Although considerable evidence exists on the efficacy of
lithium as an augmenting agent in
refractory depression, the underlying neurobiology of this phenomenon is unknown. In patients with major depression, changes of the hypothalamic-pituitary-adrenocortical (HPA) system have been detected by means of the
dexamethasone suppression test (DST), when administered during treatment with
tricyclic antidepressants. We investigated whether the DST also reveals alterations of the HPA system during
lithium augmentation. We also sought to identify whether response to
lithium augmentation can be predicted with the DST. Twenty-five patients with unipolar major depression, who did not respond to an adequate
antidepressant monotherapy of at least 4 weeks, were measured for basal (pre-dexamethasone, 0800h)
cortisol and
ACTH levels and were administered the DST the day before initiation of
lithium augmentation treatment. The same neuroendocrine procedures were repeated after 3 to 4 weeks. Criteria of response to
lithium augmentation, defined as a reduction of the Hamilton Depression Rating Scale (HDRS17) score by > or =50% and an end point score of 9 or less, were determined by weekly HDRS ratings. The DST revealed a statistically significant increase of the post-
dexamethasone cortisol values (P = 0.021) and an increase in the post-
dexamethasone ACTH values (P = 0.051) during
lithium augmentation as compared to pre-treatment baseline evaluations. The pre-
dexamethasone hormone values were unchanged. The number of non-suppressors at baseline was one and increased to three at follow-up. Results of DST did not predict response to
lithium augmentation, which occurred in 40% of subjects. Results suggest that
lithium augmentation increases HPA system activity, as indicated by the increase of post-
dexamethasone cortisol and
ACTH levels measured by the DST. This is in contrast to the established decline of HPA system activity during treatment with
tricyclic antidepressants.