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Madhukar H. Trivedi, MD: Hello, I am Dr Madhukar Trivedi. Welcome to season 2 of Medscape's InDiscussion series on major depressive disorder. Today we will be discussing sexual dysfunction associated with major depressive disorder and antidepressant treatments.
It is a pleasure for me to introduce our guest today. We couldn't have asked for anybody better to address this topic: Dr Anita Clayton, who is a great colleague of mine, is Wilford Spradlin Professor and Chair, Department of Psychiatry and Neurobehavioral Sciences, and Professor of Clinical Obstetrics and Gynecology, University of Virginia School of Medicine, Charlottesville, Virginia. But most importantly, she is a great colleague and is one of the world's experts on this topic. I am so very pleased to have her. Welcome to InDiscussion.
Dr Clayton, obviously this is an important topic, but this is an area that you have worked in significantly. So I am very pleased to have you on the call. Maybe if you want to, give us your overview of what are the important things we should be thinking about as providers and clinicians in this space?
Anita H. Clayton, MD: It's really been a problem helping providers to be able to talk about this with patients because we don't receive education on this in medical school or in residency training to any great degree. But that's our job. We need to bring these topics up with patients. We need to introduce it ourselves because they may be reluctant to begin with. We know people really underreport if you're only looking at spontaneous reports of sexual dysfunction.
I think the next thing is that we have to consider both the psychiatric condition, major depressive disorder, and its effect on sexual functioning. We have to look at the comorbidities, either psychiatric or medical, that may also contribute. We need to look at substances, including the medications we're prescribing for depression.
And then we need to know what the patient's preferences are in regard to what kinds of adverse effects they want to avoid. I think that finally, then, we need to choose something that's appropriate for that. If it doesn't work or it still causes sexual dysfunction, then we need to switch or add something else, because we really need to improve people's quality of life if they remain adherent. The other alternative is they stop taking the medicine overall.
Trivedi: Dr Clayton, I think that there is a clear understanding that antidepressants may cause sexual dysfunction, but then there are a whole lot of patients who come in even before you start any treatment with major depressive disorder who may have sexual dysfunction, obviously associated with medical illnesses. How do you advise people to approach this so that you don't fall into the pitfall of coming to this problem later and then not knowing what happened?
Clayton: Well, you know, psychiatrists really haven't been well educated about talking to patients about sex — not for a long time, since we were doing more psychoanalytic or psychodynamic work. But we do need to talk to people about their sexual lives and their orientation and their activities, because those all impact everything we need to do in their care.
We need to bring it up, though, because often patients are reluctant to bring it up because they think the providers are going to be uncomfortable. When we do that, we can do it in the context of other health questions. So you can either preface it by saying, "I'm also going to ask you about your sexual functioning and your sexual life," or you can just put that in the context of asking about other comorbid medical conditions, about substance use, exercise, and other health issues.
Trivedi: As you know, my interest, our interest has been in measurement-based care. Especially with depression and also with things like side effects and suicidal ideation, et cetera, we have depended on and developed a lot of measurement tools for self-rating so that it becomes automatic. Do you recommend that people routinely use any rating instruments? I know you have developed wonderful ones. Or do you wait, how do you do this in practice yourself?
Clayton: We have found in most of the clinical trials for antidepressants that about 70% of people who come into clinical trials already have sexual dysfunction, either from their depression, from a comorbid medical condition, or potentially from a medical substance or possibly illicit substances. Lots of cardiovascular meds can cause this problem. So we need to be thinking about that.
If we're starting with a baseline like that and we're planning what to do to treat this patient, we want to know what their preferences are. Do they not want something that causes weight gain? Do they not want something that causes sexual dysfunction? Do they need to be cognitively aware? Those kinds of things play a role in the decisions we make.
And when we think about what kind of treatment we're going to give, then we need to measure it. We use our Changes in Sexual Functioning Questionnaire (CSFQ), and the ASEX, the Arizona Sexual Experiences Scale, is available. Even if you're looking at just a particular phase, like low sexual desire is the problem, then we should also screen for primary sexual disorders. Did this exist before they even became depressed? For example, hypoactive sexual desire disorder (HSDD) in women or erectile dysfunction (ED) in men — those are also conditions that can overlap. You can have it induced by conditions or meds or substances, or it can be a primary condition for people. So we measure it at baseline.
After we've initiated treatment, we also then review those data and they are self-reported. Patients get very used to filling out [the questionnaires] and they only take a few minutes.
Trivedi: I'd love to get a little more granular about these measurement tools. Your measurement tool — can you describe how it is rated, how does it help you monitor, et cetera?
Clayton: The Changes in Sexual Functioning Questionnaire has 14 items. They map to subdomains: satisfaction, desire/interest, desire/frequency, how often are you actually participating in sex, arousal, and orgasmic function. There are separate versions for men and women. The threshold scores for indicating sexual dysfunction differ between men and women because those were validated using the nonoverlap of confidence intervals around the mean. The scoring is between 1 and 5 points. So, 14-70 would be the total score and two of the items are not included in those subdomains. They have something else to do with their sexual functioning. Scores ≤ 41 for men and ≤ 47 for women indicate sexual dysfunction, and sexual functioning worsens with higher scores. We use it at baseline.
It's really very self-explanatory. We're talking about any kind of sexual activity. It doesn't matter who your partner is or what kind of sex you're having, if you anticipate finding pleasure with that.
The ASEX, the Arizona Sexual Experience Scale, has five questions, and the scoring is a little bit different because it's not linear; it's broken down a little bit differently. The same cutoff is used for men and women, which is a score of 19.
Trivedi: In terms of the critical question about the selection of antidepressant and how to monitor it, can you give a general overview of selective serotonin reuptake inhibitors (SSRIs), bupropion, mirtazapine, and the traditional antidepressants? How does one go about calculating the risks and benefits?
Clayton: Recently, the US Food and Drug Administration (FDA) required that package inserts for SSRIs include information about talking to patients about sexual functioning in advance, talking about how the medicines may contribute to that and eliciting their preferences, which I think is a big advance. In general, the medications are grouped by classes in terms of their effects on sexual functioning. The most negative effects on sexual functioning occur with the SSRIs and with venlafaxine. Mostly because it's still an SSRI until you get to 225 and above. So they have about a 70% rate of sexual dysfunction too when you're considering any phase of the sexual response cycle.
So you've got a 70% risk from the depression, you've got potential additional risk, and then you've got 70% risk from the SSRI. That matters to some people.
If you look at the serotonin-norepinephrine reuptake inhibitors (SNRIs) — duloxetine, desvenlafaxine, et cetera — those have a lower rate of sexual dysfunction. Norepinephrine probably mitigates some of these effects because serotonin is inhibitory on sexual functioning, and dopamine and norepinephrine are excitatory. The rate with SNRIs is that about 45% of patients will have some type of sexual dysfunction.
Tricyclics are slightly above SNRIs. And then when we look at more atypical types of antidepressants, many of them don't have sexual dysfunction associated with them and may reverse it if added to an SSRI because they don't enhance the serotonin inhibition of sexual desire and also sexual functioning.
When we're talking about bupropion, you need to get to dosages of 300 mg/d. Studies looking at 150 mg/d as an augmenting strategy to try to get rid of these sexual side effects really weren't effective. We're talking about mirtazapine, which has also been around for a long time. 15 or 30 milligrams or much higher, may even be required or effective in adding that in. When treating people who don't want to have sexual dysfunction, obviously, you need to get to therapeutic doses there. There are not very many data about mirtazapine, but it clearly is less likely to cause sexual dysfunction than are SSRIs.
If you look at some of the newer agents like vilazodone, which is an SSRI plus a 5-HT1A agonist, that is like buspirone. Buspirone also can be used as an antidote for antidepressant-associated sexual dysfunction, and so those rates are lower.
And then vortioxetine actually has labeling because they did the studies required by the FDA that shows at 5, 10, and 15, it really does not separate from placebo in terms of worse functioning. At 20 mg/d, sometimes we do see that, but still at very low rates — closer to 10% rather than the 45% or 70% with the others.
When somebody says they don't want to experience sexual dysfunction from their medicine, I talk to them. Is there anything else? If they don't want to experience weight gain, then generally, we'll think about going only to mirtazapine later or if we need it because anxiety or something like that is a problem. But bupropion is an easy add-on or an easy transition to that. Unless somebody really has significant anxiety symptoms, then I generally switch them to vortioxetine or vilazodone. And we follow that, we track that with the measures, as I mentioned. We can look for improvement. And patients will come in and openly talk about it or spontaneously say they'll fill it out.
Trivedi: Since SSRIs and SNRIs remain the most commonly used medications, as you very rightly outlined, a lot of patients come in with sexual dysfunction as part of their depression. We all get into this dilemma where patients are better, but they now have sexual dysfunction that is threatening them sustaining the treatments. What kinds of treatment approaches do you use for that group of patients where they are better, so therefore you are reluctant to stop them on their antidepressants? How do you address that challenge?
Clayton: I think that's actually even worse for people who have previously been on other antidepressants that didn't have efficacy for them. Then they're on something that is causing at least partial efficacy but is causing sexual dysfunction. So, the worries we have are that they will be nonadherent at least some of the time or they will just outright discontinue their medication. Or they will live with a low quality of life. Neither of those are good options. So I tend to talk about those options.
If we want to do something about it, we can either add in something that hopefully will also augment the antidepressant efficacy of the medication they're currently taking, as well as counter the sexual side effects. That would be things like bupropion, buspirone, and mirtazapine. If they only want to be on one medication or they've not been tried on anything else before, if they've been tried on an SSRI so they think, well, something else would work too, then I usually try to switch them maybe to an SNRI depending on other factors involved. If somebody has only been on one antidepressant therapy and it's been partially efficacious, they're usually okay with changing. So it's better to change to one of the medicines less likely to cause sexual dysfunction: vortioxetine, bupropion, mirtazapine, and potentially vilazodone. And then if they still have sexual dysfunction or they're not responding, then we need to switch that too.
We need to be tracking both efficacy and side effects — not just sexual dysfunction, but if other things are being impacted as well, because they can contribute to sexual dysfunction and also just general tolerability and adherence. We want to get rid of those side effects that are bothersome and enhance their quality of life.
Trivedi: Switching topics a little bit, are there any novel pharmacologic approaches that have come out for even primary sexual dysfunction that independently you would think of adding when you run into sexual dysfunction with medications?
Clayton: Sildenafil has been looked at. In fact, in the original studies of sildenafil, about 25% of the men in those studies were on an SSRI. That hasn't been allowed for female sexual dysfunction, but we definitely can use sildenafil for men who have arousal problems or ED, and sometimes potentially for orgasmic dysfunction. It's been tried in women on SSRIs, but unfortunately it didn't really improve arousal, and it certainly didn't improve desire because it doesn't get into your brain. But it did improve orgasmic function, which is sort of an interesting phenomenon because we don't have any other treatments for orgasmic dysfunction, specifically.
We also have available treatments now for women for HSDD. Things like flibanserin, a 5-HT1A agonist and 5-HT2A antagonist, and also bremelanotide, which is a melanocortin-4 receptor active drug that comes in an injection. Those are about 50% effective in women with HSDD. It is likely they would also work in men who have HSDD too. So sex, the physiology of it anyway, is very similar in men and women and we can think about it in that context.
Trivedi: Fantastic. I have a couple of other additional questions. What do we know about sexual dysfunction with ketamine/esketamine? And then does TMS have one way or the other effects on sexual function?
Clayton: As far as I know, we don't have data about ketamine and sexual functioning that are helpful. But the one thing about it is that it's administered intermittently, so that is helpful. We did a study years ago where patients were started on a novel treatment, but those data weren't published, and then they were started on paroxetine or placebo. There were normal healthy controls. We tracked their sexual functioning and found that they had problems with orgasmic function by day 4. And by [day] 6 or 8, they also had problems with arousal. You can see the sexual response cycle is going backward. By day 14 they had problems with desire and satisfaction and overall function. So then they had global dysfunction. We know, sort of, the pattern with SSRIs is about when it starts. It's not like it starts late; it starts within a few days after steady state is reached, and people don't care about it until their depression is improving. It doesn't seem different to them from what they might have come in on. So I think we can think about that kind of factor in something like ketamine.
I think that might also be true, potentially, with zuranolone. We actually did look at sexual functioning in one of the trials using the CSFQ, and we did not find differences from placebo. But remember, it's only a short course, a 14-day course of treatment. So I think that those kinds of things may turn out to be wonderful for patients, at least in part because they don't have that as a side effect, but they also don't have a lot of the other side effects we worry about with long-term use of SRIs.
Trivedi: Finally, a couple of concrete questions. I know that there was some talk in the past about drug holidays for people who are having sexual dysfunction. Where is that arena now? Are we comfortable with it? Obviously, there is still always a risk for relapse if you do that drug holiday. But what do you advise people now?
Clayton: I don't use that recommendation partly because fluoxetine was not included in that study because it has such a long half-life. But if you want to have sex on Saturday, then you might not take your medicine Saturday morning and you might have sex Saturday night and maybe Sunday morning, and then hopefully you take your med after that. But then that worked for you, so then you want to have sex on Tuesday. So then you also don't take it on Tuesday, and pretty soon you're not taking that. It was also not particularly effective, and short-acting SSRIs had discontinuation symptoms in that setting.
Trivedi: I think that you have raised a lot of important questions practically about how to deal with it. This is a very common issue that we should be addressing, and thank you for pointing that out. I love the idea of including measurements.
I would love to end with any final thoughts, maybe summarize bullet points for somebody who is listening and treating patients with depression. What are the three or four things they should always keep in mind?
Clayton: Treat to remission. Listen to patient preferences and what's important to them. Make changes if they are experiencing sexual dysfunction or lack of efficacy, or both. Improve their quality of life.
Trivedi: Fantastic. Today, we've talked to Dr Anita Clayton about providers introducing the topic of sexual function at baseline. Determine potential contributors to sexual dysfunction and patient preferences. Monitor the effects of intervention, and treat to remission. Consider switching treatment or adding another medication if sexual dysfunction persists or develops, and monitor it at every visit.
I cannot thank you enough Dr Clayton. You are, as I mentioned earlier, the world's expert in this area. Thank you for taking the time to address this topic.
Thank you for tuning in. If you have not already done so, take a moment to download the Medscape app to listen and subscribe to this podcast series on major depressive disorder.
This is Dr Madhukar Trivedi for InDiscussion. Thank you.
Listen to additional seasons of this podcast.
Resources
Treatment-Emergent Sexual Dysfunction Related to Antidepressants: A Meta-Analysis
Citizen Petition: Sexual Side Effects of SSRIs and SNRIs
Association of Major Depression With Sexual Dysfunction in Men
The Changes in Sexual Functioning Questionnaire (CSFQ): Development, Reliability, and Validity
Structured Review of the Use of the Arizona Sexual Experiences Scale in Clinical Settings
Hypoactive Sexual Desire Disorder: A Review of Epidemiology, Biopsychology, Diagnosis, and Treatment
Overview of the Rapid Antidepressant Effects Observed in the Zuranolone Clinical Development Program
Flibanserin prescribing information
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Cite this: Sexual Dysfunction Associated With Major Depressive Disorder and Antidepressant Treatment - Medscape - Apr 06, 2023.
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