How should I manage a 17‑year‑old female with depression, ADHD, PTSD, and PMDD on lisdexamfetamine (Vyvanse), bupropion XL (Wellbutrin), clonidine, lamotrigine, and trazodone who has a worsening depressive episode, profound fatigue, inability to care for herself, daily marijuana use, and has stopped therapy?

Management of a 17-Year-Old with Treatment-Refractory Depression, ADHD, PTSD, and PMDD

This patient requires immediate reassessment of her current medication regimen, discontinuation of daily marijuana use, and urgent re-engagement with psychotherapy—her current polypharmacy has failed and continuing the same approach will not reverse her functional decline. 1

Immediate Priority: Comprehensive Reassessment

The prescriber must reassess this patient immediately because she has not responded to her current medication trial as expected, which indicates either an inaccurate original assessment, inadequate treatment adherence, unaddressed psychosocial factors, or that behavioral reactions to stressors are being mistaken for symptoms requiring medication adjustment. 1

Critical Factors to Evaluate

• Daily marijuana use is likely contributing significantly to her depressive symptoms, fatigue, and amotivation—cannabis use disorder commonly presents with these exact symptoms and directly undermines antidepressant efficacy 1
• Stopping therapy represents a major treatment failure because combined psychotherapy (especially CBT) plus medication demonstrates superior outcomes compared to medication alone for depression, anxiety, and PTSD 2
• Her current medication regimen includes five psychotropic agents, yet she has profound functional impairment—this suggests the polypharmacy approach is ineffective and requires fundamental restructuring rather than adding more medications 1

Medication Optimization Strategy

Step 1: Address the Wellbutrin Dosing

Increase bupropion XL from 300 mg to 450 mg daily (the FDA-approved maximum for depression), as she remains profoundly depressed and fatigued at a sub-maximal dose 3. Bupropion's norepinephrine-dopamine reuptake inhibition specifically targets low motivation and energy deficits 4.

• Monitor closely for seizure risk during the first 1-2 weeks after dose increase, as bupropion carries dose-dependent seizure risk (approximately 0.4% at 300-450 mg/day) 3
• Contraindications to increasing bupropion include any history of seizures, eating disorders (anorexia/bulimia), abrupt alcohol discontinuation, or current severe agitation 3
• If seizure history or eating disorder is present, do NOT increase bupropion and consider aripiprazole augmentation instead 4

Step 2: Optimize Lamotrigine for Mood Stabilization

Lamotrigine 100 mg daily is a sub-therapeutic dose for mood stabilization—therapeutic dosing for bipolar depression and mood instability typically requires 200-400 mg daily 4. Given her PMDD (suggesting mood cycling) and treatment-resistant depression, gradually titrate lamotrigine to 200 mg daily over 4-6 weeks 4.

Step 3: Re-evaluate the Vyvanse

Vyvanse 20 mg is a low dose and may be contributing to her depression rather than helping it—stimulants can worsen depression in some patients, and her profound fatigue may represent stimulant-induced dopamine depletion during the "crash" phase 5.

• Consider a trial off Vyvanse for 2-4 weeks to determine if it is contributing to her depressive symptoms 1
• If ADHD symptoms are truly impairing, atomoxetine (a non-stimulant) may be preferable in the context of depression, PTSD, and substance use 1

Critical Safety Monitoring

Monitor for treatment-emergent suicidality weekly during the first month after any medication change, as all antidepressants carry FDA black-box warnings for increased suicidal thinking in patients under age 24 (14 additional cases per 1000 patients treated) 2. This risk is highest during the first 1-2 weeks after initiation or dose changes 2.

Watch for behavioral activation symptoms (agitation, restlessness, insomnia, impulsivity) during the first 2-4 weeks after bupropion dose increase, which are more common in adolescents than adults 2, 3. If activation occurs, temporarily reduce the dose 2.

Addressing Marijuana Use

Daily marijuana use must be discontinued because:

• Cannabis directly causes depressive symptoms, amotivation, and fatigue that mimic treatment-resistant depression 1
• Marijuana use undermines the efficacy of all her psychiatric medications 1
• This is not optional—continuing marijuana while adjusting medications is treating the wrong problem 1

Refer for substance use treatment as a parallel intervention, not a sequential one 1.

Re-Engaging Psychotherapy

Immediate re-engagement with a therapist is non-negotiable because:

• Combination treatment (CBT + medication) is superior to either alone for depression, anxiety, and PTSD 2
• Her inability to care for herself and social withdrawal are behavioral patterns that medication alone cannot address 1
• Trauma-focused therapy is essential for PTSD—medications provide symptom relief but do not process traumatic memories 6

If she refuses individual therapy, consider intensive outpatient programming (IOP) or partial hospitalization (PHP) given her severe functional impairment 1.

Treatment Timeline and Expectations

• Allow 6-8 weeks at optimized doses (bupropion 450 mg, lamotrigine 200 mg) before declaring treatment failure 2
• Approximately 38% of patients do not achieve response during the initial 6-12 weeks of antidepressant treatment, and 54% do not achieve remission—this is expected, not exceptional 2
• If no improvement after 8 weeks at optimized doses, consider switching to an SNRI (venlafaxine 150-225 mg daily) or augmenting with aripiprazole 2-10 mg daily 4

Common Pitfalls to Avoid

• Do not add more medications before optimizing current doses and addressing marijuana use—polypharmacy without adequate trials of individual agents leads to confusion about what is helping versus harming 1
• Do not mistake behavioral reactions to psychosocial stressors as symptoms requiring medication changes—her stopping therapy and using marijuana daily are behavioral choices that medication adjustments will not fix 1
• Do not continue ineffective treatment beyond 8 weeks at therapeutic doses—this delays recovery and worsens outcomes 2

When to Consider Higher Level of Care

Psychiatric hospitalization or residential treatment should be considered if:

• She develops suicidal ideation with intent or plan 2
• She cannot maintain basic self-care (hygiene, nutrition) despite outpatient interventions 1
• Marijuana use continues despite outpatient substance use treatment 1