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We report a 21-year-old man with bipolar disorder who was on a stable dose of escitalopram and risperidone. Tramadol and cough syrup (dextromethorphan) were added for his recent attack of upper respiratory tract infection. However, he developed various neurological symptoms. Haloperidol and ondansetron were added after hospitalisation. However, his condition deteriorated. A diagnosis of serotonin syndrome (SS) was made, and cyproheptadine was started. Cyproheptadine provided relief in most of the symptoms within 48 hours except for the presence of fever and rigidity. The addition of bromocriptine provided a complete resolution of the symptoms. We considered the presence of both SS and neuroleptic malignant syndrome (NMS) in this case. There are four similar cases in the literature. We discussed a diagnostic and therapeutic approach for patients who are on both serotonergic agents and neuroleptics and develop SS-like or NMS-like clinical features., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

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.

A case study of an 89-year-old patient is reported, who was admitted to hospital because of immobility due to pain. After the cause of the pain could initially be clarified and treated, the further clinical course in this very old woman showed an alarming symptom complex of agitation, confusion and cognitive deterioration, which took on grave forms. The work-up of this case showed a typical constellation of pain and depression in old age; however, the pharmaceutical treatment in this case is not atypical and could lead to a severe serotonin syndrome. The interaction, diagnostics, differential diagnosis, pharmacological, functional, codification and economic aspects of the course of the disease are discussed.

Serotonin syndrome and neuroleptic malignant syndrome are two drug toxidromes that have often overlapping and confusing clinical pictures. We report a case of a young man who presented with alteration of mental status, autonomic instability and neuromuscular hyperexcitability following ingestion of multiple psychiatric and antiepileptic medications. The patient satisfied criteria for serotonin syndrome and neuroleptic malignant syndrome, and based on the characteristic clinical features, laboratory findings and clinical course it was concluded that the patient had both toxidromes. The patient was managed with cyproheptadine and supportive measures, and recovered over the course of 3 weeks. A brief review of literature highlighting the diagnostic clues as well as the importance of recognising and distinguishing the often missed and confounding diagnoses follows., (2014 BMJ Publishing Group Ltd.)

A retrospective analysis was followed on 20 case reports covering the possible correlation between the atypical antipsychotic, quetiapine, and neuroleptic malignant syndrome (NMS), determined by the study of 7 different NMS criteria guidelines. A great majority (19) of the case studies did not meet the requirements of all 7 guidelines, frequently due to unreported information. Nor was quetiapine proven to be the sole cause of the possible NMS in the two age groups investigated. Only one case was found to have no other medication or medical conditions confounding the relationship of quetiapine and NMS symptoms, and that case was in the context of a significant quetiapine overdose. The other 19 cases demonstrated the difficulty of identifying the cause of NMS when polypharmacy and other medical conditions are involved. The authors note the need for caution in deciding both the presence of NMS and the causal factors of the symptoms.

Background: Serotonin syndrome (SS) and neuroleptic malignant syndrome (NMS) are uncommon but potentially life-threatening adverse reactions associated with psychotropic medications. Polypharmacy and the similar presentation of SS and NMS make diagnosis of the 2 syndromes problematic., Methods: A MEDLINE search was performed for the period 1960 to 2011 for case reports, review articles, and studies pertaining to SS and NMS., Results: The majority of available literature on SS and NMS consists of case reports, case-control studies, and retrospective reviews. In addition, diagnostic criteria have been developed to aid in the diagnosis and management of SS and NMS., Conclusions: SS presents as mental status changes, autonomic nervous system disturbances, neurologic manifestations, and hyperthermia. Similarly, NMS presents as muscle rigidity, hyperpyrexia, mental status changes, and autonomic instability. However, the clinical laboratory profile of elevations in creatine kinase, liver function tests (lactate dehydrogenase, aspartate transaminase), and white blood cell count, coupled with a low serum iron level, distinguishes NMS from SS among patients taking neuroleptic and serotonin agonist medications simultaneously. For both SS and NMS, immediate discontinuation of the causative agent is the primary treatment, along with supportive care. For NMS, dantrolene is the most effective evidence-based drug treatment whereas there are no evidence-based drug treatments for SS. A 2-week washout of neuroleptic medication minimizes the chance of recurrence.

Objective: To evaluate the use of urine dopamine and catecholamine concentrations as diagnostic aids in a patient with neuroleptic malignant syndrome (NMS) in the emergency department setting., Case Summary: A 61-year-old female on multiple medications, including several antipsychotics, rapidly deteriorated, with fever, lead-pipe rigidity, and decreased level of consciousness. The patient died 20 days after initial presentation to an emergency department. The Naranjo probability scale indicated probable causality for NMS due to quetiapine, haloperidol, and risperidone in this patient, whereas the Naranjo scale assigned only possible causality for serotonin syndrome developing with serotonergic agents. Laboratory investigations of blood and urine revealed elevations in dopamine, metanephrines, and epinephrines, as well as trazodone and risperidone. Serotonin metabolites were not elevated., Discussion: NMS is a rare and potentially severe adverse effect associated with the use of antipsychotic medications. It is mainly characterized by hyperthermia, altered mental state, hemodynamic dysregulation, elevated serum creatine kinase, and rigors. It has been associated with multisystem organ failure potentially leading to rhabdomyolysis, acute respiratory distress syndrome, and disseminated intravascular coagulation. The prevalence of this syndrome is associated with the use of neuroleptics. Serotonin syndrome is another adverse drug reaction leading to NMS associated with elevated serotonin. It occurs when multiple serotonergic medications are ingested and is associated with rapid onset of altered mental status, myoclonus, and autonomic instability. Differentiating between NMS and serotonin syndrome can be challenging because of their similar clinical presentation. This case highlights the importance of a diagnostic aid being available to help distinguish between the 2 syndromes., Conclusions: We propose that laboratory findings that include dopamine and serotonin metabolites can be used as adjuncts to clinical and prescription histories in the diagnosis of NMS. The use of urinary catecholamine as a diagnostic aid in NMS needs further evaluation.

Purpose: Neuroleptic malignant syndrome (NMS) is a rare and life threatening condition usually defined as a complication of treatment with antipsychotics characterized by severe rigidity, tremor, fever, altered mental status, autonomic dysfunction, and elevated serum creatine phosphokinase and white blood cell count. The literature on this topic is rather extensive, but many aspects related to the syndrome are thought to be controversial. The aim of this paper, written with the clinician in mind, is to summarize some of the most prominent controversies that may have importance in usual clinical practice., Methods: The literature was searched for reviews, reports on the series of cases, individual case reports of NMS, and other clinically and theoretically important information., Results: There are controversies associated with virtually all important aspects of NMS. At the moment, it is not clear if this drug reaction is idiosyncratic or not, what diagnostic criteria are the most appropriate for usual clinical practice, and it seems that the estimated incidence is not in accordance with the number of treated patients. There are rather different approaches to the pathophysiological mechanisms, differential diagnosis, and treatment., Conclusions: Some of the controversies related to NMS have an influence on our understanding of the condition and may have importance in clinical practice. There is a need for further research that should elucidate these controversies., ((c) 2010 John Wiley & Sons, Ltd.)

Atypical antipsychotics and selective serotonin reuptake inhibitors (SSRIs) have been prescribed extensively, often in combination with each other. When toxic encephalopathy develops with neuromuscular and autonomic symptoms in a patient taking medication including atypical antipsychotics, it has tended to be diagnosed as neuroleptic malignant syndrome (NMS). However, there have recently been several case reports where the diagnosis of serotonin syndrome is given or raised as a likely differential diagnosis to such cases. In the present review, the author addressed himself to the issues surrounding the neurotoxic reaction to the treatment regimen containing atypical antipsychotics, focusing on the "atypical" forms of NMS and pathophysiological as well as clinical features of serotonin toxicity. Although NMS is idiosyncratic in nature, it appears practically useful to comprehend this syndrome as a spectrum-based concept. Likewise, serotonin toxicity is a broad spectrum of clinical syndromes in close connection with serotomimetic drug use, including varied severity. Some of atypical antipsychotics, i.e., perospirone, aripiprazole, ziprasidone, clozapine, and quetiapine, have been shown to behave as partial agonists at 5-HT1A receptors, providing direct evidence that these atypical antipsychotics are serotomimetic per se. The reciprocal interaction between the dopaminergic and serotonergic systems disturbed by either dopaminergic blockers or serotonergic enhancers leads to the disruption of homeostasis, with typical forms of NMS and serotonin syndrome representing the ends of the common pathophysiological background. The practical and flexible way to consider and manage such cases with updated knowledge derived from basic research should be warranted to be beneficial to our patients.

Serotonin syndrome is a potentially life-threatening adverse drug reaction caused by excessive serotonergic agonism in central and peripheral nervous system serotonergic receptors (Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005;352:1112-1120). Symptoms are characterized by a triad of neuron-excitatory features, which include (a) neuromuscular hyperactivity -- tremor, clonus, myoclonus, hyperreflexia and, in advanced stages, pyramidal rigidity; (b) autonomic hyperactivity -- diaphoresis, fever, tachycardia and tachypnea; (c) altered mental status -- agitation, excitement and, in advanced stages, confusion (Gillman PK. Monoamine oxidase inhibitors, opioid analgesics and serotonin toxicity. Br J Anaesth 2005;95:434-441). It arises when pharmacological agents increase serotonin neurotransmission at postsynaptic 5-hydroxytryptamine 1A and 5-hydroxytryptamine 2A receptors through increased serotonin synthesis, decreased serotonin metabolism, increased serotonin release, inhibition of serotonin reuptake or direct agonism of the serotonin receptors (Houlihan D. Serotonin syndrome resulting from coadministration of tramodol, venlafaxine, and mirtazapine. Ann Pharmacother 2004;38:411-413). The etiology is often the result of therapeutic drug use, intentional overdosing of serotonergic agents or complex interactions between drugs that directly or indirectly modulate the serotonin system (Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005;352:1112-1120). Due to the increasing availability of agents with serotonergic activity, physicians need to more aware of serotonin syndrome. The following case highlights the complex nature in which serotonin syndrome can arise, as well as the proper recognition and treatment of a potentially life-threatening yet easily avoidable condition.

We report two cases of serotonin syndrome in elderly patients during treatment of psychotic depression with atypical antipsychotics and antidepressants. The first case is a 69-year-old man who was admitted for depression with psychosis and treated with trazodone, risperidone, and sertraline. Subsequently, he developed myoclonus, tremor, cogwheel rigidity, and diaphoresis. The second case is a 72-year-old female initially admitted to a medical inpatient unit for a change in mental status that presented as increased confusion, lethargy, slurred speech, and a fever of 101.5 degrees. She had been on phenelzine and quetiapine. In both cases, all symptoms resolved within 24 hours of the psychotropics being stopped. In both cases, we believe that serotonin syndrome was produced by a combination of an antidepressant and an atypical antipsychotic. There have been several case reports of serotonin syndrome from similar combinations of antidepressant and atypical antipsychotic treatment. Clinicians treating elderly patients with a combination of serotonergic antidepressants and atypical antipsychotics for psychotic depression should be aware of the potential for serotonin syndrome.

Background: Serotonin syndrome (SS) and neuroleptic malignant syndrome (NMS) are medical emergencies associated with psychotropic administration. Differentiation and treatment can be complex, especially when features of both syndromes are present and the patient has taken both serotonergic and neuroleptic agents., Method: Case analysis of a poly-drug overdose (venlafaxine, topiramate, divalproex sodium, risperidone, and carbamazepine) presenting with mixed SS/NMS features and whose clinical management suggests a practical algorithm for treatment of undifferentiated SS/NMS in critical care settings., Results: The suggested algorithm includes: 1) Supportive care and withdrawal of all potentially offending agents; 2) Laboratory evaluation with prompt initiation of treatment for both disorders--cyproheptadine for SS and dantrolene for NMS; 3) Do not use bromocriptine (contraindicated in SS) or chlorpromazine (contraindicated in NMS) initially; 4) Add bromocriptine when clinical presentation becomes consistent with NMS (SS can be prolonged if serotonergic agent has long half-life)., Conclusions: Prompt and appropriate identification and intervention are essential for successful management of SS and NMS. The suggested treatment algorithm allows for specific treatment of both disorders and avoids potentially exacerbating either one. The algorithm derived from this case could serve as both a practical guideline and impetus for further investigation in light of increasing psychotropic co-administration.

There appears to be considerable symptomatic overlap between neuroleptic withdrawal reactions and the serotonin syndrome. This case report is of an 8-year-old boy who developed symptoms compatible with both conditions while discontinuing pimozide and starting fluoxetine. It illustrates how the use of neuroleptic medication in young children is not without the risk of serious adverse drug events and can complicate diagnostic issues. This case report supports the suggestion that adverse drug reactions related to neuroleptics and serotonergic agents could be part of the same clinical and neurophysiological spectrum.