAS). Archives of General Psychiatry, 40, 1228–1231. https://doi.org/10.1001/archpsyc.1983.01790100074010
54.
SinghM. K.DelBelloM. P.KowatchR. A.StrakowskiS. M. (2006). Co-occurrence of bipolar and attention-deficit hyperactivity disorders in children. Bipolar Disorders, 8, 710–720. https://doi.org/10.1111/j.1399-5618.2006.00391.x
55.
SinghM. K.SpielmanD.AdlemanN.AlegriaD.HoweM.ReissA.ChangK. (2010). Brain glutamatergic characteristics of pediatric offspring of parents with bipolar disorder. Psychiatry Research, 182, 165–171. https://doi.org/10.1016/j.pscychresns.2010.01.003
56.
SmollerJ. W.FinnC. T. (2003). Family, twin, and adoption studies of bipolar disorder. American Journal of Medical Genetics - Seminars in Medical Genetics, 123C, 48–58. https://doi.org/10.1002/ajmg.c.20013
57.
SpencerA. E.UchidaM.KenworthyT.KearyC. J.BiedermanJ. (2014). Glutamatergic dysregulation in pediatric psychiatric disorders: A systematic review of the magnetic resonance spectroscopy literature. Journal of Clinical Psychiatry, 75, 1226–1241. https://doi.org/10.4088/JCP.13r08767
58.
TalA.KirovI. I.GrossmanR. I.GonenO. (2012). The role of gray and white matter segmentation in quantitative proton MR spectroscopic imaging. NMR Biomedicine, 25, 1392–1400. https://doi.org/10.1002/nbm.2812
59.
TillmanR.GellerB. (2006). Controlled study of switching from attention-deficit/hyperactivity disorder to a prepubertal and early adolescent bipolar I disorder phenotype during 6-year prospective follow-up: Rate, risk, and predictors. Development and Psychopathology, 18, 1037–1053. https://doi.org/10.1017/S0954579406060512
TräberF.BlockW.LamerichsR.GiesekeJ.SchildH. H. (2004). 1H metabolite relaxation times at 3.0 tesla: Measurements of T1 and T2 values in normal brain and determination of regional differences in transverse relaxation. Journal of Magnetic Resonance Imaging, 19, 537–545. https://doi.org/10.1002/jmri.20053
WechslerD. (1999). Wechsler abbreviated scale for intelligence. Harcourt Brace.
64.
WigunaT.GuerreroA. P.WibisonoS.SastroasmoroS. (2012). Effect of 12-week administration of 20-mg long-acting methylphenidate on Glu/Cr, NAA/Cr, Cho/Cr, and mI/Cr ratios in the prefrontal cortices of school-age children in Indonesia: A study using 1H magnetic resonance spectroscopy (MRS). Clinical Neuropharmacology, 35, 81–85. https://doi.org/10.1097/WNF.0b013e3182452572
65.
WilensT. E.BiedermanJ.FaraoneS. V.MartelonM.WesterbergD.SpencerT. J. (2009). Presenting ADHD symptoms, subtypes, and comorbid disorders in clinically referred adults with ADHD. Journal of Clinical Psychiatry, 70, 1557–1562. https://doi.org/10.4088/JCP.08m04785pur
66.
WoolrichM. W.JbabdiS.PatenaudeB.ChappellM.MakniS.BehrensT.BeckmannC.JenkinsonM.SmithS. M. (2009). Bayesian analysis of neuroimaging data in FSL. Neuroimage, 45(1), S173–S186. https://doi.org/10.1016/j.neuroimage.2008.10.055.
67.
WozniakJ.BiedermanJ.KielyK.AblonJ. S.FaraoneS. V.MundyE.MenninD. (1995). Mania-like symptoms suggestive of childhood-onset bipolar disorder in clinically referred children. Journal of the American Academy of Child & Adolescent Psychiatry, 34, 867–876. https://doi.org/10.1097/00004583-199507000-00010
68.
YamasakiH.LaBarK. S.McCarthyG. (2002). Dissociable prefrontal brain systems for attention and emotion. Proceedings of the National Academy of Sciences of the USA, 99, 11447–11451. https://doi.org/10.1073/pnas.182176499
69.
YoungR. C.BiggsJ. T.ZieglerV. E.MeyerD. A. (1978). A rating scale for mania: Reliability, validity and sensitivity. British Journal of Psychiatry, 133, 429–435. https://doi.org/10.1192/bjp.133.5.429
70.
ZhangW.NeryF. G.TallmanM. J.PatinoL. R.AdlerC. M.StrawnJ. R.FleckD. E.BarzmanD. H.SweeneyJ. A.StrakowskiS. M.LuiS.DelBelloM. P. (2021). Individual prediction of symptomatic converters in youth offspring of bipolar parents using proton magnetic resonance spectroscopy. European Child and Adolescent Psychiatry, 30, 55–64. https://doi.org/10.1007/s00787-020-01483-x
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