Metabolite profiling of antidepressant drug action reveals novel drug targets beyond monoamine elevation.

Currently used antidepressants elevate monoamine levels in the synaptic cleft. There is good reason to assume that this is not the only source for antidepressant therapeutic activities and that secondary downstream effects may be relevant for alleviating symptoms of depression. We attempted to elucidate affected biochemical pathways downstream of monoamine reuptake inhibition by interrogating metabolomic profiles in DBA/2Ola mice after chronic paroxetine treatment. Metabolomic changes were investigated using gas chromatography-mass spectrometry profiling and group differences were analyzed by univariate and multivariate statistics. Pathways affected by antidepressant treatment were related to energy metabolism, amino acid metabolism and hormone signaling. The identified pathways reveal further antidepressant therapeutic action and represent targets for drug development efforts. A comparison of the central nervous system with blood plasma metabolite alterations identified GABA, galactose-6-phosphate and leucine as biomarker candidates for assessment of antidepressant treatment effects in the periphery.

Psychiatric disorders biomarker identification: from proteomics to systems biology.

The pathobiology of psychiatric disorders remains mostly obscure. Diagnosis is often imprecise and current treatments are empirical and at best symptomatic. The identification of biomarkers can help with developing improved drugs and establishing more precise disease diagnoses. Proteins are prime biomarker candidates, because of the central role they play in both, disease etiology and treatment. Today's high throughput methods are capable to detect potential biomarkers by screening complex proteome mixtures of different disease states. A meaningful interpretation of the candidates is indispensable for deeper insights into affective disorders and requires investigation on multiple levels of the cellular system. Thus a systems biology approach is critical to understand and explain the behavior of biomarker candidates and to make use of them in psychiatry.