CNS Drugs

, Volume 21, Issue 12, pp 971–981 | Cite as

Cognitive Dysfunction in Bipolar Disorder

Future Place of Pharmacotherapy
  • Katherine E. Burdick
  • Raphael J. Braga
  • Joseph F. Goldberg
  • Anil K. Malhotra
Leading Article

Abstract

Bipolar disorder is an episodic affective illness, once believed to involve complete inter-episode remission. More recent data have highlighted the presence of persistent symptoms during purported periods of Wellness, including subsyndromal affective symptoms and neurocognitive impairment. These unremitting symptoms are of extreme clinical importance, as they are directly related to a worsening of clinical course, functional impairments and psychosocial difficulties in patients with bipolar disorder. Although there is now substantial evidence demonstrating the prevalence of neurocognitive impairment during euthymia, there have been few studies, to date, targeting this disabling aspect of the illness using pharmacological strategies.

While treatment approaches have previously focused on primary affective and psychotic symptoms of the disease, it is important to consider the debilitating impact that impaired cognition has on patients with bipolar disorder. A recent focus has been placed on the significant need for large-scale clinical trials designed to specifically target cognitive impairment in patients with schizophrenia, with a parallel need existing in the field of bipolar research.

There is now early evidence for the presence of neurocognitive deficits in patients with bipolar disorder and a relationship between these impairments and functional disability, making this a symptom domain that requires immediate clinical attention. Convergent data indicate a compelling need for formal assessment of cognition in patients with bipolar disorder, and for researchers and clinicans alike to consider the necessity for treatment specific to cognition in this population. Although limited data exist from cognitive enhancement trials in this population, there are a number of potential pharmacotherapy targets based on evidence from neuroimaging, molecular genetic, pharmacological and animal studies related to the pathophysiology of bipolar disorder. Future directions for potential cognitive enhancement strategies in bipolar disorder may include medications that influence dopaminergic or glutamatergic neurotransmission; however, urther work is needed to adequately assess the safety and effectiveness of these agents in bipolar patients. Finally, psychosocial intervention and/or cognitive remediation should be considered as alternatives to medications, although these techniques will also require additional systematic study.

References

  1. 1.
    Goodwin FK, Jamison KR. Manic-depressive illness. New York: Oxford University Press, 1990Google Scholar
  2. 2.
    Murray CJ, Lopez AD. Evidence-based health policy: lessons from the Global Burden of Disease Study. Science 1996; 274(5288): 740–3PubMedCrossRefGoogle Scholar
  3. 3.
    Basso MR, Lowery N, Neel J, et al. Neuropsychological impairment among manic, depressed, and mixed-episode inpatients with bipolar disorder. Neuropsychology 2002; 16(1): 84–91PubMedCrossRefGoogle Scholar
  4. 4.
    Martinez-Aran A, Vieta E, Colom F, et al. Cognitive dysfunctions in bipolar disorder: evidence of neuropsychological disturbances. Psychother Psychosom 2000; 69(1): 2–18PubMedCrossRefGoogle Scholar
  5. 5.
    Martinez-Aran A, Vieta E, Reinares M, et al. Cognitive function across manic or hypomanic, depressed, and euthymic states in bipolar disorder. Am J Psychiatry 2004; 161(2): 262–70PubMedCrossRefGoogle Scholar
  6. 6.
    Harmer CJ, Clark L, Grayson L, et al. Sustained attention deficit in bipolar disorder is not a working memory impairment in disguise. Neuropsychologia 2002; 40(9): 1586–90PubMedCrossRefGoogle Scholar
  7. 7.
    Liu SK, Chiu CH, Chang CJ, et al. Deficits in sustained attention in schizophrenia and affective disorders: stable versus state-dependent markers. Am J Psychiatry 2002; 159(6): 975–82PubMedCrossRefGoogle Scholar
  8. 8.
    Ferrier IN, Stanton BR, Kelly TP, et al. Neuropsychological function in euthymic patients with bipolar disorder. Br J Psychiatry 1999; 175: 246–51PubMedCrossRefGoogle Scholar
  9. 9.
    Rubinsztein JS, Michael A, Paykel ES, et al. Cognitive impairment in remission in bipolar affective disorder. Psychol Med 2000; 30(5): 1025–36PubMedCrossRefGoogle Scholar
  10. 10.
    van Gorp WG, Altshuler L, Theberge DC, et al. Cognitive impairment in euthymic bipolar patients with and without prior alcohol dependence: a preliminary study. Arch Gen Psychiatry 1998; 55(1): 41–6PubMedCrossRefGoogle Scholar
  11. 11.
    Zubieta JK, Huguelet P, O’Neil RL, et al. Cognitive function in euthymic bipolar I disorder. Psychiatry Res 2001; 102(1): 9–20PubMedCrossRefGoogle Scholar
  12. 12.
    Martinez-Aran A, Vieta E, Colom F, et al. Cognitive impairment in euthymic bipolar patients: implications for clinical and functional outcome. Bipolar Disord 2004; 6(3): 224–32PubMedCrossRefGoogle Scholar
  13. 13.
    Najt P, Glahn D, Bearden CE, et al. Attention deficits in bipolar disorder: a comparison based on the Continuous Performance Test. Neurosci Lett 2005; 379(2): 122–6PubMedCrossRefGoogle Scholar
  14. 14.
    Rung JP, Carlsson A, Markinhuhta KR, et al. The dopaminergic stabilizers (−)-OSU6162 and ACR16 reverse (+)-MK-801-induced social withdrawal in rats. Prog Neuropsychopharmacol Biol Psychiatry 2005; 29(5): 833–9PubMedCrossRefGoogle Scholar
  15. 15.
    Sereno AB, Holzman PS. Spatial selective attention in schizophrenic, affective disorder, and normal subjects. Schizophr Res 1996; 20(1–2): 33–50PubMedCrossRefGoogle Scholar
  16. 16.
    Clark L, Iversen SD, Goodwin GM. Sustained attention deficit in bipolar disorder. Br J Psychiatry 2002; 180: 313–9PubMedCrossRefGoogle Scholar
  17. 17.
    McGrath J, Scheldt S, Welham J, et al. Performance on tests sensitive to impaired executive ability in schizophrenia, mania and well controls: acute and subacute phases. Schizophr Res 1997; 26(2–3): 127–37PubMedCrossRefGoogle Scholar
  18. 18.
    Zalla T, Joyce C, Szoke A, et al. Executive dysfunctions as potential markers of familial vulnerability to bipolar disorder and schizophrenia. Psychiatry Res 2004; 121(3): 207–17PubMedCrossRefGoogle Scholar
  19. 19.
    Thompson JM, Gallagher P, Hughes JH, et al. Neurocognitive impairment in euthymic patients with bipolar affective disorder. Br J Psychiatry 2005; 186: 32–40PubMedCrossRefGoogle Scholar
  20. 20.
    Burt DB, Zembar MJ, Niederehe G. Depression and memory impairment: a meta-analysis of the association, its pattern, and specificity. Psychol Bull 1995; 117(2): 285–305PubMedCrossRefGoogle Scholar
  21. 21.
    Coffman JA, Bornstein RA, Olson SC, et al. Cognitive impairment and cerebral structure by MRI in bipolar disorder. Biol Psychiatry 1990; 27(11): 1188–96PubMedCrossRefGoogle Scholar
  22. 22.
    Atre-Vaidya N, Taylor MA, Seidenberg M, et al. Cognitive deficits, psychopathology, and psychosocial functioning in bipolar mood disorder. Neuropsychiatry Neuropsychol Behav Neurol 1998; 11(3): 120–6PubMedGoogle Scholar
  23. 23.
    Dixon T, Kravariti E, Frith C, et al. Effect of symptoms on executive function in bipolar illness. Psychol Med 2004; 34(5): 811–21PubMedCrossRefGoogle Scholar
  24. 24.
    Larson ER, Shear PK, Krikorian R, et al. Working memory and inhibitory control among manic and euthymic patients with bipolar disorder. J Int Neuropsychol Soc 2005; 11(2): 163–72PubMedCrossRefGoogle Scholar
  25. 25.
    Robinson LJ, Thompson JM, Gallagher P, et al. A meta-analysis of cognitive deficits in euthymic patients with bipolar disorder. J Affect Disord 2006; 93(1–3): 105–15PubMedCrossRefGoogle Scholar
  26. 26.
    Teng CT, Demetrio FN. Memantine may acutely improve cognition and have a mood stabilizing effect in treatment-resistant bipolar disorder. Rev Bras Psiquiatr 2006; 28(3): 252–4PubMedCrossRefGoogle Scholar
  27. 27.
    Khan A, Ginsberg LD, Asnis GM, et al. Effect of lamotrigine on cognitive complaints in patients with bipolar I disorder. J Clin Psychiatry 2004; 65(11): 1483–90PubMedCrossRefGoogle Scholar
  28. 28.
    Daban C, Martinez-Aran A, Torrent C, et al. Cognitive functioning in bipolar patients receiving lamotrigine: preliminary results. J Clin Psychopharmacol 2006; 26(2): 178–81PubMedCrossRefGoogle Scholar
  29. 29.
    Jacobsen FM, Comas-Diaz L. Donepezil for psychotropic-induced memory loss. J Clin Psychiatry 1999; 60(10): 698–704PubMedCrossRefGoogle Scholar
  30. 30.
    Schrauwen E, Ghaemi SN. Galantamine treatment of cognitive impairment in bipolar disorder: four cases. Bipolar Disord 2006; 8(2): 196–9PubMedCrossRefGoogle Scholar
  31. 31.
    Young AH, Gallagher P, Watson S, et al. Improvements in neurocognitive function and mood following adjunctive treatment with mifepristone (RU-486) in bipolar disorder. Neuropsychopharmacology 2004; 29(8): 1538–45PubMedCrossRefGoogle Scholar
  32. 32.
    Baumann B, Bogerts B. Neuroanatomical studies on bipolar disorder. Br J Psychiatry Suppl 2001; 41: S142–7PubMedCrossRefGoogle Scholar
  33. 33.
    Drevets WC, Ongur D, Price JL. Neuroimaging abnormalities in the subgenual prefrontal cortex: implications for the pathophysiology of familial mood disorders. Mol Psychiatry 1998; 3(3): 220–1PubMedCrossRefGoogle Scholar
  34. 34.
    Lopez-Larson MP, DelBello MP, Zimmerman ME, et al. Regional prefrontal gray and white matter abnormalities in bipolar disorder. Biol Psychiatry 2002; 52(2): 93–100PubMedCrossRefGoogle Scholar
  35. 35.
    Blumberg HP, Stern E, Martinez D, et al. Increased anterior cingulate and caudate activity in bipolar mania. Biol Psychiatry 2000; 48(11): 1045–52PubMedCrossRefGoogle Scholar
  36. 36.
    Gruber SA, Rogowska J, Yurgelun-Todd DA. Decreased activation of the anterior cingulate in bipolar patients: an fMRI study. J Affect Disord 2004; 82(2): 191–201PubMedCrossRefGoogle Scholar
  37. 37.
    Yurgelun-Todd DA, Gruber SA, Kanayama G, et al. fMRI during affect discrimination in bipolar affective disorder. Bipolar Disord 2000; 2 (3 Pt 2): 237–48PubMedCrossRefGoogle Scholar
  38. 38.
    Bilder RM, Volavka J, Czobor P, et al. Neurocognitive correlates of the COMT Val(158)Met polymorphism in chronic schizophrenia. Biol Psychiatry 2002; 52(7): 701–7PubMedCrossRefGoogle Scholar
  39. 39.
    Egan MF, Goldberg TE, Kolachana BS, et al. Effect of COMT Val108/158 Met genotype on frontal lobe function and risk for schizophrenia. Proc Natl Acad Sci U S A 2001; 98(12): 6917–22PubMedCrossRefGoogle Scholar
  40. 40.
    Rosa A, Peralta V, Cuesta MJ, et al. New evidence of association between COMT gene and prefrontal neurocognitive function in healthy individuals from sibling pairs discordant for psychosis. Am J Psychiatry 2004; 161(6): 1110–2PubMedCrossRefGoogle Scholar
  41. 41.
    Malhotra AK, Kestler LJ, Mazzanti C, et al. A functional polymorphism in the COMT gene and performance on a test of prefrontal cognition. Am J Psychiatry 2002; 159(4): 652–4PubMedCrossRefGoogle Scholar
  42. 42.
    Tsai SJ, Yu YW, Chen TJ, et al. Association study of a functional catechol-O-methyltransferase-gene polymorphism and cognitive function in healthy females. Neurosci Lett 2003; 338(2): 123–6PubMedCrossRefGoogle Scholar
  43. 43.
    Li T, Vallada H, Curtis D, et al. Catechol-O-methyltransferase Val158Met polymorphism: frequency analysis in Han Chinese subjects and allelic association of the low activity allele with bipolar affective disorder. Pharmacogenetics 1997; 7(5): 349–53PubMedCrossRefGoogle Scholar
  44. 44.
    Mynett-Johnson LA, Murphy VE, Claffey E, et al. Preliminary evidence of an association between bipolar disorder in females and the catechol-O-methyltransferase gene. Psychiatr Genet 1998; 8(4): 221–5PubMedCrossRefGoogle Scholar
  45. 45.
    Papolos DF, Veit S, Faedda GL, et al. Ultra-ultra rapid cycling bipolar disorder is associated with the low activity catecholamine-O-methyltransferase allele. Mol Psychiatry 1998; 3(4): 346–9PubMedCrossRefGoogle Scholar
  46. 46.
    Kirov G, Murphy KC, Arranz MJ, et al. Low activity allele of catechol-O-methyltransferase gene associated with rapid cycling bipolar disorder. Mol Psychiatry 1998; 3(4): 342–5PubMedCrossRefGoogle Scholar
  47. 47.
    Shifman S, Bronstein M, Sternfeld M, et al. COMT: a common susceptibility gene in bipolar disorder and schizophrenia. Am J Med Genet B Neuropsychiatr Genet 2004; 128(1): 61–4CrossRefGoogle Scholar
  48. 48.
    Funke B, Malhotra AK, Finn CT, et al. COMT genetic variation confers risk for psychotic and affective disorders: a case control study. Behav Brain Funct 2005; 1: 19–28PubMedCrossRefGoogle Scholar
  49. 49.
    Burdick KE, Funke B, Goldberg JF, et al. COMT genotype increases risk for bipolar I disorder and influences neurocognitive performance. Bipolar Disord 2007; 9(4): 370–6PubMedCrossRefGoogle Scholar
  50. 50.
    Kimberg DY, D’Esposito M. Cognitive effects of the dopamine receptor agonist pergolide. Neuropsychologia 2003; 41(8): 1020–7PubMedCrossRefGoogle Scholar
  51. 51.
    Kimberg DY, D’Esposito M, Farah MJ. Effects of bromocriptine on human subjects depend on working memory capacity. Neuroreport 1997; 8(16): 3581–5PubMedCrossRefGoogle Scholar
  52. 52.
    Luciana M, Collins PF, Depue RA. Opposing roles for dopamine and serotonin in the modulation of human spatial working memory functions. Cereb Cortex 1998; 8(3): 218–26PubMedCrossRefGoogle Scholar
  53. 53.
    Goldberg JF, Burdick KE, Endick CJ. Preliminary randomized, double-blind, placebo-controlled trial of pramipexole added to mood stabilizers for treatment-resistant bipolar depression. Am J Psychiatry 2004; 1613): 64–6CrossRefGoogle Scholar
  54. 54.
    Malhotra AK, Burdick KE, Razi K, et al. Ziprasidone-induced cognitive enhancement in schizophrenia: specificity or pseudospecificity? Schizophr Res 2006; 87(1–3): 181–4PubMedCrossRefGoogle Scholar
  55. 55.
    Harvey PD, Green MF, McGurk SR, et al. Changes in cognitive functioning with risperidone and olanzapine treatment: a largescale, double-blind, randomized study. Psychopharmacology (Berl) 2003; 169(3–4): 404–11CrossRefGoogle Scholar
  56. 56.
    Bilder RM, Goldman RS, Volavka J, et al. Neurocognitive effects of clozapine, olanzapine, risperidone, and haloperidol in patients with chronic schizophrenia or schizoaffective disorder. Am J Psychiatry 2002; 159(6): 1018–28PubMedCrossRefGoogle Scholar
  57. 57.
    Keefe RS, Bilder RM, Davis SM, et al. Neurocognitive effects of antipsychotic medications in patients with chronic schizophrenia in the CATIE trial. Arch Gen Psychiatry 2007; 64(6): 633–47PubMedCrossRefGoogle Scholar
  58. 58.
    Shi L, Schuh LM, Trzepacz PT, et al. Improvement of Positive and Negative Syndrome Scale cognitive score associated with olanzapine treatment of acute mania. Curr Med Res Opin 2004; 20(9): 1371–6PubMedCrossRefGoogle Scholar
  59. 59.
    Reinares M, Martinez-Aran A, Colom F, et al. Long-term effects of the treatment with risperidone versus conventional neuroleptics on the neuropsychological performance of euthymic bipolar patients [in Spanish]. Actas Esp Psiquiatr 2000; 28(4): 231–8PubMedGoogle Scholar
  60. 60.
    Liu L, Wong TP, Pozza MF, et al. Role of NMDA receptor subtypes in governing the direction of hippocampal synaptic plasticity. Science 2004; 304(5673): 1021–4PubMedCrossRefGoogle Scholar
  61. 61.
    Cotman CW, Monaghan DT, Ganong AH. Excitatory amino acid neurotransmission: NMDA receptors and Hebb-type synaptic plasticity. Annu Rev Neurosci 1988; 11: 61–80PubMedCrossRefGoogle Scholar
  62. 62.
    Malhotra AK, Pinals DA, Weingartner H, et al. NMDA receptor function and human cognition: the effects of ketamine in healthy volunteers. Neuropsychopharmacology 1996; 14(5): 301–7PubMedCrossRefGoogle Scholar
  63. 63.
    Duncan GE, Moy SS, Perez A, et al. Deficits in sensorimotor gating and tests of social behavior in a genetic model of reduced NMDA receptor function. Behav Brain Res 2004; 153(2): 507–19PubMedCrossRefGoogle Scholar
  64. 64.
    Detera-Wadleigh SD, McMahon FJ. G72/G30 in schizophrenia and bipolar disorder: review and meta-analysis. Biol Psychiatry 2006; 60(2): 106–14PubMedCrossRefGoogle Scholar
  65. 65.
    Goldberg TE, Straub RE, Callicott JH, et al. The G72/G30 gene complex and cognitive abnormalities in schizophrenia. Neuropsychopharmacology 2006; 31(9): 2022–32PubMedCrossRefGoogle Scholar
  66. 66.
    Chumakov I, Blumenfeld M, Guerassimenko O, et al. Genetic and physiological data implicating the new human gene G72 and the gene for D-amino acid oxidase in schizophrenia. Proc Natl Acad Sci U S A 2002; 99(21): 13675–80PubMedCrossRefGoogle Scholar
  67. 67.
    Tsai G, Yang P, Chung LC, et al. D-serine added to antipsychotics for the treatment of schizophrenia. Biol Psychiatry 1998; 44(11): 1081–9PubMedCrossRefGoogle Scholar
  68. 68.
    Heresco-Levy U, Javitt DC, Ebstein R, et al. D-serine efficacy as add-on pharmacotherapy to risperidone and olanzapine for treatment-refractory schizophrenia. Biol Psychiatry 2005; 57(6): 577–85PubMedCrossRefGoogle Scholar
  69. 69.
    Calabrese JR, Bowden CL, Sachs GS, et al. A double-blind placebo-controlled study of lamotrigine monotherapy in outpatients with bipolar I depression. Lamictal 602 Study Group. J Clin Psychiatry 1999; 60(2): 79–88PubMedCrossRefGoogle Scholar
  70. 70.
    McElroy SL, Zarate CA, Cookson J, et al. A 52-week, open-label continuation study of lamotrigine in the treatment of bipolar depression. J Clin Psychiatry 2004; 65(2): 204–10PubMedCrossRefGoogle Scholar
  71. 71.
    Schmider J, Lammers CH, Gotthardt U, et al. Combined dexamethasone/corticotropin-releasing hormone test in acute and remitted manic patients, in acute depression, and in normal controls: I. Biol Psychiatry 1995; 38(12): 797–802PubMedCrossRefGoogle Scholar
  72. 72.
    Rybakowski JK, Twardowska K. The dexamethasone/corticotropin-releasing hormone test in depression in bipolar and unipolar affective illness. J Psychiatr Res 1999; 33(5): 363–70PubMedCrossRefGoogle Scholar
  73. 73.
    Holsboer F, Lauer CJ, Schreiber W, et al. Altered hypothalamicpituitary-adrenocortical regulation in healthy subjects at high familial risk for affective disorders. Neuroendocrinology 1995; 62(4): 340–7PubMedCrossRefGoogle Scholar
  74. 74.
    Watson S, Gallagher P, Ritchie JC, et al. Hypothalamic-pituitary-adrenal axis function in patients with bipolar disorder. Br J Psychiatry 2004; 184: 496–502PubMedCrossRefGoogle Scholar
  75. 75.
    Daban C, Vieta E, Mackin P, et al. Hypothalamic-pituitary-adrenal axis and bipolar disorder. Psychiatr Clin North Am 2005; 28(2): 469–80PubMedCrossRefGoogle Scholar
  76. 76.
    Watson S, Thompson JM, Ritchie JC, et al. Neuropsychological impairment in bipolar disorder: the relationship with glucocorticoid receptor function. Bipolar Disord 2006; 8(1): 85–90PubMedCrossRefGoogle Scholar
  77. 77.
    Belanoff JK, Rothschild AJ, Cassidy F, et al. An open label trial of C-1073 (mifepristone) for psychotic major depression. Biol Psychiatry 2002; 52(5): 386–92PubMedCrossRefGoogle Scholar
  78. 78.
    DeBattista C, Belanoff J, Glass S, et al. Mifepristone versus placebo in the treatment of psychosis in patients with psychotic major depression. Biol Psychiatry 2006; 60(12): 1343–9PubMedCrossRefGoogle Scholar
  79. 79.
    Simpson GM, El Sheshai A, Loza N, et al. An 8-week open-label trial of a 6-day course of mifepristone for the treatment of psychotic depression. J Clin Psychiatry 2005; 66(5): 598–602PubMedCrossRefGoogle Scholar
  80. 80.
    Velligan DI, Gonzalez JM. Rehabilitation and recovery in schizophrenia. Psychiatr Clin North Am 2007; 30(3): 535–48PubMedCrossRefGoogle Scholar
  81. 81.
    Bellack AS. Skills training for people with severe mental illness. Psychiatr Rehabil J 2004; 27(4): 375–91PubMedCrossRefGoogle Scholar
  82. 82.
    Miklowitz DJ, Otto MW, Frank E, et al. Psychosocial treatments for bipolar depression: a 1-year randomized trial from the systematic treatment enhancement program. Arch Gen Psychiatry 2007; 64(4): 419–26PubMedCrossRefGoogle Scholar
  83. 83.
    Daban C, Martinez-Aran A, Torrent C, et al. Specificity of cognitive deficits in bipolar disorder versus schizophrenia: a systematic review. Psychother Psychosom 2006; 75(2): 72–84PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2007

Authors and Affiliations

  • Katherine E. Burdick
    • 1
    • 2
    • 3
  • Raphael J. Braga
    • 1
  • Joseph F. Goldberg
    • 4
  • Anil K. Malhotra
    • 1
    • 2
    • 3
  1. 1.Department of Psychiatry, The Zucker Hillside HospitalNorth Shore-Long Island Jewish Health SystemGlen OaksUSA
  2. 2.The Feinstein Institute for Medical ResearchManhassetUSA
  3. 3.Department of PsychiatryAlbert Einstein College of MedicineNew YorkUSA
  4. 4.Mt Sinai School of MedicineNew YorkUSA

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