Background. Depressed patients show deficits on neuropsychological tests. However, the basis of these impairments and their relationship with mood disturbance remains unclear.

Methods. This paper reviews the literature regarding the relationship between mood disturbance and neuropsychological impairment in depression and the evidence for serotonergic and hypothalamic–pituitary–adrenal (HPA) axis involvement in these two domains.

Results. Mood disturbance and neuropsychological impairment both occur in depression, but have no clear relationship in time or degree. Impairment of post-synaptic 5-HT1A receptor function may result in the symptom of low mood in depression. Depressed patients demonstrate abnormalities in the functional control of the HPA axis with a resultant hypercortisolaemia, which may impair neuropsychological function. These processes may be related given the extensive interactions between the serotonergic system and the HPA axis.

Conclusions. We argue that there is a neurobiological cause of impaired neuropsychological function in depression. The complex relationship between neuropsychological function and mood may be a result of interactions between the serotonergic system and the HPA axis, particularly in the hippocampus with involvement of serotonergic 5-HT1A and glucocorticoid receptors. A primary dysfunction in these receptors will produce a lowering of mood and neuropsychological impairment respectively. Either dysfunction will result in a secondary impairment of the alternate system. Thus, the affective and psychological changes of depressive illness are likely to have complex relationships in time and severity to one another and the illness as a whole may result from a range of primary aetio-pathologies.