A New Role for Nortriptyline in Depression Associated With Vascular Disease?

To the Editor: The study by Rudolf Uher, M.D., Ph.D., et al. (1), published in the December issue of the Journal, raises the tantalizing prospect of C-reactive protein as the first differential predictor of antidepressant response. In a retrospective analysis of an open-label multicenter trial of 12-week treatment with escitalopram or nortriptyline, the authors found that patients with low levels of C-reactive protein (<1 mg/L) at baseline showed better outcomes when prescribed escitalopram, whereas for patients with higher C-reactive protein levels, nortriptyline turned out to be more efficacious.

There is a vast clinical literature on the association between inflammation and vascular pathologies. In particular, elevated C-reactive protein levels have been linked with an increase in the subsequent incidence of coronary heart disease, peripheral vascular disease, and ischemic stroke (2).

Indeed, it has been postulated that inflammatory mechanisms may underlie the well-established relationship between depressive symptoms and cardiovascular risk. Conversely, immunological perturbations after a vascular event such as myocardial infarction or stroke have been implicated in the etiopathology of post-myocardial infarction and poststroke depression (3, 4).

The findings reported by Uher et al. could therefore be highly pertinent to depressed patients at risk for vascular symptoms or after manifestation of vascular symptoms. As the authors acknowledge themselves, it will be important to replicate their findings prospectively. Ideally, such a study would include longitudinal measurements of key cytokines, as well as of C-reactive protein and adipocyte-specific serum amyloid A, another acute phase reactant that seems to be more sensitive than C-reactive protein as a marker of the inflammatory response (5). Here, it would be particularly interesting to see whether treatment with nortriptyline or other noradrenergic antidepressants might affect circulating levels of acute-phase reactants at follow-up. Importantly, such an immune-modulating effect of nortriptyline might even hint at beneficial consequences of antidepressant treatment extending far beyond mood symptoms. Currently, selective serotonin reuptake inhibitors seem to be the preferred antidepressants in coronary heart disease and in stroke patients. However, the study by Uher et al. suggests that nortriptyline and other noradrenergic antidepressants merit further investigation in the context of depression and vascular disease.