What medication adjuncts can be used for treatment-resistant depression?

Medication Adjuncts for Treatment-Resistant Depression

For treatment-resistant depression (TRD), atypical antipsychotics—particularly aripiprazole, quetiapine, and risperidone—are the primary evidence-based medication adjuncts, with aripiprazole and quetiapine having the strongest regulatory support and clinical evidence. 1

Defining Treatment-Resistant Depression

Before considering adjunctive strategies, confirm TRD is present:

• TRD requires failure of at least two antidepressants with different mechanisms of action, each administered at minimum licensed dose for at least 4 weeks, with less than 25% symptom improvement 1
• Both treatment failures should occur within the current depressive episode and within the past two years 1
• Partial response depression (PRD) can be defined after a single treatment failure with 25-49% improvement 1

First-Line Adjunctive Medications

Atypical Antipsychotics (Preferred)

Aripiprazole is the most robustly supported adjunctive agent:

• Standard dosing: 2.5-15 mg/day, typically starting at 2.5-5 mg daily 2, 3
• Demonstrates rapid antidepressant effects, often within 1-2 weeks, through partial dopamine D2 agonism (30% intrinsic dopaminergic activity) 4, 5, 6
• Network meta-analysis shows significant efficacy (SMD -0.43 vs placebo) with relatively favorable tolerability profile 3
• Particularly beneficial for patients with comorbid fatigue or functional impairment, improving quality of life measures 3, 6
• Lower risk of metabolic side effects compared to quetiapine or olanzapine 3

Quetiapine is another well-established option:

• Standard dosing for depression: 150-300 mg/day (typically 300 mg at bedtime) 2, 3
• FDA-approved as monotherapy for bipolar depression at 300 mg/day 2
• Network meta-analysis confirms efficacy (SMD -0.27 to -0.43 vs placebo) 3
• Higher discontinuation rates due to sedation and metabolic effects (OR 1.89 for all-cause discontinuation) 3
• Should be avoided in patients with diabetes, dyslipidemia, or obesity 7

Risperidone shows comparable efficacy:

• Dosing: 0.5-2 mg/day for depression augmentation 7, 3
• Demonstrates superior improvement in quality of life/functioning compared to other atypicals (SMD -0.38) 3
• First-line choice for patients with cognitive impairment, constipation, or anticholinergic sensitivity 7
• Higher risk of extrapyramidal symptoms and prolactin elevation compared to aripiprazole 3

Important Caveats for Atypical Antipsychotics

Low-dose atypical antipsychotics (below standard ranges) are NOT significantly more efficacious than placebo 3. While some case reports suggest benefit from very low doses (2.5 mg aripiprazole), the network meta-analysis demonstrates that standard dosing is required for reliable efficacy 3, 5.

All standard-dose atypical antipsychotics except risperidone show significantly higher side-effect discontinuation rates than placebo (OR 2.72-6.40) 3. Monitor closely for:

• Metabolic syndrome (weight gain, diabetes, dyslipidemia)—especially with quetiapine and olanzapine 7, 3
• Akathisia and extrapyramidal symptoms 3, 5
• Sedation and cognitive effects 3

Second-Line Adjunctive Strategies

The American College of Physicians guideline notes that different switching and augmentation strategies provide similar symptomatic relief, though certainty of evidence is low for most comparisons 1. This suggests flexibility in second-line approaches when first-line atypicals fail or are not tolerated.

Alternative Augmentation Options

While the evidence provided focuses primarily on atypical antipsychotics, the guideline acknowledges that:

• Switching antidepressants to a different mechanism of action is equally valid as augmentation 1
• Psychological interventions (particularly CBT) can be combined with pharmacotherapy 1
• The choice should prioritize options with the most reliable evidence and consider adverse event profiles 1

Special Populations

Elderly patients (≥65 years):

• Start quetiapine at 50 mg/day, increase by 50 mg increments 2
• Risperidone 0.5-2 mg/day is first-line, with quetiapine 50-150 mg/day as high second-line 7
• Avoid clozapine, olanzapine, and conventional antipsychotics in patients with diabetes, dyslipidemia, or obesity 7

Patients with Parkinson's disease:

• Quetiapine is first-line; avoid all other antipsychotics 7

Patients with cardiac concerns:

• Avoid ziprasidone and conventional antipsychotics in QTc prolongation or congestive heart failure 7

Duration of Treatment

Once response is achieved with adjunctive antipsychotic, continue treatment for at least 6 months before attempting taper 1. The goal is to determine the lowest effective maintenance dose rather than immediate discontinuation 1.

Drug Interactions

When combining antipsychotics with antidepressants:

• Exercise caution with strong CYP450 inhibitors (fluoxetine, fluvoxamine, paroxetine, nefazodone) 2, 7
• Reduce quetiapine dose to one-sixth when co-administered with potent CYP3A4 inhibitors (ketoconazole, nefazodone) 2
• Increase quetiapine dose up to 5-fold when combined with CYP3A4 inducers (phenytoin, carbamazepine) 2
• Extra monitoring recommended when combining any antipsychotic with lithium, carbamazepine, lamotrigine, or valproate 7