A pilot study of the pharmacodynamic impact of SSRI drug selection and beta-1 receptor genotype (ADRB1) on cardiac vital signs in depressed patients: a novel pharmacogenetic approach.
The adrenergic beta-1 receptor gene (ADRB1) Ser49Gly and Arg389Gly variants differentially affect blood pressure response to beta-blocker therapy. Binding site prediction results for fluoxetine and paroxetine in a bioinformatics model estimated that each of these particular selective serotonin reuptake inhibitors (SSRIs) have high receptor affinity as an "Adrenergic (beta) Blocker," which was confirmed in vitro. This pilot study was conducted to understand the relationship between these "beta-blocking" SSRIs (fluoxetine and paroxetine) and cardiac vital signs (systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate (HR)), when subjects are stratified by ADRB1 genotype. Previously ascertained DNA and clinical data was examined from 122 subjects recruited for a cross-sectional study of health and well being during SSRI pharmacotherapy. A multivariate linear regression analysis was used to determine which variables affected cardiac vital signs. There was a significant interaction between Arg389Gly variant status and "beta-blocking" SSRIs [p = 0.0353] in relation to SBP. Specifically in homozygous Arg389 subjects, those receiving "beta-blocking" SSRIs had significantly lower SBP (mean 104 mmHg) compared to the group taking other SSRIs (mean 122 mmHg) [p = 0.0437]. In these same homozygous Arg389 subjects, those receiving "beta-blocking" SSRIs also had lower HR (mean 60 bpm) compared to the other SSRIs (mean 79 bpm) [p = 0.00877]. Future prospective studies of this phenomenon are necessary to identify all genetic markers that can predict SSRI-associated cardiovascular effects that may be related to the SSRI discontinuation syndrome and potentially influence pharmacotherapy decisions.
Thomas
Kelan L H
KL
University of Michigan, Ann Arbor, MI, USA.
Ellingrod
Vicki L
VL
Bishop
Jeffrey R
JR
Keiser
Michael J
MJ
D058671:Adrenergic beta-1 Receptor Antagonists / Q000009:adverse effects / Q000627:therapeutic use*; D000328:Adult; D018687:Antidepressive Agents, Second-Generation / Q000009:adverse effects / Q000627:therapeutic use*; D001794:Blood Pressure / Q000187:drug effects*; D003430:Cross-Sectional Studies; D003863:Depression / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology; D005260:Female; D005473:Fluoxetine / Q000627:therapeutic use*; D005787:Gene Frequency; D006339:Heart Rate / Q000187:drug effects*; D006720:Homozygote; D006801:Humans; D016014:Linear Models; D008297:Male; D017374:Paroxetine / Q000627:therapeutic use*; D010597:Pharmacogenetics; D010641:Phenotype; D010865:Pilot Projects; D018342:Receptors, Adrenergic, beta-1 / Q000187:drug effects* / Q000235:genetics*; D012189:Retrospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D017367:Selective Serotonin Reuptake Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D055815:Young Adult
D058671:Adrenergic beta-1 Receptor Antagonists; D018687:Antidepressive Agents, Second-Generation; D005473:Fluoxetine; D017374:Paroxetine; D018342:Receptors, Adrenergic, beta-1; D017367:Selective Serotonin Reuptake Inhibitors; C547787:ADRB1 protein, human