1208 Am J Psychiatry 138:9, September 1981

BRIEF COMMUNICATIONS

Wheat Gluten Challenge in Schizophrenic Patients

BY STEVEN G. POTKIN, M.D., DANIEL WEINBERGER, M.D., JOEL KLEINMAN, M.D., PH.D.,
HENRY NASRALLAH, M.D., DANIEL LUCHINS, M.D., LLEWELLYN BIGELOW, M.D.,
M. LINNOILA, M.D., PH.D., S.H. FISCHER, R.D., T.D. BJORNSSON, PH.D., JOHN CARMAN, M.D.,
J. CHRISTIAN GILLIN, M.D., AND RICHARD JED WYATF, M.D.

tients. (Celiac disease is a relatively rare-I in 2,000-

Eight chronic schizophrenic patients were
hereditary intestinal disorder that is characterized by
maintained on a dietfree ofgluten, cereal grains,
gastrointestinal symptoms and may appear with psy-
and milk (CM-F diet) and challenged in a double-
chiatric symptoms. All symptoms usually improve
blind manner with dietary wheat gluten and placebo.
after the initiation of a gluten-free diet.)
While on the CM-F diet, each patient received a
Consequently, Dohan and colleagues (7) examined
daily challenge of 30 g of gluten for 5 weeks and a
the effects of a cereal-free, milk-free (CM-F) diet on
placebo challenge for 8 weeks. No deterioration in
relapsed schizophrenic patients and found that the
clinical status as measured by the BPRS was noted
length of stay on a locked ward was shorter for
on gluten challenge. Serum a acid glycoprotein
patients on the experimental diet than for patients who
measurement demonstrated no evidence of
did not receive the CM-F diet. The acceleration of
inflammatory response to gluten challenge. The data
improvement disappeared when gluten was “secretly”
suggest that sensitivity to dietary gluten is not
added to the CM-F diet. In a subsequent investigation
characteristic of young chronic schizophrenic
of relapsed and newly admitted schizophrenic pa-
patients.
tients, Dohan and Grasberger (8) found that those
schizophrenic patients assigned to a CM-F diet were
discharged approximately twice as soon as control
In 1966, Dohan (1) suggested that a component of patients and that response to the diet occurred early
cereal grains, gluten, may exacerbate the overt during the hospitalization. Patients in both studies of
symptoms of schizophrenia and that a diet limiting this the CM-F diet were treated with standard neuroleptic
factor is of therapeutic value. Dohan (2) subsequently drugs.
provided epidemiologic support for this hypothesis, In a study of schizophrenic patients on a CM-F diet
finding a correlation of .96 between the rate of mental who were improving with neuroleptic drugs, Singh and
hospital admissions for schizophrenic women and the Kay (9) demonstrated a significant interruption or
change in wheat consumption during World War II in reversal of their therapeutic progress when wheat
Canada, Finland, Norway, Sweden, and the United gluten was given in a double-blind challenge. Twenty-
States (3-6). six of 33 measures of psychopathology and 4 of 6
This hypothesis has been bolstered by reports (3-6) measures of social avoidance and participation
of an increased incidence of celiac disease in schizo- showed a statistically significant deterioration during
phrenic patients, as well as an increased prevalence of the last week of gluten challenge. ‘ ‘The schizophrenic
psychotic and neurological symptoms in celiac pa- exacerbation with gluten was particularly marked in
the more seriously ill patients, with a less favorable
therapeutic outcome,” the authors observed.
Received July 21, 1980; accepted Nov. 7, 1980. Furthermore, Rice and associates (10) studied 16
From the Laboratory of Clinical Psychopharmacology. Division chronic schizophrenic patients treated with neunolep-
of Special Mental Health Research, Intramural Research Program,
tics who were on a normal diet and challenged with
NIMH, Saint Elizabeths Hospital. Address reprint requests to Dr.
Potkin, Saint Elizabeths Hospital, WAW Bldg. , Washington, DC gluten and subsequently were on a gluten-free, milk-
20032. free diet. In this study, 1 patient, who had been
Am J Psychiatry 138:9, September 1981 POTKIN, WEINBERGER, KLEINMAN, ET AL 1209

hospitalized for 14 years, became more agitated, unco- TABLE 1

operative, and paranoid with the gluten load. This Gluten and Placebo Challenge in Schizophrenic Patients on a Cereal-
Free, Milk-Free Diet
patient and another patient, who had been hospitalized
for 13 years, substantially improved on the gluten-free BPRS Syndrome Score’
diet. The latter patient improved to the degree that she Thought Disturbance Global______
could be discharged to the care of hen family.
Patient Placebo Gluten Placebo Gluten
These studies suggest that some schizophrenic pa-
I 2.06 1.76 3.50 3.17
tients improve when they are placed on CM-F diets,
2 1.60 1.95 3.23 3.13
and some deteriorate when given a gluten challenge. 3 .84 1.27 3.02 3.04
Patients who improve on CM-F diets tend to do so in 4 3.54 2.64 4.07 3.54
the first month of their diet, although Dohan and 5 .11 .21 1.45 1.60
6 1.37 1.54 2.29 3.27
Grasberger (8) suggested that 6-12 months of CM-F 7 1.04 .62 3.20 3.10
diet may be necessary to determine if a patient is diet 8 2.66 2.02 3.69 3.67
responsive. Chronically ill patients have been shown Mean for last 2 weeks ofeach challenge period for each patient: differences
to be diet responsive-e.g., Singh and Kay’s patients between placebo and gluten challenge were not significant on either BPRS
syndrome (paired t test).
(9) had had a mean duration ofillness of5.87 years and
Rice and associates’ patients (10) had been hospital-
ized more than 13 years-as have patients with poor meals, snacks, and free periods were supervised by
prognoses. Apparently, schizoaffective patients and staff. (Two additional patients were dropped from the
paranoid schizophrenic patients tend not to improve study because ofdietary violations in the first 2 weeks.
on the CM-F diet (11), whereas poor-prognosis or They are not included in this report.) Each challenge
nuclear schizophrenic patients show the most im- and placebo period was at least 5 weeks (5-8 weeks for
provement (11). gluten and 8-12 weeks for placebo). during which the
patients received twice daily a snack and beverage that
contained a total of either 30 g of gluten powder or
METHOD gluten-free powder (placebo). This dose of gluten is
consistent with doses used in previously reported
We undertook a gluten-challenge study of 8 young studies and was approximately twice the amount of
schizophrenic patients, 3 women and 5 men, whose gluten contained in the normal hospital diet (an aver-
mean age ±SD was 25±5.2 years. The mean length of age of 14-17 g/day). The order of assignment of
their hospital stay was 4.3±2.0 years, and their mean challenge and placebo periods for each patient was
length ofillness was 7.9±5.0 years. All ofour patients random.
met the Feighner criteria and RDC for a diagnosis of Daily behavioral ratings of each patient were made
schizophrenia. Three were subcategonized as being by biometrically trained nurses who used a modified
paranoid and 5 as chronic undifferentiated. Although form of the Brief Psychiatric Rating Scale (BPRS). All
young, all patients had a chronic illness without com- raters were blind to the patient’s dietary status.
plete restitution. According to their medical histories,
these patients all had responded to neuroleptic drugs
but not to the point that they could function indepen- RESU LTS
dently outside of a halfway house or hospital. Before
the study period, 6 of the patients were well stabilized The daily BPRS scores for each patient during the
on neuroleptics (2 received 25 mg/week i.m. of flu- last 2 weeks of the placebo challenge were averaged
phenazine
promazine;
mg/day
decanoate:
I 400 mg/day
of haloperidol).
, 2 received

Two
400 mg/day
of thionidazine,
patients were
of chlor-
and
drug
1 45
free
,
and compared
weeks
variance
of the gluten
with his or her own scores

demonstrated
challenge.
no effects
A two-way
related
for the last 2
analysis
to the order
of

during the study period and for the preceding 2 in which gluten and placebo were administered. The
months. groups were therefore combined for further statistical
During the study period, a minimum of 13 weeks, all analysis without regard to the order of gluten/placebo
patients received a strict diet free of gluten, cereal administration. Despite the absence of differences
grains,
special
and milk (CM-F

All patients
diet foods
received
diet).
and supervised
multivitamin
A dietitian
their
purchased
preparation.’
supplements.
the

All
between
of variance
paired t test,
,
gluten and placebo
the data were further
which took
challenge

advantage
compared
in the analysis
by using a
of the patient’s
being used as his or her own control and allowed for
the greater heterogeneity expected in studies of
‘For the sake ofcomparability with results ofprevious studies, we
sought the advice of Dr. Curtis Dohan regarding appropriate foods schizophrenic patients (greater variance). These ana-
for the CM-F. gluten challenge, and placebo challenge diets, as well lytical procedures were carried out for each of the

,
as regarding the overall study design. We greatly appreciate the
cooperation of Dr. Dohan in responding to our requests and
BPRS syndromes: anxiety/depression, anergia,
repeated consultations. thought disturbance, activation hostility/suspicious-
1210 WHEAT GLUTEN CHALLENGE Am J Psychiatry 138:9, September 1981

ness, and global social competence and functioning. our study may be less treatment responsive and there-
No statistical difference between gluten challenge and fore require a longer gluten-free period. This possibili-
placebo was seen in these syndromes (see table 1). The ty is suggested by clinical experience with patients
only difference suggested was a slight improvement in with dermatitis herpetiformis, who have intestinal
the anxiety/depression syndrome during gluten chal- pathology identical to celiac disease. These patients’
lenge (two-tailed paired t test: t= I .61 df=7, ,p< 15). . intestinal and skin lesions usually respond to a gluten-
Smith (12), in his criticism ofthe Singh and Kay study free diet, although from 1 to 12 months or longer may
(9), suggested use of the robust nonparametnic Wil- be required for skin changes to become clinically
coxon matched-pairs signed ranks test to analyze this apparent (18). This analogy led Dohan to suggest a
type of information; using this method, we found no lengthy trial of the CM-F diet (19).
differences for any of the syndromes. The HLA-B8 antigen has been associated with celi-
ac disease and dermatitis herpetiformis. both of which
are responsive to the CM-F diet. None of our patients
DISCUSSION had HLA-B8 antigens, although 2 patients had an early
history suggestive of possible gluten intolerance. Per-
The failure in this study to detect behavioral change haps only individuals with HLA-B8 antigen respond to
after gluten challenge in a small group of young the CM-F diet. However, the association of HLA-B8
chronic schizophrenic patients maintained on a cereal- antigen with celiac disease and dermatitis herpetifor-
free, milk-free diet offers no support for the hypothesis mis has been questioned as being possibly secondary
that a CM-F diet is useful in alleviating schizophrenic to an association with HLA-DW3 antigen (20). HLA-
symptoms. None of our patients on the CM-F diet DW3 locus antigen determinations were not available
demonstrated improvement asjudged by BPRS scores for our study patients.
when challenged with placebo as compared to gluten. Serum acid glycoprotein (an acute phase reactant) is
Other researchers (13-15) have suggested that the a measure of inflammatory conditions (21) and an
gluten-free diet exerts its effect by altering drug ab- important determinant of plasma binding of basic
sorption; however, neither the patients in the study compounds (22). it is increased in acute infections as
who were taking neuroleptics-whether orally or by well as gastrointestinal disorders such as Crohn’s
intramuscular injection-nor those who were drug free disease (21). (To our knowledge, its role in celiac
improved. Additionally, serum blood levels of neuro- disease or dermatitis herpetiformis has not been stud-
leptics did not change after administration of gluten ied.) Serum al acid glycoprotein concentrations were
challenge (16). determined by radial immunodiffusion on M-Partigen
Dietary compliance by patients is always a concern plate for each patient at least twice during each
in a study of this type. Therefore, we included in this challenge period. Our study patients had normal serum
study only patients for whom we believed dietary al acid glycoprotein on the CM-F diet and showed no
compliance was possible and whom we could super- increase when challenged with gluten, perhaps sug-
vise. Careful food preparation and availability of ap- gesting the absence of an inflammatory response to
propniate snacks and drinks helped ensure compli- gluten. Ashkenazi and colleagues (23) observed that in
ance. (The complexities of securing a cereal-grain-free a group of schizophrenic patients and nonschizophren-
and milk-free diet required the daily supervision of a ic psychotic patients about half of the patients with
dietitian.) each condition demonstrated an antigenic response in
It is possible that our patients were not on the CM-F their peripheral lymphocytes to subfractions of gluten
diet long enough to show improvement. However, as that was similar to the response ofceliac patients. The
noted previously, Dohan and Grasberger (8) observed individuals with the antigenic lymphocyte response
that ‘ ‘the effect of the [CM-F] diet on improvement of were presumably sensitized by gastrointestinal ab-
relapsed schizophrenics was most prominent within sorption ofthese polypeptides; however, none of these
the first week or two. The effect on the discharge rate patients showed any clinical evidence of the malab-
occurred in the first three months. . . .The psycholog- sorption or abnormal xylose tolerance seen in celiac
ical systems of celiac (gluten enteropathy) patients patients. Klee and colleagues (24) have shown that
also usually improved considerably within a week on polypeptides derived from gluten have endorphin and
two, often within a few days, when they were placed opioid-antagonist properties. Such compounds could
on a ‘gluten-free’ diet. ‘ ‘ (p. 687). Moreover, Singh and be absorbed from an inflamed or altered gastrointesti-
Kay (17) observed marked deterioration in their pa- nal tract and possibly cause psychotic symptoms (19,
tients’ clinical status during a 4-week gluten challenge, 23).
most marked in those patients most seriously ill, and In addition to some methodological differences, it is
‘ ‘the adverse gluten effect predominated in the pa- possible that we failed to support the findings of
tients with less favorable response to neuroleptic Dohan and colleagues and Singh and Kay because of
treatment.” differences in patient selection; however, our patients’
However, it cannot be ruled out that the patients in unresponsiveness to gluten suggests that gluten sensi-
Am J Psychiatry 138:9, September 1981 POTKIN, WEINBERGER, KLEINMAN, ET AL 1211

tivity is not characteristic of young chronic schizo- 12. Smith JM: Wheat gluten-schizophrenia findings. Science
194:448, 1976
phrenic patients.
13.

14.
Freed
absorption
Singh
WJ, Luchins
of haloperidol.
MM: Schizophrenia:
Di, Gillin JC, et al: Wheat
Biol Psychiatry
glutens
gluten
13:769-771
and neuroleptics.
,impedes
1978
Biol Psy-
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