What are the risks of combining hydroxyzine with Selective Serotonin Reuptake Inhibitors (SSRIs)?

Risks of Combining Hydroxyzine with SSRIs

The combination of hydroxyzine with SSRIs carries significant risks including QT interval prolongation, enhanced CNS depression, and potential for serotonin syndrome in susceptible individuals. 1, 2

Key Risks of the Combination

QT Interval Prolongation

• Hydroxyzine can prolong the QT interval as noted in FDA labeling 1
• Several SSRIs (particularly citalopram and fluoxetine) are also known to prolong QT interval 1
• When combined, these medications may have additive effects on cardiac conduction
• Patients with pre-existing cardiac conditions, electrolyte abnormalities, or taking other QT-prolonging medications are at higher risk 1

CNS Depression

• Hydroxyzine has potentiating effects on CNS depressants 1
• This can lead to:
  • Excessive sedation
  • Impaired cognition
  • Psychomotor impairment
  • Increased risk of falls, especially in elderly patients 1

Serotonin Syndrome Risk

• While hydroxyzine itself is not primarily serotonergic, the Mayo Clinic Proceedings notes that combinations of medications affecting serotonin can increase risk of serotonin syndrome 2
• Serotonin syndrome typically presents within 24-48 hours with symptoms including:
  • Mental status changes (confusion, agitation)
  • Neuromuscular hyperactivity (tremors, clonus, hyperreflexia)
  • Autonomic hyperactivity (fever, tachycardia, diaphoresis) 2
  • In severe cases: hyperthermia, seizures, and potentially death 2

Special Populations at Higher Risk

Elderly Patients

• More susceptible to CNS depression and sedative effects
• Higher risk of falls and cognitive impairment
• FDA labeling recommends starting hydroxyzine at lower doses in elderly patients 1
• Decreased renal function may affect medication clearance 1

Patients with Cardiac Risk Factors

• Those with:
  • Congenital long QT syndrome
  • Family history of long QT syndrome
  • Recent myocardial infarction
  • Uncompensated heart failure
  • Bradyarrhythmias 1

Clinical Implications and Monitoring

When Combination May Be Used

• Despite risks, some clinical evidence suggests this combination is sometimes used in practice:
  • A 2022 study examined SSRI+hydroxyzine in treating anxiety in avoidant/restrictive food intake disorder 3
  • The combination showed similar improvements in anxiety as SSRI monotherapy, though in a more challenging subset of patients 3

Monitoring Recommendations

• ECG monitoring for QT prolongation, especially at initiation and dose changes
• Monitor for excessive sedation or cognitive impairment
• Watch for early signs of serotonin syndrome
• Adjust dosing to minimize risks, particularly starting with lower doses
• Consider alternative anxiolytics when possible

Alternative Approaches

• Consider non-benzodiazepine anxiolytics with fewer interactions
• For short-term anxiety management, consider behavioral interventions
• If medication is necessary, buspirone may have fewer interactions with SSRIs

The combination of hydroxyzine and SSRIs should be approached with caution, with careful monitoring for adverse effects and appropriate dose adjustments to minimize risks.