Serotonin Toxicity Criteria Research Articles

Management of serotonin syndrome (toxicity)

Serotonin syndrome (toxicity), resulting from an excessive accumulation of serotonin in the central nervous system, it can occur due to various factors such as the initiation of medication, overdose or drug interactions. Diagnosing serotonin toxicity presents challenges as there are no definitive criteria. This review delves into the pathophysiology, incidence, clinical assessment and management of serotonin toxicity, stressing the significance of promptly recognizing and managing severe cases. Diagnosis relies primarily relies on clinical assessment due to the absence of specific laboratory tests. The Hunter Serotonin Toxicity criteria are commonly utilized but have only been validated in the overdose setting. Assessing the severity of toxicity is crucial for guiding management decisions. Supportive care, discontinuation of causative agents and symptomatic treatment are prioritized in management. Mild toxicity often requires withdrawal or reduction of the serotonergic agent, while more severe toxicity requires more aggressive resuscitative and supportive care. Severe serotonin toxicity characterized by hyperthermia and rigidity requires aggressive supportive measures, including benzodiazepines, intubation, paralysis and active cooling. Animal studies suggest potential benefits of 5-HT2A receptor antagonists in preventing hyperthermia and fatalities, but only at high doses. Their clinical effectiveness remains uncertain, and evidence is predominately from case series and case reports. Although commonly used, serotonin antagonists like cyproheptadine lack conclusive evidence of efficacy. Other serotonin antagonists such as chlorpromazine and olanzapine have been explored but evidence is limited to case reports. Hence, the cornerstone of treating severe cases does not lie in 'antidote' administration or even diagnosis but in effective early resuscitative and supportive care.

Serotonergic agents and linezolid: Impact of exposure to more than one agent concomitantly on risk of adverse effects

Background: The off-target effects linezolid have the potential to cause serotonin syndrome when given in conjunction with serotonergic agents. Despite package insert labeling as a contraindication, several postmarketing studies have demonstrated a low incidence of serotonin syndrome with the concomitant use of linezolid and other serotonergic agents. Linezolid provides a convenient oral option for gram-positive infections. However, due to concerns for serotonin syndrome, the use of linezolid is sometimes avoided. Methods: We performed a single-center, retrospective, medical record review of all adult inpatients from September 2021 to September 2022. Patients included had 1 administration of linezolid and 1 inpatient administration of a selective serotonin reuptake inhibitor (SSRI) or serotonin and norepinephrine reuptake inhibitor (SNRI) within 14 days. The primary outcome was the incidence of serotonin syndrome as defined by the Hunter serotonin toxicity criteria, which were retrospectively applied to each patient based on medical-record documentation. We compared patients receiving 1 versus multiple serotonergic agents. Secondary outcomes included duration of hospitalization and adverse outcomes based on concerns for serotonin syndrome such as need for rescue, ICU admission, or change in medication. Results: Of the 50 included patients from a convenience sample, 27 (54%) were on linezolid and >1 serotonergic agent. Patients had similar baseline characteristics (Table 1). The most common concomitant agent used was an SSRI. Other agents that predispose patients to serotonin syndrome included opioid analgesics and other classes of antidepressants (Fig. 1). Serotonin syndrome occurred within 48 hours in 1 patient on an SNRI and a continuous fentanyl drip. There was no need for rescue or ICU admission due to serotonin syndrome. No patients were readmitted due to serotonin syndrome, and no differences were observed in hospital lengths of stay. Conclusions: Exposure to a single serotonergic agent combined with receipt of linezolid was not associated with any cases of serotonin syndrome. Exposure to multiple serotonergic agents was not associated with a high incidence of serotonin syndrome. This small series supports previous reports demonstrating relative safety of linezolid given with serotonergic agents and encourages review of interruptive drug–drug interaction alerts for linezolid within the electronic ordering system.Disclosures: None

PAROXETINE OVERDOSE LEADING TO SEROTONIN SYNDROME

PAROXETINE OVERDOSE LEADING TO SEROTONIN SYNDROME

How accurate is the Hunter Serotonin Toxicity Criteria for diagnosing serotonin syndrome?

Carl R. Darnall Army Medical Center, Fort Hood, TX The authors declare no conflicts of interest. The opinions and assertions contained herein are those of the authors and are not to be construed as official or as reflecting the views of the U.S. Army Medical Department, the Army at large, or the Department of Defense.

SUBOXONE-INDUCED SEROTONIN SYNDROME

SESSION TITLE: Wednesday Medical Student/Resident Case Report Posters SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: 10/23/2019 09:45 AM - 10:45 AM INTRODUCTION: Buprenorphine/Naloxone (Suboxone) as part of a multi-modal pain regimen can cause serotonin syndrome CASE PRESENTATION: A 58 year-old woman was brought to the emergency department for acute confusion. Her exam was notable for tachycardia, diaphoresis, agitation, mydriasis, rigidity, hyperreflexia, and inducible clonus, consistent with serotonin syndrome (per Hunter Serotonin Toxicity Criteria). Due to the severity of her symptoms she was sedated, intubated, transferred to the ICU, and later administered a loading dose of cyproheptadine. An interval awakening trial showed significant improvement in her cognition and reduced neuromuscular hyperactivity. She was subsequently extubated in stable condition. Further review of the patient’s medications revealed a long-standing reliance on multiple agents to treat chronic pain, including morphine sulfate, gabapentin, duloxetine (SNRI), and cyclobenzaprine (TCA). One month prior to her hospitalization morphine sulfate had been discontinued in favor of buprenorphine-naloxone (suboxone), an agent increasingly used to curb narcotic dependence. Shortly after starting suboxone she was found to have intermittent episodes of confusion that improved after it was held. After conferring with her pain specialist she again up-titrated suboxone to standard dosing, however her symptoms appreciably worsened leading to her hospitalization for serotonin syndrome. Upon recognition of suboxone as the precipitant of her symptoms, it was permanently discontinued and added to her allergy list. DISCUSSION: With the growing opioid epidemic, buprenorphine has been used as an opioid replacement with less abuse potential due to its partial agonism at the mu receptor. Despite the relative dearth of studies linking it with serotonin syndrome, it is believed to have serotonergic effects similar to other phenanthrene morphine analogues resulting in increased intrasynaptic serotonin levels in both the central and peripheral nervous systems. In recent years case reports have surfaced linking buprenorphine with serotonin syndrome, mostly when used synergistically with tricyclics (1) and/or serotonin reuptake inhibitors (2). This case provides another example of the unintended synergism between these medications. CONCLUSIONS: Given the increasing trend toward multi-modal regimens for pain, this case highlights the importance of 1) understanding pain medication interactions, 2) assessing for early signs of serotonin toxicity when using pro-serotonergic agents, and 3) the potential effect of cp450 polymorphisms on serotonergic drug metabolism. Reference #1: Isenberg D, Wong SC, Curtis JA. Serotonin syndrome triggered by a single dose of suboxone. Am J Emerg Med 2008; 26 (7): 840 Reference #2: Kirk A, Kareem W, Waasil K. Serotonin syndrome associated with buprenorphine/naloxone in combination with paroxetine. Critical Care Medicine 2016; 44 (12): 540 Reference #3: Keegan MT, Brown DR, Rabenstein AA et al. Serotonin syndrome from the interaction of cyclobenzaprine with other serotoninergic agents. Anesth Analg 2006; 103 (6): 1466-8 DISCLOSURES: No relevant relationships by Mehran Giblin, source=Web Response

Desvenlafaxine overdose and the occurrence of serotonin toxicity, seizures and cardiovascular effects

Context: Desvenlafaxine is used to treat major depression. Desvenlafaxine is also the active metabolite of venlafaxine. Venlafaxine overdose can cause serotonin toxicity, seizures and cardiovascular effects, but there is limited information on desvenlafaxine overdose.Objective: We aimed at investigating the clinical effects and complications from desvenlafaxine overdose.Materials and methods: This was a retrospective observational study of desvenlafaxine overdoses over a six-year period. Demographic details, dose and timing of the overdose, together with clinical effects, treatment and complications were extracted from a local hospital network database or the medical records of patients following hospital admission with a desvenlafaxine overdose.Results: There were 182 cases of desvenlafaxine overdose included in the study. From the 182 cases, 75 were desvenlafaxine (± alcohol) only ingestions and 107 included one or more co-ingested drugs. In single-agent desvenlafaxine ingestions, median age was 25 years (range: 13–68 years) with a median ingested dose of 800 mg (range: 250–3500 mg; interquartile range (IQR): 600–1400 mg), and 54/75 (72%) were female. The Glasgow Coma Score (GCS) was 15 in 68/74 (92%) patients, 13–14 in 5/74 (7%), and was seven in one patient following aspiration. Mild hypertension (systolic blood pressure [BP] > 140–180 mmHg) occurred in 23/71 patients (32%), and tachycardia occurred in 29/74 (39%) patients. There were no abnormal QT intervals and no QRS >120 m s. Serotonin toxicity was diagnosed by the treating physician in 7/75 (9%) patients, but only one of these met the Hunter Serotonin Toxicity Criteria. None of the 75 patients who took desvenlafaxine only (± alcohol) had seizures, were admitted to intensive care or died. In comparison, the 107 patients taking desvenlafaxine in overdose with other medications developed more pronounced toxicity. Generalised seizures occurred in 5/107 (5%), but in three of these cases co-ingestants were possible proconvulsants. Fifteen patients had a GCS ≤9 and none had an abnormal QT or QRS. Severe effects appeared to be associated with coingestants.Conclusion: Desvenlafaxine overdose causes minor effects with mild hypertension and tachycardia. The risk of seizures or serotonin toxicity is low.

Unsuspected serotonin toxicity in the ICU.

BackgroundDelirium is a frequently occurring syndrome in patients admitted to the intensive care unit (ICU) or medium care unit (MCU), yet the pathophysiology remains poorly understood. An excess of central serotonin can lead to an altered mental status, associated with autonomic hyperactivity, and neuromuscular excitation. Drugs with serotonergic properties are frequently and for prolonged periods administered to ICU/MCU patients. Therefore, central serotonergic toxicity may constitute a predisposing, contributing or precipitating factor in the emergence of delirium. The purpose of the present study is to determine the number of patients admitted to the ICU or MCU who are diagnosed with delirium and who show characteristics of serotonin toxicity in association with the administration of serotonergic drugs.MethodsDuring a 10-week prospective observational cohort study in the ICU and MCU, patients aged 18 or older, diagnosed with delirium in the ICU or MCU, were included. Patients were considered as delirious in case of a positive CAM-ICU and/or at the start of haloperidol prescription on suspicion of delirium. Once included, patients were screened for recent administered serotonergic drugs and screened for physical signs associated with serotonin toxicity by a standardized physical examination by a specifically trained physician.ResultsA total of 61 patients diagnosed with delirium were enrolled. In 44 out of 61 patients (72 %), the use of drugs potentially contributing to serotonergic toxicity was recorded. Out of 44 patients, seven (16 %) patients showed physical signs of serotonin toxicity and in addition met the Hunter serotonin toxicity criteria, suggesting the presence of serotonergic toxicity. None of these patients were recognized as such by the treating physicians.ConclusionsA significant proportion of delirious patients in the ICU might in fact be classified as suffering from central serotonin toxicity. The awareness of potential serotonin toxicity is low among physicians.

Incidence of Serotonin Syndrome in Patients Treated with Fentanyl on Serotonergic Agents

Background: There has been a recent surge in the literature highlighting the association of fentanyl as precipitating serotonin syndrome in patients on a serotonergic agent. Objective: The purpose of our study was to understand the incidence of serotonin syndrome in patients who receive fentanyl while on serotonergic agents. Study Design: This retrospective analysis was conducted from 2012 to 2013 after approval from the Institutional Review Board. We searched for all patients that had received a serotonergic agent and were admitted to the hospital during the study period. Next, we split these patients into 2 groups by placing all patients who had received fentanyl and a serotonergic agent into one group. We then searched for any of the Hunter Serotonin Toxicity Criteria in the records of patients that had received both fentanyl and a serotonergic agent. Further, we searched for all patients with serotonin syndrome mentioned in their records. Setting: This study was conducted at a 900 bed tertiary care academic center. Results: Over the 2 year study period, 112,045 patients were on a serotonergic agent, and 4,538 of these patients were treated with both fentanyl and a serotonergic agent. A search for Hunter’s Criteria through the records of the patients receiving both fentanyl and a serotonergic agent revealed 23 patients had been documented with some of these symptoms. On detailed chart review, only 4 [95% CI 1 – 10] of these patients truly met Hunter’s Criteria for serotonin syndrome. We then searched all admissions for a diagnosis code of serotonin syndrome during the study period. Five additional cases of serotonin syndrome were found, but none of these patients were treated with fentanyl. Limitations: Some of the limitations of our study include that it represents a single institution, although it is a large academic center. An inherent limitation may be the under diagnosis of serotonin syndrome. Conclusion: The incidence of serotonin syndrome in patients who receive both fentanyl and a serotonergic agent is low. Key words: Fentanyl, serotonin syndrome, serotonergic drugs, opioids, SSRI, antidepressant

Opioids induced serotonin toxicity? Think again.

Sir, In a recently published article, ‘Cardiac arrest from tramadol and fentanyl combination’ by Nair and Chandy,[1] the authors concluded this case to be the first ever report of serotonin toxicity due to the co-administration of fentanyl and tramadol. We argue against this diagnosis as the patient did not fall into the diagnostic criteria of serotonin syndrome. The diagnosis of serotonin toxicity remains clinical one, and no laboratory test confirms the same. It is a syndrome characterised by a triad of neuroexcitatory features (neuromuscular hyperactivity, tremor, clonus, hyper-reflexia, pyramidal rigidity), autonomic hyperactivity (diaphoresis, fever, tachycardia, tachypnoea), and altered mental status (agitation, excitement, confusion).[2] According to another commonly used ‘Hunter's Serotonin Toxicity Criteria’, at least one out of the following five clinical feature is required for the diagnosis of serotonin syndrome: Spontaneous clonus; inducible clonus with agitation or diaphoresis; ocular clonus with agitation or diaphoresis; tremors and hyper-reflexia; hypertonia, temperature above 38°C, and ocular or inducible clonus.[3] The patient in discussion had only agitation without any clonus, hyper-reflexia, or hyperthermia. Occurrence of ventricular tachycardia and subsequent fibrillation remain unexplained using any of the diagnostic criteria's of serotonin toxicity. The same review article[3] as quoted by the authors clearly mentions that both fentanyl and tramadol are weak serotonin reuptake inhibitors (SRIs) and rarely precipitate dose-dependent serotonin toxicity in conjunction with serotonergic medications and that too only if large doses of fentanyl or tramadol are used or in susceptible individuals.[3] The patient in discussion was not on any serotonergic medications and authors had injected only 0.83 μg/kg of fentanyl and over 1 mg/kg of tramadol. They deferred injecting additional doses of fentanyl with the fear of developing chest wall rigidity, which did not appear by that time. Wooden chest syndrome usually occurs at much higher doses of fentanyl (12–15 μg/kg in an adult), or when the drug is injected at a rapid rate.[4] Lack of classical clinical presentation, the absence of administration of large doses of opioids and drug interaction with SRIs, makes the diagnosis of serotonin syndrome unlikely.

Serotonin toxicity association with concomitant antidepressants and rasagiline treatment: retrospective study (STACCATO).

The serotonin toxicity syndrome (STS) is a potential risk with concurrent use of the monoamine oxidase type-B inhibitor rasagiline and antidepressants. To assess systematically the occurrence of STS in patients with Parkinson disease (PD) treated with rasagiline plus antidepressants (R+ATD), rasagiline without antidepressants (R), or antidepressants plus anti-PD dopaminergic medications (ATD) other than either rasagiline or selegiline. A phase IV multicenter retrospective cohort study was conducted of patients with PD who began receiving R+ATD, R, or ATD between September 1, 2006, and December 31, 2008. Medical records were reviewed for patient demographics, treatment details, and hospitalizations/emergency department (ED) visits. An adjudication committee independently reviewed records to verify case ascertainment and used the Hunter Serotonin Toxicity Criteria for case definition. Outcome variables were analyzed by descriptive statistics. A total of 1504 patients with PD (471 with R+ATD; 511 with R; and 525 with ATD) were enrolled from 37 sites. In the R+ATD and ATD groups, selective serotonin reuptake inhibitors (SSRIs) were most frequently used (74.5% and 77%, respectively). In the R+ATD and ATD groups, mean duration of antidepressant use (tricyclic, SSRI, and other) were 50.5-53.5 weeks and 51.7-80.9 weeks, respectively. Overall, 195 patients (13%) from all three groups had one or more hospitalization/ED visits. No cases of STS were identified in any group. In this large multicenter retrospective cohort study, concurrent administration of R+ATD was not associated with STS. The findings of this phase IV study expand the drug interaction and pharmacovigilance safety awareness for the use of antidepressants in patients with PD.

Do serotonin reuptake inhibitors worsen outcome of patients referred to the emergency department for deliberate multi-drug exposure?

Incidence of poisonings with serotonin reuptake inhibitors (SRIs) is growing. SRI toxicity is considered low, but its actual impact in multi-drug poisonings remains unclear. Our objective was to evaluate the consequences of SRI exposure in patients referred to the emergency department (ED) for deliberate multi-drug exposure. Patients admitted for multi-drug exposure involving at least one SRI were matched with patients who did not ingest any SRI, according to age, gender, type of drug and ingested doses. Features of serotonin syndrome according to Sternbach's criteria and Hunter's serotonin toxicity criteria were evaluated from records. In 4years, 148 SRI-exposed patients were included and compared to 296 matched controls. The SRIs mainly involved were escitalopram (22%), venlafaxine (20%), fluoxetine (19%), citalopram (15%) and paroxetine (11%). Serotonin syndrome was diagnosed in one patient, but actually occurred in five SRI-exposed patients based on the retrospective evaluation of records. Twenty patients (14%) exhibited one or more serotonin syndrome criteria. At least two of 11 of Sternbach's criteria and two of nine of Hunter's serotonin toxicity criteria were missing in each chart. Using a conditional logistic regression analysis, seizures (p=0.04) and serotonin syndrome (p=0.01 based on Sternbach's criteria and p=0.004 based on Hunter's serotonin toxicity criteria) more frequently occurred in SRI-exposed patients. Requirement for mechanical ventilation was significantly increased (p=0.03), although admission to the intensive care unit was not. In multi-drug-poisoned patients admitted to the ED, exposure to SRIs significantly increases the risk of seizures and requirement for mechanically ventilation. Diagnosis of serotonin syndrome remains insufficient justifying improved training.

Headache as a presenting feature in patients with serotonin syndrome: A case series

Serotonin syndrome (SS) is a drug-induced constellation of various clinical features that result from excess central serotonergic tone. The clinical features range from barely perceptible to life-threatening conditions. We describe four patients with acute headache (four days to three weeks) who were receiving serotonergic drugs for other indications. There was a temporal relation between the administration of the serotonergic drugs and the development of the headaches. All four patients fulfilled the Hunter Serotonin Toxicity Criteria for SS. In parallel, two patients fulfilled the Sternbach's criteria for SS. Discontinuation of the serotonergic drugs and the administration of cyprohepatadine led to complete improvement in three to seven days in all four patients. A review of the literature suggests that some overlaps exist in the pathophysiology between SS and headache disorders, including medication-overuse headache. The overlap is also in the management. The drugs found to be effective in SS (cyproheptadine, chlorpromazine, olanzapine, etc.) are also known to have positive effects on some headache disorders. Physicians should consider the diagnosis of SS in patients with new onset or worsening headache after the addition of serotonergic drugs, especially in the presence of objective signs on examination suggestive of the disorder such as tremor, fever, hyperreflexia, diaphoresis or tachycardia.

A psychiatric whodunit: Serotonin syndrome in the emergency department

Serotonin syndrome is a life-threatening reaction associated with serotonergic agents. Its mortality is estimated around 11%, hence prompt diagnosis is necessary [1]. Given the variability of its presentation, physicians often misdiagnose this devastating condition. We present a case of serotonin syndrome seen in the Emergency Department by an on-call psychiatric resident and review the Hunter Serotonin Toxicity Criteria, emphasizing the importance of physician familiarity with these criteria.

Concomitant blockade of 5-HT 1A receptor and 5-HT transporter: Use of the Hunter Serotonin Toxicity Criteria in a clinical pharmacology study

There is a potential risk that 5-HT 1A receptor blockade combined with blockade of the 5-HT transporter by an SSRI may cause a toxic increase in 5-HT within the synapse, sparking concern for 'serotonin syndrome', a rare but potentially life threatening condition. We evaluated the safety and pharmacodynamics of the combination of the 5-HT 1A antagonist lecozotan and the SSRI citalopram in a well-controlled Clinical Pharmacology Unit setting using the Hunter Serotonin Toxicity Criteria (HSTC), a set of validated decision rules featuring neurological and body temperature measurements, to detect any clinically relevant serotonin toxicity. Forty-three young healthy male subjects were randomized, to 2 parallel double-blind treatment groups following a 10-day citalopram 40 mg run-in period: citalopram 40 mg/lecozotan 10 mg or citalopram 40 mg/placebo for 9 days. Overall, the combined administration of active drugs was well tolerated, however, one subject experienced moderate hyperreflexia, tremor of the hands, and sweating of hands and feet after 3 days of combined treatment. The event prompted treatment withdrawal and was regarded as mild serotonin toxicity, as per the HSTC. The onset of the event was around the time of peak plasma concentrations (t max) of both lecozotan and citalopram, and its time course corresponds to the well-defined PK profile of lecozotan. No evidence of a PK interaction was detected trough lecozotan and citalopram plasma concentrations analysis. The utility of the HSTC in detecting the non-discrete group of symptoms commonly referred to as “serotonin toxicity” was demonstrated in this clinical pharmacology study combining two 5-HT agents in a clinically controlled setting.

Bupropion, bayesian logic and serotonin toxicity.

I suggest it is important to note that there are some powerful reasons for doubting the attribution of serotonin toxicity (ST) being caused by bupropion that is made in the report by Thorpe et al. [1]. It is well recognised that case reports are low-grade scientific evidence and can be misleading, to the extent of misdirecting doctors down blind alleys [2]. This can be especially counterproductive in emergency situations where less experienced physicians may not have time for protracted deliberation. I have emphasised previously that there is overwhelming evidence that potent serotonergic activity is an absolute prerequisite if a drug is to be capable of precipitating ST [3]. It may seem obvious to state that vitamin C cannot cause ST. A case report claiming that would be regarded sceptically because there is simply no basis for supposing that vitamin C is able to affect serotonin. That is Bayesian logic in operation, i.e., using the prior probability to weigh the expected outcome [4]. As I have pointed out before, drugs like bupropion and mirtazapine, that have no significant serotonergic activity, are no more likely to cause ST than is vitamin C [5]. This scenario has already been enacted, over a decade, with the antidepressant mirtazapine, which was claimed, erroneously, to have serotonergic activity. Many poor quality case reports of ST with mirtazapine were published. This probably led to misdirected treatment of overdoses, some of which may have caused morbidity. It took several reviews to correct this error and establish that mirtazapine cannot cause ST [6–8]. These authors appear to be inviting us to repeat this time-wasting saga. There is no evidence that bupropion can increase 5-HT. Thorpe et al. carelessly and fallaciously represent Piacentini et al.’s results as reporting increased 5HT when, to the contrary, they clearly and specifically state that “5-HT showed no significant change after bupropion injection (Fig. 1C).” [9]. Bupropion has no potency as a serotonin re-uptake inhibitor [10]. There are large case series of overdoses and none of which have shown serotonergic toxicity, not even serotonergic side effects [11]. These would be expected if it had some other mysterious effect on 5-HT that is still unknown, which is unlikely after 30 years of use and research. One case report carries negligible weight when set in that context. Despite the apparent presence of clonus, this case does not meet the Hunter serotonin toxicity criteria, specifically because no drug with established serotonergic activity was given. Bayesian logic indicates there is a low probability that this case represents ST. It is both fundamentally implausible and has other possible interpretations. It is a typical example of a report that is likely to mislead rather than illuminate, about which I have previously written [2].

Serotonin Toxicity Associated with the Use of Linezolid: A Review of Postmarketing Data

Linezolid is the first oxazolidinone antimicrobial marketed in the United States. It exhibits monoamine oxidase (MAO) type A and MAO type B inhibitory effects. The concomitant administration of nonselective MAO inhibitors or MAO-A inhibitors with drugs that increase serotonin concentrations is associated with serotonin toxicity. We requested from the US Food and Drug Administration all postmarketing adverse event reports regarding linezolid that included serotonin toxicity or any report describing cognitive or behavioral symptoms and autonomic and neuromuscular excitability. We assessed the case summaries obtained from the Adverse Event Reporting System database for serotonin toxicity. A case of serotonin toxicity was defined as having the following: (1) linezolid as the primary suspect drug; (2) concurrent administration of > or =1 secondary suspect drug known to increase serotonin concentrations in the central nervous system; and (3) serotonin toxicity, as defined by the modified Hunter Serotonin Toxicity Criteria or by the reporter. Twenty-nine cases were classified as serotonin toxicity. Patients' ages ranged from 17-83 years, and the ratio of females to males was 1:1. The most common class of drugs received concurrently with linezolid was selective serotonin reuptake inhibitors (26 of 43 patients). Thirteen patients required an intervention to prevent permanent impairment or required hospitalization for the adverse event. The use of linezolid with medications that increase concentrations of serotonin in the central nervous system may result in serotonin toxicity. Prescribers must weigh risks and benefits of this combination. Patients and prescribers should be cognizant of signs and symptoms of serotonin toxicity and should initiate appropriate measures if such symptoms develop.

The Hunter Serotonin Toxicity Criteria: simple and accurate diagnostic decision rules for serotonin toxicity.

There are difficulties with the diagnosis of serotonin toxicity, particularly with the use of Sternbach's criteria. To improve the criteria for diagnosing clinically significant serotonin toxicity. Retrospective analysis of prospectively collected data We studied all patients admitted to the Hunter Area Toxicology Service (HATS) following an overdose of a serotonergic drug from January 1987 to November 2002 (n = 2222). Main outcomes were: diagnosis of serotonin toxicity by a clinical toxicologist, fulfillment of Sternbach's criteria and treatment with a serotonin receptor (5-HT(2A)) antagonist. A learning dataset of 473 selective serotonin reuptake inhibitor (SSRI)-alone overdoses was used to determine individual clinical features predictive of serotonin toxicity by univariate analysis. Decision rules using CART analysis were developed, and tested on the dataset of all serotonergic overdose admissions. Numerous clinical features were associated with serotonin toxicity, but only clonus (inducible, spontaneous or ocular), agitation, diaphoresis, tremor and hyperreflexia were needed for accurate prediction of serotonin toxicity as diagnosed by a clinical toxicologist. Although the learning dataset did not include patients with life-threatening serotonin toxicity, hypertonicity and maximum temperature > 38 degrees C were universal in such patients; these features were therefore added. Using these seven clinical features, decision rules (the Hunter Serotonin Toxicity Criteria) were developed. These new criteria were simpler, more sensitive (84% vs. 75%) and more specific (97% vs. 96%) than Sternbach's criteria. These redefined criteria for serotonin toxicity should be more sensitive to serotonin toxicity and less likely to yield false positives.