A new hypothesis on preventable neuropsychiatric illness in Africa

Communicable diseases are still the most important public health challenge in Africa. Many of them such as malaria, schistosomiasis and pneumonia are frequently treated with quinoline derived substances, which are known to have neuropsychiatric side effects. Millions of Africans have to take two or three of them simultaneously (e.g. quinine and ciprofloxacin or praziquantel). Almost nothing is known about their additive effects or interactions.

We hypothesize, that a parallel therapy with quinoline derived antimicrobial substances leads to a preventable neuropsychiatric syndrome and suggest to find the joint pathobiochemical explanation for this condition in the l-Tryptophane-Kynurenine-Serotonine pathway.

Almost all intermediary substances of the Kynurenine pathway (tryptophan, kynurenine, kynurenic acid, quinolinic acid and serotonin) are known to have neuropsychiatric properties on their own. Direct interactions between quinolines and the oxygenases of the pathway (especially with the indoleamine (2,3)-dioxygenase and kynurenine-monoxygenase) and indirect influences via the interferon-γ induced breakdown of tryptophane are discussed, as well as the modifying effect of the already existing neurotoxicity of the single quinoline related drug used. Three different mechanisms were discovered which can influence the complex, well balanced biochemical equilibrium of the kynurenine pathway. Due to the complexity of the pathway and the fact that all substances have their own, even contradictory, neuropsychiatric properties, we do not argue that through a certain type of postulated metabolism a certain drug might have a specific effect, but we do hypothesize that it is the disturbance of a well balanced equilibrium which makes a neuropsychiatric effect of the parallel antimicrobial therapy with quinolines more than probable.

If confirmed, our hypothesis demonstrates that parallel therapy with quinoline antimicrobials constitutes an under addressed public health challenge in Africa with severe diagnostic, therapeutic and financial implications. The individual physician has to take a new entity into account for the neuropsychiatric differential diagnosis, especially in patients suffering from another neurological illness, being treated with efavirenz or belonging to high risk groups affecting the health of others like mini-bus drivers. Further direct consequences apply to physicians in the rich countries dealing with migrants, refugees, long term expats or professional groups in need of a high level of psychological stability, good judgement and fine motor skills.

The hypothesis needs urgent confirmation in a randomized, prospective trial comparing levels of quinolinic acid etc., in patients on quinoline treatment versus a quinoline-naïve patients for several body fluids and ideally in the brain post-mortem.