Stacie Savage
Cox College, 2018
Abstract
Gluten disorders can manifest as schizophrenia from a result of inflammation in the brain caused by dietary gluten (Hadjivassiliou, Sanders, & Aeschlimann, 2015). Schizophrenic symptomology including hallucinations, paranoia, delusions, altered ability to understand reality, disorganized speech and thoughts, and suicide (Kraft & Westmann, 2009) and in a subset of the schizophrenic population can be caused by an autoimmune response to gluten (Cascella et al., 2013). Current biochemical testing does not appear to provide any singular laboratory test with high specificity to diagnose gluten schizophrenia, a term coined by the author. This systematic review explores six published experimental trials that studied the relationship between schizophrenia and gluten intolerance and were found via EBSCO database search and analyzed through critical appraisal. Although the research articles had study design limitations, overall results indicated that a gluten-free diet can be an effective intervention for a subset of the schizophrenic population. Understanding the pathology of gluten schizophrenia can aid clinicians in recommending and assisting this patient population in following a gluten-free diet for improved quality of life.
Keywords: schizophrenia, gluten sensitivity, IgA, IgG, celiac disease, antigliadin immunomarkers
A Systematic Review on Schizophrenia and Autoimmune Gluten Disorders
Gluten disorders, including both gluten sensitivity and celiac disease, has the potential to manifest as abnormalities of the brain caused by inflammation (Hadjivassiliou, Sanders, & Aeschlimann, 2015). Gluten comes from wheat, rye, and barley and is composed of both gliadin and glutenin protein molecules and gives bread its soft and elastic characteristics which contributes to its favorability in the Western diet. In most individuals, dietary gluten stays within the intestinal tract and is easily digested, but in some individuals, gluten triggers the immune system as it passes through a more permeable intestinal wall (Sapone et al., 2012). The intolerance to gluten and subsequent immune response classically causes gastrointestinal distress and damage to the intestinal lining, but it can also manifest into extraintestinal signs and symptoms such as arthritis, anemia, or psychotic disorders as the resulting inflammation is systemic even with no apparent gastrointestinal symptoms (Sapone et al., 2012).
Schizophrenic symptomology including hallucinations, paranoia, delusions, altered ability to understand reality, disorganized speech and thoughts, and suicide (Kraft & Westmann, 2009) and in a subset of the schizophrenic population can be caused by an autoimmune response to gluten (Cascella et al., 2013). A case study by Kraft and Westman (2009) of a 70-year-old female with longstanding schizophrenia presented with symptoms of hallucinations, paranoia, disorganized thinking, and suicide attempts in which antipsychotic medications had been largely ineffective. She was trialed on a ketogenic diet with <20g/day carbohydrate and was instructed to avoid breads, pastas, and starches which likely provided the benefit of a low-gluten diet. The individual had complete remission of schizophrenic manifestations within eight days on the diet and improvement was maintained (Kraft & Westman, 2009).
Various research studies have found an association between the prevalence of gluten disorders and neurological conditions (Lionetti et al., 2015; Hadjivassiliou et al., 2015; Lachance & Mckenzie, 2014). Dohan was the first researcher to bring awareness to occurrence of schizophrenia among those with celiac disease (Dohan, 1966; Dohan, 1970), and Lionetti et al (2015) has demonstrated a connection between gluten sensitivity with psychosis and hallucinations. The prevalence of schizophrenia is experienced by 1% of the population and celiac disease effects 0.75% of the population (Cascella et al., 2011). Of the schizophrenic population, 23.1% have been found to have moderate to high levels of immunoglobulin A (IgA), an antigliadin antibody most notable in celiac disease (Cascella et al., 2011). Gluten sensitivity in contrast to celiac disease has no apparent immunomarkers, so the associated prevalences of psychosis and gluten disorders may be even higher (Sapone et al., 2012).
An autoimmune response to gluten found in a subset of the schizophrenic population can have varying immunomarkers which complexes diagnosis (Cascella et al., 2011). Gluten autoimmune conditions are a spectrum of disorders (Sapone et al., 2012). A diagnosis for gluten sensitivity has no apparent immunomarkers, while a diagnosis of celiac disease most often has an increase in IgA but not always (Sapone et al., 2012). And gluten ataxia is more likely to have an elevation of immunoglobulin G (IgG) (Sapone et al., 2012). Other relevant antigliadin markers associated with schizophrenia are IgA against transglutaminase 2 and IgA against deamidated epitopes (Jin et al., 2010). And in most recent research, transglutaminase 6 (TG6) has been found to have a significant association with the gluten-associated neurological conditions, gluten ataxia and schizophrenia (Hadjivassiliou et al., 2015; Cascella et al., 2013). At this time, there does not appear to be any singular laboratory test with high specificity to diagnosis gluten-affected schizophrenia.
The Evidence Analysis Library of the Academy of Nutrition & Dietetics does not currently remark specifically on gluten and schizophrenia (Evidence Analysis Library, n.d.). Additionally, a diagnosis and intervention for gluten-related schizophrenia is unaddressed by UpToDate.com, a commonly used resource by practitioners in patient care. Unless clinical dietitians within the field of psychiatry have a personal interest and awareness of the connection between schizophrenia and gluten, the intervention thereof is nonexistent. Although there are several recent observational studies on the association between schizophrenia and gluten disorders, there is a great lack of experimental trials within the last three decades. Historical experimental trials between 1965 and 1986 reviewed herein may provide much value for the field of nutrition and mental health. The purpose of this paper is to review the evidence of a gluten-free diet intervention in the schizophrenic population.
Methods
Criteria for Study Inclusion
Types of studies. Only published, experimental, human studies were reviewed.
Participants. Studies were considered if participants of any age group and were diagnosed with schizophrenia.
Intervention(s). Interventions involved altering intake of dietary gluten.
Outcome measure(s). Effect on schizophrenic clinical symptoms was the desired primary outcome measure such as severity or remission of psychosis, hallucinations, and disordered thinking as measured by psychotic or behavioral assessments. Effect on inflammatory biomarkers were also considered, but no experimental trials included this outcome measure at baseline for comparison.
Search Strategy A systematic literature search was conducted on the EBSCO database using CINHAL and Medline. All years were searched due to the nature of this historical research and lack of recent experimental studies. The following are keywords and subject headings utilized for this project:
S1: Gluten free diet OR ketogenic
S2: (MH "Gluten") OR (MH "Diet, Gluten-Free") OR (MH "Celiac Disease+")
S3: (MH "Diet, Gluten-Free") OR (MH "Celiac Disease") OR (MH "Glutens+")
S4: (MH "Diet, Ketogenic")
S5: (MH "Schizophrenia+") OR (MH "Schizophrenia, Childhood")*
S6: schizophrenia
S7: S5 OR S6
S8: gliadin
S9: S1 OR S2 OR S3 OR S4 OR S8
S10: S7 AND S9
Critical appraisal for inclusion
Studies selected were confirmed to meet inclusion criteria by peer review from another graduate student of the Nutrition Diagnostics program at Cox College. Each article that met search criteria was reviewed individually to assess for inclusion. Excluded articles were observational studies, patient populations other than schizophrenia, and interventions that did not involve gluten. Articles meeting inclusion met all criteria such as experimental trials, the schizophrenic population, and gluten as an independent variable.
Results
Search Results
Out of 145 search results, only six articles met inclusion criteria involving interventional experimental trials assessing the effects of gluten consumption in schizophrenia. Most studies of this nature were published between 1965 and 1986. Newer studies found were observational studies and case studies, but more recent experimental studies were not found with this search method.
Quality of Included Study
An extensive critical appraisal was conducted for an experimental trial by Dohan and Grasberger (1973). Dohan performed a gluten-free trial on adult male schizophrenic inpatients admitted in a veterans’ psychiatric hospital ward to examine the effects of gluten on schizophrenic manifestations and was measured by length of stay (LOS). He found that the participants who trialed the gluten-free diet during their stay in the locked ward were more likely to have increased stabilization of symptoms, be advanced to the open ward, and were able to discharge from the hospital sooner than those on a gluten-containing diet, and the effects were reversed when gluten was secretly added back in. The appraisal included analysis for study bias and found a reduced risk of selection bias as participant groups were randomly allocated, but the study had increased risk of bias as the researchers were not blinded to the process. The study also had reduced risk of attrition bias because of even distribution of drop out factors. Risk of reporting bias was decreased as the LOS data, the primary outcome measurement, was clearly outlined by every 30 days. The appraisal found that the quality standards for the study as compared to Heaney’s guidelines for nutrient research was not optimal (Heaney, 2014). The study did not first measure nutrient status at baseline which would be immunomarkers for gluten toxicity. Additionally, the study quality was compromised due to short intervention duration as the cereal-free diet was only implemented during the locked ward time. As the patients improved and advanced to the open ward, the intervention was discontinued. Yet, total LOS which included both locked and open ward time was the outcome measure and may have been compromised due to the temporariness of the intervention. Further details of the critical appraisal can be found in Appendix A.
Interventions of Included Studies
Each study examined the effects of gluten, or the omission of, in the clinical progression and/or regression of schizophrenia. Four out of the six studies had varying interventional methods. All of the studies omitted gluten entirely, five of the studies had participant-blinded gluten challenges of 30g gluten daily and two of the studies had 19g gluten daily.
Duration of gluten-free period is critical for clinically meaningful results in individuals with a gluten autoimmunity. Hadjivassiliou et al. (2015) states that it may take 6-12 months on a gluten-free diet for immunomarkers to normalize, and in the Kraft and Westman (2005) case study, it took eight days for symptoms to resolve on a ketogenic diet. Of these six studies reviewed herein, duration of intervention varied from 2-10 weeks. The gluten-free interventions by Dohan and Grasberger (1973) and Dohan, Grasberger, Lowell, Johnston, and Arbegast, (1969) lasted at least 15 days and duration thereafter varied among participants. Pacheco, Easterling, and Pryer (1965) endured a two week ketogenic trial. The gluten-free intervention of Vlissides, Venulet, and Jenner (1986) lasted 10 weeks, Potkin et al. (1981) eight weeks, and Singh and Kay (1976) two weeks. Gluten quantity appeared sufficient to produce meaningful results in all studies. However, in the Dohan and Grasberger (1973) study, the gluten-free diet was maintained only temporarily and not for the entire study compared to what would be appropriate for a total LOS outcome measure.
Effectiveness of Intervention of Included Studies
Overall results of the experimental trials had varying results. For the Vissilides et al. (1986) study, schizophrenic manifestations measured using the Psychotic Inpatient Profile (PIP) did not show a statistically significant change between gluten-free and gluten-containing diets for 20 of the 22 participants. The remaining two participants, both diagnosed with psychosis schizophrenia, had remarkable improvement during the gluten-free period. Improvement was demonstrated by specific PIP scores in the perceptual disorganization and depressive mood. The two participants then had subsequent relapses when the gluten was blindly introduced back in.
In the Pacheco et al. (1965) study of schizophrenic females undergoing the intervention of a ketogenic diet, the Beckomburga Rating Scale (BRS) resulted in a statistically significant decrease in schizophrenic symptomology after two weeks on the diet compared to two days on the diet. Clinical symptomology then increased again one week after discontinuation of diet in seven out of 10 patients. The research study by Potkin et al (1981) of eight schizophrenic participants, no statistical or clinical differences were found between the gluten and gluten-free periods in Brief Psychiatric Rating Scale (BPRS) scores, serum α1 acid glycoprotein, and HLAB8-antigens on eight weeks of gluten-free intervention. Importantly, this study was limited to only eight participants and were all mostly well-stabilized schizophrenic participants at baseline. Also, gluten-inflammation biomarkers used were not measured at baseline (Heaney, 2014).
Singh and Kay (1976) found a statistically significant improvement in a behavioral assessment with a gluten-free diet. The outcome measures resulted in improvement in: preoccupied behavior p<0.01, hostile or fearful social avoidance p<0.02, tension state p<0.02, anxiety p<0.05, poor judgment and insight p<0.05, and difficulty in abstract thinking p<0.02. The clinical and statistical improvement was reverted when a gluten challenge of 30g/day, blind to the participant, was added into the diet. Significant results also came from two studies led by researcher Dohan (1973; 1969) which found that a gluten-free diet doubled the chance that a schizophrenic patient in a psychiatric locked hospital ward would have a shortened LOS compared to schizophrenic patients on a high cereal diet (Dohan & Grasberger, 1973; Dohan et al., 1969).
Discussion
Overall Findings of the Review
Four out of the six studies demonstrated gluten-triggered schizophrenic symptoms and the effectiveness of the gluten-free diet. One of the studies showed that the ketogenic diet was also an effective intervention for some schizophrenic participants. And one smaller study showed results towards the null hypothesis. Overall, results appear to support a link between a subset of the schizophrenic population and an improvement in symptoms when gluten is removed from the diet.
All studies had limitations which must be considered with the results. In Potkin et al. (1981), there were only eight participants and was the only study in which the null hypothesis was concluded. Small sample size can increase bias towards the null hypothesis (Heaney, 2014). Pacheco et al. (1965), Vissilides et al. (1986), and Singh and Kay (1976) resulted in favor of the alternative hypothesis (effectiveness of the gluten-free trial) but had small sample sizes. Dohan and Grasberger (1973) and Dohan et al. (1969) had the largest sample sizes. Dohan et al (1969), the group on the gluten-free diet were more likely to release before day seven of psychiatric ward admission compared to the high-cereal diet control group (p=0.0091). In the study by Dohan et al. (1973), studied total LOS among locked ward inpatients with severe schizophrenic symptoms. They found that during admission days 40 through 180, increased discharge rates in the cereal-free group compared to the high-cereal group was <3% probability that difference was due to chance alone (Dohan et al., 1973). The median LOS for the cereal-free trial group was 53 days and the high-cereal group was 102 days (Dohan et al., 1973). Even with these results, the short intervention duration of the cereal-free diet was maintained during the locked ward period only instead of during the entire hospital stay and may yield a bias towards the null hypothesis.
None of these historical research studies measured gluten-inflammatory markers as inclusion criteria. In part because laboratory technology and antigliadin biomarkers may not have been as advanced as they are today. The study designs largely did not factor in gluten disorders for a subset of the schizophrenic population and instead included all schizophrenics which would result in lower statistical significance of intervention effectiveness. One of the biggest shortcomings of all the articles was that antigliadin biomarkers were not measured at baseline and then measured again after the intervention. Even without biochemical assessment, Singh and Kay’s (1976) study limitation was not providing the behavioral assessment for clinical symptomology at both baseline and after intervention.
Comparability of the Studies
Dohan and Grasberger (1973) and Dohan et al. (1969) were similar studies that took place at the same hospital - published four years apart. Both studies had a blind component to staff and participants. The earlier of the two studies assessed the LOS during a locked psychiatric ward when schizophrenic manifestation were most severe and the later study looked at total LOS including both locked and open ward periods. Both studies had statistically significant and clinically important results towards effectiveness of the gluten-free by shortening LOS.
Implications for Practice
In consideration of the six experimental trials, a gluten-free diet may be effective for a subset of the schizophrenic population. Gluten disorders should be ruled in or out in individuals diagnosed with schizophrenia. Biochemical data should encompass all potential inflammatory biomarkers for gluten going beyond the traditional celiac panel in consideration that no one immunomarker has high enough specificity to diagnose gluten autoimmunity in the schizophrenic population at this time (Sapone et al, 2012; Hadjivassiliou et al., 2015; Cascella et al., 2013). A gluten-free diet is an available inpatient diet in most hospitals and can be ordered for patients as indicated. Outpatient dietary consultation for a gluten-free diet trial may be considered in this patient population and with follow ups to assess for effectiveness on symptoms and biochemical changes - understanding that clinical symptoms may change anywhere from eight days (Kraft & Westman, 2005) to 180 days (Dohan & Grasberger, 1973) and normalization of immunomarkers may take 6-12 months (Hadjivassiliou et al., 2015).
Implications for Future Research
In accordance to the search method used for this systematic review, no experimental trials examining the effectiveness of the gluten-free diet in the schizophrenic population were found to take place within the last three decades. New experimental research with the advances of modern biotechnology can make a bigger clinical impact for identifying and diagnosing gluten-affected schizophrenia. Ideal research would include measuring antigliadin biomarkers at baseline as inclusion criteria and after intervention for comparison (Heaney, 2014). Antigliadin biomarkers, IgA, IgG, and TG6, seem to be of particular relevance for gluten-affected neurological conditions (Hadjivassiliou et al., 2015; Cascella et al., 2013). The duration of the gluten-free diet intervention should last long enough to ensure optimized improvement of biomarkers within 6-12 months (Hadjivassiliou et al., 2015).
Conclusion
This systematic review explored six published experimental trials that studied the relationship between schizophrenia and gluten disorders. Nearly a quarter of the schizophrenic population have been found to have elevated IgA levels (Cascella et al., 2011); however, IgA is only one of several immunomarkers that is associated with a gluten autoimmune response (Hadjivassiliou et al., 2015; Cascella et al., 2013). Five out of the six studies had results in support of a possible connection between gluten and schizophrenia and warrants further research.
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Appendix A
Critical Appraisal, Experimental Study
Citation (first author's last name, year): Dohan,1973
Study design: RCT
Study sponsor: Grants received were from the Benevolent Foundation of Scottish Rite Freemasonry, Northern Jurisdiction, USA and the National Association for Mental Health, Inc.
Conflict of interest summary: No conflict of interest determined
Number of participants: 157
Patient population: Male veterans diagnosed with schizophrenia at Coatsville Veterans Hospital. Participants were new admits or readmits
Research purpose/question: To examine the effects on hospitalized relapsed schizophrenics of a cereal grain-free, milk-free diet during the locked ward period of time and measured by total length of stay until discharge.
Intervention: Periods I & IIIa – cereal/milk free diet (during locked stay and 7-10 days after and then was discontinued) Period II - cereal/milk free diet with gluten secretly added (to blind in order to control for staff bias).
Comparative intervention: Period I, II, IIIa – high cereal grains diet (during locked stay and 7-10 days after and then was discontinued)
Outcome Measure: Total length of stay in hospital including locked ward and open ward.
Summary of results (include measures of effect, statistical/clinical significance etc.): 10.2% of schizophrenics on gluten/milk-free diet were discharged <30 days whereas 3.6% of high cereal diet were discharged <30 days. The Fisher’s result was 15.3%. The trend towards shorter length of stay continued until the end of the study which measured stays of up to 1 year. From 60-120 day LOS, gluten/milk-free diets had shorter LOS via Fisher test of 0.8-2.7% (probability difference was due to chance) compared to high cereal diet. Within 30 days, gluten/milk-free diet group was discharged at 2 times the rate of the high cereal group. The trend of shorter total length of stay continued up to 180 day hospital stays in favor of gluten/milk-free diet. Period II - two cohorts on either gluten/milk-free with addition of 19g gluten secretly added compared to high cereal diet. Statistical results were about the same in both groups in regards to LOS with no significant statistical difference.
Quality Assessment for Dohan, 1973
Heaney's guidelines score (details below): 3
Bias summary score (details below): 3
Other considerations score (details below): 9
Total quality rating score: 15 out of 27
Annotated bibliography of Dohan, 1973: Dohan performed a gluten-free trial with gluten challenge on schizophrenic patients admitted in VA psychiatric hospital ward to see the effects of gluten on schizophrenic manifestations. He found that more participants who trialed the gluten-free diet during their stay in the locked ward had more stabilization of symptoms and therefore were able to discharge from the hospital sooner than those on a gluten-containing diet. He even found that for many schizophrenics on the gluten-free diet (with gluten secretly added for blind effect) reverted the LOS original results comparable to the group on the gluten-containing diet. Dohan's journal article is a historical piece of research on the topic of schizophrenia and its association to gluten intolerance.
Assessment of Heaney's guidelines for solid research methods for Dohan, 1973:
Basal nutrient status must be measured, used as an inclusion criterion for entry into the study, and recorded in the report of the trial.
Was basal nutrient status measured?
No; This would have been very useful information, and I have found no experimental trials whatsoever do this for this topic. If a researcher would do this, they could change practice it would be that profound for patients with schizophrenia. Also, such historical literature (1973) did not have the same laboratory tests of 2018. There are several recent observational studies which explore basal nutrient status (gluten-inflammatory markers on gluten toxicity).
The intervention (i.e., change in nutrient exposure or intake) must be large enough to change nutrient status and must be quantified by suitable analyses.
Total hospital LOS (LOS = combined locked and open ward stay) was measured. Intervention was only for locked ward stay. This outcome measure of LOS is the most simple of measures. Even though locked ward, open ward, and discharge are all indicative of schizophrenic severity level, anti-gliadin inflammatory markers would have been a great additional objective measure as well as an intervention that lasted the whole LOS and not just locked ward period.
What was the change in nutrient intake/exposure (the study intervention)?
Period I&IIIa: Gluten-free diet during locked ward stay; Period II: Gluten-free diet with 19g gluten added (blinded to staff/participants)
What was the method used to measure nutrient intake /exposure?
LOS
Was the study intervention large enough to change nutrient status?
Yes - large enough to change nutrient status for some participants, but results could have been even more profound if gluten-free diet was sustained through entire hospital stay and not just locked ward period.
If yes, was the analyses used suitable?
The analysis used was mediocre. It would have been stellar if schizophrenic symptoms were analyzed, reported, as well as anti-gliadin inflammatory markers measured.
The change in nutrient status produced in those enrolled in the trials must be measured and recorded in the report of the trial.
No biomarkers were used in this experimental trial.
Was the change in nutrient status produced in those enrolled in the trial measured?
no
The hypothesis to be tested must be that the change in nutrient status (not just the change in diet) produces the sought-for effect.
Did the hypothesis to be tested state the change in nutrient status (not just the change in diet) produced the sought-for effect (or expected outcome)?
no
If no, did the hypothesis state it was the change in diet (or intake) which produced the sought-for effect?
yes
Conutrient status must be optimized in order to ensure that the test nutrient is the only nutrition-related, limiting factor in the response.
If we think of nutritient status relevance in this topic as toxicity rather than deficiency, milk was also eliminated so as to remove any potential neural inflammatory potential coming from milk (milk intake is also associated with schizophrenia). Then gluten was added back in (and not milk) as to isolate the effects of gluten alone. Otherwise, there is no other conutrient that is known to be associated with gluten nutrikinetics.
Bias Summary for Dohan, 1973
1 point for high potential of bias and +1 for low potential for bias
Selection bias- quality of allocation sequence generation: 1
Initially participants entering the locked ward were allocated into intervention or control group based on odd or even numbered social security number and then "later by random numbers in balanced groups of four".
Selection bias- quality of allocation concealment: -1
The allocation process was not blinded to researchers. There was a blind component for staff and participants in period II when gluten was secretly added into the gluten-free diet but was not blind to researchers and did not involve the allocation process.
Performance bias- quality of blinding of participants and personnel: 1
There was a performance bias in the research design, admitted by researchers. The researchers built in a blinded component to reverse or account for the effects of bias. In period II, 19g of gluten was snuck back into the gluten-free diet without the knowledge of staff (i.e. nurses) and participants. Only the dietitian and researcher knew. The statistically significant results of the gluten-free diet were shown to nullify when the gluten was added back in. I have interpretted this as a creative and successful intervention to conteract performance bias.
Detection bias- quality of outcome assessment: 0
Methodological procedure for assessing process of LOS was unreported aside from general improvement of schizophrenic severity.
Attrition- quality of outcome data (Was it complete or incomplete?): 1
Factors effecting attrition appeared to be the same for both groups. Attrition factors: patients in locked ward for <24hrs.
Reporting bias- quality of selection outcome reporting: 1
Dohan and Grasberger include in their research article a table of LOS data outcomes for all groups, intervention and control.
Additional comments on the evaluation of Dohan, 1973:
Would implementing the studied intervention or procedure (if found successful) result in improved outcomes for the patients/clients/population group?
Yes (but see explanation)
Not all people with schizophrenia would improve from gluten abstinence as gluten is not always the etiology of schizophrenia. But in a subset of the schizophrenic population, neural inflammation from gluten is the etiology, and in this patient population, gluten-free diet is of utmost importance for improved patient outcomes.
Did the authors study an outcome (dependent variable) or topic that the patients/clients/population group would care about?
yes
The intervention has the potential to help reverse level of severity of schizophrenia symptoms.
Is the focus of the intervention or procedure (independent variable) or topic of study a common issue of concern to dietetics practice?
No, surprisingly. It is not a "common" issue of concern, but it is absolutely relevant. And it is at least a concern to me, a dietetic professional.
Is the intervention or procedure feasible?
yes; Gluten-free is easier today than it ever has been. Many grocery stores (even walmart) have a small gluten-free section. And hospitals nation-wide have the ability to omit gluten-containing ingredients in the meals they provide. Clinicians should be ruling in/out gluten as an etiology for all patients with hallucinations, pyschosis, and schizophrenia and recommending a trial of a gluten-free diet as necessary. Thus, the intervention is feasible for both patient and clinician.
Was the intensity and duration of the intervention or exposure factor sufficient to produce a meaningful effect?
yes; The intensity and duration was sufficient to produce a meaningful effect. None the less, the duration could have been longer (entire hospital stay in both locked and open ward - not just locked ward period) would have possibly produced an even stronger meaningful effect.
Were outcomes clearly defined and the measurements valid and reliable?
mostly yes; The outcomes were defined yet I still think it could have been clearer. The study itself and outcome measures were complex.
Was the period of follow-up long enough for important outcome(s) to occur?
yes; Studies were long enough for the outcome to occur (symptoms/improvements).
Were primary and secondary endpoints described and relevant to the question?
no; Primary endpoints were described losely as LOS and discharged was decided upon at a staff conference on whether patients "improved sufficiently or considered likely to experience no further benefit from hospitalization". But I feel this endpoint could have been even more well-defined than it was - as the latter half of the quote is vague.
Are conclusions supported by results with biases and limitations taken into consideration?
yes; Because of the nature of the intervention analyses, LOS provides objective data. This is opposed to a psychiatric evaluation by an unblinded researcher for example. Thus, I think the bias from lack of researcher blinding still allows for legitimate results.
Sponsorship level of involvement of Dohan, 1973:
According to the information provided in the article, which could admittedly be limited, the sponsors simply provided grants to conduct the research yet did not play a role in the outcome of the research. Though, this was more implied rather than explicitly stated.
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