Cognitive and Neuropsychiatric Side Effects of Mefloquine

We document the neuropsychological functioning of a 52-year-old master's-educated woman with no psychiatric history who used mefloquine prophylactically once a week for 3 weeks (250 mg) prior to and during a trip to Africa and who acutely developed anxiety, paranoia, visual hallucinations, confusion, and depressive symptoms during her return flight. She was initially treated as an outpatient with olanzapine, lorazepam, fluoxetine, and trazodone. When she continued to show suicidal ideation, other neuropsychiatric symptoms, and cognitive disturbances 3 months after her last dose of mefloquine, she was hospitalized for inpatient psychiatric treatment. Laboratory and infectious disease workup showed mildly elevated TSH (7.04 μU/ml) with normal free T₃ and T₄, and was positive for past exposure to hepatitis A. Brain MRI showed no abnormalities. Medical history was noncontributory. She had previously used mefloquine as a prophylaxis intermittently for about 4 years with no adverse reactions. While hospitalized, she was treated with risperidone and paroxetine and showed improvement in mood symptoms and cognition over 4 days. After initially living with her daughter following discharge, she has returned to independent functioning.

During a brief neuropsychological evaluation on day 2 of her admission, she was alert and partially oriented, misstating her age and the city, time, date, and day of the week. Her affect was sad. She reported feeling depressed, afraid, confused, and tense. Test results revealed impaired attention and mental control difficulties, with slowed performance on overlearned tasks, inaccuracies in mentally manipulating information, and inability to alternate between counting by sixes and reciting the days of the week. Psychomotor speed was slowed. Performance on several tasks of executive functioning indicated difficulty with response set maintenance, verbal fluency, and judgment/problem solving. Her copy of a complex design showed significantly impaired visuospatial and constructional skills. On a verbal list learning test, she learned 10 of 12 words, but recalled only 3 of them after a 20-minute delay. Although she correctly endorsed 11 of the words with a recognition format, she made 7 false-positive errors.

This case is the first to carefully document the neuropsychological functioning of an individual with severe mefloquine side effects and demonstrates that mefloquine may produce deficits in orientation, attention, psychomotor speed, and executive, visuospatial, and verbal memory functioning, as well as mood and psychotic symptoms. The potential mechanism of the drug in causing these deficits is not entirely clear, although there is evidence that the neuropsychiatric side effects of mefloquine are a result of a central cholinergic syndrome,³ which may also explain cognitive changes seen in the present case. Our patient's cognitive impairments were well beyond what would be expected based solely on her psychiatric symptoms and possible subclinical hypothyroidism. Although multiple factors may have contributed to her cognitive impairment, the temporal relationship between onset of her symptoms and mefloquine use suggests a high likelihood that mefloquine was the causal factor.