Mefloquine and Madness: Psychotic Disorders Related to Travel

Simon Trepel, MD, 4 th Year Psychiatry Resident

University of Manitoba, Faculty of Medicine

•  To recognize travel as a potential psychological stress, causing symptoms

•  To become familiar with Mefloquine's potential to cause psychological stress

•  To briefly reinforce the necessity of pre-travel vaccinations, and dispel potential myths associated with vaccines

Travel has been associated with psychological diseases in the medical literature. Prior studies have linked the phenomenon of “Jet Lag” to Hypomanic symptoms. Major Depressive Episodes have been associated with travel from an Eastern to a Western destination 5 . A change in usual surroundings, as occurs with travel, has been found to cause Delirium in elderly people 9 . There are many sources of stress related to travel, if we consider time zone changes, vast cultural differences, logistics of travelling- like companions, mode of transport and accommodations, new strange environments, and various other variables 3 . The relationship between travel and psychological disorders is better understood if we think of travel as a “stress”. Most Psychiatric Diseases are understood using a “Stress-Diathesis” Model.

We understand that the onset of many Psychiatric disorders is linked to an interaction between Nature and Nurture, or Genes and Environment. Thus the occurrence of psychiatric disorders is predictable if we are able to estimate one's genetic susceptibility (DIATHESIS), and balance this against the demands of the environment (STRESS). Said another way, stress is able to cause psychiatric symptoms in vulnerable individuals. What do I mean by Psychiatric Symptoms?

Psychiatry uses the DSM4, a manual (or cookbook) that describes all currently recognized psychiatric diseases as a constellation of various symptoms (or ingredients). Similar disorders are lumped into general categories. The main categories of Psychiatric disease include: Mood, Anxiety, Psychosis, Substance Use, Due to a Medical Condition, Adjustment, and Personality 9 .

This talk will focus on factors related to travel, and their ability to produce psychotic symptoms. Psychosis is defined as “a loss of ego boundaries or a gross impairment in reality testing”. It usually involves Hallucinations, (which are abnormal sensory perceptions – like “hearing voices”) and Delusions (which are fixed false beliefs - like paranoia). Typical Psychotic Disorders in Psychiatry include Schizophrenia, Delusional disorder, Substance Induced, Psychotic Depression, and Delirium. Excess Dopamine in the mesolimbic area of the brain is thought to produce psychotic symptoms, and drugs that block dopamine in this area have been shown to produce a remission in hallucinations and delusions. There are many other causes of psychosis that are not so readily understood to involve Dopamine, however. Delirium, or “Psychosis due to a Medical Condition”, is thought to be caused by a wide variety of drugs, such as Anticholinergics, Opioids and Benzodiazepines 10 . This paper will focus on one such medications, Mefloquine, an anti-malarial that has been shown to produce both Neuro-Psychiatric symptoms in some, as well as save other's lives from the deadly disease Malaria.

Malaria is the most important preventable disease for travellers to be aware of, and prepare for, when travelling many parts of the world. Malaria is a systemic disease caused by a blood parasite from the Genus Plasmodium. There are 4 species that infect humans, the most serious being Plasmodium falciparum, which is prevalent in Africa. According to the WHO in 2003 there were 300-500 million people infected worldwide, with 2 million dying per year 4 .

Death due to malaria has been linked to inappropriate chemoprophylaxis or non- compliance with an anti-malarial agent. Anti-malarial drugs may prevent or treat disease, where they are able to kill asexual blood stages of the parasite prior to colonization in the liver, via schizonticide. There are many prophylactic preparations because as resistance develops to various agents worldwide, new antimalarials have been developed. The geographic extension of chloroquine-resistant Plasmodium falciparum in many tropical areas of the world has prompted use of alternative medications, such as Mefloquine 4 .

Mefloquine Hydrochloride (or Larium) is one of the most effective antimalarial drugs available. It is a synthetic 4-quinoline methanol derivative chemically related to quinine. It is well absorbed and highly bound to plasma proteins, concentrated in the red blood cells, and is extensively distributed to the tissues, including the Central Nervous System. It is prepared orally, in a prophylactic dose of 250mg weekly, given over 3 weeks. Plasma levels of 200-300ng/ml are needed to prevent or treat falciparum infection. Mefloquine's half-life is between 15-33 days. While Mefloquine is very effective, it has many potential side effects, especially when doses exceed 1000mg, or 15mg/kg 10 .

Mefloquine has been associated with many side effects, which may be divided into mild, moderate , and severe categories 2

Mild - headache, nausea, vomiting, diarrhea, dizziness, vertigo, fatigue, asthenia, and poor concentration.

Moderate - ataxia, agitation, confusion,. anxiety, dysphoria, blurred vision, and altered sleep and wake cycles.

Severe - seizures, acute psychosis with delusions, hallucinations, and disorganization, mania, ‘anxiety neurosis', altered levels of consciousness, Major Depressive Episode, and delirium. Death has not been reported.

Weinke, T. Neuropsychiatric Side Effects After the Use of Mefloquine , American Journal of Tropical Medicine, 45(1), 1991, pp. 86-91 .

The Authors interviewed 12 people at Infectious Disease Units in Germany who had suffered adverse events after using Mefloquine. Subjects were white, had no prior psychiatric disease, and no allergies. The average age was 34 years old, there was an even gender distribution, and 10 of 12 were tourists. 7 of 12 had severe reactions characterized by acute psychosis with hallucinations, delusions and disorganized though processes, psychomotor agitation, seizures and sleep wake changes. Whereas 5 of 12 had moderate reactions, characterized by agitation, vertigo, confusion, nausea, and ataxia. Severe reactions were seen in prophylactic and treatment doses, as well as in people who had not had a serious reaction with prior Mefloquine use, and those with therapeutic (i.e. not toxic) mefloquine blood levels. The Authors speculate that the overall risk of moderate to severe side effects when using Mefloquine are about 1 in 8000 . 1 in 13000 experienced moderate side effects when using the prophylactic dose, whereas 1 in 215 had a similar reaction while using treatment doses. Thus the risk of serious side effects is about 60 times higher in treatment vs. prophylactic doses.

Van Riemsijk, MM. Neuropsychiatric Events During Prophylactic Use of Mefloquine Before Travelling, European Journal of Clinical Pharmacology, (2002) 58: 441-445.

The authors attempted to control for the possible confounder of travel itself in producing symptoms associated with Mefloquine. This study looked at Mefloquine use and side effects in 179 people, during the first 3 weeks, before they travelled. The authors used the Profile of Mood states (POMS), and the Diary of Adverse Events to describe symptoms. 32.1% of individuals endorsed neuropsychiatric events, women had twice (45%) the symptomatology vs. men (22%). First time users had more side effects than prior users of Mefloquine. Typical side effects included fatigue, anxiety, dysphoria, and vertigo.

Mechanism of Neuropsychiatric Symptoms

Mefloquine is known to have Acetylcholinesterase Inhibiting properties. Prior studies of these agents have shown symptoms of anxiety, poor memory, confusion, sleep changes and seizures. It has been proposed that disruption of Acetylcholine metabolism is linked to Dementia, Delirium, and seizures. Mefloquine has also been shown to cause “quinine like effects”, thus promoting cardiac arrhythmias 9 .

Importance of Vaccinations

While every vaccine has the potential to cause side effects, we must not forget the importance of protecting ourselves and our patients from potentially deadly endemic diseases worldwide. There are many important variables in deciding whether to vaccinate, and in choosing specific medications. Anti-vaccination groups have attempted to use anecdotal information in order to induce fear and avoidance of vaccines in some populations. There are well-described side effects, and complications to some vaccines. There have been attempts made to link Vaccinations to Autism, Mercury Poisoning, Multiple Sclerosis, Type 1 Diabetes, Guillain-Barre Syndrome, and others 7 . Several Authors have examined MMR vaccines and the potential to cause autism. To date, there is not a single example of causal evidence to link MMR and autism in the entire medical literature. Taylor (1999) examined 498 children with autism, and Patja (2000) looked at 1.8 million who had received a total of 3 million MMR vaccinations over 14 years. Both authors concluded “our analysis do not support a causal associations between MMR vaccine and autism. If such an association occurs, it is so rare that it could not be identified in (our) large regional sample” 8 . Clinicians must educate themselves using evidence-based techniques to guide their understanding and treatment recommendations.

Recommendations on the Use of Mefloquine

Various authors have looked at the specific types of side effects produced by Mefloquine, and arrived at the following recommendations 1 ;

Do not use Mefloquine in the following circumstances (prior history);

Psychiatric disease – including psychotic and mood disorders

Seizures

Cardiovascular conditions or prescribed medications

Prior reaction to Mefloquine (Allergy or Sensitivity)

High Risk Groups to be aware of;

Women

Low BMI

Low body fat content

First time users

General Guidelines

Monitor for the first 4 weeks of use

Do not exceed total doses of greater than 1000mg or 15mg/kg

Avoid other sources of mosquito bites (netting, insect repellent etc)

Avoid tasks related to fine motor control or concentration if possible

Choose Mefloquine for short trips to areas of Choloquine-Resistance

Conclusions

Mefloquine has recently emerged as an effective malaria prophylactic and treatment in various parts of the world. Mefloquine has been causally linked to specific side effects. Caution should be exercised in using Mefloquine in specific populations. Clinicians must educate themselves to be effective resources for their patients who travel, allowing appropriate choices to be made, to maximize health and to minimize disease and suffering.

References

•  Van Riemsijk, MM. Neuropsychiatric Events During Prophylactic Use of Mefloquine Before Travelling, European Journal of Clinical Pharmacology, (2002) 58: 441-445.

•  Weinke, T. Neuropsychiatric Side Effects After the Use of Mefloquine, American Journal of Tropical Medicine, 45(1), 1991, pp. 86-91.

•  Van Riemsijk, MM. Mefloquine Increases the Risk of Serious Psychiatric Events During Travel Abroad: A Nationwide Case-Control Study in the Netherlands, Journal of Clinical Psychiatry 2005; 66: 199-204.

•  Spira, A, Preparing the Traveller, Lancet, 2003, 361; 1368-1381.

•  Jahuar P, Psychiatric Morbidity and Time Zone Changes: A Study of Patients from Heathrow Airport, British Journal of Psychiatry, 1982, 140; 231-235.

•  Linton C, Travel-Induced Psychosis in the Elderly, International Journal of Geriatric Psychiatry, 2000; (15) 1070-1072.

•  Kimmel S, Vaccine Adverse Events: Separating Myth from Reality, 2002; 66, 2113-2120.

•  MacIntyre C, Immunization Myths and Realities: Responding to Arguments Against Immunization, Journal of Paediatric Child Health, 2003; (39), 487-491.

•  Kaplan, Synopsis of Psychiatry, 2001

•  Katzung B, Basic and Clinical Pharmacology, 1998.

5 Jahuar P, Psychiatric Morbidity and Time Zone Changes: A Study of Patients from Heathrow Airport, British Journal of Psychiatry, 1982, 140; 231-235

9 Kaplan, Synopsis of Psychiatry, 2001

3 Van Riemsijk, MM. Mefloquine Increases the Risk of Serious Psychiatric Events During Travel Abroad: A Nationwide Case-Control Study in the Netherlands, Journal of Clinical Psychiatry 2005; 66: 199-204.

9 Kaplan, Synopsis of Psychiatry, 2001

10 Katzung B, Basic and Clinical Pharmacology, 1998

4 Spira, A, Preparing the Traveller, Lancet, 2003, 361; 1368-1381.

4 Spira, A, Preparing the Traveller, Lancet, 2003, 361; 1368-1381.

10 Katzung B, Basic and Clinical Pharmacology, 1998

2 Weinke, T. Neuropsychiatric Side Effects After the Use of Mefloquine, American Journal of Tropical Medicine, 45(1), 1991, pp. 86-91.

9 Kaplan, Synopsis of Psychiatry, 2001

7 Kimmel S, Vaccine Adverse Events: Separating Myth from Reality, 2002; 66, 2113-2120

8 MacIntyre C, Immunization Myths and Realities: Responding to Arguments Against Immunization, Journal of Paediatric Child Health, 2003; (39), 487-491.

1 Van Riemsijk, MM. Neuropsychiatric Events During Prophylactic Use of Mefloquine Before Travelling, European Journal of Clinical Pharmacology, (2002) 58: 441-445