Safest Antidepressants to Use with Vyvanse
When combining antidepressants with Vyvanse (lisdexamfetamine), SSRIs—particularly sertraline, citalopram, or escitalopram—are the safest first-line options, as they have well-established safety profiles and minimal drug-drug interactions with stimulants. 1
Recommended Antidepressant Options
First-Line: Selective Serotonin Reuptake Inhibitors (SSRIs)
SSRIs are the preferred antidepressant class when combined with Vyvanse due to their established efficacy and generally favorable side effect profiles. 1
Sertraline (25-200 mg/day): Has less effect on metabolism of other medications compared to other SSRIs, making it particularly suitable for combination therapy 1
Citalopram (20-60 mg/day): Well-tolerated with some patients experiencing nausea and sleep disturbances; effective dose typically 20 mg 1
Escitalopram (10-20 mg/day): FDA-approved for adolescents aged 12+ years with depression; effective dose typically 10 mg 1
Fluoxetine (20-60 mg/day): The only SSRI FDA-approved for children and adolescents with depression; activating properties may complement or potentially amplify stimulant effects 1
Important Monitoring Considerations
Close monitoring is essential when initiating any antidepressant with Vyvanse, particularly in the first 1-2 weeks. 1
- Monitor for behavioral activation, agitation, irritability, or unusual changes in behavior 1
- Assess for increased anxiety, insomnia, or cardiovascular effects (both drug classes can increase heart rate and blood pressure) 1
- Watch for suicidality risk, which is elevated during the first 1-2 months of antidepressant treatment 1
- Evaluate therapeutic response and adverse effects within 1-2 weeks of initiation 1
Second-Line Options
Bupropion (37.5-150 mg twice daily) may be considered as it is activating and has rapid improvement of energy levels, though caution is warranted as it should not be used in agitated patients. 1 The combination of two activating agents (bupropion + Vyvanse) requires careful monitoring for overstimulation, anxiety, and insomnia.
Mirtazapine (7.5-30 mg at bedtime) is potent, well-tolerated, and promotes sleep, appetite, and weight gain—potentially counteracting stimulant-related appetite suppression and insomnia. 1 This may be particularly useful if the patient experiences significant sleep or appetite disturbances from Vyvanse.
Antidepressants to Avoid or Use with Extreme Caution
Paroxetine is not recommended to be started in primary care and has higher rates of sexual dysfunction and more anticholinergic effects than other SSRIs. 1
MAOIs are absolutely contraindicated with all SSRIs and should not be combined with stimulants due to risk of hypertensive crisis. 1
Dosing Strategy
Start antidepressants at the lower end of the licensed dose range when combining with Vyvanse to optimize the balance between efficacy, tolerability, and acceptability. 2
- For SSRIs, doses between 20-40 mg fluoxetine equivalents achieve optimal balance 2
- Increase dosing gradually using increments of the initial dose every 5-7 days until therapeutic benefits or significant side effects appear 1
- Allow at least 4-8 weeks for a full therapeutic trial before modifying treatment 1
Common Pitfalls to Avoid
Do not assume Vyvanse itself will treat depression: While lisdexamfetamine has been studied as augmentation for treatment-resistant depression, it did not demonstrate superiority over placebo in randomized controlled trials 3, 4
Avoid abrupt discontinuation: All SSRIs should be slowly tapered when discontinued due to risk of withdrawal effects 1
Do not start at high doses: Higher starting doses of SSRIs increase the risk of deliberate self-harm and suicide-related events 1
Monitor cardiovascular parameters: Both stimulants and some antidepressants can affect heart rate and blood pressure 1