Medication Pairing with Bupropion for Anxiety and Lack of Motivation
For patients on bupropion experiencing anxiety and lack of motivation, adding an SSRI (particularly sertraline, citalopram, or escitalopram) is the most evidence-based approach, as augmentation with bupropion has been shown to reduce depression severity more effectively than other strategies while maintaining tolerability. 1
Primary Recommendation: SSRI Augmentation
Augmenting bupropion with an SSRI addresses both the anxiety component (where bupropion alone may be less effective) and maintains the activating properties of bupropion for motivation. 1
Specific SSRI Options:
Citalopram + Bupropion: This combination has direct evidence from the STAR*D trial showing that augmenting citalopram with bupropion significantly reduces depression severity compared to augmentation with buspirone, with lower discontinuation rates due to adverse events 1
Sertraline: Head-to-head trials demonstrate that sertraline has comparable efficacy to bupropion for depression with anxiety symptoms, making it an excellent augmentation choice 1. Sertraline also shows better efficacy for psychomotor agitation, which often accompanies anxiety 1
Escitalopram: While less studied in combination with bupropion specifically, escitalopram has demonstrated efficacy for anxiety symptoms and is generally well-tolerated 1
Evidence Supporting This Approach
Why SSRIs Address the Anxiety Component:
Bupropion alone shows modest disadvantage compared to SSRIs for anxious depression. A pooled analysis of 10 studies (N=2,122) demonstrated that SSRIs had higher response rates than bupropion in patients with high anxiety levels (65.4% vs 59.4%, p=0.03) 2. The number-needed-to-treat was 17, indicating a clinically meaningful difference 2.
However, this does not mean bupropion should be discontinued - its dopaminergic and noradrenergic effects specifically target the motivational deficits and energy that SSRIs may not adequately address 3, 4
Why Maintain Bupropion:
Bupropion's unique dopamine-norepinephrine reuptake inhibition provides activating effects that directly counter lack of motivation and energy 1, 4
Bupropion causes significantly less sexual dysfunction than SSRIs, making combination therapy more tolerable than SSRI monotherapy at higher doses 4
The combination addresses different neurotransmitter systems: SSRIs target serotonin for anxiety while bupropion targets dopamine/norepinephrine for motivation 3, 4
Alternative Augmentation Strategy: Buspirone
If SSRI augmentation is contraindicated or not tolerated, buspirone can be considered, though evidence shows it is less effective than bupropion augmentation. The STAR*D trial found that augmenting with bupropion reduced depression severity more than buspirone, with better tolerability 1
- Buspirone dosing: Start 5 mg twice daily, maximum 20 mg three times daily 1
- Important caveat: Buspirone requires 2-4 weeks to become effective and is only useful for mild to moderate anxiety 1
SNRIs as Alternative Consideration
Venlafaxine may be superior to some SSRIs for treating anxiety in depression and could theoretically be paired with bupropion, though direct evidence for this combination is limited 1. One trial showed venlafaxine had better response and remission rates than fluoxetine for patients with depression and anxiety 1
However, combining two activating agents (bupropion + venlafaxine) may worsen anxiety in some patients, making SSRI augmentation generally safer 1
Common Pitfalls to Avoid
Do not discontinue bupropion and switch to SSRI monotherapy - this loses the motivational benefits of bupropion's dopaminergic effects 1
Avoid assuming bupropion is contraindicated in anxiety - while it may be less effective than SSRIs for pure anxious depression, it does not worsen anxiety when combined appropriately 2, 5
Do not use benzodiazepines as first-line augmentation - while they rapidly reduce anxiety, they do not address the underlying depression or motivation and carry dependence risks 1
Monitor for serotonin syndrome when combining medications, though the risk is low with bupropion (which has no direct serotonergic effects) plus a single SSRI 4
Dosing Considerations
When augmenting, maintain therapeutic doses of both agents rather than using subtherapeutic doses of each 1. The evidence supporting augmentation strategies comes from studies using full therapeutic doses 1
Allow 4-8 weeks for full therapeutic trial of the combination before adjusting further 1