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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

Activity

Progress
1
Course Completed

Partial Response and Nonresponse to Antidepressant Treatment

MDD is characterized by a definitive cycle of symptoms.1 Upon initial presentation, patients have many symptoms of depression and our goal as clinicians is to reduce the symptoms to achieve a response. From there, we want to move to remission, which is defined as a return to wellness or disappearance of symptoms.2 Patients who achieve sustained remission for 2 months or longer are classified as in recovery.

The danger for our patients lies in 2 main areas: relapse, which is defined by a return of symptoms rather quickly after depression has resolved; or recurrence, which is the return of symptoms after recovery.

The graphical representation of this cycle should be of great benefit to clinicians to understand the life course of MDD and to be able to explain it to our patients.

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When MDD Treatment Fails

Current MDD treatment is a combination of medications and nonmedication treatment. Regarding medication treatment, large percentages of our patients, 30% to 45%, do not achieve remission with any given antidepressant, even with appropriate dosing.3 When this occurs, we tend to switch medications. Unfortunately, approximately 50% of these patients do not respond upon switching antidepressants. Moreover, we know that antidepressants become less effective with every successive trial.4

Patients with a partial response and patients with treatment-resistant MDD are especially challenging, as they suffer from the consequences of their depression and of psychosocial disability that arises when they have not responded to treatment. In addition, these patients add greatly to the burden on clinic time and resources.5

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MDD Treatment Augmentation: Florida Best Practice Psychotherapeutic Medication Guidelines

To help clinicians address the challenges of partial response and treatment-resistant MDD, there are many available treatment guidelines. Among the more recent and widely accepted guidelines are the Florida Best Practice Psychotherapeutic Medication Guidelines for Adult Patients.6 These guidelines, authored by many esteemed experts, recommend that we consider 4 levels of care.

Level 1 is monotherapy with any of the medications listed here, and I would urge my colleagues to pick the best fit of efficacy and tolerability to match the patient’s needs. There is no evidence that one class is better than the other; therefore, individualization is necessary.

Level 2 is to add adjunctive treatment to existing therapy or “augment” therapy. This would apply to those patients who do not achieve remission with antidepressant monotherapy; as mentioned previously, this is a fairly large group of patients. Per these guidelines, the options for adding include:

  • Evidence‑based psychotherapy
  • Intranasal esketamine or intravenous racemic ketamine
  • Another antidepressant, with the caveat that we should not combine a selective serotonin reuptake inhibitor (SSRI) with a serotonin-norepinephrine reuptake inhibitor (SNRI)
  • Second-generation antipsychotic that is approved as adjunctive treatment for MDD

In this activity, we will focus on treatment augmentation with second-generation antipsychotics.

Level 3 is to consider an SSRI or SNRI combined with lithium, T3, L‑methylfolate, S-adenosylmethionine, or quetiapine.

Level 4, when needed, is to consider monoamine oxidase inhibitor augmentation (with caution to avoid contraindicated combinations) or L‑methylfolate triple-drug combinations. Of importance, as noted here, there is little evidence to support or refute this latter approach.

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MDD Treatment Augmentation: Second-Generation Antipsychotics

Despite a rather large group of agents in the class of second-generation antipsychotics, currently only 4 are approved for treatment augmentation of MDD: aripiprazole,7 olanzapine/fluoxetine combination,8 quetiapine XR,9 and brexpiprazole.10

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MDD Treatment Augmentation With Second-Generation Antipsychotics: Considerations

When selecting one of these agents approved for treatment augmentation (ie, as adjunctive treatment), we should consider the balance between efficacy and tolerability.

Regarding efficacy, all 4 approved agents have demonstrated good efficacy (we will review the data in detail in the following section). It is worth noting that having an FDA-approved indication is quite helpful, as it facilitates better access to these medications. It also gives us a solid database on the strengths and weaknesses of the data and ensures they are included in guideline recommendations.

Tolerability varies by agent. Therefore, it behooves clinicians to be aware of the strengths and weaknesses of each of these approved options.

Among the adverse events (AEs)that can arise are neuroendocrine challenges with prolactin; metabolic challenges with weight, lipids, and glucose dysregulation; and extrapyramidal symptoms such as tardive dyskinesia, neuroleptic malignant syndrome, akathisia, parkinsonian symptoms, and dystonic reactions.11

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Your patient with MDD has had partial response after 2 successive trials of antidepressant monotherapy.

If recommending treatment augmentation while following the FDA label, which of the following would you AVOID?
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