What medication adjustments and follow‑up plan are recommended for an adult female with recurrent major depressive disorder on fluoxetine 20 mg daily and trazodone 25‑50 mg nightly who now has worsening low mood, early‑morning awakenings at 3 am, obstructive sleep apnea treated with CPAP, elevated thyroid‑stimulating hormone, prediabetes, and pending pharmacogenomic testing?

Medication Adjustments for Recurrent Major Depressive Disorder with Early‑Morning Awakening and Comorbid Sleep Apnea

Immediate Fluoxetine Dose Optimization

Increase fluoxetine from 20 mg to 40–60 mg daily, administered in the morning, because the current dose is subtherapeutic for recurrent major depressive disorder with worsening mood (rated 1/10), and FDA labeling supports doses up to 80 mg/day with evidence that higher doses may be required after initial non‑response. 1

• The FDA label specifies that "a dose increase may be considered after several weeks if insufficient clinical improvement is observed," and doses above 20 mg/day should not exceed 80 mg/day. 1
• For recurrent depression, the American College of Physicians recommends continuing treatment for ≥1 year, but dose optimization is the first step when current therapy is inadequate. 2
• The patient's low serotonin levels documented in recent labs further support increasing the SSRI dose rather than switching agents. 2

Trazodone Adjustment for Sleep Architecture

Discontinue trazodone 25–50 mg and replace it with ramelteon 8 mg nightly, because trazodone has failed to prevent 3:00 AM awakenings after an initial brief response, and ramelteon specifically targets circadian rhythm and deep‑sleep architecture without dependence risk. 2

• Trazodone is effective for sleep initiation but does not reliably maintain sleep or improve deep/REM sleep architecture, which is critical for mood regulation in depression. 3, 4
• The patient's Fitbit data showing predominantly light sleep (minimal deep or REM sleep) indicates that trazodone is not addressing the core sleep pathology. 2
• Ramelteon (a melatonin receptor agonist) was explicitly discussed in the visit as an alternative to target deep sleep without the activating or dependence risks of trazodone at higher doses. 2
• If ramelteon is unavailable or ineffective after 2 weeks, consider mirtazapine 7.5–15 mg nightly, which improves sleep architecture and augments SSRI efficacy, though it carries weight‑gain risk that must be discussed given the patient's prediabetes (A1C 6.2). 2

Thyroid Optimization

Coordinate with the primary care provider to increase levothyroxine dose, because the patient has "slightly elevated TSH" documented in recent labs, and subclinical hypothyroidism is a reversible cause of treatment‑resistant depression and early‑morning awakening. 2

• Thyroid dysfunction directly impairs antidepressant response and worsens depressive symptoms, particularly fatigue and mood instability. 2
• The TSH recheck scheduled for mid‑April should occur sooner (within 2 weeks) given the acute mood deterioration. 2

Sleep Apnea and CPAP Optimization

Ensure urgent ENT evaluation (currently scheduled but not yet completed) to address nasal congestion that is compromising CPAP efficacy, because untreated obstructive sleep apnea independently worsens depression and prevents antidepressant response. 2

• The patient is using a Neti pot for congestion, but persistent nasal obstruction limits CPAP adherence and effectiveness, perpetuating sleep fragmentation. 2
• Sleep apnea causes chronic sleep deprivation and hypoxia, both of which are independent risk factors for treatment‑resistant depression. 2

Monitoring Protocol (Weeks 1–2)

Schedule a follow‑up visit within 1–2 weeks (not the currently scheduled 4‑week interval) to assess for emergent suicidal ideation, agitation, or behavioral changes, because suicide risk peaks during the first 1–2 months of SSRI dose escalation, and the patient has a family history of maternal suicide. 2

• The American College of Physicians mandates early monitoring when initiating or escalating antidepressants, particularly in patients with chronic suicide risk. 2
• The patient's current mood rating of 1/10 and emotional overwhelm warrant closer surveillance than the standard 4‑week interval. 2

Response Assessment (Weeks 6–8)

If depressive symptoms do not improve by ≥50% on the PHQ‑9 or equivalent scale by 6–8 weeks, add cognitive‑behavioral therapy (CBT) to the optimized fluoxetine regimen, because combination therapy nearly doubles remission rates (57% vs 31%) in severe depression compared with medication alone. 2

• The patient is already engaged in monthly supportive therapy with her therapist, but this should be intensified to weekly CBT sessions if pharmacologic optimization is insufficient. 2
• CBT has moderate‑quality evidence for equivalence to antidepressants as monotherapy and superior outcomes when combined with medication. 5

Pharmacogenomic Testing Integration

Prioritize review of the GeneSight results (ordered but pending) at the next visit to identify CYP2D6 or CYP2C19 polymorphisms that may explain fluoxetine's suboptimal response, because fluoxetine is metabolized by CYP2D6 and genetic variants can cause inadequate drug levels or excessive side effects. 2

• Poor metabolizers may require dose reductions or alternative agents, while ultrarapid metabolizers may need higher doses or a switch to a non‑CYP2D6‑dependent antidepressant. 2

Prediabetes and Weight Considerations

Avoid mirtazapine as a first‑line sleep agent given the patient's A1C of 6.2 (prediabetic range), because mirtazapine is associated with significant weight gain that could worsen metabolic risk. 2

• If mirtazapine becomes necessary after ramelteon failure, use the lowest effective dose (7.5 mg) and monitor weight and A1C monthly. 2

Propranolol Continuation

Continue propranolol 10 mg as needed for physical anxiety symptoms, but monitor for depressive effects if used daily, because beta‑blockers can worsen mood in some patients. 2

• The patient has not required propranolol recently while off work, suggesting situational anxiety rather than persistent autonomic hyperarousal. 2

Common Pitfalls to Avoid

• Do not switch to a different SSRI or SNRI without first optimizing the fluoxetine dose to 40–60 mg/day, because moderate‑quality evidence shows no difference in efficacy among second‑generation antidepressants, and switching prematurely delays therapeutic response. 2, 6
• Do not add benzodiazepines for sleep, because they worsen sleep architecture, increase fall risk (especially with comorbid sleep apnea), and carry dependence liability without addressing the underlying depression. 7
• Do not continue trazodone at the current dose indefinitely, because the patient has already demonstrated tolerance (initial 7–8 days of benefit followed by return of 3:00 AM awakenings), and higher trazodone doses (>50 mg) can paradoxically increase anxiety. 2, 3

Treatment Duration

Plan to continue the optimized antidepressant regimen for at least 12 months after achieving remission, because the patient has recurrent major depressive disorder (multiple prior episodes) and a family history of suicide, both of which mandate prolonged maintenance therapy. 2, 1