A 74-year-old 75 kg male presented to the emergency department with generalized shaking, tremors, clonus, and altered level of consciousness. The patient was last seen normal nine hours prior to arrival by his spouse. His past medical history included diabetes mellitus type II and traumatic brain injury (TBI), with a subdural frontal and temporal intracranial hemorrhage, incurred after falling from a ladder 3 years prior. He had no history of seizure disorder. Home medications on admission were divalproex sodium 250 mg twice/day, quetiapine 25 mg twice/day, venlafaxine 37.5 mg twice/day, trazodone 50 mg as needed (taken 2-3 times/week), donepezil 10 mg once/day, insulin glargine 15 unit once/day, melatonin 3 mg once/evening, magnesium oxide 400 mg once/day, metformin 1000 mg twice/day, pravastatin 20 mg once/evening, and tamsulosin 0.4 mg once/evening. The patient's clinical course is summarized in Figure 1.
On admission, the patient's vital signs were maximum temperature of 39.7 C, heart rate of 120 beats per minute, blood pressure of 188/84 mmHg, and respiration rate of 23. Abnormal labs included elevated creatinine kinase level of 6.34 and hypocalcemia of 6.8. Clinical examination revealed tremors, 3+ hyperreflexia in lower limbs, and Glasgow Coma Scale of 3. He was intubated and immediately transferred to the medical intensive care unit. His hyperthermia was unresponsive to antipyretics and cooling blankets. Several etiologies for encephalopathy:hepatic, endocrine, metabolic, Wernicke's, seizures:were ruled out through laboratory, diagnostic, and microbiological testing. Viral and bacterial encephalopathy remained in the differential diagnosis, but was of low suspicion due to an unremarkable cerebrospinal fluid analysis. Although the patient was at risk for seizure disorder due to his history of TBI, the neurology team conveyed a low level of suspicion for seizures due to a negative electroencephalogram (EEG) and a lack of tonic or clonic activity.
Serotonin syndrome was of high suspicion as evidenced by the patient's home medication list that included divalproex sodium, venlafaxine, and trazodone. The patient suffered from depression, agitation, aggression, migraines, and sudden mood swings resulting from the aforementioned TBI for which he took venlafaxine 37.5 mg twice/day, trazodone 50 mg 2-3 times/week, quetiapine 25 mg twice/day, and divalproex sodium 250 mg twice/day. Quetiapine and trazodone were initiated 3 years ago immediately following the patient's TBI. The patient was originally prescribed escitalopram, but was switched to venlafaxine due to persistent depressive symptoms and migraine prophylaxis twenty months prior to this admission. Divalproex sodium was started at 125 mg twice daily for migraine prophylaxis and mood swings eighteen months prior to this admission. Divalproex sodium was then increased to 250 mg twice/day 2 months prior to this admission.
The neurology team started the patient on cyproheptadine 12 mg once and then 2 mg every 2 hours and midazolam drip for serotonin syndrome within 24 hours of admission. All psychotropic medications including quetiapine, divalproex sodium, donepezil, trazodone, memantine, venlafaxine, and melatonin were held. As the patient regained baseline neurological and muscular functioning on day 3, he was extubated, and cyproheptadine was discontinued after a total of 50 hours of therapy. After a psychiatric consultation, trazodone and venlafaxine were permanently discontinued. The patient was discharged on mirtazapine 7.5 mg for insomnia and mood, memantine 5 mg for cognition, and quetiapine 25 mg twice daily for management of his aggression. Divalproex sodium was to be resumed outpatient at the discretion of his primary care physician.
The patient followed up with his physical medicine and rehabilitation (PM&R) physician 2 months after his hospital admission. He was unable to continue mirtazapine after discharge due to prohibitive cost. His spouse endorsed worsening depressive and neurobehavioral symptoms following his medication changes. The patient reported more frequent migraines and diminished quality of sleep. The patient's physician ordered a pharmacogenetic test through the clinic pharmacy services. The results indicated that the patient was an intermediate metabolizer of venlafaxine due to the presence of a CYP2D6*4/*41 polymorphism. Different enzymes that metabolized each of the drugs that the patient was taking were also examined. Trazodone and quetiapine are metabolized by CYP3A4. Divalproex sodium is primarily metabolized by glucuronosyltransferase UGT (30-50% of dose) and different CYP isoforms (10% of dose) including CYP2A6, CYP2B6, CYP2C9, and CYP3A4. Other genes relevant to mental health disorders such as CYP2C9, CYP2C19, CYP2B6, CYP3A4, CYP3A5, UGT2B15, COMT, HTR2C, and DRD2 are included in Table 1. Using this pharmacogenetic report, sertraline 50 mg once/day was initiated, and quetiapine was increased from 25 mg to 50 mg twice/day to better manage depression and aggression without SS recurrence.