Complex Membrane Channel Blockade: A Unifying Hypothesis for the Prodromal and Acute Neuropsychiatric Sequelae Resulting from Exposure to the Antimalarial Drug Mefloquine

Figure 3

The hypothetical relationship between risk and severity of adverse neuropsychiatric reactions in patients exposed to prophylactic (Px) or treatment (Tx) doses of mefloquine and their relation to the presence of genetic variation, such as channel subunit variants, CYP450, MDR1, and connexin allelic mutations, comorbidity with other neuropsychiatric disorders and “other” currently identified comorbid factors such as alcohol intake, low body mass index, age, immune suppression, and concurrent malarial disease. Within the “normal” population at low doses mild to moderate neuropsychiatric symptoms are common, with this proportion increasing with increasing doses at treatment. At low (Px) doses, individuals with predisposing conditions, such as pharmacogenetic predisposition, or comorbidity, will manifest more severe adverse reactions more quickly than the “normal” population. Individuals with additional compounding comorbid factors will present the most severe symptoms most quickly. Treatment doses will elicit the most severe symptoms, most quickly, in those with single or multiple predisposing conditions as well as in an increased proportion of the “normal” population exposed to this drug.