Antidepressant regulation of endpoints relevant to the hypothalamic-pituitary-adrenal axis: Implications for predicting treatment response in depression

Elevated hypothalamic pituitary adrenal (HPA) axis activity in depression is proposed to result from impaired HPA feedback and may be a biological marker for the disease. Antidepressant treatment has been suggested to compensate for impaired feedback by increasing brain glucocorticoid (GR) and mineralocorticoid receptors (MR) and thus inhibiting HPA activity. Although elevated HPA activity is associated with melancholic depression, other forms of depression such as atypical depression have been associated with decreased HPA activity and enhanced HPA feedback. These different forms of depression have also shown a differential responsiveness to antidepressant treatment, with melancholic depression being successfully treated with tricyclic antidepressants (TCA) and atypical depressives showing a preferential responsiveness to monoamine oxidase inhibitors (MAOI). Because successful antidepressant treatment has been correlated with normalization of HPA activity, and previous studies in our lab have shown opposing effects of TCA and MAOI on measures of HPA activity we hypothesized that chronic TCA treatment would increase and MAOI treatment would decrease corticosteroid receptor expression in glucocorticoid feedback-related brain regions. We further hypothesized that in order for antidepressants to alter glucocorticoid feedback sensitivity without exacerbating effects of glucocorticoids on mood, antidepressant-induced changes in GR and MR expression must be brain region-specific. In support of our hypothesis, we found brain region-specific, often opposing, effects of the prototypic TCA imipramine and the prototypic MAOI phenelzine on GR and MR gene expression. Currently however, selective serotonin reuptake inhibitors (SSRIs) are more often prescribed than TCA or MAOI for a wide variety of depression subtypes. We therefore hypothesized that chronic SSRI treatment would have effects on GR and MR gene expression that are shared with both TCA and MAOI. In support of this hypothesis, chronic treatment with the prototypic SSRI, fluoxetine had effects that resembled those of both TCA and MAOI treatment. Further antidepressant-induced changes in glucocorticoid-regulated endpoints were consistent with antidepressant effects on corticosteroid receptor expression, indicating that antidepressant effects on GR and MR are likely to be physiologically relevant. By, defining antidepressant-specific effects on HPA relevant-endpoints, these findings may aid in the use of the HPA testing to improve the prediction and detection of antidepressant response in depression.