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Mefloquine is an antimalarial drug that is associated with a significant risk of chronic neuropsychiatric adverse effects (AEs). The drug was licensed by the FDA in 1989 after development by scientists affiliated with Walter Reed Army Institute of Research (WRAIR). By the early 1990s, mefloquine had become the U.S. military’s drug of choice both for treatment of uncomplicated malaria and for antimalarial prophylaxis and was administered as a convenient weekly dose. Mefloquine was prescribed widely to U.S. military personnel beginning with operations in Somalia in 1992 and over the next 2 decades during certain deployments to Iraq and Afghanistan and to other malaria-endemic areas.1
In 2013, following a decline of U.S. military use, the FDA added a boxed warning to the mefloquine product documentation to caution that neuropsychiatric AEs from the drug could last years after use and even be permanent. The U.S. military subsequently deemed mefloquine to be a prophylactic “drug of last resort.”2 Recently, researchers at WRAIR have acknowledged that chronic neuropsychiatric AEs attributable to mefloquine, including nightmares, insomnia, anxiety, irritability, and cognitive dysfunction, may confound the diagnosis of posttraumatic stress disorder (PTSD).3 The VA has awarded at least 1 disability claim for service-connected psychiatric conditions that it attributed to mefloquine exposure, and it is likely that in the coming years such claims will increase.2
Susceptibility to Chronic Neuropsychiatric AEs
Why mefloquine seems to cause chronic neuropsychiatric AEs in only certain individuals is unclear, although genetic susceptibility to drug-induced toxic encephalopathy and neurotoxicity are suspected.1 There is no screening test for susceptibility to AEs before mefloquine use, so the current U.S. product documentation cautiously warns that when used for prophylaxis, mefloquine should be discontinued at the onset of any neurologic or psychiatric symptom, many of which are considered prodromal to more serious AEs that may occur with continued dosing.4
Although chronic neuropsychiatric AEs have been reported to develop after only a single weekly dose, most clinically significant chronic AEs seem to occur among those who developed at least 1 prodromal neuropsychiatric symptom during early use but who continued weekly use despite these symptoms in a manner contrary to current product documentation guidance.4 In contrast, when mefloquine is administered for the treatment of malaria, typically at 5 times the weekly prophylactic dose and commonly in split doses over 8 to 12 hours, dosing is often complete by the time prodromal symptoms develop. 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
Screening for Symptomatic Mefloquine Exposure
As the boxed warning indicates, certain psychiatric symptoms that occur with mefloquine use may become chronic and may confound psychiatric diagnosis. 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.
For example, a veteran with a history of symptomatic mefloquine exposure who later is diagnosed with PTSD may experience 1 or more symptoms, such as insomnia or cognitive dysfunction, which may be primarily attributable to the chronic AEs of the drug. The origins of the symptoms may be distinct from exposure to trauma and may not respond as effectively to certain conventional therapies for PTSD, requiring consideration of alternate therapies.3 The confounding role of psychiatric symptoms attributable to mefloquine exposure may explain failed response to medications and psychotherapy. Multidisciplinary evaluation and management may be appropriate for such patients.
If symptomatic mefloquine exposure is suspected, a clinician must establish evidence of exposure to the drug and the veteran’s development of neuropsychiatric symptoms associated with such exposure. The following sections provide guidance to aid in screening both for exposure to the drug and for the development of specific neuropsychiatric symptoms during prophylaxis or following the treatment of malaria.
Mefloquine Exposure
Mefloquine was licensed in the U.S. as a branded medication (Lariam) from 1989 to 2011, and the drug also has been available in a variety of generic equivalents from 2003 to the present. All versions of mefloquine approved in the U.S. have been formulated as a white/slightly-off-white, smaller than dime-sized round tablet, containing 250 mg of mefloquine hydrochloride.
When used for prophylaxis in military settings, the drug was often dispensed informally without documentation, sometimes including directly observed therapy under command direction.1,2 Therefore, even in the absence of prescribing documentation, a veteran who endorses a consistent history of malaria prophylaxis with mefloquine should be considered as having evidence of exposure.2
Exposure to mefloquine is unlikely if the veteran reports taking a daily antimalarial medication—more likely it was doxycycline or atovaquone/proguanil (marketed as Malarone). In rare cases, the drug may have been erroneously prescribed or been mistakenly taken daily for prophylaxis or, in more common cases, a prophylactic “loading dose” (typically 1 tablet daily for 3 days prior to weekly dosing) was used.7,8
Exposure also was unlikely if the veteran reports taking an antimalarial that was dosed weekly with a tablet that was not of the appropriate color, shape, and size. More likely that drug was chloroquine. Although most prophylactic use of mefloquine among U.S. veterans followed its licensing by the FDA in 1989, the drug is known to have been administered to a small number of U.S. military personnel prior to its licensing during clinical trials, including personnel deployed on certain operations during the 1980s.1
For treatment of malaria, mefloquine was used widely until better-tolerated drugs became available, beginning in the early 2000s, although some use of mefloquine in the military continues to this day. In most cases, clinicians should rely on records of hospitalization to identify whether mefloquine was administered. 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.
Symptoms During Prophylaxis
If prophylactic exposure to the drug has been established, the clinician should confirm the presence of neuropsychiatric symptoms during the exposure. Particularly among veterans deploying to malaria-endemic combat areas, such symptoms may have occurred during a period of heightened stress coincident with their initial deployment, and the veterans may have misattributed these symptoms to nonmefloquine factors. The clinician should therefore take a careful history to identify specific symptoms listed in the mefloquine product documentation. Many AEs will commonly manifest following the first 3 doses, and the clinician may find that focusing on this period is useful.9
When mefloquine is used for prophylaxis, anxiety and depression each affect between 1% and 10% of users. Other AEs that may develop include panic attacks; severe mood swings; behavioral AEs, including agitation, aggression, restlessness, and mania; symptoms of psychosis, including paranoia, delusions, and hallucinations; dissociative symptoms, including depersonalization; suicidal ideation; and cognitive AEs, including confusion.
The common symptoms of insomnia and abnormal dreaming affect > 10% of users. Particularly if multiple symptoms occur or if any of these symptoms occur following or coincident with symptoms of disturbed sleep, these should be considered strong evidence of symptomatic exposure.4 Veterans who report a history of continued mefloquine use despite the onset of such symptoms may be at particularly increased risk of chronic AEs.
The clinician should consider as evidence of symptomatic exposure information provided by others, including reports of obvious signs of nightmares or psychosis affecting the veteran. Clinicians should be aware that confusion and other psychiatric AEs caused by mefloquine during prophylactic use may limit the validity of self-reported history. Similarly, a history of seizure with mefloquine use or of the development of specific neurologic symptoms, particularly visual disturbances, dizziness, vertigo, disequilibrium, and paresthesias, also should be considered strong evidence of symptomatic exposure and indication of an increased risk of chronic psychiatric AEs.4
Posttreatment Adverse Effects
Although chronic psychiatric AEs following malaria infection have long been attributed to cerebral involvement, recognition that mefloquine may independently cause chronic neuropsychiatric AEs may require that individual cases be reexamined to properly assign causation.10 Particularly in uncomplicated cases of malaria, neuropsychiatric symptoms that develop only after treatment with mefloquine should be considered plausibly to be due to the drug and as evidence of symptomatic exposure.
As with use of mefloquine in prophylaxis, these neuropsychiatric symptoms may evolve in the weeks to months following exposure. They also may contribute to lasting and significant changes in personality, mood, cognition, thought, sleep, and behavior.6
Conclusion
Chronic AEs from mefloquine may provide a parsimonious explanation for the onset and persistence of a veteran’s psychiatric symptoms, particularly in cases where these may have failed to respond to treatment. Clinicians evaluating veterans who are seeking care for lasting psychiatric symptoms should ensure that they screen for prior symptomatic mefloquine exposure. As recognition grows of the drug’s chronic AEs, symptomatic mefloquine exposure is likely to emerge as a significant known confounder in the diagnosis of psychiatric disorders, including PTSD, among the current generation of U.S. veterans.
1. Nevin RL. Mefloquine and posttraumatic stress disorder. In: Ritchie EC, ed. Textbook of Military Medicine. Forensic and Ethical Issues in Military Behavioral Health. Washington, DC: Borden Institute; 2015:277-296.
2. Nevin RL, Ritchie EC. FDA black box, VA red ink? A successful service-connected disability claim for chronic neuropsychiatric adverse effects from mefloquine. Fed Pract. 2016;33(10):20-24.
3. Livezey J, Oliver T, Cantilena L. Prolonged neuropsychiatric symptoms in a military service member exposed to mefloquine. Drug Saf Case Rep. 2016;3(1):7.
4. Nevin RL, Byrd AM. Neuropsychiatric adverse reactions to mefloquine: a systematic comparison of prescribing and patient safety guidance in the US, UK, Ireland, Australia, New Zealand, and Canada. Neurol Ther. 2016;5(1):69-83.
5. Rendi-Wagner P, Noedl H, Wernsdorfer WH, Wiedermann G, Mikolasek A, Kollaritsch H. Unexpected frequency, duration and spectrum of adverse events after therapeutic dose of mefloquine in healthy adults. Acta Trop. 2002;81(2):167-173.
6. Nevin RL, Ritchie E. The mefloquine intoxication syndrome: a significant potential confounder in the diagnosis and management of PTSD and other chronic deployment-related neuropsychiatric disorders. In: Ritchie EC, ed. Posttraumatic Stress Disorder and Related Diseases in Combat Veterans. Cham, Switzerland: Springer International Publishing; 2015:257-278.
7. Cohen MR, Smetzer JL. FDA advise-ERR: mefloquine—not the same as Malarone; zoster vaccine is not for the immunosuppressed; TXA mistaken as tenecteplase; guidelines for adult IV push medications. Hosp Pharm. 2015;50(11):961-964.
8. Boudreau E, Schuster B, Sanchez J, et al. Tolerability of prophylactic Lariam regimens. Trop Med Parasitol. 1993;44(3):257-265.
9. Stürchler D, Handschin J, Kaiser D, et al. Neuropsychiatric side effects of mefloquine. N Engl J Med. 1990;322(24):1752-1753.
10. Nevin RL, Croft AM. Psychiatric effects of malaria and anti-malarial drugs: historical and modern perspectives. Malar J. 2016;15:332.
Mefloquine is an antimalarial drug that is associated with a significant risk of chronic neuropsychiatric adverse effects (AEs). The drug was licensed by the FDA in 1989 after development by scientists affiliated with Walter Reed Army Institute of Research (WRAIR). By the early 1990s, mefloquine had become the U.S. military’s drug of choice both for treatment of uncomplicated malaria and for antimalarial prophylaxis and was administered as a convenient weekly dose. Mefloquine was prescribed widely to U.S. military personnel beginning with operations in Somalia in 1992 and over the next 2 decades during certain deployments to Iraq and Afghanistan and to other malaria-endemic areas.1
In 2013, following a decline of U.S. military use, the FDA added a boxed warning to the mefloquine product documentation to caution that neuropsychiatric AEs from the drug could last years after use and even be permanent. The U.S. military subsequently deemed mefloquine to be a prophylactic “drug of last resort.”2 Recently, researchers at WRAIR have acknowledged that chronic neuropsychiatric AEs attributable to mefloquine, including nightmares, insomnia, anxiety, irritability, and cognitive dysfunction, may confound the diagnosis of posttraumatic stress disorder (PTSD).3 The VA has awarded at least 1 disability claim for service-connected psychiatric conditions that it attributed to mefloquine exposure, and it is likely that in the coming years such claims will increase.2
Susceptibility to Chronic Neuropsychiatric AEs
Why mefloquine seems to cause chronic neuropsychiatric AEs in only certain individuals is unclear, although genetic susceptibility to drug-induced toxic encephalopathy and neurotoxicity are suspected.1 There is no screening test for susceptibility to AEs before mefloquine use, so the current U.S. product documentation cautiously warns that when used for prophylaxis, mefloquine should be discontinued at the onset of any neurologic or psychiatric symptom, many of which are considered prodromal to more serious AEs that may occur with continued dosing.4
Although chronic neuropsychiatric AEs have been reported to develop after only a single weekly dose, most clinically significant chronic AEs seem to occur among those who developed at least 1 prodromal neuropsychiatric symptom during early use but who continued weekly use despite these symptoms in a manner contrary to current product documentation guidance.4 In contrast, when mefloquine is administered for the treatment of malaria, typically at 5 times the weekly prophylactic dose and commonly in split doses over 8 to 12 hours, dosing is often complete by the time prodromal symptoms develop. 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
Screening for Symptomatic Mefloquine Exposure
As the boxed warning indicates, certain psychiatric symptoms that occur with mefloquine use may become chronic and may confound psychiatric diagnosis. 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.
For example, a veteran with a history of symptomatic mefloquine exposure who later is diagnosed with PTSD may experience 1 or more symptoms, such as insomnia or cognitive dysfunction, which may be primarily attributable to the chronic AEs of the drug. The origins of the symptoms may be distinct from exposure to trauma and may not respond as effectively to certain conventional therapies for PTSD, requiring consideration of alternate therapies.3 The confounding role of psychiatric symptoms attributable to mefloquine exposure may explain failed response to medications and psychotherapy. Multidisciplinary evaluation and management may be appropriate for such patients.
If symptomatic mefloquine exposure is suspected, a clinician must establish evidence of exposure to the drug and the veteran’s development of neuropsychiatric symptoms associated with such exposure. The following sections provide guidance to aid in screening both for exposure to the drug and for the development of specific neuropsychiatric symptoms during prophylaxis or following the treatment of malaria.
Mefloquine Exposure
Mefloquine was licensed in the U.S. as a branded medication (Lariam) from 1989 to 2011, and the drug also has been available in a variety of generic equivalents from 2003 to the present. All versions of mefloquine approved in the U.S. have been formulated as a white/slightly-off-white, smaller than dime-sized round tablet, containing 250 mg of mefloquine hydrochloride.
When used for prophylaxis in military settings, the drug was often dispensed informally without documentation, sometimes including directly observed therapy under command direction.1,2 Therefore, even in the absence of prescribing documentation, a veteran who endorses a consistent history of malaria prophylaxis with mefloquine should be considered as having evidence of exposure.2
Exposure to mefloquine is unlikely if the veteran reports taking a daily antimalarial medication—more likely it was doxycycline or atovaquone/proguanil (marketed as Malarone). In rare cases, the drug may have been erroneously prescribed or been mistakenly taken daily for prophylaxis or, in more common cases, a prophylactic “loading dose” (typically 1 tablet daily for 3 days prior to weekly dosing) was used.7,8
Exposure also was unlikely if the veteran reports taking an antimalarial that was dosed weekly with a tablet that was not of the appropriate color, shape, and size. More likely that drug was chloroquine. Although most prophylactic use of mefloquine among U.S. veterans followed its licensing by the FDA in 1989, the drug is known to have been administered to a small number of U.S. military personnel prior to its licensing during clinical trials, including personnel deployed on certain operations during the 1980s.1
For treatment of malaria, mefloquine was used widely until better-tolerated drugs became available, beginning in the early 2000s, although some use of mefloquine in the military continues to this day. In most cases, clinicians should rely on records of hospitalization to identify whether mefloquine was administered. 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.
Symptoms During Prophylaxis
If prophylactic exposure to the drug has been established, the clinician should confirm the presence of neuropsychiatric symptoms during the exposure. Particularly among veterans deploying to malaria-endemic combat areas, such symptoms may have occurred during a period of heightened stress coincident with their initial deployment, and the veterans may have misattributed these symptoms to nonmefloquine factors. The clinician should therefore take a careful history to identify specific symptoms listed in the mefloquine product documentation. Many AEs will commonly manifest following the first 3 doses, and the clinician may find that focusing on this period is useful.9
When mefloquine is used for prophylaxis, anxiety and depression each affect between 1% and 10% of users. Other AEs that may develop include panic attacks; severe mood swings; behavioral AEs, including agitation, aggression, restlessness, and mania; symptoms of psychosis, including paranoia, delusions, and hallucinations; dissociative symptoms, including depersonalization; suicidal ideation; and cognitive AEs, including confusion.
The common symptoms of insomnia and abnormal dreaming affect > 10% of users. Particularly if multiple symptoms occur or if any of these symptoms occur following or coincident with symptoms of disturbed sleep, these should be considered strong evidence of symptomatic exposure.4 Veterans who report a history of continued mefloquine use despite the onset of such symptoms may be at particularly increased risk of chronic AEs.
The clinician should consider as evidence of symptomatic exposure information provided by others, including reports of obvious signs of nightmares or psychosis affecting the veteran. Clinicians should be aware that confusion and other psychiatric AEs caused by mefloquine during prophylactic use may limit the validity of self-reported history. Similarly, a history of seizure with mefloquine use or of the development of specific neurologic symptoms, particularly visual disturbances, dizziness, vertigo, disequilibrium, and paresthesias, also should be considered strong evidence of symptomatic exposure and indication of an increased risk of chronic psychiatric AEs.4
Posttreatment Adverse Effects
Although chronic psychiatric AEs following malaria infection have long been attributed to cerebral involvement, recognition that mefloquine may independently cause chronic neuropsychiatric AEs may require that individual cases be reexamined to properly assign causation.10 Particularly in uncomplicated cases of malaria, neuropsychiatric symptoms that develop only after treatment with mefloquine should be considered plausibly to be due to the drug and as evidence of symptomatic exposure.
As with use of mefloquine in prophylaxis, these neuropsychiatric symptoms may evolve in the weeks to months following exposure. They also may contribute to lasting and significant changes in personality, mood, cognition, thought, sleep, and behavior.6
Conclusion
Chronic AEs from mefloquine may provide a parsimonious explanation for the onset and persistence of a veteran’s psychiatric symptoms, particularly in cases where these may have failed to respond to treatment. Clinicians evaluating veterans who are seeking care for lasting psychiatric symptoms should ensure that they screen for prior symptomatic mefloquine exposure. As recognition grows of the drug’s chronic AEs, symptomatic mefloquine exposure is likely to emerge as a significant known confounder in the diagnosis of psychiatric disorders, including PTSD, among the current generation of U.S. veterans.
Mefloquine is an antimalarial drug that is associated with a significant risk of chronic neuropsychiatric adverse effects (AEs). The drug was licensed by the FDA in 1989 after development by scientists affiliated with Walter Reed Army Institute of Research (WRAIR). By the early 1990s, mefloquine had become the U.S. military’s drug of choice both for treatment of uncomplicated malaria and for antimalarial prophylaxis and was administered as a convenient weekly dose. Mefloquine was prescribed widely to U.S. military personnel beginning with operations in Somalia in 1992 and over the next 2 decades during certain deployments to Iraq and Afghanistan and to other malaria-endemic areas.1
In 2013, following a decline of U.S. military use, the FDA added a boxed warning to the mefloquine product documentation to caution that neuropsychiatric AEs from the drug could last years after use and even be permanent. The U.S. military subsequently deemed mefloquine to be a prophylactic “drug of last resort.”2 Recently, researchers at WRAIR have acknowledged that chronic neuropsychiatric AEs attributable to mefloquine, including nightmares, insomnia, anxiety, irritability, and cognitive dysfunction, may confound the diagnosis of posttraumatic stress disorder (PTSD).3 The VA has awarded at least 1 disability claim for service-connected psychiatric conditions that it attributed to mefloquine exposure, and it is likely that in the coming years such claims will increase.2
Susceptibility to Chronic Neuropsychiatric AEs
Why mefloquine seems to cause chronic neuropsychiatric AEs in only certain individuals is unclear, although genetic susceptibility to drug-induced toxic encephalopathy and neurotoxicity are suspected.1 There is no screening test for susceptibility to AEs before mefloquine use, so the current U.S. product documentation cautiously warns that when used for prophylaxis, mefloquine should be discontinued at the onset of any neurologic or psychiatric symptom, many of which are considered prodromal to more serious AEs that may occur with continued dosing.4
Although chronic neuropsychiatric AEs have been reported to develop after only a single weekly dose, most clinically significant chronic AEs seem to occur among those who developed at least 1 prodromal neuropsychiatric symptom during early use but who continued weekly use despite these symptoms in a manner contrary to current product documentation guidance.4 In contrast, when mefloquine is administered for the treatment of malaria, typically at 5 times the weekly prophylactic dose and commonly in split doses over 8 to 12 hours, dosing is often complete by the time prodromal symptoms develop. 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
Screening for Symptomatic Mefloquine Exposure
As the boxed warning indicates, certain psychiatric symptoms that occur with mefloquine use may become chronic and may confound psychiatric diagnosis. 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.
For example, a veteran with a history of symptomatic mefloquine exposure who later is diagnosed with PTSD may experience 1 or more symptoms, such as insomnia or cognitive dysfunction, which may be primarily attributable to the chronic AEs of the drug. The origins of the symptoms may be distinct from exposure to trauma and may not respond as effectively to certain conventional therapies for PTSD, requiring consideration of alternate therapies.3 The confounding role of psychiatric symptoms attributable to mefloquine exposure may explain failed response to medications and psychotherapy. Multidisciplinary evaluation and management may be appropriate for such patients.
If symptomatic mefloquine exposure is suspected, a clinician must establish evidence of exposure to the drug and the veteran’s development of neuropsychiatric symptoms associated with such exposure. The following sections provide guidance to aid in screening both for exposure to the drug and for the development of specific neuropsychiatric symptoms during prophylaxis or following the treatment of malaria.
Mefloquine Exposure
Mefloquine was licensed in the U.S. as a branded medication (Lariam) from 1989 to 2011, and the drug also has been available in a variety of generic equivalents from 2003 to the present. All versions of mefloquine approved in the U.S. have been formulated as a white/slightly-off-white, smaller than dime-sized round tablet, containing 250 mg of mefloquine hydrochloride.
When used for prophylaxis in military settings, the drug was often dispensed informally without documentation, sometimes including directly observed therapy under command direction.1,2 Therefore, even in the absence of prescribing documentation, a veteran who endorses a consistent history of malaria prophylaxis with mefloquine should be considered as having evidence of exposure.2
Exposure to mefloquine is unlikely if the veteran reports taking a daily antimalarial medication—more likely it was doxycycline or atovaquone/proguanil (marketed as Malarone). In rare cases, the drug may have been erroneously prescribed or been mistakenly taken daily for prophylaxis or, in more common cases, a prophylactic “loading dose” (typically 1 tablet daily for 3 days prior to weekly dosing) was used.7,8
Exposure also was unlikely if the veteran reports taking an antimalarial that was dosed weekly with a tablet that was not of the appropriate color, shape, and size. More likely that drug was chloroquine. Although most prophylactic use of mefloquine among U.S. veterans followed its licensing by the FDA in 1989, the drug is known to have been administered to a small number of U.S. military personnel prior to its licensing during clinical trials, including personnel deployed on certain operations during the 1980s.1
For treatment of malaria, mefloquine was used widely until better-tolerated drugs became available, beginning in the early 2000s, although some use of mefloquine in the military continues to this day. In most cases, clinicians should rely on records of hospitalization to identify whether mefloquine was administered. 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.
Symptoms During Prophylaxis
If prophylactic exposure to the drug has been established, the clinician should confirm the presence of neuropsychiatric symptoms during the exposure. Particularly among veterans deploying to malaria-endemic combat areas, such symptoms may have occurred during a period of heightened stress coincident with their initial deployment, and the veterans may have misattributed these symptoms to nonmefloquine factors. The clinician should therefore take a careful history to identify specific symptoms listed in the mefloquine product documentation. Many AEs will commonly manifest following the first 3 doses, and the clinician may find that focusing on this period is useful.9
When mefloquine is used for prophylaxis, anxiety and depression each affect between 1% and 10% of users. Other AEs that may develop include panic attacks; severe mood swings; behavioral AEs, including agitation, aggression, restlessness, and mania; symptoms of psychosis, including paranoia, delusions, and hallucinations; dissociative symptoms, including depersonalization; suicidal ideation; and cognitive AEs, including confusion.
The common symptoms of insomnia and abnormal dreaming affect > 10% of users. Particularly if multiple symptoms occur or if any of these symptoms occur following or coincident with symptoms of disturbed sleep, these should be considered strong evidence of symptomatic exposure.4 Veterans who report a history of continued mefloquine use despite the onset of such symptoms may be at particularly increased risk of chronic AEs.
The clinician should consider as evidence of symptomatic exposure information provided by others, including reports of obvious signs of nightmares or psychosis affecting the veteran. Clinicians should be aware that confusion and other psychiatric AEs caused by mefloquine during prophylactic use may limit the validity of self-reported history. Similarly, a history of seizure with mefloquine use or of the development of specific neurologic symptoms, particularly visual disturbances, dizziness, vertigo, disequilibrium, and paresthesias, also should be considered strong evidence of symptomatic exposure and indication of an increased risk of chronic psychiatric AEs.4
Posttreatment Adverse Effects
Although chronic psychiatric AEs following malaria infection have long been attributed to cerebral involvement, recognition that mefloquine may independently cause chronic neuropsychiatric AEs may require that individual cases be reexamined to properly assign causation.10 Particularly in uncomplicated cases of malaria, neuropsychiatric symptoms that develop only after treatment with mefloquine should be considered plausibly to be due to the drug and as evidence of symptomatic exposure.
As with use of mefloquine in prophylaxis, these neuropsychiatric symptoms may evolve in the weeks to months following exposure. They also may contribute to lasting and significant changes in personality, mood, cognition, thought, sleep, and behavior.6
Conclusion
Chronic AEs from mefloquine may provide a parsimonious explanation for the onset and persistence of a veteran’s psychiatric symptoms, particularly in cases where these may have failed to respond to treatment. Clinicians evaluating veterans who are seeking care for lasting psychiatric symptoms should ensure that they screen for prior symptomatic mefloquine exposure. As recognition grows of the drug’s chronic AEs, symptomatic mefloquine exposure is likely to emerge as a significant known confounder in the diagnosis of psychiatric disorders, including PTSD, among the current generation of U.S. veterans.
1. Nevin RL. Mefloquine and posttraumatic stress disorder. In: Ritchie EC, ed. Textbook of Military Medicine. Forensic and Ethical Issues in Military Behavioral Health. Washington, DC: Borden Institute; 2015:277-296.
2. Nevin RL, Ritchie EC. FDA black box, VA red ink? A successful service-connected disability claim for chronic neuropsychiatric adverse effects from mefloquine. Fed Pract. 2016;33(10):20-24.
3. Livezey J, Oliver T, Cantilena L. Prolonged neuropsychiatric symptoms in a military service member exposed to mefloquine. Drug Saf Case Rep. 2016;3(1):7.
4. Nevin RL, Byrd AM. Neuropsychiatric adverse reactions to mefloquine: a systematic comparison of prescribing and patient safety guidance in the US, UK, Ireland, Australia, New Zealand, and Canada. Neurol Ther. 2016;5(1):69-83.
5. Rendi-Wagner P, Noedl H, Wernsdorfer WH, Wiedermann G, Mikolasek A, Kollaritsch H. Unexpected frequency, duration and spectrum of adverse events after therapeutic dose of mefloquine in healthy adults. Acta Trop. 2002;81(2):167-173.
6. Nevin RL, Ritchie E. The mefloquine intoxication syndrome: a significant potential confounder in the diagnosis and management of PTSD and other chronic deployment-related neuropsychiatric disorders. In: Ritchie EC, ed. Posttraumatic Stress Disorder and Related Diseases in Combat Veterans. Cham, Switzerland: Springer International Publishing; 2015:257-278.
7. Cohen MR, Smetzer JL. FDA advise-ERR: mefloquine—not the same as Malarone; zoster vaccine is not for the immunosuppressed; TXA mistaken as tenecteplase; guidelines for adult IV push medications. Hosp Pharm. 2015;50(11):961-964.
8. Boudreau E, Schuster B, Sanchez J, et al. Tolerability of prophylactic Lariam regimens. Trop Med Parasitol. 1993;44(3):257-265.
9. Stürchler D, Handschin J, Kaiser D, et al. Neuropsychiatric side effects of mefloquine. N Engl J Med. 1990;322(24):1752-1753.
10. Nevin RL, Croft AM. Psychiatric effects of malaria and anti-malarial drugs: historical and modern perspectives. Malar J. 2016;15:332.
1. Nevin RL. Mefloquine and posttraumatic stress disorder. In: Ritchie EC, ed. Textbook of Military Medicine. Forensic and Ethical Issues in Military Behavioral Health. Washington, DC: Borden Institute; 2015:277-296.
2. Nevin RL, Ritchie EC. FDA black box, VA red ink? A successful service-connected disability claim for chronic neuropsychiatric adverse effects from mefloquine. Fed Pract. 2016;33(10):20-24.
3. Livezey J, Oliver T, Cantilena L. Prolonged neuropsychiatric symptoms in a military service member exposed to mefloquine. Drug Saf Case Rep. 2016;3(1):7.
4. Nevin RL, Byrd AM. Neuropsychiatric adverse reactions to mefloquine: a systematic comparison of prescribing and patient safety guidance in the US, UK, Ireland, Australia, New Zealand, and Canada. Neurol Ther. 2016;5(1):69-83.
5. Rendi-Wagner P, Noedl H, Wernsdorfer WH, Wiedermann G, Mikolasek A, Kollaritsch H. Unexpected frequency, duration and spectrum of adverse events after therapeutic dose of mefloquine in healthy adults. Acta Trop. 2002;81(2):167-173.
6. Nevin RL, Ritchie E. The mefloquine intoxication syndrome: a significant potential confounder in the diagnosis and management of PTSD and other chronic deployment-related neuropsychiatric disorders. In: Ritchie EC, ed. Posttraumatic Stress Disorder and Related Diseases in Combat Veterans. Cham, Switzerland: Springer International Publishing; 2015:257-278.
7. Cohen MR, Smetzer JL. FDA advise-ERR: mefloquine—not the same as Malarone; zoster vaccine is not for the immunosuppressed; TXA mistaken as tenecteplase; guidelines for adult IV push medications. Hosp Pharm. 2015;50(11):961-964.
8. Boudreau E, Schuster B, Sanchez J, et al. Tolerability of prophylactic Lariam regimens. Trop Med Parasitol. 1993;44(3):257-265.
9. Stürchler D, Handschin J, Kaiser D, et al. Neuropsychiatric side effects of mefloquine. N Engl J Med. 1990;322(24):1752-1753.
10. Nevin RL, Croft AM. Psychiatric effects of malaria and anti-malarial drugs: historical and modern perspectives. Malar J. 2016;15:332.
