No abstract

Although the search for reliable biomarkers of depression and/or treatment outcome is ongoing, the rapidly-expanding field of research along with promising new technologies may provide the foundation for identifying key factors which will ultimately help direct patients toward a quicker and more effective treatment for MDD.

GPCR signaling is modified both in major depressive disorder and by chronic antidepressant treatment. Endogenous Ga s redistributes from raft-to nonraft-membrane fractions after chronic antidepressant treatment. Modification of G protein anchoring may participate in this process. Regulation of Ga s signaling by antidepressants was studied using fluorescence recovery after photobleaching (FRAP) of GFP-Ga s . Here we find that extended antidepressant treatment both increases the half-time of maximum recovery of GFP-Ga s and decreases the extent of recovery. Furthermore, this effect parallels the movement of Ga s out of lipid rafts as determined by cold detergent membrane extraction with respect to both dose and duration of drug treatment. This effect was observed for several classes of compounds with antidepressant activity, whereas closely related molecules lacking antidepressant activity (eg, R-citalopram) did not produce the effect. These results are consistent with previously observed antidepressant-induced translocation of Ga s , but also suggest an alternate membrane attachment site for this G protein. Furthermore, FRAP analysis provides the possibility of a relatively high-throughput screening tool for compounds with putative antidepressant activity.

Metabolomics is a developing and promising tool for exploring molecular pathways underlying symptoms of depression and predicting depression recovery. The AbsoluteIDQ™ p180 kit was used to investigate whether plasma metabolites (sphingomyelins, lysophosphatidylcholines, phosphatidylcholines, and acylcarnitines) from a subset of participants in the Combining Medications to Enhance Depression Outcomes (CO-MED) trial could act as predictors or biologic correlates of depression recovery. Participants in this trial were assigned to one of three pharmacological treatment arms: escitalopram monotherapy, bupropion-escitalopram combination, or venlafaxine-mirtazapine combination. Plasma was collected at baseline in 159 participants and again 12 weeks later at study exit in 83 of these participants. Metabolite concentrations were measured and combined with clinical and sociodemographic variables using the hierarchical lasso to simultaneously model whether specific metabolites are particularly informative of depressive recovery. Increased baseline concentrations of phosphatidylcholine C38:1 showed poorer outcome based on change in the Quick Inventory of Depressive Symptoms (QIDS). In contrast, an increased ratio of hydroxylated sphingomyelins relative to non-hydroxylated sphingomyelins at baseline and a change from baseline to exit suggested a better reduction of symptoms as measured by QIDS score. All metabolite-based models performed superior to models only using clinical and sociodemographic variables, suggesting that metabolomics may be a valuable tool for predicting antidepressant outcomes.

Dietary fish oil, a source of polyunsaturated fatty acids (n-3 PUFA), has become increasingly popular for antidepressant therapy, in part because about half of patients treated with conventional antidepressants either fail to remit or discontinue therapy due to side effects. The inception of n-3 PUFA as a putative depression therapeutic may have stemmed from reports suggesting that dietary n-3 PUFA deficiency is linked to both altered membrane PUFA content as well as clinical depression. Several studies have examined n-3 PUFA treatment in depression, either singly or in combination with conventional antidepressant drugs. While results have been encouraging, fish oil treatment remains controversial. At least some of the reason for this is the lack of a defined site of action for n-3 PUFA that would be consistent with an antidepressant effect. This review will address this issue. While it is possible, even likely, that n-3 PUFA have multiple sites of action, this chapter will focus on sites at which n-3 PUFA modify G protein signaling and how those sites relate to both depression and antidepressant action. Much of the focus herein will be on specialized membrane domains (lipid rafts) and the effects that agents modifying those rafts have on elements of G protein signaling cascades. The relevance of specific alterations of G protein signaling for both depression and antidepressant action will be discussed, as will the ability for n-3 PUFA to act either as an antidepressant or in concert with conventional antidepressants.