P-glycoprotein (PGP) polymorphisms and sexual dysfunction in female patients with depression and SSRI-associated sexual side effects.

Sexual dysfunction is common with selective serotonin reuptake inhibitor use for major depressive disorder. Studies have shown associations between genetic variation in the adenosine triphosphate (ATP)-binding cassette, subfamily B, member 1 gene (ABCB1), which encodes the drug efflux transporter P-glycoprotein (PGP), and selective serotonin reuptake inhibitor response. This study measured functionally implicated ABCB1 variants (rs2235015, rs1128503, rs2032582, and rs1045642) and sexual dysfunction using the Changes in Sexual Functioning Questionnaire. This study included outpatients (18-40 years of age) treated for major depressive disorder with a selective serotonin reuptake inhibitor for 6 weeks. Changes in Sexual Functioning Questionnaire outcomes were stratified by ABCB1 genotype and PGP substrate status. The authors recruited 82 individuals (22 men and 57 women). Women receiving a PGP substrate with a rs1128503 TT genotype had a significantly lower Changes in Sexual Functioning Questionnaire total score (37.2 ± 5.4), indicating greater sexual dysfunction, than did those with the CT (42.9 ± 6.3) or CC genotypes (46.6 ± 5.6), F(2) = 6.00, p = .005, p = .02, with multiple testing correction. The results indicate a relationship between genotypes at rs1128503, total sexual dysfunction, and PGP substrates use for women and may explain some of the sexual dysfunction variability seen with selective serotonin reuptake inhibitor treatment. Results need to be confirmed with a larger sample size that includes men.

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.

OBJECTIVE: 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.

Predicting new molecular targets for known drugs.

Although drugs are intended to be selective, at least some bind to several physiological targets, explaining side effects and efficacy. Because many drug-target combinations exist, it would be useful to explore possible interactions computationally. Here we compared 3,665 US Food and Drug Administration (FDA)-approved and investigational drugs against hundreds of targets, defining each target by its ligands. Chemical similarities between drugs and ligand sets predicted thousands of unanticipated associations. Thirty were tested experimentally, including the antagonism of the beta(1) receptor by the transporter inhibitor Prozac, the inhibition of the 5-hydroxytryptamine (5-HT) transporter by the ion channel drug Vadilex, and antagonism of the histamine H(4) receptor by the enzyme inhibitor Rescriptor. Overall, 23 new drug-target associations were confirmed, five of which were potent (<100 nM). The physiological relevance of one, the drug N,N-dimethyltryptamine (DMT) on serotonergic receptors, was confirmed in a knockout mouse. The chemical similarity approach is systematic and comprehensive, and may suggest side-effects and new indications for many drugs.

Pharmacogenetics of selective serotonin reuptake inhibitors and associated adverse drug reactions.

The selective serotonin reuptake inhibitors (SSRIs) have become one of the most widely prescribed classes of drugs. They are relatively safe for the pharmacologic treatment of various psychiatric disorders; however, certain patients cannot tolerate some adverse drug reactions associated with this drug class. In addition, clinicians currently have no way to predict who will respond appropriately to a given SSRI, and the paradigm of trial and error is especially distressing for patients with mental illness. Pharmacogenetic association studies may provide insight into which genetic polymorphisms might be clinically relevant for individualizing pharmacotherapeutic regimens. Thus, we reviewed and summarized the literature regarding the pharmacogenomics of SSRI-associated adverse drug reactions. This growing body of knowledge may inform subsequent design of pharmacogenetic studies with respect to adverse drug reactions. As we appreciate the many pharmacologic mechanisms related to adverse drug reactions and gain polymorphic functional data, we will have opportunities to refine hypotheses for future pharmacogenetic association analyses.