Serotonin Toxicity in Aripiprazole Augmentation

To the Editor: Aripiprazole is approved for treatment of schizophrenia, bipolar disorder, irritability with autistic disorder, and as adjunctive treatment of major depressive disorder.¹ Although atypical antypsychotics have lower potential for extrapyramidal symptoms, they are not completely without risk.¹ We describe a patient who developed serotonin toxicity (ST) after a single dose of aripiprazole.

Case Report

A 64-year-old white male hospital employee developed agitation, diaphoresis, tremors, and nausea while working on a medical floor. He reported taking his morning medications, which consisted of citalopram 60 mg and aripiprazole 5 mg, approximately 1 hour before arriving at work. He had taken his first dose of aripiprazole that morning, whereas the citalopram dose was unchanged for many years. While commuting to work, he experienced worsening somnolence and yawning. His symptoms progressed to lightheadedness, vertigo, and “seeing different colors,” by the time he arrived at work. His medical history included hypertension and coronary artery disease. He denied smoking, alcohol, or illicit drug use. He reported compliance with his antihypertensives and statin medications. In the emergency room, he had large blood pressure fluctuations and complained of nausea and urinary retention. He was somnolent, but oriented and following commands. His pupils were dilated (6 mm) and briskly reactive to light. Motor examination showed diffuse fasciculations, upper-extremity postural tremors, and cogwheel rigidity in the extremities. He had diffuse hyperreflexia, with clonus elicited at both knees and ankles. He had appendicular ataxia and was unable to stand independently. Laboratory and imaging studies, including creatinine phosphokinase, thyroid-stimulating hormone, and urine toxicology and brain MRI and MRA were unremarkable. He was treated with cyproheptadine and admitted for observation and supportive care. Psychiatric medications were held. Within 24 hours, the patient had resolution of all symptoms and clinical findings.

Discussion

Sternbach (in Dunkley et al.²) first described a syndrome of serotonin excess symptoms derived from published case reports;² however, these criteria have been criticized as being too vague, and overlapping with other syndromes. Given the lack of specificity of Sternbach's criteria, the Hunter Serotonin Criteria were created for ST diagnosis.^2,3 This diagnostic algorithm has been validated for identifying significant ST.³ Our patient met both diagnostic criteria for ST, and to our knowledge, is the first report of ST with aripiprazole. Drug–drug interactions are paramount in most cases of ST, and rapid onset of symptoms is typical.³ Many published studies of toxicity exist with co-administration of SSRIS, SNRIS, and MAOIS, but other medications have been implicated, as well (i.e., linezolid, opiate analgesics).³ Combinations of serotonergic agents produce a greater degree of toxicity than a single agent.³ This patient was taking two medications with known serotonin (5-HT) activity:¹ 1) Citalopram, a potent inhibitor of 5-HT reuptake; and 2) aripiprazole, a partial agonist at dopamine-2 (D₂) receptors and a partial agonist at serotonin_1A (5HT_1A) receptors. Aripiprazole is equally metabolized via both CYP3A4 and CYP2D6 isozymes; therefore, hepatic metabolism may be implicated in our patient's presentation.¹ CYP2D6 poor metabolizers may be at increased risk of st, particularly with concomitant administration of citalopram, a CYP2D6 inhibitor;⁴ 5%–10% of caucasians are CYP2D6 poor metabolizers, whereas up to 30% of African Americans are ultra-rapid metabolizers.⁴ Poor metabolism of aripiprazole via CYP2D6 has been implicated in the development of adverse effects in one patient and may have been important in our case.⁵

Conclusion

It is important to discuss the potential development of serotonin toxicity with patients when prescribing aripiprazole for augmentation in treatment-resistant depression.