Choosing Sexual Function-Sparing Medications

BRAIN TRUST: CONVERSATIONS IN PSYCHOPHARMACOLOGY

Series Editor Joseph F. Goldberg, MD

Continuing their conversation, Joseph F. Goldberg, MD, and Anita Clayton, MD, turn to the pharmacology behind medication-induced sexual dysfunction and the strategies available to counteract it. Dr Clayton describes how serotonergic activity, hyperprolactinemia, and 5-HT2A agonism can each impair desire, arousal, or orgasm, and why agents such as vortioxetine carry a lower burden of sexual side effects than more serotonergic options.¹ The discussion turns to bupropion, phosphodiesterase-5 inhibitors, and 5-HT1A partial agonists such as buspirone and gepirone as antidote strategies for antidepressant-induced sexual dysfunction, along with practical dosing considerations.² Dr Clayton also weighs in on vilazodone and other lower-risk agents, and on why attention to a molecule's effects on prolactin, serotonin 2A, and 5-HT1A receptors can guide more informed prescribing decisions. She closes with a reminder that sexual function, and its treatment-related disruption, remain clinically relevant across the lifespan, including in older adults.

See the first part of this discussion here.

Joseph F. Goldberg, MD: Before we get to antidote strategies—first, do no harm—everybody thinks about hyperprolactinemia as a consequence, but there are other ways our drugs cause mischief, serotonergic and otherwise. Can you speak to why and how our medicines disrupt sexual function?

Anita H. Clayton, MD: We need to think about sexual functioning as having excitatory and inhibitory elements. The inhibitory elements include serotonin, and also cannabis, because of the endocannabinoid system—chronic daily cannabis use can be problematic. There's also a lack of excitation if you don't have adequate norepinephrine and dopamine, which are important in desire, and norepinephrine and dopamine matter for arousal, too. We don't see as much of that effect from serotonin, but we definitely see it contributing to orgasmic dysfunction. Serotonergic drugs essentially overwhelm the system regarding norepinephrine and dopamine, because serotonin is the biggest inhibitor. If your serotonin is really up and inhibiting, you're going to have a problem all the way through, because you won't have the same level of arousal and pleasure.

Goldberg: Is 5-HT2A a particularly problematic target? If you agonize it, do you cause sexual dysfunction?

Clayton: Presumably, yes. And that's where prolactin comes in, too—if prolactin is elevated, it starts to cause problems with arousal, and it spreads everywhere; the more elevated the prolactin, the worse the sexual function usually is. People who need to be on antipsychotics, if they have a psychotic disorder, don't have that many pleasures in life—usually it's eating, sex, and drugs.

Goldberg: Speaking of favoring prolactin-sparing atypical antipsychotics when you can—even with something like aripiprazole or brexpiprazole, which are fairly prolactin sparing, do you still get sexual dysfunction, or markedly less?

Clayton: It's less. Aripiprazole and brexpiprazole—cariprazine hasn't shown it as well, but lumateperone has. We just presented a paper using the Changes in Sexual Functioning Questionnaire, which I developed and validated in a clinical trial, and sexual function markedly improved.

Goldberg: Is that because lumateperone is such a potent 5-HT2A antagonist?

Clayton: Well, it is that, yes.

Goldberg: In the antidepressant world, everybody learns in residency that if you want sexually sparing antidepressants, you think of bupropion, mirtazapine—another powerful 5-HT2A blocker—nefazodone, with all due respect to the liver, and a few agents like vortioxetine. Can you speak to what's kind and gentle in the sexual realm, beyond what I've mentioned?

Clayton: Yes, vortioxetine, for sure. I was also involved in studies demonstrating it was superior to escitalopram in a direct comparison. It has 7 receptor or system effects in serotonin, some of which are positive for cognition and some for sleep—flibanserin does something similar, improving sleep, which we had to study because the FDA was concerned it might make people sleepy and impair driving the next morning. That comparison was done against a drug like zolpidem, in Canada, and people's cognition and driving—tested with a driving simulator—improved dramatically with flibanserin, because it wasn't just working on sexual interest, it was also improving sleep. Vortioxetine does similar things, improving cognition through 5-HT7 receptor effects, which people had never even heard of before.

Goldberg: So your study actually controlled for baseline, pre-randomization sexual complaints that might be explainable by depression itself, and still showed that, after accounting for that confounding factor, vortioxetine was a better choice for minimizing sexual dysfunction that would otherwise be iatrogenic, say, with an SSRI?

Clayton: Absolutely. That's an important point—about 70% of people who present with a major depressive episode have sexual dysfunction at baseline, before treatment, so you want to ask about that. When you treat them, it can be 30% to 80%, but the studies really favor the high number, a substantial majority. It could be different people within that 70%, but in truth we want to avoid it as a result of our medications, and you have to monitor for it afterward, because otherwise, about 70% of people on SSRIs have sexual dysfunction. That's why I ask about preferences—do they want to avoid sexual dysfunction, do they want to avoid weight gain—because some of these drugs carry both risks.

Goldberg: I imagine among our listeners the word bupropion is on a lot of minds right now. Why should they be thinking about bupropion, and should they?

Clayton: Yes, they should be. This was one of the early things I was involved in—an advisory board, I related to bupropion. I had patients report improved sexual functioning, and we studied it and confirmed improvements, not just sparing. We also studied adding it to an SSRI that was working but causing sexual dysfunction, whether as a primary drug or an add-on. People have gotten that message, which I think is a good thing. Some people don't tolerate bupropion, but when we only had the immediate-release formulation, it was harder to manage; the sustained-release, and especially the extended-release formulation made it much easier, with the same benefits.

Goldberg: Some of the handful of studies looking at bupropion as an antidote for antidepressant-induced sexual dysfunction have used daily dosing; I know of at least 1 study that treated it like a phosphodiesterase inhibitor, dosed just before sex. What's your advice if a clinician is contemplating bupropion—certainly if augmentation for depression, weight loss, and smoking cessation are also goals, that's a nice runway—but if everything else is fine except the sexual dysfunction, and the clinician doesn't want to take away a drug that's helping, what do you advise on dosing and preparation?

Clayton: There were studies adding bupropion at 150 milligrams per day that weren't effective—you really have to get to 300 milligrams a day. Nobody has studied giving people 300 milligrams just before sex, and I haven't recommended that, though I do have people who take things PRN, like buspirone PRN, and it helps them—whether that's placebo or belief, it's benign, so I don't object if they're not doing it every day. I favor daily dosing, especially when working on desire.

There's a drug for hypoactive sexual desire disorder called bremelanotide, or Vyleesi—an injection taken about 45 minutes before sex that lasts 24 to 36 hours, so for a weekend, that could be reasonable. I thought people would object to the injections, but they didn't; some had partners administer it. It causes nausea in about 40% of people, so if that happens, I'd suggest giving it Friday night before bed, for sex Saturday and Sunday with increased desire. It acts on the melanocortin system, which we're now starting to look at for other things in psychiatry. It's been approved for a little less than 10 years.

Goldberg: What's the story with phosphodiesterase inhibitors for treating iatrogenic sexual dysfunction, in women as well as men?

Clayton: There was 1 study that showed some positive results, though not as much as expected, in part because it may not have used the right measurement tool. In women I use lower doses, 50 milligrams; in men, 50 or 100.

Goldberg: Sildenafil, as opposed to—any preference?

Clayton: I have far more familiarity with sildenafil, so that's what I've used over the years, and if it's specifically an arousal problem, it can be quite helpful.

Goldberg: Is that because it doesn't get into the brain—it's not about expectancy bias? Is the mechanism the vasodilatory effect and orgasmic quality, or would it impact arousal and interest because expectancy is better? And relatedly, if a man finds his erectile dysfunction improved, will that translate to improved interest and arousal?

Clayton: It very well might, because if he has erectile dysfunction, he's probably anxious about sex, fearful of another problem. If that's resolved, it might very well increase his desire and level of activity.

Goldberg: So we've covered the bupropion story and the phosphodiesterase story. How about buspirone? We talked about 5-HT1A earlier, and I know there's one study, the Landén study, suggesting it can help.

Clayton: The data are poor, but that doesn't really matter to me, because I know it works. A lot of people say buspirone doesn't even work, but it does—it received approval for generalized anxiety disorder first; benzodiazepines don't have that approval. Subsequent clinical use has shown it can be a benefit, and it can also enhance antidepressant treatment, not just for sexual functioning, but for depression, too.

Goldberg: Do you think gepirone, which got approved a few years ago and just came out here in 2026, will have an appeal in the same vein as buspirone—sparing sexual side effects but also having a counteracting, antidote value?

Clayton: Yes. I've been involved with gepirone since it was owned by Organon, 15 or 20 years ago, and other companies had it before it was finally approved and brought to market. During those studies, we were very concerned about SSRIs and sexual dysfunction, so they looked at sexual functioning extensively, which is probably why some studies didn't cleanly separate depression efficacy from placebo—people don't do that anymore, because they don't want to complicate a phase 3 trial.

We recently had a paper, with Tierney Lorenz as first author, looking at gepirone and sexual functioning, and it's quite positive—certainly at least as good as placebo, with potentially pro-sexual effects. If people get past the idea that it's like buspirone and not intended for depression, they'll see it's an antidepressant that works a bit differently, with positive effects on sexual functioning. It will have a niche. You do have to watch QT intervals with that drug.

Goldberg: So says the FDA.

Clayton: Well, that's based on the immediate-release formulation, which is very different. We should probably be getting ECGs on people taking tricyclics, too, but we don't always. I think it's wise to check it at the beginning—we check it with a lot of our medications anyway, for the QTc.

Goldberg: As we're wrapping up, anything else in the bag of tricks? Is there still a place in 2026 for yohimbine, or periactin, or the things I was taught 100 years ago?

Clayton: Those should be left behind—they don't work well and are cumbersome, with problematic adverse effects. We have better drugs now.

Vilazodone is another option with lower sexual side effects, because it has a 5-HT1A effect in addition to serotonin reuptake inhibition, so it's not as strong an inhibitor. For our listeners thinking about how to elevate their game in psychopharmacology, when you look at a molecule, consider whether it's prolactin sparing, and its effects on serotonin 2A and 5-HT1A—those are 3 important targets worth talking about more in training. Rather than shrugging and trying something to see what happens, if a patient identifies sexual dysfunction as an issue, those elements should come to the forefront—for instance, when looking at an atypical antipsychotic, since some, but not all, are 5-HT2A partial agonists. And lumateperone, as I mentioned, does have some effect on 5-HT2A, which was clearly demonstrated to have a positive effect on sexual dysfunction.

Goldberg: What an opportunity this has been—almost like a window into thinking about receptors, targets, and symptoms, and their interplay with underlying psychiatric conditions. Any last thoughts before we wrap up?

Clayton: Sex is important to almost everybody, and if you have good sex when you're young, you're still having good sex when you're old. So don't forget about older people who are having sex, and how our medications, or their illnesses, may be contributing to sexual dysfunction—keep them in mind, too.

Dr Goldberg is a clinical professor of psychiatry at The Icahn School of Medicine at Mount Sinai in New York, NY and the immediate-past president of the American Society of Clinical Psychopharmacology.

Dr Clayton is chair of psychiatry and neurobehavioral sciences and professor of clinical obstetrics and gynecology at the University of Virginia. She is also current president of the American Society for Clinical Psychopharmacology.

References

1. Jacobsen PL, Nomikos GG, Zhong W, et al. Clinical implications of directly switching antidepressants in well-treated depressed patients with treatment-emergent sexual dysfunction: a comparison between vortioxetine and escitalopram. CNS Spectr. 2020;25(1):50-63.

2. Fabre LF, Clayton AH, Smith LC, et al. The effect of gepirone-ER in the treatment of sexual dysfunction in depressed men. J Sex Med. 2012;9(3):821-829.