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MDD Treatment Augmentation

CME

Guidelines Overview: Augmentation Therapies in Major Depressive Disorder

Physicians: Maximum of 1.00 AMA PRA Category 1 Credit™

Released: February 26, 2020

Expiration: February 25, 2021

Roger S McIntyre
Roger S McIntyre, MD, FRCPC
CME/CE Information

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Your patient is a 34-year-old working mother with a 10-year history of MDD. She received 2 successive trials of first-line SSRIs with a partial response to both. She is currently receiving an SNRI, but after 4 weeks, some symptoms are affecting her performance at work and at home.

If you are following current guidelines, what would you recommend for this patient?
Guidelines: When MDD Treatment Fails

When patients do not achieve remission, it is important to re‑evaluate the diagnosis and evaluate patient adherence. It is also important to determine whether the current treatment is appropriate for the patient.

The patient and the healthcare provider should then work together to identify barriers to optimal improvement in depression symptoms. Guidelines generally recommend that if the index treatment is insufficient, one should either augment it or switch to an alternative treatment.8-10

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Switch or Augment? CANMAT 2016 MDD Guidelines

Switching or augmenting treatment each has its own advantages.

The advantages of switching include avoiding unwanted adverse events if the index agent is not well tolerated. Patients may also prefer to switch agents if symptom relief with the first agent was insufficient.

The advantage of augmentation is that it allows you to take advantage of some of the therapeutic gains made with the index therapy. Additionally, augmentation allows the physician to tailor therapy to target specific symptoms. Finally, augmentation offers the possibility of using synergistic combinations that may provide greater efficacy overall. This is recommended across many guidelines.

When considering switching or augmenting therapy, the data are unclear. Augmentation has been the most studied approach to date, and the FDA has approved multiple agents that can serve as augmentation strategies when the index antidepressant is inadequate.

Nonetheless, there is uncertainty around which patients will benefit from augmentation vs switching to a mechanistically dissimilar antidepressant.

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If you are following current guidelines, what would you recommend for this patient?
Augmentation: Florida Best Practice Psychotherapeutic Medication Guidelines

The Florida Best Practice Psychotherapeutic Medication Guidelines, which were updated in 2020 and are the most current guidelines, provide algorithms for clinicians who care for adults with MDD.10

If antidepressant monotherapy is deemed insufficient, augmentation strategies (shown in Level 2 on the slide) may be considered, including evidence‑based psychotherapy such as CBT, a second-generation FDA-approved atypical antipsychotic agent, or a second antidepressant.

Failing that, various other combinations are available. The recommendations for augmentation after 2 failed treatment steps (shown in Level 3 on the slide) include adding a mechanistically dissimilar approach to an SSRI or SNRI, such as lithium, L-methylfolate, or S-adenosylmethionine.

Finally, for patients who move into level 2 or level 3 treatment resistance—that is, they have had 2‑3 prior failures (shown in Level 4 in the slide)—novel treatment strategies are considered, including triple-drug combinations or augmentation with a monoamine oxidase inhibitor.

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Predictive Value of Early Antidepressant Response

One of the key observations in clinical research is the early response. Simply stated, after 2 weeks of treatment with an antidepressant, patients exhibiting a ≥ 20% reduction in total depression symptom severity have a modest chance of achieving full remission after an additional 6 weeks. Hence, there is a modest positive predictive value in an early response.

If the patient does not exhibit a significant benefit during the first 2 weeks on the index treatment (ie, < 20% improvement in the overall depression symptom severity score), there is a 90% chance that the patient will not achieve remission at that dose. Hence, the lack of an early response has a very high negative predictive value.

The predictive value of this early response is the empirical basis for recommendations across guidelines to optimize therapy as early as 2 weeks, or certainly within 2-4 weeks of starting therapy. Thus, if no significant improvement is detected within 2-4 weeks, the clinician should work on dose optimization followed by a repeat visit and reassessment.

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Adjunctive Therapies for MDD: Second-Generation Antipsychotic Agents

The second-generation atypical antipsychotics have been the most studied as augmentation strategies in MDD. Therapies currently approved by the FDA for adjunctive treatments of MDD are aripiprazole, brexpiprazole, and quetiapine XR.11-13 The combination olanzapine/fluoxetine pill is approved for “treatment‑resistant depression” in patients who did not respond to 2 previous trials of antidepressant monotherapy.14

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Adjunctive Therapies for MDD: Add-on Treatments

Other agents that are used off‑label to augment antidepressants include lithium, psychostimulants, triiodothyronine, risperidone, L‑methylfolate, and S‑adenosylmethionine.8,10 For treatment‑resistant depression, esketamine delivered intranasally has also been approved.15

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Second-Generation Antipsychotic Agents: Potential Adverse Events

Second-generation atypical antipsychotics can produce adverse events that are intolerable for some patients. These adverse events include weight gain, metabolic changes, and neurologic effects such as akathisia, parkinsonism, and tardive dyskinesia.8,10 Some of these agents are also associated with prolactin elevation or QTc prolongation.

Clinicians are encouraged to become familiar with the tolerability and safety profile of each atypical antipsychotic, because they differ across agents.

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Second-Generation Antipsychotic Agents: Managing Adverse Events

Management of the adverse events of second-generation atypical antipsychotics begins with the search for the underlying cause. Before prescribing an atypical antipsychotic, the physician must weigh the expected benefits vs risks carefully.

It is clear that lower doses will result in a lower risk for certain adverse events, such as neurologic effects. Patients can also engage in lifestyle changes to minimize their risk for certain adverse events. Healthier lifestyle choices—such as adequate sleep, routine exercise, and nutritional food choices—can be very effective in preventing weight gain, diabetes, and dyslipidemia.

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Recommendations for Long-term Therapy

Regarding long‑term treatment for more resistant cases of MDD, clinicians should integrate rational and complex pharmacology with psychosocial treatments, such as CBT, mindfulness therapy, and/or functional and cognitive remediation, to improve symptoms, daily functions, and quality of life over time. As stated earlier, patients with MDD sometimes require more integrated approaches to achieve the best outcomes.

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