Psychiatry & Psychotherapy Podcast - Duloxetine and the SNRIs Deep Dive Part 2

Episode Date: April 17, 2021

In today's episode of the podcast, we'll be continuing our deep dive into duloxetine, a serotonin-norepinephrine reuptake inhibitor (SNRI). In this second part, we'll be covering the approved indications and off-label uses of duloxetine.  By listening to this episode, you can earn 0.75 Psychiatry CME Credits. Link to blog. Link to YouTube video.

Hello and welcome to the Psychiatry and Psychotherapy Podcast. I'm here to talk about getting rid of burnout, increasing job satisfaction, and feeling like an expert in what you do. One thing that created a lot of burnout and angst for me was trying to get continued medical education right at the last minute. So why not join the CME membership and do CMEE while listening to this podcast? Go to Psychiatrypodcast.com, sign up, sign in, take the test, and the certification is email to you in seconds. Welcome back to the podcast. I am here with Dr. Cummings. to be doing part two of deloxetine and SNRIs and today our focus is going to be on the efficacy of the

medications and yeah welcome to the podcast dr. comies thank you i'm happy to be back and do part two indeed we're talking about duloxatine as well as some of the other SNRIs just to bring people back to the primary drug we're talking about. Duloxetine is a serotonin noraphyneur re-uptake inhibitor, meaning it blocks the transporter for serotonin and for norapinephrine. It was introduced into the market by Eli Lilly and Company in 2004, initially indicated by the FDA for treatment of major depressive disorder, then neuropathic pain related to diabetes, albeit that indication has grown into other areas, generalized anxiety disorder, and a bit later on, a number of pain syndromes as well. Yeah. It is one that I often see prescribed, and I hope that the first episode was helpful for you guys,

and in this episode, we're going to be trying to get into some of the nuance of how we look at how effective it is. I thought it would be interesting to start talking about, like, Ham D, how how we measure in these studies if change is occurring. And one of the common measures is the Hamd, which is a clinician rated response, pre and post-depression. And anything you want to say on that, or shall I say a couple things out of? Yeah, the Hamilton Depression rating scale was developed essentially as a research tool. It now comes in three versions. There's a 17 item version, which was the original and which is still used, at least the score from the first 17 items, is used as the basis of most research studies.

There's also a 21 item version and a 24 item version. On the original 17 item version, scores of less than 16, between 8 and 16 were considered mild depression. 16 to 23 was moderate depression and 24 and up was severe depression. Yeah. Yeah, I don't know how you remember this stuff off the top of your head. I was a research fellow at UC San Diego and trust me, I got to administer a lot of Hamilton Depression rating scales. Yeah, okay, okay, so that makes sense.

It's commonly used and when I was thinking about that, this and how, you know, when I read these studies, you know, how much of a change in the score compared to placebo is meaningful is one of the things I was asking myself. There's this one study in particular that shows like Symbolta for depression and Paxil for depression. And it showed that, so they had, they had an 80 milligram per day group, and then they had a placebo, and they were using the 17-item, Hamilton Depression Rating Scale,

and they showed that the deloxetine 80 decreased the Hamdi 3.62 points. And at 40 milligrams, it decreased the Hamdi 2.4 points, and Paxil didn't decrease it at all. compared to placebo. The P value was 0.15. So they were saying,

you know, they concluded that deloxetine 80 was superior to placebo for most measures, including the overall pain severity. It did improve pain severity. And it was superior to paroxetine, which is probably my least favorite antidepressant just because of the sexual side effects

and antichlinergic side effects. But I was thinking of myself, this 3.6 point change. You know, is this really, is this a lot? Is this clinically significant, you know? It depends on the nature of the study and the severity, the average severity of the depression being studied. Something I'm very pleased with that has occurred in more recent years

is that typically journals and journal editors have begun to require that research groups, report not just change in score on an instrument like the hamd, but also report effects size and remission rates. Because those are actually better measures of whether something is clinically relevant or not. If something is statistically significant, all that really means is that the result did not come from chance, but it doesn't tell you

whether it's important or not. Effect size gives you a sense of, well, how big an impact did it have? 0.3 or less for effect size is pretty small. 0.4 to 0.6 is moderate effect size, and better than 0.6 is really a pretty good effect size for whatever the intervention or treatment was. Now, if I recall the study you're talking about correctly,

I think the remission rate for the deloxetine, meaning a hamd score of less than 8, was a little over 50%, which is pretty good. It was 57% for deloxetine 80, 34% for peroxitine. Yeah, see, that's a much clinically much more meaningful number. Now, one of the things that you have to watch out for

in depression studies, when they say that something had achieved an effect, that classically has been defined as it produced a 50% decline in Hamilton depression rating scale scores. And for most of the antidepressant studies, that number ranges somewhere between 60 and 70%. But, you know, frankly, if I'm suffering from severe depression, getting halfway better isn't ideal. It's better, but it's certainly not a cure. Whereas, you know, if I get a remission, that's a meaningful measure of how clinically effective this is. One of the elements in this is historically clinicians have tended to view our drugs as being better than the patients do.

One overall look at the antidepressants found that around 45% of clinicians tend to rate antidepressants as effective, only 26% of patients. do. And I think that's because the patients are looking to return to a state of wellness and the clinicians are looking at it from the other end and saying, well, you're better than you were when you walked in the door. There was a placebo study where they found that clinician-rated response rate for placebo was higher as well. Yes. It was 45% for the clinician-rated response compared to 26% for the patient-related response.

I thought that that was very interesting. Yes. Yeah, clinicians tend to view things as being more effective or a bigger size than the patients do. But I think that's in a large part because people are looking for different things. The clinicians are looking to see if the treatment has any effect at all, and the patients are looking to be well. Right. Okay, so thinking back about the Hamd, when I looked at that,

and there's one study in particular where they looked at severity of depression and the effect size. In this particular paper, they broke it up a little bit different than other papers. But what they found was that the effect size for the low moderate depression

was 0.5. For the high moderate group was 0.54. For moderate severe group was 0.77. And for the severe group was 1.09. Right. This was the con study, I believe. Yeah, the con study. I sent it to you. I don't know if I sent it to you pretty early this morning. And from this article, it really makes me think like, okay, you know, although a lot of studies show the overall effectiveness of these antidepressants, the effect size maybe around 0.3 to 0.5, when you get up in the severity, the higher severity of depressions, you know, when your ham score, is 29 or greater,

antidepressants are going to make a huge difference. Yes. And part of that is a reflection of the fact that if you're dealing with someone who is at the milder end of the depressed spectrum, essentially you have less room for improvement. You know, the distance they have to go from where they are to being well is less, much less often than the person who is severely depressed. so that if the drug does have a positive effect, the effect is larger, if you will,

and the person who is more ill. When I looked at this study in detail, one thing that was interesting to me was that the placebo's decreased the ham D score across the board around eight. Even for the severe group, they decreased at eight points. So, you know, what does that mean? Well, it likely means that what we count as placebo So, in truth is not. When you enroll somebody in a research study, they are coming into the clinic frequently.

They're getting a lot of attention and a lot of psychosocial support. It's not therapy per se, but they're no longer living alone with their depression, if you will. So in that sense, it's not a real absolute no effect, no influence, placebo. Right. Just having people witness that you're feeling depressed, having them not be overwhelmed, having them listen, you know, receiving some warmth makes a big difference. Yes. And another part of that is probably spontaneous remission. You know, in any given treatment, there's going to be some people who are going to be getting better irrespective of treatment or no, you know, if there was treatment or no treatment. So there's probably some of that as well.

Indeed, that's one of the well, that's indeed one of the most central rationales for having a control group is so that you can see what happened not as a result of your identified treatment. Because without a control group,

you can measure whether something changed, but you can't really say why it changed because it could have been something completely other than the treatment that you're testing. Yeah. And that's one of my critiques on a lot of the psilocybin studies that are going on right now is they test one group with a psilocybin therapy and then they test the other side with psilocybin therapy. And so they're testing the whole group and then they follow them for a period of time. You know, everyone gets better. They say, look, the effect size is huge compared to where they started from. But there is really. really no placebo in the way that we're talking about these antidepressant studies?

Yeah, and that's a very important point. If you look at, you know, trials come in different types and data comes in different quality levels. Open trials, meaning the patient knows what they're getting, the clinician knows what they're getting, there is no control group. If you compare how often those studies are positive versus placebo-controlled, blinded studies, about half the time, the stuff that appeared to be effective and the open trial turns out not to be when it's tested under more rigorous conditions. And it's not that this, I don't know if you would call the psilocybin studies an open trial because there is some, there's some blinding, but they're both getting a lot of therapy. Both groups are getting a lot of therapy. and both groups are getting the active treatment by the end of the and last time period,

partially because people who enroll in psilocybin studies really, really want to get psilocybin therapy. Yes. They don't want just a placebo psilocybin therapy. One of the problems with a molecule like psilocybin or other medications that have a pronounced subjective effect is those are, very difficult studies to blind because even if no one says it out loud, people often know whether they got the active drug or not based on the effects the drug had. Right. And the providers know too. Yes. In the studies that listed the provider knew like 90% of the time if they got it or not, even though the provider was blinded, the therapist in the

room. Yeah. That just means no one actually confirmed for them what they knew. But And that's been a problem, not just for the psilocybin studies, but for any drug that has a substantial subjective effects when given, unless you can find an active placebo that mimics those effects, then you don't really have a placebo-controlled study. Let me take a small detour and pick your brain on. What do you think of low-dose daily psilocybin use, or Lillacin use? us to use. People are like using this sort of microdosing they're calling it. And I even know one psychiatrist who told me, you know, they were trying this out. And I hear it a lot of the

pop culture. Joe Rogan talks about it. Tim Ferriss talks about it. You know, so a lot of these people in that world are talking about it. Basically, I think they're getting well ahead of any sort of data. I'm old enough that I lived through the 1960s and the initial flirtation that psychiatry had with psychedelic medications and, frankly, how that didn't work out very well in the long run. Yeah. Because since these drugs are potently antidepressant, you know, they are exceedingly 5HT2A serotonin agonists. Universally, though, what tends to happen with them is the longer somebody takes them, the less antidepressant effect they exert and the more psychotomimetic they become.

Are you seeing any studies on this sort of microdosing or is that? No, so far that's in the realm of speculative use, basically. Okay. So for this podcast, we try to stay with where the science is today. And there you've heard it from Dr. Cummings. Well, as I said, I live through the 1960s and the attempts to expand the mind. And initially people who were believers in psychedelic meds said, well, this is going to essentially create a brand-new human species that is better, more insightful. more enlightened, less prone to mood disorder.

As it turned out, that didn't happen. Yeah. Well, I think the wish for utopia is in all of us to some degree. And unfortunately, there's probably never going to be a utopia. Probably not that we can get out of a wafer or pill. Yeah, yeah. Okay, getting back to this study about, severity of depression and the antidepressant response.

There's one other thing I wanted to say. So if you look at the change with the antidepressant, the change in low moderate depression was like 10.6, high moderate depression, 12.4, moderately severe, 15, and severe 16.5. So when we talk about placebo versus the pill, It may be for the severe, it's a difference of basically 8.3, but the overall response to the antidepressant is 16 in that severe category.

And that to me is actually a pretty significant decrease. Yes, it is. You know, it would be fair to say that the antidepressants, and in particular the SNRIs and more severe depression, have been a major blessing in terms of evading suffering. Depression is the fourth leading cause of disability in the world. Duloxetine has played a major role in that in 2018, it was the 36th most commonly prescribed medication in the United States

with some 21 million prescriptions. Okay. So I wanted to touch a little bit about general anxiety disorder. But before we get there, maybe the final question I would have for you is, is there a best antidepressant for depression? Like if you, in your knowledge of all the papers you've read, when they stack antidepressants up against each other, like, is there a better one or a worse one? Or how do you make a choice which one to use? There is not an a priori way to pick a single drug that will work best for every patient. If you take them in groups, probably the most effective antidepressant molecules we've come across are the monoimmune oxidase inhibitors,

but they are seldom used because of their risk profile. The SNRIs are next, again, because they can increase both serotonin and noropenephrine, they in turn appear to be more effective than the SSRIs, although the SSRIs account for about 70% of all antidepressant prescriptions. And that's largely because the SSRIs are very generally safe medications. All right. Yeah, I would say that it's like, how do I pick which antidepressant I choose? You know, there's so many different little factors that come into play.

specifically with deloxetine what i think we're going to highlight in in this next sort of discussion is how the different things outside of depression that it treats and sometimes if you're if you're having a patient who struggles with chronic pain you know sort of bodily issues like that then it can be a good one to use to try to take care of two things with one med so okay let's talk about generalized anxiety disorder and the effect of of deloxetine. Okay. Generalized anxiety disorder is characterized, of course, by chronic anxiety and worry,

a very miserable condition for people to have. Essentially, it's an overactivation of the fear circuit involving the frontal cortex, thalamus, an amygdala. Serotonin directly inhibits the activity of the amygdala, so that takes one element, element down, which is why the SSRIs are often effective as well for generalized anxiety disorder. Do Loxetine and the other SNRIs go one step beyond that, however, and also increase norapinephrine, which subsequently downregulates alpha-1 and beta-1 noradternergic receptors in that circuit, also decreasing activity. An important clinical element, though, to tell people about when starting

them on an SNRI for generalized anxiety disorder is that the anxiety symptoms will initially tend to get worse because you're increasing noraphenephrine because the downregulation of the post-synaptic receptors lags behind and doesn't begin until really about two weeks after the person initiates the drug yeah i i tell patients it's it's it's It's going to sometimes take six weeks for the anxiety to get to where the new baseline is. Yeah. Yeah, indeed. And it's important to warn people.

You know, people are a lot more tolerant of things that are adverse or negative. If they know it's coming and it doesn't come as a surprise. Yeah. Now, there was one case that I heard recently of a guy that when he took an antidepressant, I think it was Louvaux. He was up for three days straight. pacing around extremely extremely anxious. Would you consider that like just a normal increase anxiety,

or what would you consider that to be? That was a bit of an extreme example. With all of the antidepressants, including the SSRIs, there is initially typically an increase in anxiety, usually not to that extent. The reason being with the SSRIs, although they're not directly increasing noropenephrine, the serotonergic system in the raffa nucleus and the locus serulius, which produces norepinephrine, are cross-linked so that when serotonin goes up, it stimulates the locus serulius to release more norein.

So with either class of antidepressant SSRI or SNRI, people with an anxiety disorder often initially experienced an increase in anxiety, albeit not to that extent. Yeah, two things came to my mind. First of all, this person thought it was a bipolar episode, which I did not think it was because I thought it would take weeks to kind of enter into that level of mania. Could it have been disturbed sleep and anxiety? I was leaning more towards like an acesia sort of response, the way that they described it.

It could be because, of course, one of the other effects of any of the drugs that increased serotonin, serotonin binds to 5HT2A receptors in the nigerostridal pathway and decreased dopamine release which in vulnerable individuals can set them up for acetheia and have particularly in the elderly

even resulted in dyskynetic symptoms yeah okay so in one meta analysis this is Band-a-Loe-E-Loe-T-Lat-all 2015, which compared the efficacy of pharmacological, psychological combined treatments for the three main anxiety disorders, panic disorder, generalized anxiety, disorder, social phobia. Pharmacotherapy was associated with a statistically significant higher average pre-post effect size as compared to psychotherapy.

So pharmacotherapy was around two, whereas psychotherapy 1.2. And SNRIs had the greatest effect size as compared with the SSRIs, 2.25 versus 2.08. Yes, which I think speaks to, and the pharmacological interventions tend to be more immediately robust. Conversely, for those people who do cognitive behavioral therapy,

The effects of the CBT tend to be longer lasting. You know, obviously, the tendency with the medications is if we stop them or we taper them and discontinue them, the symptoms tend back toward baseline, more so than with the psychotherapy. So that even though in some studies combining the treatments has not been shown always to produce a bigger effect size in terms of treatment, For many patients, there may be an advantage to combining pharmacotherapy and psychotherapy in terms of producing a more robust, immediate effect, but also a longer-lasting adaptation in the person's ability to essentially cope with life and manage their anxiety. Yeah. Yeah. And often the patients that I see are already on antidepressants and still

anxious and you know that's where using psychotherapy using exercise as as treatments you know it's very important oh indeed oh indeed if you read many of these studies what you'll find is that they're quoting you look at the symptom reduction they're quoting symptom severity reductions of 25 35 in a really effective study 50% well that doesn't mean the person is now free of anxiety it means their anxiety, intensity has declined. Okay, there's this other study, Jakoboski et al, 2019, and they did find that higher doses of SSRIs

within the FDA recommended dose range were shown to be marginally more effective than lower doses for treating anxiety disorders, whereas higher doses of SNRIs were not. So I'd be curious what your thoughts on that study were, and just in general, like, sometimes when you treat with an SSRI at, like, let's say, Zolov 50, and someone's still anxious after six weeks, I think to myself, okay, I could increase this to 75, six weeks later, they're still anxious, but a little bit decreased. I can increase it to 100.

And it seems like the more, the higher the dose of the SSRI, the better the anxiety decreases. But it seems like this study is saying that higher doses of SNRRR, doesn't really have that same impact. I think the SNRI is because they are directly increasing both serotonin and noraphenophenaphrin essentially reach a sealing effect sooner. With the SSRIs, the concentration effect curve for most drugs is a sigmoid shape so that as the dose goes up, the effect goes up until you reach a point where it begins to flatten and that flattening occurs earlier for the SNRIs than for the SSRIs,

which is why once you reach that ceiling and that curve is now flat, increasing the concentration of the drug doesn't produce any further effect. Okay. Let's move on to neuropathic pain. And so, you know, SNRIs increase serotonergic and neurotic and nor. large energetic neuron activity in the descending inhibitory spinal pathways of the dorsal horn yes and it's it's thought that this inhibits dorsal horn neurons suppressing excessive nociceiceptive input and decreasing pain transmission to the brain yes actually also it directly decreases substance p in the dorsal horn

which is the neurotransmitter that transmits the pain signal between the incoming nerve fiber and the neuron body in the dorsal horn that then is going to give rise to the ascending pain signal. And then with the SNRIs, then you also get the advantage that the neuroadernergic component also inhibits the ascending pain pathway in the brainstem. So you get both an inhibition top-down and an inhibition during the ascent of the pain signal as well, which is why the SNRIs have universally been more effective for pain than more purely serotonergic drugs. So generally speaking, the more noradrenergic, the SNRI, the better it is for pain control. Yes, that's why if you were rank ordering them,

vinlifaxine would be at the bottom, because it's the most serotonergic compared to its noradrenergic effect. Duloxatine would be next, 10 times as serotonergic as noradrenergic. Milnasopran is one to one, and levo-milnasopran is one to two, so it's the most noradrenergic of the SNRI drugs. of course it's disadvantages it's so proprietary and expensive whereas duloxatine is available as a generic drug yeah so specifically

with fibromyalgia which i find that it used to be more in vogue to diagnose people with fibromyalgia now it's a little bit less in vogue but i think still people have this sort of constellation of you know a pain disorder psychosomatic disorder that the brain is lighting up with more pain than they're experiencing. So if you put their brain in an MRI and you cause pain to them, you know, someone with fibromyalysis, pain areas in their brain are going to light up 10 times more than the average person. Yes.

And so, you know, although psychotherapy helps and exercise helps, the question is like what medication to prescribe if you're going to prescribe a medication? Oh, I think indeed this may be an area, and indeed it's an area where the SNRI is. have gotten a lot of use, including duloxatine, because, again, this is related to pain perception and also to the affective response to pain signaling and increasing central norapinephrine and serotonin certainly help that. There also have been a few studies looking at increasing dopamine signaling along with that, usually in the context of MAOI studies. occasionally combined use of a stimulant and antidepressant, and all of those tend to be effective

in fibromyalgia cases. Certainly, worldwide, the most common treatment is melanasopran, although duloxatine has also been used for treatment of fibromyalgia. So one of the treatments is deloxetine, which is a pretty common one in my practice, It's just because the nor-tryptylene, amatryptylene seem to have so much more side effects. Of course, other meds that I commonly see these people come in on are, come in on, are like pre-gabalin. And that seems to be helpful for some, but carry some side effects. So I tend to have the most success with deloxetine if I'm trying to get rid of the side effects of, like, daytime sedation that they might feel from being on the amatryptylene or nortyptylene. Yes. And as you point out, the pre-gabalin also tends to be sedating because it essentially is a gamma-amino-butyric acid re-uptake inhibitor, so it increases central GABA, which of course has anxiolytic effects as well as some dampening effect on the pain response, but at the price sometimes of making the person foggy and sedated.

Yeah. Okay. Then there's like general. chronic musculoskeletal pain, which is extremely prevalent in the adult population with chronic lower back pain, osteoarthritis of joints, and greater than 50% of adults, age 60 year older. And although my first thought is if they can get stronger,

they'll have less pain, sometimes we want to use also medications to try to help them. Do you think Simbalta would be a good option for someone with just chronic back pain? Yes. certainly worth a try. There are a number of pain specialists who use duoxetine usually as an adjunctive treatment to other things such as physical therapy, massage, topical agents such as capsacin or direct local anesthetics. Because indeed, these people often are dealing

with chronic pain that is debilitating. Fortunately, people have gotten much more cautious about use of opiates since we've had an opioid epidemic. So it's very rare for me to see one of these people on a monotherapy. Usually what you see is they're on something like duloxatine or another SNRI, plus topical agents, plus some program of exercise and physical therapy. Mm-hmm. Okay, so we talked about anxiety disorders. We talked about pain a little bit.

Let's talk about OCD, obsessive-compulsive disorder. Do you, where does deloxetine SNRIs sort of fall into sort of the treatment of OCD in your perspective? Deloxetine's desirable. The highly noradrynergic drugs are not very effective. That is melnaceprane and levo-malanacopran because they don't have. have enough of a serotonergic effect for OCD. Ventilofaxine and duloxatine can be very useful because they have a pretty good serotonergic punch, which is the increasing serotonin, has been the mainstay of OCD treatment for a long time now.

But they also replicate, to some extent, the noradrygnergic effects with that of anaphrinil. so that if you have somebody whose YBOX score doesn't decline adequately with an SSRI, even at high doses, then moving to duloxatine is a very reasonable choice because it's far safer and far more tolerable than anaphranil is. When we think about anaphrone, we're thinking something like very, very serenergic. Anaphrano is very serenergic, but it also has, because, because it's a tricyclic and it is metabolized to its own secondary amine. It does have a noradryngic component as well, as well as also an antihistaminic component. Okay.

So it's like many of the tricyclics, an aphrenil is a fairly dirty drug, if you will, and that it affects a number of transmitter systems. But like all of the tricyclics, its therapeutic index is narrow. I think what has made the tricyclics, it's therapeutic index is narrow. I think what has made the tricyclics much, much less desirable as safer agents have come along, is that for all of them, the therapeutic index ranges from about six to eight, meaning it only takes a little more than a week's worth of therapeutic dosing to kill 50% of people if they overdose on it. Yeah.

Okay, what about ADHD? you know, does the norpenephyne uptake in Simbalta help ADHD enough to consider it an option? It is certainly not a first-line treatment for ADHD, but I think for some people it may be a good second-line choice if they've had difficulty, for example, tolerating or responding adequately to either direct dopamine stimulants or to a more pure neuroadrenergic drug like atomoxetine, particularly if they all have comorbid mood issues. Again, people with ADHD sometimes also have issues with mood disorder,

comorbidity, because having ADHD makes life more difficult. Let's see here. How about binge eating disorder? So binge eating disorder is defined as recurrent episodes, of eating that in an amount of food that is definitely larger than most people would eat in a similar situation. And it's associated with a sense of lack of control over eating during the episode. And these episodes occur on average at least one day a week for three months. So would you consider, where does deloxetine sort of fit in your conceptualization of what you might consider

for binge eating disorder? I think, again, it, fits into this category as a second-line agent. The first-line agents have typically been the SSRI antidepressants, but if people can't tolerate those, for example, due to sexual side effects, then considering duloxatine as an alternative is certainly worthwhile. And indeed, there are a lot of disorders like this for which duloxatein may not be the first-line drug, but it frequently winds up in the role of being a second-line choice when either the first-line choices are not effective or not well- tolerated.

Yeah, so there's several studies that I'll put in the handout, and this handout right now is like, for this episode is 30 pages or so. So if you want more details on any of these things, check out the handout on my website, Psychiatrypodcast.com. Okay, how about PTSD?

Where does Symbolta fit in sort of your thoughts on treatment of PTSD. And be useful in PTSD, again, like the SSRIs, it has a substantial serotonergic component. You do have to be careful because PTSD is inherently a hyper-naradrenergic state, but if started gradually and titrated gently, you can get a down-regulation of the post-estrientary. synaptic noradrynergic receptors that you don't get out of the SSRIs to the same extent. So in some people for whom the SSRI isn't adequately effective, a trial of dulyoxetine may be worth entertaining.

Okay. What about vasomotor symptoms? We're talking about perimenopausal women with or without depression. Go ahead. Yeah. This has become one of its most recent popular uses for which it appears to be quite effective along with the other SNRIs, and also another unique indication of late has been urinary urgency and incontinence, responding again to the neuroidrenergic component of the drug.

Yeah, that's some good stuff. And peri-menstrual dysporic disorder. Indeed. Also, one of the things that's true about premenopausal dysphoric disorder is that there's an actual decline in serotonin release in relation to that phase of the menstrual cycle. And indeed, this is a case where serotonergic drugs, including those like duloxatine, can directly benefit PMDD and can do so very quickly. You don't have the same delayed time lag that you do with major depressive disorder. These people take something that boosts serotonin release, or in this case, blocks re-uptake, and their symptoms are better essentially overnight.

So what do you think about timing SSRIs with the cycle? If you have somebody, the caveat is you have to have somebody who has a very rare, regular menstrual cycle so that you know when the next minces is coming. If that's the case, and usually most people who practice in this area will have people track their mencies for two or three months, and if they're very stable, their cycle is stable, then you can start an SSRI or do loxetine a few days before their mincees and then discontinue it one or two days afterward, and they don't have to take the medication the entire time.

Now, if you have somebody with an erratic menstrual cycle, then you're pretty much stuck with administering the medication all the time because you can't know for sure where the person is in their cycle. Okay, let's talk about migraine prophylaxis. You know, sometimes with migraine prophylaxis, people will think propanololol. They'll think Botoxys. now popular, which seems to be nice because it doesn't have a lot of side effects. And then also like nortryptylene.

But sometimes there's side effects, nortyptylene, amyptylene, and so the consideration is Simbalta. And it has some studies showing varying degrees of, you know, efficaciousness regarding this. Mm-hmm. Again, and this is another case where it doesn't appear to be a first-line treatment, but if the first-line treatments either don't work or are not tolerated, duLoxetine is a worthwhile thought.

Different practice standards suggest different points at which prophylaxis is indicated. Most of the neurology protocols that are out there, algorithms suggest that if somebody's having more than two to three migraines a month, it's worth thinking about prophylactic treatment rather than simply rescue treatment with a triptan. And certainly I think this is an area where the patient should have input. They know how disabling their migraines are. And if they have a migraine and it's taking them out of circulation for two or three days, then looking for prophylaxis,

worthwhile doing even if their migraines are less frequent yeah so yeah in conclusion second line maybe if they don't tolerate tcAs and if they if they fail a couple of them i i think um botox is an option for for migraines that i've seen a lot of people benefit from yes as well yes we're finding a lot of uses for botulinum toxin other than the initial cosmetic indications Just as an aside, one of the treatment areas that's been a major benefit in the state hospitals is botulinum toxin is highly effective in treating clozapine-induced scyalleria. What do you think about a borderline personality disorder, deloxetine? Any thoughts on how efficacious it is? It is probably as efficacious, maybe a little more so than the SSRIs.

When the SSRIs were introduced, they became, for a while, the major pharmacologic intervention for borderline personality disorder due to the ongoing dysphoria that many borderline individuals suffer from. That has shifted over the last few years toward the mood stabilizers in response to a reconceptualization of borderline personality disorder as really being an act. effective discontrol disorder. But I think for those individuals who have a lot of prominent dysphoria, then certainly do loxatine as a worthwhile consideration. Yeah. So let's see. Any other things? Premature ejaculation. There's some, there's some studies on that. Yes. Again, you know, premature ejaculation has been treated with the SSRIs because it's the serenergic component that delays orgasm. However, in some people, the SSRIs are overly effective and produce not only a delay in ejaculation

that can produce outright anorgasmia and erectal dysfunction. The fact that duloxatine contains a noradryngic component as well tends to offset that robust response to some extent so that you may be able to correct the delay, but without, making the person sexually non-functional. Yeah. Okay, so what are your big clinical pearls and key takeaways for this drug class? I think for the SNRIs, the big takeaway is that they are a much safer and probably equally effective treatment in many contexts compared to the tricyclic antidepressants, such that in many cases, That's why the tricyclics, except in lower doses, have become much more commonly drugs of history rather than drugs of current use.

They are useful because I think indeed in the primary indication of depression, they are clearly more effective than the SSRIs for the moderate to more severe depressions. and you know we need given how severe depression can be and that it's the fourth leading cause of disability we need more effective treatments yeah i think i think one of my key takeaways is consider when you think about the effect size that the effect size is going to increase in the more severe ranges of depression um consider learning a little bit about the hamd and how your patient may score and that may give you an idea of the severity of their depression. And, you know, when we look at the efficacy of this class of medication, it's, it's worth considering, especially if you haven't quite responded to some other medications like SSRIs. I think it's

worth trying an SNRI. And it also treats a whole host of other issues, including pain issues, migraines. And although it's second line for migraines or maybe third line, it still might be worth a try. So yeah, any final thoughts? Just in terms of people who treat a lot of depressive, depressed or anxious patients, I would encourage them to use a rating scale periodically. it gives people a much more concrete measure of what their patient status is. Beyond the score, it forces clinicians and patients to think about the individual components of their illness. I can't tell you how many charts I've read where the notes every month say, oh, the patient's better, but that's vague.

It doesn't really tell you in what way they're better, whereas a series of rating scales can very nicely pin that down for you. Yeah. Very good. Well, deloxetine is FDA approved for major depression, generalizing anxiety disorder, diabetic peripheral neuropathic pain, chronic musculoskeletal pain. It's not FDA approved for stress urinary incontinence and some of the other things. But yeah, it's an option. And I think it's a good deep dive that we went into. And thank you, Dr. Cummings, for your time. Okay, it's good to see you again, David. And yeah, we'll leave it there.