Residents’ Voices

Ketamine and serotonin syndrome: A case report

Clay Gueits, MD, and Martin Witkin, DO

ong utilized as a rapid anesthetic, ket- with haloperidol (dose unknown) with amine has been increasingly used in reportedly good effect. On Day 7, she was Lsub-anesthetic doses for several psy- discharged home. chiatric indications, including depression, Upon returning home, she experienced suicidality, and chronic pain. Recently, persistent altered mental status. Her signifi- an intranasal form of esketamine—the cant other brought her to our hospital for fur- S-enantiomer of ketamine—was FDA- ther workup. Ms. O’s body temperature was Clay Gueits, MD approved for treatment-resistant depression. 37.6°C, and she was diaphoretic. Her blood Previously, researchers believed ketamine pressure was 154/100 mm Hg, and her heart mediated its analgesic and psychotropic rate was 125 bpm. On physical examination, effects solely via N-methyl-d-aspartate she had 4+ patellar and Achilles reflexes (NMDA) receptor antagonism, but emerg- with left ankle clonus and crossed adductors. ing research has described a seemingly more Her mental status exam showed increased complex receptor profile.1 One such ancillary latency of thought and speech, with bizarre pharmacologic mechanism is occupation of affect as evidenced by illogical mannerisms Martin Witkin, DO the serotonin receptor.1,2 However, there and appearance. She said she was “not feel-

is sparse literature describing the possible ing myself” and would stare at walls for pro- Dr. Gueits is a PGY-2 Psychiatry extent of ketamine’s involvement in sero- longed periods of time, appearing internally Resident, Department of Psychiatry, tonin syndrome.3 Here, we describe a case preoccupied and confused. Albert Einstein Medical Center, Philadelphia, Pennsylvania. of serotonin syndrome that might have been Ms. O was treated with IV lorazepam, Dr. Witkin is a PGY-2 Psychiatry induced by ketamine. 2 mg. Fourteen hours later, her tempera- Resident, Department of Psychiatry, Albert Einstein Medical Center, ture returned to normal, but she remained Philadelphia, Pennsylvania.

tachycardic, hypertensive, and altered. She Disclosures CASE REPORT received 2 additional doses of 2 mg and The authors report no financial Ms. O, age 41, has a history of endometrio- 1 mg. Seventeen hours after the initial dose relationships with any companies whose products are mentioned in sis, anticardiolipin antibody syndrome, major of IV lorazepam was administered (and 3 this article, or with manufacturers depressive disorder, and generalized anxiety hours after the second dose), Ms. O’s heart of competing product. The views expressed in this case report do not disorder. She initially presented to an out- rate returned to normal. She was ultimately represent the views of Albert Einstein side hospital and was admitted for chronic converted to oral lorazepam, 1 mg every 12 Medical Center. endometriosis pain. During that admis- hours. Two hours later, Ms. O’s blood pressure sion, her pain was treated with IV ketamine, 40 mg/hour, on hospital Days 1 through 4. While hospitalized, she continued to receive LET YOUR VOICE BE HEARD her home medications: fluoxetine, 40 mg/d, Current Psychiatry invites psychiatry residents coumadin, 5 mg/d, and diphenhydramine, to share their views on professional or clinical 25 mg/d. On Day 5, Ms. O experienced visual topics for publication in Residents’ Voices. hallucinations and was diagnosed with ket- E-mail [email protected] for author guidelines. Current Psychiatry amine-induced delirium. She was treated Vol. 19, No. 3 e1 Residents’ Voices

returned to normal, and her physical exam makes serotonin syndrome the most likely showed normal reflexes. diagnosis. She improved after receiving Ms. O was given a presumptive diagnosis lorazepam, which is often used to treat of ketamine-induced serotonin syndrome. hypertonicity, decrease autonomic insta- She made a good recovery and was dis- bility, and prevent seizures seen in sero- charged home. tonin syndrome.5 There is sparse literature describing sero- tonin syndrome related to ketamine use. A suspected association Ketamine has been shown to increase lev- Serotonin syndrome is caused by increased els of glutamate in the medial prefrontal levels of the neurotransmitter serotonin cortex. Higher levels of glutamine in turn in the CNS. Clinical features of serotonin stimulate excitatory glutamatergic neurons Clinical Point syndrome include agitation, restlessness, that project to the dorsal raphe nucleus. We suspected that mydriasis, altered mental status or confu- When stimulated, the dorsal raphe nucleus sion, tachycardia, hypertension, muscle releases serotonin.6 There is also evidence administration rigidity, diaphoresis, diarrhea, piloerection, that ketamine inhibits uptake of serotonin of ketamine in headache, fasciculations, clonus, and shiv- in synapses.7 These mechanisms combine to conjunction with ering. Severe cases can be life-threatening create a net increase in CNS-wide serotonin. fluoxetine, 40 mg/d, and may present with high fever, seizures, Ketamine is being increasingly used to arrhythmias, and loss of consciousness. treat depression and other conditions. This led to serotonin Serotonin syndrome is a clinical diagnosis; case report underscores the importance of syndrome the Hunter Serotonin Toxicity Criteria are considering serotonin syndrome when treat- often used to make the diagnosis. To meet ing patients receiving ketamine, especially these criteria, a patient must have received when it is used in conjunction with selective a serotonergic agent, and at least one of the serotonin reuptake inhibitors. following must be present4: • spontaneous clonus References 1. du Jardin KG, Müller HK, Elfving B, et al. Potential involvement • inducible clonus and agitation or of serotonergic signaling in ketamine’s antidepressant actions: diaphoresis A critical review. Prog Neuropsychopharmacol Biol Psychiatry. 2016;71:27-38. • ocular clonus and agitation or diaphoresis 2. Gigliucci V, O’Dowd G, Casey S, et al. Ketamine elicits • tremor and hyperreflexia sustained antidepressant-like activity via a serotonin- dependent mechanism. Psychopharmacology (Berl). 2013; • hypertonia, temperature >38°C, and 228(1):157-166. ocular clonus or inducible clonus. 3. Warner ME, Naranjo J, Pollard EM, et al. Serotonergic medications, herbal supplements, and perioperative serotonin For Ms. O, we suspected that admin- syndrome. Can J Anaesth. 2017;64(9):940-946. istration of ketamine in conjunction with 4. Dunkley EJ, Isbister GK, Sibbritt D, et al. The Hunter Serotonin Toxicity Criteria: simple and accurate diagnostic decision rules fluoxetine, 40 mg/d, led to serotonin syn- for serotonin toxicity. QJM. 2003;96(9):635-642. drome. Ms. O exhibited ocular clonus and 5. Frank C. Recognition and treatment of serotonin syndrome. Can Fam Physician. 2008;54(7):988-992. diaphoresis, thus satisfying the Hunter 6. López-Gil X, Jiménez-Sánchez L, Campa L, et al. Role of Serotonin Toxicity Criteria, and she also serotonin and noradrenaline in the rapid antidepressant action had inducible clonus, altered mental sta- of ketamine. ACS Chem Neurosci. 2019;10(7):3318-3326. 7. Martin LL, Bouchal RL, Smith DJ. Ketamine inhibits serotonin tus, hypertension, and tachycardia, which uptake in vivo. Neuropharmacology. 1982;21(2):113-118. Discuss this article at www.facebook.com/ MDedgePsychiatry

Current Psychiatry e2 March 2020