Treatment-Resistant Depression: Augmentation with Second-Generation Antipsychotics (Aripiprazole vs Quetiapine)

Prof. Philip Cowen

Professor of Psychopharmacology
Department of Psychiatry
University of Oxford, UK

Last updated: February 2, 2018

This presentation compares advantages and disadvantages of using quetiapine vs. aripiprazole as augmentation for treatment-resistant depression. It also addresses the common question of when to augment (antidepressant + SGA) vs. when to switch (prescribing a different antidepressant).

Combination and Augmentation: Clarifying Concepts

So if a patient has not responded to a switch in antidepressant treatment, the next approach that’s often used is to employ drugs in combination. And this consists of adding two drugs together to obtain a better effect than if either were given alone.

This normally means going on with the current treatment which would generally be an antidepressant which hasn’t been particularly effective and to then add a second agent. Conventionally, the phrase combination treatment refers to adding a second drug that’s also an antidepressant in its own right, so a drug such as mirtazapine.

Augmentation consists of adding a drug that’s not normally thought to be an antidepressant by itself but can produce an antidepressant effect when added to an ineffective antidepressant treatment. An example of this will be lithium. In fact, people tend to swap between the two kinds of expressions.

Combination or augmentation are used fairly interchangeably. Generally, augmentation treatment seems a bit more effective than switching particularly if patients have made a partial response to the first treatment.

And this is probably because if you add something in, then you don’t lose the effects of the first treatment when you withdraw it as you might in a switch.

The problem with adding two drugs together is of course the side effect burden tends to be greater and the risk of interaction is there.

So just to summarize the key points there, adding a second drug in either combination or augmentation is slightly more effective and faster acting than a switch in treatment.

On the other hand, there’s a greater risk of side effects and drug interaction.

Augmentation with Second-Generation Antipsychotics

So moving on to second generation antipsychotic drugs. So the augmentation strategy with the best evidence base is the addition of atypical antipsychotic drugs.

So it’s been found in a series of placebo-controlled randomized trials in over 3000 patients that adding drugs such as olanzapine, quetiapine, aripiprazole, brexpiprazole can be useful in securing an antidepressant response in patients who failed to respond to an SSRI.

The same kind of effect seems to occur in patients taking SNRIs though this is not being studied so systematically.

The doses of atypicals used for this purpose are distinctly lower than that used to treat psychosis.

So one is thinking of a dose of about 2.5 to 10 mg of aripiprazole, 50 to 300 mg of quetiapine.

Pharmacologically, 5-HT2 receptor blockade has been implicated.

The drugs that are most commonly used for this purpose are quetiapine and aripiprazole. They’ve got the best number needed to treat for the meta-analysis and they got rather different side effect profiles.

So for a patient who is sleeping poorly with anxiety, adding quetiapine at night might be helpful.

Patients who seem to have more problems with motivation and anhedonia can be helped by the addition of aripiprazole.

So though this seems quite an effective strategy, there’s a high side effect burden. And in the controlled trials, the number needed to harm in terms of people dropping out of treatment was only about twice that of the number needed to treat.

So though this is a usual strategy, it’s not particularly well tolerated. And one has to look out for side effects such as sedation, weight gain with quetiapine, and movement disorders and anxiety with aripiprazole.

One thing that I’m sometimes asked is how long should patients stay on this augmentation, combination of treatments if they do respond to the addition of an atypical? The answer is that it’s not very clear at the moment. These studies and literature suggest that often the combined treatment needs to be carried on for several months.

And that’s my experience that if you try and stop the atypical which is what you want to do, relatively quickly, patients will often relapse. So if you are going to withdraw the atypical eventually which is a very reasonable thing to do, go slowly and go carefully watching out for signs of relapse as you go.

I think where a patient has shown a partial response to an antidepressant, it can be better to augment with an atypical antipsychotic at that stage rather than switch. That’s because you don’t want to lose the effect, the partial response which you’ve already obtained with the antidepressant because the patient will feel worse.

Another thing to add is particularly if you want to avoid weight gain, I would avoid mirtazapine with which that’s a major problem and go for something like aripiprazole or bupropion. Just another thing to mention is that bupropion is not licensed in the treatment of depression in the UK where it’s licensed only for the management of smoking cessation.



  1. Gaynes BN, Dusetzina SB, Ellis AR, et al (2012) Treating depression after initial treatment failure: directly comparing switch and augmenting strategies in STAR*D. Journal of Clinical Psychopharmacology, 32: 114–9.
  2. Spielmans GI, Berman MI, Linardatos E, Rosenlicht NZ, Perry A, Tsai AC (2013). Adjunctive atypical antipsychotic treatment for major depressive disorder: a meta-analysis of depression, quality of life, and safety outcomes. PLoS Med 10, e1001403.
  3. Citrome L. The ABC’s of dopamine receptor partial agonists–aripiprazole, brexpiprazole and cariprazine: the 15‐min challenge to sort these agents out. International journal of clinical practice. 2015 Nov 1;69(11):1211-20.
  4. Nelson JC, Papakostas GI (2009). Atypical antipsychotic augmentation in major depressive disorder: a meta-analysis of placebo-controlled randomized trials. American Journal of Psychiatry 166, 980–91.
  5. Pae CU, Wang SM, Han C, Lee SJ, Patkar AA, Masand PS (2015). Quetiapine augmentation for depression: dosing pattern in routine practice. International Clinical Psychopharmacology 30, 54-8.

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