Skip to main content

Meta-analyses of cognitive functioning in euthymic bipolar patients and their first-degree relatives

  • B. Arts (a1), N. Jabben (a1), L. Krabbendam (a1) and J. van Os (a1) (a2)

Previous work suggests that impairments in executive function and verbal memory in particular may persist in euthymic bipolar patients and serve as an indicator of genetic risk (endophenotype).


A systematic review of the literature was undertaken. Effects sizes were extracted from selected papers and pooled using meta-analytical techniques.


In bipolar patients, large effect sizes (d>0.8) were noted for executive functions (working memory, executive control, fluency) and verbal memory. Medium effect sizes (0.5<d<0.8) were reported for aspects of executive function (concept shifting, executive control), mental speed, visual memory, and sustained attention. Small effect sizes (d<0.5) were found for visuoperception. In first-degree relatives, effect sizes were small (d<0.5), but significantly different from healthy controls for executive function and verbal memory in particular.


Executive function and verbal memory are candidate bipolar endophenotypes given large deficits in these domains in bipolar patients and small, but intermediate, cognitive impairments in first-degree relatives.

Corresponding author
*Address for correspondence: B. M. G. Arts, Department of Psychiatry and Neuropsychology, South Limburg Mental Health Research and Teaching Network, EURON, Maastricht University, PO Box 616 (KAP2), 6200 MD Maastricht, The Netherlands. (Email:
Hide All
Altshuler LL, Ventura J, van Gorp WG, Green MF, Theberge DC, Mintz J (2004). Neurocognitive function in clinically stable men with bipolar I disorder or schizophrenia and normal control subjects. Biological Psychiatry 56, 560569.
Balanza-Martinez V, Tabares-Seisdebos R, Selva-Vera G, Martinez-Aran A, Torrent C, Salazar-Fraile J, Leal-Cerbos C, Vieta E, Gomez-Beneyto M (2005). Persistent cognitive dysfunctions in bipolar I disorder and schizophrenic patients: a 3-year follow-up study. Psychotherapy and Psychosomatics 74, 113119.
Bath KG, Lee FS (2006). Variant BDNF (Val66Met) impact on brain structure and function. Cognitive, Affective and Behavioral Neuroscience 6, 7985.
Benton AL, Hamsher K (1978). Multilingual Aphasia Examination Manual, revised. University of Iowa: Iowa.
Bertolino A, Caforio G, Petruzzella V, Latorre V, Rubino V, Dimalta S, Torraco A, Blasi G, Quartesan R, Mattay VS, Callicott JH, Weinberger DR, Scarabino T (2006). Prefrontal dysfunction in schizophrenia controlling for COMT Val158Met genotype and working memory performance. Psychiatry Research 147, 221226.
Bilder RM, Volavka J, Lachman HM, Grace AA (2004). The catechol-O-methyltransferase polymorphism: relations to the tonic-phasic dopamine hypothesis and neuropsychiatric phenotypes. Neuropsychopharmacology 29, 19431961.
Blumberg HP, Leung HC, Skudlarski P, Lacadie CM, Fredericks CA, Harris BC, Charney DS, Gore JC, Krystal JH, Peterson BS (2003). A functional magnetic resonance imaging study of bipolar disorder: state- and trait-related dysfunction in ventral prefrontal cortices. Archives of General Psychiatry 60, 601609.
Bozikas VP, Andreou C, Giannakou M, Tonia T, Anezoulaki D, Karavatos A, Fokas K, Kosmidis MH (2005). Deficits in sustained attention in schizophrenia but not in bipolar disorder. Schizophrenia Research 78, 225233.
Brand N, Jolles J (1985). Learning and retrieval rate of words presented auditorily and visually. Journal of General Psychology 112, 201210.
Brooks JO 3rd, Wang PW, Strong C, Sachs N, Hoblyn JC, Fenn R, Ketter TA (2006). Preliminary evidence of differential relations between prefrontal cortex metabolism and sustained attention in depressed adults with bipolar disorder and healthy controls. Bipolar Disorders 8, 248254.
Burdick KE, Goldberg JF, Harrow M, Faull RN, Malhotra AK (2006). Neurocognition as a stable endophenotype in bipolar disorder and schizophrenia. Journal of Nervous and Mental Disease 194, 255260.
Cannon TD, Hennah W, van Erp TG, Thompson PM, Lonnqvist J, Huttunen M, Gasperoni T, Tuulio-Henriksson A, Pirkola T, Toga AW, Kaprio J, Mazziotta J, Peltonen L (2005). Association of DISC1/TRAX haplotypes with schizophrenia, reduced prefrontal gray matter, and impaired short- and long-term memory. Archives of General Psychiatry 62, 12051213.
Cavanagh JT, Van Beck M, Muir W, Blackwood DH (2002). Case-control study of neurocognitive function in euthymic patients with bipolar disorder: an association with mania. British Journal of Psychiatry 180, 320326.
Christensen MV, Kyvik KO, Kessing LV (2006). Cognitive function in unaffected twins discordant for affective disorder. Psychological Medicine 36, 11191129.
Clark L, Iversen SD, Goodwin GM (2002). Sustained attention deficit in bipolar disorder. British Journal of Psychiatry 180, 313319.
Clark L, Kempton MJ, Scarna A, Grasby PM, Goodwin GM (2005 a). Sustained attention-deficit confirmed in euthymic bipolar disorder but not in first-degree relatives of bipolar patients or euthymic unipolar depression. Biological Psychiatry 57, 183187.
Clark L, Sarna A, Goodwin GM (2005 b). Impairment of executive function but not memory in first-degree relatives of patients with bipolar I disorder and in euthymic patients with unipolar depression. American Journal of Psychiatry 162, 19801982.
Craddock N, O'Donovan MC, Owen MJ (2006). Genes for schizophrenia and bipolar disorder? Implications for psychiatric nosology. Schizophrenia Bulletin 32, 916.
Deckersbach T, McMurrich S, Ogutha J, Savage CR, Sachs G, Rauch SL (2004 a). Characteristics of non-verbal memory impairment in bipolar disorder: the role of encoding strategies. Psychological Medicine 34, 823832.
Deckersbach T, Savage CR, Reilly-Harrington N, Clark L, Sachs G, Rauch SL (2004 b). Episodic memory impairment in bipolar disorder and obsessive-compulsive disorder: the role of memory strategies. Bipolar Disorders 6, 233244.
Delis DC, Kramer JH, Kaplan E, Ober BA (1987). California Verbal Learning Test: Adult version. The Psychological Corporation: San Antonio, TX.
Dixon T, Kravariti E, Frith C, Murray RM, McGuire PK (2004). Effect of symptoms on executive function in bipolar illness. Psychological Medicine 34, 811821.
Drabant EM, Hariri AR, Meyer-Lindenberg A, Munoz KE, Mattay VS, Kolachana BS, Egan MF, Weinberger DR (2006). Catechol O-methyltransferase Val158Met genotype and neural mechanisms related to affective arousal and regulation. Archives of General Psychiatry 63, 13961406.
Duff K, Schoenberg MR, Scott JG, Adams RL (2005). The relationship between executive functioning and verbal and visual learning and memory. Archives of Clinical Neuropsychology 20, 111122.
Ferrier IN, Chowdhury R, Thompson JM, Watson S, Young AH (2004). Neurocognitive function in unaffected first-degree relatives of patients with bipolar disorder: a preliminary report. Bipolar Disorders 6, 319322.
Ferrier IN, Stanton BR, Kelly TP, Scott J (1999). Neuropsychological function in euthymic patients with bipolar disorder. British Journal of Psychiatry 175, 246251.
Fleck DE, Shear PK, Zimmerman ME, Getz GE, Corey KB, Jak A, Lebowitz BK, Strakowski SM (2003). Verbal memory in mania: effects of clinical state and task requirements. Bipolar Disorders 5, 375380.
Frangou S, Donaldson S, Hadjulis M, Landau S, Goldstein LH (2005 a). The Maudsley Bipolar Disorder Project: executive dysfunction in bipolar disorder I and its clinical correlates. Biological Psychiatry 58, 859864.
Frangou S, Haldane M, Roddy D, Kumari V (2005 b). Evidence for deficit in tasks of ventral, but not dorsal, prefrontal executive function as an endophenotypic marker for bipolar disorder. Biological Psychiatry 58, 838839.
Glahn DC, Bearden CE, Bowden CL, Soares JC (2006). Reduced educational attainment in bipolar disorder. Journal of Affective Disorders 92, 309312.
Glahn DC, Bearden CE, Niendam TA, Escamilla MA (2004). The feasibility of neuropsychological endophenotypes in the search for genes associated with bipolar affective disorder. Bipolar Disorders 6, 171182.
Goldberg TE, Egan MF, Gscheidle T, Coppola R, Weickert T, Kolachana BS, Goldman D, Weinberger DR (2003). Executive subprocesses in working memory: relationship to catechol-O-methyltransferase Val158Met genotype and schizophrenia. Archives of General Psychiatry 60, 889896.
Goswami U, Gulrajani C, Moore PB, Varma A, Young AH, Khastgir U, Sharma AN (2002). Neurocognitive decline in bipolar mood disorder: role of mood stabilizers. Journal of Psychopharmacology 16, A45.
Goswami U, Sharma A, Khastigir U, Ferrier IN, Young AH, Gallagher P, Thompson JM, Moore PB (2006). Neuropsychological dysfunction, soft neurological signs and social disability in euthymic patients with bipolar disorder. British Journal of Psychiatry 188, 366373.
Gottesman II, Gould TD (2003). The endophenotype concept in psychiatry: etymology and strategic intentions. American Journal of Psychiatry 160, 636645.
Gourovitch ML, Torrey EF, Gold JM, Randolph C, Weinberger DR, Goldberg TE (1999). Neuropsychological performance of monozygotic twins discordant for bipolar disorder. Biological Psychiatry 45, 639646.
Green EK, Raybould R, Macgregor S, Gordon-Smith K, Heron J, Hyde S, Grozeva D, Hamshere M, Williams N, Owen MJ, O'Donovan MC, Jones L, Jones I, Kirov G, Craddock N (2005). Operation of the schizophrenia susceptibility gene, neuregulin 1, across traditional diagnostic boundaries to increase risk for bipolar disorder. Archives of General Psychiatry 62, 642648.
Grober E, Sliwinski M (1991). Development and validation of a model for estimating premorbid verbal intelligence in the elderly. Journal of Clinical and Experimental Neuropsychology 19, 933949.
Harkavy-Friedman JM, Keilp JG, Grunebaum MF, Sher L, Printz D, Burke AK, Mann JJ, Oquendo M (2006). Are BPI and BPII suicide attempters distinct neuropsychologically? Journal of Affective Disorders 94, 255259.
Harrison PJ, Law AJ (2006). Neuregulin 1 and schizophrenia: genetics, gene expression, and neurobiology. Biological Psychiatry 60, 132140.
Hasler G, Drevets WC, Gould TD, Gottesman II, Manji HK (2006). Toward constructing an endophenotype strategy for bipolar disorders. Biological Psychiatry 60, 93105.
Heaton RK (1981). A Manual for the Wisconsin Card Sorting Test. Psychological Assessment Resources: Odessa, FL.
Heydebrand G (2006). Cognitive deficits in the families of patients with schizophrenia. Current Opinion in Psychiatry 19, 277281.
Kéri S, Kelemen O, Benedek G, Janka Z (2001). Different trait markers for schizophrenia and bipolar disorder: a neurocognitive approach. Psychological Medicine 31, 915922.
Kieseppa T, Tuulio-Henriksson A, Haukka J, Van Erp T, Glahn D, Cannon TD, Partonen T, Kaprio J, Lonnqvist J (2005). Memory and verbal learning functions in twins with bipolar-I disorder, and the role of information-processing speed. Psychological Medicine 35, 205215.
Krabbendam L, Arts B, van Os J, Aleman A (2005). Cognitive functioning in patients with schizophrenia and bipolar disorder: a quantitative review. Schizophrenia Research 80, 137149.
Krabbendam L, Honig A, Wiersma J, Vuurman EF, Hofman PA, Derix MM, Nolen WA, Jolles J (2000). Cognitive dysfunctions and white matter lesions in patients with bipolar disorder in remission. Acta Psychiatrica Scandinavica 101, 274280.
Kremen WS, Faraone SV, Seidman LJ, Pepple JR, Tsuang MT (1998). Neuropsychological risk indicators for schizophrenia: a preliminary study of female relatives of schizophrenic and bipolar probands. Psychiatry Research 79, 227240.
Kurtz MM, Ragland JD, Bilker W, Gur RC, Gur RE (2001). Comparison of the continuous performance test with and without working memory demands in healthy controls and patients with schizophrenia. Schizophrenia Research 48, 307316.
Larson ER, Shear PK, Krikorian R, Welge J, Strakowski SM (2005). Working memory and inhibitory control among manic and euthymic patients with bipolar disorder. Journal of the International Neuropsychological Society 11, 163172.
Lezak MD (1995). Neuropsychological Assessment. Oxford University Press: New York.
Malhi GS, Lagopoulos J, Sachdev PS, Ivanovski B, Shnier R (2005). An emotional Stroop functional MRI study of euthymic bipolar disorder. Bipolar Disorders 7 (Suppl. 5), 5869.
Martinez-Aran A, Vieta E, Reinares M, Colom F, Torrent C, Sanchez-Moreno J, Benabarre A, Goikolea JM, Comes M, Salamero M (2004). Cognitive function across manic or hypomanic, depressed, and euthymic states in bipolar disorder. American Journal of Psychiatry 161, 262270.
Mata I, Arranz MJ, Staddon S, Lopez-Ilundain JM, Tabares-Seisdedos R, Murray RM (2006). The high-activity Val allele of the catechol-O-methyltransferase gene predicts greater cognitive deterioration in patients with psychosis. Psychiatric Genetics 16, 213216.
McIntosh AM, Harrison LK, Forrester K, Lawrie SM, Johnstone EC (2005). Neuropsychological impairments in people with schizophrenia or bipolar disorder and their unaffected relatives. British Journal of Psychiatry 186, 378385.
Minzenberg MJ, Xu K, Mitropoulou V, Harvey PD, Finch T, Flory JD, New AS, Goldman D, Siever LJ (2006). Catechol-O-methyltransferase Val158Met genotype variation is associated with prefrontal-dependent task performance in schizotypal personality disorder patients and comparison groups. Psychiatric Genetics 16, 117124.
Murray RM, Sham P, Van Os J, Zanelli J, Cannon M, McDonald C (2004). A developmental model for similarities and dissimilarities between schizophrenia and bipolar disorder. Schizophrenia Research 71, 405416.
Nehra R, Chakrabarti S, Pradhan BK, Khehra N (2006). Comparison of cognitive functions between first- and multi-episode bipolar affective disorders. Journal of Affective Disorders 93, 185192.
Newcomer JW (2006). Medical risk in patients with bipolar disorder and schizophrenia. Journal of Clinical Psychiatry 67 (Suppl. 9), 2530.
Pirkola T, Tuulio-Henriksson A, Glahn D, Kieseppa T, Haukka J, Kaprio J, Lonnqvist J, Cannon TD (2005). Spatial working memory function in twins with schizophrenia and bipolar disorder. Biological Psychiatry 58, 930936.
Porteous DJ, Thomson P, Brandon NJ, Millar JK (2006). The genetics and biology of DISC1 – an emerging role in psychosis and cognition. Biological Psychiatry 60, 123131.
Reitan RM (1958). Validity of the Trail Making Test as an indicator of organic brain damage. Perceptual and Motor Skills 8, 271276.
Rey A (1941). Psychological examination in cases of traumatic encephalopathy: problems [in French]. Archives de Psychologie 28, 215285.
Rey A (1964). L'Examen Psychologique dans les Cas d'Encephalopathie Traumatique. Presses Universitaires de France: Paris.
Robinson LJ, Ferrier IN (2006). Evolution of cognitive impairment in bipolar disorder: a systematic review of cross-sectional evidence. Bipolar Disorders 8, 103116.
Robinson LJ, Thompson JM, Gallagher P, Goswami U, Young AH, Ferrier IN, Moore PB (2006). A meta-analysis of cognitive deficits in euthymic patients with bipolar disorder. Journal of Affective Disorders 93, 105115.
Rosa A, Peralta V, Cuesta MJ, Zarzuela A, Serrano F, Martinez-Larrea A, Fananas L (2004). New evidence of association between COMT gene and prefrontal neurocognitive function in healthy individuals from sibling pairs discordant for psychosis. American Journal of Psychiatry 161, 11101112.
Ross CA, Margolis RL, Reading SA, Pletnikov M, Coyle JT (2006). Neurobiology of schizophrenia. Neuron 52, 139153.
Savitz J, Solms M, Ramesar R (2005 a). Neuropsychological dysfunction in bipolar affective disorder: a critical opinion. Bipolar Disorders 7, 216235.
Savitz JB, Solms M, Ramesar RS (2005 b). Neurocognitive function as an endophenotype for genetic studies of bipolar affective disorder. Neuromolecular Medicine 7, 275286.
Schillo S, Pejovic V, Hunzinger C, Hansen T, Poznanovic S, Kriegsmann J, Schmidt WJ, Schrattenholz A (2005). Integrative proteomics: functional and molecular characterization of a particular glutamate-related neuregulin isoform. Journal of Proteome Research 4, 900908.
Schubert EW, McNeil TF (2005). Neuropsychological impairment and its neurological correlates in adult offspring with heightened risk for schizophrenia and affective psychosis. American Journal of Psychiatry 162, 758766.
Scolnick EM, Petryshen T, Sklar P (2006). Schizophrenia: do the genetics and neurobiology of neuregulin provide a pathogenesis model? Harvard Review of Psychiatry 14, 6477.
Sitskoorn MM, Aleman A, Ebisch SJ, Appels MC, Kahn RS (2004). Cognitive deficits in relatives of patients with schizophrenia: a meta-analysis. Schizophrenia Research 71, 285295.
Snitz BE, Macdonald AW 3rd, Carter CS (2006). Cognitive deficits in unaffected first-degree relatives of schizophrenia patients: a meta-analytic review of putative endophenotypes. Schizophrenia Bulletin 32, 179194.
Sobczak S, Honig A, Schmitt JA, Riedel WJ (2003). Pronounced cognitive deficits following an intravenous l-tryptophan challenge in first-degree relatives of bipolar patients compared to healthy controls. Neuropsychopharmacology 28, 711719.
Strakowski SM, Adler CM, Holland SK, Mills N, DelBello MP (2004). A preliminary FMRI study of sustained attention in euthymic, unmedicated bipolar disorder. Neuropsychopharmacology 29, 17341740.
Strakowski SM, Delbello MP, Adler CM (2005). The functional neuroanatomy of bipolar disorder: a review of neuroimaging findings. Molecular Psychiatry 10, 105116.
Stroop JR (1935). Studies of interference in serial verbal reactions. Journal of Experimental Psychology 18, 643662.
Szoke A, Schurhoff F, Golmard JL, Alter C, Roy I, Meary A, Etain B, Bellivier F, Leboyer M (2006). Familial resemblance for executive functions in families of schizophrenic and bipolar patients. Psychiatry Research 144, 131138.
Szoke A, Schurhoff F, Mathieu F, Meary A, Ionescu S, Leboyer M (2005). Tests of executive functions in first-degree relatives of schizophrenic patients: a meta-analysis. Psychological Medicine 35, 771782.
Thompson JM, Gallagher P, Hughes JH, Watson S, Gray JM, Ferrier IN, Young AH (2005). Neurocognitive impairment in euthymic patients with bipolar affective disorder. British Journal of Psychiatry 186, 3240.
Thompson JM, Hamilton CJ, Gray JM, Quinn JG, Mackin P, Young AH, Ferrier IN (2006). Executive and visuospatial sketchpad resources in euthymic bipolar disorder: implications for visuospatial working memory architecture. Memory 14, 437451.
Torrent C, Martinez-Aran A, Daban C, Sanchez-Moreno J, Comes M, Goikolea JM, Salamero M, Vieta E (2006). Cognitive impairment in bipolar II disorder. British Journal of Psychiatry 189, 254259.
Toulopoulou T, Quraishi S, McDonald C, Murray RM (2006). The Maudsley Family Study: premorbid and current general intellectual function levels in familial bipolar I disorder and schizophrenia. Journal of Clinical and Experimental Neuropsychology 28, 243259.
Tunbridge EM, Harrison PJ, Weinberger DR (2006). Catechol-o-methyltransferase, cognition, and psychosis: Val158Met and beyond. Biological Psychiatry 60, 141151.
van Gorp WG, Altshuler L, Theberge DC, Wilkins J, Dixon W (1998). Cognitive impairment in euthymic bipolar patients with and without prior alcohol dependence. A preliminary study. Archives of General Psychiatry 55, 4146.
Varga M, Magnusson A, Flekkoy K, Ronneberg U, Opjordsmoen S (2006). Insight, symptoms and neurocognition in bipolar I patients. Journal of Affective Disorders 91, 19.
Wechsler D (1955). Wechsler Adult Intelligence Scale (Manual). Psychological Corporation: New York.
Wechsler D (1981). Wechsler Adult Intelligence Scale – Revised. Psychological Corporation: New York.
Woodward ND, Jayathilake K, Meltzer HY (2007). COMT Val108/158Met genotype, cognitive function, and cognitive improvement with clozapine in schizophrenia. Schizophrenia Research 90, 8696.
Yurgelun-Todd DA, Ross AJ (2006). Functional magnetic resonance imaging studies in bipolar disorder. CNS Spectrums 11, 287297.
Zalla T, Joyce C, Szoke A, Schurhoff F, Pillon B, Komano O, Perez-Diaz F, Bellivier F, Alter C, Dubois B, Rouillon F, Houde O, Leboyer M (2004). Executive dysfunctions as potential markers of familial vulnerability to bipolar disorder and schizophrenia. Psychiatry Research 121, 207217.
Zubieta JK, Huguelet P, O'Neil RL, Giordani BJ (2001). Cognitive function in euthymic bipolar I disorder. Psychiatry Research 102, 920.
Recommend this journal

Email your librarian or administrator to recommend adding this journal to your organisation's collection.

Psychological Medicine
  • ISSN: 0033-2917
  • EISSN: 1469-8978
  • URL: /core/journals/psychological-medicine
Please enter your name
Please enter a valid email address
Who would you like to send this to? *



Altmetric attention score

Full text views

Total number of HTML views: 20
Total number of PDF views: 173 *
Loading metrics...

Abstract views

Total abstract views: 895 *
Loading metrics...

* Views captured on Cambridge Core between September 2016 - 21st November 2017. This data will be updated every 24 hours.