Lithium augmentation increases post-dexamethasone cortisol in the dexamethasone suppression test in unipolar major depression

Abstract

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.

The Anti-Apoptotic, Glucocorticoid Receptor Cochaperone Protein BAG-1 Is a Long-Term Target for the Actions of Mood Stabilizers

“…Thus, in this test, an attenuation of GR signaling by lithium would be manifested by an enhanced ACTH/cortisol response. This is indeed the case, with chronic lithium treatment resulting in an enhanced cortisol and ACTH response in this test (Bschor et al, 2002(Bschor et al, , 2003Kunzel et al, 2003). Together, the data suggest that lithium does attenuate GR signaling in BD patients.…”

Glucocorticoids as Predictors of Treatment Response in Depression

“…45,47 On the contrary, the mood stabilizers lithium and carbamazepine interfere with plasma ACTH and cortisol concentrations at baseline and under stimulation conditions. 45,48,49 Carbamazepine likely alters the liver metabolism of dex via the cytochrome P450 system, 50,51 leading to insufficient dex suppression.…”

Different responses to dexamethasone and prednisolone in the same depressed patients

“…We also tested whether there were any effects of lithium treatment on baseline cortisol levels or suppression by prednisolone or by dexamethasone, as lithium has been shown to increase post-dexamethasone cortisol levels in the standard DST (Bschor et al 2003). Compared to patients not on lithium, patients on lithium (n=8) had higher cortisol (AUCs) values at baseline (107.8±15.5 vs 59.3±9.9 nmol X h/l, p=0.014) and after both dexamethasone (64.0±14.7 vs 29.1±14.5 nmol X h/l, p=0.1) and prednisolone (76.8±15.0 vs 29.2±4.2 nmol X h/l, p=0.004), but there was no effect of lithium on the percentage suppression of cortisol (AUCs) by either dexamethasone (p=0.6) or prednisolone (p=0.3).…”