Comment on: Antidepressants act by directly binding to TRKB neurotrophin receptors

We recently published a paper in Molecular Psychiatry entitled, Re-assessing the Catecholamine Hypothesis of Depression: The Case of Melancholic Depression [1]. We cited our data published in PNAS that patients with melancholic depression have increased plasma and cerebrospinal fluid norepinephrine levels in around-the-clock samples taken hourly for thirty consecutive hours. These patients also had significantly elevated norepinephrine spillover into arterial plasma at baseline in response to a mild stressor and to yohimbine, an alpha 2 noradrenergic blocker. The symptom complex of melancholic depression is compatible with norepinephrine hypersecretion in multiple ways. Melancholia contradicts the term depression in that it is not always a state of behavioral and physiological suppression, but rather, often a state of hyperarousal and a tortured sense of worthlessness. Norepinephrine promotes anxiety and hyperarousal, stimulates corticotropin-releasing hormone-mediated hypercortisolism, is neurotoxic, promotes insulin resistance, and is an important mediator of bone loss relevant to melancholic depression [2].

We noted that the initial catecholamine hypothesis was based on the impact of imipramine on plasma norepinephrine levels after a single administration, contrary to the two weeks or more it takes for antidepressants like imipramine to work. In addition, reserpine has been used to treat depression effectively  on several occasions [3], probably of the melancholic subtype, this represents a salutary effect of antagonizing norepinephrine synthesis. On the other hand, reserpine probably induces depression when used as an antihypertensive by depleting dopamine [1].