Ignorance about causal relationships is not due to a lack of theories about important pathways. For example, for major depression we can identify at least seven: (i) alterations in cAMP signaling pathway [47], (ii) impaired corticosteroid receptor signaling [48], (iii) neurotrophins [49], (iv) alterations in fibroblast growth factors [50], (v) GABAergic deficits [51], (vi) epigenetic changes at glucocorticoid receptors and brain derived neurotrophic factor [52], and (vi) alterations in glutamate [53] and (vii) alterations in serotonin signaling [54]. Each theory suggests possibilities for collecting intermediate phenotypes, at multiple levels (for instance, measuring GABA and glutamate concentrations by proton magnetic resonance spectroscopy [55]). Since we know so little about the origins of psychiatric disease, we are left in the situation of collecting a large number of intermediate phenotypes in the hope that some might aid our understanding of the disease.
