Anxiety Management: What To Do When An SSRI Isn’t Enough?

Ok so what the heck is anxiety anyway? We have all had experiences with anxiety, right? But clearly we don’t all have anxiety disorders. Anxiety is a very complicated term. People use the same word Anxiety to describe many many different possible internal states and experiences.  If you ask someone what their anxiety feels like, they could answer you with a whole variety of experiences, from things like restlessness to butterflies in the stomach, to actual stomach pains, palpitations or even chest pain, breathing really fast, maybe feeling confused or overwhelmed, sweating, getting shakes, feeling like they’re floating or out of body, and more. So there’s a whole array of experiences that people will describe with the same term of anxiety.  

Complicating things further is the fact that there can be an wide array of etiologies or states that actually drive or cause those symptoms of anxiety. Right so these sensations or experiences of anxiety can present if someone is in a state of withdrawal, if they’ve experienced a trauma, if they have a phobia, if they’re feeling fearful, if they’re over-interpreting somatic sensations, when they’ve been socially isolated, or even if they have certain medical conditions, right like hyperthyroidism for example. So we have single term Anxiety that is used to describe a vast array of experiences that themselves have a vast array of potential etiologies. Understanding the underlying etiology as well as the physical experience of someone’s anxiety can be very helpful in guiding our decisions around treatment 

Now we’re not going to talk much about diagnosis here because we’ll cover all of that and more in our Anxiety Management module, but I think it’s helpful to review what an anxiety disorder is, especially because the word anxiety is so vague and can refer to so many different things.  

First of all, it’s important to remember that anxiety is a totally normal experience for the vast majority of people in conditions of stress. It’s not something we want to totally medicate away because, despite how we tend to pathologize it these days, it can be useful and is actually important to survival. It is an evolutionarily preserved trait after all. Much like everything else in psychiatry, we only call something an Anxiety Disorder when the symptoms become impairing to the day-to-day functioning of the individual.  

Now of course there are a large number of psychiatric (as well as medical) disorders that can result in symptoms or sensations of anxiety and we’ll have more specifics around diagnosis in another module, but just to review the common psychiatric disorders that can present with anxiety right, we have most clasically Generalized Anxiety Disorder, Social Anxiety Disorder, Panic Disorder, Specific Phobias (fears of snakes, flying etc). Those are the officical Anxiety Disorders listed in the most recent version of the DSM, but there are other disorders that frequently lead to those experiences and symptoms of anxiety, a brief list of which would include PTSD, OCD, MDD and Personality disorders.  

So that would be the broadest differential to consider when someone is coming in with symptoms or experiences of anxiety that are impairing their day to day functioning. 

The next question obviously is how do we manage these symptoms of anxiety when they have become impairing to one of our patients.  

Now because Anxiety as a phenomenon and sensation is something that is intrinsic to the human experience, it’s important that we and our patients don’t over pathologize it. It’s not a comfortable state to be in, but it plays a role and we’re all going to feel anxious at times. The goal of any treatment we provide is not to eliminate anxiety. The goal is to make it manageable and learn how to live with it.  

That’s why I think non-pharmacologic approaches to managing anxiety are so important. People who struggle with anxiety disorders see all sensations of anxiety as the enemy and a lot of times are scared of them. They need to develop tools that they can use to cope with the anxiety that is intrinsic to the human experience. Obviously psychotherapy is a huge learning ground for developing coping skills, but there are a whole host of things that people can do on their own as well, from mindfulness meditation to journaling, exercise, yoga, sleep hygiene and more. For every pharmacologic intervention we do, the patient should be working on a non-pharmacologic intervention as well.  

Now when it comes to the meds themselves, I describe our psychotropics as blunt instruments when it comes to managing the symptoms of anxiety. They will all target the surface level symptoms and experiences of anxiety but are often not specific to the underlying causes of anxiety symptoms. So even though the underlying processes at work in say generalized anxiety disorder and PTSD are very different and distinct, we will typically use similar medications to manage them. To some degree that is nice because it means when you’re thinking about these meds and using them, the clinical management will be overall similar regardless of the underlying diagnosis. On the flip side, I think this also explains why anxiety disorders can be so difficult to manage—we’re using blunt instruments and often aren’t targeting the specific underlying processes at work that are driving the anxiety symptoms in that particular individual.  

All that being said, right the backbone of treatment for any anxiety disorder, especially in the primary care setting, is usually going to be an antidepressant, generally either an SSRI, SNRI or Mirtazapine. They are all effective. We’ll go into more details on the Pharmacology of these medications and more in the Anxiety Pharmacology module, and we’re also going to have a separate module specifically on Benzodiazepines, which is a whole other can of worms that we’ll get into in that module. But the question often arises–what are our other options? The antidepressants take time to work and it can be difficult to find the right one or right dose for every individual. So what we’re going to focus on in the rest of this module is other adjunctive medications that can aid in the treatment of anxiety. These are medications that we’re typically going to be adding on to antidepressants to augment the effect, and in rare cases can be used in the absence of an antidepressant as stand-alone treatments for anxiety.  

The 6 medications we’re going to talk about here and which have evidence for use in this role are: Hydroxyzine, Buspirone, Gabapentin and Pregabalin, Propanolol and Clonidine. Now I will say that overall with all of these medications, their use for this indication is poorly studied. Truthfully with these guys we’re going more off of accumulated clinical history and experience and use in practice as opposed to extensive and rigorous studies. 

That being said, these medications are certainly not unstudied in the treatment of anxiety, and I want to go through them in the loose order of those that on my read have the most evidence to those with the least. That order is as follows: Pregabalin, Hydroxyzine, Buspirone, Gabapentin, Propanolol and then Clonidine. That’s not to say that Pregabalin is necessarily the best, it’s just that it happens to have been studied more rigorously than say clonidine. Ok so let’s dive in: 

Of all these medications, pregabalin or Lyrica may have the strongest studies supporting its effectiveness as an adjunct treatment for anxiety disorders– most specifically in GAD. Now as most people will be familiar with, mechanistically and in terms of prescribing indications pregabalin is very similar to another medication on our list—gabapentin. It also shares a common misconception with gabapentin—that because of the gaba in each of their names they somehow work through the GABA system in the brain. GABA is of course the neurotransmitter system that alcohol, benzos and other sedative work on. It is not, however the system that Prebabapin or Gabapentin work on—these medications work instead through antagonism of the voltage-gated calcium channel receptor in the brain and exert their anxiolytic and antiepileptic effects through this system 

In terms of dosing, I would typically start it at around 75mg BID, though it can be given at 50mg TID as well—essentially you’re starting at 150mg total daily in split dosing. It may be most effective at a TID dosing schedule, but due to adherence concerns with TID dosing I’ll usually start it BID. From there depending on response it can be titrate up to 225 or 250mg total, and then ultimately up to 300mg total in the same BID dosing. You can continue to go up from there—the maximum daily dose is 600mg—but after 300mg total you start to run out of evidence and it’s not clear if there will be increased therapeutic effects or just increased side effects.  

In terms of the side effects here, obviously with a lot of these anti-anxiety medications they’re working by slowing down firing in the brain which can result in sedation or fatigue. There can also be dizziness with pregabalin, dry mount and the potential for weight gain—this is dose dependent though and typically more of an issue once you get above the 300mg range.  

In terms of reproductive concerns, the common refrain for most of these meds today is that there aren’t enough studies. For pregablin specifically, the most recent studies do not show risk of teratogenicity, but many other things have not been well studied. Some amount will pass through breast milk in lactation, so we’d recommend just keeping any eye out for any sedation in the baby, but we don’t have any data showing signs of toxicity to the baby through this mechanism.  

Like gabapentin, pregabalin is excreted unchanged and unmetabolized in the urine, so no dose adjustment is needed in hepatic impairment. In renal impairment you’re going to want to adjust dosing based off of the creatinine clearance, with the main concern being if they’re not clearing it as well they’ll be at higher risks of side effects and sedation. 

Now some other things to just take note of here—there’s decent evidence for a relatively fast time to onset of effect of anxiolysis when taken regularly. In some studies they have started to see positive effects as early as just a few days of treatment. Now this time frame is likely clinically true for most of the meds today aside from buspirone, it’s again just that pregabalin has the actual studies and evidence to back that up. It’s similar in many ways to gabapentin, however one way in which it differs is that its absorption into the blood stream is independent of dose. Gabapentin does this funny thing where at higher doses, the bioavailability actually decreases and you absorb less of the molecule percentage-wise as you do at smaller doses. That’s not a problem with pregabalin.  

And then finally it is listed as a schedule V controlled substance, so will show up on many state prescription monitoring programs and may have some controlled substance-prescribing restriction depending on where you’re working. This would hint at some potential for abuse liability and dependence/withdrawal. And Pregablin does likely have some street value (it’s known as “buds” or “budweisers” presumable for inducing a state similar to tipsiness), but when studies have looked specifically at risk of abuse, dependence/withdrawal, most evidence seems to suggest it is low risk on that front. 

Hydroxyzine or Atarax is another very standard and time-tested choice to use in the augmentation of anxiety treatment. It is a centrally acting antihistamine much like benadryl, but has good evidence in the treatment of anxiety. Like many of the others it has been primarily studied in GAD, but in that population has several RCTs and a Cochrane Review showing it to be better than placebo and  comparable efficacy to benzodiazepines and buspirone.  

It comes in 10, 25 and 50mg tablets and is typically dosed TID. It is often used as a prn but may be more effective overall if taken regularly—I will generally use it in both forms depending on what the patient wants. While it can be started at the 10mg dose, I’ve rarely seen that effective and so will typically start people at 25mg TID either standing or prn. If that’s not enough, going up to 50mg TID is very reasonable and is typically where I stop, though it can be titrated to a max of 100mg QID in certain situations if there is only a partial response to 50mg.  

It has standard antihistamine side effects, with the primary histamine-related side effects being, not surprisingly, sedation. The other side effects result more from its anticholinergic activity and include dry mouth, headaches, constipation, possibly urinary retention and a small but present risk of QTc prolongation. 

The jury’s still out regarding reproductive safety. It seems like it’s most likely safe in pregnancy, though there’s some thought that it’s safer to avoid early on in pregnancy. There may be some transfer in breastfeeding, which is likely safe but at higher doses you’d want to recommend just keeping an eye out for any drowsiness in the infant.  

For hepatic and renal impairment, there aren’t specific guidelines, however given its metabolism we want to be more careful and judicious in dosing in severe impairment. 

The idea with hydroxyzine is really that we’re looking for that sweet spot where it exerts its anxiolytic effects and is not sedating. It’s generally quite well tolerated and I’ve seen it be effective for a lot of patients, we’d obviously just want to be careful around the sedation and anticholinergic side effects in geriatric populations or other patients who have more vulnerabilty to those kinds of effects. 

Buspirone is a classic here–It’s been around for a long time. It works through the serotonin system, functioning as a partial agonist at the Serotonin 1A receptors, which is different from our ssris, right, but obviously there are going to be some similarities here as well given we’re going through serotonin. 

Usually we’re going to start buspirone at 5mg TID or 7.5mg BID, again BID dosing may increase adherence. So you start at 15mg total daily and it can be increased over time to a max of 60mg total daily in divided doses. Typically I’ve seen it become effective in the 20-30mg total daily dose range, so 10-15mg BID.  

The side effects here–It’s a little less sedating than the the other two, but can cause some dizziness, some people describe very vivid dreams (and this can interpreted as a good or bad thing depending on the person). There can sometimes be some initial GI distress because of the serotonin receptors in the guy, but that will typically go away after a few days just like SSRIs. And finally, it does not have sexual side effects—which is one of the most annoying side effects of SSRIs. There’s even some evidence that if you add it on to an SSRI in someone who’s having sexual side effects, it can reduce them, which is great. 

Same refrain regarding reproduction here—it’s poorly studied but overall seem like its use in pregnancy or lactation when clinically indicated is low risk.  

In hepatic and renal impairement, we’re probably going to titrate a bit more slowly and carefully. It’s not that we’re worried about making things worse, it’s just that there would be greater likelihood or clinical and side effects at lower doses due to reduced clearance. In severe hepatic impairement, the general recommendations are to avoid its use.  

The other thing to keep in mind is that unlike the other two we spoke about thus far, buspirone takes some time to exert its therapeutic effects—again a little bit more like SSRIs. We’re talking in the 2-4 week time frame here for people taking it regularly. Some people will use it PRN, however most likely what they’re getting there is just a solid placebo effect. And finally, food does increase its bioavailability—which really just means that they should be consistent about taking it either with or without food so we can be sure they’re getting a consistent dose and we know how to titrate. 

Gabapentin as mentioned earlier is similar in a lot of ways to Pregabalin. The reason it’s a little further down on this list is just that it hasn’t been looked at for this indication in as many studies as pregabalin.  

It has a wide wide range of effective doses from 100mg TID up to really a max of 1200mg TID. I think for a lot of individuals it ends up being underdosed. I’ve seen a lot of people start gabapentin at 100mg TID and titrate slowly from there, but I’ll typically start it at 300mg TID and then scale back in the rare case that someone feels oversedated at that dose. The reason for this is I do want them to feel something—if I start it too low and they don’t feel anything at all, their level of engagement with it or faith that it’ll help them will be reduced even if we go up on the dose later on. 

Given it’s been around for a longer time we have a bit more data in pregnancy than some of the others. Generally speaking it’s probably ok, though it may carry a very small risk of cardiac malformation in early pregnancy and potential for contributing to preterm labor in later pregnancy, so if you’re playing things super conservatively it may be avoided for those reasons. In terms of lactation, a small amount may be transmitted through breast milk but it doesn’t seem to cause problems.  

Like pregablin, it’s cleared unchanged through the kidneys, so you don’t have to worry about it’s use in hepatic impairment but will have to adjust dose in renal impairment.  

Finally, I mentioned this briefly when we talked about pregabalin but it’s worth repeating—the absorption of gabapentin is actually reduced at higher doses for some reason: the bioavailability goes down as you go up on the total daily dose. It doesn’t ultimately change how we’d approach titration, but it just means things can be a bit more variable from one individual to the next when we’re getting up to those higher doses.  

The nice thing about gabapentin is that is does have a ton of other off-label indications, from neuropathy to restless leg, fibromyalgia, insomnia, hot flashes, essential tremor, alcohol withdrawal and cravings, and more. So it makes it a good medication for addressing potentially several issues at once, along with anxiety—and I think this accounts for why it’s so commonly used.  

Propanolol is an interesting one here, obviously more known in the medical setting as a non-selective B adrenergic antagonist.  

In its use for anxiety, we can use it as a standing or prn medication. It has really strong evidence as a prn for public speaking/performance related anxiety, as well as decent evidence for its use in social anxiety disorder, but honestly hasn’t been very well studied in other specific anxiety disorders—though clinically can still be used pretty broadly. Interestingly, there is some evidence coming out that it may be useful after traumatic events for acute stress symptoms in preventing the transition to PTSD, and I’ve also found it helping in patients with actual PTSD as well. Usually here we’re starting it at 10mg either on a scheduled TID or prn basis, and it can be titrated up tot 40mg TID or 60mg as a one-time dose when used as a prn and less frequently. 

Side effects generally pertain to its B antagonism—so bradycardia, drowsiness, dizziness, erectile dysfunction, and potentially wheezing or bronchospasm—so we want to be careful in asthma or COPD. 

In pregnancy it dose cross over the placental, so can cause neonate bradycardia, hypotension and even possibly respiratory depression, so often we’ll stop it sometime before the end of the third trimester if someone has been on it and it may not be my go to during pregnancy. There’s minimal transmission in lactation, so it seems safe to use in breast feeding. 

In terms of end organ impairment, we don’t have great guidelines so broadly speaking we’d just want to be more careful with dosing in more severe hepatic or renal impairment 

The same medical considerations that you’d take if used for its cardiac effects should also be taken into consideration when used for anxiety—so we’d want to be careful in DM about masking symptoms of hypoglycemia, as well as in COPD and ashtma as mentioned above. 

Our final option here is Clonidine. And this is one that in general I think is used less frequently and probably with good reason. It really hasn’t been studied very well for this indication and there are definitely concerns around potentially dangerous rebound hypertension if it’s stopped abruptly after chronic use.  

It works through suppression of the overall sympathetic aka adrenergic tone in the brain and the body though agonism of a central alpha-2 receptor. So in someways like propanolol, it can help to block some of the autonomic sensations of anxiety—it reduces heart rate, BP, and generally slows things down through its opposition of the adrenaline system in the brain. There are a number of different formulations including long-acting forms and a patch, but I think for this purpose it’s easiest to just use the classic IR form. And here we’d be starting someone at 0.05mg BID and then increasing by 0.05mg BID weekly until an effective dose, which is typically in the total daily dose range on 0.2-0.6mg.  

Side effects here include abdominal pain, headaches, hypotension, fatigue, sexual dysfunction, dry mouth and constipation. 

Much like the rest of these meds, we don’t have great data related to pregnancy and lactation, however the little data we do have seems to suggest that there may be negative effects in both and so it’s better to avoid in those situations.  

For renal and hepatic impairment we don’t have great guidelines but the general approach would be to be more and more careful in step with the degree of impairment. 

Ok! So that wraps up our introductory course. As a recap, when anxiety shows up, our job isn’t to erase it—it’s to make it manageable. Start by separating sensations of anxiety from Anxiety Disorders, and whenever possible, try to identify the source—fear, withdrawal, trauma, medical causes, or learned reactivity—because the “why” guides the “what.” Pair every medication plan with at least one skill or habit whether that’s psychotherapy techniques, mindfulness, sleep, exercise, journaling. 

When it comes to augmentation, remember the six meds: hydroxyzine, buspirone, pregabalin, gabapentin, propranolol, and clonidine. Choose PRN vs. standing depending on what fits for the problem and the person. 

• For a simple, well-tolerated PRN, start with hydroxyzine; use propranolol when symptoms are somatic or fear-based (performance, phobic, trauma-linked). 

• For standing options, reach first for hydroxyzine or buspirone (set expectations: buspirone needs daily dosing and a few weeks). 

• Escalate to pregabalin if you need faster onset or stronger effect; 

• Favor gabapentin when comorbidities make it a two-birds-one-stone choice; 

• Reserve clonidine for last line given limited evidence and rebound hypertension risks. 

Monitor sedation, anticholinergic burden, respiratory disease, reproductive concerns and and adjust pregabalin/gabapentin for renal function. The take-home: define the anxiety, pair a skill, pick the simplest effective augmentor, and titrate—you’re aiming for better function, not zero anxiety. 

With that I’d like to say thank youfor joining me for this audio course on Anxiety Augmentation.  

All PDFs, show notes, and the full transcript are available at collaborative-psychiatry.org/courses/anxiety-augmentation. That page has any tools I mentioned today, as well as a variety of clinical references and patient handouts, including several quick reference resources regarding the medications, a prescribing flowchart, a taper and discontinuation guide, as well a patient handout describing anxiety augmentation and another for medication and coping skill use tracking.  

If you found this course helpful, please consider sharing it with a colleague, and check out our other courses and resources at collaborative-psychiatry.org. If you want more bite-sized clinical learning in addition to our courses, our QuickTake series will be available under the free Collaborative Psychiatry podcast feed as well as on our website with associated resources. Thank you for the work you do—and see you next time.