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Re-assessing the catecholamine hypothesis of depression: the case of melancholic depression

Molecular Psychiatry volume 26, pages 6121–6124 (2021)Cite this article

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The hypothesis that major depression represents a deficiency of norepinephrine (NE) at critical synapses in the central nervous system has been extremely influential since the mid-1960s. First espoused by Schildkraut [1] and Bunney and Davis [2], the hypothesis was based on the following pharmacological evidence: (i) that imipramine acutely increased NE neurotransmission; (ii) that MAO (monoamine oxidase) inhibitors blocked the metabolism of NE, and hence increased NE neurotransmission; (iii) reserpine, which produced depression, depleted NE from noradrenergic neurons [1, 2]. Though several have questioned the validity of the hypothesis, it has never been definitively challenged. We report here that noradrenergic neurotransmission and locus caeruleus activity is increased rather than decreased in the specific subtype of major depression, melancholia [3,4,5]. The symptom complex of melancholic depression is compatible with NE hypersecretion in multiple ways [5]. Melancholia contradicts the term depression, in that it is not a state of behavioral and physiological suppression, but rather, often a state of hyperarousal and a tortured sense of worthlessness. NE promotes anxiety and hyperarousal, stimulates corticotropin-releasing hormone (CRH)-mediated hypercortisolism, is neurotoxic promotes insulin resistance, and is an important mediator of bone loss, all of which are relevant to melancholic depression (reviewed in [5]).

We also found that in both patients and controls, CSF and plasma NE had virtually identical diurnal variations and their diurnal variations were also superimposable with that of plasma cortisol (Fig. 1) [3, 4]. Detrended lag correlations revealed that around-the-clock CSF and plasma NE and plasma cortisol levels were significantly correlated independent of the diurnal rhythm [4]. Not only are CSF and plasma NE levels elevated around-the-clock in depressed patients, but their linkage with the hypercortisolism of melancholia makes it virtually inconceivable that plasma and CSF NE are reduced in depressed patients in the setting sustained elevations in plasma cortisol. This is further supported by the well-known close linkage between the CRH and locus caeruleus/NE systems. Valentino has shown that CRH stimulates the locus caeruleus, while we have shown that NE stimulates CRH release [6]. In addition, it has been found that differential blockade of CRF-evoked behaviors occurs by depletion of NE in rats. Finally, data confirm that CRH engagement of the locus caeruleus-NE system mediates stress-induced anxiety [7].

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Fig. 1: Hourly around-the-clock sampling for thirty consecutive hours of CSF and plasma NE, CSF and plasma EPI, and plasma cortisol in severely depressed, medication-free patients with melancholic depression before and after ECT-induced remission.
Fig. 2: Norepinephrine spillover into arterial plasma in mild-moderately depressed, medication-free melancholic patients at baseline, after a video game, and after yohimbine, an a2 noradrenergic antagonist.

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  1. Intramural Research Program, National Institute of Mental Health, Bethesda, MD, USA

    Philip W. Gold

  2. Departments of Psychiatry and Behavioral Sciences, and Neurosciences and Physiology, State University of New York, Upstate Medical University, Syracuse, NY, USA

    Ma-Li Wong

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Gold, P.W., Wong, ML. Re-assessing the catecholamine hypothesis of depression: the case of melancholic depression. Mol Psychiatry 26, 6121–6124 (2021). https://doi.org/10.1038/s41380-021-01133-x

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