Is it appropriate to increase hydroxyzine to 50 mg TID and add low-dose doxepin for a 60-year-old patient with depression, anxiety, and possible Parkinson's disease or restless legs syndrome, taking fluoxetine, bupropion, ropinirole, hydroxyzine, and mirtazapine?

Recommendation on Increasing Hydroxyzine and Adding Doxepin in a 60-Year-Old Patient

I do not recommend increasing hydroxyzine to 50 mg TID or adding low-dose doxepin to this patient's current regimen. This 60-year-old patient is already on a complex polypharmacy regimen with significant anticholinergic burden and drug interaction risks that would be substantially worsened by these proposed changes.

Primary Concerns with the Proposed Plan

Excessive Anticholinergic Burden

• Hydroxyzine at 150 mg/day (50 mg TID) represents a dangerously high dose for an elderly patient, particularly when combined with other medications in this regimen 1.
• Elderly patients are at significantly greater risk of adverse drug reactions, and cognitive impairment, renal insufficiency, and polypharmacy are major predictors of drug-related problems in this population 1.
• The current hydroxyzine use of 30 mg TID (90 mg/day) is already concerning; tripling the intended dose to 150 mg/day would dramatically increase risks of confusion, falls, cognitive impairment, and urinary retention 1.

Problematic Drug Interactions with Doxepin

• Doxepin is primarily metabolized by CYP2D6, and fluoxetine is a potent CYP2D6 inhibitor 2.
• This patient is taking fluoxetine 40 mg daily, which will significantly increase doxepin plasma concentrations and risk of serious anticholinergic toxicity (severe dry mouth, urinary retention, blurred vision, confusion) 2.
• The FDA label explicitly warns that SSRIs may increase plasma concentrations of doxepin when administered concomitantly, and it is desirable to monitor TCA plasma levels whenever co-administering with CYP2D6 inhibitors 2.

Concerns About Current Antidepressant Regimen

• Fluoxetine should generally be avoided in older adults due to higher rates of adverse effects, greater risk of agitation, very long half-life, and extensive CYP2D6 interactions 1, 3.
• The combination of fluoxetine, bupropion, and mirtazapine represents significant polypharmacy without clear evidence of synergistic benefit 1.
• Neither fluoxetine, bupropion, nor mirtazapine have comparable evidence of analgesic efficacy if pain is a component of this patient's presentation 1.

Alternative Recommendations

Optimize Current Anxiety Management

• The preferred first-line pharmacotherapy for anxiety in elderly patients is sertraline or escitalopram, not hydroxyzine 3.
• Start sertraline at 25 mg daily (half the standard adult starting dose) and titrate at 1-2 week intervals, monitoring for tolerability 3.
• Escitalopram has the least effect on CYP450 isoenzymes compared to other SSRIs, resulting in lower propensity for drug interactions—critical in this polypharmacy situation 3.

Address the Hydroxyzine Overuse

• Hydroxyzine at current doses (up to 90 mg/day) should be tapered and discontinued, not increased 3.
• The American Geriatrics Society strongly recommends avoiding sedating antihistamines in older adults due to increased risk of cognitive impairment, delirium, falls, and fractures 3.
• If acute anxiety management is needed during transition, consider buspirone 5 mg twice daily as a safer alternative for relatively healthy elderly patients, though it takes 2-4 weeks to become effective 3.

Simplify the Antidepressant Regimen

• Consider transitioning from fluoxetine to sertraline or escitalopram given the better safety profile in elderly patients 1, 3.
• Fluoxetine is associated with more anticholinergic effects and should not be used in older adults per guidelines 1.
• The current combination of three antidepressants (fluoxetine, bupropion, mirtazapine) increases risk without clear evidence of benefit and should be rationalized 1.

Address the Ropinirole Indication

• Ropinirole 0.5 mg suggests treatment for restless legs syndrome (RLS) or early Parkinson's disease 4.
• Importantly, SSRIs (particularly fluoxetine) and mirtazapine can induce or worsen RLS symptoms 5, 6.
• Mirtazapine may be associated with higher rates of RLS and periodic limb movements compared to other antidepressants 6.
• Bupropion may actually reduce RLS symptoms, at least in the short term, and could be the preferred antidepressant in this patient if RLS is present 7, 6.

Specific Action Plan

Immediate Steps

• Do not increase hydroxyzine or add doxepin 1, 2.
• Conduct comprehensive assessment for declining function, cognitive status, and fall risk 1.
• Review all current medications for potential interactions, particularly with CYP450 substrates 3.

Medication Rationalization (Over 4-8 Weeks)

• Taper and discontinue hydroxyzine gradually to avoid withdrawal symptoms 3.
• Transition from fluoxetine to sertraline (requires 4-5 week washout given fluoxetine's long half-life) or escitalopram for both depression and anxiety 1, 3.
• Consider whether the combination of three antidepressants is truly necessary; if RLS is present, bupropion may be the most appropriate single agent 7, 6.
• Optimize mirtazapine dosing (currently 15 mg) if sedation and appetite stimulation are treatment goals, but consider discontinuation if contributing to RLS 1, 6.

Monitoring

• Assess treatment response at 4 weeks and 8 weeks using standardized validated instruments 3.
• Monitor for symptom relief, side effects, adverse events, cognitive function, and fall risk 1, 3.
• If symptoms are stable or worsening after 8 weeks despite good adherence, adjust the regimen by switching to a different SSRI or SNRI (venlafaxine or duloxetine) 3.

Critical Pitfalls to Avoid

• Never combine multiple anticholinergic agents in elderly patients—the cumulative burden dramatically increases risk of delirium, falls, and cognitive impairment 1, 2.
• Do not add TCAs (like doxepin) to patients taking fluoxetine without careful consideration of CYP2D6 interactions and potential for severe anticholinergic toxicity 2.
• Avoid the temptation to add medications when the current regimen needs simplification—polypharmacy itself is a major risk factor in elderly patients 1.
• Start low and go slow with any medication changes in elderly patients, using doses approximately 50% of standard adult starting doses 1, 3.
• Do not discontinue SSRIs or mirtazapine abruptly—taper gradually over 10-14 days to avoid discontinuation syndrome (dizziness, paresthesias, anxiety, irritability) 3, 8.