Background
Scientists, together with medical experts, express that Schizophrenia remains the most puzzling, chronic, and disabling condition as compared to other severe mental disorders (Shore and Keith, 1996). Schizophrenia (SCZ) has been defined as “a group of disorders manifested by disordered thinking, hallucinations, delusions, social withdrawal and mood and behavioural disturbances” (Escott-Stump, 2008, p.262). It is estimated that about 1% of the population develops SCZ whereby the onset is generally manifested between ages 15-25 years and men in most cases manifest earlier onset than females (Feng, Song, Xin, and Hu 2009). As a medical condition, SCZ is described to have a genetic component whereby genetic predisposition accounts for a large proportion of the cognitive deficits (Feng, Song, Xin, and Hu 2009). At the present, five genes have been identified and their role in the development of SCZ is being investigated, they include COMT, GRM3, G72, DISCI, and the BDNF (Roffman et al. 2006). Further research has been carried out by Velakoulis et al. (2006) on magnetic resonance imaging and the results have indicated that hippocampal volume reduces in SCZ (Feng, Song, Xin, and Hu 2009). Individuals who suffer from SCZ have been found to possess low levels of folate (Muskiet and Kemperman 2006; Feng, Song, Xin and Hu 2009).
The link between folate and SCZ can be deduced from the fact that glucose carboxypeptidase 11 (GCP11) is responsible for the regulation of folate absorption and also responsible for activation of N-methyl-D- aspartic acid receptors (Escott-Stump 2008). In this way, numerous hypotheses have been developed on the existence of a link between folate and SCZ. Some of the hypothesized statements include, that low maternal folate, maternal stress, and childhood infections may lead to SCZ in the later life of an individual (Brown and Susser 2008). Further, Benton (2002) found out that selenium might also have a role to play (Escott-Stump 2008).
It should be remembered that clinical trials carried out for the last thirty years have shown that antipsychotic medications are effective in reducing the positive symptoms of schizophrenia (Shore and Keith 1996). Further, psychosocial treatment has also been identified as having the ability to enhance patient outcomes (Shore and Keith 1996). In general, research findings have established that treatment of schizophrenia continues to be a major challenge to clinicians not only because of the severity and complexity of the disease but because of the need to integrate and address biological, psychosocial, and environmental effects and influences (Shore and Keith 1996). Folate deficiency has been linked to an increased risk of schizophrenia and many pieces of research continue to take place in this area (Cohen 2006). For instance, it has been revealed that by increasing homocysteine levels, there is a decreased level of folate. A decrease in folate in turn “increases interleukin 6 and tumour necrosis factor-alpha levels,” leading to the occurrence of schizophrenia disease (Cohen 2006). As a result, today, there exist numerous amounts of case reports, open studies and to a lesser extent case-control studies on the topic of psychopathology and folate deficiency. Findings in the majority of these studies reveal that high levels of serum folate deficiency are associated with individuals or patients with various psychiatric disorders (Cohen 2006). At the same time, cross-analysis of the findings shows that folate deficiency is largely manifested by patients who appear to be depressed.
Nevertheless, analysis of the findings from the various studies and informed comparison evidence across hospitals records shows less convincing evidence between the association of folate status and schizophrenia patients. This problem may be attributed to the availability of less rigorous methodology such as the inclusion of age and sex-matched controls and as a result, less conclusive results are realized. Motivated by this knowledge gap, the purpose of this research paper will be to carry out a case-control study on the relationship between Schizophrenia and folate. At the end of the control experiment study, there will be a tendency to generate and analyze data on the levels of folate in the population of patients with schizophrenia and establish the existence of any relationship. In doing so, this research will particularly pay attention to methodological design, clinical characteristics and folate measurement. Therefore, research on this topic is perceived to be important and timely to clarify the relationship between folate status and schizophrenia and effort will be made to avoid the methodological pitfalls identified above that other studies reveal.
Statement of problem
Population suffering from schizophrenia is relatively low but with the increasing revelation of the factors that results in the disease, it is apparent that the rate may go up in near future. Genetic factors have been identified to results in schizophrenia, but recent studies have identified the positive role of environmental factors in major psychiatric disorders (Mattson 2002). For some time now, various researches have been carried out on the role of folate in modifying the symptoms of depression, and in a majority of the studies, it has been revealed that individuals affected by depression are likely to have reduced folate levels as compared to non-depressed controls (Reynolds et al. 1970 cited in Mattson 2002). In another related study, patients suffering from dyskinesia and schizophrenia were administered with dietary supplements of vitamin B6 and after a certain period, the patients demonstrated improved symptoms (Lerner et al. 2001 cited in Mattson 2002). On her part, Susser et al. (1998) carried out a comparison study of homocysteine levels in schizophrenia cases and controls in relation to folate levels (Mattson 2002). The findings of the study revealed that there were increased chances of individuals having schizophrenia when the levels of folate were measured to be low and when levels of homocysteine were high (Mattson 2002).
The findings further pointed to the role of homocysteine whereby it indicated that an increase of homocysteine levels is mechanically involved in the pathogenesis of schizophrenia (Mattson 2002). It is evident that research on levels of folate and the role it plays in reducing schizophrenia disease are numerous. However, methodological pitfalls have accompanied the majority of the research. In light of this, there have been divergent, sometimes confusing evidence of the relationship between folate and schizophrenia and as such, this research aims to fill that gap of methodological deficiency. Clarity is needed on the clear relationship of schizophrenia and folate for future treatment decision-making and for creating supportive care programs for schizophrenia patients. In addition, it is from this understanding that the problem of schizophrenia and how folate can reduce it need to be investigated in detail, through the employment of the right methods of investigation.
The rationale for the research
As schizophrenia disease continues to be identified, and its impact continues to affect individuals and society, there is a need to carry out in-depth research on the condition and preventive mechanisms. There are preventive mechanisms that have been suggested for the disease, but little has been done on the role of diet in preventing schizophrenia. The available data that has been generated has been criticized largely due to the employment of inaccurate methods of data collection and analysis. As a result, inconclusive information and data have been generated and its applicability still demonstrates little progress. Therefore, this research builds on the understanding that there is a need to carry out accurate experimental research that adopts accurate and conclusive methods. In this way, there are high chances of clarifying the relationship between schizophrenia and folate.
Research questions
Research questions constitute that part of the research paper that provides overall guidance for the research work. It constitutes key areas that the research aims to answer through literature, data collection, and investigation techniques. The aim of this research paper is to investigate the relationship between Schizophrenia and folate. To achieve this aim, the research will further be guided by the following research questions:
- In what way is folate related to schizophrenia development?
- Which specific diet can be used to prevent schizophrenia?
- How complicated is the schizophrenia treatment process?
- Which type of polymorphisms of a gene is related to folate metabolism?
Research hypothesis
Hypotheses are educated guesses at what the outcome of the study may be. Experimental studies typically have both research hypotheses and statistical hypotheses. In this particular research study, the hypothesis to be statistically investigated is:
It is hypothesized that there is a significant difference as a result of an increased level of serum folate, which reduces serum homocysteine and leads to negative symptoms of schizophrenia.
Statistical hypotheses
H0: σ1 ≠ σ2
H1: σ1 = σ2
Research goals and objectives
Researchers have explored the association of schizophrenia development and reduced levels of folate and overall, there is some evidence that supports the existence of this relationship (Cohen 2006). As a result, more treatment programs continue to be created and designed from research findings generated. However, evaluation and analysis of these profound studies indicate that there have been instances of methodological pitfalls, which in turn have negatively influenced the study findings and application. Therefore, the major objective or goal of this research is to fill the identified void through the employment of accurate study methods and techniques. The success of this will enable the research to accurately identify and clarify the relationship between folate and schizophrenia and whether diet treatment option for the disease is a complicated process. In doing so, the other objective of the research will be ingrained in the need to generate accurate data and information that future research work can rely on to derive useful information. Further, the generated information will be useful for practitioners and clinicians in designing appropriate diet-based treatment programs and solutions for schizophrenia.
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 out 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, the 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 the generation and availability of an accurate body of knowledge that can be of great use to many stakeholders.
Literature Review
Approximately half of the people diagnosed with schizophrenia “suffer from treatment-resistant psychotic symptoms and these may include social withdrawal, apathy, and depression” (Mattson 2002). The manifestation and persistence of these negative symptoms can result in “substantial distress for those affected, often disrupting social and occupational functioning and resulting in hospitalization” (Muntjewerff and Blom 2005). Mattson (2002) further is on the view that majority of atypical antipsychotic medications have shown the ability in “treating negative symptoms” but in observed cases, “the degree to which many negative symptoms respond remains unclear”; moreover, “depression and the poor response to antidepressant medication” have been associated with lack of enough vitamin’s folate and B12. Through a number of experimental researches, it has been established that vitamins provided with folate and B12 have high chances of providing a safe and inexpensive approach to improvement of outcomes among the people diagnosed with schizophrenia (Hoffer 1975). More so, Mattson (2002) seems to be on the opinion that these people suffering from the condition mentioned above tend to have residual negative symptoms and, in most cases, and more likely to exhibit some kind of resistance to treatment, that is, they tend to manifest poor treatment response (Mattson 2002).
Studies to find out the role of nutrition in the well-functioning of individuals and patients suffering from various conditions have been numerous (Hoffer 1975). Barbara Hesselgrave observes that folate is important to human beings since it constitutes an important and critical factor in proper methylation metabolism (Hesselgrave 2011). For example, there exists a lot of research work on the role of nutrition on individuals’ mood, psychosocial functioning, and mental ability and functioning (Hoffer 1975; Rinomhota and Marshall 2000). For instance, research carried out by Alpert and Fava (1997) established that depressive symptoms constitute the most common neuropsychiatry manifestation of folate deficiency (Rinomhota and Marshall 2000). In the same measure, Herbert (1961) found out through detailed research the existence of a relationship between a folic acid deficiency and depression (Muntjewerff and Blom 2005; Rinomhota and Marshall 2000).
On the other part, Reynolds (1967) established through research that patients with mental problems manifested improvement when administered with folic treatment (Muntjewerff and Blom 2005). The success of the experimental study was manifested among 22 out of 26 folate-deficient epileptic patients who further reported improvement with regard to their drive, initiative, and mood (Kim and Moon 2011). Carrying out similar research, Ghadirian et al (1980) established that serum folic acid levels were significantly lower in depressed patients than in medical and other psychiatric patients (Rinomhota and Marshall 2000). In addition, patients with the lowest folic acid levels obtained higher ratings on depressed mood and decreased work productivity (Rinomhota and Marshall 2000).
More studies have been carried out that shows a relationship exists between nutrition and reduction of schizophrenia (Hoffer 1975). Ramchand et al (1992) through detailed research established that folate deficiency does not cause schizophrenia but a deficiency in folate may result in both the severity and chronicity of the illness as well as the medication given to treat sufferers (Rinomhota and Marshall 2000). The findings of the authors’ study raised many questions that precipitated further research undertakings. Thus Godfrey et al (1990) carried out research on a sub-group of patients diagnosed with schizophrenia by administration of methyl folate (Muntjewerff and Blom 2005). After some time, the patients were investigated and found to exhibit better clinical and social recovery as compared to a group under control (Muntjewerff and Blom 2005). In recent times, case-controlled studies have been carried out to establish a relationship between folate and schizophrenia. For instance, Freeman et al (1975) found out that there was a reduction in MTHFR activity in a patient who was diagnosed with schizophrenia (Mattson 2002). At the same time, Regland et al (1997) established that about 5% of the population 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).
More research work has been carried out to establish whether there are associations 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). Homocysteine constitutes a type of amino acid that is largely found in individuals’ blood (Guinotte et al. 2003). Medical experts have established that individuals who turn out to have higher levels of homocysteine in the blood, exhibit high risks of developing depression, congenital birth defects and more so, psychiatric problems (Roffman et al. 2008; 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). In research carried out by Hammons et al (2009), it was found that among women in the study MCP-1 concentrations correlated positively with Hcy and correlated negatively with both serum and red blood cell folate (Hammons et al. 2009). Further, results showed that women in the study smoking who also happened to be MTHFR C677T carriers had increased chances of MCP-1 concentrations (Hammons et al. 2009). In opposite, such a relationship was not established among men in the study. The concentration of Hcy has been linked to multiple factors where the common one indicates that the availability of vitamin B, specifically folate increases Hcy (Guinotte et al. 2003).
Other identified factors responsible for this include the functional polymorphisms that are found in certain and specific enzymes in the folate and Hcy metabolic pathway, which in turn affect the overall distribution of the intermediates in the pathway and eventually result in increased Hcy (Hammons et al. 2009). Among the identified polymorphisms, the MTHFR C677T exhibit the highest and greatest quantity effect whereby 677TT genotype manifest 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 demonstrate high chances of deregulation of folate and Hcy metabolism (Vilella et al. 2005; Muntjewerff, Khan, Blom and Heijer 2006). The above research carried out on this phenomenon only point to little knowledge generated and as such, evidence shows that the relationship between folate and Hcy phenotypes and the development of schizophrenia has not fully been investigated and established.
Nevertheless, other research works have postulated the contribution of folate to the reduction of negative symptoms of depressive disorders. Meta-analysis of recent studies has shown that folate contributes to the constant reduction of depression disorders (Mischoulon and Rosenbaum 2008). For example, clinical studies indicated that patients who demonstrated low serum or RBC folate and serum MTHF levels were found to exhibit greater symptoms severity (Hill et al. 2010 Mischoulon and Rosenbaum 2008). At the same time, studies that failed to establish this relationship still postulated that an inverse relationship existed at 95% between folate and the duration of the depressive episode and 96% with the period of hospitalization (Mischoulon and Rosenbaum 2008). As such, the studies showed that a relationship exists between folate and treatment outcome. More so, research work by the University of Michigan Health System has found out that schizophrenic patients diagnosed are likely or show high rates of suffering from folic deficiency (Stannard 2011).
By carrying out a control-experiment study, the health system established that providing daily supplements of 15 mg of folic acid to schizophrenic patients resulted in the observation of improvement of symptoms among the patients (Stannard 2011). Further, in a study dubbed “Homocysteine-Reducing Strategies Improve Symptoms in Chronic Schizophrenic Patients with Hyperhomocysteinemia’ it was found out that patients diagnosed with schizophrenia had high levels of homocysteine (Stannard 2011). After being administered with 2mg of folic acid, 400 mcg of vitamin B12 and 25mg of vitamin B6, the patients had improved symptoms after a period (Stannard 2011).
Methodology
This study aims at evaluating the relationship between serum folate, serum homocysteine, and improvement in symptoms of schizophrenia. Attainment of research questions and hypothesis goals will be realized through the adoption of appropriate and accurate methodological tools.
Research design
The research will seek the consent of 100 consecutive patients diagnosed with schizophrenia. Identification of schizophrenia patients will largely be determined by a research psychiatrist who after carrying out diagnosis will recommend the 100 patients for the study. The selection of 100 patients will randomly be from the population identified of schizophrenia patients. The other schizophrenia patients will act as the control group on whom no folic acid supplements will be administered. The purpose will be to administer folic acid supplements to the patients under experiment. The period for this process will be 16 weeks whereby at the end the results will be compiled for analysis and recommendations. Control measures will be undertaken, for instance, patients will be excluded from any of the following categories: those in active usage of alcohol and those with renal insufficiency.
Research instruments
After administration of folic acid supplements to the patients in the study, there is a need to carry out an assessment. Assessment will involve the adoption of particular and specific instruments. The instruments to be utilized include Positive and Negative Syndrome Scale-PANSS; Scale for the Assessment of Negative Symptoms-SANS (Maruish 2004); Hamilton Depression Rating Scale (Goff et al. 2004). More instruments to be incorporated include Global Assessment Scale; Simpson-Angus Rating Scale and Abnormal Involuntary Movement Scale-AIMS (Roffman et al. 2006; Goff et al. 2004). To add up to these assessment instruments, the research will also make use of cognitive battery instruments, which will be administered to the patients. Some of the 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).
PANSS will be used to measure the reduction in schizophrenia symptoms, largely as a result of changes in the baseline total score and this will be measured at week thirteen (Goff et al. 2004). Hamilton Depression Rating Scale will be utilized in the measurement of cognitive deficits largely based on cognitive battery composite score, which also will be carried out at week thirteen. Scale for the Assessment of Negative Symptoms, on the other hand, will be used to measure negative symptoms largely from the total score obtained on the baseline rating at week thirteen (Goff et al. 2004).
Research setting/process
Participants in this study will have to participate in the research for a maximum of 16 weeks. After all, processes have been set, the participants will be required to take part in preliminary screening, and this will involve undergoing “medical and psychiatric evaluation, physical exam, blood draw, urine sampling and questionnaires” (Arzaghi, Hossein-Nezhad, Shariat, Ghodsipour and Larijani 2011). At the same time, it will be necessary to ask permission from the participants so that their portion of a blood sample can be used for genetic analysis. Those participants deemed to be eligible will be randomly assigned to take folate supplements. For a start, the participants will have to complete a 2-week stabilization phase, which upon expiry will be followed by 14 weeks of treatment study. There will be medication visits every two weeks during the treatment and the aim of the visits will be to establish the occurrence of any medication side effects and also will be used for the distribution of study medication. Further, participants will need to make use of questionnaires, which will be important in filling in data related to various health aspects.
Phlebotomy will be carried out whereby ‘serum samples (nonfasting) were assayed for folate, total homocysteine, B 12, glycine, and serine concentrations” (Tonin, et al. 1997). There will be the need to compare folate and homocysteine concentrations among the patients in the experiment and those regarded as non-psychiatric representatives (Tonin et al. 1997). In addition, there will be the need to establish “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). Overall, there will be the utilization of published mean plasma folate and homocysteine concentrations. The sample to draw this from will be 248 identified individuals largely from the sixth examination of the Framingham Offspring Study who have not been administered with folate supplements.
To establish the level of serum folate, there will be the utilization of “cloned enzyme donor immunoassay kits,” which in essence have to show no boil for folate according to the instructions attached in the kit. On the other hand, “serum homocysteine will be measured using fluorescence polarization immunoassay method that will have a coefficient of variation ranging from 3.7% to 5.2%” (Pfeiffer 2002). Association that is exhibited between the clinical rating scale scores will need to be tested and the best way to do this will be to use 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 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 out at week thirteen to establish the existence of any relationship. At the same time, the relationship between the 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.
Data analysis and discussion
After the methodology of carrying out the research has been identified and instituted, the actual research process will take place whereby there will be a generation of raw data and information as results. The results will form a ground for the analysis process to be undertaken. As a highlight as to how analysis of the generated data will be carried out, the following key aspects will be noted. 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 result in an analysis of findings and discussion. Moreover, the study will analyze whether homocysteine differs between men and women. To make an 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.
Conclusion
This research proposal has explored extensively the relationship between folate and schizophrenia. Schizophrenia is a medical condition that affects about 1% of the population as research findings indicate, it is important to carry out detailed and methodologically rich research in the area. Some preventive and treatment mechanisms have been suggested for the disease. However, one area that is drawing a lot of research interest is the role of diet-related supplements in the treatment of schizophrenia. Early research works have associated improved symptoms of schizophrenic patients with increased levels of folate. As a result, more literature is available on the role of folate in reducing schizophrenic cases. However, analyses of the majority of research work indicated that a gap exists especially with regard to methodology. This aspect was identified and was the motivation for this research. Throughout the research, the aim has to fill the identified methodological gap with the right and accurate instruments. It is believed 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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