Table II. Potential mechanism-based therapeutic interventions. LHPA, limbic-hypothalamic-pituitary-adrenal; GC, glucocorticoid; GR, glucocorticoid receptor; CRH, corticotrophin-releasing hormone; DHEA, dehydroepiandrosterone; BDNF brain-derived neurotrophic factor; TNF, tumor necrosis factor; SSRI, selective serotonin reuptake inhibitor .

Biochemical mediator	Potential treatment interventions
Stress vulnerability	Stress reduction; meditation; lifestyle changes7,142,154
Epigenetic changes	Epigenetic reprogramming155,156
LHPA axis dysregulation	Antidepressants upregulate GR function71
(Hypercortisolemia + GC resistance)	CRH antagonists157
	Cortisol antagonists and GR antagonists or agonists66,69
Glucose/insulin dysregulation	Insulin receptor sensitizers99,146
Glutamate/excitotoxicity	Glutamate antagonists147
Oxidative stress	Antidepressants have antioxidant effects120
	Antioxidants150,158
Intracellular calcium	Calcium blockers148
Inflammation	Antidepressants have anti-inflammatory effects20
	Anti-inflammatory drugs, TNF-a antagonists, etc149
Decreased counter-regulatory neurosteroids	SSRIs increase allopregnanolone synthesis77,78
	DHEA administration17
Decreased BDNF	Antidepressants (esp SSRIs) increase BDNF concentrations122,123
	Environmental enrichment143,144
	Exercise143
	Dietary restriction143
	BDNF administration via novel routes or vectors124,151
Cell aging (telomeres; telomerase)	Telomerase activation152,153