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