What are the recommended adjunct therapies for patients with depression who do not respond to Selective Serotonin Reuptake Inhibitors (SSRIs)?

Medical Advisory BoardAll articles are reviewed for accuracy by our Medical Advisory Board
Educational purpose only • Exercise caution as content is pending human review
Article Review Status
Submitted
Under Review
Approved

Last updated: June 3, 2025View editorial policy

Personalize

Help us tailor your experience

Which best describes you? Your choice helps us use language that's most understandable for you.

From the Guidelines

For patients with depression who do not respond to SSRIs, cognitive behavioral therapy (CBT) is a viable adjunct therapy option. According to a systematic review published in the Annals of Internal Medicine 1, CBT and antidepressants have similar efficacy for the initial treatment of major depressive disorder (MDD). This suggests that CBT could be considered as an adjunct therapy for patients who do not respond to SSRIs.

Some key points to consider when using CBT as an adjunct therapy include:

  • CBT is a psychological intervention that can be used in conjunction with pharmacological treatments
  • It has been shown to be efficacious for MDD compared to placebo or other inactive interventions 1
  • CBT can be used as a second-step intervention for patients who do not respond to initial treatment with SSRIs
  • The evidence for CBT is limited by high dropout rates, dosing inequalities, small sample sizes, and poor assessment of adverse events 1

In terms of other adjunct therapies, the evidence is limited, and CBT is the most clearly supported option. Other treatments, such as medication combinations, psychotherapy, or complementary and alternative medicine (CAM) treatments, may be considered, but the evidence for these options is not as strong.

When using CBT as an adjunct therapy, it is essential to:

  • Continue treatment for at least 4-6 weeks to assess effectiveness
  • Monitor patients closely for side effects and adjust treatment as needed
  • Consider switching to a different antidepressant class or non-pharmacological approaches if augmentation fails after adequate trials of 2-3 different strategies.

From the FDA Drug Label

Aripiprazole was superior to placebo on the primary endpoint, time from randomization to relapse to any mood event An adjunctive maintenance trial was conducted in adult patients meeting DSM-IV criteria for bipolar I disorder with a recent manic or mixed episode. Patients were initiated on open-label lithium (0.6 to 1. 0 mEq/L) or valproate (50 to 125 μg/mL) at therapeutic serum levels, and remained on stable doses for 2 weeks At the end of 2 weeks, patients demonstrating inadequate response (Y-MRS total score ≥16 and ≤35% improvement on the Y-MRS total score) to lithium or valproate received aripiprazole with a starting dose of 15 mg/day with the option to increase to 30 mg or reduce to 10 mg as early as day 4, as adjunctive therapy with open-label lithium or valproate

Aripiprazole can be used as an adjunct therapy for patients with depression who do not respond to SSRIs, specifically in patients with bipolar I disorder. The recommended dose is 15 mg/day, with the option to increase to 30 mg or reduce to 10 mg. However, it is essential to note that this is in the context of bipolar I disorder, and its use as an adjunct to SSRIs for unipolar depression is not directly addressed in the provided drug label 2.

From the Research

Adjunct Therapies for Depression

When patients with depression do not respond to Selective Serotonin Reuptake Inhibitors (SSRIs), several adjunct therapies can be considered. These include:

  • Augmentation with lithium, thyroid hormone, or second-generation antipsychotics such as quetiapine or aripiprazole 3, 4
  • Combination of antidepressants, including bupropion, tricyclics, or mirtazapine 4
  • Use of atypical antipsychotics, such as aripiprazole, as an augmentor of SSRIs 5
  • Augmentation with buspirone, stimulants, or lamotrigine 6

Factors to Consider

When selecting an adjunct therapy, several factors should be considered, including:

  • Patient's response to previous treatments
  • Tolerability of the adjunct therapy
  • Disease severity
  • Presence of co-morbid mental or physical disorders
  • History of exposure to childhood maltreatment or abuse
  • Job satisfaction and personality disorders 7

Treatment Approach

A personalized treatment approach is recommended, taking into account the individual patient's factors that contribute to their depression and treatment resistance 7. This approach involves "deconstructing depression" to understand the nature of the depression and developing a treatment plan that addresses the specific factors contributing to the patient's hard-to-treat depression.

Effective Strategies

Several effective strategies for treating patients with treatment-resistant depression have been identified, including:

  • Augmentation with quetiapine or aripiprazole 3, 4
  • Combination of olanzapine and fluoxetine 4
  • Use of ketamine or esketamine 4
  • Augmentation with lithium, liothyronine (T3), or lamotrigine 4

Professional Medical Disclaimer

This information is intended for healthcare professionals. Any medical decision-making should rely on clinical judgment and independently verified information. The content provided herein does not replace professional discretion and should be considered supplementary to established clinical guidelines. Healthcare providers should verify all information against primary literature and current practice standards before application in patient care. Dr.Oracle assumes no liability for clinical decisions based on this content.

Have a follow-up question?

Our Medical A.I. is used by practicing medical doctors at top research institutions around the world. Ask any follow up question and get world-class guideline-backed answers instantly.