Writing in the journal Schizophrenia Research , the new theory suggests an ‘hidden’ epidemic of a disease called pellagra may play a key role in the incidence of schizophrenia and psychosis in developing countries.
Led by Professor Esme Fuller-Thomson from the University of Toronto's Factor-Inwentash Faculty of Social Work (FIFSW), the team noted several ‘unsolved mysteries’ around schizophrenia have long plagued the medical community.
For example, several studies have shown that the offspring of mothers who experience famine in their first trimester of pregnancy have double the chance of developing schizophrenia, and most researchers have assumed some form of nutrient deficiency must be playing a role. The particular nutrient has yet to be identified, however Fuller Thomson now speculates that niacin may be the key nutrient involved.
‘Lightbulb moment’
The theory came about after learning of new research conducted in South India that identified a link between schizophrenia and a variant of the gene NAPRT1, which lowers the body's ability to use niacin, or vitamin B3, which naturally occurs in meat, poultry, fish, and eggs.
"When I read this study a light bulb went on in my head," said Fuller-Thomson. "This seems to be the missing link that explains all these medical mysteries."
The researchers speculated that there is a critical interaction between an expectant mother's prenatal niacin deficiency due to malnourishment and the NAPRT1 variant that impedes the fetus' ability to use niacin.
This interaction between the gene and the prenatal environment may predispose the offspring to develop a psychotic disorder, they suggested.
"We acknowledge that this hypothesis is highly speculative, but feel further exploration of these ideas are warranted," said Fuller-Thomson. "In cases where the psychosis is due to pellagra, these patients could be inexpensively, quickly, and permanently cured with high dose niacin, allowing them to live a healthy normal life."
Genetic link
Identifying the NAPRT1 risk variant, also provides some insights into a second medical mystery, said the team.
Normally, when people are given high doses of niacin, their skin reddens and can tingle, burn, or itch; however, many individuals with schizophrenia experience limited or no flushing to the same high dose amount.
The authors suggest that the presence of a gene inhibiting the uptake of niacin may explain why people with schizophrenia do not show the same reddening of the skin in response to large doses: they simply have a lower ability to absorb the vitamin.
And the link between pellagra could be also an important part of the puzzle as well, said the team.
Vitamin deficiency
Between 1906 to 1940, almost three million Americans developed pellagra due to a niacin deficient diet. Symptoms included dermatitis, dementia, and death. In four to ten percent of cases, active psychosis develops, which mimics schizophrenia.
Pellagra became the leading cause of death in psychiatric hospitals in the Southern United States in the era.
"Treatment with niacin quickly and permanently cures the disease including the psychosis and the dermatitis," commented co-author Rukshan Mehta. "By 1941, flour was fortified with niacin in the USA and the disease was soon after largely eradicated."
Today, diagnosis of pellagra is rare, but Fuller-Thomson and Mehta wondered if it might be going undetected in the developing world.
In most cases of pellagra, a bad rash is the first symptom, and this is usually how the disorder is diagnosed. However, the researchers suggest that individuals with psychosis and the risky NAPRT1 gene variant may not present with dermatitis.
This would result in the patients being mis-classified as having schizophrenia instead of the easily treatable psychosis associated with niacin deficiency, they suggested.
‘Medical mysteries’ no more?
The new theory could also provide new insights into the most perplexing of the medical mysteries associated with schizophrenia.
Studies by the World Health Organization (WHO) show that patients with schizophrenia in the developing world recover at a markedly higher rate than those in western nations, despite the fact that those in the west receive more extensive medical interventions.
If some of the schizophrenia patients in the developing world were, in fact, undiagnosed pellagra cases, their psychosis may have been cured inadvertently by simply spending time in a hospital where nutritious niacin-rich food such as meat and eggs are provided, said the team.
A final medical mystery that has also been generating debate for half a century.
Six randomised controlled trials conducted in Saskatchewan, Canada in the 1950s found excellent results treating patients with schizophrenia with high doses of niacin, but multiple efforts to replicate the study in the 1970s found the intervention ineffective.
However, the team point out that the 1950s Canadian studies were conducted among patients born in the Great Depression before niacin fortification of flour was adopted.
"It is highly probable that those with schizophrenia in Saskatchewan had malnourished, niacin-deficient mothers," said Fuller-Thomson. "If the patients' psychosis was due to undiagnosed pellagra, of course the niacin treatment would be effective. The pregnant mothers of the participants in the later study benefited from universal niacin fortification and therefore the patients were unlikely to have pellagra."