Serotonergic Properties Research Articles

Serotonin syndrome controversies: A need for consensus

Serotonin syndrome (SS) is a drug-induced clinical syndrome resulting from increased serotonergic activity in the central nervous system. Although more than seven decades have passed since the first description of SS, it is still an enigma in terms of terminology, clinical features, etiology, pathophysiology, diagnostic criteria, and therapeutic measures. The majority of SS cases have previously been reported by toxicology or psychiatry centers, particularly in people with mental illness. However, serotonergic medications are used for a variety of conditions other than mental illness. Serotonergic properties have been discovered in several new drugs, including over-the-counter medications. These days, cases are reported in non-toxicology centers, such as perioperative settings, neurology clinics, cardiology settings, gynecology settings, and pediatric clinics. Overdoses or poisonings of serotonergic agents constituted the majority of the cases observed in toxicology or psychiatry centers. Overdose or poisoning of serotonergic drugs is uncommon in other clinical settings. Patients may develop SS at therapeutic dosages. Moreover, these patients may continue to use serotonergic medications even if they develop mild to moderate SS due to several reasons. Thus, the clinical presentation (onset, severity, and clinical features) in such instances may not exactly match what toxicologists or psychiatrists observe in their respective settings. They produce considerable diversity in many aspects of SS. However, other experts discount these new developments in SS. Since SS is a potentially lethal illness, consensus is required on several concerns related to SS.

Black Cohosh Interactions with Prescription Medications Associated with Serotonin Toxicity and Rhabdomyolysis: A Case Report

BackgroundSerotonin toxicity is a well-described phenomenon that is commonly attributed to a variety of drug–drug combinations. Some unregulated herbal supplements have been implicated in the onset of serotonin toxicity, however, there is currently minimal literature available on the potential for black cohosh to contribute to rhabdomyolysis and serotonin toxicity, in spite of its known serotonergic properties. Case ReportA middle-aged woman presented to the emergency department with serotonin toxicity and rhabdomyolysis shortly after taking black cohosh supplements in the setting of long-term dual antidepressant use. The serotonin toxicity and rhabdomyolysis resolved with IV fluids, benzodiazepines, and discontinuation of the offending drugs. Why Should an Emergency Physician Be Aware of This?Patients are sometimes not aware of how over-the-counter supplements might interact with their prescription medications. Female patients taking black cohosh to manage hot flashes and menopausal symptoms could be at risk for developing rhabdomyolysis and serotonin toxicity if they are also taking other serotonergic agents.

Differentiated HT22 cells as a novel model for in vitro screening of serotonin reuptake inhibitors.

The mouse hippocampal neuronal cell line HT22 is frequently used as an in vitro model to investigate the role of hippocampal cholinergic neurons in cognitive functions. HT22 cells are derived from hippocampal neuronal HT4 cells. However, whether these cells exhibit the serotonergic neuronal phenotype observed in mature hippocampal neurons has not been determined yet. In this present study, we examined whether the differentiation of HT22 cells enhances the serotonergic neuronal phenotype, and if so, whether it can be used for antidepressant screening. Our results show that differentiation of HT22 cells promoted neurite outgrowth and upregulation of N-methyl-D-aspartate receptor and choline acetyltransferase, which is similar to that observed in primary cultured hippocampal neurons. Furthermore, proteins required for serotonergic neurotransmission, such as tryptophan hydroxylase 2, serotonin (5-hydroxytryptamine, 5-HT)1a receptor, and serotonin transporter (SERT), were significantly upregulated in differentiated HT22 cells. The transcription factor Pet-1 was upregulated during HT22 differentiation and was responsible for the regulation of the serotonergic neuronal phenotype. Differentiation also enhanced the functional serotonergic properties of HT22 cells, as evidenced by increase in intracellular 5-HT levels, serotonin transporter SERT glycosylation, and 5-HT reuptake activity. The sensitivity of 5-HT reuptake inhibition by venlafaxine in differentiated HT22 cells (IC50, 27.21nM) was comparable to that in HEK293 cells overexpressing serotonin transporter SERT (IC50, 30.65nM). These findings suggest that the differentiation of HT22 cells enhances their functional serotonergic properties, and these cells could be a potential in vitro system for assessing the efficacy of antidepressant 5-HT reuptake inhibitors.

The BE (2)-M17 cell line has a better dopaminergic phenotype than the traditionally used for Parkinson´s research SH-SY5Y, which is mostly serotonergic.

SH-SY5Y is a cell line derived from human neuroblastoma. It is one of the most widely used in vitro models to study Parkinson's disease. Surprisingly, it has been found that it does not develop a dopaminergic phenotype after differentiation, questioning its usefulness as a Parkinson's model. There are other in vitro models with better dopaminergic characteristics. BE (2)-M17 is a human neuroblastoma cell line that differentiates when treated with retinoic acid. We compared the dopaminergic and serotonergic properties of both cell lines. BE (2)-M17 has higher basal levels of dopaminergic markers and acquires a serotonergic phenotype during differentiation while maintaining the dopaminergic phenotype. SH-SY5Y has higher basal levels of serotonergic markers but does not acquire a dopaminergic phenotype upon differentiation.

Reported Cases of Serotonin Syndrome in MDMA Users in FAERS Database

3,4-Methylenedioxymethamphetamine (MDMA), is investigated as a treatment for post-traumatic stress disorder and other anxiety-related conditions in multiple placebo-controlled and open label studies. MDMA-assisted therapy is projected for approval by the United States Food and Drug Administration (FDA) and other regulatory agencies worldwide within the next few years. MDMA is a monoamine releaser and uptake inhibitor affecting serotonin, potentially increasing the risk of serotonin syndrome (SS). No instances of SS have occurred in clinical trials. The relatively small number of patients in controlled trials warranted a survey of FDA Adverse Event Reporting System data for the occurrence of SS in a larger database. We found 20 SS cases in people exposed to MDMA, all of which had also taken one or more substances with serotonergic properties in addition to MDMA, including amphetamines, stimulants, and opioids. There were no cases of SS associated with MDMA where MDMA was the sole reported compound taken.

Schizophrenia with Co-morbid Obsessive-Compulsive Disorder: A Case Series

The frequency of co-morbidities like Obsessive Compulsive Disorder (OCD) is common in schizophrenia. Some studies have reported earlier age of onset, more positive and negative symptoms, more depressive symptoms, and worse prognosis in such patients. The phenomenology and management of OCD in schizophrenia is understudied. Evidence claims that the course of illness of both schizophrenia and bipolar disorders may be affected by obsessive-compulsive disorder whereas in other cases antipsychotic induced obsessive-compulsive symptoms have been observed. A meta-analysis of of schizophrenia and its co-morbid psychiatric conditions, found a prevalence of 12.1% for obsessive compulsive disorder, 9.8% for panic disorders, 12.4% for post-traumatic stress disorder and 14.9% for social phobia. SGAs like amisulpride and aripiprazole are found to be useful in the treatment of comorbid OCD in schizophrenia due to their negligible serotonergic properties. A combination of selective serotonin reuptake inhibitors (SSRI) with antipsychotics has been recommended by the American Psychiatric Association (APA) for treatment of comorbid OCD in schizophrenia. Escitalopram at a dose of 20 mg/day has been found to be beneficial in such cases while psychosis worsened with the use of fluvoxamine and clomipramine. Below is a series of seven cases of schizophrenia with co-morbid obsessive-compulsive symptoms who are on treatment for their illness from the psychiatric outpatient department of a rural hospital in central India.

Traditional Uses, Chemical Profile and Biological Activities of Piper hispidum Sw.: a Review

Piper hispidum Sw. (Piperaceae) (syn. Piper hispidinervum) is a medicinal shrub distributed in Central and South America, widely used as an astringent, diuretic, stimulant for unblocking the liver and stopping hemorrhages. The plant has great interest among researchers due to the production of essential oil and important raw material for the chemical industry, which has a high demand for cosmetic, insecticide, and pesticide industries. In this review, traditional uses, phytochemicals, and biological activities of P. hispidum are comprehensively and systematically summarized through searching scientific databases, including Science Direct, PubMed, Google Scholar, Scopus, and Web of Science. Phytochemical studies revealed the presence of amides, benzoic acids, flavonoids, phenylpropanoids, butenolides, phenol, and essential oils; hence it has several activities, such as antioxidant, antibacterial, α-amylase, insecticidal, schistosomicidal, leishmanial, larvicidal, antiplasmodial, cytotoxicity, estrogenic and serotonergic properties. This review is expected to draw the attention of medical professionals and the general public towards P. hispidum as well as to open the door for detailed research in the future.

Serotonin syndrome due to duloxetine and tramadol use in an older patient

This case report describes a 92-year old woman presenting with acute confusion and agitation. She was initially diagnosed as having a hyperactive delirium. However, based on the presence of additional and evolving features of twitchiness, reduced coordination, palpitations and headaches, the diagnosis was re-evaluated. The clinical presentation was subsequently recognised as being that of the serotonin syndrome. In this instance, the serotonin syndrome was judged to have arisen from the concurrent use of duloxetine and tramadol. Duloxetine is an antidepressant with serotonergic properties. Tramadol is an analgesic agent with weak opiate agonist receptor effects, and also exerts reuptake inhibition of noradrenaline and serotonin. The patient’s polypharmacy was reviewed, and alongside other general supportive care measures, her symptoms and signs resolved within 48 hours. This report serves as a clinical reminder on the potential pitfalls of polypharmacy in older patients. Delirium is a common presentation in older patients, and on occasions, clearly establishing the underlying causes or risk factors may prove challenging or even elusive. The report prompts clinicians to bear in mind that the presentation and diagnosis of the serotonin syndrome requires a high index of suspicion, and that patients may present atypically. In support of pharmacovigilance reporting, two scales of causality assessment are employed in this case review. The application of these systems exemplifies their potential in promoting and enhancing objectivity when clinicians report suspected adverse drug reactions (ADRs) noted in routine clinical practice.

Responding to Regulatory Pressure About Nursing Home Abuse

Responding to Regulatory Pressure About Nursing Home Abuse

Obsessive-compulsive disorder comorbid with schizophrenia and bipolar disorder.

Obsessive Compulsive Disorder (OCD) and Obsessive Compulsive Symptoms (OCS) are known to be highly comorbid with bipolar disorder and schizophrenia. Comorbid OCD/OCS influences the course of schizophrenia and bipolar disorder. There is also some evidence to suggest that a diagnosis of OCD may be associated with elevated risk for later development of psychosis and bipolar disorder. Comorbid OCD/OCS is associated with a greater severity of schizophrenia phenotype and poorer prognosis. In addition, certain atypical antipsychotics, clozapine in particular are known to induce or worsen OCS in schizophrenia. OCD when comorbid with bipolar disorder mostly runs an episodic course with worsening and improvement of OCD/OCS in depressive and in manic/hypomanic phases respectively. There is limited systematic data on the treatment of OCD in schizophrenia and bipolar disorder. When OCD presents in the context of schizophrenia, management may include treatment with atypical antipsychotics with limited serotonergic properties, changing the antipsychotic, reduction in the dose of the antipsychotic, addition of cognitive-behavior therapy (CBT), or a specific serotonin reuptake inhibitor (SSRI). When OCD is comorbid with bipolar disorder, mood stabilization is the priority. CBT may be preferred over SSRIs to treat OCD/OCS that persist in between the mood episodes because SSRIs may induce a switch or worsen the course of bipolar disorder. SSRIs when indicated have to be used judiciously under the cover of adequate mood stabilization.

Serotonin neurotrasmission and treatment options for depression

The efficacy of modern antidepressants is largely related to their ability to enhance neurotransmission of serotonin. The medicines with serotonergic properties include trazodone, which is intermediate between tricyclic antidepressants with their powerful antidepressive effect and selective serotonin reuptake inhibitors, as first-line agents in the treatment of depression and anxiety disorders. The value of trazodone for clinical practice is determined by the effective elimination of the symptoms of major depressive disorder in combination with good tolerability, including in elderly patients. Among the advantages of trazodone is the absence of such undesirable effects as sexual dysfunction and weight gain. Trazodone has significant hypnotic and anxiolytic properties, which gives it special meaning in the treatment of depression, combined with insomnia and anxiety. It is emphasized that the beneficial effect of trazodone on sleep should not prevent its main use as a drug for treating major depressive disorder regardless of whether depression is accompanied by insomnia or not.

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.

Schizo-Obsessive Disorder: the Epidemiology, Diagnosis, and Treatment of Comorbid Schizophrenia and OCD

Schizophrenia and obsessive–compulsive disorder (OCD) appear to share clinical features and tend to co-occur more commonly than would be expected by chance. Obsessive–compulsive symptoms (OCS) are commonly observed in schizophrenia. Large-scale follow-up studies are needed to probe this intriguing relationship and to examine the diagnostic stability of the subgroup of patients, who present with features of both. In addition, there is a need for valid and reliable diagnostic instruments in this population. Treatment of schizo-obsessive patients is a challenging endeavor. Though the evidence base is small, patients with schizophrenia and co-occuring OCS are clinically challenging, as their response to traditional treatments can be unusual. Typical antipsychotics are seldom used to treat schizo-obsessive patients owing to their limited serotonergic properties and heightened sensitivity to motor side effects. Evidence points toward a potential bidirectional effect of atypical antipsychotics (improvement and worsening) on OCS in schizophrenia patients. Compared with risperidone and clozapine, olanzapine may show more ameliorating effects on both OCS and schizophrenic symptoms, while aripiprazole has shown a meaningful clinical improvement of OCS in schizophrenia patients. Second-generation antipsychotics may be effective as monotherapy, but a combination with antiobsessional agents is usually required. Cognitive–behavioral therapy, electroconvulsive therapy, and other nonpharmacological interventions may be useful options in select patients with this comorbidity. Most importantly, clinician awareness of the co-occurrence of obsessive–compulsive and psychotic symptoms is important for early identification and treatment of both.

Mania Induced by <em>Garcinia cambogia</em>

To the Editor: Despite that the putative mechanism of action of the weight loss supplement Garcinia cambogia is considered to be serotonergic, literature about its psychiatric effects is limited.1,2 We report 3 stable, euthymic adults whose mania emerged when they began taking G.cambogia. Case 1. Mr A, a 50-year-old man with bipolar I disorder, had been stable off medications for 6 years before presenting to the emergency department with mania. Two months prior, Mr A had begun dieting and taking 2 pills of G. cambogia daily. One month later, he developed grandiosity, irritability, pressured speech, excessive spending, increased social activity, and decreased need for sleep. He was admitted to the psychiatric unit and diagnosed with bipolar I disorder, manic, severe (DSM-5). After a 16-day hospitalization, he was discharged on olanzapine and valproic acid treatment and counseled to avoid G. cambogia. Case 2. Mr B, a 25-year-old man without a psychiatric history, presented to the emergency department with mania. He had begun dieting, exercising, and consuming G. cambogia 1–2 pills daily for 2 months prior to presentation. Within weeks of starting this regimen, he developed inflated self-esteem, grandiosity, decreased need for sleep, increased activities, excessive spending, and pressured speech. Later symptoms included paranoia and religious delusions. He was admitted to the psychiatric unit with bipolar I disorder, manic, severe, with psychosis (DSM-5). He was discharged 8 days later on olanzapine and valproic acid treatment and counseled about cessation of G. cambogia. Case 3. Ms C, a 34-year-old woman with bipolar II disorder and past selective serotonin reuptake inhibitor (SSRI)–induced hypomania, had begun dieting, exercising, and taking G. cambogia for 4–6 weeks prior to onset of symptoms, which included irritability, pressured speech, decreased need for sleep, and agitation. She saw her psychiatrist 1 month after symptom onset and was diagnosed with a recurrence of bipolar II disorder, hypomanic, moderate (DSM-5). Her symptoms remitted with low-dose lorazepam, cessation of G. cambogia, and continuation of preexisting medications (aripiprazole, bupropion, topiramate). This case series describes 3 stable patients whose manias emerged during use of Garcinia cambogia, an over-the-counter weight loss supplement. The putative mediator of G. cambogia’s weight loss effect is hydroxycitric acid (HCA), a substance with demonstrated serotonergic activity in animals and humans.2,3 HCA is thought to promote release and synaptic availability of serotonin, influencing appetite. There are 2 known case reports4,5 that suggest HCA-containing weight loss supplements may contain psychoactive serotonergic properties. One involved mania that emerged on Hydroxycut (Iovate Health Sciences International, Inc), an HCA-containing supplement.4 The other involved a patient who developed serotonin syndrome when an SSRI was combined with G. cambogia.5 Antidepressants have been theorized to promote a switch to mania through action on neurotransmitters.6 Other medical conditions and substances have also been implicated in generating symptoms and in altering the course of bipolar disorder.7–14 Our case series suggests that G. cambogia may induce mania or hypomania in predisposed euthymic individuals. Our patients were euthymic, and manic symptoms developed after G. cambogia was started. Two patients had previously diagnosed bipolar illness; the third did not. Given the multifactorial mechanisms of mania, it is impossible to establish G. cambogia as causative. Furthermore, supplements have inherent variability in dosages and ingredients. However, identifying G. cambogia as a risk is important. For the 2 patients with known bipolar disorder, it seems that G. cambogia altered the course of their disorder by precipitating episodes during stable phases. In Mr B’s case, G. cambogia either unmasked primary bipolar illness or created a substance-induced disorder. In all 3 cases, recovery included cessation of G. cambogia and usual clinical treatment. We remind clinicians of the importance of inventorying all medications, vitamins, and supplements during a patient’s psychiatric evaluation and suggest further research is needed to clarify the psychiatric effects or side effects of Garcinia cambogia.

Interactions of Cathinone NPS with Human Transporters and Receptors in Transfected Cells.

Pharmacological assays carried out in transfected cells have been very useful for describing the mechanism of action of cathinone new psychoactive substances (NPS). These in vitro characterizations provide fast and reliable information on psychoactive substances soon after they emerge for recreational use. Well-investigated comparator compounds, such as methamphetamine, 3,4-methylenedioxymethamphetamine, cocaine, and lysergic acid diethylamide, should always be included in the characterization to enhance the translation of the in vitro data into clinically useful information. We classified cathinone NPS according to their pharmacology at monoamine transporters and receptors. Cathinone NPS are monoamine uptake inhibitors and most induce transporter-mediated monoamine efflux with weak to no activity at pre- or postsynaptic receptors. Cathinones with a nitrogen-containing pyrrolidine ring emerged as NPS that are extremely potent transporter inhibitors but not monoamine releasers. Cathinones exhibit clinically relevant differences in relative potencies at serotonin vs. dopamine transporters. Additionally, cathinone NPS have more dopaminergic vs. serotonergic properties compared with their non-β-keto amphetamine analogs, suggesting more stimulant and reinforcing properties. In conclusion, in vitro pharmacological assays in heterologous expression systems help to predict the psychoactive and toxicological effects of NPS.

Serotonin syndrome: a spectrum of toxicity

SummarySerotonin syndrome (serotonin toxicity or serotonin toxidrome) is a potentially serious and theoretically predictable reaction that appears to be rarely diagnosed in practice in the UK. Some symptoms of serotonin syndrome overlap with features of other presentations in psychiatry and thus may be misattributed to mental illness (‘diagnostic overshadowing’). Further, there may be diagnostic dilemmas in patients on combinations of drugs, those receiving drugs with previously unknown serotonergic properties or where there are drug interactions. Prescriber vigilance and holistic review of the patient, including the pharmacotherapy, may be helpful in avoiding progression of serotonin syndrome to more serious outcomes.

Monoamine transporter and receptor interaction profiles of novel psychoactive substances: Para-halogenated amphetamines and pyrovalerone cathinones

The pharmacology of novel psychoactive substances is mostly unknown. We evaluated the transporter and receptor interaction profiles of a series of para-(4)-substituted amphetamines and pyrovalerone cathinones. We tested the potency of these compounds to inhibit the norepinephrine (NE), dopamine (DA), and serotonin (5-HT) transporters (NET, DAT, and SERT, respectively) using human embryonic kidney 293 cells that express the respective human transporters. We also tested the substance-induced efflux of NE, DA, and 5-HT from monoamine-loaded cells, binding affinities to monoamine receptors, and 5-HT2B receptor activation. Para-(4)-substituted amphetamines, including 4-methylmethcathinone (mephedrone), 4-ethylmethcathinone, 4-fluoroamphetamine, 4-fluoromethamphetamine, 4-fluoromethcatinone (flephedrone), and 4-bromomethcathinone, were relatively more serotonergic (lower DAT:SERT ratio) compared with their analogs amphetamine, methamphetamine, and methcathinone. The 4-methyl, 4-ethyl, and 4-bromo groups resulted in enhanced serotonergic properties compared with the 4-fluoro group. The para-substituted amphetamines released NE and DA. 4-Fluoramphetamine, 4-flouromethamphetamine, 4-methylmethcathinone, and 4-ethylmethcathinone also released 5-HT similarly to 3,4-methylenedioxymethamphetamine. The pyrovalerone cathinones 3,4-methylenedioxypyrovalerone, pyrovalerone, α-pyrrolidinovalerophenone, 3,4-methylenedioxy-α-pyrrolidinopropiophenone, and 3,4-methylenedioxy-α-pyrrolidinobutiophenone potently inhibited the NET and DAT but not the SERT. Naphyrone was the only pyrovalerone that also inhibited the SERT. The pyrovalerone cathinones did not release monoamines. Most of the para-substituted amphetamines exhibited affinity for the 5-HT2A receptor but no relevant activation of the 5-HT2B receptor. All the cathinones exhibited reduced trace amine-associated receptor 1 binding compared with the non-β-keto-amphetamines. In conclusion, para-substituted amphetamines exhibited enhanced direct and indirect serotonergic agonist properties and are likely associated with more MDMA-like effects. The pharmacological profile of the pyrovalerone cathinones predicts pronounced stimulant effects and high abuse liability.

Lorcaserin: A novel antiobesity drug.

Obesity is a major co-morbidity with hypertension and diabetes mellitus. There are few drugs for treatment of obesity like orlistat and recentlty approved drug lorcaserin. Lorcaserin has serotonergic properties and acts as an anorectic. It may cause serious side effects, including serotonin syndrome, particularly when taken with certain medicines that increase serotonin levels or activate serotonin receptors. Although, mainstay and first line of approach of treatment will always remain in having low calorie diet and increase in physical activity. Lorcaserin has come as a new hope to achieve success in treating obese patients but still a long road with further extensive research to be undertaken in the treatment of obesity.

Serotonin syndrome: Risk with concurrent use of SSRIs and other serotonergic meds

M depressive disorder affects 14.8 million Americans, with another 3.3 million having mild depression.1 Both conditions are commonly treated with selective serotonin reuptake inhibitors (SSRIs) and other medications that affect serotonin, such as serotonin norepinephrine reuptake inhibitors (SNRIs). Other commonly prescribed medications that affect serotonin include the triptans and tramadol. A rare adverse effect of taking one or multiple serotonin-modulating agents is serotonin syndrome, which ranges from mild to life-threatening symptoms of agitation, restlessness, muscle rigidity, and autonomic hyperactivity.2

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Introduction: Case Presentation: A 69 year-old woman with a history of depression on paclitaxel and chondrosarcoma underwent left proximal femur resection and replacement in our hospital. Post-operatively, she was noted to have some "shivering" movements and was given fentanyl for pain as well as a dose of meperidine and was admitted to the ward for care. At 4am the following morning, the patient was found to be poorly responsive with a MAP (mean arterial pressure) around 40 mmHg. She then became hypertensive with SBPs in the 200s and MAPs > 100, for which she received 10mg of IV metoprolol and a nicardipine drip was initiated as the patient was transferred to the ICU, where her blood pressure again dropped to MAPs in the 40s and her heart rate slowed to the 50s; nicardipine was stopped, and epinephrine and levophed drips were initiated. Her temperature increased to 38.4°C. The patient had a waxing and waning mental status and bizarre, pressured speech. She also had bilateral myoclonic motions as well as clonus in her lower extremities. The patient was diagnosed with serotonin syndrome by fulfilling Hunter Toxicity Criteria. She received care with withdrawal of paclitaxel, benzodiazepines, and a dose of cyproheptadine with normalization of her blood pressure, mental status, and neurological exam within 24 hours. She has not been restarted on an SSRI (selective serotonin reuptake inhibitor). Discussion: This case provides an opportunity to review the pharmacology, differential diagnosis, clinical spectrum, and management of serotonin syndrome. Our patient met Hunter Toxicity Criteria for the serotonin syndrome by her use of an SSRI as well as one of the following: 1) Spontaneous clonus 2) Inducible clonus plus agitation or diaphoresis, 3) Ocular clonus plus agitation or diaphoresis, 4) tremor plus hyperreflexia, or 5) hypertonism plus temperature > 38 °C (100 °F) plus ocular clonus or inducible clonus. She met multiple criteria. In 2004, there were 48,204 SSRI exposures resulting in an adverse outcome, including over 100 deaths. Several experts argue that "serotonin toxicity" is a more appropriate term than serotonin syndrome, since the clinical spectrum is a predictable consequence of high levels of serotonin rather than an idiosyncratic reaction, such as neuroleptic malignant syndrome. The clinical presentation can run the spectrum from mild tremor to severe autonomic instability, fever and altered mental status. Many medications result in increases in serotonin by a variety of pathways or direct agonism of the serotonin receptor. Common classes that include multiple offending agents include: antidepressants, opiates, anti-emetics, atypical antipsychotics and illicit drugs such as MDMA (Ecstasy). Both fentanyl and meperidine have serotonergic properties, and this patient classically showed symptoms within 24 hours of the additional serotonergic agents. She received supportive care with removal of the agent, which is essential, as well as with short-acting vasoactive medications and benzodiazepines. Antipyretics such as acetaminophen are not advised for serotonin-syndrome related pyrexia. She also received a dose of cyproheptadine, a histamine-1 receptor antagonist with nonspecific 5-HT1A and 5-HT2A antagonism, which can be used in patients who are still having agitation or unstable vital signs despite supportive care. Conclusion: Serotonin syndrome has significant prevalence in the increasing population of patients on chronic SSRI therapy, and its presence is frequently under recognized by physicians as it has a varied clinical presentation. There are many medications that have serotonergic properties and can precipitate serotonin toxicity. It is essential for clinicians to maintain a high suspicion for this disorder to avoid the potentially severe and lethal complication of missing it. It may also be more appropriate to refer to this disease as serotonin toxicity, as it is a predictable consequence of excess serotonin.