Professional Documents
Culture Documents
Brief Communications
Brief Communications
Brief Communications
BRIEF COMMUNICATIONS
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.
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-
REFERENCES
chiatry 14:853-855, 1979
15. Baker GA: Effects of nutrition on schiLophrenia (Itr to ed). Am J
I . Dohan FC: Cereals and schizophrenia-data and hypotheses. Psychiatry 130:1400, 1973
Acta Psychiatr Scand 42:125-152, 1966 16. Luchins D, Freed WJ, Potkin 5G. et al: Gluten and haloperidol
2. Dohan FC: The possible pathogenic effect of cereal grains in absorption (ltr to ed). Biol Psychiatry 15:819-820, 1980
schizophrenia-celiac disease as a model. Acta Neurologica 17. Singh MM, Kay SR: Gluten and schizophrenia. Lancet 2:689-
31:195-205, 1976 690, 1976
3. Dohan FC: Celiac disease and schizophrenia. Lancet I :897-898. 18. Reunala T. Blomqvist K. Tarpila S. et al: Gluten-free diet in
1970 dermatitis herpetiformis. Br J Dermatol 97:473-480. 1977
4. Prugh DG: A preliminary report on the role offunctional factors 19. Dohan FC: Celiac-type diets in schizophrenia. Am J Psychiatry
in idiopathic celiac disease. Psychosom Med 3:220-241 . 1951 136:732-733, 1979
5. Sheldon W: Celiac disease. Pediatrics 23:132-145, 1959 20. Keuning JJ, Pe#{241}a AS, van HooffJP, et al: HLA-DW3 associated
with celiac disease. Lancet 4:506-507. 1976
6. Cooke WT, Smith WT: Neurological disorders associated with
21. Schmid K: al Acid glycoprotein. in The Plasma Proteins. vol 1.
adult celiac disease. Brain 89:683-772, 1966
Edited by Putnam FW. New York, Academic Press, 1975
7. Dohan FC, Grasberger JC, Lowell FM, et al: Relapsed schizo-
22. Piafsky KM, Borg#{227}0. Odar-CederlOf I, et al: Increased plasma
phrenics: more rapid improvement on a milk and cereal-free
protein binding of propranolol and chorpromazine mediated by
diet. Br J Psychiatry 1 15:595-596, 1969
disease-induced elevations of plasma a acid glycoprotein. N
8. Dohan FC, Grasberger JC: Relapsed schizophrenics: earlier
EngI J Med 299:1435-1439, 1978
discharge from the hospital after cereal-free. milk-free diet. Am
23. Ashkenazi A. Krasilowsky D. Levin S. et al: Immunologic
J Psychiatry 130:685-688, 1973
reaction of psychotic patients to fractions of gluten. Am J
9. Singh MM. Kay SR: Wheat gluten as a pathogenic factor in Psychiatry 136:1306-1309, 1979
schizophrenia. Science 191:401-402. 1976 24. Klee WA, Ziovdrov C. Streaty RA: Exorphins-peptides with
10. Rice JR, Ham CH, Gore WE: Another look at gluten in opioid activity isolated from wheat gluten and their possible role
schizophrenia. Am J Psychiatry 135:1417-1418, 1978 in the etiology ofschizophrenia. in Endorphins in Mental Health
1 1 . Singh MM: Celiac-type diets in schizophrenia (Itr to ed). Am J Research. Edited by Usdin E. New York. Oxford University
Psychiatry 136:733, 1979 Press, 1978