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Scientific Rational

Tackling cognitive dysfunction in affective disorders: focus on monoamines and corticosteroids

Introduction

Affective disorders are chronic and highly recurrent conditions that have a major impact on health and social and economic prosperity. WHO statistics show that depression and bipolar disorder are both in the top ten leading causes of disability1. Although defined by alterations in mood, affective disorders are also characterised by cognitive symptoms. Indeed these are among some of the most frequently self-reported symptoms. Cognitive symptoms significantly contribute to psychosocial dysfunction and are particularly unresponsive to conventional treatments. The biological basis of the symptoms of affective disorders is poorly understood though there is evidence of monoaminergic abnormalities, particularly of serotonin (5-HT). An additional possible contributory factor is the elevation of the trough of the daily rhythm of corticosteroid hormones. This 'corticosteroid dysrhythmia' is found in many patients with affective disorders, is associated with cognitive dysfunction. In rats and man, corticosteroids have been shown to have effects on brain structure and function, including aspects of 5 HT neurotransmission and cognition.

Brief Scientific Background

Cognitive dysfunction in mood disorders
Although mood disorders are defined clinically by alterations in affect, they are also characterised by cognitive symptoms. Deficits include episodic and spatial memory, attention and executive function2,3,4 as well as alterations in emotional processing5,6. The hippocampus and prefrontal cortex (i.e. the regions subserving these functions) have been shown in imaging studies to have reduced volume in patients with mood disorders7. Furthermore, post-mortem histological studies have shown abnormalities of glial and/or neuronal number or structure in these same regions8.

5-HT abnormalities in mood disorders
5‑HT dysfunction is implicated in the pathophysiology of mood disorders. Thus, 5‑HT depletion provokes depressive symptomatology in subjects with history of depression9. Furthermore, neuroendocrine challenge studies have shown an impairment of postsynaptic 5‑HT1A receptor function in depressed patients10,11. Consistent with this, some12,13, but not all14, PET studies have shown a reduction in 5-HT1A receptor number including in hippocampus and prefrontal cortex (PFCx), in depressed patients. An association between a polymorphism of the 5-HT1A receptor promoter gene and depression has also been identified14.  Experimentally induced reductions in 5-HT in healthy subjects lead to a number of cognitive effects including impairments in episodic memory15,16 as well as disruption of inhibitory and emotional processing similar to that seen in depression17.

Corticosteroid abnormalities in mood disorders
In healthy adults, corticosteroid (cortisol in man and corticosterone in rodents) release occurs in a diurnal rhythm with the zenith occurring on waking and the trough later in the activity cycle. Abnormalities of corticosteroid secretion are reported in 40 to 80% patients with mood disorders18,19, with highest prevalence in patients with the most severe illnesses20. There can be continued corticosteroid dysregulation21 and neurocognitive impairment22 even after recovery of mood. Plasma profiles over 24h show that in mood disorder patients cortisol levels are particularly elevated during the diurnal trough16,23. Corticosteroids can have widespread effects through the central nervous system via actions on intracellular transcription-regulating receptors (glucocorticoid and mineralocorticoid receptors). A link between altered corticosteroid rhythm and the pathophysiology underlying mood disorders is strongly suggested by evidence that 5-HT neurotransmission24,25,26,27,28,29,30,31,32, cognition33,34,35,36 and synaptic plasticity37,38,39,40, all of which are altered in mood disorders, can be modulated by corticosteroids (vide infra).

References

1Murray and Lopez (1997) Alternative projections of mortality and disability by cause 1990-2020: Global Burden of Disease Study. Lancet 349:1498.
2. Elliott et al. (1996) Neuropsychological impairments in unipolar depression: the influence of perceived failure on subsequent performance. Psychological Medicine 26:975.
3. McAllister-Williams et al. (1998) Mood and neuropsychological function in depression: the role of corticosteroids and serotonin. Psychological Medicine 28:573.
4. Porter et al. (2003) Neurocognitive impairment in drug-free patients with major depressive disorder. Br J Psychiatry 182:214.
5. Langenecker et al. (2005) Face emotion perception and executive functioning deficits in depression. J Clin Exp Neuropsychol. 27:320.
6. Surguladze et al. (2005) A differential pattern of neural response toward sad versus happy facial expressions in major depressive disorder. Biol Psychiatr. 57:201.
7. Haldane & Frangou (2004) New insights help define the pathophysiology of bipolar affective disorder: neuroimaging and neuropathology findings. Prog Neuropsychopharmacol Biol Psychiatr. 28:943.
8. Harrison (2002) The neuropathology of primary mood disorder. Brain. 125:1428.
9. Delgado et al. (1994) Serotonin and the neurobiology of depression. Effects of tryptophan depletion in drug-free depressed patients. Arch Gen Psychiatr 51:865.
10. Cowen (1993) Serotonin receptor subtypes in depression: evidence from studies in neuroendocrine regulation. Clin Neuropharmacol. 16 Suppl 3:S6.
11. Deakin (1998) The role of serotonin in panic, anxiety and depression. Int Clin Psychopharmacol. 13 Suppl 4:S1.
12. Drevets et al. (1999) PET imaging of serotonin 1A receptor binding in depression. Biol Psychiatr 46:1375.
13. Sargent et al. (2000) Brain serotonin1A receptor binding measured by positron emission tomography with [11C]WAY-100635: effects of depression and antidepressant treatment. Arch Gen Psychiatr 57:174.
14. Parsey et al. (2006) Altered serotonin 1A binding in major depression: a [carbonyl-C-11]WAY100635 positron emission tomography study. Biol Psychiatr 59:106.
15. McAllister-Williams et al. (2002) Effects of tryptophan depletion on brain potential correlates of episodic memory retrieval. Psychopharm 160:434.
16.  Schmitt et al. (2006) Serotonin and human cognitive performance. Cur Pharm Design 12:2473.
17.  Murphy et al. (2002) The effects of tryptophan depletion on cognitive and affective processing in healthy volunteers. Psychopharm 163:42.
18. Heuser I et al. (1994) The combined dexamethasone/CRH test: a refined laboratory test for psychiatric disorders. J Psychiatric Res 28:341.
19. Kunugi et al. (2006) Assessment of the dexamethasone/CRH test as a state-dependent marker for hypothalamic-pituitary-adrenal (HPA) axis abnormalities in major depressive episode: a Multicenter Study. Neuropsychopharmacol. 31:212.
20. Rush et al. (1996) The dexamethasone suppression test in patients with mood disorders. J Clin Psychiatry 57:470.
21. Watson et al. (2004) Hypothalamic-pituitary-adrenal axis function in patients with bipolar disorder. Br J Psychiatry 184:496.
22. Deuschle et al. (2004) Impaired declarative memory in depressed patients is slow to recover: clinical experience. Pharmacopsychiatry. 37:147.
23. Wong et al. (2000) Pronounced and sustained central hypernoradrenergic function in major depression with melancholic features: relation to hypercortisolism and corticotropin-releasing hormone. Proc Natl Acad Sci 97:325.
24. Young et al. (1994) Effects of glucocorticoids on 5-HT1A presynaptic function in the mouse. Psychopharmacol 114:360.
25. Man et al. (2002) Corticosterone modulation of somatodendritic 5‑HT1A receptor function in mice. J Psychopharmacol 16:245.
26. Leitch et al. (2003) Flattening the corticosterone rhythm attenuates 5-HT1A autoreceptor function in the rat: relevance for depression. Neuropsychopharmacol 28:119.
27. Fairchild et al. (2003) Acute and chronic effects of corticosterone on 5-HT1A receptor-mediated autoinhibition in the rat dorsal raphe nucleus. Neuropharmacol 45:925.
28. McAllister-Williams et al. (2004) Somatodendritic 5‑HT1A autoreceptor downregulation by cortisol - A mechanism for resilience to stress in man? Biol Psychiatry 55:36S.
29. Takao et al. (1997) Effects of corticosterone on 5-HT1A and 5-HT2 receptor binding and on the receptor-mediated behavioral responses of rats. Eur J Pharmacol 333:123.
30. Beck et al. (1996) Corticosterone alters 5-HT1A receptor-mediated hyperpolarization in area CA1 hippocampal pyramidal neurons. Neuropsychopharmacol 14:27.
31. Bijak et al. (2001) Opposite effects of antidepressants and corticosterone on the sensitivity of hippocampal CA1 neurons to 5-HT1A and 5-HT4 receptor activation. N-S Arch Pharmacol 363:491.
32. Porter et al. (2002) The effects of sub-chronic administration of hydrocortisone on hormonal and psychological responses to L-tryptophan in normal male volunteers. Psychopharmacol 163:68.
33. Young et al. (1999) The effects of chronic administration of hydrocortisone on cognitive function in normal male volunteers. Psychopharmacol 145:260.
34. McAllister-Williams & Rugg (2002) Effects of repeated cortisol administration on brain potential correlates of episodic memory retrieval. Psychopharmacol 160:74.
35. Wolf et al. (2004) Cortisol and memory retrieval in humans: influence of emotional valence. Ann NY Acad Sci. 1032:195.
36. Van Honk et al. (2003) Attentionally modulated effects of cortisol and mood on memory for emotional faces in healthy young males. Psychoneuroendocrinol. 28:941.
37. Aleisa et al. (2006) Chronic psychosocial stress-induced impairment of hippocampal LTP: Possible role of BDNF. Neurobiol Dis. In press.
38. Gerges et al. (2004) Reduced basal CaMKII levels in hippocampal CA1 region: possible cause of stress-induced impairment of LTP in chronically stressed rats. Hippocampus 14:402.
39. Schaaf et al. (2000) Corticosterone effects on BDNF expression in the hippocampus. Implications for memory formation. Stress. 3:201.
40. Smith et al. (1995) Stress and glucocorticoids affect the expression of brain-derived neurotrophic factor and neurotrophin-3 mRNAs in the hippocampus. J Neurosci. 15:1768.