Recommended Pharmacological Adjustments for Persistent Anxiety and Insomnia
Primary Recommendation
Discontinue trazodone 100mg nightly and replace with a first-line insomnia agent (eszopiclone 2-3mg, zolpidem 10mg, or doxepin 3-6mg), while simultaneously increasing duloxetine to 90mg daily (given as 30mg increments) for inadequate GAD response. 1, 2
Critical Medication Interactions and Safety Concerns
Before making any adjustments, recognize that this patient is on Eliquis (apixaban) with aspirin, creating significant bleeding risk when combined with duloxetine, which inhibits serotonin reuptake and can impair platelet aggregation. 3 Monitor closely for bleeding complications with any SNRI dose increase.
The patient is also on Lyrica (pregabalin) 300mg BID, which has sedating effects and may be contributing to both therapeutic benefit and adverse effects related to insomnia complaints. 1
Insomnia Management: Replace Trazodone
The American Academy of Sleep Medicine explicitly recommends AGAINST using trazodone for insomnia treatment. 1 Despite its widespread off-label use, trazodone 50mg showed insufficient evidence for efficacy in treating sleep onset or sleep maintenance insomnia. 1
Recommended First-Line Alternatives:
- Eszopiclone 2-3mg nightly for both sleep onset and maintenance insomnia 1
- Zolpidem 10mg nightly for sleep onset and maintenance insomnia 1
- Doxepin 3-6mg nightly specifically for sleep maintenance insomnia 1
Avoid benzodiazepines (temazepam, triazolam) in this patient given concurrent use of Eliquis, aspirin, and multiple CNS-active medications (pregabalin, duloxetine, hydroxyzine), which increases fall risk and bleeding complications. 1
The 2008 AASM guidelines suggest that when pharmacotherapy is used, short-intermediate acting benzodiazepine receptor agonists or ramelteon should be first-line, with sedating antidepressants reserved for patients with comorbid depression/anxiety. 1 However, the 2017 guidelines supersede this recommendation by explicitly advising against trazodone. 1
Anxiety Management: Optimize Duloxetine Dosing
Current Duloxetine Status:
The patient recently increased from 30mg to 60mg daily but continues to report anxiety. 2
Evidence-Based Dose Escalation:
Increase duloxetine to 90mg daily (add 30mg to current 60mg dose), with potential further titration to 120mg daily if inadequate response after 4 weeks. 2, 4
FDA labeling states: "While a 120mg once daily dosage was shown to be effective, there is no evidence that doses greater than 60mg/day confer additional benefit. Nevertheless, if a decision is made to increase the dosage beyond 60mg once daily, increase dosage in increments of 30mg once daily." 2
Clinical trial data demonstrate that duloxetine 60-120mg daily significantly improved HAM-A scores compared to placebo in multiple GAD trials. 2, 4
Approximately 38% of patients do not achieve treatment response during initial 6-12 weeks of SSRI/SNRI therapy, warranting dose optimization before switching agents. 3
Timeline for Assessment:
- Reassess anxiety symptoms at 4 weeks and 8 weeks after dose increase using standardized measures. 3
- Allow 6-8 weeks minimum at therapeutic doses before concluding treatment failure. 3
Abilify (Aripiprazole) 5mg: Consider Discontinuation
Aripiprazole is NOT a first-line agent for GAD and lacks FDA approval for this indication. 1 The 2008 AASM guidelines list atypical antipsychotics (quetiapine, olanzapine) as "other sedating agents" suitable only for patients with comorbid insomnia who may benefit from the primary action of these drugs. 1
Given that this patient has no documented psychotic features or bipolar disorder, and aripiprazole is generally activating rather than sedating, discontinue aripiprazole 5mg daily after optimizing duloxetine and addressing insomnia with appropriate agents. 1 Taper gradually (reduce to 2.5mg for 1-2 weeks, then discontinue) to avoid withdrawal dyskinesia.
Hydroxyzine 50mg BID PRN: Reassess Usage Pattern
Hydroxyzine has limited evidence for GAD treatment. 5 A 2010 Cochrane review found hydroxyzine more effective than placebo (OR 0.30,95% CI 0.15 to 0.58) but noted high risk of bias in included studies and could not recommend it as reliable first-line treatment. 5
- Maintain hydroxyzine 50mg BID PRN for acute anxiety breakthrough while optimizing duloxetine dosing. 5
- Hydroxyzine is associated with higher rates of sleepiness/drowsiness (OR 1.74,95% CI 0.86 to 3.53), which may contribute to daytime sedation complaints. 5
- If the patient requires daily scheduled hydroxyzine (not truly PRN), this indicates inadequate baseline anxiety control and further supports duloxetine dose escalation. 5
Monitoring and Follow-Up
At 2 Weeks After Changes:
- Assess for treatment-emergent suicidality (FDA black box warning for all antidepressants). 3
- Monitor for bleeding complications given Eliquis + aspirin + duloxetine combination. 3
- Evaluate sleep quality and insomnia symptoms with new agent. 1
At 4 Weeks:
- Assess anxiety symptom relief using standardized measures (GAD-7 or HAM-A). 3
- Evaluate medication adherence and side effects. 3
- Consider further duloxetine titration to 120mg daily if inadequate response. 2
At 8 Weeks:
- If little improvement despite good adherence, switch to alternative SSRI (sertraline, escitalopram) or SNRI (venlafaxine XR). 3
- Add cognitive behavioral therapy for insomnia (CBT-I) if sleep disturbance persists. 1
Common Pitfalls to Avoid
- Do not continue trazodone based on historical practice patterns when evidence-based guidelines explicitly recommend against it. 1
- Do not prematurely switch antidepressants before allowing 6-8 weeks at therapeutic duloxetine doses (90-120mg). 3
- Do not add benzodiazepines for insomnia in this medically complex patient with fall/bleeding risk. 1
- Do not abruptly discontinue duloxetine if switching agents—taper over 2 weeks minimum to avoid discontinuation syndrome. 3
- Do not ignore the sedating effects of pregabalin 600mg daily, which may be contributing to both insomnia complaints (paradoxical effect) and daytime sedation. 1
Alternative Strategy If Duloxetine Optimization Fails
If anxiety remains inadequately controlled after 8 weeks at duloxetine 120mg daily:
Switch to venlafaxine XR 75-225mg daily, which demonstrated statistically better response rates than fluoxetine specifically for depression with prominent anxiety symptoms. 3 Venlafaxine has equivalent efficacy to duloxetine for GAD but may be better tolerated in some patients. 4, 6
Add cognitive behavioral therapy (CBT) as combination treatment (CBT + medication) is superior to either alone for anxiety disorders. 3