SSRI Augmentation for Uncontrolled Depression
For uncontrolled depression on an SSRI, augment with bupropion or buspirone as first-line pharmacological options, with bupropion showing stronger evidence for efficacy. 1
Verify Adequate Initial Treatment
Before implementing any augmentation strategy, confirm the initial SSRI trial was adequate:
- Duration of 8-12 weeks at maximum tolerated doses 1
- Verify medication adherence 1
- Ensure dosing was optimized 1
First-Line Augmentation Options
Bupropion (Preferred)
- Bupropion augmentation produces response rates of 54-62% and remission rates of 50-60% in patients with inadequate SSRI response 2, 3, 4
- The American College of Physicians recommends augmenting citalopram with bupropion when the initial SSRI produces inadequate response 1
- Dosing: Start at 150 mg daily, may increase to 300 mg daily after 4-7 days 5
- Maximum dose is 450 mg daily to minimize seizure risk 5
- Bupropion is the most widely chosen augmenting agent among clinicians (30% preference) 6
Buspirone (Alternative)
- Buspirone may be considered for augmentation when the initial SSRI produces inadequate response 1
- Evidence for buspirone is less robust than bupropion, with one systematic review showing no evidence of clinical efficacy 7
Second-Line Augmentation: Atypical Antipsychotics
Atypical antipsychotics (risperidone, aripiprazole) should be considered when first-line augmentation fails:
- Approximately one-third of SSRI-resistant patients show clinically meaningful response 1
- Higher response rates compared with antidepressant monotherapy 7
- Mandatory monitoring required: weight, blood glucose, lipid profiles for metabolic side effects 1
- Higher withdrawal rates due to adverse events compared to other augmentation strategies 7
Alternative Strategy: Switching vs. Augmentation
Switching to a different antidepressant represents an alternative to augmentation:
- No significant difference in response or remission when switching between SSRIs (bupropion vs. sertraline vs. venlafaxine) 1
- No difference in response when switching to cognitive therapy versus switching to another SSRI 1
Common Pitfalls to Avoid
- Do not use two antidepressants or two antipsychotics as an initial treatment approach without empirical support 1
- Avoid bupropion in patients with seizure disorder, current/prior bulimia or anorexia nervosa, or those abruptly discontinuing alcohol/benzodiazepines 5
- Do not combine bupropion with MAOIs (14-day washout required) 5
- Monitor for serotonin syndrome when combining serotonergic medications 1
- Bupropion can cause false-positive urine tests for amphetamines 5
Dosing Adjustments for Special Populations
Hepatic impairment:
Renal impairment:
- Consider reducing dose and/or frequency 5