Selective Serotonin Reuptake Inhibitors and Adverse Drug Reactions
Selective Serotonin Reuptake Inhibitors and 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.
Selective serotonin reuptake inhibitors (SSRIs) have become one of the most widely prescribed classes of drugs. Antidepressants took over the top ranking for prescriptions dispensed in the United States in 2007, with 232.7 million. Overall, the SSRIs have fewer adverse drug reactions than the other classes of antidepressants, such as tricyclic or heterocyclic antidepressants and monoamine oxidase inhibitors. However, some patients discontinue therapy because of intolerable adverse drug reactions. 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. Once SSRI therapy is started, 4–8 weeks may be required to establish efficacy. During this period, adverse events may cause some patients to stop treatment before their symptoms of depression improve. However, such reactions might be avoided if clinicians could predict them on the basis of a patient's genetic profile and, thus, individualize drug therapy.
Most of the pharmacogenetics literature related to SSRI use has focused on efficacy as the primary outcome. A thorough review of this literature recognized the fundamental challenge of selecting appropriate candidate polymorphisms for making efficacy associations when the exact mechanism by which SSRIs reduce depression symptoms is not entirely certain.
Candidate polymorphisms for adverse drug reactions have traditionally been selected on the basis of their potential involvement in the pharmacokinetic or pharmacodynamic properties of SSRIs. Because it is easiest to objectively measure plasma concentrations and pharmacokinetic parameters, much initial attention focused on metabolic enzymes, particularly those in the cytochrome P450 (CYP) family. In the past few years, researchers began to question the clinical relevance of this information for SSRIs due to a wide therapeutic index and the lack of evidence reliably supporting a link between tolerability and plasma concentrations. Most recently, though, association studies of adverse drug reactions have focused on the pharmacodynamic effects of these drugs that may be mediated by alterations in transporters and postsynaptic receptors due to genetic variation.
This review summarizes the current pharmacogenetic studies that were designed to test associations between SSRI-related adverse drug reactions and genetic variation, as this body of literature is expanding quickly in the 21st century. However, it has many limitations, as most of these studies are retrospective or have open-label designs, or are case reports. Regardless, the combined results of these studies illustrate trends observed from pharmacogenetic association analyses as they relate to global and specific adverse drug reactions. To compare results across the genetic polymorphisms tested, we categorized each study according to the drug-induced adverse drug reactions and the specific SSRIs investigated.
Abstract and Introduction
Abstract
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.
Introduction
Selective serotonin reuptake inhibitors (SSRIs) have become one of the most widely prescribed classes of drugs. Antidepressants took over the top ranking for prescriptions dispensed in the United States in 2007, with 232.7 million. Overall, the SSRIs have fewer adverse drug reactions than the other classes of antidepressants, such as tricyclic or heterocyclic antidepressants and monoamine oxidase inhibitors. However, some patients discontinue therapy because of intolerable adverse drug reactions. 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. Once SSRI therapy is started, 4–8 weeks may be required to establish efficacy. During this period, adverse events may cause some patients to stop treatment before their symptoms of depression improve. However, such reactions might be avoided if clinicians could predict them on the basis of a patient's genetic profile and, thus, individualize drug therapy.
Most of the pharmacogenetics literature related to SSRI use has focused on efficacy as the primary outcome. A thorough review of this literature recognized the fundamental challenge of selecting appropriate candidate polymorphisms for making efficacy associations when the exact mechanism by which SSRIs reduce depression symptoms is not entirely certain.
Candidate polymorphisms for adverse drug reactions have traditionally been selected on the basis of their potential involvement in the pharmacokinetic or pharmacodynamic properties of SSRIs. Because it is easiest to objectively measure plasma concentrations and pharmacokinetic parameters, much initial attention focused on metabolic enzymes, particularly those in the cytochrome P450 (CYP) family. In the past few years, researchers began to question the clinical relevance of this information for SSRIs due to a wide therapeutic index and the lack of evidence reliably supporting a link between tolerability and plasma concentrations. Most recently, though, association studies of adverse drug reactions have focused on the pharmacodynamic effects of these drugs that may be mediated by alterations in transporters and postsynaptic receptors due to genetic variation.
This review summarizes the current pharmacogenetic studies that were designed to test associations between SSRI-related adverse drug reactions and genetic variation, as this body of literature is expanding quickly in the 21st century. However, it has many limitations, as most of these studies are retrospective or have open-label designs, or are case reports. Regardless, the combined results of these studies illustrate trends observed from pharmacogenetic association analyses as they relate to global and specific adverse drug reactions. To compare results across the genetic polymorphisms tested, we categorized each study according to the drug-induced adverse drug reactions and the specific SSRIs investigated.