Gluten and schizophrenia

Background

I’m often asked if there are any dietary solutions or recommendations for people with schizophrenia. This letter suggests that the answer – for some patients – might be ‘yes.’ We will focus here on the topic of grain-free or gluten-free diet studies in schizophrenia.

Case Reports

A 29-year-old Italian woman was diagnosed with schizophrenia according to DSM-III-R criteria. Notable symptoms included social and occupational dysfunction, affective flattening and delusional thoughts and auditory hallucinations. Symptoms persisted despite treatment with antipsychotic medications Two years after her initial diagnosis, she developed weight loss and diarrhea and showed signs of malnutrition. Medical tests for these physical complaints revealed numerous abnormalities that ultimately led to upper GI endoscopy and a diagnosis of celiac disease. When placed on a gluten-free diet, her psychiatric symptoms completely resolved (De Santis et al., 1997)

A 20-year-old Swedish man with no prior psychiatric history presented to the emergency department following several weeks of “feeling strange” and described intense distress over being watched by strangers. He also disclosed that he had cut open the pillows on his bed to locate the radios that he was convinced were the sources of the voices he was hearing. He was diagnosed with schizophrenia and was treated (unsuccessfully) with a succession of maximally-dosed medications: chlorpromazine, haloperidol, and fluphenazine. Subsequent medical evaluation of anemia led to a series of studies that ultimately led to endoscopy and a diagnosis of celiac disease. Whereas his psychotic symptoms had not responded to antipsychotic medications, they eventually disappeared after starting a gluten free diet (Jansson et al., 1984)

7-fold higher prevalence of celiac-related antibodies in schizophrenia

Antibodies against gliadin and tissue transglutaminase are elevated in celiac disease. Gliadin is a component of gluten. Elevated titers of gliadin-directed antibodies suggest abnormal presentation of dietary gluten to the immune system. Tissue tranglutaminase is an enzyme whose function is the cross-linking of proteins, and is the target of the autoimmune response in celiac disease.

Blood samples from volunteers in the CATIE study showed significantly higher prevalence of these antibodies among the 1,401 patients with schizophrenia, who were compared to 900 control subjects. 5.4% of the patients in the schizophrenia group had high levels of tissue transglutaminase antibodies, versus 0.8% in the matched control group. And a striking 23.1% of those in the schizophrenia group had high levels of gliadin antibodies versus just 3.1% of the control group (Cascella et al., 2011).

Review Article

Paola Bressan & Peter Kramer (2016) published an open-access review article with one of the best titles ever for an academic journal paper: ‘Bread and other edible agents of mental disease.’ It’s a fabulously-written, plain-English article that starts with a high-level survey of the last 12,000 years of human history and drills down to the evidence that mental illness is, to some extent, a casualty of the agricultural revolution.

Bressan & Kramer cite epidemiological observations linking wheat consumption to schizophrenia:

“in several countries, hospitalization rates for schizophrenia during World War II dropped in direct proportion to wheat shortages. In the United States, where over that same period the consumption of wheat rose rather than diminished, such rates increased instead (Dohan, 1966a,b). In South Pacific islands with a traditionally low consumption of wheat, schizophrenia rose dramatically (roughly, from 1 out of 30,000 to 1 out of 100) when Western grain products were introduced (Dohan et al., 1984).”

They argue that the relationship between grains and mental illness may arise from three possible mechanisms:

• Grain consumption increases the permeability of both the gut and the blood-brain barriers
• In those with genetic vulnerability, grain proteins set off an immune reaction
• Digestion of grains produces protein fragments with psychotropic activity

They also cite work suggesting gastrointestinal abnormalities are more common in schizophrenia:

“A post-mortem study of 82 schizophrenia patients found rates of stomach, small intestine, and large intestine inflammation as impressive as respectively 50%, 88%, and 92% (Buscaino, 1953; cited in Buscaino, 1978). The association between gastrointestinal pathologies and psychiatric disorders had already been noticed at least 2,000 years ago and has been confirmed repeatedly (for a brief review see Severance et al., 2015).

Dietary treatment for schizophrenia?

Dohan and colleagues conducted some studies in the 1960s and 1970s in which patients with schizophrenia were randomized to a secure ward with standard diets (55 patients) or to a secure ward with grain-free, dairy-free diet (47 patients). Their outcome measure was time until symptoms subsided to the point that they could be transferred to a non-secure ward. They found that 62% of those on the grain-free/dairy-free diet met step-down criteria within 7 days versus 36% on the standard diet. The grain-free/gluten-free group met transfer criteria in 17.3 days on average, while it took 30.6 days for the standard diet group – a 43% faster improvement. The benefit was unique to patients with schizophrenia; the diet was ineffective in patients with other psychiatric diagnoses. The benefits of the diet rapidly vanished when gluten was secretly added to the diet of recovering patients (Dohan et al., 1969).

Kalaydjian et al. (2006) reviewed several additional studies of gluten-withdrawal in schizophrenia. They noted that large-scale trials are lacking but that existing data suggested that “drastic reduction, if not full remission of schizophrenia symptoms” had been noted in a variety of studies. Citing WHO directives, Kalaydjian and colleagues recommended that every patient with schizophrenia be screened for celiac-related antibodies.

Conclusions

As with so many other findings in the schizophrenias, there is not a ‘one size fits all’ theory – or treatment. Clearly, as a group, people with schizophrenia are more likely than people without to have an unusual physiological relationship with grains and their metabolism. Yet this subset may be relatively small. Similarly, among the limited number of small-sample-sized studies of dietary intervention, it appears that gluten-free or grain-free/dairy-free diets can be substantially beneficial for at least some people with schizophrenia. Whether this diet-helped subset is tiny, small, or not so small is an open question at this time.

The data so far suggest that people with schizophrenia should be screened for tissue transglutaminase and gliadin antibodies. These tests are widely available and inexpensive. Those with elevated antibody titers should consider a gluten-free or grain-free/dairy-free diet to see if their psychiatric symptoms respond. However, most of the dietary intervention studies did not pre-screen participants based on antibody status. So it’s not clear whether a person needs to have elevated antibodies in order to possibly benefit from diet change.

As with everything else in schizophrenia treatment, both clinicians and affected people should regularly assess and dutifully record the status of symptoms, functioning, and quality of life. With a regular assessment system in place, it will be easier to tell whether or not a dietary intervention is successful.

References

Bressan, P., and Kramer, P. (2016).Bread and Other Edible Agents of Mental Disease. Front Hum Neurosci 10. (Open-access publication)

Cascella, N.G., Kryszak, D., Bhatti, B., Gregory, P., Kelly, D.L., Mc Evoy, J.P., Fasano, A., and Eaton, W.W. (2011). Prevalence of celiac disease and gluten sensitivity in the United States clinical antipsychotic trials of intervention effectiveness study population. Schizophr Bull 37, 94–100. (Open-access publication)

De Santis, A., Addolorato, G., Romito, A., Caputo, S., Giordano, A., Gambassi, G., Taranto, C., Manna, R., and Gasbarrini, G. (1997). Schizophrenic symptoms and SPECT abnormalities in a coeliac patient: regression after a gluten-free diet. J. Intern. Med. 242, 421–423.

Dohan, F.C., Grasberger, J.C., Lowell, F.M., Johnston, H.T., Jr, and Arbegast, A.W. (1969). Relapsed schizophrenics: more rapid improvement on a milk- and cereal-free diet. Br J Psychiatry 115, 595–596.

Jansson, B., Kristjánsson, E., and Nilsson, L. (1984). Schizophrenic psychosis disappearing after patient is given gluten-free diet(article in Swedish). Läkartidningen 81, 448–449.

Kalaydjian, A.E., Eaton, W., Cascella, N., and Fasano, A. (2006). The gluten connection: the association between schizophrenia and celiac disease. Acta Psychiatr Scand 113, 82–90.