Keith Byron

ABCB1 polymorphism predicts escitalopram dose needed for remission in major depression

The ATP-binding cassette family of transporter proteins, subfamily B (MDR/TAP), member 1 (ABCB1) (P-glycoprotein) transporter is a key component of the blood–brain barrier. Many antidepressants are subject to ABCB1 efflux. Functional polymorphisms of ABCB1 may influence central nervous system bioavailability of antidepressants subject to efflux. Single-nucleotide polymorphisms (SNPs) at rs1045642 (C3435T) of ABCB1 have been associated with efflux pump efficiency. This may explain part of the interindividual variation in antidepressant dose needed to remit. Individuals (N=113) with DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition) major depressive disorder (MDD) were treated with escitalopram (ESC) or venlafaxine (VEN) over 8 weeks. The17-item Hamilton Depression Rating Scale was assessed serially, blind to genotype. SNP rs1045642 of ABCB1 along with two SNPs previously reported to be in linkage disequilibrium with it (rs2032582 and rs1128503) were genotyped. Demographic features, clinical features, P450 metabolizer status and 5-HTTLPR (serotonin-transporter-linked promoter region) genotype were controlled for. Carriers of rs1045642 TT needed on average 11 mg of ESC to remit, whereas TC and CC carriers required 24 and 19 mg, respectively (P=0.0001). This equates to a 2.0- (95% confidence interval=1.5–3.4; P<0.001) fold greater ESC dose needed to remit for C carriers compared with TT carriers at rs1045642. Of VEN-treated subjects carrying TT genotype at rs1045642, 73.3% remitted compared with 12.5% for CC genotype (odds ratio=6.69; 95% confidence interval=1.72–25.9, P=0.006). These data suggest that antidepressant dose needed to remit can be predicted by an ABCB1 SNP. This has the potential clinical translation implications for dose selection and remission from MDD.

Pharmacogenetic polymorphisms and response to escitalopram and venlafaxine over 8 weeks in major depression

The objective of this study is to investigate the influence of the 5‐HTTLPR (serotonin transporter‐linked promoter region), cytochrome P450 2C19, and cytochrome P450 2D6 polymorphisms on escitalopram (ESC) and venlafaxine (VEN) responses in major depressive disorder.

Psychomotor depressive symptoms may differentially respond to venlafaxine.

Predicting differential antidepressant efficacy remains an elusive goal in major depressive disorder (MDD). The aims of this study were three-fold. Firstly, to examine if psychomotor retardation symptoms (item 8 on the 17-item Hamilton Depression Rating Scale) improve preferentially to venlafaxine (VEN) over escitalopram (ESC) treatment. Secondly, whether the 18 item CORE psychomotor signs scale predicted antidepressant remission. Finally, to investigate the role of two norepinephrine transporter gene (NET) polymorphisms (rs2242446 and rs5569) on antidepressant efficacy. Adults with Diagnostic and Statistical Manual of Mental Disorders, 4th ed. MDD (n=113) were treated with ESC or VEN prospectively for 8 weeks and rated serially with the Hamilton Depression Rating Scale. In a subsample (n=51) of patients from one of the three recruitment sites, the CORE psychomotor signs scale was also administered at baseline. Participants treated with VEN had significantly greater reduction in psychomotor retardation symptoms than those treated with ESC. The CORE scale did not predict antidepressant response or remission. Neither NET polymorphism moderated antidepressant efficacy. Findings suggest possible preferential utility of a selective serotonin and noradrenaline reuptake inhibitor in cases of MDD presenting with greater psychomotor retardation. The moderate to small sample size makes a type II error risk possible, and the negative findings need to be interpreted with caution. The positive finding of preferential efficacy of VEN for psychomotor retardation symptoms has potential translational utility.

Concordance between actual and pharmacogenetic predicted desvenlafaxine dose needed to achieve remission in major depressive disorder: a 10-week open-label study.

Background Pharmacogenetic-based dosing support tools have been developed to personalize antidepressant-prescribing practice. However, the clinical validity of these tools has not been adequately tested, particularly for specific antidepressants. Objective To examine the concordance between the actual dose and a polygene pharmacogenetic predicted dose of desvenlafaxine needed to achieve symptom remission. Materials and methods A 10-week, open-label, prospective trial of desvenlafaxine among Caucasian adults with major depressive disorder (n=119) was conducted. Dose was clinically adjusted and at the completion of the trial, the clinical dose needed to achieve remission was compared with the predicted dose needed to achieve remission. Results Among remitters (n=95), there was a strong concordance (Kendall’s &tgr;-b=0.84, P=0.0001; Cohen’s &kgr;=0.82, P=0.0001) between the actual and the predicted dose need to achieve symptom remission, showing high sensitivity (≥85%), specificity (≥86%), and accuracy (≥89%) of the tool. Conclusion Findings provide initial evidence for the clinical validity of a polygene pharmacogenetic-based tool for desvenlafaxine dosing.

Effects of persisting emotional impact from child abuse and norepinephrine transporter genetic variation on antidepressant efficacy in major depression: a pilot study

Objective Previous studies suggest child abuse and serotonergic polymorphism influence depression susceptibility and anti-depressant efficacy. Polymorphisms of the norepinephrine transporter (NET) may also be involved. Research in the area is possibly clouded by under reporting of abuse in researcher trials. Methods Adults (n=51) with major depressive disorder has 8 weeks treatment with escitalopram or venlafaxine. Abuse history was obtained, the ongoing emotional impact of which was measured with the 15-item impact of event scale (IES-15). The 17-item Hamilton Depression Rating Scale (HDRS) was applied serially. Two NET polymorphisms (rs2242446 and rs5569) were assayed, blinded to HDRS ratings and abuse history. Results No subjects reporting abuse with high impact in adulthood (IES-15 ≥26, n=12) remitted; whereas 77% reporting low impact (IES-15 <26; n=26) remitted (p<0.001). Subjects reporting high impact abuse (n=12) had a 50-fold (95% confidence interval=4.85–514.6) greater odds of carrying rs2242446-TT genotype, but the small sample size leaves this finding vulnerable to type I error. Conclusion The level of persisting impact of child abuse appears relevant to antidepressant efficacy, with susceptibility to such possibly being influence by NET rs2242446 polymorphism. Larger studies may be merited to expand on this pilot level finding given potential for biomarker utility.