Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

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

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

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.


  1. 1.

    Schildkraut JJ. The catecholamine hypothesis of affective disorders: a review of supporting evidence. Am J Psychiatry. 1965;122:509–22.

    CAS  Article  Google Scholar 

  2. 2.

    Bunney WE Jr., Davis JM. Norepinephrine in depressive reactions. A review. Arch Gen Psychiatry. 1965;13:483–94.

    CAS  Article  Google Scholar 

  3. 3.

    Gold PW, Wong ML, Goldstein DS, Gold HK, Ronsaville DS, Esler M, et al. Cardiac implications of increased arterial entry and reversible 24-h central and peripheral norepinephrine levels in melancholia. Proc Natl Acad Sci USA. 2005;102:8303–8.

    CAS  Article  Google Scholar 

  4. 4.

    Wong ML, Kling MA, Munson PJ, Listwak S, Licinio J, Prolo P, et al. Pronounced and sustained central hypernoradrenergic function in major depression with melancholic features: relation to hypercortisolism and corticotropin-releasing hormone. Proc Natl Acad Sci USA. 2000;97:325–30.

    CAS  Article  Google Scholar 

  5. 5.

    Gold PW. The organization of the stress system and its dysregulation in depressive illness. Mol Psychiatry. 2015;20:32–47.

    CAS  Article  Google Scholar 

  6. 6.

    Calogero AE, Gallucci WT, Chrousos GP, Gold PW. Catecholamine effects upon rat hypothalamic corticotropin-releasing hormone secretion in vitro. J Clin Investig. 1988;82:839–46.

    CAS  Article  Google Scholar 

  7. 7.

    McCall JG, Al-Hasani R, Siuda ER, Hong DY, Norris AJ, Ford CP, et al. CRH Engagement of the Locus Coeruleus Noradrenergic System Mediates Stress-Induced Anxiety. Neuron. 2015;87:605–20.

    CAS  Article  Google Scholar 

  8. 8.

    Huang YH, Maas JW, Hu GH. The time course of noradrenergic pre- and postsynaptic activity during chronic desipramine treatment. Eur J Pharm. 1980;68:41–7.

    CAS  Article  Google Scholar 

  9. 9.

    Grant MM, Weiss JM. Effects of chronic antidepressant drug administration and electroconvulsive shock on locus coeruleus electrophysiologic activity. Biol Psychiatry. 2001;49:117–29.

    CAS  Article  Google Scholar 

  10. 10.

    Brady LS, Whitfield HJ Jr., Fox RJ, Gold PW, Herkenham M. Long-term antidepressant administration alters corticotropin-releasing hormone, tyrosine hydroxylase, and mineralocorticoid receptor gene expression in rat brain. Therapeutic implications. J Clin Investig. 1991;87:831–7.

    CAS  Article  Google Scholar 

  11. 11.

    Vetulani J, Stawarz RJ, Dingell JV, Sulser F. A possible common mechanism of action of antidepressant treatments: reduction in the sensitivity of the noradrenergic cyclic AMP gererating system in the rat limbic forebrain. Naunyn Schmiedebergs Arch Pharm. 1976;293:109–14.

    CAS  Article  Google Scholar 

  12. 12.

    Davies DL, Shepherd M. Reserpine in the treatment of anxious and depressed patients. Lancet. 1955;269:117–20.

    CAS  Article  Google Scholar 

  13. 13.

    Price LH, Charney DS, Heninger GR. Reserpine augmentation of desipramine in refractory depression: clinical and neurobiological effects. Psychopharmacol (Berl). 1987;92:431–7.

    CAS  Article  Google Scholar 

  14. 14.

    Axelrod J, Whitby LG, Hertting G. Effect of psychotropic drugs on the uptake of H3-norepinephrine by tissues. Science. 1961;133:383–4.

    CAS  Article  Google Scholar 

  15. 15.

    Gold PW, Chrousos GP. The endocrinology of melancholic and atypical depression: relation to neurocircuitry and somatic consequences. Proc Assoc Am Phys. 1999;111:22–34.

    CAS  Article  Google Scholar 

Download references

Author information



Corresponding authors

Correspondence to Philip W. Gold or Ma-Li Wong.

Ethics declarations

Conflict of interest

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Gold, P.W., Wong, ML. Re-assessing the catecholamine hypothesis of depression: the case of melancholic depression. Mol Psychiatry (2021).

Download citation


Quick links