It is important to comprehend the complex neurological and biochemical processes underlying manifestations of mental illness to treat the disease in novel, more accessible ways. Historically, mental illness has either been attributed to divine punishment or devilish infestations of the body until around 400 BC, when the illnesses were beginning to be considered physical. Even so, personal judgments were implied in the beliefs surrounding mental illness, as the treatments involved penitence and prayer. With the advent of deductive science in the 18th century, psychological and social stressors were finally acknowledged as the source of mental illness, rather than the divine . Moving forward, research supported by brain imaging, psychotherapy’s advance (with a basis in neurology), and treatment with medication pressed the transformation of society’s understanding of mental illness as a legitimate disease forward. Despite these strides, schizophrenia still carries a stigma. I believe this is due to the complexity of the disease and thus the lack of understanding we have of its nature. I plan to perform a meta-analysis of research to investigate the link between gut microbiota, medication, and manifestations of schizophrenia.

Schizophrenia not only has been historically misconstrued in popular literature but also is, in and of itself, quite a variable disease—the current DSM entry qualifies it as “Two (or more) of the following, each present for a significant portion of time during a 1-month period (or less if successfully treated): (1) delusions (2) hallucinations (3) disorganized speech (e.g., frequent derailment or incoherence) (4) grossly disorganized or catatonic behaviour (5) negative symptoms, i.e., affective flattening, alogia (poverty of speech), or avolition (lack of motivation).” The greater we can understand schizophrenia and scientifically classify it, the more traction we will have towards removing the social stigma associated with it and providing more accessible treatment to patients by moving away from medication and towards lifestyle applications.

Recent applications of medical research have already greatly expanded our biochemical understanding of the physiological basis of schizophrenia. A study published in October of 2016 applied membrane lipodimics, an analysis of the lipid content of erythrocytes by liquid chromatography and mass spectrometry, to find a link between fatty acid composition of red blood cells and the severity of manifestations of schizophrenia . This required the application of PANSS (Positive and Negative Syndrome Scale), a medical assessment created by psychiatrists and recommended by the American Psychiatric Association. The results of this study elucidate the fact that our biochemical and psychological concepts of schizophrenia are becoming more clear and scientific by removing bias or assumptions.

Despite rapidly advancing research, there are still great gaps in our understanding of how the discoveries about the biological nature of the disease translate into psychological manifestations. For example, a study from 2016 identified prenatal choline deficiency as a definite link to neonatal iron deficiency, which is known to cause behavioral abnormalities. It identified iron deficiency as the cause of an increased risk for schizophrenia and even proposed that this is through the reprogramming of hippocampal transcriptomes, yet this was only applied in a rat model and the way in which the rearranged hippocampus translates into schizophrenic symptoms is unclear, so this information can’t currently improve treatment. Other current studies on schizophrenia create more questions than they do answers. One reports weight loss associated with clozapine, a common anti-schizophrenic drug, in select patients, the opposite of normal side-effects of the drug, while failing to identify any mechanism by which the phenomenon takes place or a common variable within the patients it manifests in. Another study investigated the link between the consumption level of certain fatty acids and carbohydrates with the gain of visceral fat in schizophrenic and bipolar patients, yet found no correlation. It is crucial that we investigate the link between information on the disease and its manifestation and further investigate questions generated by studies so we could influence pathways of signaling to better treat schizophrenia.

An underappreciated aspect to consider when examining weight fluctuation and medication/disease is how the gut microbiota is affected. Microscopic organisms residing in our gut have recently been studied in more detail and it has been discovered that the symbiotic relationship we share with them can actually alter brain development and function. The intestinal microbiome alters behavior by altering levels of neurotransmitters and the immune system such that the central nervous system is affected. While the immunological aspects of health have long been known to be affected by gut microbiome, since this is where many diseases take hold, it is novel to find scientific evidence for a link between gut microbiota and neurological afflictions, not even those such as disease but also minor symptoms such as social anxiety; This opens the door to the possibility of explaining the occurrence of seemingly random or occasionally ephemeral diseases such as schizophrenia.

Mice are the primary model for these studies, but can be quite analogous to humans and the current findings are monumental. Mice lacking gut germs display increased levels of cortisol and thus behave as more stressed in a restraint situation and this can be reversed by gut colonization with Bifidobacterium infantis (one of many non-pathogenic gut symbionts). These gut supplementations studies also revealed effects on depressive behavior, learning, and memory. Autism was found to have a correlation with a specific pathogenic bacteria, Bifidobacterium fragilis, as was discovered due to the high incidence of constipation and GI complications in autistic children. Gut microbiota was found to increase levels of neurotransmitters, specifically the 5-HT ones derived from tryptophan, which is synthesized by the intestinal biota themselves. These results are astounding but leave a desire to know how they may apply to the manifestations of schizophrenia.

The biggest question that asks to be investigated is the current phenomenon of weight fluctuations in schizophrenics, both medicated and un-medicated as seen in the aforementioned clozapine and visceral fat studies. One clue to the link between obesity and schizophrenia is a study which found that obese-type microbiota induced behavioral changes in mice recolonized with such gut bacteria prior to any weight gain, such that it is proven that some symptoms that may be previously attributed to obesity itself may have actually been misdiagnosed, such as anxiety. Such a possibility is investigated in a study of the long-standing phenomenon of type II diabetes in schizophrenia patients which finds that is indeed caused by the schizophrenia itself, not the medication used to treat it or chronic illness from the disease. Another study examines a specific antipsychotic drug and finds that secondary weight gain, as a side effect, is attributable to an altered gut microbiota in children. Such as in previous studies, food intake remained constant and was not found to be the cause of weight gain. This is clear evidence of proof that obesity is in reality either a result of altered gut microbiome due to treatment medication or pre-existing obese-type gut microbiome which exacerbated schizophrenia symptoms.

Other studies provide proposals of the link between diet and neurological health, either identifying the actual antigens found within consumed food or the gut microbiota resultant from a combination of diet and maternal inheritance as the main influence 10,11. One study found that diet imposed ketosis (a metabolic state reliant on fatty molecules) greatly decreased symptoms in two case studies—an interesting application of the discovery of the importance of fatty acids proposed in the aforementioned study on erythrocyte fatty acid composition. Imposing a ketogenic metabolic state to treat diseases that may be generally resistive to traditional medicinal treatment has actually been successful in regards to other disorders such as attention deficit hyperactive disorder (ADHD), epilepsy, Depression, and bipolar disorder. A study on using ketosis to treat epilepsy found that ketosis reduces brain inflammation, due to its metabolism of ketone bodies rather than sugar-based molecules, and proposed that it could be, at least, a supplementary treatment for many other neurological disorders or even brain injury. Another study goes even further into examining the ketogenic diet and studied rats to discover that just a ketogenic diet alone is not sufficient in reducing spontaneous seizures in juvenile rats with induced epilepsy, but rather that the fats composing the majority of the calories in the ketogenic diet had to be derived from monounsaturated fatty acids rather than polyunsaturated fatty acids 18. This is quite interesting considering the membrane lipodimics study of schizophrenic patient’s red blood cells and their altered fatty acid composition.

Even further, I find it incredible that there has yet to have been a mice study conducted on how ketosis affects the gut microbiome. The few articles concerning this matter have been likely funded by dairy organizations and thus concern cattle. One such article identified specific colonies, finding that in the state of ketosis Lactobacillaceae and Streptococcaceae bacteria increased while Veillonellaceae bacteria decreased. If we were to have a better idea of which bacteria were specifically responsible for schizophrenia symptoms, such as we are beginning to have for certain disorders, e.g. autism, it would be beneficial because we could find ways to supplement these specific bacterial strains into the diet through probiotic supplementation in the form of pills or dietary intake.

In order for this to take place, the scientific understanding of gut microbiota would have to continue to increase to such a point that it would be beneficial to study the specific biological mechanisms of certain disorders with the intent to immediately thereafter be able to understand the correlations between the presence or absence of certain biological strains and then supplement certain strains or target other ones in order to treat the illness. Prior to this point, we would have to acquire a catalog and understanding of every common and rare human intestinal bacterium, which could take decades to centuries. I propose that, for the time being, we attempt to use the ketogenic diet to treat schizophrenia, specifically in patients who are unresponsive to treatment, or in whom side effects are greater than unmedicated schizophrenic symptoms.

I hope for treatment to become more accessible to anyone regardless of their income, more effective by having less side effects, and less invasive by not requiring foreign compounds to be ingested frequently; I hope for all of this to be possible in the meantime before science is advanced enough to utilize gut microbiology in order to treat schizophrenia through bacteria, with less side effects. While it may seem strange, or even primitive and overly simplistic, to propose diet as an approach to treating such a complex disease, as medicine advances and our current understanding of the scientific basis of things has improved, the possibility of providing lifestyle-centric treatments that are effective increases; this is due to adherence and monitoring. Lifestyle approaches to disease often get disregarded because you cannot ensure that the patient will adhere to the prescribed instructions, yet I believe that a patient will be incredibly more likely to follow treatment if there is a clear, specific, scientific proof encouraging the behavior. In addition to this, the greater understanding of the physiological source of the symptoms will allow for them to be monitored and tested along the course of treatment to positively reinforce adherence and further reinforce the link between lifestyle and disease.

In order for more scientific proof to support ketosis as a treatment for schizophrenia, smaller scale independent studies on the biochemical origin of schizophrenic symptoms will continue until a big enough discovery is made or enough small discoveries coalesce to stimulate a clinical trial of diet therapy. Realistically, a large scale clinical trial of a ketogenic diet as schizophrenia treatment cannot occur until there is more proof; It is very hard to get human studies approved. While I hope that these studies elucidate the metabolic basis of schizophrenia in the near future, this may not be realistic because most funding of studies is provided by big pharmaceutical companies in a form of investment; They will only fund studies which promise the future promotion of a specific drug therapy. I believe that it is important to strive towards more application of ketosis to schizophrenia treatment such that more case studies can be conducted to incite further studies and use of this accessible and affordable treatment. Everyone deserves to have access to treatment for this mental disease and the current medications can cause crippling side effects and are therefore not an acceptable final solution—The path to a final solution is long and convoluted but the current solution seems to be application of a  ketogenic diet.

https://www.psychologytoday.com/blog/hide-and-seek/201209/brief-history-schizophrenia

http://schizophrenia.com/history.htm

https://www.dnalc.org/view/899-DSM-IV-Criteria-for-Schizophrenia.html

http://www.nature.com/tp/journal/v6/n10/full/tp2016142a.html

http://www.mhs.com/product.aspx?gr=cli&id=overview&prod=panss

http://jn.nutrition.org/content/146/3/484

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5036136/

http://www.scielo.cl/scielo.php?script=sci_arttext&pid=S0034-98872016000900010&lng=en&nrm=iso&tlng=en

http://www.sciencedirect.com/science/article/pii/S0920996417300634

http://psychiatriapolska.pl/uploads/images/PP_4_2016/ENGver747KarakulaJuchnowicz_PsychiatrPol2016v50i4.pdf

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4892191/

http://jamanetwork.com/journals/jamapsychiatry/fullarticle/2597705

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