Antidepressant Dosing in Major Depression: A Pharmacogenomic Approach

Major depressive disorder (MDD) is the most predominant mental disorder in the United States, with serious and costly health risks if not successfully managed. Pharmacotherapy is a standard option for MDD treatment, but patients often require extensive therapy adjustments to find a suitable regimen. Pharmacogenomics may enable greater precision in antidepressant therapy. Genotypic variations in CYP2D6 and CYP2C19 metabolic enzymes are reliable predictors of serum drug concentration, but the complex dose-response relationship of antidepressants prevents such variations from predicting therapy success. Additionally, ABCBl has been examined for its role in P-glycoprotein efflux of antidepressants in the brain, yet it is still inconclusive as to which variations are correlated with drug response. Current genotypic guidelines are largely proactive and clinical trials utilizing genotypic dosing have shown significant reductions in side effects and health care costs. Further studies of genotypic targets are needed and, if the possible clinical benefits are confirmed, the use of genotyping will be an important tool in optimizing antidepressant therapy

The Effect of CYP3A5 Polymorphism on Kidney Transplant Recipients Given Tacrolimus

Tacrolimus, an immunosuppressant agent indicated for organ transplants, is commonly administered to reduce the risk of renal graft rejection in patients with chronic kidney disease (CKD) and end stage renal disease (ESRD). Due to its narrow therapeutic index and high inter-patient variability, studies have suggested that CYP3A5-based dosing provides specialized regimens which may significantly improve the chances of achieving therapeutic concentrations. According to the Clinical Pharmacogenetics Implementation Consortium (CPIC) recommendations, extensive (CYP3A5*1/*1) and intermediate metabolizers (CYP3A5*1/*3) require a higher initial dose while poor metabolizers (CYP3A5*3/*3) require a lower initial dose in order to achieve target tacrolimus concentrations. Studies concluded that CYP3A5 expressers present a greater risk for chronic nephrotoxicity and acute transplant rejection, supporting the need to closely monitor patients for severe adverse events. Further trials considering CYP3AS polymorphisms are needed to determine whether this genotype dosing improves clinical outcomes, which includes reducing rejection and toxicity, before testing can be recommended

RGS5 Protein Protects Against Anxiety- and Depression-Like Behavior

Anxiety and depression are a major health burden. Angiotensin II, via activation of angiotensin II type 1 receptor (AT1R)-mediated brain oxidative stress and inflammation may contribute to these emotional abnormalities. In this study, we investigated the role of a regulator of G-protein signaling 5 (RGS5) protein, which regulates AT1R activity, in angiotensin II-induced brain oxidative stress, inflammation and anxiety-, and depression-like behavior. We hypothesized that deletion of the RGS5 protein would worsen angiotensin II-induced anxiety- and depression-like behavior, cerebral vascular oxidative stress, and brain inflammation. Adult male wild-type and RGS5-deficient mice were implanted with osmotic minipumps delivering either vehicle (saline) or angiotensin II (1 mg/kg/d) for three weeks. Subsequently, mice were tested for locomotor activity, anxiety-like behavior (using the elevated plus maze), and depression-like behavior (using the tail suspension test). After behavioral testing, brain tissue was collected to assess oxidative stress and inflammatory proteins. RGS5 deletion resulted in anxiety-like but not depression-like behavior when compared to wild-type mice. Combined deletion of RGS5 and angiotensin II treatment did not further worsen anxiety-like behavior observed in RGS5-deficient mice. In contrast, depression-like behavior was worsened in RGS5-deficient mice treated with angiotensin II. Interestingly, RGS5 deficiency and angiotensin II treatment had no effect on cerebral vascular oxidative stress, or on expression of the inflammatory marker vascular cell adhesion molecule-1 in the brain. RGS5 deficiency was also associated with decreased blood pressure and an enhanced pressor response to angiotensin II. These data suggest that RGS5 protects against anxiety-like behavior and against angiotensin II-induced depression-like behavior

Evidence that regulator of g-protein signaling 5 protein modulates emotional behaviors in adult mice

Many actions of angiotensin II (Ang II), such as oxidative stress and inflammation in the cerebral vasculature and brain, are mediated by the Ang II type 1 receptor, a G-protein coupled receptor (GPCR). Ang II-induced brain inflammation may contribute to emotional abnormalities, such as anxiety and depression. Regulator of G-protein signaling (RGS) proteins modulate responses to extracellular signals such as Ang II acting through GPCRs by terminating G-protein activity. Among the many types of RGS proteins, RGS5 is expressed in the brain and vasculature and modulates Ang II-induced pressor responses and vascular contractility. We hypothesized that RGS5 deficiency would worsen Ang II-induced anxiety- and depression-like behavior, cerebral vascular oxidative stress, and brain inflammation. Adult male wild-type (RGS5+/+) and RGS5-deficient (RGS5−/−) mice were treated with Ang II (1 mg/kg/d) or vehicle (saline) for 21 days using osmotic minipumps. Systolic blood pressure (SBP, measured using tail cuff), anxiety (measured using elevated plus maze) and depression (measured using tail suspension test)-like behaviors, and spontaneous locomotor activity were assessed in conscious mice; superoxide levels (measured using chemiluminesence) were examined in isolated cerebral arteries, and protein expression of VCAM-1, NOX4 and eNOS were examined in left brain hemispheres. SBP was lower in RGS5−/− compared to RGS5+/+ mice (SBP in RGS5+/+=153±3 mmHg, n=22; RGS5−/− =140±5 mmHg, n=23, P\u3c0.05), suggesting that RGS5 contributes to blood pressure maintenance. Ang II treatment caused a greater increase in SBP in RGS5−/− vs RGS5+/+ mice (eg. ΔSBP at Day 17 in Ang II–treated RGS5+/+= 16±7mmHg, n=10; Ang II-treated RGS5−/−= 37±5 mmHg, n=10, P\u3c0.05), confirming that RGS5 modulates Ang II-induced pressor responses. In vehicle-treated RGS5−/− mice, anxiety-like behavior was increased compared to vehicle-treated RGS5+/+ mice (time spent in open arms [secs] in veh-treated RGS5+/+=79±12, n=7; veh-treated RGS5−/−=36±5, n=8, P\u3c0.05), suggesting that RGS5 deficiency causes anxiety-like behavior. There was no effect of Ang II treatment on anxiety-like behavior in RGS5−/− mice when compared with Ang II-treated RGS5+/+. RGS5 deficiency alone had no effect on depression-like behavior, however combined RGS5 deficiency and Ang II treatment resulted in increased depression-like behavior compared to Ang II treatment in RGS5+/+ mice (time immobilized [secs] in Ang II-treated RGS5+/+=170±10, n=10; Ang II-treated RGS5−/−=202±10, n=11, P\u3c0.05). Ang II treatment or RGS5 deficiency had no effect on spontaneous locomotor activity, cerebrovascular superoxide levels, and protein expression of VCAM-1, NOX4 and eNOS. Overall, these data suggest that RGS5 deficiency increases vulnerability to Ang II-induced increases in blood pressure, and that RGS5 deficiency differentially influences Ang II-induced anxiety- and depression-like behaviors

Role of regulator of G-protein signaling 5 protein in modulating emotional behaviors in the presence and absence of angiotensin 2-induced hypertension

Angiotensin II (Ang II), through its actions on the Ang II type 1 receptor, a G-protein coupled receptor (GPCR), increases blood pressure and causes oxidative stress and inflammation in multiple tissues, including in the cerebral vasculature. Ang II-induced brain inflammation may also contribute to emotional abnormalities, such as anxiety- and depression-like behavior. Regulator of G-protein signaling (RGS) proteins modulate responses to extracellular signals (such as Ang II) acting through GPCRs by accelerating GTPase activity on Gα subunits, thus terminating G-protein activity. RGS5, which is expressed in the brain and cerebral vasculature, mediates Ang II-induced increases in blood pressure and vascular structure. In this study, we examined the role of RGS5 in modulating cerebral vascular oxidative stress, and anxiety- and depression-like behavior in the absence and presence of elevated Ang II levels in adult (20–24 week old) male mice. Wild-type (RGS5+/+) and RGS5-deficient (RGS5−/−) mice were treated with vehicle (veh, saline) or Ang II (1 mg/kg/d) via osmotic minipumps for 21 days. Systolic blood pressure (SBP, measured using tail cuff), anxiety (measured using elevated plus maze) and depression (measured using tail suspension test)-related behaviors were assessed in conscious mice; superoxide levels (measured using LO12 chemiluminesence) were examined in isolated cerebral vessels. Ang II treatment caused a greater increase in SBP in RGS5−/− compared to RGS5+/+ mice (ΔSBP at Day 17 in Ang II–treated RGS5+/+= 16±7mmHg, n=10; Ang II-treated RGS5−/−= 37±5 mmHg, n=10, P\u3c0.05), confirming that RGS5 modulates Ang II-induced increases in blood pressure. In RGS5+/+ mice, Ang II treatment increased anxiety-like behavior (time spent in open arms [secs] in veh-treated RGS5+/+=79±12, n=7; Ang II-treated=49±5, n=8, P\u3c0.05). In vehicle-treated RGS5−/− mice, anxiety-like behavior was increased compared to vehicle-treated RGS5+/+ mice (time spent in open arms [secs] in veh-treated RGS5−/−=36±5, n=8, P\u3c0.05 vs veh-treated RGS5+/+), suggesting that RGS5 deficiency causes anxiety-like behavior. There was no further effect of Ang II treatment on anxiety-like behavior in RGS5−/− mice (time spent in open arms [secs] in Ang II-treated RGS5−/−=44±7, n=9, P\u3e0.05 vs veh-treated RGS−/−). Ang II treatment, and RGS5 deficiency alone had no effect on depression-like behavior (time immobilized [secs] in veh-treated RGS5+/+=164±10, n=11; Ang II-treated RGS5+/+=170±10, n=10, P\u3e0.05 vs vehicle; veh-treated RGS5−/−=178±12, n=10, P\u3e0.05 vs veh-treated RGS5+/+); however combined RGS5 deficiency and Ang II treatment resulted in an increase in depression-like behavior (time immobilized [secs] in Ang II-treated RGS5−/−=202±10, n=11, P\u3c0.05 vs Ang II-treated RGS5+/+), suggesting that combined RGS5 deficiency and Ang II treatment increased depression-like behavior compared to Ang II treatment alone. There was no effect of Ang II treatment or RGS5 deficiency on cerebral vascular superoxide levels. Overall, these data suggest important roles for RGS5 in modulating Ang II-induced increases in blood pressure, and anxiety- and depression-like behavior