Etiological classification of depression based on the enzymes of tryptophan metabolism

BMC Psychiatry

Katsuhiko Fukuda¹ 

[1] Soka Clinic of Psychosomatic Medicine, Fujimoto Bld. 4 F, 2-18-16 Takasago, Soka, Saitama 340-0015, Japan

关键词: Cybernetics;    Kynurenine-3-monooxygenase;    Indoleamine 2,3-dioxygenase;    Tryptophan 2,3-dioxygenase;    Tryptophan hydroxylase;    Kynurenine;    Serotonin;    Depression;   

Others  :  1123305
DOI  :  10.1186/s12888-014-0372-y

 received in 2014-10-10, accepted in 2014-12-18,  发布年份 2014

【 摘 要 】

Background

Viewed in terms of input and output, the mechanisms of depression are still akin to a black box. However, there must be main pivots for diverse types of depression. From recent therapeutic observations, both the serotonin (5-HT) and kynurenine pathways of tryptophan metabolism may be of particular importance to improved understanding of depression. Here, I propose an etiological classification of depression, based on key peripheral and central enzymes of tryptophan metabolism.

Discussion

Endogenous depression is caused by a larger genetic component than reactive depression. Besides enterochromaffin and mast cells, tryptophan hydroxylase 1 (TPH1), primarily expressed in the gastrointestinal tract, is also found in 5-hydroxytryptophan-producing cells (5-HTP cells) in normal intestinal enterocytes, which are thought to essentially shunt 5-HT production in 5-HT-producing cells. Genetic studies have reported an association between TPH1 and depression, or the responsiveness of depression to antidepressive medication. Therefore, it is possible that hypofunctional 5-HTP cells (reflecting TPH1 dysfunction) in the periphery lead to deficient brain 5-HT levels. Additionally, it has been reported that higher TPH2 expression in depressed suicides may reflect a homeostatic response to deficient 5-HT levels. Subsequently, endogenous depression may be caused by TPH1 dysfunction combined with compensatory TPH2 activation. Reactive depression results from life stresses and involves the hypothalamic-pituitary-adrenal axis, with resulting cortisol production inducing tryptophan 2,3-dioxygenase (TDO) activation. In secondary depression, caused by inflammation, infection, or oxidative stress, indoleamine 2,3-dioxygenase (IDO) is activated. In both reactive and secondary depression, the balance between 3-hydroxykynurenine (3-HK) and kynurenic acid may shift towards 3-HK production via kynurenine-3-monooxygenase (KMO) activation. By shifting the equilibrium position of key enzymes of tryptophan metabolism, the classical classification of depression can be reorganized, as below.

Peripheral classification of depression by key enzymes

TPH1 dysfunction

TDO activation

IDO activation

Central classification of depression by key enzymes

TPH2 activation

KMO activation

Summary

Etiological classification of depression expressed by peripheral (TPH1, TDO, IDO) and central (TPH2, KMO) enzymes of tryptophan metabolism may enable depression to be viewed as a clear box, with the inner components available for inspection and treatment.

【 授权许可】

   
2014 Fukuda; licensee BioMed Central.

【 图 表 】

Figure 1.

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