Is there an interaction between lithium and hydroxyzine (Vistaril), particularly in elderly patients or those with impaired renal function?

Lithium and Hydroxyzine Interaction

There is no direct pharmacokinetic or pharmacodynamic interaction between lithium and hydroxyzine documented in clinical guidelines or drug interaction databases, but their combined use in elderly patients or those with renal impairment requires heightened caution due to overlapping risks of CNS depression, anticholinergic effects, and the potential for lithium toxicity when renal function is compromised.

Understanding the Lack of Direct Interaction

• No evidence from major clinical guidelines identifies a specific drug-drug interaction between lithium and hydroxyzine that would alter the metabolism, clearance, or therapeutic effect of either medication. 1
• The primary concern is not a direct chemical interaction but rather the additive risks when combining these medications, particularly in vulnerable populations.

Critical Safety Considerations in Combined Use

Central Nervous System Effects

• Hydroxyzine produces sedation in approximately 80% of elderly patients and significantly prolongs reaction times, increasing the risk of over-sedation, falls, and cognitive impairment. 1
• When hydroxyzine is combined with other CNS-active medications (including mood stabilizers like lithium), the sedative burden is substantially increased. 1
• Lithium toxicity itself manifests with CNS symptoms ranging from confusion and ataxia to seizures, and the addition of a sedating antihistamine could mask early warning signs of lithium toxicity or compound neurological impairment. 2

Anticholinergic Burden

• Hydroxyzine's anticholinergic activity adds to that of other anticholinergic drugs, resulting in CNS impairment, delirium, visual disturbances, urinary retention, constipation, and heightened fall risk in older adults. 1
• The European Heart Journal advises a mandatory medication review for CNS depressants and anticholinergic drugs before initiating hydroxyzine therapy. 1
• Elderly patients are at particularly high risk for anticholinergic side effects, and hydroxyzine is specifically listed among medications that should be avoided or deprescribed in this population. 1

Renal Function: The Critical Link

Lithium's Renal Dependence

• Lithium is eliminated almost exclusively by the kidneys, and any factor that impairs renal function dramatically increases the risk of lithium toxicity. 2, 3
• Chronic lithium treatment commonly causes progressive impairment of distal tubular responsiveness to vasopressin, leading to nephrogenic diabetes insipidus with polyuria and polydipsia. 4
• Volume depletion from lithium-induced nephrogenic diabetes insipidus is the most common cause of chronic lithium poisoning. 2
• Patients with compromised renal function prior to starting lithium have a 6.7-fold increased risk (95% CI 3.1-14.3) of progressing to severe renal impairment (CKD stage 4-5) compared to those with normal baseline function. 5

Hydroxyzine in Renal Impairment

• In patients with moderate renal impairment (creatinine clearance 10-20 mL/min), hydroxyzine dosage must be reduced by 50%. 1
• In severe renal impairment (creatinine clearance <10 mL/min), hydroxyzine is absolutely contraindicated. 1
• Elderly patients frequently have reduced renal function even when serum creatinine appears normal, because reduced muscle mass masks impairment; creatinine clearance calculation (e.g., Cockcroft-Gault or CKD-EPI equation) is mandatory. 6, 1

Practical Management Algorithm

Before Prescribing This Combination

1. Calculate creatinine clearance using CKD-EPI or Cockcroft-Gault equation—do not rely on serum creatinine alone in elderly patients. 6, 1

2. If creatinine clearance is <10 mL/min: Hydroxyzine is contraindicated; do not prescribe. 1

3. If creatinine clearance is 10-20 mL/min: Reduce hydroxyzine dose by 50% (e.g., 5-25 mg at bedtime instead of 10-50 mg). 1

4. Review all concurrent medications for other CNS depressants (benzodiazepines, opioids, antipsychotics, muscle relaxants) and anticholinergic agents (tricyclic antidepressants, antihistamines, bladder antimuscarinics). 1

5. Verify lithium level is within therapeutic range (typically 0.6-1.2 mEq/L) and stable; avoid this combination if lithium levels are elevated or fluctuating. 2, 3

Dosing Strategy When Combination Is Necessary

• Use hydroxyzine only as a bedtime adjunct (10-50 mg, adjusted for renal function) to a non-sedating antihistamine if treating pruritus or urticaria; never use hydroxyzine as monotherapy. 1
• Start at the lowest effective dose (10 mg at bedtime) in elderly patients, even with normal renal function, due to heightened sensitivity to sedative and anticholinergic effects. 1
• Avoid multiple daily dosing of hydroxyzine, as this significantly increases daytime drowsiness, performance impairment, and cognitive effects. 1

Monitoring Requirements

• Monitor for excessive sedation, confusion, or altered mental status that exceeds mild drowsiness—these may signal either hydroxyzine toxicity or early lithium toxicity. 1, 2
• Check lithium levels more frequently (every 1-2 weeks initially, then monthly) when hydroxyzine is added, as volume depletion from any cause (including anticholinergic-induced reduced fluid intake) can precipitate lithium toxicity. 2, 3
• Reassess renal function (creatinine clearance) every 3-6 months in patients on chronic lithium, as progressive renal impairment is common and necessitates hydroxyzine dose adjustment or discontinuation. 5, 3, 7
• Evaluate for falls, urinary retention, constipation, and cognitive decline at each visit, as these anticholinergic effects are particularly problematic in older adults. 1

Common Pitfalls to Avoid

• Do not assume normal serum creatinine equals normal renal function in elderly or low-muscle-mass patients; always calculate creatinine clearance. 6, 1
• Do not overlook volume depletion from lithium-induced nephrogenic diabetes insipidus, as this is the most common precipitant of chronic lithium toxicity and would be worsened by hydroxyzine's anticholinergic reduction of thirst perception. 2
• Do not prescribe hydroxyzine for long-term daily use as monotherapy or in combination with lithium, as prolonged use impairs concentration, work performance, and increases occupational accident risk. 1
• Do not ignore subjective denial of drowsiness—hydroxyzine causes performance impairment even when patients report feeling alert, and drivers taking hydroxyzine are 1.5 times more likely to be responsible for fatal automobile accidents. 1

When to Avoid This Combination Entirely

• Severe hepatic disease: Hydroxyzine is absolutely contraindicated due to risk of excessive sedation and hepatic encephalopathy. 1
• Severe renal impairment (CrCl <10 mL/min): Hydroxyzine is contraindicated. 1
• Early pregnancy: Hydroxyzine is the only antihistamine explicitly contraindicated in the first trimester. 1
• Patients requiring optimal cognitive function (e.g., operating machinery, driving professionally): Hydroxyzine impairs learning and work performance and should be avoided. 1
• Patients with multiple CNS depressants or anticholinergic medications: The additive burden dramatically increases risk of delirium, falls, and cognitive impairment. 1