Developing strategies to predict who may be at the highest risk for adverse changes in their sexual well-being is an important step in improving the quality of life and treatment of patients who require antidepressant therapy. The results of studies investigating genetic variations in drug metabolism enzymes and their relationships to antidepressant-associated adverse effects have been mixed. Continued efforts to characterize the relationships between genetic markers and antidepressant outcomes, and to translate this knowledge to patient care, have the potential to significantly improve the empiric selection of antidepressant agents and to minimize the risk for intolerable side effects.
Approximately 19 million Americans suffer from depression every year, with estimates that Selective serotonin reuptake inhibitors SSRIs such as citalopram, fluoxetine, fluvoxamine, escitalopram, paroxetine, and sertraline are common choices as first-line antidepressants.
The efficacy of these drugs is superior to placebo and comparable to other classes of antidepressants in treating patients with major depression [ 23 ]. Side effects and medication non-adherence to therapies are two reasons for inadequate responses to Difference between maois and ssris and sexual dysfunction agents. These sexual side effects are particularly disconcerting to patients because they are persistent and generally do not abate like headache, nausea, insomnia, diarrhea, and other early onset side effects, which generally dissipate after the first few weeks of therapy.
However, the occurrence of sexual side effects and the specific domain s of the sexual experience affected differ greatly from patient to patient. Pharmacogenetic studies of antidepressant-associated SD are relatively new, with the oldest published results dating back to The high prevalence of SSRI-associated sexual side effects and the negative impact they may have on drug therapy underscores the importance of conducting investigations to identify and characterize variables associated with these undesirable outcomes.
In the context of a growing cadre of antidepressants with differing mechanisms of action and metabolic pathways, the therapeutic potential of a pharmacogenetic test to identify risk for SSRI-associated SD, if developed, is extremely high.
The results to date implicate gene variants relating to the pharmacokinetics as well as the pharmacodynamics of these medications and include variants in genes coding for drug metabolizing enzymes, as well as serotonin signaling, glutamate activity, and neurotrophic factors. The results of these queries were searched for research studies investigating genetic predictors of outcomes from SSRI treatment.
These studies were further narrowed to those specifically assessing measures of SD and relationships with genetic markers which are summarized in this review. The sexual experience can broadly be divided into three phases. Dopamine, serotonin 5HTtestosterone, and estrogen influence sexual interest and desire libido. Nitric oxide, acetylcholine, and 5HT are important modulators of physiological sexual arousal.
Finally, norepinephrine and 5HT play important roles in orgasm. Recent evidence suggests that additional neurotransmitters such as glutamate may also be involved with sexual physiology [ 14 ].
While importance of other neurobiological contributors to the sexual experience should not be underestimated, the current review will focus on the mechanisms hypothesized to be associated with SSRI-associated sexual side effects and the pharmacogenetic studies of these factors.
Although the underlying mechanisms are not completely elucidated, it is generally accepted that 5HT serves to diminish sexual function [ 1316 ] and dopamine enhances sexual function [ 17 ]. The specific effects of serotonin on the sexual experience may result from signaling through specific subtypes of 5HT receptors. Relevant to the pharmacology of antidepressant agents, it is thought that stimulation of 5HT2A receptors has negative effects on sexual function [ 12131718 ].
Stimulating 5HT pathways in the raphe nuclei, which project down the spine as well as into the brain, are hypothesized to negatively influence the three stages of the sexual experience [ 12131718 ]. Consistent with this hypothesis, pharmacological stimulation of 5HT2 and 5HT3 receptors impairs sexual function in rodents [ 16 ]. Furthermore, in humans, antidepressant drugs which increase 5HT signaling e.
Until recently, the influence of genetic variation in the serotonin system and other pathways Difference between maois and ssris and sexual dysfunction changes in sexual function during antidepressant treatment has remained relatively unstudied.
However, initial pharmacogenetic studies provide further insight into these relationships and are informative for the development of future research strategies to investigate these mechanisms and genetic risk factors.
Thus it is reasonable to hypothesize that genetic variation in enzymes essential for SSRI metabolism which result in reduced enzymatic activity may increase systemic exposure to an antidepressant and increase the likelihood of experiencing sexual side effects.
Variation in the metabolic capacity of one of these enzymes, CYP2D6, has been studied for associations with sexual side effect outcomes, and may be stratified to four phenotypic classes: The overall goal of the first investigation was to characterize predictors of SD in subjects treated with the SSRI paroxetine [ 21 ], which is predominantly metabolized by CYP2D6 [ 19 ].
Of the 52 participants in the parent investigation, 30 gave their consent to participate in an exploratory study of CYP2D6 metabolizer status and paroxetine-associated sexual dysfunction. A total of 21 women and nine men ages years were phenotyped for CYP2D6 metabolic status using standard dextromethorphan measures and categorized to either EM or PM metabolizer status. In this study, none of the 30 participants investigated possessed a PM genotype.
Comparisons of ASEX total scores and subscale scores between genotype groups did not result in significant findings. When CYP2D6 metabolic activity was assessed using dextromethorphan measures, those classified as having a PM phenotype reported significantly Difference between maois and ssris and sexual dysfunction rates of anorgasmia males and females and impaired lubrication females only than those with normal CYP2D6 metabolic activity.
The attitudes of subjects toward SD during paroxetine therapy were also assessed. This study was limited by the small sample size and the non-comprehensive genotyping strategy used to characterize CYP2D6 metabolizer status by genotype. Using a phenotyping method, the authors identified associations between metabolizer status and some measures of the ASEX scale. Notably, the metabolizer status observed in these participants was likely a function of paroxetine exposure, which is a potent CYP2D6 inhibitor [ 19 ].
Conclusive explanations of these findings warrant further investigation. Nonetheless, this small study is one indicator that drug metabolism and dose response may be an important consideration in the development of SSRI-associated sexual side effects.
CYP2D6 phenotyping was completed as previously outlined Zourkova Women were more likely to develop SD than men in this population. Women had greater ASEX scores on all of the subscale measures that were also assessed in males. Separating ASEX scores by genotype groups did not result in significant differences.
When CYP2D6 metabolizer status was determined using dextromethorphan phenotyping procedures, a total of seven men and 12 women were assigned to the EM phenotype group, while 26 women and 10 men were categorized as PMs.
However, female PMs had higher worse total, satisfaction, orgasm, and lubrication scores than EMs. Similar to the first study by this research group, the genotyping methods and sample sizes were likely inadequate for assessing the relationship between genetically derived PM status and paroxetine-associated sexual dysfunction.
However, the PM phenotype differences may be a proxy for paroxetine exposure and support previous evidence that sexual dysfunction may be a dose-dependent phenomenon. Initial studies investigating variations in genes related to the pharmacodynamics of SSRIs are yielding promising results while providing insight on additional pathways and variables for further study. InBishop et al. The A variant exhibits greater gene expression in cell lines which express endogenous 5HT2A [ 24 ] and the genetic variation in GNB3T allele is thought to increase second messenger signaling [ 2526 ].
This point prevalence study included 89 outpatients between the ages of 18 and 40 years with depression who had been treated with an SSRI for at least six weeks and had not experienced problems with sexual functioning before starting treatment. The investigators excluded individuals with concomitant disease states known to influence sexual well-being e. Subjects were recruited if they had been taking an SSRI for at least six weeks to minimize the confounding effects of depressive symptoms.
Participants were assessed with clinical ratings of depression and anxiety, and the Changes in Sexual Functioning Questionnaire CSFQwhich is a validated measure of global sexual function as well as several aspects of sexual well-being e. The primary outcome variable of this study was a global measure SD, defined as exceeding predefined sex-specific thresholds on CSFQ total scores.
Secondary outcomes included CSFQ subscale measures. The authors concluded that the HTR2A rs SNP is an important predictor of SD in patients who were clinically asymptomatic and at otherwise low risk of sexual side effects. A follow up study by Bishop et al. The primary outcome variable as before was exceeding the sex-specific thresholds for SD "Difference between maois and ssris and sexual dysfunction" the CSFQ total scale scores with arousal and orgasm subscale measures assessed as secondary outcomes separately in males and females.
The relationship between promoter genotypes and sexual well-being differed in men and women, and was dependent on whether or not women were taking an oral contraceptive OC medication.