The Effects of Fatty Acid Supplementation in the Treatment of Schizophrenia
NUTR 421: Macronutrient Metabolism
November 29, 2012
Sydney Reichhardt
Introduction
Schizophrenia is a severe neurological disorder that results in the individuals inflicted having mental health difficulties, especially with regards to separating reality from their own hallucinations and delusions. It is estimated that schizophrenia effects about one percent of the population (1). The disorder can range in severity to the point of being almost entirely debilitating to the individual.
In an effort to decrease the signs and symptoms associated with schizophrenia, powerful psychiatric medications are often prescribed, including Chlorpromazine (Thorazine), Haloperidol (Haldol), Risperidone (Risperdal), and Olanzapine (Zyprexa). Prolonged use of these medications, as well as other antipsychotic medications, can lead to a condition called tardive dyskinesia. Tardive dyskinesia results in the individuals losing control of some motor functions, and individuals that develop this often have constant tremors that are present even after the medication is discontinued (2). Because of the potential devastating side effects of some of the current medications used as a treatment for schizophrenia, it is important for researchers to look into alternative treatment options for individuals with schizophrenia.
The initial reasoning for exploration of fatty acid supplementation as a form of treatment for schizophrenia came from the discovery of altered levels of essential fatty acids in patients with schizophrenia. Because fatty acids are a critical component of the phospholipid membrane surrounding cells, researchers started to investigate a distorted membrane composition in individuals with schizophrenia.
Two important tools of note when discussing schizophrenia are the Diagnostic and Statistical Manual of Mental Disorders IV (DSM-IV): Diagnostic Criteria for Schizophrenia and the Positive and Negative Syndrome Scale (PANSS) for Schizophrenia. The DSM-IV determines the guidelines for a diagnosis of schizophrenia that includes the time frame, severity, and combination of symptoms that need to be present for the diagnosis (3). The PANSS is a tool that is used to evaluate the severity of symptoms once an individual has been diagnosed with schizophrenia. This scale is commonly used in pharmaceutical and behavioral therapy research with regards to schizophrenia to evaluate the effectiveness of treatments (4).
Metabolic Basis
Researchers began exploring what is commonly referred to as the membrane hypothesis in relation to schizophrenia over twenty years ago. At this time, research was focused on determining a reason behind the altered structure of the phospholipid cell membranes in individuals with schizophrenia, especially with regards to low levels of polyunsaturated essential fatty acids. The general concept behind the membrane hypothesis was that polyunsaturated essential fatty acids cannot be synthesized with the body, so when individuals do not have access to these specific fatty acids, the membrane structure will become more abnormal. More specifically cell membranes become rigid in the absence of unsaturated fatty acids, because saturated fatty acids lack the double bonds that lead to kinking that create flexibility within the membrane (6).
While the membrane hypothesis does not suggest that individuals with individuals have low intake levels of the unsaturated essential fatty acids, it is believed that there is an error in the usage of these fatty acids. The current accepted idea is an increase in the activity of phospholipase A2 (PLA2). PLA2 is responsible for hydrolyzing phospholipids to create fatty acids[i]. If PLA2 is hydrolyzing phospholipids at an increased rate, there will be an increase in the number of saturated fatty acids present, and the individual will have a decreased availability of unsaturated fatty acids to incorporate into the phospholipid membrane. The proposed over activity of PLA2 in individuals with schizophrenia would result in a depletion of unsaturated fatty acids from phospholipid membranes, because they would be hydrolyzed to form saturated fatty acids (5).
Due to the fact that proteins behave differently based on whether they are embedded in a rigid membrane (primarily saturated fatty acids) or a flexible membrane (mixture of saturated and unsaturated fatty acids), it is reasonable to consider that altered membrane structure could result in some of the neurological alterations seen in individuals with schizophrenia.
One rationale for reversing the effects of increased PLA2 activity, and consequently increased concentrations of saturated fatty acids in the phospholipid membranes, is to provide individuals with schizophrenia fatty acid supplementation that could overcome the rate that PLA2 hydrolyzes the phospholipids. If unsaturated essential fatty acid supplementation could occur that would allow for there to still be unsaturated fatty acids available even when PLA2 is working at full capacity, then there would likely be increased amounts of unsaturated fatty acids seen in the phospholipid membranes. Restoring the balance of unsaturated and saturated fatty acids would result in a more flexible phospholipid membrane that could function properly.
Clinical Trial One
The first research study examined was a double blind clinical trial that tested the effects of ethyl-eicosapentaenoate treatments in patients with schizophrenia. The goal of the study was to determine the ideal dosage of the unsaturated fatty acid as treatment for schizophrenia so that further research could be performed. The fatty acid supplementation was done as a co-therapy, meaning that all individuals involved in the study were on other anti-schizophrenic drugs. All individuals involved in the research study met the DSM-IV diagnostic criteria for schizophrenia.
There were 115 individuals involved in the study, and they were divided into three groups based on the classification of anti-schizophrenic medication they were taking as treatment before and throughout the research study. Researchers determined this division was necessary because they were interested in the impact of fatty acid supplementation on the phospholipid membrane, and the different classifications of medications are expected to have varying impacts on the membrane composition. The three medication classes used were typical neuroleptics, atypical neuroleptics, and clozapine drugs. Each of the three groups that were divided based on medication classification were then assigned to a dosage group using double-blind methods. There were four dose-ranging groups, the first being a placebo (liquid paraffin), and the other three groups receiving one-gram, two-grams, or four-grams of ethyl-eicosapentaenoate daily throughout the study. These divisions created a total of twelve groups that the researchers were studying for variances.
The study lasted for twelve weeks, and assessments were done at regular intervals throughout the trial, specifically a baseline measurement, and then measurements at four, eight and twelve weeks. The primary assessments were on based on responses to PANSS and levels of fatty acids in red blood cells.
Within the groups of patients taking typical neuroleptic and atypical neuroleptic medications, researchers found a significant improvement (decrease) in PANSS scores, however, when compared to the group of individuals taking a placebo versus the ethyl-eicosapentaenoate treatment there was not a significant difference. For instance, in the group of individuals taking atypical neuroleptics in conjunction with two-grams of ethyl-eicosapentaenoate daily (the dosage found to be the most effective), subjects showed an average 23.5% decrease in PANSS scores from their baseline scores, while subjects receiving only the placebo showed an average 23.7% decrease in PANSS scores from their baseline scores.
Because the decrease in scores across all treatment groups was so significant and undoubtedly led to a positive impact in the patients’ lives, researchers hypothesized possible reasons for the large placebo effects seen in the study. One particular hypothesis is that the subjects altered their diets because they received education on foods that were particularly high in essential fatty acids as part of the consent process of the study. Another hypothesis was that the subjects altered behaviors due to increased contact with medical professionals as a result of the study. Typically individuals with schizophrenia would only visit a physician when something drastic occurs that may result in a necessary medication change. This theory is supported by the results from the group taking medications within the clozapine class.
The outcome of the subject group taking clozapine medications in conjunction with the ethyl-eicosapentaenoate supplements was significant. Individuals receiving the placebo treatment saw an average 6% decrease in PANSS’ scores from their baseline scores, while individuals receiving two grams of ethyl-eicosapentaenoate supplementation (again the most effective dose) saw an average of 26% decrease in PANSS’ scores from their baseline. The 26% decrease is a significant change from the baseline scores, as well as significantly different than the change seen in the placebo when an ANCOVA test was performed. The theory that increased contact with medical professionals that explains the large placebo effect seen in the first two groups holds up in this example, because patients taking clozapine medications must have blood work completed regularly so they are used to having high amounts of contact with medical professionals (7).
As a side note, one of the common side effects of clozapine medications is increased triglyceride levels (8), and the fatty acid supplementation resulted in significantly decreased triglyceride levels in these patients. These results indicate that in addition to the treatment of signs and symptoms associated with schizophrenia, essential fatty acid supplementation in individuals with schizophrenia could be beneficial in improving cardiovascular health.
Clinical Trial Two
The second clinical trial also looked at the effects of supplementation of ethyl-eicosapentaenoate in patients with schizophrenia. Again, the unsaturated fatty acid supplementation therapy was used as a co-therapy in addition to the anti-schizophrenic medications the patients were already using as treatment prior to the start and throughout the clinical trial.
This trial was smaller than the first study, and it only included forty patients. Again, the patients had to meet the DSM-IV diagnostic criteria schizophrenia to be involved in the trial. The study was conducted over twelve weeks, and patients were assessed at zero (baseline measurement), three, six, nine, and twelve weeks. The main assessment tool was PANSS total scores. The patients in this double-blind trial received either a three-gram dose of ethyl-eicosapentaenoic acid or a three-gram dose of a placebo (liquid paraffin).
Unlike in the first study, researchers in this trial took dietary consumption of polyunsaturated fatty acids into consideration. The research subjects were all required to keep a diet log, which was then analyzed by a dietitian. No significant differences were noted in unsaturated fatty acid consumption between the two groups, treatment or placebo, however, the final study results were still adjusted prior to analysis to reflect the small differences in dietary consumption.
Using the above research methods, individuals receiving the ethyl-eicosapentaenoic acid treatment, in conjunction with their anti-schizophrenia medications, showed a significant improvement (decrease) in PANSS’ scores. These results were also significant when they were compared against the group that received a placebo in addition to their anti-schizophrenia medications. The average decrease in the patients receiving the fatty acid supplementation was a 12.6-point score decrease using PANSS, while the patients receiving the placebo showed a 3.1-point score decrease (9).
Discussion
While the results from the studies discussed look promising initially, it is evident that more research still needs to be done before the results will be conclusive. It is also important to note that both of these studies used ethyl-eicosapentaenoate as an add-on therapy to the patients’ previous anti-schizophrenic medication regimens. Even though the research does not definitively indicate that supplementation of unsaturated essential fatty acids is beneficial in the treatment of schizophrenia, as assessed by PANSS’ scores, no negative side effects were reported as a result of the supplementation (6).
Overactivity of PLA2 likely causes a depletion of unsaturated fatty acids in the plasma membrane, which results in a rigid plasma membrane. This rigidity alters the way in which proteins are able to function, resulting in the abnormal neurological symptoms commonly seen in individuals with schizophrenia. The membrane hypothesis and treatment of schizophrenia with fatty acid supplementation would likely benefit from further research into the reasoning behind the malfunction of PLA2 activity, and if this altered function could be improved so that supplementation is not necessary to restore the normal balance of unsaturated and saturated fatty acids in the cell membrane.
The research indicated that changed in plasma and red blood cell concentrations of ethyl-eicosapentaenoate did not directly correlate with the positive behavioral changes seen, the levels of arachidonic acid were directly related to the improvements seen. This explains why the two gram dosage of ethyl-eicosapentaenoate may have been more effective, because at the higher four gram dosage, the ethyl-eicosapentaenoate would have been competing with arachidonic acid for transporters.
Because the fatty acid supplementation resulted in significant decreases in the PANSS scores, it would be worthwhile to continue research in this area. However, the large placbo effect results in the need for further studies to examine why this occurred and what was the actual cause of the change seen. With this information, as well as the evidence that supplementation of unsaturated essential fatty acids promotes cardiovascular health in individuals regardless of schizophrenia (10), it is likely safe to recommend supplementation as a possible treatment until further research is produced.
References Cited
1. Regier DA, Narrow WE, Rae DS, Manderscheid RW, Locke BZ, Goodwin FK. The de facto US mental and addictive disorders service system. Epidemiologic catchment area prospective 1-year prevalence rates of disorders and services. Archives of General Psychiatry. 1993 Feb;50(2):85-94.
2. National Institutes of Health. Schizophrenia. National Institutes of Mental Health: Bethesda, Maryland, 2009. pp. 3-17.
3. Cold Spring Harbor Laboratory. Diagnostic and statistical manual of mental disorders IV-TR: Schizophrenia. Retrieved from http://www.dnalc.org/view/899-DSM-IV-Criteria-for-Schizophrenia.html.
4. The PANSS Institute. PANSS. New York, New York: 2012. Retrieved from http://www.panss.org/home/index.php?option=com_content&task=view&id=15&Itemid=47.
5. K. Schulten, and F Zhou. Molecular dynamics study of the activation of phospholipase A2 on a membrane surface. PROTEINS: Structure, Function, and Genetics, 25:12-27, 1996.
6. Horrobin, DF, AIM Glen, and K Vaddadi. The membrane hypothesis of schizophrenia. Schizophrenia Research 13:195-207, 1994.
7. Peet, M, and DF Horrobin. A dose-ranging exploratory study of the effects of ethyl-eicosapentaenoate in patients with persistent scizophrenic symptoms. Journal of Psychiatric Research. 36: 7-18, 2002.
8. Gaulin BD, Markowitz JS, Caley CF, Nesbitt LA, and Dufresne RL. Clozapine-associated elevation in serum triglycerides. American Journal of Psychiatry. 156:1270-2, 1999.
9. Emsley, R, C Myburgh, P Oosthuizen, and SJ van Rensburg. Randomized, placebo-controlled study of ethyl-eicosapentainoic acid as supplemental treatment in schizophrenia. The American Journal of Psychiatry 159: 1596-1598, 2002.
10. Chowdhury R, Stevens S, Gorman D, Pan A, Warnakula S, Chowdhury S, Ward H, Johnson L, Crowe F, Hu FB, Franco OH. Association between fish consumption, long chain omega 3 fatty acids, and risk of cerebrovascular disease: systematic review and meta-analysis. BMJ 345, 2012.
NUTR 421: Macronutrient Metabolism
November 29, 2012
Sydney Reichhardt
Introduction
Schizophrenia is a severe neurological disorder that results in the individuals inflicted having mental health difficulties, especially with regards to separating reality from their own hallucinations and delusions. It is estimated that schizophrenia effects about one percent of the population (1). The disorder can range in severity to the point of being almost entirely debilitating to the individual.
In an effort to decrease the signs and symptoms associated with schizophrenia, powerful psychiatric medications are often prescribed, including Chlorpromazine (Thorazine), Haloperidol (Haldol), Risperidone (Risperdal), and Olanzapine (Zyprexa). Prolonged use of these medications, as well as other antipsychotic medications, can lead to a condition called tardive dyskinesia. Tardive dyskinesia results in the individuals losing control of some motor functions, and individuals that develop this often have constant tremors that are present even after the medication is discontinued (2). Because of the potential devastating side effects of some of the current medications used as a treatment for schizophrenia, it is important for researchers to look into alternative treatment options for individuals with schizophrenia.
The initial reasoning for exploration of fatty acid supplementation as a form of treatment for schizophrenia came from the discovery of altered levels of essential fatty acids in patients with schizophrenia. Because fatty acids are a critical component of the phospholipid membrane surrounding cells, researchers started to investigate a distorted membrane composition in individuals with schizophrenia.
Two important tools of note when discussing schizophrenia are the Diagnostic and Statistical Manual of Mental Disorders IV (DSM-IV): Diagnostic Criteria for Schizophrenia and the Positive and Negative Syndrome Scale (PANSS) for Schizophrenia. The DSM-IV determines the guidelines for a diagnosis of schizophrenia that includes the time frame, severity, and combination of symptoms that need to be present for the diagnosis (3). The PANSS is a tool that is used to evaluate the severity of symptoms once an individual has been diagnosed with schizophrenia. This scale is commonly used in pharmaceutical and behavioral therapy research with regards to schizophrenia to evaluate the effectiveness of treatments (4).
Metabolic Basis
Researchers began exploring what is commonly referred to as the membrane hypothesis in relation to schizophrenia over twenty years ago. At this time, research was focused on determining a reason behind the altered structure of the phospholipid cell membranes in individuals with schizophrenia, especially with regards to low levels of polyunsaturated essential fatty acids. The general concept behind the membrane hypothesis was that polyunsaturated essential fatty acids cannot be synthesized with the body, so when individuals do not have access to these specific fatty acids, the membrane structure will become more abnormal. More specifically cell membranes become rigid in the absence of unsaturated fatty acids, because saturated fatty acids lack the double bonds that lead to kinking that create flexibility within the membrane (6).
While the membrane hypothesis does not suggest that individuals with individuals have low intake levels of the unsaturated essential fatty acids, it is believed that there is an error in the usage of these fatty acids. The current accepted idea is an increase in the activity of phospholipase A2 (PLA2). PLA2 is responsible for hydrolyzing phospholipids to create fatty acids[i]. If PLA2 is hydrolyzing phospholipids at an increased rate, there will be an increase in the number of saturated fatty acids present, and the individual will have a decreased availability of unsaturated fatty acids to incorporate into the phospholipid membrane. The proposed over activity of PLA2 in individuals with schizophrenia would result in a depletion of unsaturated fatty acids from phospholipid membranes, because they would be hydrolyzed to form saturated fatty acids (5).
Due to the fact that proteins behave differently based on whether they are embedded in a rigid membrane (primarily saturated fatty acids) or a flexible membrane (mixture of saturated and unsaturated fatty acids), it is reasonable to consider that altered membrane structure could result in some of the neurological alterations seen in individuals with schizophrenia.
One rationale for reversing the effects of increased PLA2 activity, and consequently increased concentrations of saturated fatty acids in the phospholipid membranes, is to provide individuals with schizophrenia fatty acid supplementation that could overcome the rate that PLA2 hydrolyzes the phospholipids. If unsaturated essential fatty acid supplementation could occur that would allow for there to still be unsaturated fatty acids available even when PLA2 is working at full capacity, then there would likely be increased amounts of unsaturated fatty acids seen in the phospholipid membranes. Restoring the balance of unsaturated and saturated fatty acids would result in a more flexible phospholipid membrane that could function properly.
Clinical Trial One
The first research study examined was a double blind clinical trial that tested the effects of ethyl-eicosapentaenoate treatments in patients with schizophrenia. The goal of the study was to determine the ideal dosage of the unsaturated fatty acid as treatment for schizophrenia so that further research could be performed. The fatty acid supplementation was done as a co-therapy, meaning that all individuals involved in the study were on other anti-schizophrenic drugs. All individuals involved in the research study met the DSM-IV diagnostic criteria for schizophrenia.
There were 115 individuals involved in the study, and they were divided into three groups based on the classification of anti-schizophrenic medication they were taking as treatment before and throughout the research study. Researchers determined this division was necessary because they were interested in the impact of fatty acid supplementation on the phospholipid membrane, and the different classifications of medications are expected to have varying impacts on the membrane composition. The three medication classes used were typical neuroleptics, atypical neuroleptics, and clozapine drugs. Each of the three groups that were divided based on medication classification were then assigned to a dosage group using double-blind methods. There were four dose-ranging groups, the first being a placebo (liquid paraffin), and the other three groups receiving one-gram, two-grams, or four-grams of ethyl-eicosapentaenoate daily throughout the study. These divisions created a total of twelve groups that the researchers were studying for variances.
The study lasted for twelve weeks, and assessments were done at regular intervals throughout the trial, specifically a baseline measurement, and then measurements at four, eight and twelve weeks. The primary assessments were on based on responses to PANSS and levels of fatty acids in red blood cells.
Within the groups of patients taking typical neuroleptic and atypical neuroleptic medications, researchers found a significant improvement (decrease) in PANSS scores, however, when compared to the group of individuals taking a placebo versus the ethyl-eicosapentaenoate treatment there was not a significant difference. For instance, in the group of individuals taking atypical neuroleptics in conjunction with two-grams of ethyl-eicosapentaenoate daily (the dosage found to be the most effective), subjects showed an average 23.5% decrease in PANSS scores from their baseline scores, while subjects receiving only the placebo showed an average 23.7% decrease in PANSS scores from their baseline scores.
Because the decrease in scores across all treatment groups was so significant and undoubtedly led to a positive impact in the patients’ lives, researchers hypothesized possible reasons for the large placebo effects seen in the study. One particular hypothesis is that the subjects altered their diets because they received education on foods that were particularly high in essential fatty acids as part of the consent process of the study. Another hypothesis was that the subjects altered behaviors due to increased contact with medical professionals as a result of the study. Typically individuals with schizophrenia would only visit a physician when something drastic occurs that may result in a necessary medication change. This theory is supported by the results from the group taking medications within the clozapine class.
The outcome of the subject group taking clozapine medications in conjunction with the ethyl-eicosapentaenoate supplements was significant. Individuals receiving the placebo treatment saw an average 6% decrease in PANSS’ scores from their baseline scores, while individuals receiving two grams of ethyl-eicosapentaenoate supplementation (again the most effective dose) saw an average of 26% decrease in PANSS’ scores from their baseline. The 26% decrease is a significant change from the baseline scores, as well as significantly different than the change seen in the placebo when an ANCOVA test was performed. The theory that increased contact with medical professionals that explains the large placebo effect seen in the first two groups holds up in this example, because patients taking clozapine medications must have blood work completed regularly so they are used to having high amounts of contact with medical professionals (7).
As a side note, one of the common side effects of clozapine medications is increased triglyceride levels (8), and the fatty acid supplementation resulted in significantly decreased triglyceride levels in these patients. These results indicate that in addition to the treatment of signs and symptoms associated with schizophrenia, essential fatty acid supplementation in individuals with schizophrenia could be beneficial in improving cardiovascular health.
Clinical Trial Two
The second clinical trial also looked at the effects of supplementation of ethyl-eicosapentaenoate in patients with schizophrenia. Again, the unsaturated fatty acid supplementation therapy was used as a co-therapy in addition to the anti-schizophrenic medications the patients were already using as treatment prior to the start and throughout the clinical trial.
This trial was smaller than the first study, and it only included forty patients. Again, the patients had to meet the DSM-IV diagnostic criteria schizophrenia to be involved in the trial. The study was conducted over twelve weeks, and patients were assessed at zero (baseline measurement), three, six, nine, and twelve weeks. The main assessment tool was PANSS total scores. The patients in this double-blind trial received either a three-gram dose of ethyl-eicosapentaenoic acid or a three-gram dose of a placebo (liquid paraffin).
Unlike in the first study, researchers in this trial took dietary consumption of polyunsaturated fatty acids into consideration. The research subjects were all required to keep a diet log, which was then analyzed by a dietitian. No significant differences were noted in unsaturated fatty acid consumption between the two groups, treatment or placebo, however, the final study results were still adjusted prior to analysis to reflect the small differences in dietary consumption.
Using the above research methods, individuals receiving the ethyl-eicosapentaenoic acid treatment, in conjunction with their anti-schizophrenia medications, showed a significant improvement (decrease) in PANSS’ scores. These results were also significant when they were compared against the group that received a placebo in addition to their anti-schizophrenia medications. The average decrease in the patients receiving the fatty acid supplementation was a 12.6-point score decrease using PANSS, while the patients receiving the placebo showed a 3.1-point score decrease (9).
Discussion
While the results from the studies discussed look promising initially, it is evident that more research still needs to be done before the results will be conclusive. It is also important to note that both of these studies used ethyl-eicosapentaenoate as an add-on therapy to the patients’ previous anti-schizophrenic medication regimens. Even though the research does not definitively indicate that supplementation of unsaturated essential fatty acids is beneficial in the treatment of schizophrenia, as assessed by PANSS’ scores, no negative side effects were reported as a result of the supplementation (6).
Overactivity of PLA2 likely causes a depletion of unsaturated fatty acids in the plasma membrane, which results in a rigid plasma membrane. This rigidity alters the way in which proteins are able to function, resulting in the abnormal neurological symptoms commonly seen in individuals with schizophrenia. The membrane hypothesis and treatment of schizophrenia with fatty acid supplementation would likely benefit from further research into the reasoning behind the malfunction of PLA2 activity, and if this altered function could be improved so that supplementation is not necessary to restore the normal balance of unsaturated and saturated fatty acids in the cell membrane.
The research indicated that changed in plasma and red blood cell concentrations of ethyl-eicosapentaenoate did not directly correlate with the positive behavioral changes seen, the levels of arachidonic acid were directly related to the improvements seen. This explains why the two gram dosage of ethyl-eicosapentaenoate may have been more effective, because at the higher four gram dosage, the ethyl-eicosapentaenoate would have been competing with arachidonic acid for transporters.
Because the fatty acid supplementation resulted in significant decreases in the PANSS scores, it would be worthwhile to continue research in this area. However, the large placbo effect results in the need for further studies to examine why this occurred and what was the actual cause of the change seen. With this information, as well as the evidence that supplementation of unsaturated essential fatty acids promotes cardiovascular health in individuals regardless of schizophrenia (10), it is likely safe to recommend supplementation as a possible treatment until further research is produced.
References Cited
1. Regier DA, Narrow WE, Rae DS, Manderscheid RW, Locke BZ, Goodwin FK. The de facto US mental and addictive disorders service system. Epidemiologic catchment area prospective 1-year prevalence rates of disorders and services. Archives of General Psychiatry. 1993 Feb;50(2):85-94.
2. National Institutes of Health. Schizophrenia. National Institutes of Mental Health: Bethesda, Maryland, 2009. pp. 3-17.
3. Cold Spring Harbor Laboratory. Diagnostic and statistical manual of mental disorders IV-TR: Schizophrenia. Retrieved from http://www.dnalc.org/view/899-DSM-IV-Criteria-for-Schizophrenia.html.
4. The PANSS Institute. PANSS. New York, New York: 2012. Retrieved from http://www.panss.org/home/index.php?option=com_content&task=view&id=15&Itemid=47.
5. K. Schulten, and F Zhou. Molecular dynamics study of the activation of phospholipase A2 on a membrane surface. PROTEINS: Structure, Function, and Genetics, 25:12-27, 1996.
6. Horrobin, DF, AIM Glen, and K Vaddadi. The membrane hypothesis of schizophrenia. Schizophrenia Research 13:195-207, 1994.
7. Peet, M, and DF Horrobin. A dose-ranging exploratory study of the effects of ethyl-eicosapentaenoate in patients with persistent scizophrenic symptoms. Journal of Psychiatric Research. 36: 7-18, 2002.
8. Gaulin BD, Markowitz JS, Caley CF, Nesbitt LA, and Dufresne RL. Clozapine-associated elevation in serum triglycerides. American Journal of Psychiatry. 156:1270-2, 1999.
9. Emsley, R, C Myburgh, P Oosthuizen, and SJ van Rensburg. Randomized, placebo-controlled study of ethyl-eicosapentainoic acid as supplemental treatment in schizophrenia. The American Journal of Psychiatry 159: 1596-1598, 2002.
10. Chowdhury R, Stevens S, Gorman D, Pan A, Warnakula S, Chowdhury S, Ward H, Johnson L, Crowe F, Hu FB, Franco OH. Association between fish consumption, long chain omega 3 fatty acids, and risk of cerebrovascular disease: systematic review and meta-analysis. BMJ 345, 2012.