Executive Summary
The population suffering from schizophrenia is relatively small, but all indications from various studies point to the likelihood of this rate increase in the future. Genetic factors have been identified to results in schizophrenia but the majority of research works have been hampered by methodological pitfalls. At the same time, findings indicate that individuals having schizophrenia exhibit low levels of folate and accelerated levels of homocysteine. In an attempt to fill the gap exposed by earlier methodological pitfalls, this research project employs multiple methodological procedures and instruments, with emphasis on the validity and reliability of the entire process of data collection and analysis. As a result, the research establishes that folate plays a great role in reducing schizophrenia disease. The findings further point to the role diet can play in reducing the prevalence of the disease. Overall, the project takes twelve months and results constitute a body of knowledge that forms a base for future research in the field. Further, clarity has been established on the clear relationship of schizophrenia and folate and this makes future treatment decisions more achievable.
Introduction
Many severe mental disorders affect individuals, but Schizophrenia is identified to be the most chronic, puzzling, and disabling condition compared to others (Shore and Keith, 1996). Escott-Stump (2008) defines Schizophrenia as “group of disorders manifested by disordered thinking, delusions, social withdrawal and mood and behavioral disturbances” (p.262). Currently, about 1% of the population is estimated to have the disease where men, unlike women, manifest early onset of the disease (Feng, Song, Xin, and Hu, 2009). About 50% of those diagnosed with SCZ suffer from treatment-resistant psychotic symptoms that in most cases include social withdrawal, apathy, and depression (Mattson 2002). Many people who are diagnosed with SCZ experience distress that disrupts their social and occupational functioning and often leads to hospitalization (Muntjewerff and Blom, 2005).
Inadequate folate has been associated with increased risks of schizophrenia, and today, this particular area has drawn the interest and enthusiasm of many researchers (Cohen, 2006; Brown and Susser, 2008). The link between folate and SCZ can be attached to the fact that glucose carboxypeptidase 11 (GCP11) is responsible for the regulation of folate absorption and activation of N-methyl-D-aspartic acid receptors (Escott-Stump, 2008). At the same time, it has been established that an increase in homocysteine levels results in decreased levels of folate and what follows later is that, when the level of folate decrease, there is always an increase in interleukin 6 and tumor necrosis factor-alpha level that lead to the development of SCZ (Cohen, 2006).
Different types of medications have been proposed for the treatment of SCZ, but some notable disease symptoms have revealed poor responses to treatment. Poor response to the antidepressant medication has been linked to a lack of enough vitamins folate and B12. Hoffer (2005) observed that vitamins, when provided with folate and B12, provide safe and most affordable means of improving outcomes among those diagnosed with SCZ. According to Mattson (2002), those found to have SCZ and lack the above supplements have responded poorly to treatment. Therefore, the role of nutrition in the treatment of SCZ cannot be ignored. Hesselgrave (2011) conducted research whereby it was established that folate is important, especially with regard to critical factors it contains in proper methlation metabolism. Other researchers have established that folate deficiency tends to accelerate symptoms of SCZ (Hoffer, 1975; Rinomhota and Marshall 2000; Muntjewerff and Blom, 2005).
To ascertain the role of nutrition in reducing symptoms of SCZ, numerous experimental studies have been conducted; Reynolds (1967) found out those patients with mental problems exhibited improvement in symptoms when administered with folic treatment (Muntjewerff and Blom, 2005). In another related experiment, Kim and Moon (2011) found out that folate-deficient epileptic patients manifested improved drive, initiative, and mood when induced with folic supplements. Moreover, Ghadirian et al. (1980) found out that serum folic acid levels were lower among depressed patients and other diagnosed psychiatric patients (Rinomhota and Marshall, 2000). Meta-analysis of recent studies has shown that folate contributes to the constant reduction of depression disorders (Hill et al. 2010; Mischoulon and Rosenbaum, 2008; Stannard, 2011). Further, case-controlled studies have established a relationship between folate and schizophrenia; Freeman et al (1975) established a reduction in MTHFR activity in a patient diagnosed with schizophrenia when folic is administered (Mattson, 2002). Moreover, Regland et al (1997) established that 5% of the population in their research exhibited polymorphism in the MTHFR gene (C677T), which was found to result in a greater than 70% reduction in enzyme activity, and this was linked to the development of schizophrenia (Kim and Moon, 2011).
At the same time, more efforts have been made to establish whether there exists a relationship between monocyte chemoattractant protein (MCP-1) concentration and folate/homocysteine-Hcy phenotype or methylenetetrahydrofolate reductase (MTHFR-C677T) genotype (Roffman et al., 2007; Hammons et al., 2009; Muskiet and Kemperman, 2006). Homocysteine constitutes a type of amino acid that is largely found in individuals’ blood (Guinotte et al., 2003). Some of the patients diagnosed with schizophrenia have demonstrated higher levels of homocysteine in their blood (Arzaghi, Hossein-Nezhad, Shariat, Ghodsipour, and Larijani, 2011). This is brought about by the presence of functional polymorphisms found in certain and specific enzymes in the folate and Hcy metabolic pathway. The presence of functional polymorphisms affects the overall distribution of the intermediates in the pathway, hence leading to an increased level of Hcy (Hammons et al., 2009).
Among the identified polymorphisms, the MTHFR C677T exhibits the highest and greatest quantity effect whereby 677TT genotype manifests relatively high Hcy concentrations in most instances when folate status is low (Vilella et al., 2005; Guinotte et al., 2003). From the above scenario, research has established that increased Hcy demonstrates high chances of deregulation of folate and Hcy metabolism (Vilella et al., 2005; Muntjewerff, Khan, Blom and Heijer, 2006). In a study dubbed ‘Homocysteine-Reducing Strategies Improve Symptoms in Chronic Schizophrenic Patients with Hyperhomocysteinemia’, it was found that schizophrenic patients possessed high levels of homocysteine (Stannard, 2011). However, after being administered with 2mg of folic acid, 400 mcg of vitamin B12 and 25mg of vitamin B6, the patients manifested improved symptoms after a certain period of time (Stannard, 2011).
Aims and Objectives
Cohen (2006) establishes that there exists a relationship between reduced levels of folate and the development of SCZ, but no succinct research work has accurately established this relationship. Building on this observation, this research work aims to determine how the type of polymorphism gene related to folate metabolism is linked to schizophrenia development and this will be attained through experimental study. Objectives to be attained include:
- Establish a relationship between increased level of serum folate, reduced serum homocysteine and the decrease of severity of SCZ symptoms.
- Identify the specific diet that can be used to prevent schizophrenia.
- Ascertain how Schizophrenia treatment can be achieved.
Hypothesis and Research Questions
This research is centered on investigating relationship between Schizophrenia and folate. Therefore, to attain the broad objectives of the research, the following research questions will be explored:
- In what way is folate supplementary related to schizophrenia development?
- Which specific diet can be used to prevent schizophrenia?
- How complicated is schizophrenia treatment process?
- Which type of polymorphisms of a gene is related to folate metabolism?
Hypothesis
It is hypothesized that there is a significant difference as a result of increased level of serum folate, which reduce serum homocysteine and lead to negative symptoms of schizophrenia.
Statistical hypotheses
- H0: σ1 ≠ σ2
- H1: σ1 = σ2
Significance of the Study
Schizophrenia is a condition that continues to affect many individuals and society. Identifying the factors associated with the disease has been a great milestone in understanding the disease. Further, this has led to more research work being carried in an attempt to identify the most suitable treatment solutions for the disease. Nevertheless, the role of diet in reducing the severity of the disease needs to be investigated, as this will contribute to the increasing body of knowledge concerning schizophrenia. More so, the role of folate in reducing cases of schizophrenia is important, as it will enable more research to be carried out based on genes on the best folate diet to be used. In general, significance of this research has to do with finding out and accurately clarifying the relationship between increased serum folate, reduced serum homocysteine, and subsequently manifestation of negative symptoms of schizophrenia. This will enable generation and availability of accurate body of knowledge that can be of great use to many stakeholders.
Research plan, methods, and techniques
This research project aims to establish and determine relationship that exists between serum folate, serum homocysteine, and the improvement of symptoms of schizophrenia. The study will be experimental in nature where an experiment on a sample of 100 participants will be done for a period of 12 months. In experimental research, the research plans an intervention, and subsequently studies its effects on groups or individuals (Hicks, 2004). The intervention is known as independent variable (or treatment) while the outcome measure is dependent variable. Dependent variable will be used to assess the effectiveness of the intervention. Further, experimental study will involve the use of statistical tests to investigate and compare groups. Making comparison in experimental studies, treatment is introduced to the experimental group members while members in control group may or may not receive any treatment. The goal of the experiment will be to carry out genetic testing for 100 participants to determine who has the polymorphism. Attainment of research goal will require employment of research instruments that possess capacity to answer research hypothesis and research questions. Instrumentation in the research process originates from research aim and research hypothesis and as a result, multiple instruments will be utilized to achieve the research results.
Sampling
Genetic testing will be done on a sample of 100 participants and the aim will be to determine presence of polymorphism among them. The research project will take place in the identified hospital in the state of Michigan. The first step will be to seek consent of the 100 consecutive patients to take part in the research project and this will be done in conjunction with administration of the identified hospital in which the project will take place. The project will last twelve months. Selection of study sample will be attained through random sampling technique. This technique sometimes, known as probability sampling, has been identified as the most common and preferred best way of selecting sample (Hicks, 2004). The approach to be adopted will ensure that all the important subsets of the population under study are represented in the study. Selection of sample is premised on the need to minimize sample bias, which may contribute to decrease in validity of the results. To carry out the process after being authorized by hospital administration, services of a psychiatrist will be utilized in identifying and recommending the 100 participants for the study.
As a first step, the identified participants will be required to undergo initial screening that will largely involve medical and psychiatric evaluation, physical examination of health condition, blood draws, sampling of urine elements and completion of initial questionnaires (Arzaghi, Hossein-Nezhad, Shariat, Ghodsipour, and Larijani, 2011). At the same time, permission consent will be sought from the participants so that their blood samples can be used for genetic testing and analysis. Participants whose health records and lab results indicate to be diagnosed with schizophrenia are the ones who will be included in the experiment study. After the selection of sample has been attained, the next step will involve sub-dividing the sample into two categories (groups). The first group will include sixty participants who have been diagnosed and found to possess MTHFR C677T polymorphism and the second group will consist of forty participants who have no polymorphism. After this process has been completed, the next step will involve sub-dividing the first group into two sub-sets, where the first sub-set will consist of thirty participants who will be provided with folate supplements, while the second sub-set will have thirty participants and it will not be administered with any folate supplements. This process will also be carried out on the second group, whereby it will be sub-divided into two sub-sets with the first subset (non-polymorphism) of twenty participants will be provided with folate supplements, and the second sub-set of twenty participants will not be provided with folate supplements.
Data collection
Data collection will largely depend on adoption and utilization of appropriate instruments. Instrumentation in this experimental study will greatly reflect clinical instruments and project objectives. Given that the entire project will take a maximum of twelve months, the instruments to be used have ability to carry out measurement and assessment for the entire period of the project. After the participants have been placed in the four major sub-groups identified above, folate supplements will be introduced to the first sub-set of group, one consisting thirty members diagnosed with polymorphism. Another folate supplements will be introduced to second sub-set of group two consisting of twenty members who have no polymorphism. The other two sub-sets from the two major groups will not be provided with any folate supplement (placebo). The first one month of the project will largely constitute stabilization activities as participants and all involved in the project become acquainted to the project and its needs.
After the one-month period has elapsed, the participants now will be subjected to an eleven-month treatment study. During the period, the study will be characterized by medical visits, taking place after every one month during the treatment period. During the medical visits, the following aspects or activities will take place; questions will be asked as to whether the participants under treatment experience some forms of side effects and questions concerning the distribution of study medication. The medical visits will have to be specified and communicated to participants before they take place. During the visits, major activities will include asking participants to complete various designed assessments and these assessments will have information concerning questionnaires about schizophrenia, learning and memory tests, blood tests carried out on repeated occasions, and other identified and suitable tests. The visits in most cases will take 2-6 hours depending on the nature of assessment to be carried out.
The above project process will utilize clinical research instruments that will again be necessary during the 12-month of the study. The use of Positive and Negative Syndrome Scale-PANSS as instrument in the study will be necessary and will be used to measure reduction in schizophrenia symptoms largely because of changes in the baseline total score, which will take place at the tenth-month (Maruish, 2004; Goff et al., 2004; Hoelzle and University of Toledo, 2008). Hamilton Depression Rating Scale will also come in handy, and the research will utilize this instrument in measuring the cognitive battery composite score of participants under treatment and the period for this to take place will be during the tenth month (Goff et al., 2004). Further, Scale for the Assessment of Negative Symptoms, on the other hand will be used to measure negative symptoms largely from total score obtained on the baseline rating during the tenth month (Goff et al. 2004).
Other instruments that, in one way or the other, will become useful during the study include Global Assessment Scale; Simpson-Angus Rating Scale and Abnormal Involuntary Movement Scale-AIMS (Roffman et al., 2006, 2007, 2009; Goff et al., 2004). Cognitive battery instruments to be used include WAIS-111; FAS verbal fluency test (Cicchetti and Rourke, 2004), Wisconsin Card Sorting Test (Ono et al. 2003), Stroop Test (Vogel, Maas and Gebauer, 2010); Finger Tapping Test (Hoelzle and University of Toledo, 2008), and California Verbal Learning Test (Davis, 2010).
Data Handling
Quality of research work depends on the effective way the data has been handled. In this research project, all ideas and concepts generated in the process of research work will be explored and stored in an easily accessible way. The presence of numerous statistical software packages makes the process of data handling more accurate and fast due to improved means of collecting, storing, and analysis. Therefore, the research will utilize SPSS statistical package. Coding of data will be carried out, and this will involve single-coded variables and multi-coded variables. The topic will be broken into subtopics, and the review will be carried out through field studies. Throughout the process, focus will be put on achieving consistency, speed, reliability, and efficiency. On the other hand, quantitative data will also be handled through SPSS tools. This Process will enable extraction of important features of central tendency, standard deviation, and inter-quartile range.
Data Analysis
Data analysis will largely originate from medical assessment reports and records obtained during medical visits and this will take place during the twelve month. Phlebotomy will be carried out whereby serum samples will be assayed for folate, total homocysteine, B12, glycine and serine concentrations (Tonin, et al., 1997). Clinical rating for serum folate and serum homocysteine will be recorded; the mean folate level will be compared with the general population mean level and this will results into analysis of findings and discussion. Moreover, the study will analyze whether homocysteine differ among between men and women. To make analysis depending on the hypothesis statement, the research will first have to find out the concentration of serum folate and homocysteine in both patients in the study and those under control, especially after the administration of folate supplements. Positive or negative symptoms will have to be established first, especially after the administration of folate supplements among the patients.
Comparison of folate and homocysteine concentrations among the sample participants in the experiment and those under control will be carried out (Tonin et al., 1997). At the same time, efforts will be made to analyze the “effect of MTHFR genotype on treatment effects and on changes in serum folate by grouping participants with T/T genotype together with C/T genotype and comparing their interactions to patients with C/C genotype” (Hill et al., 2010). The study project will emphasize the utilization of published mean plasma folate and homocysteine concentrations, and this will originate from data from participants under control and the instrument to use will be the Framingham Offspring Study to participants not provided with folate supplements.
To establish level of serum folate, the researcher will integrate use of “cloned enzyme donor immunoassay kits,” which should indicate absence of boil for folate according to the instructions attached in the kit (Pfeiffer, 2002). On the other hand, analysis of serum homocysteine will originate from measurement results attained through utilization of fluorescence polarization immunoassay method that should have a coefficient of variation ranging from 3.7% to 5.2%” (Pfeiffer, 2002). Analysis will be carried out on the association that is evident between clinical rating scale scores and tests, for these will be best carried out using Pearson’s correlation coefficient (Kim and Moon, 2011). Moreover, according to Shier (2004), “unpaired t-tests will largely be used to test for significant differences in mean scores on the clinical rating scales and the levels from the serum assays between the subjects with and without the deficit syndrome.” To ensure there is maximum protection against biased p values due to unequal group sizes, the nonparametric Mann-Whitney U test will be used for accuracy (Shier 2004).
Further, all analyses will be two-sided, and for accuracy, the alpha will be set at <0.05. Relationship among PANSS total score; negative and positive symptoms; cognitive performance; baseline serum folate, plasma homocysteine; and MTHFR C677T gene status will be carried during the tenth month. In addition, relationship between response of negative and positive symptoms and the change in serum folate, and plasma homocysteine concentrations will also be measured at week thirteen and both are designated as safety issues.
Enhancing Research Quality
Validity in clinical experiments is an important issue that will determine the relevance of outcome and results. In most cases, a good experiment is one in which the treatment has an effect on the outcome and all other effects have been excluded. As a result, the validity of the study will be premised on efforts of researchers to avoid personal bias especially when conducting treatment on participants and carrying out assessment. Further, the research procedures and instrumentation will be designed in the most appropriate way and this will be achieved through aligning research goals and research questions with instruments used and entire procedure adopted. Effort will be aimed at reducing variability that may originate from instruments and procedures. Moreover, sound sampling strategy is necessary and that is what the study adopts in order to minimize research errors. On overall, research validity will be obtained and achieved through adopting fundamental control through adoption and utilization of combination of good research questions and linked to appropriate research designs (Houser and Bokovoy, 2006).
Research Justification
As it was identified in the introduction part of the research project, earlier research work has utilized availability of less rigorous methodology, which in turn has led to less conclusive results being realized. As a result, the strength of this research rests on use of appropriate and multiple methodologies approach to investigate the research hypothesis. Therefore, research results to be generated are believed will be appropriate, more accurate and valid, and the subsequent level of their generalizability and future use will be high as compared to earlier researchers.
Research Timeline
Research timeline is detailed allocation of time to each specific activity. The project intends to take 12 months in which a detailed report will be developed. Project proposal has already been undertaken, permission sought and authorization for project to take place has been authorized. As a first step in the first month of the project, will largely constitute stabilization activities as participants and all involved in the project become acquainted to the project and its needs. Thereafter, treatment will be introduced and the process for next 11 months will involve observation of changes, interviews, and assessment. As the timeline framework indicates, overlap of some activities will be inevitable and this will ensure accurate assessment and control of any bias.
| Activity/Time | 1-2 month period | 3-4 month period | 5-6 month period | 7-8 month period | 9-10 month period | 11-12 month period |
| Research proposal development, acceptance and authorization |  | |||||
| Proposal introduced to relevant authorities, permission sought, identification of study site/samples and instruments |  | |||||
| Commence of study, participants provided with treatment |  | |||||
| Medical visits, assessment and adjustments |  | |||||
| Measurement of variables, data collection, analysis |  | |||||
| Evaluation |  | |||||
| Report writing and presentation |  |
Research Budget
Item (Activity) Cost ($) 12 months
Proposal Development expenses 00
Field trip expenses 00
Data Collection expenses 00
Literature Review collection 00
Transport expenses 00
Printing of materials 00
Purchases of necessary materials and stationery 00
Purchases of folate supplements 00
Research participants daily upkeep 00
Medical visits, assessment expenses 00
Questionnaire development expenses 00
Research assistants’ expenses and wages 00
Monitoring, evaluation expenses 00
Report writing expenses 00
Miscellaneous expenses 00
Description of facilities/resources required
This is a research project that will need different resources in terms of time, financial, human and transport. Financial resources will be necessary to purchase necessary materials, transport, daily upkeep, and pay research assistants. Given the nature of the project, a number of research assistants (6) will be required. Some facilities to be used in the field will belong to the hospital, and they will require seeking permission to use them. On overall, availability of resources on time will enable successful completion of the project on time.
Research Limitations
Research on the polymorphisms and the subsequent medication of schizophrenia is a complex and time-consuming undertaking and as a result, time and financial resources may be a limitation. This is particularly about large number of respondents the research will want to interview, carry experiment on, and conduct assessment and re-testing for the 12-month period. Time, coupled with inadequate finances will largely pose strain on researchers and related activities. Another limitation may arise from research instrumentation, whereby the selected samples may engage in aspects and activities that may influence research results for the 12-months period. What needs to be known is that working with people in a complex process and total control may not be possible. Lastly, limitation of the research will be exhibited in terms of content, whereby the research will confine itself to establishing presence of polymorphism MTHFR gene (C677T. Thus, information on other available polymorphism will be irrelevant and of less interest.
Ethics in Research
Research ethics imply the cautious administration of research procedures especially when it comes to human subjects. This study shall be composed of human participants, thus, ethical processes must be observed. First permission will be sought from relevant regulatory boards for the research proposal. After obtaining the necessary approval, finding the right settings for the study and participants who will be involved in the research will be the next step. Thus, participants will be gauged from the list obtained from the hospital administration. To apply fairness, a random selection technique shall be applied. In this manner, anonymity and confidentiality of information are important considerations. Prior to continuing with the research, it is vitally important that consent be derived from the participants. Apart from this, the objective of the study is also explained to the hospital administration and participants so as for them to know the honest intention of the research. Likewise, they will be guaranteed access to the results of the study and information on best practices, which can be applied in their context.
Conclusion
By the time the project is completed, it is believed that relationship between folate and schizophrenia will be established. Schizophrenia, being a medical condition that affects about 1% of the population, requires carrying out detailed and methodologically rich research in the area. Preventive and treatment mechanisms will be suggested derived from research results and evidence. More important, the role of diet, as well as how well diet can be introduced and managed in the treatment of the disease will be recommended and an outline plan developed. Given that numerous research works have been undertaken in this area, it is believed that by adopting and utilizing the right methodological approach, the results to be derived from the study will be enriching in knowledge and in initiating action activities. Further, it is perceived that information generated through this will be important for future research work and for clinicians in creating treatment-related programs for schizophrenic patients.
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