FDA black box, VA red ink? Rare reports of anticholinergic syndrome157 may indicate further brainstem involvement. Neuropsychiatric side effects after the use of mefloquine. Historically, the forensic application of a claim of mefloquine intoxication has been made challenging by missed diagnosis and the attribution of psychiatric effects to other causes.178 These problems may now be ameliorated by an improved understanding of the unique clinical presentation of mefloquine intoxication and by insight into the pathophysiology of related neurotoxic effects.40 Successful forensic application of a claim of mefloquine intoxication today rests on establishing that plausible exposure to the drug has occurred and in demonstrating the onset of characteristic or pathognomonic signs or symptoms of intoxication and subsequent neurotoxicity, in temporal association to exposure and to the reasonable exclusion of other plausible etiologies, by record review, careful clinical history, or neuropsychiatric evaluation and in consultation with other medical specialists. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Subject: Updated health care provider information on use of mefloquine hydrochloride (Lariam) for malaria prophylaxis, Memorandum. This content does not have an Arabic version. Careers, Unable to load your collection due to an error. At the clinical level, Croft and Herxheimer critically reviewed 516 case reports and proposed that mefloquine exerts its CNS effects via primary hepatotoxicity and symptomatic thyroid dysfunction [26]. Milatovic D, Jenkins JW, Hood JE, Yu Y, Rongzhu L, Aschner M. Neurotoxicology. Malaria prophylaxis for long-term travellers. Our recent data have established that mefloquine can also trigger oxidative damage and subsequent neurodegeneration in rat cortical primary neurons. For example, it is now well established that symptoms of mefloquine intoxication may confound the diagnosis of posttraumatic stress disorder and traumatic brain injury.65 In certain cases, particularly those involving U.S. service members or veterans in whom these conditions may be common or may not be ruled out, the combination of certain symptoms on careful history, including auditory, visual, or olfactory hallucinations; confusion; and anterograde amnesia, developing in proper temporal relation to exposure, may aid in establishing the diagnosis of mefloquine intoxication to a reasonable degree of certainty, even in the presence of these comorbid conditions. and transmitted securely. Less common events included anxiety, depression, confusion and hallucinations [16]. Since mefloquine was introduced in 1985, the most commonly reported adverse events have been gastrointestinal and neuropsychiatric events [4,5]. In the treatment of uncomplicated falciparum malaria with mefloquine regimens, randomized, controlled trials in Thailand have consistently shown dose-related increases in both moderate and severe neuropsychiatric adverse events [18-21]. *Significant difference between values from control and mefloquine-treated neuronal cells (p<0.05). Bethesda, MD 20894, Web Policies Schwartz E, Potasman I, Rotenberg M, Almog S, Sadetzki S. Serious adverse events of mefloquine in relation to blood level and gender. 2021 Dec;464:152995. doi: 10.1016/j.tox.2021.152995. Copyright: Merative US L.P. 1973, 2023. 8600 Rockville Pike This site needs JavaScript to work properly. Clipboard, Search History, and several other advanced features are temporarily unavailable. He did not return to work the rest of the week and tried to relieve his anxiety with exercise and outdoor activities. In rare cases where documentation is unavailable, exposure should be assumed if the veteran reports a reliable history of taking about 5 tablets (corresponding to the usual treatment dose of 1,250 mg) of appropriate color, shape, and size in response to confirmed or suspected malaria infection, either in 1 dose, or in split doses over 8 to 12 hours. NOTE: We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail. Gap junction channels, composed of proteins called connexins, are involved in coordinated synchronization of neuronal activity, particularly of inhibitory interneurons121 found throughout the limbic system.122 At concentrations consistent with limbic accumulation, mefloquine has been demonstrated to inhibit electrical coupling of neurons with effects on limbic inhibition123,124 and resultant mesolimbic dopaminergic tone.125,126 In dysregulating limbic inhibition, this mechanism may mimic to some degree what is also seen with intoxication by phencyclidine (PCP),127 ketamine,128 and other dissociative amnestics and hallucinogens,129,,131 whose effects share many schizomimetic properties in common with those of mefloquine intoxication and limbic encephalitis. Drug information provided by: Merative, Micromedex. amiodarone will increase the level or effect of mefloquine by affecting hepatic/intestinal Sign In to Email Alerts with your Email Address. These side effects may go away during treatment as your body adjusts to the medicine. WebCialis Together 10mg Tablets - Tadalafil - 4 Tablets. sharing sensitive information, make sure youre on a federal Atovaquone-proguanil versus mefloquine for malaria prophylaxis in nonimmune travelers: results from a randomized, double-blind study. In all cases, the relationship between the drug's administration and the symptoms in question must be carefully evaluated and the temporal relationship adequately established,198 to assign causation confidently. :5 case reports (in French), Effects of mefloquine alone and with alcohol on psychomotor and driving performance, The limbic system conception and its historical evolution, Hepatic encephalopathy: from pathophysiology to treatment, Proposition: limbic encephalitis may represent limbic status epilepticusa review of clinical and EEG characteristics, Drug interactions and pharmacogenetic reactions are the basis for chloroquine and mefloquine-induced psychosis, The antimalarial drug mefloquine binds to membrane phospholipids, Stereoselective passage of mefloquine through the blood-brain barrier in the rat, Central nervous system exposure of next generation quinoline methanols is reduced relative to mefloquine after intravenous dosing in mice, Mefloquine distribution in postmortem cases, Potent block of Cx36 and Cx50 gap junction channels by mefloquine, Electrical synapses in the mammalian brain, The role of gap junctions in the brain in health and disease, Connexin-36 gap junctions mediate electrical coupling between ventral tegmental area GABA neurons, Brain stimulation reward is integrated by a network of electrically coupled GABA neurons, The role of connexin-36 gap junctions in alcohol intoxication and consumption, Mefloquine effects on ventral tegmental area dopamine and GABA neuron inhibition: a physiologic role for connexin-36 gap junctions, Chloroquine psychosis masquerading as PCP: a case report, The N-methyl-D-aspartate antagonists phencyclidine, ketamine and dizocilpine as both behavioral and anatomical models of the dementias, Drugs of abuse and the elicitation of human aggressive behavior, Suicide by hanging under the influence of ketamine and ethanol, The sensed presence: an epileptic aura with religious overtones, Numinous-like auras and spirituality in persons with partial seizures, Phenomenology of hallucinations, illusions, and delusions as part of seizure semiology, Gamma-aminobutyric acid and mefloquine-induced seizures in mice, Cerebral spasm during malaria prophylaxis with mefloquine (in German), Neuropsychiatric problems in 2,500 long-term young travelers to the tropics, Energy deprivation transiently enhances rhythmic inhibitory events in the CA3 hippocampal network in vitro, Nonspecific effects of the gap junction blocker mefloquine on fast hippocampal network oscillations in the adult rat in vitro, Electrical synapses control hippocampal contributions to fear learning and memory, Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies, Limbic encephalitis presenting with seizures, anterograde amnesia, and psychosis in a patient seven weeks status post immature ovarian teratoma removal, Hypersexuality or altered sexual preference following brain injury, Multifocal myoclonus associated with mefloquine chemoprophylaxis, Suspected convulsive side-effect of mefloquine (Lariam) (in German), Anti-malaria drug mefloquine induces motor learning deficits in humans, Anti-Huassociated paraneoplastic encephalomyelitis/sensory neuronopathy: a clinical study of 71 patients, Acute nonparaneoplastic limbic encephalitis in childhood: a case series in Japan, The brain circuitry underlying the temporal evolution of nausea in humans, Mefloquine prophylaxis and hearing, postural control, and vestibular functions, Peripheral polyneuropathy and mefloquine prophylaxis, Mefloquine induces dose-related neurological effects in a rat model, Severe orthostatic hypotension during treatment of falciparum malaria, Postural orthostatic tachycardia syndrome: a case report of palpitations and dizziness following prophylactic mefloquine use, Sequential treatment with quinine and mefloquine or quinine and pyrimethamine-sulfadoxine for falciparum malaria, Central anticholinergic syndrome with the antimalarial drug mefloquine, Limbic encephalitis: a cause of temporal lobe epilepsy with onset in adult life, Animal model of schizophrenia: dysfunction of NMDA receptor-signaling in mice following withdrawal from repeated administration of phencyclidine, Delayed sclerosis, neuroprotection, and limbic epileptogenesis after status epilepticus in the rat, The acute neurotoxicity of mefloquine may be mediated through a disruption of calcium homeostasis and ER function in vitro, The antimalarial potential of 4-quinolinecarbinolamines may be limited due to neurotoxicity and cross-resistance in mefloquine-resistant Plasmodium falciparum strains, Mefloquine induces oxidative stress and neurodegeneration in primary rat cortical neurons, The effect of certain quinoline compounds upon the nervous system of monkeys, Effects of pamaquine on the central nervous system, Neurotoxicity of the 8-aminoquinolines; reactions of various experimental animals to plasmocid, The selective effect of drugs upon nuclei of the oculogyric system, Plasmocid encephalopathy in the rhesus monkey: a study of selective vulnerability, Canadian Department of National Defense (DND), Report of the somalia commission of inquiry: the mefloquine issue, Minister of Public Works and Government Services, Exclusive: Army surrenders to coward GI, U.S. army base tries to stop soldier suicides, Toxic cocktail: army struggles with mental-health care, Malaria chemoprophylaxis: in war and peace, Prevention of malaria in long-term travelers, Tolerability of malaria chemoprophylaxis in non-immune travellers to sub-Saharan Africa: multicentre, randomised, double blind, four arm study, Malaria chemoprophylaxis: strategies for risk groups, Divided-dose kinetics of mefloquine in man, Kinetic studies of mefloquine and of one of its metabolites, Ro 21-5104, in the dog and in man, Mefloquine prophylaxis and neurotoxicity: report of a case (in French), Acute brain syndrome after mefloquine treatment (in German), Cerebral uptake of mefloquine enantiomers in fatal cerebral malaria, Serious adverse events of mefloquine in relation to blood level and gender, Mefloquine tolerability during chemoprophylaxis: focus on adverse event assessments, stereochemistry and compliance, Pharmacokinetic considerations in the repositioning of mefloquine for treatment of progressive multifocal leukoencephalopathy, Polymorphism at the MDR1 locus as a cause of mefloquine-induced psychosis (in Hebrew), MDR1 gene polymorphisms are associated with neuropsychiatric adverse effects of mefloquine, Cerebral uptake of mefloquine enantiomers with and without the P-gp inhibitor elacridar (GF1210918) in mice, Modulation of the function of human MDR1 P-glycoprotein by the antimalarial drug mefloquine. For Current or past users of the drug may claim that exposure has caused physical or mental injury. and transmitted securely. The latter two medicines were both started during his previous hospitalization for hypertensive crisis. A direct causality between mefloquine and severe reactions among travelers has been partly confounded by factors associated with foreign travel and, in the case of therapeutic doses of mefloquine, the central nervous system manifestations of Plasmodium infection itself. Dr. Ritchie is Chief Medical Officer, Department of Mental Health, District of Columbia Department of Health, Washington, DC. The current package insert cautions that mefloquine should not be prescribed for prophylaxis in patients with active depression, a recent history of depression, generalized anxiety disorder, psychosis, or schizophrenia or other major psychiatric disorders.70, It is tempting to speculate that the more serious event referenced in the package insert is a euphemism for psychosis. HHS Vulnerability Disclosure, Help x. Pharmacy product. Current literature lacks evidence of such interactions aside from one study which demonstrated that mefloquine inhibited the metabolism of metoprolol [6]. Dow GS, Koenig ML, Wolf L, Gerena L, Lopez-Sanchez M, Hudson TH, Bhattacharjee AK. Check with your doctor immediately if any of the following side effects occur: Some side effects may occur that usually do not need medical attention. National Library of Medicine Toxic encephalopathy caused by mefloquine (in French)? ter Kuile FO, Luxemburger C, Nosten F, Thwai KL, Chongsuphajaisiddhi T, White NJ. Mefloquine-induced panic attacks and psychosis appear to be even rarer events; an observational study of 16,491 subjects on mefloquine prophylaxis described only 9 and 3 events, respectively, during the course of mefloquine use [14]. Exposure to the drug has been associated with acts of violence and suicide. Nevin RL, Byrd AM. Dr. Nevin is a doctoral student in the Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland. Particularly among veterans, these symptoms risk being misattributed, potentially affecting treatment decisions.6 Clinicians caring for veterans with persistent psychiatric symptoms should therefore screen for prior symptomatic mefloquine exposure and consider the possible AEs of the drug when formulating a differential diagnosis and treatment plan. A successful service-connected disability claim for chronic neuropsychiatric adverse effects from mefloquine. You can mix your dose with a little water if needed. 1998-2023 Mayo Foundation for Medical Education and Research (MFMER). FOIA The insights of the present review also emphasize the critical importance of thoroughly documenting patient education should mefloquine be prescribed, including informing patients of those prodromal symptoms that should compel them to discontinue the medication immediately and seek medical assistance.96 However, as mefloquine intoxication that adversely affects decision-making may occur after only a single 250-mg tablet,40 and as the onset of psychosis may take place suddenly and even without prodromal symptoms, such education may minimize, but will clearly not eliminate,96 the risk of acute harm and subsequent neurotoxicity associated with the drug. Dow GS, Koenig ML, Wolf L, Gerena L, Lopez-Sanchez M, Hudson TH, Bhattacharjee AK. He then went to the emergency department of an outside hospital and was admitted for a hypertensive emergency. The .gov means its official. Consequently, when mefloquine is used for treatment of malaria, the risks of more serious AEs are significantly higher than when the drug is used as directed in prophylaxis.5. He eventually agreed to the nursing staff dispensing all his medications and to routine management of his diabetes. All rights reserved. This question is for testing whether or not you are a human visitor and to prevent automated spam submissions. Livezey J, Oliver T, Cantilena L. Prolonged neuropsychiatric symptoms in a military service member exposed to mefloquine. F, Thwai KL, Chongsuphajaisiddhi T, Cantilena L. Prolonged neuropsychiatric symptoms a! A little water if needed a doctoral student in the Department of Mental Health, District Columbia. Cells ( p < 0.05 ) neuropsychiatric symptoms in a military service member exposed to mefloquine of. And hallucinations [ 16 ] included anxiety, depression, confusion and hallucinations [ ]. 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