CNS Drugs

, Volume 21, Issue 7, pp 535–557

Treatment of Cognitive Deficits Associated with Schizophrenia

Potential Role of Catechol-O-Methyltransferase Inhibitors
Leading Article


In the last two decades, understanding of the dynamics of dopamine function in the prefrontal cortex and its role in prefrontal cortex physiology has opened up new avenues for therapeutic interventions in conditions in which prefrontal cortex function is compromised. Neuropsychological and imaging studies of prefrontal information processing have confirmed specific cognitive and neurophysiological abnormalities in individuals with schizophrenia. Because such findings are also observed in the healthy siblings of patients with schizophrenia, they may represent intermediate phenotypes related to schizophrenia susceptibility genes.

Catechol-O-methyltransferase (COMT) represents an important candidate as a susceptibility gene for cognitive dysfunction in schizophrenia because of the unique role this enzyme plays in regulating prefrontal dopaminergic function. A functional COMT polymorphism (Vall58Met) predicts performance in tasks of prefrontal executive function and the neurophysiological response measured with electroencephalography and functional magnetic resonance imaging in tasks assessing working memory. In fact, individuals with the Val/Val genotype, which encodes for the high-activity enzyme resulting in lower dopamine concentrations in the prefrontal cortex, perform less well and are less efficient physiologically than Met/Met individuals.

These findings raise the possibility of new pharmacological interventions for the treatment of prefrontal cortex dysfunction and of predicting outcome based on COMT genotype. One strategy consists of the use of CNS-penetrant COMT inhibitors such as tolcapone. A second strategy is to increase extracellular dopamine concentrations in the frontal cortex by blocking the noradrenaline (norepinephrine) reuptake system, a secondary mechanism responsible for the disposal of dopamine from synaptic clefts in the prefrontal cortex. A third possibility involves the use of modafinil, a drug with an unclear mechanism of action but with positive effects on working memory in rodents.

The potential of these drugs to improve executive cognitive function by selectively increasing dopamine load in the frontal cortex but not in subcortical territories, and the possibility that response to them may be modified by a COMT polymorphism, provides a novel genotype-based targeted pharmacological approach without abuse potential for the treatment of cognitive disorder in schizophrenia and in other conditions involving prefrontal cortex dysfunction.


  1. 1.
    Lewis DA, Campbell MJ, Foote SL, et al. The distribution of tyrosine hydroxylase-immunoreactive fibers in primate neocortex is widespread but regionally specific. J Neurosci 1987; 7: 279–90PubMedGoogle Scholar
  2. 2.
    Selemon LD, Goldman-Rakic P. The reduced neuropil hypothesis: a circuit based model of schizophrenia. Biol Psychiatry 1999; 45: 17–25PubMedCrossRefGoogle Scholar
  3. 3.
    Honer WG, Falkai P, Chen C, et al. Synaptic and plasticity-associated proteins in anterior frontal cortex in severe mental illness. Neuroscience 1999; 91: 1247–55PubMedCrossRefGoogle Scholar
  4. 4.
    Karson CN, Mrak RE, Schluterman KO, et al. Alterations in synaptic proteins and their encoding mRNAs in prefrontal cortex in schizophrenia: a possible neurochemical basis for hypofrontality. Mol Psychiatry 1999; 4: 39–45PubMedCrossRefGoogle Scholar
  5. 5.
    Abrams R, Taylor M. Differential EEG patterns in affective disorder and schizophrenia. Arch Gen Psychiatry 1979; 36: 1355–8PubMedCrossRefGoogle Scholar
  6. 6.
    Karson CN, Coppola R, Morihisa JM, et al. Computed electroencephalographic activity mapping in schizophrenia: the resting state reconsidered. Arch Gen Psychiatry 1987; 44: 514–7PubMedCrossRefGoogle Scholar
  7. 7.
    Tauscher J, Fischer P, Neumeister A, et al. Low frontal electroencephalographic coherence in neuroleptic-free schizophrenic patients. Biol Psychiatry 1998; 44: 438–47PubMedCrossRefGoogle Scholar
  8. 8.
    Goldberg TE, Gold JM, Coppola R, et al. Unnatural practices, unspeakable actions: a study of delayed auditory feedback in schizophrenia. Am J Psychiatry 1997; 154: 858–60PubMedGoogle Scholar
  9. 9.
    Gold JM, Carpenter C, Randolph C, et al. Auditory working memory and Wisconsin Card Sorting Test performance in schizophrenia. Arch Gen Psychiatry 1997; 54: 159–65PubMedCrossRefGoogle Scholar
  10. 10.
    Goldberg TE, Weinberger DR, Berman KF, et al. Further evidence for dementia of the prefrontal type in schizophrenia? A controlled study of teaching the Wisconsin Card Sorting Test. Arch Gen Psychiatry 1987; 44: 1008–14PubMedCrossRefGoogle Scholar
  11. 11.
    Goldberg TE, Weinberger DR. Probing prefrontal function in schizophrenia with neuropsychological paradigms. Schizophr Bull 1988; 14: 179–83PubMedCrossRefGoogle Scholar
  12. 12.
    Keefe RS, Roitman SE, Harvey PD, et al. A pen-and-paper human analogue of a monkey prefrontal cortex activation task: spatial working memory in patients with schizophrenia. Schizophr Res 1995; 17: 25–33PubMedCrossRefGoogle Scholar
  13. 13.
    Weickert TW, Goldberg TE, Gold JM, et al. Cognitive impairments in patients with schizophrenia displaying preserved and compromised intellect. Arch Gen Psychiatry 2000; 57: 907–13PubMedCrossRefGoogle Scholar
  14. 14.
    Wexler BE, Stevens AA, Bowers AA, et al. Word and tone working memory deficits in schizophrenia. Arch Gen Psychiatry 1998; 55: 1093–6PubMedCrossRefGoogle Scholar
  15. 15.
    Andreasen N. Pieces of the schizophrenia puzzle fall into place. Neuron 1996; 16: 697–700PubMedCrossRefGoogle Scholar
  16. 16.
    Berman KF, Torrey EF, Daniel DG, et al. Regional cerebral blood flow in monozygotic twins discordant and concordant for schizophrenia. Arch Gen Psychiatry 1992; 49: 927–34PubMedCrossRefGoogle Scholar
  17. 17.
    Callicott JH, Ramsey NF, Tallent K, et al. Functional magnetic resonance imaging brain mapping in psychiatry: methodological issues illustrated in a study of working memory in schizophrenia. Neuropsychopharmacology 1998; 18: 186–96PubMedCrossRefGoogle Scholar
  18. 18.
    Callicott JH, Bertolino A, Mattay VS, et al. Physiological dysfunction of the dorsolateral prefrontal cortex in schizophrenia revisited. Cereb Cortex 2000; 10: 1078–92PubMedCrossRefGoogle Scholar
  19. 19.
    Bunney WE, Bunney BG. Evidence for a compromised dorsolateral prefrontal cortical parallel circuit in schizophrenia. Brain Res Brain Res Rev 2000; 31: 138–46PubMedCrossRefGoogle Scholar
  20. 20.
    Goldman-Rakic P. The physiological approach: functional architecture of working memory and disordered cognition in schizophrenia. Biol Psychiatry 1999; 46: 650–61PubMedCrossRefGoogle Scholar
  21. 21.
    Weinberger DR, Egan MF, Bertolino A, et al. Prefrontal neurons and the genetics of schizophrenia. Biol Psychiatry 2001; 50: 825–44PubMedCrossRefGoogle Scholar
  22. 22.
    Carlsson A, Lindquist M. Effect of chorpromazine or haloperidol on formation of 3-methoxytyramine and normetanephrine in mouse brain. Acta Pharmacol Toxicol (Copenh) 1963; 20: 140–4CrossRefGoogle Scholar
  23. 23.
    Anden NE, Butcher SG, Corrodi H, et al. Receptor activity and turnover of dopamine and noradrenaline after neuroleptics. Eur J Pharmacol 1970; 11: 303–14PubMedCrossRefGoogle Scholar
  24. 24.
    Creese I, Burt DR, Snyder S. Dopamine receptor binding predicts clinical and pharmacological potencies of antischizophrenic drugs. Science 1976; 192: 481–3PubMedCrossRefGoogle Scholar
  25. 25.
    Creese I, Hess E. Biochemical characteristics of D1 dopamine receptors: relationship to behavior and schizophrenia. Clin Neuropharmacol 1986; 9 Suppl. 4: 14–6Google Scholar
  26. 26.
    Weinberger D. Implications of normal brain development for the pathogenesis of schizophrenia. Arch Gen Psychiatry 1987; 44: 660–9PubMedCrossRefGoogle Scholar
  27. 27.
    Davis KL, Kahn RS, Ko G, et al. Dopamine in schizophrenia: a review and reconceptualization. Am J Psychiatry 1991; 148: 1474–86PubMedGoogle Scholar
  28. 28.
    Lewis DA. The catecholaminergic innervation of primate prefrontal cortex. J Neural Transm 1992; Suppl. 36: 179–200Google Scholar
  29. 29.
    Siomopoulos V. Amphetamine psychosis: overview and a hypothesis. Dis Nerv Syst 1975; 36: 336–9PubMedGoogle Scholar
  30. 30.
    Luchins D. The dopamine hypothesis of schizophrenia: a critical analysis. Neuropsychobiology 1975; 1: 365–78PubMedCrossRefGoogle Scholar
  31. 31.
    Farde L. Brain imaging of schizophrenia: the dopamine hypothesis. Schizophr Res 1997; 28: 157–62PubMedCrossRefGoogle Scholar
  32. 32.
    Laruelle M, Abi-Dargham A, Gil R, et al. Increased dopamine transmission in schizophrenia: relationship to illness phases. Biol Psychiatry 1999; 46: 56–72PubMedCrossRefGoogle Scholar
  33. 33.
    Abi-Dargham A, Gil R, Krystal J, et al. Increased striatal dopamine transmission in schizophrenia: confirmation in a second cohort. Am J Psychiatry 1998; 155: 761–7PubMedGoogle Scholar
  34. 34.
    Jaskiw GE, Weinberger D. Ibotenic acid lesions of medial prefrontal cortex augment swim-stress-induced locomotion. Pharmacol Biochem Behav. 1992; 41: 607–9PubMedCrossRefGoogle Scholar
  35. 35.
    Carlsson A, Waters N, Waters S, et al. Network interactions in schizophrenia: therapeutic implications. Brain Res Brain Res Rev 2000; 31: 342–9PubMedCrossRefGoogle Scholar
  36. 36.
    Seeman P, Lee T, Chauwong M, et al. Antipsychotic drug doses and neuroleptic-dopamine receptors. Nature 1976; 261: 717–9PubMedCrossRefGoogle Scholar
  37. 37.
    Ingvar DH, Franzen G. Abnormalities of cerebral blood flow distribution in patients with chronic schizophrenia. Acta Psychiatr Scand 1974; 50: 425–62PubMedCrossRefGoogle Scholar
  38. 38.
    Catafau AM, Parellada E, Lomena FJ, et al. Prefrontal and temporal blood flow in schizophrenia: resting and activation technetium-99m-HMPAO SPECT patterns in young neuroleptic-naive patients with acute disease. J Nucl Med 1994; 35: 935–41PubMedGoogle Scholar
  39. 39.
    Weinberger DR, Berman KF, Zec RF. Physiologic dysfunction of dorsolateral prefrontal cortex in schizophrenia: I. Regional cerebral blood flow evidence. Arch Gen Psychiatry 1986; 43: 114–24Google Scholar
  40. 40.
    Weinberger DR, Berman KF. Speculation on the meaning of cerebral metabolic hypofrontality in schizophrenia. Schizophr Bull 1988; 14: 157–68PubMedCrossRefGoogle Scholar
  41. 41.
    Lipska BK, Jaskiw GE, Weinberger D. The effects of combined prefrontal cortical and hippocampal damage on dopamine-related behaviors in rats. Pharmacol Biochem Behav 1994; 48: 1053–7PubMedCrossRefGoogle Scholar
  42. 42.
    Carter CJ, Pycock C. Behavioural and biochemical effects of dopamine and noradrenaline depletion within the medial prefrontal cortex of the rat. Brain Res 1980; 192: 163–76PubMedCrossRefGoogle Scholar
  43. 43.
    Jaskiw GE, Karoum FK, Weinberger D. Persistent elevations in dopamine and its metabolites in the nucleus accumbens after mild subchronic stress in rats with ibotenic acid lesions of the medial prefrontal cortex. Brain Res 1990; 534: 321–3PubMedCrossRefGoogle Scholar
  44. 44.
    Deutch A. The regulation of subcortical dopamine systems by the prefrontal cortex: interactions of central dopamine systems and the pathogenesis of schizophrenia. J Neural Transm Suppl 1992; 36: 61–89PubMedGoogle Scholar
  45. 45.
    Saunders RC, Kolachana BS, Bachevalier J, et al. Neonatal lesions of the medial temporal lobe disrupt prefrontal cortical regulation of striatal dopamine. Nature 1998; 393: 169–71PubMedCrossRefGoogle Scholar
  46. 46.
    Meyer-Lindenberg AS, Olsen RK, Kohn PD, et al. Regionally specific disturbance of dorsolateral prefrontal-hippocampal functional connectivity in schizophrenia. Arch Gen Psychiatry 2005; 62: 379–86PubMedCrossRefGoogle Scholar
  47. 47.
    Bertolino A, Weinberger D. Proton magnetic resonance spectroscopy in schizophrenia. Eur J Radiol 1999; 30: 132–41PubMedCrossRefGoogle Scholar
  48. 48.
    Akil M, Kolachana BS, Rothmond DA, et al. Catechol-O-methyltransferase genotype and dopamine regulation in the human brain. J Neurosci 2003; 23: 2008–13PubMedGoogle Scholar
  49. 49.
    Park S, Holzman P. Schizophrenics show spatial working memory deficits. Arch Gen Psychiatry 1992; 49: 975–82PubMedCrossRefGoogle Scholar
  50. 50.
    Pantelis C, Barnes TR, Nelson HE, et al. Frontal-striatal cognitive deficits in patients with chronic schizophrenia. Brain 1997; 120 (Pt 10): 1823–43PubMedCrossRefGoogle Scholar
  51. 51.
    Goldberg TE, Patterson KJ, Taqqu Y, et al. Capacity limitations in short-term memory in schizophrenia: tests of competing hypotheses. Psychol Med 1998; 28: 665–73PubMedCrossRefGoogle Scholar
  52. 52.
    Goldberg TE, Egan MF, Gscheidle T, et al. Executive sub-processes in working memory: relationship to catechol-O-methyltransferase Val158Met genotype and schizophrenia. Arch Gen Psychiatry 2003; 60: 889–96PubMedCrossRefGoogle Scholar
  53. 53.
    Weinberger DR, Berman KF, Daniel DG. Mesoprefrontal cortical dopaminergic activity and prefrontal hypofunction in schizophrenia. Clin Neuropharmacol 1992; 15Suppl. 1: 568–9ACrossRefGoogle Scholar
  54. 54.
    Curtis VA, Bullmore ET, Morris RG, et al. Attenuated frontal activation in schizophrenia may be task dependent. Schizophr Res 1999; 37: 35–44PubMedCrossRefGoogle Scholar
  55. 55.
    Stevens AA, Goldman-Rakic PS, Gore JC, et al. Cortical dysfunction in schizophrenia during auditory word and tone working memory demonstrated by functional magnetic resonance imaging. Arch Gen Psychiatry 1998; 55: 1097–103PubMedCrossRefGoogle Scholar
  56. 56.
    Goldman-Rakic P. The cortical dopamine system: role in memory and cognition. Adv Pharmacol 1998; 42: 707–11PubMedCrossRefGoogle Scholar
  57. 57.
    Winterer G, Weinberger DR. Genes, dopamine and cortical signal-to-noise ratio in schizophrenia. Trends Neurosci 2004; 27: 683–90PubMedCrossRefGoogle Scholar
  58. 58.
    Sawaguchi T, Goldman-Rakic P. The role of D1-dopamine receptor in working memory: local injections of dopamine antagonists into the prefrontal cortex of rhesus monkeys performing an oculomotor delayed-response task. J Neurophysiol 1994; 71: 515–28PubMedGoogle Scholar
  59. 59.
    Fuster JM. The prefrontal cortex: anatomy, physiology and neuropsychology of the frontal lobe. Philadelphia (PA): Lippincott-Raven Publishers, 1997Google Scholar
  60. 60.
    Tzschentke TM, Schmidt W. The development of cocaine-induced behavioral sensitization is affected by discrete quinolinic acid lesions of the prelimbic medial prefrontal cortex. Brain Res 1998; 795: 71–6PubMedCrossRefGoogle Scholar
  61. 61.
    Bannon MJ, Roth R. Pharmacology of mesocortical dopamine neurons. Pharmacol Rev 1983; 35: 53–68PubMedGoogle Scholar
  62. 62.
    Thierry AM, Tassin JP, Blanc G, et al. Selective activation of mesocortical DA system by stress. Nature 1976; 263: 242–4PubMedCrossRefGoogle Scholar
  63. 63.
    Mantz J, Thierry AM, Glowinski J. Effect of noxious tail pinch on the discharge rate of mesocortical and mesolimbic dopamine neurons: selective activation of the mesocortical system. Brain Res 1989; 476: 377–81PubMedCrossRefGoogle Scholar
  64. 64.
    Paspalas CD, Goldman-Rakic P. Microdomains for dopamine volume neurotransmission in primate prefrontal cortex. J Neurosci 2004; 24: 5292–300PubMedCrossRefGoogle Scholar
  65. 65.
    Agnati LF, Zunarelli E, Genedani S, et al. On the existence of a global molecular network enmeshing the whole central nervous system: physiological and pathological implications. Curr Protein Pept Sci 2006; 7: 3–15PubMedCrossRefGoogle Scholar
  66. 66.
    Garris PA, Collins LB, Jones SR, et al. Evoked extracellular dopamine in vivo in the medial prefrontal cortex. J Neurochem 1993; 61: 637–47PubMedCrossRefGoogle Scholar
  67. 67.
    Garris PA, Wightman RM. Distinct pharmacological regulation of evoked dopamine efflux in the amygdala and striatum of the rat in vivo. Synapse 1995; 20: 269–79PubMedCrossRefGoogle Scholar
  68. 68.
    Sharp T, Zetterstrom T, Ungerstedt U. An in vivo study of dopamine release and metabolism in rat brain regions using intracerebral dialysis. J Neurochem 1986; 47: 113–22PubMedCrossRefGoogle Scholar
  69. 69.
    Chiodo LA, Bannon MJ, Grace AA, et al. Evidence for the absence of impulse-regulating somatodendritic and synthesis-modulating nerve terminal autoreceptors on subpopulations of mesocortical dopamine neurons. Neuroscience 1984; 12: 1–16PubMedCrossRefGoogle Scholar
  70. 70.
    Nicholson C. Interaction between diffusion and Michaelis-Menten uptake of dopamine after iontophoresis in striatum. Biophys J 1995; 68: 1699–715PubMedCrossRefGoogle Scholar
  71. 71.
    Giros B, Jaber M, Jones SR, et al. Hyperlocomotion and indifference to cocaine and amphetamine in mice lacking the dopamine transporter. Nature 1996; 379: 606–12PubMedCrossRefGoogle Scholar
  72. 72.
    Moron JA, Brockington A, Wise RA, et al. Dopamine uptake through the norepinephrine transporter in brain regions with low levels of the dopamine transporter: evidence from knockout mouse lines. J Neurosci 2002; 22: 389–95PubMedGoogle Scholar
  73. 73.
    Lewis DA, Melchitzky DS, Sesack SR, et al. Dopamine transporter immunoreactivity in monkey cerebral cortex: regional, laminar, and ultrastructural localization. J Comp Neurol 2001; 432: 119–36PubMedCrossRefGoogle Scholar
  74. 74.
    Carboni E, Tanda GL, Frau R, et al. Blockade of the noradrenaline carrier increases extracellular dopamine concentrations in the prefrontal cortex: evidence that dopamine is taken up in vivo by noradrenergic terminals. J Neurochem 1990; 55: 1067–70PubMedCrossRefGoogle Scholar
  75. 75.
    Cenci MA, Kalen P, Mandel RJ, et al. Regional differences in the regulation of dopamine and noradrenaline release in medial frontal cortex, nucleus accumbens and caudate-putamen: a microdialysis study in the rat. Brain Res 1992; 581: 217–28PubMedCrossRefGoogle Scholar
  76. 76.
    Moghaddam B, Bunney B. Differential effect of cocaine on extracellular dopamine levels in rat medial prefrontal cortex and nucleus accumbens: comparison to amphetamine. Synapse 1989; 4: 156–61PubMedCrossRefGoogle Scholar
  77. 77.
    Karoum F, Chrapusta SJ, Egan M. 3-Methoxytyramine is the maj or metabolite of released dopamine in the rat frontal cortex: reassessment of the effects of antipsychotics on the dynamics of dopamine release and metabolism in the frontal cortex, nucleus accumbens, and striatum by a simple two pool model. J Neurochem 1994; 63: 972–9PubMedCrossRefGoogle Scholar
  78. 78.
    Di Chiara G, Tanda GL, Frau R, et al. Heterologous monoamine reuptake: lack of transmitter specificity of neuron-specific carriers. Neurochem Int 1992; 20 Suppl.: 231–5SGoogle Scholar
  79. 79.
    Mundorf ML, Joseph JD, Austin CM, et al. Catecholamine release and uptake in the mouse prefrontal cortex. J Neurochem 2001; 79: 130–42PubMedCrossRefGoogle Scholar
  80. 80.
    Seamans JK, Yang C. The principal features and mechanisms of dopamine modulation in the prefrontal cortex. Prog Neurobiol 2004; 74: 1–58PubMedCrossRefGoogle Scholar
  81. 81.
    Axelrod J, Tomchick R. Enzymatic O-methylation of epinephrine and other catechols. J Biol Chem 1958; 233: 702–5PubMedGoogle Scholar
  82. 82.
    Karhunen T, Tilgmann C, Ulmanen I, et al. Catechol-O-methyltransferase (COMT) in rat brain: immunoelectron microscopic study with an antiserum against rat recombinant COMT protein. Neurosci Lett 1995; 187: 57–60PubMedCrossRefGoogle Scholar
  83. 83.
    Mannisto PT, Kaakkola S. Catechol-O-methyltransferase (COMT): biochemistry, molecular biology, pharmacology, and clinical efficacy of the new selective COMT inhibitors. Pharmacol Rev 1999; 51: 593–628PubMedGoogle Scholar
  84. 84.
    Kaplan GP, Hartman BK, Creveling CR. Immunohistochemical demonstration of COMT in mammalian brain. Brain Res 1979; 167: 241–50PubMedCrossRefGoogle Scholar
  85. 85.
    Matsumoto M, Weickert CS, Beltaifa S, et al. Catechol O-methyltransferase (COMT) mRNA expression in the dorso-lateral prefrontal cortex of patients with schizophrenia. Neuropsychopharmacology 2003; 28: 1521–30PubMedCrossRefGoogle Scholar
  86. 86.
    Huotari M, Gogos JA, Karayiorgou M, et al. Brain catecholamine metabolism in catechol-O-methyltransferase (COMT)-deficient mice. Eur J Neurosci 2002; 15: 246–56PubMedCrossRefGoogle Scholar
  87. 87.
    Gogos JA, Morgan M, Luine V, et al. Catechol-O-methyltransferase-deficient mice exhibit sexually dimorphic changes in catecholamine levels and behavior. Proc Natl Acad Sci U S A 1998; 95: 9991–6PubMedCrossRefGoogle Scholar
  88. 88.
    Tunbridge EM, Bannerman DM, Sharp T, et al. Catechol-o-methyltransferase inhibition improves set-shifting performance and elevates stimulated dopamine release in the rat prefrontal cortex. J Neurosci 2004; 24: 5331–5PubMedCrossRefGoogle Scholar
  89. 89.
    Salminen M, Lundstrom K, Tilgmann C, et al. Molecular cloning and characterization of rat liver catechol-O-methyltransferase. Gene 1990; 93: 241–7PubMedCrossRefGoogle Scholar
  90. 90.
    Bertocci B, Miggiano V, Da Prada M, et al. Human catechol-O-methyltransferase: cloning and expression of the membrane-associated form. Proc Natl Acad Sci U S A 1991; 88: 1416–20PubMedCrossRefGoogle Scholar
  91. 91.
    Lundstrom K, Salminen M, Jalanko A, et al. Cloning and characterization of human placental catechol-O-methyltransferase cDNA. DNA Cell Biol 1991; 10: 181–9PubMedCrossRefGoogle Scholar
  92. 92.
    Lotta T, Vidgren J, Tilgmann C, et al. Kinetics of human soluble and membrane-bound catechol O-methyltransferase: a revised mechanism and description of the thermolabile variant of the enzyme. Biochemistry 1995; 34: 4202–10PubMedCrossRefGoogle Scholar
  93. 93.
    Lundstrom K, Tenhunen J, Tilgmann C, et al. Cloning, expression and structure of catechol-O-methyltransferase. Biochim Biophys Acta 1995; 1251: 1–10PubMedCrossRefGoogle Scholar
  94. 94.
    Grossman MH, Emanuel BS, Budarf M. Chromosomal mapping of the human catechol-O-methyltransferase gene to 22q11.1-q11.2. Genomics 1992; 12: 822–5PubMedCrossRefGoogle Scholar
  95. 95.
    Winqvist R, Lundstrom K, Salminen M, et al. The human catechol-O-methyltransferase (COMT) gene maps to band q11.2 of chromosome 22 and shows a frequent RFLP with BglI. Cytogenet Cell Genet 1992; 59: 253–7PubMedCrossRefGoogle Scholar
  96. 96.
    Weinshilboum R, Raymond F. Variations in catechol-O-methyltransferase activity in inbred strains of rats. Neuropharmacology 1977; 16: 703–6PubMedCrossRefGoogle Scholar
  97. 97.
    Spielman RS, Weinshilboum R. Genetics of red cell COMT activity: analysis of thermal stability and family data. Am J Med Genet 1981; 10: 279–90PubMedCrossRefGoogle Scholar
  98. 98.
    Boudikova B, Szumlanski C, Maidak B, et al. Human liver catechol-O-methyltransferase pharmacogenetics. Clin Pharmacol Ther 1990; 48: 381–9PubMedCrossRefGoogle Scholar
  99. 99.
    Aksoy S, Klener J, Weinshilboum R. Catechol O-methyltransferase pharmacogenetics: photoaffinity labelling and western blot analysis of human liver samples. Pharmacogenetics 1993; 3: 116–22PubMedCrossRefGoogle Scholar
  100. 100.
    Reilly DK, Rivera-Calimlim L, Van Dyke D. Catechol-O-methyltransferase activity: a determinant of levodopa response. Clin Pharmacol Ther 1980; 28: 278–86PubMedCrossRefGoogle Scholar
  101. 101.
    Campbell NR, Dunnette JH, Mwaluko G, et al. Platelet phenol sulfotransferase and erythrocyte catechol-O-methyltransferase activities: correlation with methyldopa metabolism. Clin Pharmacol Ther 1984; 35: 55–63PubMedCrossRefGoogle Scholar
  102. 102.
    Goldstein M, Lieberman A. The role of the regulatory enzymes of catecholamine synthesis in Parkinson’s disease. Neurology 1992; 42 Suppl. 4: 41–8Google Scholar
  103. 103.
    Chen J, Lipska BK, Halim N, et al. Functional analysis of genetic variation in catechol-O-methyltransferase (COMT): effects on mRNA, protein, and enzyme activity in postmortem human brain. Am J Hum Genet 2004; 75: 807–21PubMedCrossRefGoogle Scholar
  104. 104.
    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: 6917–22PubMedCrossRefGoogle Scholar
  105. 105.
    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: 652–4PubMedCrossRefGoogle Scholar
  106. 106.
    Mattay VS, Goldberg TE, Fera F, et al. Catechol O-methyltransferase val158-met genotype and individual variation in the brain response to amphetamine. Proc Natl Acad Sci U S A 2003; 100: 6186–91PubMedCrossRefGoogle Scholar
  107. 107.
    Daniel DG, Weinberger DR, Jones DW, et al. The effect of amphetamine on regional cerebral blood flow during cognitive activation in schizophrenia. J Neurosci 1991; 11: 1907–17PubMedGoogle Scholar
  108. 108.
    Mattay VS, Berman KF, Ostrem JL, et al. Dextroamphetamine enhances ‘neural network-specific’ physiological signals: a positron-emission tomography rCBF study. J Neurosci 1996; 16: 4816–22PubMedGoogle Scholar
  109. 109.
    Callicott JH, Egan MF, Mattay VS, et al. Abnormal fMRI response of the dorsolateral prefrontal cortex in cognitively intact siblings of patients with schizophrenia [published erratum appears in Am J Psychiatry 2004; 161 (6): 1145]. Am J Psychiatry 2003; 160: 709–19PubMedCrossRefGoogle Scholar
  110. 110.
    Cannon TD, Rosso IM, Ollister JM, et al. A prospective cohort study of genetic and perinatal influences in the etiology of schizophrenia. Schizophr Bull 2000; 26: 351–66PubMedCrossRefGoogle Scholar
  111. 111.
    de Chaldee M, Laurent C, Thibaut F, et al. Linkage disequilibrium on the COMT gene in French schizophrenics and controls. Am J Med Genet 1999; 88: 452–7PubMedCrossRefGoogle Scholar
  112. 112.
    Palmatier MA, Kang AM, Kidd K. Global variation in the frequencies of functionally different catechol-O-methyltransferase alleles. Biol Psychiatry 1999; 46: 557–67PubMedCrossRefGoogle Scholar
  113. 113.
    Kunugi H, Vallada HP, Sham PC, et al. Catechol-O-methyltransferase polymorphisms and schizophrenia: a transmission disequilibrium study in multiply affected families. Psychiatr Genet 1997; 7: 97–101PubMedCrossRefGoogle Scholar
  114. 114.
    Li T, Sham PC, Vallada H, et al. Preferential transmission of the high activity allele of COMT in schizophrenia. Psychiatr Genet 1996; 6: 131–3PubMedCrossRefGoogle Scholar
  115. 115.
    Li T, Ball D, Zhao J, et al. Family-based linkage disequilibrium mapping using SNP marker haplotypes: application to a potential locus for schizophrenia at chromosome 22q11. Mol Psychiatry 2000; 5: 77–84PubMedCrossRefGoogle Scholar
  116. 116.
    Munafo MR, Bowes L, Clark TG, et al. Lack of association of the COMT (Val158/108 Met) gene and schizophrenia: a meta-analysis of case-control studies. Mol Psychiatry 2005; 10: 765–70PubMedCrossRefGoogle Scholar
  117. 117.
    Tsai SJ, Hong CJ, Hou SJ, et al. Lack of association of catechol-O-methyltransferase gene Val108/158Met polymorphism with schizophrenia: a family-based association study in a Chinese population. Mol Psychiatry 2006; 11: 2–3PubMedCrossRefGoogle Scholar
  118. 118.
    Williams HJ, Glaser B, Williams NM, et al. No association between schizophrenia and polymorphisms in COMT in two large samples. Am J Psychiatry 2005; 162: 1736–8PubMedCrossRefGoogle Scholar
  119. 119.
    Szoke A, Schurhoff F, Meary A, et al. Lack of influence of COMT and NET genes variants on executive functions in schizophrenic and bipolar patients, their first-degree relatives and controls. Am J Med Genet B Neuropsychiatr Genet 2006; 141: 504–12Google Scholar
  120. 120.
    Fan JB, Zhang CS, Gu NF, et al. Catechol-O-methyltransferase gene Val/Met functional polymorphism and risk of schizophrenia: a large-scale association study plus meta-analysis. Biol Psychiatry 2005; 57: 139–44PubMedCrossRefGoogle Scholar
  121. 121.
    Tunbridge EM, Harrison PJ, Weinberger D. Catechol-O-methyltransferase, cognition, and psychosis: Val(158)Met and beyond. Biol Psychiatry 2006; 60(2): 141–51PubMedCrossRefGoogle Scholar
  122. 122.
    Shifman S, Bronstein M, Sternfeld M, et al. A highly significant association between a COMT haplotype and schizophrenia. Am J Hum Genet 2002; 71: 1296–302PubMedCrossRefGoogle Scholar
  123. 123.
    Bray NJ, Buckland PR, Williams NM, et al. A haplotype implicated in schizophrenia susceptibility is associated with reduced COMT expression in human brain. Am J Hum Genet 2003; 73: 152–61PubMedCrossRefGoogle Scholar
  124. 124.
    Caspi A, Moffitt TE, Cannon M, et al. Moderation of the effect of adolescent-onset cannabis use on adult psychosis by a functional polymorphism in the catechol-O-methyltransferase gene: longitudinal evidence of a gene X environment interaction. Biol Psychiatry 2005; 57: 1117–27PubMedCrossRefGoogle Scholar
  125. 125.
    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: 1–9CrossRefGoogle Scholar
  126. 126.
    Sweet RA, Devlin B, Pollock BG, et al. Catechol-O-methyltransferase haplotypes are associated with psychosis in Alzheimer disease. Mol Psychiatry 2005; 10: 1026–36PubMedCrossRefGoogle Scholar
  127. 127.
    Axelrod J, Senoh S, Witkop B. Methylation of catechol amines in vivo. J Biol Chem 1958; 233: 697–701PubMedGoogle Scholar
  128. 128.
    Guldberg HC, Marsden C. Catechol-O-methyl transferase: pharmacological aspects and physiological role. Pharmacol Rev 1975; 27: 135–206PubMedGoogle Scholar
  129. 129.
    Ericsson A. Potentiation of the L-Dopa effect in man by the use of catechol-O-methyltransferase inhibitors. J Neurol Sci 1971; 14: 193–7PubMedCrossRefGoogle Scholar
  130. 130.
    Reilly DK, Hershey L, Rivera-Calimlim L, et al. On-off effects in Parkinson’s disease: a controlled investigation of ascorbic acid therapy. Adv Neurol 1983; 37: 51–60PubMedGoogle Scholar
  131. 131.
    Reches A, Fahn S. Catechol-O-methyltransferase and Parkinson’s disease. Adv Neurol 1984; 40: 171–9PubMedGoogle Scholar
  132. 132.
    Schultz E, Nissinen E. Inhibition of rat liver and duodenum soluble catechol-O-methyltransferase by a tight-binding inhibitor OR-462. Biochem Pharmacol 1989; 38: 3953–6PubMedCrossRefGoogle Scholar
  133. 133.
    Borgulya J, Bruderer H, Bernauer K, et al. COMT-inhibiting pyrocatechol derivates: synthesis and strucure-activity studies. Hel Chim Acta 1989; 72: 952–68CrossRefGoogle Scholar
  134. 134.
    Nissinen E, Linden IB, Schultz E, et al. Inhibition of catechol-O-methyltransferase activity by two novel disubstituted catechols in the rat. Eur J Pharmacol 1988; 153: 263–9PubMedCrossRefGoogle Scholar
  135. 135.
    Backstrom R, Honkanen E, Pippuri A, et al. Synthesis of some novel potent and selective catechol O-methyltransferase inhibitors. J Med Chem 1989; 32: 841–6PubMedCrossRefGoogle Scholar
  136. 136.
    Adler CH, Singer C, O’Brien C, et al. Randomized, placebo-controlled study of tolcapone in patients with fluctuating Parkinson disease treated with levodopa-carbidopa. Tolcapone Fluctuator Study Group III. Arch Neurol 1998; 55: 1089–95Google Scholar
  137. 137.
    Mannisto PT, Kaakkola S. New selective COMT inhibitors: useful adjuncts for Parkinson’s disease? Trends Pharmacol Sci 1989; 10: 54–6PubMedCrossRefGoogle Scholar
  138. 138.
    Kaakkola S. Clinical pharmacology, therapeutic use and potential of COMT inhibitors in Parkinson’s disease. Drugs 2000; 59: 1233–50PubMedCrossRefGoogle Scholar
  139. 139.
    Sharpless NS, Tyce GM, Owen CJ. Effect of chronic administration of L-dopa on catechol-O-methyltransferase in rat tissues. Life Sci 1973; 12: 97–106CrossRefGoogle Scholar
  140. 140.
    Borges N, Vieira-Coelho MA, Parada A, et al. Studies on the tight-binding nature of tolcapone inhibition of soluble and membrane-bound rat brain catechol-O-methyltransferase. J Pharmacol Exp Ther 1997; 282: 812–7PubMedGoogle Scholar
  141. 141.
    Zürcher G, Colzi A, Da Prada M. Ro 40-7592: inhibition of COMT in rat brain and extracerebral tissues. J Neural Transm Suppl 1990; 32: 375–80PubMedGoogle Scholar
  142. 142.
    Zürcher G, Keller HH, Kettler R, et al. Ro 40-7592, a novel, very potent, and orally active inhibitor of catechol-O-methyltransferase: a pharmacological study in rats. Adv Neurol 1990; 53: 497–503PubMedGoogle Scholar
  143. 143.
    Forsberg M, Lehtonen M, Heikkinen M, et al. Pharmacokinetics and pharmacodynamics of entacapone and tolcapone after acute and repeated administration: a comparative study in the rat. J Pharmacol Exp Ther 2003; 304: 498–506PubMedCrossRefGoogle Scholar
  144. 144.
    Da Prada M, Zurcher G, Kettler R, et al. New therapeutic strategies in Parkinson’s disease: inhibition of MAO-B by Ro 19-6327 and of COMT by Ro 40-7592. In: Bernardi G, Carpenter M, Di Chiara G, et al., editors. Proceedings of the 3rd Triennial Meeting of “Basal Ganglia 89”. New York: Plenum Press, 1991: 723–32Google Scholar
  145. 145.
    Zürcher G, Dingemanse J, Da Prada M. Ro 40-7592, a potent inhibitor of extracerebral and brain catechol-O-methyltransferase: preclinical and clinical findings. In: Agnoli A, Campanella G, editors. New development in therapy of Parkinson’s disease. Rome: John Libbey S.R.L., 1991: 37–43Google Scholar
  146. 146.
    Vieira-Coelho MA, Soares-da-Silva P. Effects of tolcapone upon soluble and membrane-bound brain and liver catechol-O-methyltransferase. Brain Res 1999; 821: 69–78PubMedCrossRefGoogle Scholar
  147. 147.
    Mannisto PT, Tuomainen P, Tuominen R. Different in vivo properties of three new inhibitors of catechol O-methyltransferase in the rat. Br J Pharmacol 1992; 105: 569–74PubMedCrossRefGoogle Scholar
  148. 148.
    Khromova I, Rauhala P, Zolotov N, et al. Tolcapone, an inhibitor of catechol O-methyltransferase, counteracts memory deficits caused by bilateral cholinotoxin lesions of the nucleus basalis of Meynert. Neuroreport 1995; 6: 1219–22PubMedCrossRefGoogle Scholar
  149. 149.
    Khromova I, Voronina T, Kraineva VA, et al. Effects of selective atechol-O-methyltransferase inhibitors on single-trial passive avoidance retention in male rats. Behav Brain Res 1997; 86(1): 49–57PubMedCrossRefGoogle Scholar
  150. 150.
    Liljequist R, Haapalinna A, Ahlander M, et al. Catechol O-methyltransferase inhibitor tolcapone has minor influence on performance in experimental memory models in rats. Behav Brain Res 1997; 82: 195–202PubMedCrossRefGoogle Scholar
  151. 151.
    Jorga K, Fotteler B, Heizmann P, et al. Metabolism and excretion of tolcapone, a novel inhibitor of catechol-O-methyltransferase. Br J Clin Pharmacol 1999; 48: 513–20PubMedCrossRefGoogle Scholar
  152. 152.
    Jorga K. Pharmacokinetics, pharmacodynamics, and tolerability of tolcapone: a review of early studies in volunteers. Neurology 1998; 50: S31–8PubMedCrossRefGoogle Scholar
  153. 153.
    Bonifati V, Meco G. New, selective catechol-O-methyltransferase inhibitors as therapeutic agents in Parkinson’s disease. Pharmacol Ther 1999; 81: 1–36PubMedCrossRefGoogle Scholar
  154. 154.
    Kaakkola S, Gordin A, Jarvinen M, et al. Effect of a novel catechol-O-methyltransferase inhibitor, nitecapone, on the metabolism of L-DOPA in healthy volunteers. Clin Neuropharmacol 1990; 13: 436–47PubMedCrossRefGoogle Scholar
  155. 155.
    Keränen T, Gordin A, Harjola VP, et al. The effect of catechol-O-methyl transferase inhibition by entacapone on the pharmacokinetics and metabolism of levodopa in healthy volunteers. Clin Neuropharmacol 1993; 16: 145–56PubMedCrossRefGoogle Scholar
  156. 156.
    Siderowf A, Kurlan R. Monoamine oxidase and catechol-O-methyltransferase inhibitors. Med Clin North Am 1999; 83: 445–67PubMedCrossRefGoogle Scholar
  157. 157.
    Gasparini M, Fabrizio E, Bonifati V, et al. Cognitive improvement during tolcapone treatment in Parkinson’s disease. J Neural Transm 1997; 104: 887–94PubMedCrossRefGoogle Scholar
  158. 158.
    Moreau JL, Borgulya J, Jenck F, et al. Tolcapone: a potential new antidepressant detected in a novel animal model of depression. Behav Pharmacol 1994; 5: 344–50PubMedCrossRefGoogle Scholar
  159. 159.
    American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 4th ed. Washington, DC: American Psychiatric Association, 1994Google Scholar
  160. 160.
    Fava M, Rosenbaum JF, Kolsky A, et al. Open study of the catechol-O-methyltransferase inhibitor tolcapone in major depressive disorder. J Clin Psychopharm 1999; 19: 329–35CrossRefGoogle Scholar
  161. 161.
    Mattay VS, Tessitore A, Callicott JH, et al. Dopaminergic modulation of cortical function in patients with Parkinson’s disease. Ann Neurol 2002; 51: 156–64PubMedCrossRefGoogle Scholar
  162. 162.
    de Frias CM, Annerbrink K, Westberg L, et al. COMT gene polymorphism is associated with declarative memory in adulthood and old age. Behav Genet 2004; 34: 533–9PubMedCrossRefGoogle Scholar
  163. 163.
    Bertolino A, Rubino V, Sambataro F, et al. Prerfrontal-hippocampal coupling during declarative memory is modulated by COMT Val[158]Met genotype. Biol Psychiatry 2006; 147: 221–6Google Scholar
  164. 164.
    Syvanen AC, Tilgmann C, Rinne J, et al. Genetic polymorphism of catechol-O-methyltransferase (COMT): correlation of genotype with individual variation of S-COMT activity and comparison of the allele frequencies in the normal population and parkinsonian patients in Finland. Pharmacogenetics 1997; 7: 65–71PubMedCrossRefGoogle Scholar
  165. 165.
    Dingemanse J, Jorga KM, Schmitt M, et al. Integrated pharmacokinetics and pharmacodynamics of the novel catechol-O-methyltransferase inhibitor tolcapone during first administration to humans. Clin Pharmacol Ther 1995; 57: 508–17PubMedCrossRefGoogle Scholar
  166. 166.
    Apud JA, Mattay V, Das B, et al. COMT genotype and cognition: effects of tolcapone on working memory and fMRI in normal volunteers [abstract]. 60th Annual Meeting of the Society of Biological Psychiatry; 2005 May 19–21; Atlanta (GA)Google Scholar
  167. 167.
    Apud JA, Mattay VS, Chen J, et al. Tolcapone improves cognition and cortical information processing in normal human subjects. Neuropsychopharmacology 2007; 32: 1011–20PubMedCrossRefGoogle Scholar
  168. 168.
    Mattay VS, Callicott JH, Bertolino A, et al. Effects of dextroamphetamine on cognitive performance and cortical activation. Neuroimage 2000; 12: 268–75PubMedCrossRefGoogle Scholar
  169. 169.
    de Jong A, Giel R, Slooff CJ, et al. Social disability and outcome in schizophrenic patients. Br J Psychiatry 1985; 147: 631–6PubMedCrossRefGoogle Scholar
  170. 170.
    Prouteau A, Verdoux H, Briand C, et al. Cognitive predictors of psychosocial functioning outcome in schizophrenia: a follow-up study of subjects participating in a rehabilitation program. Schizophr Res 2005; 77: 343–53PubMedCrossRefGoogle Scholar
  171. 171.
    Lewis DA, Anderson S. The functional architecture of the prefrontal cortex and schizophrenia. Psychol Med 1995; 25: 887–94PubMedCrossRefGoogle Scholar
  172. 172.
    Manoach DS, Gollub RL, Benson ES, et al. Schizophrenic subjects show aberrant fMRI activation of dorsolateral prefrontal cortex and basal ganglia during working memory performance. Biol Psychiatry 2000; 48: 99–109PubMedCrossRefGoogle Scholar
  173. 173.
    Manoach DS, Press DZ, Thangaraj V, et al. Schizophrenic subjects activate dorsolateral prefrontal cortex during a working memory task, as measured by fMRI. Biol Psychiatry 1999; 45: 1128–37PubMedCrossRefGoogle Scholar
  174. 174.
    Perlstein WM, Carter CS, Noll DC, et al. Relation of prefrontal cortex dysfunction to working memory and symptoms in schizophrenia. Am J Psychiatry 2001; 158: 1105–13PubMedCrossRefGoogle Scholar
  175. 175.
    Abi-Dargham A, Mawlawi O, Lombardo I, et al. Prefrontal dopamine D1 receptors and working memory in schizophrenia. J Neurosci 2002; 22: 3708–19PubMedGoogle Scholar
  176. 176.
    Muller U, Werheid K, Hammerstein E, et al. Prefrontal cognitive deficits in patients with schizophrenia treated with atypical or conventional antipsychotics. Eur Psychiatry 2005; 20: 70–3PubMedCrossRefGoogle Scholar
  177. 177.
    Sharma T, Hughes C, Soni W, et al. Cognitive effects of olanzapine and clozapine treatment in chronic schizophrenia. Psychopharmacology (Berl) 2003; 169: 398–403CrossRefGoogle Scholar
  178. 178.
    Jann M. Implications for atypical antipsychotics in the treatment of schizophrenia: neurocognition effects and a neuroprotective hypothesis. Pharmacotherapy 2004; 24: 1759–83PubMedCrossRefGoogle Scholar
  179. 179.
    Tyson PJ, Roberts KH, Mortimer A. Are the cognitive effects of atypical antipsychotics influenced by their affinity to 5HT-2A receptors? Int J Neurosci 2004; 114: 593–611PubMedCrossRefGoogle Scholar
  180. 180.
    Zocchi A, Fabbri D, Heidbreder C. Aripiprazole increases dopamine but not noradrenaline and serotonin levels in the mouse prefrontal cortex. Neurosci Lett 2005; 387: 157–61PubMedCrossRefGoogle Scholar
  181. 181.
    Kuroki T, Meltzer HY, Ichikawa J. Effects of antipsychotic drugs on extracellular dopamine levels in rat medial prefrontal cortex and nucleus accumbens. J Pharmacol Exp Ther 1999; 288: 774–81PubMedGoogle Scholar
  182. 182.
    Bertolino A, Caforio G, Blasi G, et al. Interaction of COMT (Val(108/158)Met) genotype and olanzapine treatment on prefrontal cortical function in patients with schizophrenia. Am J Psychiatry 2004; 161: 1798–805PubMedCrossRefGoogle Scholar
  183. 183.
    Weickert TW, Goldberg TE, Mishara A, et al. Catechol-O-methyltransferase val108/158met genotype predicts working memory response to antipsychotic medications. Biol Psychiatry 2004; 56: 677–82PubMedCrossRefGoogle Scholar
  184. 184.
    Meltzer HY, McGurk SR. The effects of clozapine, risperidone, and olanzapine on cognitive function in schizophrenia. Schizophr Bull 1999; 25: 233–55PubMedCrossRefGoogle Scholar
  185. 185.
    Goldberg TE, Bigelow LB, Weinberger DR, et al. Cognitive and behavioral effects of the coadministration of dextroamphetamine and haloperidol in schizophrenia. Am J Psychiatry 1991; 148: 78–84PubMedGoogle Scholar
  186. 186.
    Li YH, Wirth T, Huotari M, et al. No change of brain extracellular catecholamine levels after acute catechol-O-methyltransferase inhibition: a microdialysis study in anaesthetized rats. Eur J Pharmacol 1998; 356: 127–37PubMedCrossRefGoogle Scholar
  187. 187.
    de Saint Hilaire Z, Orosco M, Rouch C, et al. Variations in extracellular monoamines in the prefrontal cortex and medial hypothalamus after modafinil administration: a microdialysis study in rats. Neuroreport 2001; 12: 3533–7PubMedCrossRefGoogle Scholar
  188. 188.
    Beracochea D, Cagnard B, Celerier A, et al. First evidence of a delay-dependent working memory-enhancing effect of modafinil in mice. Neuroreport 2001; 12: 375–8PubMedCrossRefGoogle Scholar
  189. 189.
    Turner DC, Robbins TW, Clark L, et al. Cognitive enhancing effects of modafinil in healthy volunteers. Psychopharmacology (Berl) 2003; 165: 26026–9Google Scholar
  190. 190.
    Dauvilliers Y, Neidhart E, Billiard M, et al. Sexual dimorphism of the catechol-O-methyltransferase gene in narcolepsy is associated with response to modafinil. Pharmacogenomics 2002; 2: 65–8CrossRefGoogle Scholar
  191. 191.
    Kratochvil CJ, Vaughan BS, Harrington MJ, et al. Atomoxetine: a selective noradrenaline reuptake inhibitor for the treatment of attention-deficit/hyperactivity disorder. Expert Opin Pharmacother 2003; 4: 1165–74PubMedCrossRefGoogle Scholar
  192. 192.
    Bymaster FP, Katner JS, Nelson DL, et al. Atomoxetine increases extracellular levels of norepinephrine and dopamine in prefrontal cortex of rat: a potential mechanism for efficacy in attention deficit/hyperactivity disorder. Neuropsychopharmacology 2002; 27: 699-711PubMedCrossRefGoogle Scholar

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© Adis Data Information BV 2007

Authors and Affiliations

  1. 1.Clinical Brain Disorders Branch, Genes, Cognition and Psychosis ProgramNational Institute of Mental Health, National Institutes of HealthBethesdaUSA

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