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Babaker MA, Ibolgasm Alazabi N, Haredy SA, Mohamed Algohary A, Anwar MM, Yousef EM, Ahmed-Farid OA. Mitigative and neuroprotective effects of Lavandula angustifolia essential oil on serotonin syndrome-induced neurotoxicity in male albino rats. Drug Chem Toxicol 2025:1-19. [PMID: 39894758 DOI: 10.1080/01480545.2025.2458618] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2024] [Revised: 01/13/2025] [Accepted: 01/21/2025] [Indexed: 02/04/2025]
Abstract
The term serotonin syndrome (SS) is a potentially life-threatening devastating condition triggered by the excessive accumulation of serotonin, often due to an overdose or the concurrent use of multiple serotonergic drugs. Lavandula angustifolia (lavender), a known plant from the Lamiaceae family, is very rich in essential oils, minerals, and tannins. This study aimed to elucidate the detrimental effects of SS on the brain and to evaluate the neuroprotective potential of L. angustifolia essential oil. Male rats were randomly divided into the following groups: control (Group 1); L. angustifolia-treated (Group 2); ondansetron-treated high-dose (Group 3); sertraline-treated high-dose (Group 4); low-dose ondansetron + sertraline-treated (Group 5); high-dose ondansetron + sertraline-treated (Group 6); low-dose ondansetron + sertraline + L. angustifolia-treated (Group 7); and high-dose ondansetron + sertraline + L. angustifolia-treated (Group 8). Neurotransmitter levels, dopamine metabolites, and expressed cytokines were quantified. Additionally, histological assessment of the hippocampus was performed. The results revealed significant disruptions in neurotransmitter and amino acid levels within the hippocampus across the treated groups. Notably, the high-dose ondansetron + sertraline group presented pronounced increases in serotonin, 5-HIAA, and proinflammatory cytokines, resulting in neurotoxicity and pronounced alterations in the hippocampus. Conversely, treatment with L. angustifolia significantly attenuated these neurotoxic effects. The findings suggest that L. angustifolia confers neuroprotection against the deleterious effects of SS, particularly by counteracting the neurotoxic impact of combined serotonin 5-HT3 receptor antagonists and serotonin reuptake inhibitors within the hippocampus. These findings highlight the potential of L. angustifolia as a natural therapeutic agent for mitigating SS-induced neurotoxicity.
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Affiliation(s)
- Manal A Babaker
- Department of Chemistry, Faculty of science, Majmaah University, Al Majmaah, Saudi Arabia
| | | | - Shimaa A Haredy
- Department of Physiology, Egyptian Drug Authority, Giza, Egypt
| | - Ayman Mohamed Algohary
- Department of Chemistry, Faculty of science, Majmaah University, Al Majmaah, Saudi Arabia
| | - Mai M Anwar
- Department of Biochemistry, National Organization for Drug Control and Research (NODCAR)/Egyptian Drug Authority (EDA), Cairo, Egypt
| | - Einas M Yousef
- Department of Anatomy & Genetics, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
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Prakash S, Shah CS, Prakash A. Serotonin syndrome controversies: A need for consensus. World J Crit Care Med 2024; 13:94707. [PMID: 38855279 PMCID: PMC11155509 DOI: 10.5492/wjccm.v13.i2.94707] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2024] [Revised: 04/26/2024] [Accepted: 05/11/2024] [Indexed: 06/03/2024] Open
Abstract
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.
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Affiliation(s)
- Sanjay Prakash
- Department of Neurology, Smt. B.K. Shah Medical Institute and Research Centre, Sumandeep Vidyapeeth, Vadodara 391760, Gujarāt, India
| | - Chetsi S Shah
- Department of Neurology, Smt. B.K. Shah Medical Institute and Research Centre, Sumandeep Vidyapeeth, Vadodara 391760, Gujarāt, India
| | - Anurag Prakash
- Medicine, Parul Institute of Medical Sciences and Research Centre, Parul University Waghodia, Vadodara 391760, India
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Popova NK, Tsybko AS, Naumenko VS. The Implication of 5-HT Receptor Family Members in Aggression, Depression and Suicide: Similarity and Difference. Int J Mol Sci 2022; 23:ijms23158814. [PMID: 35955946 PMCID: PMC9369404 DOI: 10.3390/ijms23158814] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2022] [Revised: 07/21/2022] [Accepted: 08/06/2022] [Indexed: 11/16/2022] Open
Abstract
Being different multifactorial forms of psychopathology, aggression, depression and suicidal behavior, which is considered to be violent aggression directed against the self, have principal neurobiological links: preclinical and clinical evidence associates depression, aggression and suicidal behavior with dysregulation in central serotonergic (5-HT) neurotransmission. The implication of different types of 5-HT receptors in the genetic and epigenetic mechanisms of aggression, depression and suicidality has been well recognized. In this review, we consider and compare the orchestra of 5-HT receptors involved in these severe psychopathologies. Specifically, it concentrates on the role of 5-HT1A, 5-HT1B, 5-HT2A, 5-HT2B, 5-HT2C, 5-HT3 and 5-HT7 receptors in the mechanisms underlying the predisposition to aggression, depression and suicidal behavior. The review provides converging lines of evidence that: (1) depression-related 5-HT receptors include those receptors with pro-depressive properties (5-HT2A, 5-HT3 and 5-HT7) as well as those providing an antidepressant effect (5-HT1A, 5-HT1B, 5-HT2C subtypes). (2) Aggression-related 5-HT receptors are identical to depression-related 5-HT receptors with the exception of 5-HT7 receptors. Activation of 5-HT1A, 5-HT1B, 5-HT2A, 5-HT2C receptors attenuate aggressiveness, whereas agonists of 5-HT3 intensify aggressive behavior.
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Hutchison L, Hartman JS, Lerea Y. Serotonin Toxicity in Children and Adolescents: A Systematic Review and Meta-Analysis of Cases. J Child Adolesc Psychopharmacol 2021; 31:394-403. [PMID: 33909452 DOI: 10.1089/cap.2020.0176] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Objectives: Serotonin toxicity is a state of central nervous system (CNS) excitation classically featuring altered mental status, neuromuscular excitation, and autonomic instability. While retrospective studies and reviews have characterized serotonin toxicity in adults, there have been no systematic reviews of serotonin toxicity in pediatric populations. The goal of this review was to use published case reports to describe serotonin toxicity in pediatric patients and to consider the impact of age on clinical presentation. Methods: A search for case reports of serotonin toxicity in patients younger than 18 years was conducted. Cases were systematically screened for inclusion using serotonin toxicity diagnostic tools, and a meta-analysis of case characteristics was conducted. Results: Sixty-six cases of serotonin toxicity in pediatric patients were reviewed. Only 56.1% met diagnostic criteria for serotonin toxicity on all three of the most commonly used diagnostic tools. Antidepressants were found to be the most common trigger of toxicity, implicated in 78.8% of cases. While onset of toxicity was rapid following overdose, toxicity was more likely to be delayed in the setting of medication titration (71.8% vs. 0%, p < 0.0001). Signs of neuromuscular excitation were prevalent, occurring in 92.4% of cases with 81.8% showing the full triad of neuromuscular symptoms, altered mental status, and autonomic instability. The only age-related differences occurred in relation to activation symptoms (more likely to be reported in children than in adolescents) and seizures (less likely to be reported in children than in adolescents or toddlers). Treatment was primarily supportive in nature, although 25.8% of patients received cyproheptadine. In all but one reviewed case, the patient survived. Conclusions: The presentation of serotonin toxicity in the pediatric population is similar to that seen in adults. Treatment is supportive with most patients achieving full recovery. Further exploration of the age-related differences in serotonin activity within the CNS is needed.
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Affiliation(s)
- Lisa Hutchison
- Department of Psychiatry and Behavioral Sciences, Montefiore Medical Center and Albert Einstein College of Medicine, Bronx, New York, USA
| | - Jacob S Hartman
- Department of Psychiatry and Behavioral Sciences, Montefiore Medical Center and Albert Einstein College of Medicine, Bronx, New York, USA
| | - Yehuda Lerea
- Department of Psychiatry and Behavioral Sciences, Montefiore Medical Center and Albert Einstein College of Medicine, Bronx, New York, USA
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Prakash S, Rathore C, Rana K. The prevalence of serotonin syndrome in an intensive care unit: A prospective observational study. J Crit Care 2020; 63:92-97. [PMID: 33621893 DOI: 10.1016/j.jcrc.2020.12.014] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2020] [Revised: 12/11/2020] [Accepted: 12/17/2020] [Indexed: 10/22/2022]
Abstract
PURPOSE In spite of life-threatening nature of serotonin syndrome (SS), it remains an under-diagnosed condition. The availability of epidemiological data about SS, especially in the ICU setting, may help physicians make early diagnoses and interventions. MATERIALS AND METHODS This was a 6-month prospective study in a medical ICU of a tertiary hospital to find out the prevalence of SS. All consecutive adult patients admitted to the medical ICU were evaluated to see if they fulfilled the Hunter criteria of SS. Patients who met the Hunter criteria were evaluated further for other details. RESULTS Overall, 309 patients were identified of which 24 (7.8%) met the Hunter criteria. The mean age was 52.4 years, and 75% were male. Most patients received two or more serotonergic drugs. Ondansetron was the most common serotonergic drug (58%), followed by tramadol (38%), and cough syrup (dextromethorphan or chlorpheniramine, 21%). None of the patients received a diagnosis of SS by the treating physicians. Chronic obstructive pulmonary disease exacerbation with respiratory failure and metabolic encephalopathy were the two most common admission diagnoses (17% each). Twenty-two patients received cyproheptadine. There were no fatalities. CONCLUSION SS is not uncommon in the ICU setting. There is a need to increase awareness among physicians.
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Affiliation(s)
- Sanjay Prakash
- Department of Neurology, Smt. B. K. Shah Medical Institute and Research Centre, Sumandeep Vidyapeeth, Piparia, Waghodia, Vadodara 391760, Gujarat, India.
| | - Chaturbhuj Rathore
- Department of Neurology, Smt. B. K. Shah Medical Institute and Research Centre, Sumandeep Vidyapeeth, Piparia, Waghodia, Vadodara 391760, Gujarat, India.
| | - Kaushik Rana
- Department of Neurology, Smt. B. K. Shah Medical Institute and Research Centre, Sumandeep Vidyapeeth, Piparia, Waghodia, Vadodara 391760, Gujarat, India
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Prakash S, Rathore C, Rana K, Prakash A. Fatal serotonin syndrome: a systematic review of 56 cases in the literature. Clin Toxicol (Phila) 2020; 59:89-100. [PMID: 33196298 DOI: 10.1080/15563650.2020.1839662] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
INTRODUCTION Serotonin syndrome (SS) is a drug-induced potentially life-threatening clinical condition. There is a paucity of data on the risk factors, clinical course, and complications associated with fatal SS. OBJECTIVE To characterize the epidemiological profile, clinical features, and risk factors associated with fatal SS through a systematic review. METHODS We performed a systematic review of MEDLINE and Google Scholar for case reports, case series, or cohort studies of fatal SS. RESULTS Initial database search identified 2326 articles of which 46 (56 patients) were included in the final analysis. The mean age was 42.3 years (range 18-87 years) with female predominance (57%). North America and Europe constitute 80% of the reported fatal SS. The symptoms evolved very rapidly, within 24 h after the administration of serotonergic drugs in 59% of the cases. Fever (61%) was the most common symptom, followed by seizure (36%) and tremors (30%). The mean temperature in the reported cases (25 patients) was 41.6 ± 1.3 °C (range 38.3-43.5 °C). SS was reported to occur with the maintenance dosage of serotonergic agents, after initiation of the drug for the first time, and addition of the drugs for the development of another unrelated illness. Creatine kinase (CK) activities were elevated (>3 times of the upper limit of normal) in eighteen patients, and it was very high (>25,000 IU/L) in four patients. Presence of high grade fever, seizures, and high CK activities may be associated with severe SS. Nine patients (16%) received 5-HT2A antagonists as a therapy. About 50% of patients died within 24 h of the onset of symptoms. CONCLUSIONS While fatal SS is rare, frequently observed features include hyperthermia, seizures, and high CK activities. Cyproheptadine use appears infrequent for these patients.
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Affiliation(s)
- Sanjay Prakash
- Department of Neurology, Smt. B. K. Shah Medical Institute and Research Centre, Sumandeep Vidyapeeth, Vadodara, India
| | - Chaturbhuj Rathore
- Department of Neurology, Smt. B. K. Shah Medical Institute and Research Centre, Sumandeep Vidyapeeth, Vadodara, India
| | - Kaushik Rana
- Department of Neurology, Smt. B. K. Shah Medical Institute and Research Centre, Sumandeep Vidyapeeth, Vadodara, India
| | - Anurag Prakash
- Parul Institute of Medical Sciences & Research, Parul University, Waghodia, Vadodara, India
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Abstract
OBJECTIVE This review of serotonin syndrome or serotonin toxicity covers the years 2014 to 2019, including information on pathophysiology, etiology, and diagnosis, 3 criteria for diagnosing serotonin syndrome, and criteria for neuroleptic malignant syndrome. IMPORTANCE The review highlights the potential lethal combinations of commonly prescribed medications used to treat both veteran and nonveteran patients and includes the latest information on offending medications. CONCLUSIONS Prevention of serotonin toxicity includes informed clinicians, patient education, careful prescribing and monitoring, and avoidance of multidrug regimens.
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Affiliation(s)
- Cynthia Wright Talton
- is a Nurse Practitioner in the Outpatient Mental Health Clinic at the Veterans Affairs Medical Center in Salem, Virginia
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Scotton WJ, Hill LJ, Williams AC, Barnes NM. Serotonin Syndrome: Pathophysiology, Clinical Features, Management, and Potential Future Directions. Int J Tryptophan Res 2019; 12:1178646919873925. [PMID: 31523132 PMCID: PMC6734608 DOI: 10.1177/1178646919873925] [Citation(s) in RCA: 105] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2019] [Accepted: 08/13/2019] [Indexed: 12/18/2022] Open
Abstract
Serotonin syndrome (SS) (also referred to as serotonin toxicity) is a potentially life-threatening drug-induced toxidrome associated with increased serotonergic activity in both the peripheral (PNS) and central nervous systems (CNS). It is characterised by a dose-relevant spectrum of clinical findings related to the level of free serotonin (5-hydroxytryptamine [5-HT]), or 5-HT receptor activation (predominantly the 5-HT1A and 5-HT2A subtypes), which include neuromuscular abnormalities, autonomic hyperactivity, and mental state changes. Severe SS is only usually precipitated by the simultaneous initiation of 2 or more serotonergic drugs, but the syndrome can also occur after the initiation of a single serotonergic drug in a susceptible individual, the addition of a second or third agent to long-standing doses of a maintenance serotonergic drug, or after an overdose. The combination of a monoamine oxidase inhibitor (MAOI), in particular MAO-A inhibitors that preferentially inhibit the metabolism of 5-HT, with serotonergic drugs is especially dangerous, and may lead to the most severe form of the syndrome, and occasionally death. This review describes our current understanding of the pathophysiology, clinical presentation and management of SS, and summarises some of the drugs and interactions that may precipitate the condition. We also discuss the newer novel psychoactive substances (NPSs), a growing public health concern due to their increased availability and use, and their potential risk to evoke the syndrome. Finally, we discuss whether the inhibition of tryptophan hydroxylase (TPH), in particular the neuronal isoform (TPH2), may provide an opportunity to pharmacologically target central 5-HT synthesis, and so develop new treatments for severe, life-threatening SS.
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Affiliation(s)
- William J Scotton
- Department of Neurology, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | - Lisa J Hill
- Institute of Clinical Sciences, University of Birmingham, Birmingham, UK
| | - Adrian C Williams
- Department of Neurology, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | - Nicholas M Barnes
- Institute of Clinical Sciences, University of Birmingham, Birmingham, UK
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Opioid analgesic drugs and serotonin toxicity (syndrome): mechanisms, animal models, and links to clinical effects. Arch Toxicol 2018; 92:2457-2473. [DOI: 10.1007/s00204-018-2244-6] [Citation(s) in RCA: 56] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2018] [Accepted: 06/13/2018] [Indexed: 12/11/2022]
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Nordstrom K, Vilke GM, Wilson MP. Psychiatric Emergencies for Clinicians: Emergency Department Management of Serotonin Syndrome. J Emerg Med 2015; 50:89-91. [PMID: 26454578 DOI: 10.1016/j.jemermed.2015.07.046] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2015] [Accepted: 07/30/2015] [Indexed: 10/22/2022]
Affiliation(s)
- Kimberly Nordstrom
- Denver Health Medical Center, Denver, Colorado; University of Colorado Denver, School of Medicine, Aurora, Colorado
| | - Gary M Vilke
- University of California at San Diego Medical Center, San Diego, California; Department of Emergency Medicine Behavioral Emergencies Research Laboratory, University of California San Diego, San Diego, California
| | - Michael P Wilson
- University of California at San Diego Medical Center, San Diego, California; Department of Emergency Medicine Behavioral Emergencies Research Laboratory, University of California San Diego, San Diego, California
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Kushwaha S, Panda AK, Malhotra HS, Kaur M. Serotonin syndrome following levodopa treatment in diffuse Lewy body disease. BMJ Case Rep 2014; 2014:bcr-2013-201375. [PMID: 25246451 DOI: 10.1136/bcr-2013-201375] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022] Open
Abstract
Serotonin syndrome results from an acute hyperserotonergic state. It is a rare and potentially fatal complication of drugs that affect the central nervous system serotonin levels. It is characterised by a triad of clinical features comprising altered sensorium, autonomic instability and neuromuscular hyperexcitability, in different combinations. We present an atypical case of serotonin syndrome related to levodopa use in a patient of probable Lewy body dementia. This case highlights the difficulty in diagnosis and management of cases with serotonin syndrome in the absence of history of a known serotonergic drug and the fact that levodopa can contribute to its occurrence.
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Affiliation(s)
- Suman Kushwaha
- Department of Neurology, Institute of Human Behaviour and Allied Sciences (IHBAS), Delhi, India
| | - Akhila Kumar Panda
- Department of Neurology, Institute of Human Behaviour and Allied Sciences (IHBAS), Delhi, India
| | - Hardeep Singh Malhotra
- Department of Neurology, Chhatrapati Shahuji Maharaj Medical University, Lucknow, Uttar Pradesh, India
| | - Manmeet Kaur
- Department of Neurology, Institute of Human Behaviour and Allied Sciences (IHBAS), Delhi, India
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Bordelon S, Brett Lloyd R, Rosenthal LJ. Serotonin syndrome and stiff-person syndrome: diagnostic challenges in psychosomatic medicine. PSYCHOSOMATICS 2013; 55:506-11. [PMID: 24360526 DOI: 10.1016/j.psym.2013.08.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/30/2013] [Revised: 07/29/2013] [Accepted: 07/30/2013] [Indexed: 11/30/2022]
Affiliation(s)
- Sean Bordelon
- Department of Psychiatry and Behavioral Sciences, Northwestern University, Chicago, IL.
| | - Robert Brett Lloyd
- Department of Psychiatry and Behavioral Sciences, Northwestern University, Chicago, IL
| | - Lisa J Rosenthal
- Department of Psychiatry and Behavioral Sciences, Northwestern University, Chicago, IL
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Haberzettl R, Bert B, Fink H, Fox MA. Animal models of the serotonin syndrome: a systematic review. Behav Brain Res 2013; 256:328-45. [PMID: 24004848 DOI: 10.1016/j.bbr.2013.08.045] [Citation(s) in RCA: 74] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2013] [Revised: 08/26/2013] [Accepted: 08/28/2013] [Indexed: 11/16/2022]
Abstract
The serotonin syndrome (SS) is a potentially life-threatening disorder in humans which is induced by ingestion of an overdose or by combination of two or more serotonin (5-HT)-enhancing drugs. In animals, acute administration of direct and indirect 5-HT agonists also leads to a set of behavioral and autonomic responses. In the current review, we provide an overview of the existing versions of the animal model of the SS. With a focus on studies in rats and mice, we analyze the frequency of behavioral and autonomic responses following administration of 5-HT-enhancing drugs and direct 5-HT agonists administered alone or in combination, and we briefly discuss the receptor mediation of these responses. Considering species differences, we identify a distinct set of behavioral and autonomic responses that are consistently observed following administration of direct and indirect 5-HT agonists. Finally, we discuss the importance of a standardized assessment of SS responses in rodents and the utility of animal models of the SS in translational studies, and provide suggestions for future research.
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Affiliation(s)
- Robert Haberzettl
- Institute of Pharmacology and Toxicology, School of Veterinary Medicine, Freie Universität Berlin, Koserstrasse 20, 14195 Berlin, Germany
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Stewart AM, Cachat J, Gaikwad S, Robinson KS, Gebhardt M, Kalueff AV. Perspectives on experimental models of serotonin syndrome in zebrafish. Neurochem Int 2013; 62:893-902. [DOI: 10.1016/j.neuint.2013.02.018] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2013] [Revised: 02/10/2013] [Accepted: 02/14/2013] [Indexed: 01/07/2023]
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Abstract
OBJECTIVE Catatonia, a disorder of movement and mood, was described and named in 1874. Other observers quickly made the same recognition. By the turn of the century, however, catatonia was incorporated as a type within a conjured syndrome of schizophrenia. There, catatonia has lain in the psychiatric classification for more than a century. METHOD We review the history of catatonia and its present status. In the 1970s, the tie was questioned when catatonia was recognized among those with mood disorders. The recognition of catatonia within the neuroleptic malignant syndrome offered effective treatments of high doses of benzodiazepines and electroconvulsive therapy (ECT), again questioning the tie. A verifying test for catatonia (the lorazepam sedation test) was developed. Soon the syndromes of delirious mania, toxic serotonin syndrome, and the repetitive behaviors in adolescents with autism were recognized as treatable variations of catatonia. RESULTS Ongoing studies now recognize catatonia among patients labeled as suffering from the Gilles de la Tourette's syndrome, anti-NMDAR encephalitis, obsessive-compulsive disease, and various mutisms. CONCLUSION Applying the treatments for catatonia to patients with these syndromes offers opportunities for clinical relief. Catatonia is a recognizable and effectively treatable neuropsychiatric syndrome. It has many faces. It warrants recognition outside schizophrenia in the psychiatric disease classification.
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Affiliation(s)
- Max Fink
- Department of Psychiatry and Neurology Emeritus, Stony Brook University, Long Island, NY, USA.
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Shen YB, Voilqué G, Odle J, Kim SW. Dietary L-tryptophan supplementation with reduced large neutral amino acids enhances feed efficiency and decreases stress hormone secretion in nursery pigs under social-mixing stress. J Nutr 2012; 142:1540-6. [PMID: 22739380 DOI: 10.3945/jn.112.163824] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
Tryptophan (Trp), the rate-limiting substrate of serotonin [5-hydroxytryptoamine (5-HT)] synthesis in the brain, competes with large neutral amino acids (LNAA) to cross the blood-brain barrier. This study was designed to evaluate the effect of L-Trp supplementation on nursery pigs experiencing social-mixing stress and fed diets varying in LNAA concentrations. Forty-eight individually housed barrows at 6 wk of age were randomly allotted to 4 dietary treatments based on a 2 × 2 factorial arrangement, with L-Trp supplementation (0 or 0.6%) and LNAA concentrations (4.5 or 3.8%) as the 2 main factors. Pigs were fed the diets for 7 d. On d 4, pigs within a treatment were paired in a new pen to create social-mixing stress and behavior was recorded for 24 h. Body weight was measured on d 0, 4, 5, and 7. Saliva and blood were collected on d 4 and 7. On d 7, pigs were killed to obtain hypothalami. During the entire period excluding the mixing day (d 5), L-Trp supplementation improved (P < 0.01) feed efficiency of pigs and lowering the LNAA further enhanced (P < 0.05) the effects of L-Trp. Supplementation of 0.6% L-Trp increased (P < 0.001) hypothalamic 5-HT and 5-hydroxyindoleacetic acid. The salivary cortisol concentration was reduced (P < 0.05) by lowering the LNAA. Collectively, lowering the LNAA further enhanced the improvement of feed efficiency by L-Trp supplementation of nursery pigs under social-mixing stress in association with reduced stress hormones, indicating that reducing LNAA in the diet can facilitate the effect of L-Trp on the stress response of pigs.
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Affiliation(s)
- Yan Bin Shen
- Department of Animal Science, North Carolina State University, Raleigh, NC, USA
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Schmid CL, Bohn LM. Serotonin, but not N-methyltryptamines, activates the serotonin 2A receptor via a ß-arrestin2/Src/Akt signaling complex in vivo. J Neurosci 2010; 30:13513-24. [PMID: 20926677 PMCID: PMC3001293 DOI: 10.1523/jneurosci.1665-10.2010] [Citation(s) in RCA: 126] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2010] [Revised: 08/05/2010] [Accepted: 08/09/2010] [Indexed: 11/21/2022] Open
Abstract
Hallucinogens mediate many of their psychoactive effects by activating serotonin 2A receptors (5-HT(2A)R). Although serotonin is the cognate endogenous neurotransmitter and is not considered hallucinogenic, metabolites of serotonin also have high affinity at 5-HT(2A)R and can induce hallucinations in humans. Here we report that serotonin differs from the psychoactive N-methyltryptamines by its ability to engage a β-arrestin2-mediated signaling cascade in the frontal cortex. Serotonin and 5-hydroxy-L-tryptophan (5-HTP) induce a head-twitch response in wild-type (WT) mice that is a behavioral proxy for 5-HT(2A)R activation. The response in β-arrestin2 knock-out (βarr2-KO) mice is greatly attenuated until the doses are elevated, at which point, βarr2-KO mice display a head-twitch response that can exceed that of WT mice. Direct administration of N-methyltryptamines also produces a greater response in βarr2-KO mice. Moreover, the inhibition of N-methyltransferase blocks 5-HTP-induced head twitches in βarr2-KO mice, indicating that N-methyltryptamines, rather than serotonin, primarily mediate this response. Biochemical studies demonstrate that serotonin stimulates Akt phosphorylation in the frontal cortex and in primary cortical neurons through the activation of a β-arrestin2/phosphoinositide 3-kinase/Src/Akt cascade, whereas N-methyltryptamines do not. Furthermore, disruption of any of the components of this cascade prevents 5-HTP-induced, but not N-methyltryptamine-induced, head twitches. We propose that there is a bifurcation of 5-HT(2A)R signaling that is neurotransmitter and β-arrestin2 dependent. This demonstration of agonist-directed 5-HT(2A)R signaling in vivo may significantly impact drug discovery efforts for the treatment of disorders wherein hallucinations are part of the etiology, such as schizophrenia, or manifest as side effects of treatment, such as depression.
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Affiliation(s)
- Cullen L. Schmid
- The Scripps Research Institute, Molecular Therapeutics and Neuroscience, Jupiter, Florida 33458, and
- The Ohio State University Neuroscience Graduate Studies Program, Columbus, Ohio 43210
| | - Laura M. Bohn
- The Scripps Research Institute, Molecular Therapeutics and Neuroscience, Jupiter, Florida 33458, and
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The serotonin syndrome-the need for physician's awareness. Int J Emerg Med 2010; 3:373-7. [PMID: 21373307 PMCID: PMC3047867 DOI: 10.1007/s12245-010-0195-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2008] [Accepted: 05/30/2010] [Indexed: 01/21/2023] Open
Abstract
Background Serotonin syndrome is a potentially life-threatening adverse drug reaction that results from therapeutic drug use, usually of selective serotonin reuptake inhibitors (SSRIs), intentional excessive use or interactions between various drugs. Case presentation A 16-year-old Caucasian boy presented to our emergency department (ED) with alteration in his mental status for 6 h prior to arrival. On physical examination in our ED, he was combative and disoriented to time, place and person. He was febrile, hypertensive and tachycardic as well. He had intermittent rigid extremities with myoclonus of both lower extremities. A diagnosis of serotonin syndrome (SS) was made based on history of intake of fluoxetine and clinical signs, which included presence of inducible clonus and agitation. The child received supportive care involving intravenous fluids and intravenous lorazepam. The child was back to his baseline mental status and had a normal neurological exam by 24 h and was discharged home later for follow-up with a psychiatrist. Conclusions SS occurs with increasing frequency, and most cases resolve with prompt recognition and supportive care. Failure to make an early diagnosis and to comprehend adverse pharmacological effects of therapy can lead to adverse outcomes.
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Electroconvulsive therapy as a potentially effective treatment for severe serotonin syndrome: two case reports. J Clin Psychopharmacol 2010; 30:350-2. [PMID: 20473084 DOI: 10.1097/jcp.0b013e3181df6130] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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Murphy DL, Fox MA, Timpano KR, Moya PR, Ren-Patterson R, Andrews AM, Holmes A, Lesch KP, Wendland JR. How the serotonin story is being rewritten by new gene-based discoveries principally related to SLC6A4, the serotonin transporter gene, which functions to influence all cellular serotonin systems. Neuropharmacology 2008; 55:932-60. [PMID: 18824000 PMCID: PMC2730952 DOI: 10.1016/j.neuropharm.2008.08.034] [Citation(s) in RCA: 157] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2008] [Revised: 08/15/2008] [Accepted: 08/15/2008] [Indexed: 12/19/2022]
Abstract
Discovered and crystallized over sixty years ago, serotonin's important functions in the brain and body were identified over the ensuing years by neurochemical, physiological and pharmacological investigations. This 2008 M. Rapport Memorial Serotonin Review focuses on some of the most recent discoveries involving serotonin that are based on genetic methodologies. These include examples of the consequences that result from direct serotonergic gene manipulation (gene deletion or overexpression) in mice and other species; an evaluation of some phenotypes related to functional human serotonergic gene variants, particularly in SLC6A4, the serotonin transporter gene; and finally, a consideration of the pharmacogenomics of serotonergic drugs with respect to both their therapeutic actions and side effects. The serotonin transporter (SERT) has been the most comprehensively studied of the serotonin system molecular components, and will be the primary focus of this review. We provide in-depth examples of gene-based discoveries primarily related to SLC6A4 that have clarified serotonin's many important homeostatic functions in humans, non-human primates, mice and other species.
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Affiliation(s)
- Dennis L Murphy
- Laboratory of Clinical Science, NIMH Intramural Research Program, NIH, Building 10, Room 3D41, 10 Center Drive, MSC 1264, Bethesda, MD 20892, USA.
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Storch EA, Murphy TK, Lack CW, Geffken GR, Jacob ML, Goodman WK. Sleep-related problems in pediatric obsessive-compulsive disorder. J Anxiety Disord 2008; 22:877-85. [PMID: 17951025 PMCID: PMC2413417 DOI: 10.1016/j.janxdis.2007.09.003] [Citation(s) in RCA: 90] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2007] [Revised: 09/11/2007] [Accepted: 09/11/2007] [Indexed: 01/02/2023]
Abstract
Although attention has been given to presence of sleep related problems (SRPs) in children with psychiatric conditions, little has been reported on SRPs in youth with obsessive-compulsive disorder (OCD). Sixty-six children and adolescents with OCD were administered the Children's Yale Brown Obsessive-Compulsive Scale and completed the Children's Depression Inventory and Multidimensional Anxiety Scale. Their parents completed the Child Behavior Checklist and Children's Obsessive-Compulsive Impact Scale. A subset of youth (n=41) completed a trial of cognitive-behavioral therapy. Frequency of eight specific SRPs was examined in relation to age, gender, OCD symptom severity, child-rated symptoms of depression and anxiety, parent-proxy ratings of internalizing and externalizing problems, and functional impairment. Ninety-two percent of youth experienced at least one SRP, with 27.3% reporting five or more SRPs. Total SRPs were positively associated with OCD symptom severity, child-rated anxiety, and parent-proxy ratings of internalizing problems. Total and several specific SRPs were reduced following cognitive-behavioral treatment. These results suggest that SRPs are relatively common in youth with OCD, are associated with symptom severity, and warrant attention during assessment and treatment.
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Affiliation(s)
- Eric A Storch
- Department of Psychiatry, University of Florida, Gainesville, FL 32610, USA.
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Murphy DL, Aulakh CS, Garrick NA. How antidepressants work: cautionary conclusions based on clinical and laboratory studies of the longer-term consequences of antidepressant drug treatment. CIBA FOUNDATION SYMPOSIUM 2007; 123:106-25. [PMID: 3028721 DOI: 10.1002/9780470513361.ch7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
Time-dependent alterations in the functional activity of adrenergic and serotonergic neurotransmitter systems and, in particular, a frequently observed down-regulation of brain beta-adrenoceptors have been implicated in antidepressant drug effects. Current studies of catecholamine and serotonin neurotransmitter systems suggest that the net physiological output changes in neuroendocrine responses, blood pressure, sleep and motor activity which follow various antidepressant treatments in psychiatric patients, normal controls and different experimental animals are not indicative of a common response pattern to all therapeutically effective agents. Rather, antidepressant treatment effects differ according to many variables, including the pre-existing state of the organism (e.g. depressed, stressed or normal), the species, the duration of treatment and the particular brain or peripheral circuits investigated. Examples are cited from our studies of the effects of monoamine oxidase inhibitors and other antidepressants on noradrenergic-serotonergic interactions that affect melatonin release and other neuroendocrine responses, on some additional functional end-points, and on depressive mood and other symptoms in patients with depression or other tricyclic-responsive disorders. These examples illustrate the complexity found in attempts to identify a unitary mechanism of antidepressant drug action.
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BRENT JEFFREY, PALMER ROBERT. Monoamine Oxidase Inhibitors and Serotonin Syndrome. HADDAD AND WINCHESTER'S CLINICAL MANAGEMENT OF POISONING AND DRUG OVERDOSE 2007:561-577. [DOI: 10.1016/b978-0-7216-0693-4.50034-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Nisijima K, Shioda K, Iwamura T. Neuroleptic malignant syndrome and serotonin syndrome. PROGRESS IN BRAIN RESEARCH 2007; 162:81-104. [PMID: 17645916 DOI: 10.1016/s0079-6123(06)62006-2] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
This chapter is focused on drug-induced hyperthermia with special regard to use of antipsychotics and antidepressants for the treatment of schizophrenia and major depression, respectively. Neuroleptic malignant syndrome (NMS) develops during the use of neuroleptics, whereas serotonin syndrome is caused mainly by serotoninergic antidepressants. Although both syndromes show various symptoms, hyperthermia is the main clinical manifestation. In this review we describe the historical background, clinical manifestations, diagnosis, and differential diagnosis of these two syndromes based on our observations on the experimental and clinical data.
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Affiliation(s)
- Koichi Nisijima
- Department of Psychiatry, Jichi Medical University, Minamikawachi-Machi, Kawachi-Gun, Tochigi-Ken 329-0498, Japan.
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Isbister GK, Buckley NA. The pathophysiology of serotonin toxicity in animals and humans: implications for diagnosis and treatment. Clin Neuropharmacol 2006; 28:205-14. [PMID: 16239759 DOI: 10.1097/01.wnf.0000177642.89888.85] [Citation(s) in RCA: 132] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
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.
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Affiliation(s)
- Geoffrey K Isbister
- Department of Clinical Toxicology and Pharmacology, Newcastle Mater Misericordiae Hospital and University of Newcastle, NSW, Australia.
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Sato A, Okura Y, Minagawa S, Ohno Y, Fujita S, Kondo D, Hayashi M, Komura S, Kato K, Hanawa H, Kodama M, Aizawa Y. Life-threatening serotonin syndrome in a patient with chronic heart failure and CYP2D6*1/*5. Mayo Clin Proc 2004; 79:1444-8. [PMID: 15544025 DOI: 10.4065/79.11.1444] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
We report a case of serotonin syndrome that occurred in a patient with chronic heart failure associated with a panic disorder. The 39-year-old Japanese man had been treated with paroxetine at 20 mg/d for 1 1/2 years. He presented with rhabdomyolysis, renal failure, fulminant liver failure, cardiac conduction disturbance, and disseminated intravascular coagulation, as well as conventional symptoms of serotonin syndrome including alterations in cognition (disorientation, confusion) and behavior (restlessness), autonomic nervous system dysfunction (fever, shivering), and abnormal neuromuscular activity (ataxia, hyperreflexia, myoclonus). All medications prescribed before hospital admission were discontinued. After 24 hours of continuous venovenous hemofiltration, diuresis resumed and renal and liver function improved rapidly. Disorientation, restlessness, hyperreflexia, and myoclonus abated slowly over the next 72 hours. The patient's anxiety subsided more slowly, and he recovered completely 1 week later. The plasma concentration of paroxetine was elevated far above the upper limit of the therapeutic range. The patient had cytochrome P-450 (CYP) 2D6*1/*5, a heterozygosity of an inactivated allele of CYP2D6, which metabolizes paroxetine. The patient was determined to be an intermediate metabolizer who was potentially vulnerable to paroxetine, a major inhibitor of CYP2D6. Heart failure is often accompanied by psychiatric disorders. A wide range of drugs commonly prescribed for these conditions, including beta-blockers, antiarrhythmics, and antidepressants, are metabolized by CYP2D6. Genetic screening for CYP2D6 in patients with these conditions may prevent life-threatening drug intoxication.
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Affiliation(s)
- Akinori Sato
- Division of Cardiology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
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Dunkley EJC, Isbister GK, Sibbritt D, Dawson AH, Whyte IM. The Hunter Serotonin Toxicity Criteria: simple and accurate diagnostic decision rules for serotonin toxicity. QJM 2003; 96:635-42. [PMID: 12925718 DOI: 10.1093/qjmed/hcg109] [Citation(s) in RCA: 602] [Impact Index Per Article: 27.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND There are difficulties with the diagnosis of serotonin toxicity, particularly with the use of Sternbach's criteria. AIM To improve the criteria for diagnosing clinically significant serotonin toxicity. DESIGN Retrospective analysis of prospectively collected data METHODS 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. RESULTS 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. DISCUSSION These redefined criteria for serotonin toxicity should be more sensitive to serotonin toxicity and less likely to yield false positives.
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Affiliation(s)
- E J C Dunkley
- School of Medical Practice and Population Health, University of Newcastle, Newcastle, NSW, Australia
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Kawanishi C. Genetic predisposition to neuroleptic malignant syndrome : implications for antipsychotic therapy. AMERICAN JOURNAL OF PHARMACOGENOMICS : GENOMICS-RELATED RESEARCH IN DRUG DEVELOPMENT AND CLINICAL PRACTICE 2003; 3:89-95. [PMID: 12749726 DOI: 10.2165/00129785-200303020-00002] [Citation(s) in RCA: 19] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/02/2022]
Abstract
The pathogenetic mechanism of neuroleptic malignant syndrome (NMS), a potentially lethal adverse effect of antipsychotics, is not well understood. In addition to acquired risk factors, clinical observations suggest a number of genetic factors predisposing patients to NMS. Recent findings in pharmacogenetics indicate that the genetic polymorphisms for drug-metabolizing enzymes, drug transporters, and possibly drug-targeting molecules, are associated with the interindividual differences in drug responses concerning both efficacy and adverse reactions. Genetic association studies have sought to identify polymorphisms influencing susceptibility to NMS, especially with respect to the dopamine D(2) receptor, serotonin receptor, and cytochrome p450 2D6. While a few candidate polymorphisms were associated with NMS, a large controlled study is needed to attain statistical power. On the other hand, NMS might include heterogeneous conditions with common characteristic symptoms but different causative mechanisms. Further analysis of individuals with identified genetic mutations or polymorphisms should advance our understanding of mechanisms underlying NMS.
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Affiliation(s)
- Chiaki Kawanishi
- Department of Psychiatry, Yokohama City University School of Medicine, Yokohama, Japan.
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Hernández JL, Ramos FJ, Infante J, Rebollo M, González-Macías J. Severe serotonin syndrome induced by mirtazapine monotherapy. Ann Pharmacother 2002; 36:641-3. [PMID: 11918514 DOI: 10.1345/aph.1a302] [Citation(s) in RCA: 40] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022] Open
Abstract
OBJECTIVE To document a case of serotonin syndrome (SS) associated with mirtazapine monotherapy, review the previously reported cases of SS associated with this tetracyclic antidepressant, and discuss the possible pathogenic mechanisms leading to this serious adverse drug reaction. CASE SUMMARY A 75-year-old man developed agitation, confusion, incoordination, and gait disturbance because of progressive rigidity. Mirtazapine had been started 8 days earlier to control major depression. Physical examination revealed diaphoresis, low-grade fever, hypertension, tachycardia, bilateral cogwheel rigidity, hyperreflexia, tremor, and myoclonus, symptoms and signs that are consistent with severe SS. DISCUSSION A review of the cases of SS with implication of mirtazapine as the cause was performed. The possible pathogenic mechanisms leading to this adverse reaction in this patient are also discussed, and pathophysiologic hypotheses are formulated. CONCLUSIONS Although mirtazapine offers clinicians a combination of strong efficacy and good safety, we suggest bearing SS in mind when prescribing this drug, especially in frail, elderly patients with underlying chronic conditions. In these patients, it might be more adequate to start mirtazapine therapy at a lower dose (<15 mg/d).
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Affiliation(s)
- José L Hernández
- Department of Internal Medicine, Hospital Marqués de Valdecilla, Santander, Spain.
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Chechani V. Serotonin syndrome presenting as hypotonic coma and apnea: potentially fatal complications of selective serotonin receptor inhibitor therapy. Crit Care Med 2002; 30:473-6. [PMID: 11889332 DOI: 10.1097/00003246-200202000-00033] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
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.
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Radomski JW, Dursun SM, Reveley MA, Kutcher SP. An exploratory approach to the serotonin syndrome: an update of clinical phenomenology and revised diagnostic criteria. Med Hypotheses 2000; 55:218-24. [PMID: 10985912 DOI: 10.1054/mehy.2000.1047] [Citation(s) in RCA: 132] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Serotonin-related adverse side-effects of psychotropic drugs were first recorded in humans in 1960. However, since 1991, these related cases have been diagnosed as 'serotonin syndrome (SS)' according to the criteria reported by Sternbach. In this article, we have reviewed and further explored the validity of these criteria. The clinical profile of 24 cases of the SS published between 1991 and 1995 has been analysed in detail and compared with the symptomatology of 38 previous cases which were also further analysed. Mainly Medline and references from other reports were used to review these cases. The general concept put forward by Sternbach has been approved. On the basis of the severity of overall clinical presentation, it appeared that there is a need to further classify SS into three main groups as: (1) mild state of serotonin-related symptoms; (2) serotonin syndrome (full-blown form); (3) toxic states. Furthermore, the detailed analysis of the SS cases published so far suggests that 'the diagnostic criteria for SS' also require further revision, and these are presented here. We also review, present and discuss the guidelines for the management and treatment of SS.
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Abstract
Serotonin syndrome is caused by drug induced excess of intrasynaptic 5-hydroxytryptamine. The clinical manifestations are mediated by the action of 5-hydroxytryptamine on various subtypes of serotonin receptors. There is no effective drug treatment established. The history of the treatment of serotonin syndrome with 5-hydroxytryptamine blocking drugs is reviewed. A literature search was undertaken using both Medline and a manual search of the older literature. Reports of cases treated with the 5-HT2 blockers cyproheptadine and chlorpromazine were identified and analysed. There is some evidence suggesting the efficacy of chlorpromazine and cyproheptadine in the treatment of serotonin syndrome. The evidence for cyproheptadine is less substantial, perhaps because the dose of cyproheptadine necessary to ensure blockade of brain 5-HT2 receptors is 20-30 mg, which is higher than that used in the cases reported to date (4-16 mg).
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Affiliation(s)
- P K Gillman
- Consultant Psychiatrist, Mount Pleasant, Queensland, Australia.
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Abstract
This review focuses on the history of investigations into the behavioural reaction resulting from excess stimulation of post-synaptic 5-hydroxytryptamine receptors and the relative risk of this occurring with different combinations of drugs. Other aspects, particularly treatment with 5-hydroxytryptamine receptor antagonists, are reviewed in a recent separate paper [44]. The first human case was in 1955 and animal work had defined the characteristic features by 1958, and established they were lessened by chlorpromazine. Substantial evidence of a 'dose-effect' relationship existed by 1984. The relative risk with different drug combinations is assessed from available evidence and argued to be strongly associated with the degree of elevation of 5-hydroxytryptamine, which is greatest following combinations of irreversible inhibitors of monoamine oxidase A and B with potent serotonin reuptake inhibitors. The various serotonergic drugs that may be implicated in serotonin syndrome are tabulated and discussed in relation to the relative risk. It is suggested that the proposed 'diagnostic criteria' for serotonin syndrome are inappropriate since there is a continuous spectrum from side effects to toxicity. The term 'serotonin syndrome' may encourage the presumption that it is an idiosyncratic response, as neuroleptic malignant syndrome is usually considered to be. The terms 'toxic serotomimetic reaction' or 'toxic serotonin syndrome' may be preferable alternatives. The differences between serotonin syndrome and neuroleptic malignant syndrome are highlighted with examples from difficult or questionable cases in the recent literature. It is proposed that more systematic national collection of toxicity data is essential in order to quantify the relative risk of serotonin syndrome with various combinations of serotonergic drugs.
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Abstract
The selective serotonin reuptake inhibitors (SSRIs) may occasionally induce extrapyramidal side-effects (EPS) and/or akathisia. This may be a consequence of serotonergically-mediated inhibition of the dopaminergic system. Manifestations of these effects in patients may depend on predisposing factors such as the presence of psychomotor disturbance, a previous history of drug-induced akathisia and/or EPS, concurrent antidopaminergic and/or serotonergic therapy, recent monoamine oxidase inhibitor discontinuation, comorbid Parkinson's disease and possibly deficient cytochrome P450 (CYP) isoenzyme status. There is increasing awareness that there may be a distinct form of melancholic or endogenous depression with neurobiological underpinnings similar to those of disorders of the basal ganglia such as Parkinson's disease. Thus, it is not surprising that some individuals with depressive disorders appear to be susceptible to developing drug-induced EPS and/or akathisia. In addition, the propensity for the SSRIs to induce these effects in individual patients may vary within the drug class depending, for example, on their selectivity for serotonin relative to other monoamines, affinity for the 5-HT2C receptor, pharmacokinetic drug interaction potential with concomitantly administered neuroleptics and potential for accumulation due to a long half-life. The relative risk of EPS and akathisia associated with SSRIs have yet to be clearly established. The potential risks may be reduced by avoiding rapid and unnecessary dose titration. Furthermore, early recognition and appropriate management of EPS and/or akathisia is required to prevent the impact of these effects on patient compliance and subjective well-being. It is important that the rare occurrence of EPS in patients receiving SSRIs does not preclude their use in Parkinson's disease where their potentially significant role requires more systematic evaluation.
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Affiliation(s)
- R M Lane
- Pfizer Inc., New York, NY 10017, USA.
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Dalvi A, Ford B. Antiparkinsonian Agents : Clinically Significant Drug Interactions and Adverse Effects, and Their Management. CNS Drugs 1998; 9:291-310. [PMID: 27521014 DOI: 10.2165/00023210-199809040-00005] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/02/2022]
Abstract
The treatment of Parkinson's disease for most patients entails long term exposure to multiple agents, including anticholinergics, levodopa, amantadine, dopamine receptor agonists, catechol-O-methyltransferase inhibitors, selegiline (deprenyl) and clozapine. Patients with Parkinson's disease require medication for the control of the motor symptoms of their condition, for related medical or psychiatric symptoms of the disorder, and for concurrent medical problems, such as hypertension or cardiac disease.All these agents may cause adverse effects. There is a potential for drug-drug interactions between different antiparkinsonian agents and between antiparkinsonian medication and the other drugs a patient may be taking. Clinicians caring for patients with Parkinson's disease must be knowledgable about the potential adverse effects and drug interactions of an expanding array of medications for this condition.
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Affiliation(s)
- A Dalvi
- Department of Neurology, Columbia College of Physicians and Surgeons, New York, New York, USA
| | - B Ford
- Department of Neurology, Columbia College of Physicians and Surgeons, New York, New York, USA.
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Butzkueven H. A case of serotonin syndrome induced by moclobemide during an extreme heatwave. AUSTRALIAN AND NEW ZEALAND JOURNAL OF MEDICINE 1997; 27:603-4. [PMID: 9404601 DOI: 10.1111/j.1445-5994.1997.tb00980.x] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
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Grounds D. Grounds for more backup. AUSTRALIAN AND NEW ZEALAND JOURNAL OF MEDICINE 1997; 27:602. [PMID: 9404600 DOI: 10.1111/j.1445-5994.1997.tb00979.x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
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Abstract
Serotonin syndrome is characterized by varied degrees of cognitive, autonomic, and neuromuscular dysfunction and can only be produced by drug therapy that increases central nervous system serotonin neurotransmission. Information gained from a retrospective review of 127 cases of serotonin syndrome is presented. It is not uncommon for severe cases of serotonin syndrome to be confused with neuroleptic malignant syndrome. Treatment is mainly supportive, but specific pharmacologic therapy with serotonin antagonists may be potentially beneficial.
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Affiliation(s)
- K C Mills
- Department of Emergency Medicine and Medical Toxicology, Wayne State University School of Medicine, Detroit, Michigan, USA
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Phillips S, Brent J, Kulig K, Heiligenstein J, Birkett M. Fluoxetine versus tricyclic antidepressants: a prospective multicenter study of antidepressant drug overdoses. The Antidepressant Study Group. J Emerg Med 1997; 15:439-45. [PMID: 9279692 DOI: 10.1016/s0736-4679(97)00072-3] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
This study compares the clinical course of tricyclic antidepressant and fluoxetine overdose. The study was a prospective case series of 9 urban hospital systems. Consecutive sampling of overdose patients presenting to emergency departments provided the participants for the study. The therapy was determined by each institution. Clinical, laboratory, economic impact, and coroners' information was gathered. Of 622 patients, 482 were excluded because of significant coingestants or lack of laboratory confirmation, leaving 124 tricyclic antidepressant and 16 fluoxetine cases. Twenty-seven percent of tricyclic antidepressant patients were alert on arrival to the emergency department; only 12.9% remained alert. The following were significantly more frequent after tricyclic antidepressant overdose: agitation, tachycardia, QRS prolongation, terminal R-wave deviation, intubation, coma, and admission to the intensive care unit. The mean tricyclic plus metabolite level was 777.6 ng/mL (range = 20-5260 ng/ mL), and the mean fluoxetine plus metabolite level was 496.4 ng/mL (range = 120-1930 ng/mL). There were two tricyclic antidepressant deaths. Of 179 total drug-ingestion deaths from the coroners' records, 38 were from tricyclic antidepressants and none from fluoxetine. Thus, tricyclic antidepressant overdoses resulted in more toxicity and more frequent admissions to the intensive care unit than did fluoxetine overdoses.
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Affiliation(s)
- S Phillips
- Toxicology Associates, Rocky Mountain Poison Center, University of Colorado Health Sciences Center, Denver 80210, USA
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Abstract
The use of psychotropic drugs has dramatically changed the lives of many; yet as often occurs with technological advances, negative outcomes can be encountered. Potentially fatal reactions to neuroleptic drugs and serotonin-enhancing agents (e.g., antidepressants) have been presented in Part 1, with the intent of alerting and informing psychiatric nurses. Part 2 will complete this series on catastrophic consequences of psychotropic drugs with a discussion of agranulocytosis and lithium toxicity.
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Affiliation(s)
- N L Keltner
- Graduate Programs, School of Nursing, University of Alabama at Birmingham 35294, USA
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Ackerman DL, Greenland S, Bystritsky A, Katz RJ. Relationship between early side effects and therapeutic effects of clomipramine therapy in obsessive-compulsive disorder. J Clin Psychopharmacol 1996; 16:324-8. [PMID: 8835709 DOI: 10.1097/00004714-199608000-00009] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Early adverse effects of a drug may be a manifestation of individual differences in drug metabolism or of different pathologic processes. These differences may influence therapeutic responsiveness. Using data from Ciba-Geigy's multicenter 10-week clinical trial, we studied the relationship between early side effects and subsequent therapeutic response to clomipramine (CMI) in obsessive-compulsive disorder. We used tabular analyses and multiple regression to evaluate associations between early complaints and change in score on the Yale-Brown Obsessive-Compulsive Scale. We also evaluated whether early complaints were drug related (i.e., true side effects). It appeared that dry mouth, constipation, dizziness, insomnia, male impotence, nervousness, palpitation, and tremor reported during the first 4 weeks were predictive of good response to CMI. Myoclonus and tinnitus appeared weakly associated with treatment success. Most of these complaints were reported more by the CMI group than the placebo group, and more during CMI treatment than before. The more common complaints may reflect an individual's ability to metabolize CMI appropriately so that adequate therapeutic blood levels are attained. The less common complaints may reflect a sensitivity to CMI's serotonergic actions.
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Affiliation(s)
- D L Ackerman
- Department of Psychiatry and Biobehavioral Sciences, UCLA School of Medicine, USA
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Abstract
Serotonin syndrome, a condition with numerous clinical neurological manifestations, is the result of central serotonergic hyperstimulation. Features of the syndrome include mental status and behavioral changes (agitation, excitement, hypomania, obtundation), motor system involvement (myoclonus, hemiballismus, tremor, hyperreflexia, motor weakness, dysarthria, ataxia) and autonomic symptoms (fever, chills, diarrhea). Serotonin syndrome has been reported exclusively in patients on medications for psychiatric illness and Parkinsonism, despite the fact that the putative action of many antimigraine agents also involves the serotonin system. We herein report six patients with migraine who developed symptoms suggestive of the serotonin syndrome. Five were taking one or more serotomimetic agents for migraine prophylaxis (sertraline, paroxetine, lithium, imipramine, amitriptyline). In each case the symptoms and signs developed in close temporal proximity with use of a migraine abortive agent known to interact with serotonin receptors. In three instances the agent was subcutaneous sumatriptan and, in three, intravenous dihydroergotamine. In each instance the symptoms were transient and there was full recovery. With the ever increasing use of migraine medications active at serotonin receptor sites, cases of serotonin syndrome will likely occur more frequently. It is important that physicians treating migraine are aware of the serotonin syndrome and are able to recognize its varying presentations.
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