Table 1.

Table 1 Clinically relevant neurobiological hypotheses of major depressive disorder (MDD)

Hypothesis	Main strength	Main weakness
Genetic vulnerability	Solid evidence from twin studies that 30-40% of MDD risk is genetic	No specific MDD risk gene or gene-environment interaction has been reliably identified
Altered HPA axis activity	Plausible explanation for early and recent stress as MDD risk factor	No consistent antidepressant effects of drugs targeting the HPA axis
Deficiency of monoamines	Almost every drug that inhibits monoamine reuptake has antidepressant properties	Monoamine deficiency is likely a secondary downstream effect of other, more primary abnormalities
Dysfunction of specific brain regions	Stimulation of specific brain regions can produce antidepressant effects	Neuroimaging literature in MDD provides limited overlap of results
Neurotoxic and neurotrophic processes	Plausible explanation of “kindling” and brain volume loss during the course of depressive illness	No evidence in humans for specific neurobiological mechanisms
Reduced GABAergic activity	Converging evidence from magnetic resonance spectroscopy and post-mortem studies	No consistent antidepressant effect of drugs targeting the GABA system
Dysregulation of glutamate system	Potentially rapid and robust effects of drugs targeting the glutamate system	Questionable specificity, since glutamate is involved in almost every brain activity
Impaired circadian rhythms	Manipulation of circadian rhythms (e.g., sleep deprivation) can have antidepressant efficacy	No molecular understanding of the link between circadian rhythm disturbances and MDD
HPA – hypothalamic-pituitary-adrenal; GABA – gamma-aminobutyric acid