Be Ready to Manage Treatment-Resistant Depression

One in 3 adults with depression don’t experience significant improvement...despite trying multiple antidepressants.

Help manage meds for treatment-resistant inadequate response to monotherapy with 2 or more optimized antidepressants.

Assess for and try to modify contributing factors, such as nonadherence, difficulty affording meds, or meds with depressive effects (beta-blockers, etc). And continue to encourage nondrug measures (cognitive behavioral therapy, physical activity, etc).

Did you know you can earn continuing education credits for reading this article? Learn How

Then weigh whether to switch antidepressants...or augment current therapy. There’s no clear evidence that either approach is best.

Switching antidepressants may be preferred for patients with little to no response...or side effects.

Plus adherence is often better with just one med...cost is generally lower...and adverse effects or drug interactions are usually less likely than with adding another med.

Trying another med in the same class is okay. But some evidence suggests switching to a new antidepressant type improves response rates.

Clarify that there are not good data about which med class is best to switch to...consider side effects, comorbidities, and cost. Expect many patients who didn’t respond to SSRIs to try an SNRI next.

With either method, if patients don’t improve within 6 to 12 weeks of reaching target doses, try a new med or different approach.

Use our resource, Choosing and Switching Antidepressants, for advice about tapering or cross-tapering in a variety of scenarios.

Augmentation is often preferred if patients partially responded to their antidepressant. Plus it may work faster than switching meds.

Consider adding an atypical antipsychotic. Several are FDA approved...but lean toward aripiprazole due to tolerability and cost.

Despite buzz about the recent approval of cariprazine (Vraylar), it has no clear benefit over other options and costs about $1,400/month.

Counsel about possible side effects...including akathisia, hyperglycemia, sedation, and weight gain...and watch for interactions.

Or consider a second antidepressant from a different class. This may treat other conditions...and side effects may be less than atypicals.

For example, suggest adding bupropion to an SSRI or SNRI for those with fatigue or low sexual desire...or mirtazapine for those with insomnia or poor appetite. But using an SSRI plus an SNRI may be risky.

If in doubt about whether an antidepressant combo is intended instead of a switch, confirm and document this in the patient profile.

Anticipate esketamine (Spravatoto be saved as a last-line option. Not all studies show a benefit...and it must be given at a clinic or hospital enrolled in its REMS program due to monitoring requirements and misuse and abuse risk.

Expect augmentation to continue at least until the patient has a stable response.

Review our resource, Combining and Augmenting Antidepressants, for guidance about other add-ons...buspirone, lithium, liothyronine, etc.

Key References

  • Jha MK, Mathew SJ. Pharmacotherapies for Treatment-Resistant Depression: How Antipsychotics Fit in the Rapidly Evolving Therapeutic Landscape. Am J Psychiatry. 2023 Mar 1;180(3):190-199.
  • Mojtabai R, Amin-Esmaeili M, Spivak S, Olfson M. Use of Non-Psychiatric Medications With Potential Depressive Symptom Side Effects and Level of Depressive Symptoms in Major Depressive Disorder. J Clin Psychiatry. 2023 May 24;84(4):22m14705.
  • American Psychological Association. APA Clinical Practice Guideline for the Treatment of Depression Across Three Age Cohorts. February 2019. (Accessed August 17, 2023).
  • Voineskos D, Daskalakis ZJ, Blumberger DM. Management of Treatment-Resistant Depression: Challenges and Strategies. Neuropsychiatr Dis Treat. 2020 Jan 21;16:221-234.
  • Medication pricing by Elsevier, accessed Aug 2023.
Pharmacist's Letter. September 2023, No. 390903

Get concise advice on drug therapy, plus unlimited access to CE

Pharmacist's Letter includes:

  • 12 issues every year, with brief articles about new meds and hot topics
  • 200+ CE courses, including the popular CE-in-the-Letter
  • Quick reference drug comparison charts
  • Access to the entire archive

Already a subscriber? Log in

Volume pricing available. Get a quote