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Cross-Disorder Cognitive Impairments in Youth Referred for Neuropsychiatric Evaluation

  • Alysa E. Doyle (a1) (a2) (a3) (a4), Pieter J. Vuijk (a3), Nathan D. Doty (a1) (a2), Lauren M. McGrath (a5), Brian L. Willoughby (a1) (a2), Ellen H. O’Donnell (a1) (a2), H. Kent Wilson (a1) (a2), Mary K. Colvin (a1) (a2), Deanna C. Toner (a3), Kelsey E. Hudson (a3), Jessica E. Blais (a3), Hillary L. Ditmars (a3), Stephen V. Faraone (a6), Larry J. Seidman (a2) (a7) and Ellen B. Braaten (a1) (a2)...


Objectives: Studies suggest that impairments in some of the same domains of cognition occur in different neuropsychiatric conditions, including those known to share genetic liability. Yet, direct, multi-disorder cognitive comparisons are limited, and it remains unclear whether overlapping deficits are due to comorbidity. We aimed to extend the literature by examining cognition across different neuropsychiatric conditions and addressing comorbidity. Methods: Subjects were 486 youth consecutively referred for neuropsychiatric evaluation and enrolled in the Longitudinal Study of Genetic Influences on Cognition. First, we assessed general ability, reaction time variability (RTV), and aspects of executive functions (EFs) in youth with non-comorbid forms of attention-deficit/hyperactivity disorder (ADHD), mood disorders and autism spectrum disorder (ASD), as well as in youth with psychosis. Second, we determined the impact of comorbid ADHD on cognition in youth with ASD and mood disorders. Results: For EFs (working memory, inhibition, and shifting/ flexibility), we observed weaknesses in all diagnostic groups when participants’ own ability was the referent. Decrements were subtle in relation to published normative data. For RTV, weaknesses emerged in youth with ADHD and mood disorders, but trend-level results could not rule out decrements in other conditions. Comorbidity with ADHD did not impact the pattern of weaknesses for youth with ASD or mood disorders but increased the magnitude of the decrement in those with mood disorders. Conclusions: Youth with ADHD, mood disorders, ASD, and psychosis show EF weaknesses that are not due to comorbidity. Whether such cognitive difficulties reflect genetic liability shared among these conditions requires further study. (JINS, 2018, 24, 91–103)


Corresponding author

Correspondence and reprint requests to: Alysa E. Doyle, Center for Genomic Medicine, Massachusetts General Hospital, 185 Cambridge Street, CPZN 6240, Boston, MA 02114. E-mail:


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Agnew-Blais, J., & Seidman, L.J. (2013). Neurocognition in youth and young adults under age 30 at familial risk for schizophrenia: A quantitative and qualitative review. Cognitive Neuropsychiatry, 18(1-2), 4482.
Alderson, R.M., Kasper, L.J., Hudec, K.L., & Patros, C.H. (2013). Attention-deficit/hyperactivity disorder (ADHD) and working memory in adults: A meta-analytic review. Neuropsychology, 27(3), 287302.
Barkley, R.A. (1997). Behavioral inhibition, sustained attention, and executive functions: Constructing a unifying theory of ADHD. Psychological Bulletin, 121(1), 6594.
Bidwell, L.C., Willcutt, E.G., Defries, J.C., & Pennington, B.F. (2007). Testing for neuropsychological endophenotypes in siblings discordant for attention-deficit/hyperactivity disorder. Biological Psychiatry, 62(9), 991998.
Biederman, J., Petty, C., Fried, R., Fontanella, J., Doyle, A.E., Seidman, L.J., && Faraone, S.V. (2006). Impact of psychometrically defined deficits of executive functioning in adults with attention deficit hyperactivity disorder. American Journal of Psychiatry, 163(10), 17301738.
Bora, E., Vahip, S., & Akdeniz, F. (2006). Sustained attention deficits in manic and euthymic patients with bipolar disorder. Progress in Neuro-psychopharmacologogy & Biological Psychiatry, 30(6), 10971102.
Bora, E., Yucel, M., & Pantelis, C. (2009). Cognitive endophenotypes of bipolar disorder: A meta-analysis of neuropsychological deficits in euthymic patients and their first-degree relatives. Journal of Affective Disorders, 113(1-2), 120.
Bourne, C., Aydemir, O., Balanza-Martinez, V., Bora, E., Brissos, S., Cavanagh, J.T., & Goodwin, G.M. (2013). Neuropsychological testing of cognitive impairment in euthymic bipolar disorder: An individual patient data meta-analysis. Acta Psychiatrica Scandinavica, 128(3), 149162.
Brotman, M.A., Rooney, M.H., Skup, M., Pine, D.S., & Leibenluft, E. (2009). Increased intrasubject variability in response time in youths with bipolar disorder and at-risk family members. Journal of the American Academy of Child and Adolescent Psychiatry, 48(6), 628635.
Buckley, P.F., Miller, B.J., Lehrer, D.S., & Castle, D.J. (2009). Psychiatric comorbidities and schizophrenia. Schizophrenia Bulletin, 35(2), 383402.
Conners, C. (2000). Conners Continuous Performance Test II (CPT-II): Technical Guide and Software Manual. North Tonwanda, NY: Multi-Health Systems.
Craddock, N., Kendler, K., Neale, M., Nurnberger, J., Purcell, S., Rietschel, M., & Thapar, A. (2009). Dissecting the phenotype in genome-wide association studies of psychiatric illness. British Journal of Psychiatry, 195(2), 9799.
Craig, F., Margari, F., Legrottaglie, A.R., Palumbi, R., de Giambattista, C., & Margari, L. (2016). A review of executive function deficits in autism spectrum disorder and attention-deficit/hyperactivity disorder. Neuropsychiatric Disease and Treatment, 12, 11911202.
Cuthbert, B.N. (2015). Research domain criteria: Toward future psychiatric nosologies. Dialogues in Clinical Neuroscience, 17(1), 8997.
Dajani, D.R., Llabre, M.M., Nebel, M.B., Mostofsky, S.H., & Uddin, L.Q. (2016). Heterogeneity of executive functions among comorbid neurodevelopmental disorders. Scientific Reports, 6, 36566.
Delis, D.C., Kramer, J.H., Kaplan, E., & Holdnack, J. (2004). Reliability and validity of the Delis-Kaplan Executive Function System: An update. Journal of the International Neuropsychological Society, 10(2), 301303.
Denckla, M.B. (1994). Measurement of excutive function. In G.J. Lyon (Ed.), Frames of reference for the assessment of learning disabilities: New views on measurement issues (pp. 117142). Baltimore: Brooks.
Doyle, A.E., Wozniak, J., Wilens, T.E., Henin, A., Seidman, L.J., Petty, C., & Biederman, J. (2009). Neurocognitive impairment in unaffected siblings of youth with bipolar disorder. Psychological Medicine, 39(8), 12531263.
Fioravanti, M., Bianchi, V., & Cinti, M.E. (2012). Cognitive deficits in schizophrenia: An updated metanalysis of the scientific evidence. BMC Psychiatry, 12, 64.
Fombonne, E., Bolton, P., Prior, J., Jordan, H., & Rutter, M. (1997). A family study of autism: Cognitive patterns and levels in parents and siblings. Journal of Child Psychology and Psychiatry, and Allied Disciplines, 38(6), 667683.
Forbes, N.F., Carrick, L.A., McIntosh, A.M., & Lawrie, S.M. (2009). Working memory in schizophrenia: A meta-analysis. Psychological Medicine, 39(6), 889905.
Frazier, J.A., Giuliano, A.J., Johnson, J.L., Yakutis, L., Youngstrom, E.A., Breiger, D., & Hooper, S.R. (2012). Neurocognitive outcomes in the Treatment of Early-Onset Schizophrenia Spectrum Disorders study. Journal of the American Academy of Child and Adolescent Psychiatry, 51(5), 496505.
Geurts, H.M., van den Bergh, S.F., & Ruzzano, L. (2014). Prepotent response inhibition and interference control in autism spectrum disorders: Two meta-analyses. Autism Research, 7, 407420.
Goldberg, M.C., Mostofsky, S.H., Cutting, L.E., Mahone, E.M., Astor, B.C., Denckla, M.B., &&Landa, R.J. (2005). Subtle executive impairment in children with autism and children with ADHD. Journal of Autism and Developmental Disorders, 35(3), 279293.
Green, M.F. (2006). Cognitive impairment and functional outcome in schizophrenia and bipolar disorder. The Journal of Clinical Psychiatry, 67(10), e12.
Iverson, G.L., Lange, R.T., Viljoen, H., & Brink, J. (2006). WAIS-III General Ability Index in neuropsychiatry and forensic psychiatry inpatient samples. Archives of Clinical Neuropsychology, 21(1), 7782.
Jacobson, M.W., Delis, D.C., Bondi, M.W., & Salmon, D.P. (2002). Do neuropsychological tests detect preclinical Alzheimer’s disease: Individual-test versus cognitive-discrepancy score analyses. Neuropsychology, 16(2), 132139.
Joseph, M.F., Frazier, T.W., Youngstrom, E.A., & Soares, J.C. (2008). A quantitative and qualitative review of neurocognitive performance in pediatric bipolar disorder. Journal of Child and Adolescent Psychopharmacology, 18(6), 595605.
Kaiser, S., Roth, A., Rentrop, M., Friederich, H.C., Bender, S., & Weisbrod, M. (2008). Intra-individual reaction time variability in schizophrenia, depression and borderline personality disorder. Brain and Cognition, 66(1), 7382.
Karalunas, S.L., Geurts, H.M., Konrad, K., Bender, S., & Nigg, J.T. (2014). Annual research review: Reaction time variability in ADHD and autism spectrum disorders: Measurement and mechanisms of a proposed trans-diagnostic phenotype. Journal of Child Psychology and Psychiatry, and Allied Disciplines, 55(6), 685710.
Kasper, L.J., Alderson, R.M., & Hudec, K.L. (2012). Moderators of working memory deficits in children with attention-deficit/hyperactivity disorder (ADHD): A meta-analytic review. Clinical Psychology Review, 32(7), 605617.
Kofler, M.J., Rapport, M.D., Sarver, D.E., Raiker, J.S., Orban, S.A., Friedman, L.M., &&Kolomeyer, E.G. (2013). Reaction time variability in ADHD: A meta-analytic review of 319 studies. Clinical Psychology Review, 33(6), 795811.
Krukow, P., Szaniawska, O., Harciarek, M., Plechawska-Wojcik, M., & Jonak, K. (2017). Cognitive inconsistency in bipolar patients is determined by increased intra-individual variability in initial phase of task performance. Journal of Affective Disorders, 210, 222225.
Kuntsi, J., Eley, T.C., Taylor, A., Hughes, C., Asherson, P., Caspi, A., &&Moffitt, T.E. (2004). Co-occurrence of ADHD and low IQ has genetic origins. American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics, 124B(1), 4147.
Kuntsi, J., Rogers, H., Swinard, G., Borger, N., van der Meere, J., Rijsdijk, F., &&Asherson, P. (2006). Reaction time, inhibition, working memory and ‘delay aversion’ performance: Genetic influences and their interpretation. Psychological Medicine, 36(11), 16131624.
Landis, J.R., & Koch, G.G. (1977). The measurement of observer agreement for categorical variables. Biometrics, 33, 159174.
Lee, S.H., Ripke, S., Neale, B.M., Faraone, S.V., Purcell, S.M., Perlis, R.H., & Wray, N.R. (2013). Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs. Nature Genetics, 45(9), 984994.
Lipszyc, J., & Schachar, R. (2010). Inhibitory control and psychopathology: A meta-analysis of studies using the stop signal task. Journal of the International Neuropsychological Society, 16(6), 10641076.
Loring, D.W. (1999). INS Dictionary of Neuropsychology. Oxford: Oxford University Press.
Malhotra, D., & Sebat, J. (2012). CNVs: Harbingers of a rare variant revolution in psychiatric genetics. Cell, 148(6), 12231241.
McLean, R.L., Johnson Harrison, A., Zimak, E., Joseph, R.M., & Morrow, E.M. (2014). Executive function in probands with autism with average IQ and their unaffected first-degree relatives. Journal of the American Academy of Child and Adolescent Psychiatry, 53(9), 10011009.
Miyake, A., & Friedman, N.P. (2012). The nature and organization of individual differences in executive functions: Four general conclusions. Current Directions in Psychological Science, 21(1), 814.
Morgan, V.A., Croft, M.L., Valuri, G.M., Zubrick, S.R., Bower, C., McNeil, T.F., && Jablensky, A.V. (2012). Intellectual disability and other neuropsychiatric outcomes in high-risk children of mothers with schizophrenia, bipolar disorder and unipolar major depression. British Journal of Psychiatry, 200(4), 282289.
Mosconi, M.W., Kay, M., D’Cruz, A.M., Guter, S., Kapur, K., Macmillan, C., & Sweeney, J.A. (2010). Neurobehavioral abnormalities in first-degree relatives of individuals with autism. Archives of General Psychiatry, 67(8), 830840.
Oerlemans, A.M., Hartman, C.A., de Bruijn, Y.G., Franke, B., Buitelaar, J.K., & Rommelse, N.N. (2015). Cognitive impairments are different in single-incidence and multi-incidence ADHD families. Journal of Child Psychology and Psychiatry, and Allied Disciplines, 56(7), 782791.
Owens, S.F., Rijsdijk, F., Picchioni, M.M., Stahl, D., Nenadic, I., Murray, R.M., &&Toulopoulou, T. (2011). Genetic overlap between schizophrenia and selective components of executive function. Schizophrenia Research, 127(1-3), 181187.
Pennington, B.F. (2006). From single to multiple deficit models of developmental disorders. Cognition, 101(2), 385413.
PGC Cross Disorder Group (2013). Identification of risk loci with shared effects on five major psychiatric disorders: A genome-wide analysis. Lancet, 381(9875), 13711379.
Prifitera, A., Weiss, L.G., & Saklofske, D.H. (1998). The WISC-III in context. In A. Prifitera & D.H. Saklofske (Eds.), W1SC-1II clinical use and interpretation: Scientist-practitioner perspective (pp. 138). San Diego, CA: Academic Press.
RDoC Cognitive Group. (2011). Cognitive Systems: Workshop Proceedings, Rockville, MD: RDoC Cognitive Group.
Sattler, J.M. (2008). Assessment of children: Cognitive foundations (5th ed.). Mesa, CA: Jerome M. Sattler, Publisher.
Seidman, L.J., Biederman, J., Valera, E.M., Monuteaux, M.C., Doyle, A.E., & Faraone, S.V. (2006). Neuropsychological functioning in girls with attention-deficit/hyperactivity disorder with and without learning disabilities. Neuropsychology, 20(2), 166177.
Seidman, L.J., Bruder, G., & Giuliano, A.J. (2008). Neuropsychological testing and neurophysiological assessment. In A. Tasman, J. Kay, J.A. Lieberman, M.B. First & M. Maj (Eds.), Psychiatry (3rd ed., pp. 556569). London: John Wiley and Sons.
Slaats-Willemse, D.I., Swaab-Barneveld, H.J., de Sonneville, L.M., & Buitelaar, J.K. (2007). Family-genetic study of executive functioning in attention-deficit/hyperactivity disorder: Evidence for an endophenotype? Neuropsychology, 21(6), 751760.
Snijders, T.A.B., & Bosker, R.J. (2012). Multilevel analysis: An introduction to basic and advanced multilevel modeling (2nd ed.). Thousand Oaks, CA: Sage Publishers.
Snitz, B.E., Macdonald, A.W. III, & Carter, C.S. (2006). Cognitive deficits in unaffected first-degree relatives of schizophrenia patients: A meta-analytic review of putative endophenotypes. Schizophrenia Bulletin, 32(1), 179194.
Snyder, H.R. (2013). Major depressive disorder is associated with broad impairments on neuropsychological measures of executive function: A meta-analysis and review. Psychological Bulletin, 139(1), 81132.
StataCorp. (2015). Stata Statistical Software: Release 14. College Station, TX: StataCorp LP.
Stefanopoulou, E., Manoharan, A., Landau, S., Geddes, J.R., Goodwin, G., & Frangou, S. (2009). Cognitive functioning in patients with affective disorders and schizophrenia: A meta-analysis. International Review of Psychiatry (Abingdon, England), 21(4), 336356.
Tamm, L., Narad, M.E., Antonini, T.N., O’Brien, K.M., Hawk, L.W. Jr., & Epstein, J.N. (2012). Reaction time variability in ADHD: A review. Neurotherapeutics, 9(3), 500508.
Thissen, A.J., Luman, M., Hartman, C., Hoekstra, P., van Lieshout, M., Franke, B., & Buitelaar, J.K. (2014). Attention-deficit/hyperactivity disorder (ADHD) and motor timing in adolescents and their parents: Familial characteristics of reaction time variability vary with age. Journal of the American Academy of Child and Adolescent Psychiatry, 53(9), 10101019.
Toulopoulou, T., Goldberg, T.E., Mesa, I.R., Picchioni, M., Rijsdijk, F., Stahl, D., &&Murray, R.M. (2010). Impaired intellect and memory: A missing link between genetic risk and schizophrenia? Archives of General Psychiatry, 67(9), 905913.
Toulopoulou, T., Picchioni, M., Rijsdijk, F., Hua-Hall, M., Ettinger, U., Sham, P., …Murray, R. (2007). Substantial genetic overlap between neurocognition and schizophrenia: Genetic modeling in twin samples. Archives of General Psychiatry, 64(12), 13481355.
Tulsky, D.S., Saklofske, D.H., Wilkins, C., & Weiss, L.G. (2001). Development of a general ability index for the Wechsler Adult Intelligence Scale--Third Edition. Psychological Assessment, 13(4), 566571.
Volkert, J., Haubner, J., Kazmaier, J., Glaser, F., Kopf, J., Kittel-Schneider, S., &&Reif, A. (2016). Cognitive deficits in first-degree relatives of bipolar patients: The use of homogeneous subgroups in the search of cognitive endophenotypes. Journal of Neural Transmission (Vienna), 123(8), 10011011.
Wagner, S., Muller, C., Helmreich, I., Huss, M., & Tadic, A. (2015). A meta-analysis of cognitive functions in children and adolescents with major depressive disorder. European Child & Adolescent Psychiatry, 24(1), 519.
Wechsler, D. (2004). The Wechsler Intelligence Scale for Children—Fourth Edition. New York: Springer.
Wechsler, D. (2008). Wechsler Adult Intelligence Scales -Fourth Edition. New York: Springer.
Westerhausen, R., Kompus, K., & Hugdahl, K. (2011). Impaired cognitive inhibition in schizophrenia: A meta-analysis of the Stroop interference effect. Schizophrenia Research, 133(1-3), 172181.
Willcutt, E.G., Doyle, A.E., Nigg, J.T., Faraone, S.V., & Pennington, B.F. (2005). Validity of the executive function theory of attention-deficit/hyperactivity disorder: A meta-analytic review. Biological Psychiatry, 57(11), 13361346.
Willcutt, E.G., Sonuga-Barke, E., Nigg, J., & Sergeant, J. (2008). Recent developments in neuropsychological models of childhood psychiatric disorders. In T. Banaschewski & L. Rohde (Eds.), Biological Child Psychiatry: Recent Trends and Developments (Vol. 24, pp. 195226). Basel, Karger.
Wong, D., Maybery, M., Bishop, D.V., Maley, A., & Hallmayer, J. (2006). Profiles of executive function in parents and siblings of individuals with autism spectrum disorders. Genes, Brain, and Behavior, 5(8), 561576.
Wood, A.C., Rijsdijk, F., Johnson, K.A., Andreou, P., Albrecht, B., Arias-Vasquez, A., & Kuntsi, J. (2011). The relationship between ADHD and key cognitive phenotypes is not mediated by shared familial effects with IQ. Psychological Medicine, 41(4), 861871.


Cross-Disorder Cognitive Impairments in Youth Referred for Neuropsychiatric Evaluation

  • Alysa E. Doyle (a1) (a2) (a3) (a4), Pieter J. Vuijk (a3), Nathan D. Doty (a1) (a2), Lauren M. McGrath (a5), Brian L. Willoughby (a1) (a2), Ellen H. O’Donnell (a1) (a2), H. Kent Wilson (a1) (a2), Mary K. Colvin (a1) (a2), Deanna C. Toner (a3), Kelsey E. Hudson (a3), Jessica E. Blais (a3), Hillary L. Ditmars (a3), Stephen V. Faraone (a6), Larry J. Seidman (a2) (a7) and Ellen B. Braaten (a1) (a2)...


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