GAD Pharmacotherapy: Augmenting vs Switching in Partial Responders

David N. Osser, MD

Associate Professor of Psychiatry
Harvard Medical School

Last updated: October 11, 2018


  • Augmentation could be considered if a partial response is due to pharmacotherapy, and not due to a placebo effect.
  • The three recommended augmenters are: hydroxyzine, pregabalin, and benzodiazepines.
  • Second-generation antipsychotics are not recommended as augmenters in partial responders.
  • If you conclude that partial response was due to placebo, do not augment but instead switch agents.



We come now to node 3B. 3B is when you have tried your SSRI, our first-line treatment and you got a partial response.
They’re somewhat better. Should you try augmenting with something or switch? This is a problem one has in a lot of psychopharmacology whether it’s for depression or PTSD. So you could consider augmentations. The three that we’re going to discuss that you could use for that purpose are hydroxyzine, pregabalin or a benzodiazepine. But we do not recommend a second-generation antipsychotic until the third trial because of the side effects that they have.


Now, this augmentation could be considered if you think the partial improvement that they got is really due to the medication and not due to a placebo effect or due to nonspecific aspects of care such as their psychotherapy, such as the fact that you did a thorough evaluation and you have a nice alliance and they have confidence in you. So you want to augment when the effect you’re seeing is really from the drug, not from a placebo effect. Because if it was a placebo effect and now you’re adding a second drug with more side effects, this is the worst kind of polypharmacy. You’re augmenting an ineffective drug with side effects with another drug. But how are you going to determine if this partial improvement was due to the drug or placebo? So at the least, you should think about asking the patient first as a start. That’s what I think is the best way. They may know very well that something good happened to them since you last saw them and that’s what’s really reduced their anxiety or they don’t really feel anything is happening from the drug but they like you and it was very helpful when you explained their diagnosis but they don’t really think the drug is doing anything. And besides, they’re having sexual side effects already. So that’s a person who probably is a better candidate for a switch and going to the next node of the algorithm rather than an add-on augmentation. Also, there are other causes of incomplete response that you should check on. Nonadherence is a huge cause. That’s what we have from some recent studies in depression. And it’s probably true in anxiety as well. So suspect adherence issues. And finally, there are occasional pharmacokinetic or pharmacogenetic variables that result in low blood levels, very low levels due to ultrarapid metabolism, etc.


So if we decide that we do think the drug is really causing this partial response, then our most favorite augmentation agents are hydroxyzine, pregabalin and benzos. Now, with hydroxyzine, we have no augmentation trials actually. I have zero evidence to offer you of using it as an augmenter. I’m purely recommending it as such because it has three studies where it’s effective as monotherapy. So I’m thinking it could augment a drug that’s working by a totally different mechanism, namely the SSRI. So that’s one option.


The second option is pregabalin. That actually has one placebo-controlled augmentation trial with an SSRI. It was a small effect size. The dose ranged from 150 to 600. So there’s a small evidence base on pregabalin.


And then there’s benzodiazepine. They again have no GAD augmentation trials. Again, they are effective as monotherapy so that suggests they might work. The mechanism may be different. An interesting possibly relevant set of evidence is that there has been a trial of clonazepam added to sertraline for social anxiety disorder, a quite large well-controlled nicely designed study finding that clonazepam was effective and reasonably safe for people not responding well to sertraline for their social anxiety disorder. This study needs to be replicated in patients with GAD to be completely convinced of it. But I think it’s reasonable to consider it as an augmentation.


The next option could be buspirone but we don’t recommend that as an augmentation. Why not? There are no studies first of all. However, what we do have is buspirone’s role in STAR*D as an augmenter in depression with comorbid anxiety. I already showed you the results of that study where bupropion soundly beat at least numerically the buspirone. It didn’t look like it worked very well to augment the antidepressant for these people with comorbid anxiety and depression. So based on that, I would say we just don’t have any solid basis to think of this as a good choice for augmentation.


And finally, we have antipsychotic augmentation. We actually have some evidence on it though we don’t recommend it. The evidence is that there are actually three placebo-controlled augmentation randomized trials with quetiapine. They have gone to the trouble to do three studies of that. Add quetiapine to an SSRI for GAD that’s not responding well. Only one was actually positive and it was the smallest of the three. So that’s not too impressive. Risperidone has two positive augmentation studies, however. And olanzapine has one, small one. So there is some evidence base that atypical antipsychotics could work as augmentations. But given their high risk of metabolic side effects, negative effects on insulin resistance, you heard a lot about that from me in my talk on treatment of schizophrenia, weight gain, I do not recommend second generation antipsychotics at this point in the algorithm, after one trial of an SSRI and the response is only partial.


So to summarize the key points in this augmentation node, if the patient seemed to have a partial response and the side effects were acceptable, think about whether this improvement was more likely due to placebo effect rather than a real medication effect. Get the patient to weigh in on that question as well. If you conclude it was placebo, do not augment but instead switch. Go to node 4 which we’ll soon discuss. But if you do decide to augment, the three augmenters that seem most likely to help and be reasonably safe are hydroxyzine, pregabalin and benzodiazepines.



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Also, you can access to the original version in Spanish:  “Farmacoterapia del TAG: potenciación vs rotación en pacientes con respuesta parcial”

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