What medication adjustments are recommended for a 17‑year‑old female with persistent depressive symptoms for two months despite being on bupropion (Wellbutrin) XL 300 mg daily, clonidine 0.1 mg daily, lisdexamfetamine (Vyvanse) 20 mg daily, sertraline (Zoloft) 50 mg daily, lamotrigine (Lamictal) 100 mg daily, and daily cannabidiol oil use?

Medication Management for Treatment-Resistant Depression in an Adolescent

Primary Recommendation

Increase sertraline (Zoloft) from 50 mg to 100-150 mg daily as the first-line intervention, as this patient is receiving a subtherapeutic dose for persistent depression. 1, 2

Rationale for Sertraline Optimization

• Sertraline 50 mg is below the effective therapeutic range for adolescent depression—the effective dose is 50-200 mg daily with a maximum of 200 mg 1
• Sertraline is specifically recommended as first-line for patients with both depression and anxiety due to its optimal balance of efficacy, safety, and tolerability 2
• This patient is already on bupropion 300 mg, which is inherently activating and commonly causes anxiety—a problematic choice given her likely anxiety symptoms (clonidine and Vyvanse suggest ADHD with possible anxiety) 2, 3

Critical Safety Monitoring

• Monitor weekly for the first month after any dose increase for treatment-emergent suicidality, as all SSRIs carry FDA black box warnings for suicidal thinking in individuals younger than 24 years 1
• Contact should occur within 1 week of dose adjustment, either in-person or by telephone, to assess depressive symptoms, suicide risk, adverse effects, adherence, and environmental stressors 1
• Continue monitoring at weeks 2,4,6, and 8 after dose changes 1

Address the Bupropion Problem

• Consider discontinuing or reducing bupropion if anxiety symptoms are prominent, as bupropion is FDA-labeled with warnings against use in agitated patients and commonly causes anxiety, insomnia, and agitation 2, 3
• Bupropion may lower seizure threshold, particularly concerning given the concurrent lamotrigine (typically used for seizure prophylaxis or mood stabilization) 1
• The combination of bupropion and sertraline can be effective for treatment-resistant depression 4, but also carries risk of serotonin syndrome through bupropion's inhibition of CYP2D6, which increases SSRI blood levels 5

Evaluate CBD Use as Contributing Factor

• Daily CBD use may be contributing to persistent depression—cannabinoids can worsen depressive symptoms and interfere with antidepressant efficacy
• Counsel on discontinuation or significant reduction of CBD use before making further medication adjustments

If Sertraline Optimization Fails After 8-12 Weeks

• Switch to venlafaxine extended-release 75-225 mg daily, which demonstrated statistically significantly better response rates than fluoxetine specifically for depression with prominent anxiety symptoms 2
• Alternative: Consider augmentation with mirtazapine 15-45 mg at bedtime, which has faster onset of action (1-2 weeks) compared to SSRIs and addresses insomnia if present 1, 3

Reassess the Polypharmacy Regimen

• This patient is on 5 psychiatric medications plus CBD—evaluate whether lamotrigine 100 mg is addressing bipolar depression versus unipolar depression, as this fundamentally changes the treatment algorithm
• If bipolar disorder is confirmed, the treatment approach shifts entirely and bupropion becomes contraindicated due to risk of inducing mania 1
• Clonidine 0.1 mg may be addressing ADHD, anxiety, or sleep—clarify its indication to determine if it remains necessary

Specific Titration Schedule for Sertraline

• Increase sertraline from 50 mg to 100 mg daily for 2 weeks 1
• If inadequate response at 4 weeks, increase to 150 mg daily 1
• If inadequate response at 6 weeks, increase to 200 mg daily (maximum dose) 1
• Allow full 8-12 weeks at therapeutic dose before declaring treatment failure 1

Common Pitfall to Avoid

• Do not add another antidepressant before optimizing the sertraline dose—38% of patients do not respond to initial antidepressant therapy, but this patient has never received an adequate trial of sertraline at therapeutic doses 1
• Do not continue subtherapeutic dosing hoping for spontaneous improvement—2 months of persistent depression on inadequate medication requires immediate dose adjustment 1

Consider Cognitive Behavioral Therapy

• Add evidence-based psychotherapy (CBT or interpersonal therapy) concurrently with medication optimization, as combination treatment is superior to either alone for adolescent depression 1
• CBT is particularly important given the complex polypharmacy and need to address underlying psychosocial stressors 1