Can hydroxyzine cause serotonin syndrome?

Hydroxyzine and Serotonin Syndrome

Hydroxyzine is not typically associated with causing serotonin syndrome when used alone, as it does not have significant serotonergic activity. While the available evidence does not specifically mention hydroxyzine as a causative agent for serotonin syndrome, understanding this condition and its common triggers is important for clinical practice.

Medications Associated with Serotonin Syndrome

Serotonin syndrome is caused by excessive serotonergic activity in the central nervous system, typically resulting from:

• Selective serotonin reuptake inhibitors (SSRIs) 1, 2
• Serotonin-norepinephrine reuptake inhibitors (SNRIs) 2
• Monoamine oxidase inhibitors (MAOIs) 1, 3, 2
• Tricyclic antidepressants 3, 2
• Opioids with serotonergic activity (tramadol, meperidine, fentanyl, methadone, tapentadol) 1, 4, 2
• Stimulants (amphetamines, cocaine) 2
• Antimigraine medications (triptans) 5
• Some antibiotics (ciprofloxacin has been implicated) 6
• Herbal supplements (St. John's Wort) 5, 2

Clinical Presentation of Serotonin Syndrome

Serotonin syndrome presents with a clinical triad of:

1. Mental status changes (confusion, agitation) 1, 5
2. Autonomic hyperactivity (tachycardia, hypertension, hyperthermia, diaphoresis) 1, 5
3. Neuromuscular abnormalities (tremor, hyperreflexia, myoclonus, rigidity) 1, 5

• Symptoms typically develop within 24-48 hours after combining serotonergic medications or changing dosages 5, 4
• Myoclonus is the most common clinical finding, occurring in approximately 57% of cases 1, 5
• Clonus and hyperreflexia are considered highly diagnostic when they occur in the setting of serotonergic drug use 1, 5

Diagnosis

• Hunter criteria are most commonly used for diagnosis and have higher sensitivity (84%) and specificity (97%) than older criteria 1, 5
• According to modified Dunkley criteria, diagnosis can be made if the patient has taken a serotonergic drug within the last 5 weeks and has specific clinical findings such as tremor and hyperreflexia, spontaneous clonus, or ocular clonus with agitation or diaphoresis 1

Management

If serotonin syndrome is suspected:

1. Immediately discontinue all serotonergic agents 5, 4
2. Provide supportive care:
   • Benzodiazepines for agitation and tremor 1, 5, 2
   • IV fluids for autonomic instability 5, 4
   • External cooling for hyperthermia 1, 5
   • Continuous cardiac monitoring 5
3. Consider serotonin antagonists in severe cases:
   • Cyproheptadine (4-8 mg orally) has shown efficacy in case reports 5, 7, 8
   • Higher doses of cyproheptadine (20-30 mg) may be necessary for effective blockade of brain 5-HT2 receptors 8

Severe Complications

Severe serotonin syndrome (temperature >41.1°C) can lead to:

• Rhabdomyolysis 1, 5
• Metabolic acidosis 5
• Elevated serum aminotransferase 5
• Renal failure 1, 5
• Seizures 5
• Disseminated intravascular coagulopathy 5
• Death (mortality rate approximately 11%) 5

Clinical Implications

• While hydroxyzine is not specifically listed as a serotonergic agent in the available evidence, caution should be exercised when combining any medications in patients already on multiple serotonergic drugs 2, 6
• Particular attention should be paid to drug interactions that may occur through both pharmacokinetic (e.g., cytochrome P450 inhibition) and pharmacodynamic mechanisms 6
• Awareness of this potentially fatal condition is essential, as it is often overlooked in clinical practice 2

Prevention Strategies

• Use caution when prescribing multiple serotonergic medications concurrently 5, 6
• Start with low doses when adding a second serotonergic medication to an existing regimen 5
• Monitor closely for early signs of serotonin syndrome, especially during the first 24-48 hours after medication changes 5, 4
• Consider patient-specific risk factors such as age, medication dosages, and concomitant use of CYP2D6 inhibitors 5