Psychiatry & Psychotherapy Podcast - Duloxetine and the SNRIs Deep Dive Part 1 with Dr. Cummings

Episode Date: March 11, 2021

In today's episode of the podcast, we will be doing a deep dive into duloxetine, a serotonin-norepinephrine reuptake inhibitor (SNRI). In part one of this two-part series, we will cover the history of SNRIs as well as mechanisms of action, cytochrome P450 issues, side effects, and contraindications to consider when prescribing duloxetine and this class of medications. By listening to this episode, you can earn 1.25 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 emailed to you in seconds. Welcome back to the podcast.

I am here with Dr. Michael Cummings. He is an excellent psychopharmacologist. We've had him on many episodes before. If you haven't listened to them, you should go back and check them out, especially if you're a psychiatrist or a resident or a medical student or a provider of psychiatric medication. So Dr. Cummings, welcome to the podcast. Thank you very much. I'm very pleased to be back and looking forward to talking about duoxetine and the SNRIs.

Yeah, these are great. These are medications often used to treat things like depression, anxiety, and pain. And so we're going to get into all of the mechanism of action, the history, the side effects, precaution, contradications in this episode. And we'll touch on the efficacy a little bit, but in part two, we'll probably get into more of the details of the efficacy of these medications. Great.

So maybe we could start with the history. Okay. Basically, as you may recall, the very first classic antidepressants were the tricyclic antidepressants and the monoimmune oxidase inhibitors. Both of those groups were problematic in the sense that they were potentially quite dangerous. The LD50 or a lethal dose for 50% of the population for TCA's is only 6 to 8 times the therapeutic concentration. and of course, M-A-O-I inhibitors, M-A-O-I's, carried the risk of hypertensive crisis, also known as the cheese response. That changed dramatically with the introduction of the SSRIs.

They were much safer. It's very difficult to actually kill yourself with an SSRI alone. Unfortunately, one of the things that came to be observed with the SSRIs was that while they were clearly, as effective as the older antidepressants in mild to moderate depression and more severe depression, sometimes the SSRIs didn't perform as well in some studies, which was at least theoretically people thought, well, maybe it's because we're really only pushing one neurotransmitter very hard, and were not directly affecting noropenephrine or dopamine.

Research then led to development of the SNRIs, which are, as a group, re-uptake inhibitors of both serotonin and noraphenephine. The first drug introduced was Vinla-Faxine, a FXer, first in the immediate release formulation, and then in an extended release formulation. Later, that also was joined by desmethyl or des Vinlifaxine Pristique, which is actually the metabolite of venlofaxine. In between the development of those two, you had the introduction of duloxatine by Eli Lilly, which was somewhat unique in that it was the first one to get an indication for both treatment of depression and treatment of diabetic neuropathy. Although all of the SNRIs do have some analgesic properties in terms of decreasing neuropathic pain.

And then most recently, the last member to be added to the group of four in the U.S. indicated for depression is levo-melnasopran, which is the metabolite or the levo in the antimur, rather, of melnasopran, which everywhere else in the world is marketed for depression. but in the U.S. is marketed only for fibromyalgia. Yeah, and looking at the mechanism of action, so they have that dual serotonergic, noradrenergic, transporter re-uptake inhibition. They do, although they are not equal in that regard.

They are not all the same. With vanilla vaccine, the ratio of serotonin reuptake blockade to noropenephrine reuptake blockade is roughly 30 to 1. The metabolite is 10 to 1. Duoxetine is also 10 to 1 serotonin over norapinephrine. Milnasopran is actually dead even one-to-one. And levo-malnasopran is 1-2. It's actually more noradrenergic than serotonergic.

Yeah, yeah. And there's some, I was reading that because there aren't very many dopamine transporters in the prefrontal area, and dopamine is reuptaked by the norpenephrine reuptake system, there is some increase in dopamine in the frontal lobe with deloxetine and these SNRIs. There is. And indeed, if you look at the, re-uptake profile of all of these drugs, they are weak inhibitors of the dopamine re-uptake

transporter, but the re-uptake inhibition is not zero for any of them. And indeed, in the prefrontal cortex, the norendrenergic system, if you inhibit its re-uptake, it also will increase dopamine. So they all do, to some extent, increased dopamine, albeit it's a minimal effect compared to serotonin and norapine. The one exception to that is if people, as you know, I work in a forensic setting, and indeed people will inhale a vinlofaxine. The street name for vinlofaxine is Red Dragon, because if you inhale it and you push the concentration very high, very fast,

fast, you can get enough of a dopamine response that it looks sort of like a weaker version of amphetamine. Wow, I did not. I learned something new. Red dragon. Yeah, you only find out these things when you work in forensic settings. Sounds. What a name.

I wonder why I got that name. Essentially because some of the early tablets were red in color. Okay. and people would crush the tablets into a powder and then insufflate or snort the powder in order to get high. So deloxetine and these SNRIs also work on increasing serenergic and norahedogenic neuron activity in the descending spinal pathways of the dorsal horn. Yes. This then inhibits the dorsal horn neurons, suppressing excessive input, which decreases pain, transmission in the brain? Yes, and that appears to be that and some direct inhibition by

NORADRNERG input in the brain stem in terms of the ascending pain pathways appears to be how these drugs are beneficial for treating neuropathic pain. And indeed, they do see some use for that, you know, prior to their introduction, people have historically used low-dose tricyclic antidepressants for the same purpose via the same mechanisms. These drugs, however, as we pointed out at the beginning, are safer and consequently can be used with fewer side effects, fewer risks. DeLoxetine is not musklorinic, cholinergic, isminergic, and has no alpha-2 activity, which is, I think, important to note,

so it's not going to cause some of the other issues that those drugs might, or drugs that have those activities. Yeah, indeed, as a group, including duloxatine, these drugs are much less prone to cause adverse effects. In fact, in large part, with the exception of rare adverse effects, paying attention to pulse and blood pressure during titration is probably the largest clinical issue, especially in people who are prone to hypertension. And frankly, that also depends on the rate of titration.

Slower titration tends to mitigate against tachycardia or hypertension. Yeah, so let's talk about how they're broken down a little bit. Venlo-vaccine affects her in one of the pathways is broken down by, 2D6. Now this goes to the RSO-des methyl phenylophaxine, which is pristique essentially. And so I've had patients who don't have any 2D6 activity, and then it's kind of shoved into another pathway that doesn't really lead to anything that's active. Do you see it that way? Yes. If they don't have the 2D6 and the 2C.

the 2D6, I think being the big one. And so what they found is that if you have decreased 2D6 activity, effects are has been associated with cardiovascular toxicity. And usually patients can't tolerate more than 75 milligrams. Yes. Yeah. Fortunately, poor metabolizers at 2D6, while they are prevalent in some ethnic groups,

by and large, 2D6 is not in short supply in most of the population, which is why you don't see that effect broadly. But it is something to pay attention to. Even more importantly, if you're giving somebody another medication, which is a 2D6 inhibitor, then, of course, you can very quickly get the person into difficulty with vinlofaxine. The three drugs, the three other antidepressants, because people do, of course, combine antidepressants at times. The three antidepressants that are potent 2D6 inhibitors are peroxitine, SSRI,

fluoxetine, also SSRI, and buproprione, well vitrine. And basically people should really avoid combining those with vinlifaxine. Yeah, and think about that if you're like trying to taper someone off of venlofaxine onto fluoxetine. Fluoxetine, that 2D6 blockade can shove that venlofaxine away from the active metabolite and cause some issues. So yeah, 2D6 is important for a, effectser. I've had some patients who by history or by trying afexer venlo

vaccine, they don't do well on like 150. And I can switch them to the death venlo vaccine, which is broken down without 2D6, and they do just okay. They do just fine. Yeah, and what you've likely what you've done is you've inadvertently discovered somebody who's a poor metabolizer at 2D6. Yep. Yep. So. That's one interesting thing. Of course, des Van der Lefaxine is more expensive, and I hate prioroths. Yes.

Yes, the other thing, the other thing to note about does vanilla vaccine is, interestingly, you know, it comes in two doses, 50 and 100 milligrams. In clinical trials, no one's ever demonstrated that the 100 milligrams is superior to the 50. You know, I was going to get to that later, but interestingly, what I found was that SSRIs, as you increase the dose, it can continue to help with anxiety. But SNRIs don't seem to have that effect. So it doesn't make sense if they're still anxious to push up the dose of the SNRI. No, in fact, usually what that does is you start to get into difficulty with adverse effects from essentially the person having too much noraphenephrine and epinephrine, because of course the other, related monoamine that is whose reuptake is inhibited by these drugs is epinephrine peripherally. Being psychiatrists, we sometimes forget that there are things outside the brain.

And indeed, that can essentially lead the person into having too great a sympathetic tone, which, of course, is related to pulse, blood pressure, so forth. De laxatine is broken down in the liver by 1A2, and 2D6. So if you have a potent inhibitor of either one of those, like fluoxetine, I don't know why you would put that together with Sybalta,

but that could inhibit 1A2 or if you have something like buproprion, that can inhibit 2D6, so that can increase the level of Simbalta, which you may not want. No, you may not. And indeed, I think one of the things we're touching on here

is that when people think about polypharmacy, they need to really look at two aspects. One, rational polypharmacy involves using different therapeutic mechanisms of action. It doesn't make any sense to give two drugs that have exactly the same therapeutic effect in terms of their effect on neurotransmitters. But the other aspect people really need to pay attention to is, are there potential drug-drug interactions, particularly with respect to metabolism of these drugs. One of the caveats that did come along with the introduction of the SSRIs was everyone got

introduced to the cytochrome P-450 system, because indeed, as we've already noted, peroxitine and fluoxetine are both potent 2D6 inhibitors. Fluvoxamine is a very potent 1A2 inhibitors. So you have to be very careful about combining them with drugs that depend on those pathways for metabolism and clearance. Cytalopram, S-cytalopram, and cerchroline, among the SSRIs, on the other hand, while they inhibit a number of the cytochrome P-450 enzymes, they're not very potent inhibitors of any of them. consequently they have far fewer drug-drug interactions. This is one of my pep thieves actually with the genetic testing that people sometimes order, which I think at this point is not very helpful,

is that they will say to not use selexa or acetylopram or Xoloft based off of their P450 profile, whereas really actually it's not like very important, I think, in those meds. I don't know. Do you disagree? No, it's not important in those meds. medications, frankly, a far better way to tell if someone is, and frankly, cheaper way to tell if somebody is a good or poor or average metabolizer of a given drug is to titrate the drug to steady state, and then simply measure a plasma concentration. That's a much more precise way than getting a genetic

profile. My other pet peeve with the genetic profile companies is they have advertised themselves as being able to predict which antidepressant people will respond to. Frankly, they don't have the data to make that prediction adequately. Yeah. And one of my other pet peeves is they talk about the shorthand of the serotonin gene and like, oh, you should use these SNRIs if you have a shorthand of the serotonin gene. And that actually in the newer research doesn't seem to make any difference. No. People thought early on

that there was a difference between the two isoforms, but in later research, that difference basically vanished and is no longer thought to have been a valid observation. Yep. So I think the CYP stuff, the helpful aspect is

when you're putting one med onto another med to know some of the basic, like, what the CYPs are going to potentially be doing and where you might have issues. Yeah. It's especially important if you're considering polypharmacy and you have somebody on a drug that is a potent inhibitor, of course, then you don't want to combine that with a drug that depends on what you've inhibited. The classic example that can have lethal outcome in the context where I work is if someone combines a fully therapeutic dose of fluvoxamine with a drug like olanzapine or clozapine, you're talking about potentially a tenfold 1,000 percent increase in plasma concentration of the clozapine or olanzapine, which can you're well up into the lethal toxic range. of those drugs then.

The one that I see in my practice is they'll come in on risperol and Prozac. And the Prozac fluoxetine inhibits the 2D6 of the Risperol breakdown. So the amount of Risperol can jump up considerably. Yes. And those people often come in with this like restlessness and, you know, they're moving around and they feel this, you know, basically they're having the acesia. Yeah, because indeed they're D2. antagonism has gone through the roof.

Yep. Okay, let's jump into side effects a little bit. I was going to start with nausea. You know, often patients will have nausea when starting these meds. Yes. And basically this speaks to the issue of with most patients, duoxetine is a drug that really should be started at the lower end of its available doses, 20 or 30 milligrams, and then titrate it up.

probably at increments not more frequently than a week. That will permit most people to tolerate the drug much better. They won't have nearly as much nausea. Yeah. If I have someone who's drug naive, I usually start at 20 or 30, and then I'll wait a couple weeks, see what kind of effect that had before I go up. You know, it takes four to six weeks for anxiety to decrease.

So like sometimes instead of pushing it up faster, I'll just wait to see what the lowest possible dose can do. Yes. Yeah, one of the faults currently in medicine is sometimes we are too impatient. And we forget there is value to be had in applying a treatment and then indeed giving ourselves enough time to evaluate the treatment response. I've seen patients who indeed wind up on too much of a given medication, simply because their clinician essentially blew right past the effective dose of the drug. They were going up so quickly that they missed the fact that the person was responding to a lower dose.

Yeah. Sometimes I'll have residents. They'll come from inpatient, you know, and they'll be starting clinic. And one of the things I try to teach them is you have a lot more time. You can go slow. You can make one change at a time. see what the change does. If the med that you start doesn't make any impact, then you might just want to try something else rather than just adding on more and more meds onto something that's not working at all. So I try to get them to make one change and go slow

and be patient with the process. Now, if someone's severe enough that that's not a good idea to do, then, of course, you can make that decision, but usually they need partial or IOP at that point. Yes. if you're really worried about them. Yes. Yeah, in an outpatient setting, going slowly and observing change, both positive and negative,

will help you make much better clinical choices than rushing and making changes without really waiting to see what the outcome of those changes are. So I wanted to talk about sexual dysfunction, which is probably for me as an outpatient psychiatrist, like the number one issue with using these meds, it's the most common side effect that men and women are going to have. And if you don't talk to them about sex before you start the medication, you won't have a baseline. So that would be my first sort of thing that I would recommend is just kind of get a baseline. You know, how are there three stages of normal sexual function, right? the first stage being desire, libido, the second stage being arousal, excitement,

and the third stage being orgasm. Like, are they able to do all three stages and are they enjoying sex on a regular basis? Is it, you know, once a year, once a month, once every week, you know, and just write that in the chart, what's going on? Yeah, and I think it's important that indeed people ask, one of these statistics I've always been impressed by, If you go back to the original package inserts for the SSRIs, the quoted sexual dysfunction rates for those drugs were, oh, you know,

and maybe 5 to 10 percent. Well, that's certainly not true. When they actually asked rather than waiting for people to spontaneously complain, with serotonergic drugs, you not uncommonly see some degree of dysfunction in 50 to 70 percent of. treated patients. So it's important to ask at baseline and then to continue to ask, particularly after each dose change, if the person has encountered any difficulty. Yeah, it seems very dose dependent. It is. And also, there are some aspects of gender dependency or, you know, different genders are

going to respond to these meds differently. Specifically, in one study of 3,000, adults, either on an SSRI or an SNRI, they found that men were significantly more likely to experience dysfunction in the desire and the orgasm stage, whereas women were more likely to experience dysfunction in the arousal stage. Yes. Yeah, although men and women are phenotypically and genetically more similar than different, this is one area where these drugs affect different phases. of sexual functioning in the genders, although some unlucky people get dysfunction across the board. And that's another, indeed, reason to go up slowly and to find what the minimal effective dose is for the person. Because as you point out, the sexual side effects of these drugs are dose dependent.

Yes. And so that's where like getting a baseline before you start them on the med, and then checking in every time you increase the med can be very, very helpful. I've been the faxing of the group of SNRIs, I think, is the highest risk of sexual side effects because it has the greatest serotonin reuptake inhibition. Yes. And Levo-Milmasopran is the lowest because, of course, it has the least serotonin re-uptake inhibition. Oh, man. It really is outpatient, like a big deal.

deal because people come in depressed, they don't care about sex, and then they get undepressed, and they're like, wait a minute. And, you know, of course I talk to patients about, like, this is probably the one side effect that, you know, we need to watch. And if it gets worse, we'll try something else. We'll try something like mertazapine, except that one causes weight gain. Yeah, you can try mertazapine. The two, if the person is an SSRI responder, then you you have drugs like valazidone and vortyoxetine, which are also 5HT1A, partial agonists, and that tends to mitigate against the sexual side effects of seraternurgic drugs. So those are options as well, albeit they're expensive options.

Yeah, so stimulation of the 5HT1A contributes to ejaculation, whereas stimulation of the 5H2A and 5HT3 leads to negative effects on sex function. Yes. Yes. I'll put all these notes, by the way, on my podcast, Psychiatrypodcast.com. I know there's a lot of details here. You might want to take a look at this later. Yes, we're taking people through alphabet soup. Yeah. Yeah. Not all those things stick the first time around. So I want to jump to kind of the increased risk of suicidality. We've talked about this before in episode 24, the history mechanism and use of antidepressants. But it's something that always comes up and it's worth kind of reiterating. What are your thoughts on this for this class of medication? It applies to this class as well as

to other classes of antidepressants, it became prominent with the introduction of the SSRIs, particularly in adolescents and young adults, when people noticed that people who were started on an antidepressant in those age groups had a report of increased suicidal ideation, which led the FDA to issue a warning. The intent of the warning was not to decrease use, but to have people check in with their patient sooner rather than later. In other words, come see me next week, or if you have this, let me know, not I'll see you in a month as is common in some clinics. This was not the first time, however, that was observed. The same things were observed with the MAO inhibitors, the tricyclics, and have also now been observed with the SNRIs as well.

And I think my own understanding of this is that essentially depression does not get better uniformly. When we treat people with an antidepressant, typically there are neurovegetative signs and symptoms, their appetite, their energy level, their sleep, those things improve first, well-wegetative. before their mood improves. So essentially what you have is now an activated person who is still depressed. And in particular, that may put them at higher risk of thinking about suicide or even acting towards suicide. If you have somebody with zero energy, well, they may think about suicide, but they're

not likely to do anything. So there isn't an elevation of risk in beginning. antidepressant treatment. Unfortunately, after the FDA issued its warning, the effect was to cause a sudden and abrupt decrease in the amount of antidepressants used in adolescents and young adults. And what happened is the actual suicide rate went up as a result, because now, of course, you had untreated depression. Yeah.

And, you know, I've, when I've looked at the, you know, when I've looked at the, you know, this, it's interesting to me that the places of the highest suicide in the U.S. are often the places with lower psychiatrists and lower therapists, more rural areas of the United States. So, you know, it's not like the places with the highest amount of antidepressant use have the highest rates of suicide. That's just not the case. No. And frankly, there's also, there's a corollary there.

frankly, psychiatrists are not the most common prescribers of antidepressant medications. Most antidepressants are prescribed in primary care clinics, and unfortunately, one of the outcomes of that is, and this was an estimate done by the American Psychiatric Association a number of years ago, they surveyed clinics and asked, well, how much are you typically prescribing? And they found that if people were being treated in a primary care clinic for major depression, their odds of actually receiving a therapeutic dose was only 41%. So you had a lot of sort of under-treated depression. Yeah, and I also looked at the studies of, you know,

people who actually complete suicide, there's one study in England that showed that the majority of them were not receiving any mental health care for the proceeding, like three months. So it's it's that's the kind of study that really interests me is like okay what what is going on in these people leading up to their actual suicide attempts. Yeah. And we look at blood levels of physicians for example who commit suicide and they have you know alcohol in their system or benzodiazepines at much higher rates than you would desire and other things like a lack of

treatment lack of effective treatment. Yeah, indeed. I think it's fair to say that, you know, depression is listed by the World Health Organization as essentially the fourth leading cause of death and disability worldwide, with lifetime prevalence rates in the United States of up around 17%. It's frankly, vastly under-treated. You know, a number of people who have major depression receive no treatment, as you point out. And because many of the clinicians haven't been well trained in using antidepressants who are prescribing them, people are winding up undertreated. And, you know, it's like everything else in terms of pharmacology, if you give somebody a sub-therapeutic dose of medication, you should not be expecting them to get better as a result. Yep. Okay. There is a very slight risk of hepatotoxicity. I've never seen this. Do you have any thoughts on this, any knowledge?

It is a very rare effect. And there's also a, you know, if you want to talk about the rare adverse effects, there's effect of hepatotoxicity, eocinophilic pneumonia, which I've never seen either. and upper GI bleeding. All of these are possibilities with the SNRIs and with duloxatine. They are, however, exceedingly rare effects. I think people should be aware of them mostly that if you, you know, in your lifetime happen to come across the one patient who has that response, of course, when they start to turn yellow,

it would be good to think, oh, well, this could be their duly. Loxitine, maybe we should check their liver functions. Yeah, very, very rare. Very rare. What about your thoughts on like the withdrawal symptoms of getting off of these? Some people report shock-like sensations, electric zaps, very unpleasant. Yes. Well, essentially what you're looking at in terms of the zaps and those sensations are,

we talked a bit about how these drugs inhibit. essentially sensory overload in the dorsal horns and inhibit ascending pain pathways, when these drugs are discontinued abruptly, those pathways essentially are now open and they haven't remodulated yet. So you get spontaneous firing of those neurons, which is very unpleasant. For all of the SNRIs, you can also get a flu-like syndrome that will go on for one to two weeks with abrupt discontinuation. Unless it's an emergency, you have an urgent reason to discontinue the SNRI. These drugs, discontinuation is much better tolerated if they are tapered

over one to two weeks. Oh, yeah. And I mean, if someone's been on these medications for a couple years, I'm going as slow as I can, right? I want to make a small change, wait six weeks, make another small change. So we might taper them over a year even. The other element in this, of course, is, you know, it used to be dogma that if somebody recovered from their major depression, that after a year, you could taper them off of their antidepressant. Well, we quickly found out that wasn't true for everyone. And it's a indeed the current treatment recommendations are that if somebody's had two or more episodes of major depression, they really are likely looking at lifetime treatment with an antidepressant

because other, you know, and if people have recurring major depression, each episode of depression makes the next one more likely and also makes the next one more resistant to treatment. so that taking them off of the antidepressant is just a, it sets them up for relapse of their illness. Yeah. For me, if someone's really wanting to get off and they've had a couple episodes, I'll usually highly encourage psychotherapy, exercise, diet, stuff like that. If those things are all going on and they've been going on, you know, I may try to very, very, very, slowly get them off. But with the idea that like, you know, we're going to be monitoring this

every, every month, you know, we're going to make very small changes and sometimes use a compounding pharmacy or, you know, with Simbalta, they can count the beads and then slowly go down. Yes. The other element in that that I've had people do, because obviously the patient's going to be the first one to notice a change in their mood, energy level, appetite. I've asked people who are coming off of an antidepressant who are at risk for recurrence to keep a daily log just you know get a calendar they can write on and at the end of every day what has their mood been like that day what's their energy like that day what's their appetite been like that day because they can often that way spot trends early that's good there's a good study on mentalization

based therapy and some of these longer term partial programs that show that, you know, at five-year follow-up, the people who went through the intensive program, you know, these, these ones in this particular study are like a year and a half long. So it's like good luck getting your insurance to pay for a year and a half partial program. But these patients were in that. And then, you know, five years down the road, they were on considerably less medication. Yes. Like, Yeah, similar effects have been found for cognitive behavioral therapy and essentially, as you pointed out, also for substantial changes in lifestyle in terms of exercise and even things as simple as greater sunlight exposure also have been helpful in terms of decreasing long-term risk of depression. I'm getting some good sunlight exposure. every morning I've been going rowing on the lake here in Florida.

Oh, excellent. And I'm getting back into crew. I did crew in college at a high level, and I've been getting back into it. So that's been nice. Yes, yes. Some good self-care. I try to, you know, model it for my listeners, the importance of exercise, the importance of taking care of ourselves, right?

Because, you know, this is a marathon. Being a psychiatrist, being a psychiatrist, being a. mental health professional, it's a marathon. It's exhausting work at times. It's, it's a draining work. You know, we are around some of the most depressed, grumpy, upset people out there. And it, we absorb it. Indeed, as I've told residents, trust me, if you talk to 40 depressed people in a row, you won't feel very well at the end. Yeah. Yeah. Indeed, that's one reason. If you're treating people, try to see a variety of patients.

You know, if you see too many of one thing, it can begin to get to you just a bit. Yeah. And moving out here, I actually specifically thought to myself, okay, I'm going to take three months before I get a job or, you know, I'll see some private patients. I have some coaching clients, but I'm kind of letting myself reset a little bit, which is nice. And not, I'm seeing some depressed people. I have some clients that are still, I'm still seeing. but I'm trying to kind of reboot a little bit, which has been good.

Good. Excellent. For caregivers in general, because I know a number of your listeners, of course, are going to be in the mental health field, it's very important for people in the caring professions to remember to take care of themselves, because as a group, we are prone to not do that. Yeah.

Yep. But we're often not very good at that. We're often not very good at that. So I'm trying to get better at that as I go on in life here. Let's talk about activation of mania hypomania. If someone has a history of bipolar type 2, history of bipolar 1, that's clearly diagnosed. Like, no question that they actually have it. Is there ever a reason they should be on an intubal?

antidepressant, like an SNRI? No. And the short answer is no. Basically, there have now been a number of studies, starting with a seminal study in 2007, published in the New England Journal of Medicine that found that in bipolar patients, basically the antidepressants don't offer effective treatment for the depressed phase of the illness. What they do, however, is shortened cycling time and also, of course, risk direct switches into hypomania or mania. Unfortunately, we've had very few treatments that were highly effective for bipolar depression.

There are some, however, lithium has antidepressant properties. Lomotrogen, anti-epileptic, also is effective in bipolar depression. does not, however, offer much in terms of protection against mood elevation, something to be wary of if you're giving it as a monotherapy. Larazidone, the antipsychotic medication, turns out to be very highly effective for treatment of bipolar depression at doses far below those required to treat psychosis, 20 to 60 milligrams a day. And interestingly, the dopamine agonist,

Pramapexel also appears to be effective in treating bipolar depression. And then, of course, electroconvulsive therapy is also effective in treating both treatment-resistant mania and depression. Yeah. What about TMS? Where would you put that on the bipolar depression? The data, frankly, has been mixed for bipolar illness. It, clearly is effective, both as an adjunct, also as monotherapy in unipolar major depressive disorder. I have not seen literature suggesting that it has the negative consequences of the antidepressants, but frankly, whether it is effective or not, I think remains an open question. Some studies report yes, some know. Many of them have methodical.

to logic issues about whether they were truly sham treatments or whether the sample sizes were adequate to actually distinguish treatment response from non-response. Okay. Now onto the side effect of hyponotremia and S-I-A-D-H, along with SSRIs, SNRIs, are known to cause rare, but it's something we need to know about, hyponotremia. Yeah, any thoughts on this? Any? Yeah.

Hyponatremia, it's especially, it's at two elements play into the risk. Dose, higher doses, higher risk, and also age. The older patient is more likely to develop hyponatremia in response to an SSRI. It may indeed be prudent to, again, if you're going to treat with an SSR, SNRI in an older patient, get electrolytes at baseline, and then periodically measure electrolytes. The good news is, as long as hyponatremia does not evolve rapidly, most people will actually tolerate gradually evolving hyponatremia unless their sodium declines to less than 120-molts per liter. What kind of, so they'll have lightheadedness, dizziness, what are some of the main side effects that you should be looking for?

Yeah, they'll have lightheadedness, dizziness. They will also exhibit some degree of confusion if it's a rapid decline. And in its most virulent form, rapidly evolving hyponotremia can, of course, result in an overt, delirium, seizure, and coma. Luckily, those cases are exceedingly rare. In most cases, the SNRIs cause the sodium level to gradually drift downward, which neurons and other cells will adapt to if it's a slow enough change. But it is worthwhile, especially during the first several months of treatment,

to periodically check the person's electrolytes. Okay. Okay. Pregnancy in breastfeeding, deloxetine is FDA pregnancy category C, which means the risk of fetal development cannot be ruled out. In animal reproductive studies, deloxetine demonstrated adverse effects in the embryo fetal development. In breast milk, only 2.3% gets across to the breast milk, which is pretty low. Yeah, deloxetine appears to be safe in breastfeeding, except perhaps in the very first few days of neonatal life. The first few days may be a critical period because for many infants, their liver really hasn't come online, if you will, until a few days after they were born, which means they can't metabolize the drug.

It doesn't happen often, especially because the concentration in breast milk is very low. The issue with pregnancy, and this applies to actually all of the SNRIs is, you know, the FDA abandoned the lettering system, although I'm not quite sure why it was a nice shorthand. But now they're all described as risk and not ruled out in human pregnancy. they all can cause some growth retardation in neonates. That can be tracked, of course, in the third trimester in terms of whether growth is staying on the expected curve. And also very rarely, very, very rarely, they can cause neonatal pulmonary hypertension,

another one of those very rare side effects, however. So I was listening to a talk by an expert on this, and they were talking about in general SSRIs, it's hard to know when you compare SSRI and not SSRI, are you comparing the group that are not taking the SSRIs as depressed women, or are they women that are not depressed? And the person was trying to make the case that if you compare it to women that are depressed, there may not be that much of a difference between the two groups. I don't know what your thoughts are on this, or if you've heard this kind of argument? I've heard this argument in terms of the SNRIs and the SSRIs and post-natal risk,

I'm not convinced that the mother's diagnosis is a major influence on whether the neonate, has an adverse response, either a withdrawal syndrome, or, for example, in the case of peroxatine, postnatal seizure, or, frankly, we don't understand the risk factors for neonatal pulmonary hypertension well-off because it's such a rare and sporadic event. I'm not sure how you would compare those in terms of systematic studies. But I think that, you know, looked at in terms of risk to the neonate I suspect that probably the major risk for all of the SSRIs and SNRIs is decreased fetal growth in the third trimester and increased risk of premature birth. And is there a better option like SSRI-wise or SNRI?

Like, is there one that you would say that's the go-to? That's the one that's talked about. That's the safest. I think the one, it's more the opposite. of that is the one to avoid likely is paroxetine. It has been specifically identified with cardiac malformation and with a somewhat worse post-delivery withdrawal syndrome than the other either SSRIs or SNRIs. I think the chief element, though, is to be sure that the mother who is taking the antidepressant, and I think they should take the antidepressant because the risk of relapse

without the antidepressant in pregnancy is actually elevated. There was a myth that pregnancy was protective against depression. Well, that's not true. The risk of relapse without an antidepressant during pregnancy is about 70%. So they should take the antidepressant, but they need to be monitored by their OBGYN, and, you know, fetal growth and development should be tracked. In other words, these women should not neglect their prenatal care. Okay. The next side effect to mention is increased blood pressure. We touched on it a bit. There's this one recent study. It was a 52-week open-label clinical extension that followed 13 week randomized double

blind placebo controlled trial and they found that the safety of deloxetine 60 milligrams BID which is a higher dose was assessed compared against routine care in patients with diabetic peripheral neuropathy

and they've sustained elevation in blood pressure was defined as blood pressure greater than 130 over 85 or a increase in their systolic diastolic pressure of 10 millimeters HG over three consecutive visits. And they found that there was not a significant difference observed in blood pressure between

the deloxetine and the routine care groups. So that was one study that sort of said there is not an increased risk of blood pressure. Yeah. I think in general there is not where I've seen blood pressure elevation occur are one. and people who have baseline difficulty with essential hypertension. And two, specifically in their case, during titration, because during titration you are, of course, increasing norapinephrine and epinephrine levels. And I think this gets back to something we touched on earlier

that these drugs, including with respect to hypertension, are much more likely to be tolerated if the titration is not overly rapid. In other words, give the person's vascular tone time to adapt to the increased monoamine levels. Okay.

One very rare side effect, which I think it's worth mentioning, is acesia. There's been some case reports that I found of deloxetine and venlo-faxing. Just as a point of review, exthesis is defined as a feeling of restlessness

and an urgent need to move with subjective symptoms of restlessness, intertension, anxiety, panic, irritability, discomfort, sleeplessness, objective symptoms of leg movements, difficulty sitting, standing, and mobile, so they want to keep moving. They may be rubbing or rocking while sitting.

They may be grunting or moaning. there may be repetitive movements such as leg crossing back and forth, persistent shifting from one foot to another. And when it's severe, they can have disorganized thoughts, impaired judgment, impulsive behavior, suicidal ideation. It's usually from antipsychotics, but it can also be from antidepressants, anti-epileptics, anticholinergics, calcium channel blockers, even, lithium, Parkinson's drugs. So if you're a C&L psychiatrist, you may be called up if this person's on a Parkinson's drug, you know? And it's like, oh, this person has anxiety. No, they have aceshesia. And it can also be from amphetamines, methamphetamines, cocaine, so they could be coming into the ER with aceshesia.

It's worse in people with renal disease, diabetes, hyperthyroidism, iron anemia, Parkinson's disease, peripheral neuropathy. and the thought is that SNRIs can cause decreased mesolimbic dopaminergic activity, which potentially could cause it, and it could start in days to weeks of drug starting or increasing the doses. It can also be caused by these drug-drug interactions. Yes. In terms of the SNRIs, it's thought to be related specifically to the increase in serifes. The same reason the SSRIs can cause acetheia, the nigrostriatal pathway from the pars compacted to the basal ganglia has 5HT2A serotonin receptors on the bodies of those dopamine neurons.

When serotonins increased, dopamine release decreases from the viewpoint of the neurons in the basal ganglia blocking the post-a. synaptic D2 receptor and decreasing the presynaptic release of dopamine essentially has the same effect in terms of decreasing dopamine signal. So in that sense, the underlying mechanism for the antipsychotics and the SSRIs slash SNRIs is the same. Okay. Let's see. Other things to consider.

Oh, in one review, they looked at a community sample of schizophrenic patients. and they found that 15 to 35% had some level of aceshesia. So this is not just like a super rare issue. And every new schizophrenic patient I have, I'm considering if they're anxious, is it because of their meds? Is it because of some med combination? When did their anxiety start?

What does their anxiety look like? Is the anxiety anxiety, or is it? Accaesia. So they may come in presenting with a symptom and as, you know, mental health professionals, then we're trying to figure out, okay, what are we actually looking at? Are we, are our medications causing this, you know, and like Apoccrates, who reported 60% of his cases were bad, you know, as psychiatrists, we have to look at, you know, are we causing bad outcomes or our medications it's making things worse. Yes, and this is an area where indeed temporal association can be very helpful.

If you've just put the person on an antipsychotic, you've just increased the dose, or if you've just put them on an antidepressant, or just increase the dose, and they come back and say, well, I can't sit still. I feel this tension, this urge to move. or this is also associated with restless leg syndrome at night. They go, well, I lie down at night and my legs feel awful. I have to get back out of the bed and walk around, and then I try to lie down and go to sleep, and then I get up.

Those are all clues because of the association temporally with a change in the medication that indeed the medication may be causing a decrease in dopamine signal and associated acetheasia. Okay, so you're saying that if they may complain of something that sounds like restless legs, but it's actually acosthesia. As you know, one of the treatments for restless leg syndrome is a nocturnal dose of a dopamine agonist. It's a slightly different pathology, but it's related to ecthesia. And if you do anything that decreases dopamine availability in the basal ganglia, either by decreasing

release or by a direct blockade, you can set the person up for both Acetheus and or Russell Sweg syndrome, or if they have any other condition that decreases their dopamine availability. As you know, Acethesia was actually first described in 1901 in the Czech, well, now the Czech Republic, in Parkinson's patients. You know, well before the introduction of either antidepressants or antipsychotics. That's good. I want to do a full episode on it. So if you're a listener and you want that episode, shoot me an email.

Encourage me. And we'll come back and we'll go through hundreds of articles on it to give you all the good stuff. Yeah. If somebody wants to look up the person who originally described, it, his name was Haslovak. He was a neuropsychiatrist who was a check, and indeed he was treating Parkinson's patients, and he literally described it as Can't Sit Still syndrome. Yeah, I was reading that. I haven't told you this, but a number of people have sent me an email and say, is Dr. Cummings a walking encyclopedia? And I'm like, yeah, yeah, he is.

I'm always interested in history, so it's fun to find out where things came from. Yeah. Okay, so contraindications, at least what they, you know, Eli and Lili company was saying, you don't want to use these SNRIs with MAOIs because that may increase the risk of serotonin syndrome. Patients must discontinue MAOI usage for at least 14 days before starting deloxetine. and patients should discontinue deloxetine at least five days before starting an MAOI. And then there's also risk of linazolid and methylene blue. Yes.

Which can increase serotonin syndrome. There's also a risk of if they have uncontrolled acute angle glaucoma, then deloxetine should be avoided. Yeah, that applies to the other SNR. eyes as well. When you increase sympathetic tone, it causes pupil dilation, which if they have vulnerability to narrow angle glaucoma that can close off the canal of Schlem and they can no longer drain fluid from the eye. So also, if you have liver failure or severe renal dysfunction, you should avoid it. That's what I was reading. I don't know if you have any caveat, sir. Yes. The renal failure in particular is important because duoxetine is renally dependent for elimination.

So if somebody has moderate renal impairment, they need to be on lower doses. You know, if they have between 30 and 50 milliliters per minute, EGFR, doses basically should not be higher than 80. and if they're worse, they're between 20 and 30, they really shouldn't be higher than 40 milligrams a day. And if they're an in-stage renal disease, they need a medication other than duoxetine. And what about, like, with liver failure, is there an antidepressant that's your go-to antidepressant?

With liver failure, with category, well, child puberty, scale, whichever would encourage everyone to look out because it's a great way to figure out if your patient needs an adjustment in med dose. It's a scale that was originally designed for liver transplant patients to categorize their degree of liver failure. And basically, it will give you points for different lab tests as well as whether the person is jaundiced or not. Category A basically means their liver function is okay. You don't have to adjust anything.

Category B, moderate liver impairment, and you may need to reduce the dose of many drugs, including in this case, duloxatine. Again, you may want to reduce the maximum dose the person takes. Category C is really terminal liver failure, and for duloxatine, it's listed as contrainsol. indicated in that circumstance, as are most of the antidepressants. But, you know, frankly, that doesn't arise very often for us because most of the people who are child puke category C are terminally ill and close to dying of liver failure. Okay.

So I wanted to go through a little bit on the treatment of depression, anxiety, and different things like fibromyalgia talk about how these medications are used because we've talked mostly about treatment of major depression however these drugs the SNRIs are also indicated for a variety of anxiety disorders ranging from generalized anxiety disorder to panic disorder to social phobia as well as, I'll bet they're not FDA indicated for it, they're also effective in many cases of PTSD. So there's a broad application to anxiety disorders. And in terms of fibromyalgia,

they're also useful as in, we talked about decreasing the ascending pain pathways input, and that appears to be very helpful for fibromyalgia. Particularly, the more noradrenergic, the drug, the better it seems to be for pain control. So if you were rank ordering them, vinlifaxine would be at the bottom, does vinlifaxine and duloxatine next, and leave them on nasopran, likely the most effective for fibromyalgia. Yeah, it can also be used for vasomotor symptoms. In postmenopausal women, it seems to be helpful. Yes. Yes. It seems to be

helpful. We'll talk about that more next time. Urinary incontinence. It seems to be helpful for stress urinary incontinence and overactive bladder, although it's not FDA approved for that. Also effective in treating late-Ludial phase dysphoric disorder and has seen some use as well for migraine prophylaxis. But then I think almost every drug on the planet has been used for migraine. and prophylaxis. Yeah. Or at least tried for that purpose. Yeah.

So we'll get to the treatment in part two. I think there's some nuance to pull out and looking at some of the details of the studies. I know I would like to look at like, you know, what is the difference between placebo and the active medication and for the different disorders? And, you know, interestingly, I was looking at this one study that showed that for a placebo,

if the clinician rated the response rate, the placebo worked 45% of the time, and if the patient rated the response rate, you know, of the success of the treatment of depression, the placebo worked 26% of the time. That was a meta-analysis. So I want to go through some of that information, some of the different, you know, effect sizes

for the different treatments. So we'll do that in part two. Okay, great. Thank you. All right. Well, I hope you, really enjoyed this episode. And if you want to dive into some of the details, there's no better way than getting our free 130 citation summary of this episode at Psychiatrypodcast.com in the resource tab. It's just www.com.com. And a special thanks to Harrison Bay and Joseph Wong, who are amazing

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