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This column is the third in a 3-part series describing cases in which general medical knowledge, including psychiatric and clinical pharmacology, was instrumental in determining whether dereliction was the direct cause of damages in a malpractice suit. This case illustrates how not taking into account the following variables can result in a false-positive diagnosis of a lethal serotonin syndrome: (a) the time course of treatment, (b) the time course of symptoms, (c) the difference between antemortem plasma and postmortem whole-blood levels of highly protein bound and highly lipophilic drugs. The case also illustrates how taking those 3 variables into account led to the conclusion that there was no dereliction in the care of the patient that was the direct cause of his death, and hence, there was no medical malpractice., Competing Interests: Over his 45-year career, S.H.P. has worked with over 145 pharmaceutical and biotech companies in the United States and throughout the world. Over the past year, he has received grants/research support from or has served as a consultant, on the advisory board, or on the speaker’s bureau for Alkermes, BioXcel, and Janssen. There were no clinical trial and study contracts during the 2 years preceding this paper, but any would have been with and payments made to the Kansas University Medical Center Research Institute, a research institute affiliated with the Kansas University School of Medicine-Wichita. The remaining author declares no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Rationale: Serotonin syndrome is a potentially life-threatening condition resulting from the use of antidepressants, their interactions with other serotonergic medications, or poisoning. It presents with a triad of psychiatric, dysautonomic, and neurological symptoms and is sometimes fatal. While cyproheptadine is a specific treatment option, the optimal duration of its administration remains unclear. The purpose of this report is to quantitatively assess the endpoints of serotonin syndrome treatment. Based on the hypothesis that neurological pupil index (NPi) on a digital pupil recorder would correlate with the severity of the serotonin syndrome, we administered cyproheptadine using NPi as an indicator., Patient Concerns: A patient with a history of depression was brought to our hospital after he overdosed on 251 tablets of serotonin and noradrenaline reuptake inhibitors., Diagnoses: On day 3, the patient was diagnosed with serotonin syndrome., Interventions: Cyproheptadine syrup was administered at 4 mg every 4 hours. The NPi of the automated pupillometer was simultaneously measured. On day 5, the NPi exceeded 3.0 cyproheptadine was discontinued., Outcomes: The patient was discharged on day 7., Lessons: The lack of considerable improvement during the treatment period suggests that the patient may have improved on his own. In this case, the relationship between NPi and the severity of serotonin syndrome could not be determined., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Neuroleptic malignant syndrome (NMS) and serotonin syndrome (SS) are serious medical conditions associated with commonly prescribed psychiatric medications. Although the mechanisms differ, they can be clinically difficult to distinguish. We report a case of a pediatric patient with complicated psychiatric history that developed features of both syndromes in the setting of polypharmacy., Case: A 12-year-old boy with a history of developmental delay, attention-deficit hyperactivity disorder, and posttraumatic stress disorder presented to the emergency department with behavior changes consisting of delayed reactions, gait instability, drooling, and slowed movements. Ten days before presentation, his outpatient psychiatrist had made multiple medication changes including discontinuation of cyproheptadine (an appetite stimulant) and initiation of aripiprazole. On arrival, the patient was noted to be tachycardia and hypertensive for age. He was disoriented, intermittently agitated, and tremulous with increased tonicity, clonus in the lower extremities, and mydriasis. He was supportively treated with lorazepam and intravenous fluids while discontinuing potential offending agents. His course was complicated by hypertension and agitation managed with dexmedetomidine infusion and benzodiazepines. His mental status, tremors, and laboratory values began to improve over the next 2 days, and eventually transitioned to the inpatient psychiatric unit on hospital day 7., Discussion: Diagnosis of NMS or SS can be difficult when there is overlap between syndromes, particularly in the setting of multiple potential offending agents or underlying developmental delay. In addition, pediatric patients may present atypically as compared with adult patients with the same condition., Conclusion: The use of antipsychotic medications for young children with behavioral problems has risen dramatically in the last decade, increasing their risk for developing SS or NMS.

Rationale: As increasing frequency of serotonergic drug use, SS (serotonin syndrome) occurred more than ever. But clinicians have not enough knowledge and experience about SS as a potentially life-threatening condition. SS is usually caused by the increased serotonin activity in the central nervous system which may due to a serotonergic agent overdose or the concomitant use of 2 or more serotonergic antidepressants. We report a case of SS due to a normal dose of selective serotonin inhibitors (SSRIs) thus to remind clinicians to pay attention to such patients and make an early diagnosis and initiation of therapy in the clinical practice., Patient Concerns: We report here a 49-year-old man presented with lethargic, less communicative, and insomnia for 20 days while a diagnosis of depression was considered and he was treated with SSRIs., Diagnosis: The patient in our case fulfilled the 3 criteria existed now for diagnosing SS, including the Sternbach criteria, Radomski revised diagnostic criteria, and the Hunter serotonin toxicity criteria., Interventions: All the antidepressants were stopped and cyproheptadine with an initial dose of 12 mg a day was started along with supportive care. The patient was also admitted to emergency intensive care unit for further treatment. He was sedated and paralyzed by intravenous Midazolam and Clonazepam along with physical cooling and supportive care., Outcomes: All of the patient's symptoms abated gradually and he soon could get off the bed and be communicative. Finally, the patient made a full recovery and he was discharged from the hospital., Lessons: Our case suggests an atypical clinical course while the medicine the patient takes was not in so much dose. We assumed that there may have been some variation in metabolism of these agents, resulting in increased possibility that led to the subsequent syndrome. Thus, it is essential for clinicians to keep in mind when patients taking serotonergic agents who demonstrate acute change in their mental status. Besides, clinicians should be aware of such patients who seem to be sensitive to SSRIs, who may require a genetic testing before the initiation of SSRI therapy.

Serotonin syndrome (SS) is a serious toxicity that manifests with symptoms such as tremor, hyperthermia, agitation, and altered mental status that may lead to seizures, coma, or death. Selective serotonin reuptake inhibitors may precipitate SS, particularly in combination with other drugs that possess serotonergic activity. We present a case of SS in a 14-month-old after an ingestion of the selective serotonin reuptake inhibitor vilazodone.

Objective: The aim of this study was to report an acute onset of symptoms erroneously attributed to serotonin syndrome in a child who had been given both anticholinergic and serotonergic agents., Case Summary: A 9-year-old girl with chronic anxiety and gastrointestinal problems was prescribed oral sertraline 6.25 mg daily, as well as hyoscyamine, ondansetron, montelukast, and a course of nitazoxanide. She was also routinely given diphenhydramine and omeprazole. Three days after increasing sertraline to 12.5 mg, she presented to the emergency department with altered mental status, hallucinations, mydriasis, tachycardia, and pyrexia. She was admitted to the pediatric intensive care unit and subsequently treated unsuccessfully for serotonin syndrome, with blurred vision and clonus persisting at discharge 4 days after admittance. Upon follow-up with her outpatient clinic, all anticholinergic agents were discontinued, and symptoms slowly resolved., Conclusions: This case illustrates the importance of differential diagnosis between toxidromes and how clinical presentation can be altered by preexisting conditions as well as the use of medications that affect multiple neurotransmitter systems.

Objectives: To review the diagnosis and management of four selected psychiatric emergencies in the intensive care unit: agitated delirium, neuroleptic malignant syndrome, serotonin syndrome, and psychiatric medication overdose., Data Sources: Review of relevant medical literature., Data Synthesis: Standardized screening for delirium should be routine. Agitated delirium should be managed with an antipsychotic and, possibly, dexmedetomidine in treatment-refractory cases. Delirium management should also include ensuring a calming environment and adequate pain control, minimizing benzodiazepines and anticholinergics, normalizing the sleep-wake cycle, providing sensory aids as required, and providing early physical and occupational therapy. Neuroleptic malignant syndrome should be treated by discontinuing dopamine blockers, providing supportive therapy, and possibly administering medications (benzodiazepines, dopamine agonists, and/or dantrolene) or electroconvulsive therapy, if indicated. Serotonin syndrome should be treated by discontinuing all serotonergic agents, providing supportive therapy, controlling agitation with benzodiazepines, and possibly administering serotonin2A antagonists. It is often unnecessary to restart psychiatric medications upon which a patient has overdosed in the intensive care unit, though withdrawal syndromes should be prevented, and communication with outpatient prescribers is vital., Conclusions: Understanding the diagnosis and appropriate management of these four psychiatric emergencies is important to provide safe and effective care in the intensive care unit.

The use of selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors in treating depression, mood disorders, and behavioral disorders has escalated dramatically in the last 20 years, resulting in increased risk and clinical presentation of serotonin toxicity. Health care providers must also be aware of other medications and substances with proserotonergic activity that can cause serotonin toxicity when used in combination with these medications. There are many adverse effects of selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors, although their toxicity profile compared to older antidepressants seems to be safer. Serotonin syndrome is described as a clinical triad of mental status changes, autonomic hyperactivity, and neuromuscular abnormalities. It encompasses a spectrum of clinical findings ranging from a few nonspecific symptoms to significant clinical toxicity that can result in death. The objectives of this article are to review specific serotonergic medications including their adverse effects and toxicity in overdose, to describe other medications/substances that have proserotonergic effects, which could result in serotonin excess in combination with traditional serotonergic agents, and to define the criteria for serotonin syndrome/toxicity and its treatment.

Serotonin syndrome is a toxic condition due to serotoninergic hyperstimulation, which is caused mostly by serotonergic agents either in overdose or in combination. The diagnosis is purely clinical and poorly validated. We described a patient with tremor, mydriatic pupils, clonus, and ataxia after a single dose of duloxetine; on the dosage of admission. Duloxetine belongs to a large class of antidepressants called reuptake inhibitors. The case is presented to emphasize this possible toxicity due to increasing availability of serotonergic agents. It is a complex but easily preventable and recognizable condition. We believe this to be one of the rare reports of serotonin syndrome associated with duloxetine.

Hyperthermia is frequently seen in the intensive care setting and is associated with significant morbidity and mortality. It is often initially misdiagnosed as fever associated with infection. Atypical presentations of classic syndromes are common. Clinical suspicion is the key to diagnosis. Adverse drug reactions are a frequent culprit. Syndromes include adrenergic "fever," anticholinergic "fever," antidopaminergic "fever," serotonin syndrome, malignant hyperthermia, uncoupling of oxidative phosphorylation, and withdrawal from baclofen. This review describes the pathophysiology of hyperthermia, as distinct from fever, and the physiology, diagnosis, and treatment of serotonin syndrome, neuroleptic malignant syndrome, malignant hyperthermia, and baclofen withdrawal. Much of the available evidence regarding the treatment of these disorders is based on single case reports, case series, or animal models. Therapeutic modalities consist of identification/withdrawal of possible offending agent(s), support directed at lowering temperature and preventing/treating complications, as well as targeted pharmacologic therapy directed at the specific cause. Early recognition and treatment using a multidisciplinary approach are essential to achieve the best possible outcome.

Herein, we report a patient treated preoperatively with multiple psychiatric medications who developed serotonin syndrome (SS) during the perioperative period. SS was diagnosed using the Hunter Criteria (use of multiple serotonergic drugs preoperatively, hypertonia, and spontaneous clonus) and was presumed to have been triggered by the combination of perioperative and intraoperative serotonergic medications. It is essential that perioperative physicians, especially anesthesiologists, understand the risk factors, clinical scenario, and treatment of SS.

Intrathecal baclofen (ITB) is increasingly being used to reduce spasticity among children with cerebral palsy, dystonia, and spinal cord injuries. However, complications such as withdrawal, which is a potentially life-threatening condition, can occur. Intrathecal baclofen withdrawal should be differentiated with autonomic dysreflexia, malignant hyperthermia, neuroleptic malignant syndrome, and serotonin syndrome. We report a case of ITB withdrawal secondary to low residual volume in the pump reservoir and resembling serotonin syndrome in an adolescent with cerebral palsy. He presented with agitation, diaphoresis, increasing spasticity, rigidity, jitteriness, hyperreflexia, clonus, tachycardia, hypertension, and rhabdomyolysis. Treatment consisted of emergent refilling of the pump, intravenous diazepam, and oral cyproheptadine. We also emphasize the importance of prompt recognition of ITB withdrawal among high-risk patients.

An 18-year-old male developed a severe serotonin syndrome after recreational ingestion of Coricidin HBP (chlorpheniramine 4 mg and dextromethorphan hydrobromide 30 mg). Propofol infusion rapidly normalized his agitation, neuromuscular hyperactivity, and autonomic instability. Confirmatory analysis demonstrated a dextromethorphan serum concentration of 930 ng/mL. Dextromethorphan can produce serotonin syndrome in the absence of another serotonergic drug.

Serotonin toxicity (or serotonin syndrome) has become an increasingly common and important clinical problem in medicine over the last 15 years with the introduction of many new antidepressants that can cause increased levels of serotonin (5-HT) in the central nervous system (CNS). Severe and life-threatening cases are almost exclusively a result of combinations of antidepressants (usually monoamine oxidase inhibitors and selective serotonin reuptake inhibitors). Unfortunately, the term serotonin syndrome has a number of quite different meanings, and many people writing on this subject have failed to differentiate them. This has led to false conclusions regarding the 5-HT receptor subtypes responsible for the life-threatening effects in animal and human toxicity, and suggestions of ineffective treatment strategies. This review primarily addresses the serotonin receptor subtypes that underlie the clinical manifestations of excess CNS serotonin in humans and animals, and their implications for diagnosis and treatment. More specific diagnostic criteria for serotonin toxicity are required to identify situations when specific antidotes are likely to be useful. However, the mainstay of treatment of severe cases is good supportive care and early intubation and paralysis in life-threatening serotonin toxicity.

An 85-year-old woman developed sudden confusion and dysarthria progressing to mutism, orobuccal dyskinesias, generalized tremors worse with activity, ataxia, and rigidity with cog wheeling without high-grade fevers or dysautonomia. These findings were related temporally to the institution of mirtazapine as monotherapy for a major depressive illness with superimposed anxiety disorder. Withdrawal of the agent resulted in early notable clinical resolution with only residual hypertonia after 2 weeks. This is a rare report of serotonin syndrome induced by mirtazapine monotherapy. The hypothesized pathophysiologic mechanism in this case is overstimulation of serotonin (5-hydroxytryptamine or 5-HT) type 1A receptors (5-HT(1A)) in the brainstem and spinal cord in an individual with risk factors for hyperserotoninemia resulting from reduced, acquired endogenous serotonin metabolism.

Objective: To describe a patient who developed serotonin syndrome on four separate occasions as a result of monotherapy with two different selective serotonin receptor inhibitors (fluoxetine and cetalopram)., Design: Case report., Setting: Community hospital., Patients: Single patient with four episodes of serotonin syndrome., Measurements and Main Results: The syndrome was characterized by coma/unresponsiveness (four episodes), dilated pupils (four episodes), salivation (two episodes), dryness of mouth (two episodes), myoclonus like activity of eyelids (four episodes), oculogyric crisis (four episodes), flaccid paralysis of all extremities (four episodes), tremors (two episodes), apnea (two episodes), restlessness (one episode). Recovery occurred within 24 hrs, although muscle pain and weakness persisted for 2 months after stopping fluoxetine. Apnea occurred in both episodes associated with fluoxetine therapy., Conclusion: Apnea and coma may occur in serotonin syndrome.