What other drug therapy options are available for an adult patient with depression who has not responded to initial treatment with a selective serotonin reuptake inhibitor (SSRI) or cognitive behavioral therapy (CBT)?

Treatment Options for SSRI-Resistant Depression

For an adult patient with depression who has not responded to initial SSRI treatment or CBT, switch to bupropion or add CBT to the existing SSRI, as both strategies show equivalent efficacy with approximately 40-60% remission rates in treatment-resistant depression. 1, 2

First-Line Alternatives After SSRI Failure

Switching Strategies

Switch to bupropion as the preferred alternative antidepressant, as it demonstrates equivalent efficacy to other second-generation antidepressants with a significantly lower rate of sexual dysfunction and no evidence of worsening bruxism or TMJ symptoms. 1, 2

• Initiate bupropion SR at 150 mg once daily for 3-4 days, then increase to 150 mg twice daily as the therapeutic dose. 2
• Allow a minimum of 8 weeks at therapeutic dose before determining treatment failure. 1, 2
• Moderate-quality evidence shows no difference in response or remission rates when switching between different second-generation antidepressants (bupropion vs. sertraline vs. venlafaxine). 1

Switching to another SSRI or SNRI (venlafaxine, duloxetine) is equally effective but offers no clear advantage over bupropion, with low-quality evidence showing similar remission rates across all switching strategies. 1

Augmentation Strategies

Add CBT to the existing SSRI rather than switching medications if the patient achieved partial response (25-50% symptom reduction) to the initial SSRI trial. 1, 3

• Patients who responded to SSRI monotherapy but did not achieve remission had 53% remission rates when CBT was added, compared to 89% remission when medication was added to CBT. 3
• CBT requires 10-20 sessions with exposure and response prevention components for optimal effectiveness. 2
• Low-quality evidence shows no difference in response or remission when augmenting with bupropion versus buspirone, though bupropion decreases depression severity more than buspirone. 1

Augment with another second-generation antidepressant if CBT is unavailable or the patient prefers pharmacologic management. 1

• Bupropion augmentation of an existing SSRI shows lower discontinuation rates due to adverse events compared to buspirone augmentation. 1

Second-Line Options

Newer Interventional Treatments

Consider ketamine or esketamine for patients who have not responded to multiple prior treatments, as the 2022 VA/DoD guidelines specifically address these agents for treatment-resistant depression. 1

• These agents are recommended only after failure of other pharmacologic options. 1
• The VA/DoD guideline is the only major guideline addressing these interventions, reflecting the most recent evidence review extending to 2022. 1

Electroconvulsive Therapy

Reserve ECT for patients with multiple prior treatment failures or those requiring rapid improvement (e.g., severe suicidality, catatonia, psychotic features). 1

• Both VA/DoD and NICE guidelines recommend ECT in similar contexts. 1

Tricyclic Antidepressants

Nortriptyline can be considered as a third-line option, with approximately 40% response rates in treatment-resistant depression, though it is less commonly used due to anticholinergic side effects and higher toxicity in overdose. 4

• Target nortriptyline blood levels of 100 ng/mL with full dose titration within 1 week. 4

Non-Pharmacologic Alternatives

Cognitive Behavioral Therapy as Monotherapy

Strongly consider switching to CBT monotherapy (discontinuing the SSRI) if the patient experienced intolerable side effects, as moderate-quality evidence shows CBT has equivalent efficacy to SSRIs with lower adverse event profiles and lower relapse rates. 1, 2

Exercise

Aerobic exercise demonstrates similar benefits to antidepressants in network meta-analyses for mild to moderate depression, with no adverse effects and should be recommended as adjunctive treatment regardless of pharmacologic choices. 2

Complementary and Alternative Medicine

St. John's wort shows similar efficacy to SSRIs with lower discontinuation rates, but it induces cytochrome P450 3A4 and has significant drug-drug interactions, including with oral contraceptives and immunosuppressants. 1, 2

• St. John's wort is contraindicated with concurrent SSRI use due to serotonin syndrome risk. 1

Treatment Algorithm

1. Assess response to initial SSRI: Determine if patient had no response (<25% improvement), partial response (25-50% improvement), or response without remission (>50% improvement but residual symptoms). 1, 5

2. For non-responders (<25% improvement): Switch to bupropion or another antidepressant with a different mechanism of action (SNRI, mirtazapine). 1, 5

3. For partial responders (25-50% improvement): Consider dose escalation of the current SSRI first, then augmentation with CBT or bupropion if inadequate response persists. 1, 5

4. For responders without remission (>50% improvement): Add CBT to target residual symptoms, as this combination shows 53-61% remission rates. 3

5. After two failed adequate trials: Remission rates decrease significantly; consider referral for specialized interventions including ketamine/esketamine or ECT. 1, 6

Critical Considerations and Pitfalls

Screen for bipolar disorder before initiating bupropion, as it can precipitate manic episodes; if bipolar features are present, mood stabilizers plus CBT are preferred. 2

Bupropion is contraindicated in patients with seizure disorders or eating disorders due to dose-dependent seizure risk. 2

Allow at least 14 days between discontinuing an SSRI and starting an MAOI to avoid serotonin syndrome. 7

Higher levels of anxiety predict poorer outcomes for both medication and CBT combination strategies, warranting more aggressive or multimodal treatment approaches. 3

The order of combining CBT and antidepressants does not appear to affect outcomes, so the choice can be based on availability, patient preference, and side effect profile. 3

Avoid premature treatment changes: Ensure adequate dose (therapeutic range) and duration (minimum 4 weeks for non-response determination, 6-8 weeks for partial response) before declaring treatment failure. 1, 5