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Looking Beyond the Monoamine Hypothesis

European Neurological Review, 2006;6(1):87-92 DOI:

The monoamine hypothesis has dominated research into the pathophysiology and pharmacotherapy of depression for a long time. This has led to the development of antidepressants that are now more selective than the early tri- and tetracyclics from which they have evolved. Alternative hypotheses such as those involving adult neurogenesis or components of the hypothalamic–pituitary–adrenal (HPA) axis are either too premature or have not led to drugs with improved antidepressant activity. Recent new approaches include DNA techniques (identifying genes and gene expression)1,2 and proteomics (a complete inventory of all proteins).3,4 To date, they have not contributed to the development of new drugs. Although many exciting developments are occurring, it does not appear as easy to develop the next generation of antidepressant drugs that do not influence monoamines. In the meantime there may be no choice other than to make the best of the existing hypotheses. This is not as hopeless as it may seem, because there is still considerable potential in the concept of monoamine reuptake inhibition.

Monoamines, Neuroimaging and Sub-components of the Depressive Syndrome

The monoamine hypothesis of depression5 does not only propose the crucial involvement of monoamines in the therapeutic effects of antidepressant drugs but also suggests that depression is directly related to decreased monoaminergic transmission. In view of recent developments in molecular biology, it is relevant to consider what the actual position of this hypothesis is and whether recent findings (e.g. based on neuroimaging techniques) still support its validity.

There are new data that fit well into the monoamine hypothesis. Many of them originate from positron emission tomography (PET) studies. By using selective radioligands, evidence was found for reduced pre- and post-synaptic 5-hydroxy-tryptamine (5-HT)1A receptor binding in depression. Drevets et al.6 demonstrated that the mean 5-HT1A-receptor-binding potential (BP) was reduced in the mesiotemporal cortex and raphe area in unmedicated depressives relative to controls using PET and (11C) WAY-100635. A similar reduction was evident in the parietal cortex, striate cortex and left orbital cortex/ventrolateral pre-frontal cortex. These data are consistent with those of Sargent et al.,7 who found decreased 5-HT1A-receptor-binding potential (BP) in unmedicated depressed patients relative to healthy controls in the raphe, mesiotemporal cortex, insula, anterior cingulate, temporal polar cortex, ventrolateral pre-frontal cortex and orbital cortex. However, a subgroup of the subjects was scanned both pre- and post-paroxetine treatment and the 5-HT1A receptor BP did not significantly change in any area.

  1. Yamada M, Higuchi T, “Functional genomics and depression research. Beyond the monoamine hypothesis”, Eur Neuropsychopharmacol (2002);12: pp. 235–244.
  2. Holsboer F, “Antidepressant drug discovery in the postgenomic era”, World J Biol Psychiatry (2001);2: pp. 165–177.
  3. Marsden C A, Stanford S C, “CNS drugs III: psychotherapeutics”, Expert Opin Investig Drugs (2000);9: pp. 1,923–1,929.
  4. Davidsson P, Brinkmalm A, Karlsson G et al., “Clinical mass spectrometry in neuroscience. Proteomics and peptidomics”, Cell Mol Biol (Noisy-le-grand) (2003);49: pp. 681–688.
  5. Schildkraut J J, “The catecholamine hypothesis of affective disorders: a review of supporting evidence”, Am J Psychiatry (1965);122: pp. 509–522.
  6. Drevets W C, Frank E, Price J C et al., “PET imaging of serotonin 1A receptor binding in depression”, Biol Psychiatry (1999);46: pp. 1,375–1,387.
  7. Sargent P A, Kjaer K H, Bench C J et al., “Brain serotonin1A receptor binding measured by positron emission tomography with [11C]WAY-100635: effects of depression and antidepressant treatment”, Arch Gen Psychiatry (2000);57: pp. 174–180.
  8. Dolan R J, Bench C J, Brown R G et al., “Regional cerebral blood flow abnormalities in depressed patients with cognitive impairment”, J Neurol Neurosurg Psychiatry (1992);55: pp. 768–773.
  9. Drevets W C, “Neuroimaging studies of mood disorders”, Biol Psychiatry (2000);48: pp. 813–829.
  10. Meyer J H, Houle S, Sagrati S et al., “Brain serotonin transporter binding potential measured with carbon 11-labeled DASB positron emission tomography: effects of major depressive episodes and severity of dysfunctional attitudes”, Arch Gen Psychiatry (2004);61: pp. 1,271–1,279.
  11. Milak M S, Parsey R V, Keilp J et al., “Neuroanatomic correlates of psychopathologic components of major depressive disorder”, Arch Gen Psychiatry (2005);62: pp. 397–408.
  12. Booij L, project title: “Experimental manipulations of tryptophan: insight into depression”, undertaken at Leiden University Medical Center, The Netherlands (2005).
  13. Smith K A, Morris J S, Friston K J, Cowen P J, Dolan R J, “Brain mechanisms associated with depressive relapse and associated cognitive impairment following acute tryptophan depletion”, Br J Psychiatry (1999);174: pp. 525–529.
  14. Barr L C, Goodman W K, McDougle C J et al., “Tryptophan depletion in patients with obsessive-compulsive disorder who respond to serotonin reuptake inhibitors”, Arch Gen Psychiatry (1994);51: pp. 309–317.
  15. Shopsin B, Gershon S, Goldstein M, Friedman E, Wilk S, “Use of synthesis inhibitors in defining a role for biogenic amines during imipramine treatment in depressed patients”, Psychopharmacol Commun (1975);1: pp. 239–249.
  16. Shopsin B, Friedman E, Gershon S, “Parachlorophenylalanine reversal of tranylcypromine effects in depressed patients”, Arch Gen Psychiatry (1976);33: pp. 811–819.
  17. Delgado P L, Charney D S, Price L H et al., “Serotonin function and the mechanism of antidepressant action. Reversal of antidepressant-induced remission by rapid depletion of plasma tryptophan”, Arch Gen Psychiatry (1990);47: pp. 411–418.
  18. Miller H L, Delgado P L, Salomon R M et al., “Acute tryptophan depletion: a method of studying antidepressant action”, J Clin Psychiatry (1992);53(suppl.): pp. 28–35.
  19. Bell C, Abrams J, Nutt D, “Tryptophan depletion and its implications for psychiatry”, Br J Psychiatry (2001);178: pp. 399–405.
  20. Reilly J G, McTavish S F, Young A H, “Rapid depletion of plasma tryptophan: a review of studies and experimental methodology”, J Psychopharmacol (1997);11: pp. 381–392.
  21. Delgado P L, “Depression: the case for a monoamine deficiency”, J Clin Psychiatry (2000);61(suppl. 6): pp. 7–11.
  22. Hirschfeld R M, “History and evolution of the monoamine hypothesis of depression”, J Clin Psychiatry (2000);61(suppl. 6): pp. 4–6.
  23. Russo S, Kema I P, Fokkema M R et al, “Tryptophan as a link between psychopathology and somatic states”, Psychosom Med (2003);65: pp. 665–671.
  24. den Boer J A, Westenberg H G, “Effect of a serotonin and noradrenaline uptake inhibitor in panic disorder; a double-blind comparative study with fluvoxamine and maprotiline”, Int Clin Psychopharmacol (1988);3: pp. 59–74.
  25. Turner S M, Jacob R G, Beidel D C, Himmelhoch J, “Fluoxetine treatment of obsessive-compulsive disorder”, J Clin Psychopharmacol (1985);5: pp. 207–212.
  26. Perse T L, Greist J H, Jefferson J W, Rosenfeld R, Dar R, “Fluvoxamine treatment of obsessive-compulsive disorder”, Am J Psychiatry (1987);144: pp. 1,543–1,548.
  27. van Vliet I M, den Boer J A, Westenberg H G, “Psychopharmacological treatment of social phobia; a double blind placebo controlled study with fluvoxamine”, Psychopharmacology (Berl) (1994);115: pp. 128–134.
  28. den Boer J A, Westenberg H G, “Involvement of serotonin receptors in panic disorder: a critical appraisal of the evidence”, in: Westenberg H G, den Boer J A, Murphy D L (eds.), Advances in the Neurobiology of Anxiety Disorders, John Wiley & Sons, Chichester (1995): pp. 139–172.
  29. den Boer J A, Slaap B R, ter Horst G J, Cremers T I F H, Bosker F J, “Therapeutic armamentarium in anxiety disorders”, in: D’Haenen H, den Boer J A, Willner P (eds.), Biological Psychiatry, John Wiley & Sons, Chichester (2002): pp. 1,039–1,062.
  30. Neumeister A, Konstantinidis A, Stastny J et al., “Association between serotonin transporter gene promoter polymorphism (5HTTLPR) and behavioral responses to tryptophan depletion in healthy women with and without family history of depression”, Arch Gen Psychiatry (2002);59: pp. 613–620.
  31. Caspi A, Sugden K, Moffitt T E et al., “Influence of life stress on depression: moderation by a polymorphism in the 5- HTT gene”, Science (2003);301: pp. 386–389.
  32. Millan M J, “The role of monoamines in the actions of established and ‘novel’ antidepressant agents: a critical review”, Eur J Pharmacol (2004),500: pp. 371–384.
  33. Rausch J L, Ruegg R, Moeller F G, “Gepirone as a 5-HT1A agonist in the treatment of major depression”, Psychopharmacol Bull (1990);26: pp. 169–171.
  34. Jenkins S W, Robinson D S, Fabre L F Jr et al. “Gepirone in the treatment of major depression”, J Clin Psychopharmacol (1990);10: pp. 77S–85S.
  35. McGrath P J, Stewart J W, Quitkin F M et al., “Gepirone treatment of atypical depression: preliminary evidence of serotonergic involvement”, J Clin Psychopharmacol (1994);14: pp. 347–352.
  36. Wilcox C S, Ferguson J M, Dale J L, Heiser J F, “A double-blind trial of low- and high-dose ranges of gepirone-ER compared with placebo in the treatment of depressed outpatients”, Psychopharmacol Bull (1996);32: pp. 335–342.
  37. Kreiss D S, Lucki I, “Chronic administration of the 5-HT1A receptor agonist 8-OH-DPAT differentially desensitizes 5-HT1A autoreceptors of the dorsal and median raphe nuclei”, Synapse (1997);25: pp. 107–116.
  38. Bouwer C, Stein D J, “Buspirone is an effective augmenting agent of serotonin selective re-uptake inhibitors in severe treatment-refractory depression”, S Afr Med J (1997);87: pp. 534–537, abstract 540.
  39. Jacobsen F M, “Possible augmentation of antidepressant response by buspirone”, J Clin Psychiatry (1991);52: pp. 217–220.
  40. Joffe R T, Schuller D R, “An open study of buspirone augmentation of serotonin reuptake inhibitors in refractory depression”, J Clin Psychiatry (1993);54: pp. 269–271.
  41. Harvey K V, Balon R, “Augmentation with buspirone: a review”, Ann Clin Psychiatry (1995);7: pp. 143–147.
  42. Gundlah C, Hjorth S, Auerbach S B, “Autoreceptor antagonists enhance the effect of the reuptake inhibitor citalopram on extracellular 5-HT: this effect persists after repeated citalopram treatment”, Neuropharmacol (1997);36: pp. 475–482.
  43. Invernizzi R, Belli S, Samanin R, “Citalopram’s ability to increase the extracellular concentrations of serotonin in the dorsal raphe prevents the drug’s effect in the frontal cortex”, Brain Res (1992);584: pp. 322–324.
  44. Hjorth S, “Serotonin 5-HT1A autoreceptor blockade potentiates the ability of the 5-HT reuptake inhibitor citalopram to increase nerve terminal output of 5-HT in vivo: a microdialysis study”, J Neurochem (1993);60: pp. 776–779.
  45. Hjorth S, Bengtsson H J, Milano S, “Raphe 5-HT1A autoreceptors, but not postsynaptic 5-HT1A receptors or betaadrenoceptors, restrain the citalopram-induced increase in extracellular 5-hydroxytryptamine in vivo”, Eur J Pharmacol (1996);316: pp. 43–47.
  46. Gobert A, Rivet J M, Cistarelli L, Millan M J, “Potentiation of the fluoxetine-induced increase in dialysate levels of serotonin (5-HT) in the frontal cortex of freely moving rats by combined blockade of 5-HT1A and 5-HT1B receptors with WAY 100,635 and GR 127,935”, J Neurochem (1997);68: pp. 1,159–1,163.
  47. Cremers T I, de Boer P, Liao Y et al., “Augmentation with a 5-HT(1A), but not a 5-HT(1B) receptor antagonist critically depends on the dose of citalopram”, Eur J Pharmacol (2000);397: pp. 63–74.
  48. Artigas F, Perez V, Alvarez E, “Pindolol induces a rapid improvement of depressed patients treated with serotonin reuptake inhibitors”, Arch Gen Psychiatry (1994);51: pp. 248–251.
  49. McAskill R, Mir S, Taylor D, “Pindolol augmentation of antidepressant therapy”, Br J Psychiatry (1998);173: pp. 203–208.
  50. Cremers T I, Wiersma L J, Bosker F J et al., “Is the beneficial antidepressant effect of coadministration of pindolol really due to somatodendritic autoreceptor antagonism?”, Biol Psychiatry (2001); 50: pp. 13–21.
  51. Cremers T I, Giorgetti M, Bosker F J et al., “Inactivation of 5-HT(2C) receptors potentiates consequences of serotonin reuptake blockade”, Neuropsychopharmacology (2004);29: pp. 1,782–1,789.
  52. Jacobs B L, Praag H, Gage F H, “Adult brain neurogenesis and psychiatry: a novel theory of depression”, Mol Psychiatry (2000);5: pp. 262–269.
  53. Benninghoff J, Schmitt A, Mossner R, Lesch K P, “When cells become depressed: focus on neural stem cells in novel treatment strategies against depression”, J Neural Transm (2002);109: pp. 947–962.
  54. Banasr M, Hery M, Printemps R, Daszuta A, “Serotonin-induced increases in adult cell proliferation and neurogenesis are mediated through different and common 5-HT receptor subtypes in the dentate gyrus and the subventricular zone”, Neuropsychopharmacology (2004);29: pp. 450–460.
  55. Trentani A, Kuipers S D, ter Horst G, den Boer J A, “Intracellular signalling transduction dysregulation in depression and possible future targets or antidepressant therapy: beyond the serotonin hypothesis”, Kasper S, den Boer J A, Sitsen J M A (eds), Handbook of depression and anxiety, Marcel Dekker Inc., New York (2003): pp. 349–386.
  56. Westenbroek C, den Boer J A, Veenhuis M, ter Horst G J, “Chronic stress and social housing differentially affect neurogenesis in male and female rats”, Brain Res Bull (2004);64: pp. 303–308.
  57. Radley J J, Jacobs B L, “5-HT1A receptor antagonist administration decreases cell proliferation in the dentate gyrus”, Brain Res (2002);955: pp. 264–267.
  58. Malberg J E, Eisch A J, Nestler E J, Duman R S, “Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus”, J Neurosci (2000);20: pp. 9,104–9,110.
  59. Banasr M, Hery M, Brezun J M, Daszuta A, “Serotonin mediates oestrogen stimulation of cell proliferation in the adult dentate gyrus”, Eur J Neurosci (2001);14: pp. 1,417–1,424.
  60. Scharfman H, Goodman J, Macleod A et al., “Increased neurogenesis and the ectopic granule cells after intrahippocampal BDNF infusion in adult rats”, Exp Neurol (2005);192: pp. 348–356.
  61. Sairanen M, Lucas G, Ernfors P, Castren M, Castren E, “Brain-derived neurotrophic factor and antidepressant drugs have different but coordinated effects on neuronal turnover, proliferation, and survival in the adult dentate gyrus”, J Neurosci (2005);25: pp. 1,089–1,094.
  62. Taylor C, Fricker A D, Devi L A, Gomes I, “Mechanisms of action of antidepressants: from neurotransmitter systems to signaling pathways”, Cell Signal (2005);17: pp. 549–557.
  63. Bondy B, Baghai T C, Minov C et al., “Substance P serum levels are increased in major depression: preliminary results”, Biol Psychiatry (2003);53: pp. 538–542.
  64. Burnet P W, Harrison P J, “Substance P (NK1) receptors in the cingulate cortex in unipolar and bipolar mood disorder and schizophrenia”, Biol Psychiatry (2000);47: pp. 80–83.
  65. Stockmeier C A, Shi X, Konick L et al., “Neurokinin-1 receptors are decreased in major depressive disorder”, Neuroreport (2002);13: pp. 1,223–1,227.
  66. van der Hart M G, Czeh B, de Biurrun G et al., “Substance P receptor antagonist and clomipramine prevent stressinduced alterations in cerebral metabolites, cytogenesis in the dentate gyrus and hippocampal volume”, Mol Psychiatry (2002);7: pp. 933–941.
  67. Guiard B P, Przybylski C, Guilloux J P et al., “Blockade of substance P (neurokinin 1) receptors enhances extracellular serotonin when combined with a selective serotonin reuptake inhibitor: an in vivo microdialysis study in mice”, J Neurochem (2004);89: pp. 54–63.
  68. Bosker F J, Westerink B H, Cremers T I et al., “Future antidepressants: what is in the pipeline and what is missing?”, CNS Drugs (2004);18: pp. 705–732.
  69. Zobel A W, Nickel T, Kunzel H E et al., “Effects of the high-affinity corticotropin-releasing hormone receptor 1 antagonist R121919 in major depression: the first 20 patients treated”, J Psychiatr Res (2000);34: pp. 171–181.
  70. Austin M C, Janosky J E, Murphy H A, “Increased corticotropin-releasing hormone immunoreactivity in monoaminecontaining pontine nuclei of depressed suicide men”, Mol Psychiatry (2003);8: pp. 324–332.
  71. Valentino R J, Commons K G, “Peptides that fine-tune the serotonin system”, Neuropeptides (2005);39: pp. 1–8.
  72. Alonso R, Griebel G, Pavone G et al., “Blockade of CRF(1) or V(1b) receptors reverses stress-induced suppression of neurogenesis in a mouse model of depression”, Mol Psychiatry (2004);9: pp. 278–286, abstract 224.
  73. Purba J S, Hoogendijk W J, Hofman M A, Swaab D F, “Increased number of vasopressin- and oxytocin-expressing neurons in the paraventricular nucleus of the hypothalamus in depression”, Arch Gen Psychiatry (1996);53: pp. 137–143.
  74. van Londen L, Goekoop J G, van Kempen G M et al., “Plasma levels of arginine vasopressin elevated in patients with major depression”, Neuropsychopharmacology (1997);17: pp. 284–292.
  75. Frasch A, Zetzsche T, Steiger A, Jirikowski G F, “Reduction of plasma oxytocin levels in patients suffering from major depression”, Adv Exp Med Biol (1995);395: pp. 257–258.
  76. Arletti R, Bertolini A, “Oxytocin acts as an antidepressant in two animal models of depression”, Life Sci (1987);41: pp. 1,725–1,730.
  77. Osei-Owusu P, James A, Crane J, Scrogin K E, “5-Hydroxytryptamine 1A receptors in the paraventricular nucleus of the hypothalamus mediate oxytocin and adrenocorticotropin hormone release and some behavioral components of the serotonin syndrome”, J Pharmacol Exp Ther (2005);313: pp. 1,324–1,330.
  78. Uvnas-Moberg K, Hillegaart V, Alster P, Ahlenius S, “Effects of 5-HT agonists, selective for different receptor subtypes, on oxytocin, CCK, gastrin and somatostatin plasma levels in the rat”, Neuropharmacology (1996);35: pp. 1,635–1,640.
  79. Vaidya V A, Duman R S, “Depression – emerging insights from neurobiology”, Br Med Bull (2001);57: pp. 61–79.
  80. Nestler E J, Barrot M, DiLeone R J et al., “Neurobiology of depression”, Neuron (2002);34: pp. 13–25.
  81. Nibuya M, Nestler E J, Duman R S, “Chronic antidepressant administration increases the expression of cAMP response element binding protein (CREB) in rat hippocampus”, J Neurosci (1996);16: pp. 2,365–2,372.
  82. Dowlatshahi D, MacQueen G M, Wang J F, Young L T, “Increased temporal cortex CREB concentrations and antidepressant treatment in major depression”, Lancet (1998);352: pp. 1,754–1,755.
  83. Thome J, Sakai N, Shin K et al., “cAMP response element-mediated gene transcription is upregulated by chronic antidepressant treatment”, J Neurosci (2000);20: pp. 4,030–4,036.
  84. Chen A C, Shirayama Y, Shin K H, Neve R L, Duman R S, “Expression of the cAMP response element binding protein (CREB) in hippocampus produces an antidepressant effect”, Biol Psychiatry (2001);49: pp. 753–762.
  85. Conti A C, Cryan J F, Dalvi A, Lucki I, Blendy J A, “cAMP response element-binding protein is essential for the upregulation of brain-derived neurotrophic factor transcription, but not the behavioral or endocrine responses to antidepressant drugs”, J Neurosci (2002);22: pp. 3,262–3,268.
  86. Trentani A, Kuipers S D, ter Horst G J, den Boer J A, “Selective chronic stress-induced in vivo ERK1/2 hyperphosphorylation in medial prefrontocortical dendrites: implications for stress-related cortical pathology?”, Eur J Neurosci (2002);15: pp. 1,681–1,691.
  87. Lim J, Yang C, Hong S J, Kim K S, “Regulation of tyrosine hydroxylase gene transcription by the cAMP-signaling pathway: involvement of multiple transcription factors”, Mol Cell Biochem (2000);212: pp. 51–60.
  88. Smith M A, Makino S, Kvetnansky R, Post R M, “Effects of stress on neurotrophic factor expression in the rat brain”, Ann NY Acad Sci (1995);771: pp. 234–239.
  89. Rasmusson A M, Shi L, Duman R, “Downregulation of BDNF mRNA in the hippocampal dentate gyrus after reexposure to cues previously associated with footshock”, Neuropsychopharmacology (2002);27: pp. 133–142.
  90. Karege F, Perret G, Bondolfi G, Schwald M, Bertschy G, Aubry J M, “Decreased serum brain-derived neurotrophic factor levels in major depressed patients”, Psychiatry Res (2002);109: pp. 143–148.
  91. Altar C A, “Neurotrophins and depression”, Trends Pharmacol Sci (1999);20: pp. 59–61.
  92. Chen B, Dowlatshahi D, MacQueen G M, Wang J F, Young L T, “Increased hippocampal BDNF immunoreactivity in subjects treated with antidepressant medication”, Biol Psychiatry (2001);50: pp. 260–265.
  93. Mori S, Zanardi R, Popoli M et al., “cAMP-dependent phosphorylation system after short and long-term administration of moclobemide”, J Psychiatr Res (1998);32: pp. 111–115.
  94. Shelton R C, Manier D H, Peterson C S, Ellis T C, Sulser F, “Cyclic AMP-dependent protein kinase in subtypes of major depression and normal volunteers”, Int J Neuropsychopharmcol (1999);2: pp. 187–192.
  95. Perez J, Tardito D, Racagni G, Smeraldi E, Zanardi R, “cAMP signaling pathway in depressed patients with psychotic features”, Mol Psychiatry (2002);7: pp. 208–212.
  96. Hetman M, Kanning K, Cavanaugh J E, Xia Z, “Neuroprotection by brain-derived neurotrophic factor is mediated by extracellular signal-regulated kinase and phosphatidylinositol 3-kinase”, J Biol Chem (1999);274: pp. 22,569–22,580.
  97. Manji H K, Moore G J, Rajkowska G, Chen G, “Neuroplasticity and cellular resilience in mood disorders”, Mol Psychiatry (2000);5: pp. 578–593.
  98. Mai L, Jope R S, Li X, “BDNF-mediated signal transduction is modulated by GSK3beta and mood stabilizing agents”, J Neurochem (2002);82: pp. 75–83.
  99. Dwivedi Y, Rizavi H S, Roberts R C et al., “Reduced activation and expression of ERK1/2 MAP kinase in the postmortem brain of depressed suicide subjects”, J Neurochem (2001);77: pp. 916–928.
  100. Ma W, Fitzgerald W, Liu Q Y et al., “CNS stem and progenitor cell differentiation into functional neuronal circuits in three-dimensional collagen gels”, Exp Neurol (2004);190: pp. 276–288.
  101. Allen N J, Barres B A, “Signaling between glia and neurons: focus on synaptic plasticity”, Curr Opin Neurobiol (2005);15: pp. 542–548.
  102. Adell A, Castro E, Celada P et al., “Strategies for producing faster acting antidepressants”, Drug Discov Today (2005);10: pp. 578–585.
  103. van der Werf S Y, Kaptein K I, de Jonge P et al., “Major depressive episodes and random mood”, Arch Gen Psychiatry (2006, in press).