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Antipsychotics in MDD Augmentation

CME

Recent Evidence for Treatment Augmentation With Second-Generation Antipsychotics in Major Depressive Disorder

Physicians: Maximum of 0.75 AMA PRA Category 1 Credit™

Released: May 07, 2020

Expiration: May 06, 2021

Rakesh Jain
Rakesh Jain, MD, MPH
CME/CE Information

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Online Interactive Treatment Decision Support Tool for MDD Treatment

To help clinicians optimally manage MDD treatment decisions, CCO has developed an Interactive Treatment Decision Support Tool capturing the recommendations of 5 experts, including myself.

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Expert Recommendations for Case

Most experts agreed that augmentation with a second-generation antipsychotic would be their recommended approach in a patient with a suboptimal response to an antidepressant trial.

In this section, we look at some of the evidence supporting this.

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MDD Treatment Augmentation With Second-Generation Antipsychotics: 2009 Meta-analysis

The efficacy of second-generation antipsychotics in treatment augmentation for patients with MDD has been evaluated in several studies and meta-analyses.

In 2009, Nelson and colleagues12 published results from a meta-analysis of 16 randomized, placebo‑controlled trials representing 3480 patients with treatment-resistant MDD. This analysis included studies of quetiapine, risperidone (which is not FDA approved for adjunctive treatment), olanzapine, and aripiprazole.

Note that brexpiprazole was not included, as it had not yet been developed for this indication.

The key efficacy findings were (1) these agents were more effective than placebo, with statistically significant odds ratios across the board, and (2) there was no clear difference in odds ratios between the agents, suggesting that any of these medications is a good choice for effective adjunctive treatment.12 However, there were AEs, and patients who received adjunctive treatment had higher rates of discontinuation for AEs vs placebo.

Overall, these data clearly support treatment augmentation with these second-generation antipsychotics in this population with difficult-to-treat MDD.

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MDD Treatment Augmentation With Second-Generation Antipsychotics: 2015 Meta-analysis

Later, in 2015, Zhou and colleagues13 published this network meta‑analysis of 18 randomized, placebo-controlled trials of adjunctive therapy with second-generation antipsychotics in patients with treatment-resistant MDD (N = 4422). This analysis included both standard-dose and low-dose studies, as indicated in the dark diagonal squares in the table. Any square shown in dark blue (efficacy) or dark orange (discontinuation) indicates a statistically significant difference for the given comparison.

To summarize the data from this large, complex database, when administered at standard doses, the second-generation antipsychotics were more effective than placebo. That is good news for patients who suffer from this highly impairing condition.

Similar to the 2005 meta-analysis, the rates of discontinuation for AEs were higher with treatment vs placebo. Thus, when selecting among these agents, it is important for us as clinicians to consider our individual patients’ needs, including their individual risk tolerance for various AEs.

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MDD Treatment Augmentation With Second-Generation Antipsychotics: Efficacy by Degree of Resistance

The next meta-analysis, published in 2015 by Wang and colleagues,14 revealed good news for patients with a history of treatment failure.

Across 11 randomized, controlled trials of 3341 patients with treatment-resistant MDD who received adjunctive treatment with second-generation antipsychotics, treatment augmentation was more effective in patients with higher degrees of resistance, that is, those who had failed more therapies.

I want to highlight the importance of this finding, as we know from studies such as STAR*D that switching from antidepressant to antidepressant leads to lower efficacy.15 With every successive monotherapy trial, we see less response. But with second-generation antipsychotics, we see from these data that the effectiveness is higher for patients who had more previous treatment failure. This is of clinical importance: It tells me that I can consider a second-generation antipsychotic in all kinds of patients, including those who have failed multiple trials of monotherapy.

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MDD Treatment Augmentation: Key Studies of Second-Generation Antipsychotics

As we review the key studies of second-generation antipsychotics, let us look at the overall picture for the 4 FDA-approved treatment options.

In patients with an inadequate response to treatment or treatment resistance, we have strong evidence of the efficacy of each of these agents vs either placebo or an active comparator.16-19 When added as augmentation to standard antidepressants, all of these agents lead to significant improvements in the Montgomery-Asberg Depression Rating Scale (MADRS) after 6 weeks. All are superior to placebo, but none has been shown superior to each other.

Next, we review the data for each approved agent using representative studies.

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MDD Treatment Augmentation With Aripiprazole

Aripiprazole was evaluated as treatment augmentation in 362 patients with MDD and an incomplete response to antidepressants in this multicenter, randomized, double-blind, placebo-controlled phase III study from Berman and colleagues.16

In this graph, we see that patients who received aripiprazole augmentation, represented by the blue line, experienced a significant improvement in MADRS that began as early as 2 weeks after initiating treatment and was significant at Week 6, the standard endpoint for these studies.

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MDD Treatment Augmentation With Aripiprazole: Safety

This slide shows the AEs reported for each study arm, and patients who received aripiprazole generally had higher rates of AEs, especially akathisia, restlessness, upper respiratory tract infections, insomnia, and blurred vision.16

It is important for clinicians to note the potential AEs. We will discuss how to manage some of the more common AEs in a later section.

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Olanzapine/Fluoxetine in Treatment-Resistant MDD

Next is a pooled analysis of 5 studies evaluating the combination olanzapine/fluoxetine vs either olanzapine alone or fluoxetine alone in 1146 patients with treatment‑resistant MDD.17 We see in this graph that patients who received olanzapine/fluoxetine, represented by the green line, experienced an early, significant improvement in MADRS vs either olanzapine or fluoxetine.

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Olanzapine/Fluoxetine in Treatment Resistant MDD: Safety

The rates of AEs were generally higher with the combination therapy than with either monotherapy approach.17 The most frequent were increased weight, increased appetite, dry mouth, and somnolence.

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MDD Treatment Augmentation With Quetiapine XR

In this multicenter, double‑blind, placebo‑controlled phase III study, 446 patients with MDD and an incomplete response to antidepressant therapy were randomized to receive treatment augmentation with quetiapine XR or placebo.18 Quetiapine XR was administered at either 150 mg/day or 300 mg/day.

At the Week 6 endpoint, quetiapine XR 300 mg/day plus antidepressant was more effective than placebo regarding changes in MADRS. The results of this study, among others, were the basis for the FDA approval for this indication.9

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MDD Treatment Augmentation With Quetiapine XR: Safety

Regarding the AE profile, quetiapine XR was associated with higher rates of AEs at either dose vs placebo.18

Dry mouth, somnolence, sedation, dizziness, and constipation were among the most frequent AEs.

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MDD Treatment Augmentation With Brexpiprazole

Adjunctive brexpiprazole was evaluated in a randomized, placebo‑controlled phase III study in 353 patients with MDD who had an incomplete response to antidepressant therapy.19

Brexpiprazole, as treatment augmentation, was significantly better than placebo regarding improvement in MADRS by Week 6. Again, this was among the studies submitted to the FDA for approval of this indication.

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MDD Treatment Augmentation With Brexpiprazole: Safety

As we have seen with the previous studies, patients who received adjunctive treatment with brexpiprazole had higher rates of AEs vs placebo.19 Although the rates of serious AEs were low in both arms (1%), discontinuations due to AEs occurred in 6% of patients in the brexpiprazole arm vs none in the placebo arm.

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Your patient asks about the relative efficacies of second-generation antipsychotics that are approved by the FDA as adjunctive treatment in MDD. You can tell her that:
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