Effects of SNS Activation on SSRI-Induced Sexual Side Effects Differ by SSRI

Selective serotonin reuptake inhibitors (SSRIs) are associated with significant sexual side effects. By definition, all SSRIs increase overall serotonin (5HT) by binding to serotonin autoreceptors (5HTIA); however, each SSRI has a unique portfolio of secondary binding properties to other neurotransmitters such as norepinephrine (NE). As 5HTIA receptors mediate NE neurotransmission, SSRIs that are highly selective for 5HTIA are more likely to reduce NE efficiency; however, in SSRIs that are less selective for 5HTIA, this could be counteracted by secondary binding to NE. Norepinephrine is the major neurotransmitter of the sympathetic nervous system (SNS), which has been shown to mediate genital arousal in women; thus, it is possible that increasing SNS activity in women taking SSRIs that are highly selective for 5HTIA may counteract sexual side effects in those women. To test this hypothesis, we conducted a reanalysis of Meston (2004)'s 8-week, double-blind, cross-over, placebo-controlled study of the effects of ephedrine (50 mg taken 1 h prior to sexual activity) on self-reported sexual functioning of women taking paroxetine (N = 5), sertraline (N = 7), or fluoxetine (N = 7). As predicted, women taking SSRIs, which are highly selective for 5HTIA (sertraline, paroxetine), showed improvement in sexual arousal and orgasm. By contrast, women taking SSRIs, which are less selective for 5HTIA relative to NE (fluoxetine), showed no change or decrease in sexual functioning. These findings have implications for treating certain SSRI-induced sexual side effects.