Treatment Approach for Patients Remaining Depressed on Antidepressant Medication
Reassess the adequacy of the current antidepressant trial immediately—most treatment failures stem from insufficient dose or duration—and if the patient has not received 6–8 weeks at a therapeutic dose, optimize the current regimen before switching or augmenting. 1
Step 1: Verify Adequate Trial Duration and Dosing
Before declaring treatment failure, confirm the patient has completed a minimum of 6–8 weeks on a therapeutic antidepressant dose. 1 Premature switching before this window is a common pitfall that delays recovery and misses opportunities for response. 1
- For SSRIs: Therapeutic doses are typically sertraline 100–200 mg daily, escitalopram 10–20 mg daily, or fluoxetine 20–60 mg daily. 1
- For SNRIs: Venlafaxine requires 150–225 mg daily; doses below this threshold are frequently subtherapeutic. 2
- Approximately 50% of patients who ultimately achieve remission do so between weeks 6 and 14 of treatment, underscoring the need to maintain adequate dosing through this period. 2
Common error: Many patients in primary care receive subtherapeutic doses (e.g., sertraline 50 mg, venlafaxine 75 mg) that are insufficient for moderate-to-severe depression. 3, 4 If the current dose is below the therapeutic range, increase it and reassess after another 4 weeks. 1
Step 2: Assess Medication Adherence and Comorbidities
Rule out non-adherence, substance use, thyroid dysfunction, and bipolar disorder before modifying pharmacotherapy. 1, 2
- Non-adherence is a frequent cause of apparent treatment failure; therapeutic drug monitoring can confirm this when available. 5
- Substance use disorders (alcohol, cannabis, stimulants) directly worsen depression and blunt antidepressant response. 1
- Hypothyroidism mimics or exacerbates depression; obtain TSH if not recently checked. 1
- Unrecognized bipolar disorder: If the patient has a history of manic/hypomanic episodes, antidepressant monotherapy is contraindicated and may worsen mood instability. 5
Step 3: Augmentation vs. Switching—Evidence-Based Decision Algorithm
When to Augment (Preferred if Partial Response Exists)
If the patient has experienced any partial benefit from the current antidepressant (e.g., improved energy but persistent low mood), augmentation is superior to switching because it retains that partial gain. 2, 6
First-Line Augmentation: Bupropion SR
Add bupropion SR 150 mg once daily, increasing to 150 mg twice daily (300 mg total) after 3 days if tolerated. 2, 6
- Efficacy: In the STAR*D trial, bupropion augmentation of an SSRI achieved ~30% remission rates in patients who failed initial monotherapy. 2, 6
- Tolerability advantage: Bupropion has significantly lower discontinuation rates due to adverse events (12.5%) compared with buspirone augmentation (20.6%, P < 0.001). 2, 6
- Mechanism: Bupropion's norepinephrine-dopamine reuptake inhibition complements SSRI/SNRI serotonergic activity, addressing residual symptoms like low motivation and energy. 2, 6
- Sexual dysfunction benefit: Bupropion markedly reduces SSRI-induced sexual dysfunction, a common reason for treatment discontinuation. 2, 6
Contraindications to bupropion: History of seizure disorder, eating disorder (bulimia/anorexia), uncontrolled hypertension, or current agitation. 6 In these cases, consider aripiprazole augmentation (2–10 mg daily) as the next evidence-based option. 6
Reassess after 6–8 weeks at the optimized bupropion dose before declaring augmentation failure. 2, 6
Alternative Augmentation: Cognitive-Behavioral Therapy (CBT)
Initiate CBT immediately while optimizing medication; combination therapy demonstrates superior efficacy compared with medication alone. 1, 2
- CBT can begin without waiting for medication optimization, providing early psychologic support. 2
- Combination treatment (CBT + antidepressant) is superior to either modality alone for depression, supported by moderate-strength evidence. 1, 2
When to Switch (Preferred if No Partial Response)
If the patient has experienced zero benefit after 6–8 weeks at a therapeutic dose, switching to a different antidepressant class is appropriate. 1, 2
First-Line Switch: SNRI (Venlafaxine or Duloxetine)
Switch to venlafaxine XR 75 mg daily, titrating to 150–225 mg daily over 2–4 weeks. 2
- Efficacy: SNRIs demonstrate statistically significant superior response and remission rates compared with SSRIs in treatment-resistant depression. 2
- Mechanism: Dual serotonin-norepinephrine reuptake inhibition may provide greater efficacy for both depression and anxiety symptoms. 2
- Caution: Venlafaxine has slightly higher discontinuation rates than SSRIs due to nausea, dizziness, and blood pressure elevation. 2
Alternative switch within SSRI class: If switching from one SSRI to another (e.g., sertraline to escitalopram), expect ~21–25% remission rates. 2 However, there is no evidence that one SSRI is superior to another, so this strategy is less compelling than switching to a different class. 2
Step 4: Monitor for Suicidal Ideation During Treatment Changes
Assess for suicidal thoughts and behaviors at every patient contact during the first 1–2 months after any medication change, as suicide risk is greatest during this period. 1, 2
- FDA black-box warning: All antidepressants increase the risk of suicidal ideation in patients younger than 24 years, with the highest risk in the first 1–2 months. 1
- Schedule follow-up within 1 week (in-person or by telephone) after initiating augmentation or switching to evaluate adherence, tolerability, and early adverse events. 1
Step 5: Duration of Continuation Therapy After Response
Once the patient achieves remission, continue the antidepressant regimen for a minimum of 4–9 months for a first episode of major depression. 1, 2
- For recurrent depression (≥2 episodes): Consider maintenance therapy for years to lifelong, as relapse risk rises to 70% after two episodes and 90% after three episodes. 2
- Withdrawal of maintenance therapy dramatically increases relapse risk, especially within the first 6 months. 5
Common Pitfalls to Avoid
- Premature switching before 6–8 weeks at therapeutic dose: This is the most frequent error and delays recovery. 1, 2
- Underdosing antidepressants: Many patients in primary care receive subtherapeutic doses (e.g., sertraline 50 mg, venlafaxine 75 mg). 3, 4
- Continuing ineffective treatment beyond 8 weeks: If no improvement occurs by 6–8 weeks at therapeutic doses, modify the treatment approach. 1, 2
- Skipping the intensive monitoring window in weeks 1–2 after medication changes: This period carries the highest risk for emergent suicidal ideation. 1
- Ignoring comorbid substance use or bipolar disorder: These conditions directly undermine antidepressant efficacy and require specific management. 1, 5
Special Populations
Cancer Patients with Depression
For cancer patients with moderate-to-severe depression who fail initial psychological interventions, pharmacotherapy with an antidepressant is appropriate. 1
- Evidence quality is low: A 2018 Cochrane review found no difference between antidepressants (as a class) and placebo on depressive symptoms at 6–12 weeks in cancer patients, though the review was limited by low-quality studies. 1
- Choice of antidepressant: Select based on adverse effect profiles, tolerability, drug interactions, and patient preference—no specific regimen is superior. 1
Adolescents with Depression
Fluoxetine is the only FDA-approved antidepressant for pediatric depression (ages 8 years and older) and should be first-line. 1
- Black-box warning: All antidepressants carry increased risk of suicidal thoughts/behaviors in patients younger than 24 years; monitor closely during the first 1–2 months. 1
- If fluoxetine fails or is not tolerated, consider sertraline or escitalopram off-label, combined with intensive monitoring. 1
Summary Algorithm
- Verify adequate trial: 6–8 weeks at therapeutic dose? If no, optimize current regimen.
- Assess adherence and comorbidities: Rule out non-adherence, substance use, thyroid dysfunction, bipolar disorder.
- Partial response?
- Yes: Augment with bupropion SR 150–300 mg daily + CBT.
- No: Switch to venlafaxine XR 150–225 mg daily.
- Monitor suicidal ideation weekly for the first month after any change.
- Reassess at 6–8 weeks after optimization; if still no response, consider clozapine referral or ECT for severe/resistant cases. 7
- Continue treatment for 4–9 months after remission (first episode) or years to lifelong (recurrent depression). 1, 2