What medication could you add to a dose-optimized SSRI to help with anxiety?

Your patient is a 44 yo man with a mild radiculopathy from an old basketball injury and severe generalized anxiety disorder. He previously responded to trials of sertraline 100mg daily and venlafaxine XR 150mg daily, but both caused significant sexual side effects.  He stopped each of the medications after a year when he was feeling better.  When he established care with you, his initial GAD-7 was 20 indicating severe symptoms.  He was already seeing a therapist weekly.  

You decide to prescribe escitalopram 10mg tabs: take ½ pill (5mg) for 6 days, then 1 pill (10mg) daily.  After 6 weeks on escitalopram 10mg, he has no change in his anxiety, so you increase the dose to 20mg daily.  After 8 weeks on escitalopram 20mg, his anxiety has significantly improved (GAD-7 12), but he continues to spend much of his day worrying.  His anxiety is still impacting his marriage and ability to fall asleep.  You increase the escitalopram to 30mg, which is above the FDA maximum recommended dose for GAD.  Unfortunately, his anxiety does not change, and he develops severe night sweats that interfere with his sleep.  You reduce the escitalopram dose back to 20mg daily, and the night sweats resolve.

What medication could you add to the dose-optimized escitalopram to help with anxiety?

In choosing a medication for anxiety to augment an SSRI (or SNRI), you’ve got options.

But first, what does it mean to dose-optimize an SSRI (or SNRI) for anxiety? The optimum dose for an individual patient is the one that gives them the maximum benefit possible without causing bothersome side effects. We are guided by the therapeutic doses derived from research on groups of people, but we dose-optimize an SSRI or SNRI based on the response and tolerability for an individual.  Sometimes increasing the dose of an SSRI or SNRI can prevent the need for a second medication.  

In trials for OCD, the safety of  SSRIs has been evaluated at doses that are twice the FDA max.  As long as patients continue to get significant benefit with each dose increase, it is reasonable to increase the dose of an SSRI up to ~1.5x the FDA max for anxiety treatment in patients with normal liver function (i.e. sertraline 300mg, escitalopram 30mg, fluoxetine 80mg, paroxetine 80mg, or citalopram 60mg). If you use high dose citalopram you’ll need to get serial EKGs, so I’d recommend using escitalopram instead. For our patient, before adding in another medication for anxiety, we increased the dose of escitalopram to 30mg daily.  There was no further improvement in anxiety at 30mg so we decreased escitalopram back to 20mg, confident that we had “dose-optimized” the escitalopram.

So what medication could you add to the dose-optimized escitalopram to help with anxiety?  Pregabalin, gabapentin, buspirone, mirtazapine, hydroxyzine, or benzodiazepines.

There is moderate evidence for the use of gabapentinoids (pregabalin and gabapentin) in anxiety, and they can be used as monotherapy or along with an SSRI or SNRI for anxiety augmentation.  They are not FDA approved for generalized anxiety, but they have been shown to be effective in multiple RCTs.  The safety concerns about these medications should not be discounted, but for someone with generalized anxiety and neuropathic pain, like this patient, the risk-benefit ratio may be particularly favorable.  The gabapentinoids can also be excellent choices for monotherapy anxiety management in people with bipolar disorder, or people who “might have bipolar disorder,” because they don’t carry the risk of increasing mood cycling or precipitating mania that the SSRIs or SNRIs do.

Pregabalin is approved for the treatment of generalized anxiety in the UK, and is now available in the US as a generic medication.  On the basis of 8 RCTs (n= 2145), the UK clinical guidelines recommend pregabalin monotherapy as the second-line treatment for GAD in someone who cannot tolerate SSRIs (and does not have a history of addiction).  There is also one study (n=356) that looked at pregabalin (vs placebo) as adjunctive therapy in patients with GAD who partially responded to an SSRI or SNRI. 48% of these patients responded to the addition of pregabalin (vs 35% of the placebo group) (Rickels, 2012).

Most studies show a dose response for pregabalin in anxiety treatment, with total daily doses of 150mg needed for efficacy (range 50-300mg, max total dose 600mg; divide the dose BID).  The therapeutic effect for anxiety starts within the first week at a given dose.  I generally start with pregabalin 50mg bedtime and increase every few days by 50mg as tolerated to 150mg total (divided BID).  Dizziness, sedation, weight gain, and edema are common side effects.   In our patient who is taking escitalopram 20mg daily for anxiety and has a radiculopathy, I would recommend adding in pregabalin as the next medication for anxiety. Pregabalin would also be a reasonable adjunctive agent for GAD in a patient without neuropathic pain, as long as they did not have a comorbid substance use disorder.  

Gabapentin is also used off-label for anxiety, although with a more limited evidence base for GAD than pregabalin.  Most people need gabapentin doses of at least 900-1200mg (divided BID-TID) for anxiety, but I have also seen people have robust responses on gabapentin 100mg TID.

Like the gabapentinoids, buspirone can be added to a dose-optimized SSRI or SNRI to help anxiety, or used as monotherapy for GAD in someone who will not risk sexual side effects from SSRIs.  However, clinicians should be aware that buspirone has a smaller effect on anxiety (as measured by effect size in clinical trials) than SSRIs, SNRIs, pregabalin, and benzos.  Buspirone is a serotonergic medication with a different mechanism of action than the SSRIs or SNRIs. Even though both medications affect serotonin, the combination of a high dose SSRI and buspirone has been widely used and is unlikely to cause serotonin syndrome.*  Like the SSRIs, you need to start buspirone at a low dose (I usually use 7.5mg BID) and titrate up (max dose of 30mg BID).  Expect a delay of 2-4 weeks before seeing the benefit of any medication dose.  Dizziness and nausea are the most common side effects, but a slow titration can help to minimize these.

So remember, when choosing a second medication for a patient with generalized anxiety disorder on a dose-optimized SSRI or SNRI, you’ve got options! We discussed pregabalin, gabapentin, and buspirone in this PsychSnap. Please dive into our previous PsychSnap for a discussion of the role of psychotherapy & mirtazapine in anxiety augmentation.   We’ll circle back to benzodiazepines and hydroxyzine in the future.

*In the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial, one of the groups (n=286) was treated with a high-dose SSRI (citalopram flexibly dosed up to 60mg, mean dose of 55mg; this was prior to the QTc warnings) augmented with buspirone, flexibly dosed up to 60mg  (mean dose 40.9 mg).  No cases of serotonin syndrome were reported (Trivedi, 2006). 


Additional Reading: 

Hong, James SW, et al. “Gabapentin and pregabalin in bipolar disorder, anxiety states, and insomnia: Systematic review, meta-analysis, and rationale.” Molecular psychiatry 27.3 (2022): 1339-1349.

References: 

National Collaborating Centre for Mental Health (UK. “Generalised anxiety disorder in adults: management in primary, secondary and community care.” British Psychological Society, 2011. https://www.nice.org.uk/guidance/cg113/chapter/Recommendations#stepped-care-for-people-with-gad

Rickels, Karl, et al. “Adjunctive therapy with pregabalin in generalized anxiety disorder patients with partial response to SSRI or SNRI treatment.” International clinical psychopharmacology 27.3 (2012): 142-150.Trivedi, Madhukar H., et al. “Medication augmentation after the failure of SSRIs for depression.” New England Journal of Medicine 354.12 (2006): 1243-1252.

Trivedi, Madhukar H., et al. “Medication augmentation after the failure of SSRIs for depression.” New England Journal of Medicine 354.12 (2006): 1243-1252.


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