Drug interactions and pharmacogenetic reactions are the basis for chloroquine and mefloquine-induced psychosis.
BACKGROUND
Chloroquine and mefloquine used for prophylaxis and treatment of malaria sometimes causes severe mental status changes, through mechanisms that are poorly understood.


OBJECTIVE
Psychosis is caused by interactions with other drugs or by pharmacogenetic vulnerabilities that cause heightened responses to chloroquine or mefloquine alone, mediated through dopamine, acetylcholine, serotonin, P-glycoprotein, inhibited cortical activity, deranged calcium homeostasis, and impaired synaptogenesis.


METHODS
Retrospective studies can identify all other drugs taken coincident with chloroquine or mefloquine psychosis. Various genes from patients could be cloned and compared to those from individuals who tolerated chloroquine and mefloquine, culminating with transgenic animal studies. Identification of candidate genes may be aided by pharmacogenomic analysis of single nucleotide polymorphism maps. Finally, prospective studies with cerebrospinal fluid analysis and PET scanning could help verify the hypothesis.


CONCLUSIONS
If this hypothesis is correct, the incidence of chloroquine and mefloquine psychosis can be greatly reduced by avoiding interacting medications and by conducting genetic screening prior to initiating chloroquine and mefloquine. Validation of the hypothesis would also provide a paradigm to follow for avoiding neuropsychiatric side effects if antidepressants and neuroleptics are used to overcome chloroquine resistance, if new antimalarial drugs chemically related to chloroquine and mefloquine are developed and if chloroquine and mefloquine are used for non-malarial applications such as HIV and cancer.
Alisky
Joseph M
JM
Marshfield Clinic Research Foundation, 1000 Oak Avenue, Marshfield, WI 54449, USA.
Chertkova
Elena L
EL
Iczkowski
Kenneth A
KA
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000962:Antimalarials / Q000009:adverse effects / Q000627:therapeutic use; D002738:Chloroquine / Q000009:adverse effects* / Q000627:therapeutic use; D004347:Drug Interactions; D064420:Drug-Related Side Effects and Adverse Reactions / Q000453:epidemiology; D006801:Humans; D008139:Loperamide / Q000493:pharmacokinetics / Q000627:therapeutic use; D015767:Mefloquine / Q000009:adverse effects* / Q000627:therapeutic use; D001523:Mental Disorders / Q000139:chemically induced / Q000188:drug therapy; D011618:Psychotic Disorders / Q000453:epidemiology* / Q000235:genetics / Q000503:physiopathology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000962:Antimalarials; D008139:Loperamide; D002738:Chloroquine; D015767:Mefloquine