Medication Talk: Pharmacotherapy for Anxiety and Depression

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Special guest Marshall E. Cates, PharmD, BCPP, FASHP, FCCP, FALSHP, Professor of Pharmacy Practice from the McWhorter School of Pharmacy at Samford University joins us to talk about pharmacotherapy for anxiety and depression.

Listen in as we discuss pharmacotherapy for managing generalized anxiety disorder and major depression, with a focus on tailoring first- or second-line options to individual patient needs.

You’ll also hear practical advice from Craig D. Williams, PharmD, FNLA, BCPS, a member of TRC’s Editorial Advisory Board and Clinical Professor of Pharmacy Practice at the Oregon Health and Science University.

For the purposes of disclosure, Dr. Cates reports relevant financial relationships [psychiatry] with Biogen, Sage Therapeutics (honorarium); Otsuka (speakers bureau).

The other speakers have nothing to disclose.  All relevant financial relationships have been mitigated.

TRC Healthcare offers CE credit for this podcast. Log in to your Pharmacist’s Letter or Prescriber Insights account and look for the title of this podcast in the list of available CE courses.

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Welcome to Medication Talk, the official podcast of TRC Healthcare, home of Pharmacist’s Letter, Prescriber Insights, RxAdvanced, and the most trusted clinical resources.

On today’s episode, listen in as our expert panel discusses pharmacotherapy for managing generalized anxiety disorder and major depression, with a focus on tailoring first- or second-line options to individual patient needs.

Our guest today is Dr. Marshall Cates from the McWhorter School of Pharmacy at Samford University.

You’ll also hear practical advice from TRC Editorial Advisory Board member Dr. Craig Williams of the Oregon Health and Science University.

This podcast is an excerpt from one of TRC’s monthly live CE webinars. Each month, experts and frontline providers discuss and debate evidence-based practice recommendations.

The full webinar originally aired on May 16th, 2024.

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And now, the CE Information.

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This podcast offers Continuing Education credit for pharmacists, physicians, and nurses. Please log in to your Pharmacist’s Letter or Prescriber Insights account and look for the title of this podcast in the list of available CE courses.

For the purposes of disclosure… Dr. Cates reports relevant financial relationships by receiving an honorarium from Biogen and Sage Therapeutics and participating on a speakers bureau for Otsuka.

The other speakers you’ll hear have nothing to disclose.

All relevant financial relationships have been mitigated.

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Now, let’s join TRC Editor, Dr. Jeff Langford, and start our discussion!

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We’re talking about these topics now because mental health concerns remain front and center for many patients and clinicians In fact there was a recent patient based survey reporting that two thirds of adults have experienced concerns about their own mental health or the mental health of family and friends. And this represented an increase of about fifteen percentage points since 2020 During a time we were already recognizing increased mental health concerns due to COVID.

With that context let’s start by considering anxiety…disorders…And these are common often under recognized and under treated, and represent really a spectrum of conditions ranging from generalized anxiety disorder…to social anxiety, panic disorder and phobias. And while they are diagnostically different there are commonalities…across these different disorders including feelings of anxiety, fear, nervousness and worry. But where we’re gonna hone in and kind of drive our discussion today will be around realized anxiety disorder.

And Marshall I’m wondering if you can help us get started by kind of painting out the picture of generalized anxiety disorder, what that looks like and how it differs from common feelings of worry or anxiety that most of us deal with from time time…


Yes Thanks Jeff. Worry is just part of the human experience we all experience it. Generalized anxiety disorder though it goes beyond normal worry. For one thing, normal worry is really usually very specific and limited about the what the individuals worrying about whereas in generalizing anxiety disorder, there are numerous, issues that the person is worried about So it’s it’s excessive, anxiety and worry. It it’s also in general as anxiety disorder, very persistent. So according to DSM-5 criteria…those symptoms have to last at least six months. So very, very long as opposed to a short duration of normal worry. In generalized anxiety disorder, you, seeing individuals with a lot of significant subjective distress… and or, an impact on their functioning So the the worry and anxiety is is really having an impact whereas normal worry That’s not the the case.

One other…very important aspect is can you control it or not In normal worry an individual typically can whereas in generalizing anxiety disorder they they can’t So one of the things I like to ask patients…is if you’re getting ready to watch your favorite television program or do something for fun, can you turn off the worry And if if they can’t it’s it’s more likely to be GAD.

And so also in generalized anxiety disorder There are additional symptoms. and four of those are… Concentration insomnia, muscle tension restlessness there’s a few others like irritability and fatigue. but those are the the main, differentiating…factors between…Normal or in generalized anxiety disorder.


Okay So once we have a patient that has been diagnosed with generalized anxiety disorder, we can really kind of picture…two potential treatment pathways in terms of initial options and that might include psychotherapy like cognitive behavioral therapy. Or it might be a medication treatment path using agents such as SSRIs. And without necessarily getting into the details of those different options but just considering those two broad pathways Marshall what might…tip the scales to one path or another for you How how do you tailor that to your individual patient…


Well I think in in large measure it has to do with what the patient wants…. because as as you mentioned you can really go either either route. psychotherapy, you know not it’s just not available for everybody Kind of depends on where they where they live so it might be unavailable it might be unaffordable…Some of the medications that personalized medications are actually very inexpensive so, I think brachytherapy like cognitive behavioral therapy is very good. some patients prefer that route some patients prefer minutes And of course in in severe anxiety you might wanna use a combination of those.


Okay. We’re gonna…drill in or focus in on the medication pathway for purposes of the discussion today As our first line agents include SSRIs or SNRIs, some second line select choices that we could consider include buceperone, pregabalin hydroxyzine or the benzodiazepine plast, and…I’d like to talk a little bit about considerations with these different agents our article on this topic, started with a recommendation to consider SSRIs or SNRIs, first line based on overall evidence for generalized anxiety disorder. And I wonder to start with Marshall do you align with that recommendation And…if so maybe unpack a little bit of the, what we know about the effectiveness there…


Yes Absolutely i I definitely agree that those are the first line medications. several of those medications in in both classes are FDA approved We we know that these medications are very effective. One of the real…advantages of using SSRS and SNRIs…is that they also address the co morbidities that are are frequently seen with GAD so some of the other anxiety disorders you mentioned panic disorder social anxiety disorder, as well as major depression, which is comorbid So you can use these medications to really…hit all of those…

There are some disadvantages you know for all those medication classes that you’d mentioned earlier. This is the this is the class that calls uh, sexual dysfunction to the great a fairly great degree. There’s a slow onset of action. So just like in when you use these medications…to treat major depression there’s at least a few weeks, lag time. May take two to three months to really get the full effect of medications., part of the issue also is dosing So you you you typically start at a lower dose with these medications. so as to avoid what we call the jitteriness syndrome These patients are already…anxious and and so you typically start off at a lower dose but the the dosage range that you use is very similar to what you use in…major depression.


Well I think a question that often comes up especially for our primary care prescribers and our pharmacists on front lines We recognize or may recognize that these agents are first line but how do we pick within these classes There’s so many agents in both groups, do you have a go to Marshall within these classes…


Well, for one thing you’re right I mean there’s there’s a lot of different medications within an SSRIs and SNRIs that you can that you can go with So,, as a clinician, how do you select one for another for a particular patient? And and to me you you really look primarily at side effects and also potential for for drug interactions. so, even though for example you you have…five…SSRIs that are typically used, and they have this sort of common pharmacologic, action of serotonin reuptake inhibition They also have some some subtle pharmacologic differences that really…translate to different efficacy and different side effects for a particular patient so for example, you know Sertraline is a little bit more likely to cause, gastrointestinal side effects like nausea diarrhea…Peroxetine…is a is a drug that it’s got some anticholinergic…properties So it it it might cause more sedation, uh anticholinergic…side effects weight gain. fluoxetine and and even sertraline can be more…stimulating…And so there there’s these aspects. The the SNRIs, they…both double faxing and and duloxetine can cause increased blood pressure. but one of the differences between them is that Jooxetine could have some hepatic effects And so if you have someone with…the preexisting liver disorder or maybe a a heavy drinker uh alcohol drinker you might be better off going to the vaccine.

The other thing that I mentioned was drug interactions. So, peroxetine…and fluoxetine…were strong inhibitors and zotacrom p four fifty two d six. Dualoxetine…is a moderate inhibitor of that isoenzyme as well So you can look at various factors and and try to figure out you know maybe maybe there’s one that you wanna rule out or or one that’s better for a particular patient.


Agreed everything Marshall said These absolutely are first line drugs with SSRIS and SNRIS and I also don’t have a real reason to prefer a class or a particular agent but I also I think a lot of us who deal with this a lot can in the primary care, angle CV’s first line because they’re also much better tolerated and generally safer than other things we’ll talk about from a risk benefit standpoint…And I’ll just add to our time that we’re kind of fully prepared these days for patients maybe not to respond great to these medications depending how severe they’re anxiety is Sometimes patients respond well and and that’s freaked But sometimes they don’t and that that often kind of fits with literature where the the benefits really are fairly modest and you can find negative studies of both SSRIs and SNRIS, even among the data used to approve these drugs these indications by the FDA So, like mixed bag but but definitely from a risk benefit standpoint definitely our first line drugs.


Great perspective there Craig And I think that’s gonna be a nice segue as we talk about second line options, our article goes next to buspirone saying to consider it if an SSRI or SNRI isn’t tolerated or as an add on if they aren’t enough. And Marshall would like to start with you and just ask about perhaps some of the procon considerations that you would have around Busperone.


Yeah So b spiron really sort of has…I guess uh a reputation…perhaps being less efficacious there there are inconsistent…reports of efficacy…Probably some of that’s not that well deserved and I’ll I’ll talk about that in a second., one advantage of Viesborough is that it it doesn’t have any abuse potential It doesn’t have any you know physiological dependence or withdrawal like like pensil diazepines. but it also uh unlike SSRIs and SNRIS, it will not treat the common comorbidities of GAD. other anxiety disorders and, major depression in particular, it also has a slow onset of action just like in the depressants So it takes about a a few weeks to really start seeing uh effects…Generally well tolerated some some patients can’t handle particularly the dizziness and the and the nausea.

But the dosing aspect I think is part of what plays into this perception of lack of efficacy……clinicians tend to start at around ten to fifteen milligrams per day divided the idea of TID has got a short half life. But the effective dose might be anywhere from thirty to sixty milligrams per day So it’s it’s a clinician You really have to stay on the titration. Unless they just simply can’t tolerate, the draw So I think that’s part of what plays into the inefficacy because When I see it use it tends to be relatively low doses.


One more point on Busperone before we move to the next is…drug option but you mentioned dividing the dose… BID or TID Marshall but I wanted to emphasize that it should not be given PRN There’s there’s no release Brown to be used PRN And I think people still perhaps see that crop up every now and then and I think that would be an area where we’d need to make a recommendation for a therapy, a different dosing plan Do you agree with that?


Yeah Absolutely and you know you have to understand um Biesborough really kinda came on the heels of a lot of Benzo use Right And so people were trying to use based for them like they were using benzodiazepines. I think that’s part of why it does have a reputation for limited effectiveness you know people don’t…get the same feel if you will particularly physical symptoms when they take be sprung…compared to previous benzodiazepine therapy And the same thing with as needed I mean you can’t take this drug as needed.


Okay Let’s talk about pregabalin for a minute In our article we said to think of that as an alternative or an add on for generalized anxiety disorder, I think this drug also comes with a fair amount of baggage at least in terms of perception Marshall And and can you walk us through perhaps the considerations that you would really have in mind before you’re choosing to use pregabalin for anxiety.


Yeah pretty gabalin to me is a is a drug that, the evidence base doesn’t match the use., pregabalin…is not FDA approved in our country However it’s been used for a long time and it’s approved in Europe. so I think they they use it a lot more for generalizing anxiety disorder than than we do But but there is  a fairly robust evidence base…. double blind randomized controlled trials showing that pregabalin…works…does have an anxiolytic effect. So it it appears to be, as effective as you know our established drugs based on on the evidence that we have. one interesting thing is that it it has a relatively rapid onset so I think the literature points to about a week. which is not quite as quick as benzodiazepines…but certainly quicker than uh antidepressants and and v spherom.…there aren’t much data though on whether or not they it can address some of the comorbidities we’ve talked we’ve talked about Uh some of the other anxiety disorders. There’s also some concerns for abuse It is a schedule five…medication. so remember benzodiazepines are four but this is a This is a five And I and I think one of the interesting aspects of this particular drug is that it’s it’s renally excreted and so…if a person,, you know has some some renal problems that’s something to take into account and dosing. But the flip side of that is that it’s a really low risk of… drug interactions as well. adverse effect, you know it’s…It’s tolerated. Okay it it can cause some dizziness, sedation, weight gain is They’re also some peripheral edema., so something to think about. One other point I would make like, jaloxetine…and… venlafaxine. this drug can also be used for those with diabetic neuropathy so you can kill two two birds with one stone.


May I add or ask Jeff while we have Marshall in the industry and me that we’re talking about pre gabalin without, gabapentin because the gabapentinoid pretty similar if you control for dose but does Marshall know gabapentin not approved or used within Europe But I’m not used to really either of these for anxiety in our population


Well and that’s because a lot of people really don’t use pregabalin and and I think the opposite is true with gabapentin you have quite a bit of gabapentin use, but the evidence base really isn’t there So unless one is really willing to…you know because they do fall in the same class they do have similar pharmacologic mechanisms unless you’re willing to generalize…the literature that we have a pre gabalin to gabapentin. I have never really been that impressed with gabapentin’s…tolerability particularly as one goes up on the dose. but I think sticking with just evidence base I would go with pregabalin over…over gabapentin.


Yeah And just back to earlier point that we’re we’re definitely kinda moving into and these drugs definitely not the same safety profile we have with the SSRIs and SNRIs But you know obviously get Pentoids approved with anti seizure medications and they they are by denying CNS depressants in a way not surprising at the right dose they might have some anxiety benefits…


K Those are great points. I do wanna move to benzo dizapines next. Article advice saving benzodiazepines is an add on or for just a few weeks until an SSRI or SNRI starts working. Or for severe anxiety disorders. And to start with Marshall wondering if you agree with that place in therapy…


Yes. I do too And you know from a historical perspective, remember benzodiazepines used to be the gold standard treats Yes There’s a lot of anxiety before antidepressants took over But, you know you do have to worry about abuse issues we we’ve already talked about that and physical dependence and in withdrawal. And that’s the only reason these are second line I mean they they work well They they work really just as well as antidepressants.…but they will not work for comorbid depression, obviously.

I think you know where been benzodiazepines really come in where I see it come in more so, even more so than add on. Although you can certainly see that It it’s for bridge therapy which is what you refer to You know you you take advantage of the of the fast acting, action of benzodiazepine so you start and end the depressant in the benzodiazepine at the same time. And then after a couple of weeks taper off the benzodiazepine that way, you you get through sort of the lag time for all set for the end present but you’re not using, know benzodiazepines chronically which is where you can get into some of the some of the problems. So bridge therapy and and also in patients who have failed…multiple, uh other drugs you you can’t see monotherapy with benzodiazepines or add on to the um, antidepressants in particular…

But if we’re seeing it used…long term in patients, you would really see that being a patient that has not responded to multiple other regimens that we have done all the right things with in terms of dosing and optimization before we moved to long term use of a benzodiazepine?


Yeah I think you would you would According to the guidelines you know you would really want multiple trials of the of the first line drugs before you move to any of the second line drugs. I think that’s definitely true.


Okay I also I I think that’s absolutely right pharmacologically and we do sometimes find ourselves having discussions with patients where it is getting into more chronic, or it’s becoming more of the conversation that might end up The goal is overall to help the patient be more functional…in their life. and so yeah you you can get into some nice conversations about kind of overall…goals And and if they’re just using benzazepines and and not kind of becoming more functional what they wanna do that we’re not helping the patients to move their way forward And and that’s often what’s happening when you get to chronic use these medications.


Yeah And and if I could add one thing I totally agree with Craig on this And,, one mistake that clinicians sometimes make is they don’t have the conversation with patients upfront…about how long they can expect to be on benzodiazepines the last thing you wanna do is have a patient do very well, feel very well on benzodiazepines and then you know several weeks later you say oh by the way we’re gonna start taping this off. That conversation usually doesn’t go well So I always I always address…the expected duration right up front I would say that with all psychotrophic, but particularly benzodiazepine…


Well let’s turn now to depression and management of depression And Marshall, just like we started our anxiety discussion, would like you to walk us through how major depressive disorder differs, perhaps from common feelings like sadness or blueness that that many of us experience.


Yeah And it’s it’s very analogous to what we talked about before You know feeling sad or blue is just…part of the human experience. major depression is a whole other level. it affects not just mood but the way people… think their their physical health their ability to work or go to school their relationships, you know a lot of different things., the the diagnosis for major depression requires…persistent symptoms So, at at least two weeks, symptoms can last months and and and rare cases even years if you don’t treat it. there’s also…a number of symptoms There’s there’s non diagnostic symptoms. Someone has to have at least five of those, including one of those must be depressed mood or or anhedonia, which is a loss of interest or pleasure in activities. And I think one of the one of the major things is that you either have to have…clinically significant distress…or the individual has some, impairment in their ability to function whether that’s socially occupational or or some other way So so these symptoms translate…into, impairment or distress…


Okay. And for the patients that we have meeting that criteria,… we’re gonna see a similar treatment path at least initially…with psychotherapy being an option or select medications being an option. And with that thought I’d like us to spend our last block of time talking about first line medications for depression really in the SSRI SNRI bucket or bupropion or mirtazepine, And I want to really tackle those kind of one by one and ask each of you to share some thoughts on patients that you might prefer that drug or class for as well as, patients that you might use it with caution in or even steer away from from using it altogether. So let’s start with the SSRIs Marshall and I’ll ask you to kind of tackle that class and share some times you might use it times you might avoid it…


Yeah It well the the point that Craig made earlier I mean you know these these drugs clinicians are very well versed with these drugs They’re familiar with them They know how to dose them They’re familiar with the side effect profile. so these are you know crowd favorites uh they they do cover comorbid, anxiety disorders as well as a a host of other disorders.

But the the one thing that I definitely want to highlight is the potential for sexual dysfunction. it just it’s so frequent And, you know I used to joke that I I I ran a clinic of one time when I called at the end of depression and do sexual dysfunction clinic because There were so many patients on antidepressants and I’d say at least a third of the patient that incidents rates on this or…they’re all over the place in terms of…different studies But I I my take is probably about a third of patients have significant sexual dysfunction with SSRIs and it’s something you wanna tackle up front Is that possibility, I mean you can manage it on the back end but you you definitely need to mention this to to patients. But it’s a but it’s a great class of,, medications That’s why we use them so often…


Craig as we look at the SNRIs anything that kind of jumps out at you as being important factors in your mind when you’re considering when or where to use these.


Yeah I think…generally speaking very safe drugs that as Marshall alluded to we have a a big comfort level now with using this class as well Yes Surprise but you know the n is norepinephrine and it does bring along some different effects And so and the kinda agitation which often is is more subtle but…they definitely have a bit more stimulant effect and the hypertension kinda comes along with that as well So you know in terms of choosing, it’d be more Do I have one of those things to think about I want to avoid?


And to just reiterate what I made earlier the the other thing I’d say is duloxetine with liver…disease as well I I try to avoid, duloxetine. And then and then both with SSRs and this enterprise there are particular drugs, Proxiting fluoxetine galoxetine…that have…that can have some significant drawing interactions…


Very good Well let’s look at the other two classes and we’ll kind of take these in in together for sake of time but bupropion and ritazepine as far as two additional agents that are first line. And you mentioned…agents that we might consider with sexual dysfunction And I wonder if you can kind of unpack both of those for us Marshall. And how they might be preferred for patients if sexual dysfunction is a concern and in any specifics that are really top of mind with the either of those agents.


With bupropion…and or retention fees Yes Yeah. Okay Yeah It I think that bupropion uh probably even has less sexual dysfunction and them them retasipine. they’re different mechanisms. you have to remember from Perprion is the only antidepressant that we have that has nothing to do with serotonin. Right So you don’t really see sexual dysfunction. Retazepine blocks serotonin to see or to a receptors and that’s how it supposedly has…has decreased sexual dysfunction But both of these drugs are are good. for that aspect. they’re really kind of opposite…in that bupropion is a more stimulating drug though and so…it might cause…anxiety it might cause insomnia, it might, cause weight loss. mirtazapine is the opposite. Right It’s sedating. it can cause weight gain And so I think about mirtazapine and patients that having trouble sleeping and and maybe they’ve lost a lot of weight while they were depressed, but uh definitely avoid it If they’re already overweight or obese or they have diabetes or prediabetes or something like that And of course bupropion you have, seizure disorders uh is a contraindication but but even those things that can…play into seizure disorders like a significant… history of a head injury or somebody that has anorexia or bulimia, in accompanying uh electoral and abnormalities, that’s that’s not a good drug to choose…


Okay Well with those thoughts in mind around picking that first line agent I think that’s really important for us to set the stage with our patients that trial and error may be involved in this process less than a third of patients are going to achieve remission with the first antidepressant, and that can really lead us down a couple of different pathways…The first might be switching agents for patients that have either no response or perhaps intolerance…And in that case we might choose to use a different type of antidepressant or potentially switch to another medication within the same class. the other…Possibility would be patients that have a partial response and I’ll get your thoughts here Marshall, around augmentation,, if a patient has a partial but incomplete response and we need to consider…augmentation strategies…What are the things your primary go tos for augmentation if needed…


The FDA approved route is to use, second generation antipsychotic So there are several that are indicated, for this such as aripiprazole and brics Piprazole and cardiprazine and quetiapine. you you can combine with the second antidepressant i would say this is…uh they’re both frequently used of clinicians tend to prefer one over the other But if you’re going to add a a second antidepressant, uh as we were talking about earlier, it’s not absolutely wrong to use an SSR with an SNR but usually you add in a drug like mirtazepine…or Okay. To one of those because of the taking advantage of different…mechanisms. In terms of the classic um drugs that we can combine,, the the one on there that I prefer, is actually uh use for them Uh I like I like to augment with that.


Great Well that gives us several different strategies and some kind of pros and cons to keep in mind with those.

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