Resolution of Selective Serotonin Reuptake Inhibitor–Associated Sexual Dysfunction After Switching From Fluvoxamine to Fluoxetine

To the Editors:

Selective serotonin reuptake inhibitors (SSRIs) are a class of medications whose primary mechanism of action is via antagonism of the 5-HT transporter, which results in the inhibition of serotonin reentry into nerve terminals and increased levels of serotonin in the synaptic cleft.¹ Although first used to treat depression, SSRIs have also shown efficacy in treating a range of anxiety disorders and obsessive-compulsive disorder (OCD).² Although the main mechanism of the SSRI drug class is serotonin reuptake inhibition, there are variations within the drug class based on selectivity for serotonin versus noradrenaline, elimination half-life, receptor affinity, and impact on metabolism (eg, CYP inhibition)^1,3; these minor mechanistic differences across SSRIs contribute to our understanding of the differential responsiveness to medications within the same drug class. In addition to the minor mechanistic differences between the SSRIs, there are individual differences in patient factors such as metabolism, receptor subtypes, and enzymatic activity that can contribute to the differential responsiveness and experiences of adverse effects.^4,5 Furthermore, not only does the impact of SSRIs vary between medications in the class at both the behavioral and molecular levels, but also these effects differ depending on length of medication administration.

Sexual dysfunctions are a common adverse effect of all SSRIs, and these medication-associated dysfunctions may even continue after the cessation of treatment.⁶ There are 3 main types of sexual dysfunction: disorders of sexual drive (eg, loss of libido), disorders of arousal, and disorders of orgasm and ejaculation.⁷ Medication discontinuation due to sexual adverse effects is believed to be a major factor in treatment failure, so understanding these adverse effects is vital to ensuring effective treatment.⁸ Estimates suggest that between 25% and 73% of people treated with an SSRI will develop some form of sexual dysfunction; however, some SSRIs may be more likely to cause dysfunction.^6,8,9 Results of a multicenter, prospective study found that incidence of sexual dysfunction was highest for citalopram (72.7%), but incidence was still high for other SSRIs including fluvoxamine (62.3%) and fluoxetine (57.7%), results that align with similar studies.^6,8,10,11 Although the mechanism behind the relationship between SSRIs and sexual dysfunction is not yet fully understood, it is thought to be, at least in part, associated with the level of 5-HT binding to certain receptor subtypes,^6,9 a theory that is supported by the fact that the SSRIs with the highest 5-HT selectivity ratios tend to demonstrate higher rates of sexual dysfunction.¹⁰

Despite some positive reports, SSRIs in this class are generally associated with high rates of sexual dysfunction, and it is assumed that the mechanisms of these adverse effects are the same for all drugs within this class.^3,8 Although there is limited evidence available to guide management of sexual adverse effects of SSRI treatment, the prevailing responses include the addition of a phosphodiesterase inhibitor for managing erectile dysfunction, lowering medication dosage, or switching to a different class of medication.^11,12 At present, there is no evidence to suggest that switching to a different medication within the same class would alleviate symptoms. Here, we present the case of a patient with OCD and no prior history of sexual dysfunction, who experienced sexual dysfunction, including diminished sex drive and delayed ejaculation while taking fluvoxamine. Because of lack of OCD symptom resolution, he was switched to fluoxetine and found that discontinuation of fluvoxamine and introduction of fluoxetine led to the resolution of his OCD symptoms and return of sexual functioning.

CASE SUMMARY

The patient is a 36-year-old police officer referred to our Stress, Trauma, and Anxiety Research Clinic after initial treatments for OCD were ineffective. Compulsive behaviors included tilting head, scratching his abdomen, curling his toes, excessive blinking, and excessive nose movement. He denied checking behaviors and used hand sanitizers 20 to 30 times per day. When he tried to resist these urges, it would impair his concentration and resulted in him feeling restless, nervous, and easily startled. He worried that if he did not complete these behaviors, he would have bad luck. He was first seen in 2001 for symptoms of anxiety and OCD. Initially, he was prescribed paroxetine, which was switched to sertraline, and then fluvoxamine 250 mg. He was also receiving buspirone 10 mg twice a day and had been prescribed clonazepam as needed, which he rarely took. When he arrived at the clinic, he had been taking 150 mg fluvoxamine for a year but found that it had not provided much relief from OCD symptoms, and he was bothered by adverse effects, primarily fatigue and diminished sex drive. The patient had no signs or symptoms of other psychiatric conditions, and his recent annual checkup with his primary care provider was unremarkable. It was decided that he would discontinue the fluvoxamine and start fluoxetine 40 mg/d, in addition to continuing the buspirone. Twenty-five days after the initial visit, the patient stated that he had no problems transitioning between the 2 medications and that fluoxetine was helping with his anxiety. He denied adverse effects, was no longer experiencing as much fatigue, and no longer had any sexual dysfunction. His mood was good, but his anxiety symptoms had not reduced substantially. The fluoxetine dose was increased to 80 mg. On the patient’s third visit, 6 weeks after the initial consultation, he noted that his mood was much improved, and approximately 90% of his OCD symptoms were alleviated. Remaining symptoms are very mild, OCD thoughts last only 5 to 10 seconds, and he can resist most of the remaining urges. He also notes that his sex life is much improved. On the previous medication, he experienced delayed ejaculation, decreased penile sensation, and diminished ability to gain and maintain an erection, but this completely resolved since transitioning to fluoxetine. Throughout treatment on both medications, he remained in a safe, supportive, and monogamous relationship and felt that he was in a stable phase of his life. All visits were done via telemedicine, but written consent was obtained for the publication of this case report.

DISCUSSION

Sexual dysfunctions are a known and very common adverse effect of SSRIs, thought to be related to their effects on serotonergic systems.⁸ Treatments of SSRI-associated sexual dysfunction vary and may include switching treatment to a new drug class with the assumption that the mechanism of this adverse effect will be the same across all SSRIs; however, it is possible that the mechanisms behind these effects may differ, depending on the SSRI and individual differences in the patient’s responsiveness to the medications themselves.

Understanding normal sexual functioning may help to elucidate the ways in which SSRIs can contribute to sexual dysfunction. Sexual drive is strongly motivated by dopamine, which plays a central role in neural networks involved in motivation for and the anticipation of sexual activity.^13,14 The physiological responses involved in arousal occur via activation of the parasympathetic nervous system and release of nitric oxide (NO).¹⁵ Nitric oxide is the most important factor for relaxation of penile blood vessels and induction of erection, but acetylcholine in the parasympathetic nervous system is critical for the decreased smooth muscle tone and increased vasodilation necessary for erection and vaginal lubrication.^14,15 The final stage is sexual satiety, usually achieved via orgasm/ejaculation. Although some sympathetic tone is necessary for ejaculation, serotonergic and dopaminergic activities play an important role in sexual satiety.^14–16 Dopamine release is vital for sexual satiety, and increased serotonergic activity is thought to inhibit orgasm through inhibition of mesolimbic dopamine release.^14,16

The role of the serotonergic system in sexual satiety demonstrates how SSRIs may impair sexual drive, arousal, and satiety. Increased levels of serotonin may not only inhibit the dopamine activity necessary for both sexual drive and satiety, but research shows that they may also inhibit nitrous oxide synthase—the enzyme responsible for catalyzing the production of NO—which decreases the availability of NO.^8,9 Furthermore, SSRIs impact more than just the serotonergic systems; they have been shown to affect α1 adrenergic receptors, which may result in direct inhibition of both sympathetic and parasympathetic sexual functioning.^9,16 This understanding of how SSRIs may impact key neurotransmitters involved in sexual functioning also highlights why certain medications within this class may demonstrate higher levels of sexual adverse effects. Serotonin is primarily an inhibitory neurotransmitter, but specific receptor subtypes do cause excitatory signaling.¹⁷ It is known that postsynaptic antagonism of 5-HT₂ receptors has stimulating effects on sexual behavior; therefore, SSRI agonism of 5-HT₂ receptors is thought to be responsible for the sexual dysfunction adverse effects seen with most SSRIs.³ Fluoxetine and fluvoxamine have similar affinities for 5-HT_1A, 5HT_1B, and 5H_T4 receptors; however, fluoxetine has a significantly lower affinity for 5-HT_1D, 5-HT_2C, and 5-HT₃ receptors and a slightly higher affinity for 5-HT_2A receptors.¹⁷ Animal studies examining the role of 5-HT_2C receptors in sexual behavior have found that 5-HT_2C agonists inhibit certain sexual behaviors, including ejaculation.¹⁷ Evidence suggests that it is possible fluoxetine (which has a low affinity for 5-HT_2C receptors) may sometimes have a beneficial effect on sexual functioning unrelated to amelioration of psychiatric symptoms,^18,19 suggesting that our understanding of the full impact of these medications on sexual functioning is still limited. It is important to identify the cause of sexual dysfunction in these cases because sexual functioning changes can also be symptoms of the psychiatric disorders for which SSRIs are prescribed, which may lead to conflation between the independent effects of the medication and the effects of improved mental health on sexual functioning. In this case, it seems unlikely that the sexual dysfunction was a direct result of the OCD because the patient did not report these problems before taking fluvoxamine, and they resolved after discontinuation of the medication.

Another key factor that must be considered in this discussion is the role of individual differences in responsiveness to SSRIs. These individual differences can occur because of both the slight differences of selectivity within the SSRI class and individual differences affecting the patient’s response to medications (eg, sex, genetics).^4,5,20 Sexual adverse effects are not the only example; other adverse effects and even treatment efficacy may differ within this class based on individual differences. This is seen in our case wherein the patient’s symptoms were not resolved with high doses of 1 SSRI that has successfully treated OCD in many patients, but his symptoms were resolved with another SSRI. Pharmacogenetics is especially important in psychiatry because at present almost 50% of people who take psychotropic medications do not respond to them as expected, which may be due to metabolic pathway and receptor variation.^4,5

Although the exact mechanisms underlying the effects of SSRIs on sexual functioning are uncertain, the serotonergic system plays a key role. From our understanding of these mechanisms, it is assumed that a patient experiencing sexual dysfunction because of SSRI usage will continue to experience those symptoms across all medications of that class. As such, the limited guidance surrounding management of SSRI-associated sexual dysfunction does not include switching to another SSRI. Nonetheless, it is possible that there are different mechanisms behind these effects even within this same class. It is clear from our therapeutic usage of SSRIs that there are individual differences in responsiveness to SSRIs, leading to differential responses wherein one SSRI may effectively reduce psychiatric symptoms despite another medication in that class having little or no effect. It stands to reason that these individual differences in responsiveness would not be limited to therapeutic effects and would also extend to adverse effects. Clinically, physicians should be aware of the high rates of these sexual adverse effects and proactively ask patients about their experiences. Given the significant impact that adverse effects, especially those impacting sexual functioning, can have on medication adherence and quality of life, it is important to further explore the mechanisms behind the differential responses seen to different SSRIs.