Schizophrenia – Keeping It Real

by DanM@cowseatgrass · Published August 8, 2018 · Updated August 15, 2019

“A spontaneous recovery from schizophrenia…is so rare…that when it occurs psychiatrists routinely question the validity of the original diagnosis” – A Beautiful Mind

It’s sad when you realize how much is actually known about the metabolic or biochemical issues behind the symptoms of schizophrenia, and how little of it ever makes its way into treatment. And it’s not like the standard approach has ever been that successful.

“Psychosocial stress is included in most etiologic models of schizophrenia…The biological effects of stress are mediated by the hypothalamic-pituitary-adrenal (HPA) axis, which governs the release of steroids, including cortisol.” (Corcoran C, et al., 2003)

“…communication between the nervous, endocrine, and immune systems…plays an essential role in modulating the adequate response of the hypothalamic–pituitary–adrenal (HPA) axis to the stimulatory influence of cytokines and stress-related mediators…studies have shown that the interface between these complex systems is impaired in schizophrenia…Elevations in cortisol were associated with increase in both IL-2 and IL-6 in [schizophrenia]…” (Zhang XY, et al., 2005)

Officially, when it comes to diagnosing schizophrenia, no symptom is seen as definitive, and a so called ‘psychotic pathology’ of delusions, hallucinations or disorganized speech is considered central.

Cases get further assessed on the basis of arbitrary judgements, regarding social or occupational functioning, expected levels of academic achievement, interpersonal relations, and self-care.

Schizophrenia is popularly understood to be a distinct and unique, largely genetically driven disease, which relies upon a variety of ‘anti-psychotic’ medications for treatment, with limited improvement potential. It all sounds a bit contradictory, and not very promising.

From a metabolic perspective however, a potentially more practical and illuminating way to view the symptoms of schizophrenia, is to see them as existing somewhere along a spectrum of stress exposure, and the effects that stress can have upon brain and overall system function.

“The role of stress in precipitating psychotic episodes in schizophrenia…has long been acknowledged…Current neurodevelopmental models of psychosis implicate early dysfunction in biological systems regulating hypothalamic-pituitary-adrenal axis and immune function…” (Green MJ, et al., 2014)

“…increased activity of cortisol metabolism in patients with bipolar disorder and schizophrenia compared to healthy controls…is involved in the pathophysiology and stress vulnerability in these severe mental disorders.” (Steen NE, et al., 2011)

“…psychotic disorders are associated with elevated baseline and challenge-induced HPA activity…and…agents that augment stress hormone (cortisol) release exacerbate psychotic symptoms.” (Walker E, et al., 2008)

When you think about schizophrenia in terms of the function of metabolism (and the symptoms of interference which result from stress), just the mention of the HPA axis and high cortisol can be enough to make light bulbs go off in your head, inspiring a multitude of possible treatment ideas. But first you might need to do a little detective work.

Some of the signs of schizophrenia are said to include: an inability to enjoy regular activities; low energy; lack of motivation or interest in socializing; a flat voice; inability to make friends and social isolation in general; slow thinking; poor concentration and memory; difficulty understanding or expressing thoughts; and poor sleep. All potential symptoms of stress, and metabolic suppression.

The more distinct and extreme ‘psychotic manifestations’ associated with schizophrenia, are often identified based on vague, inconsistent judgements regarding what is and isn’t deemed ‘normal’ behavior and thought, with many possible metabolic explanations for their existence being ignored.

A good place to start is to look at the relationship between high stress and thyroid dysfunction. What if the provision of an abundance of energy in the face of stress, is able to support thyroid performance, enable proper cellular function, and protect against schizophrenia?

“Thyroid disorders are highly prevalent in patients with schizophrenia. Changes in the levels of thyroid hormones cause the occurrence of psychiatric disorders and affect the response to treatment.” (Telo S, et al., 2016)

“The clinical presentations of thyroid hormone deficiency are diverse, complicated, and often overlooked… Psychiatric presentations include cognitive dysfunction, affective disorders, and psychosis…Since psychiatric complaints may be one of the earliest manifestations of hypothyroidism, they are often misdiagnosed as functional psychiatric disorders…” (Heinrich TW, et al., 2003)

“Abnormal thyroid hormonal status was observed in 29.3 per cent patients with schizophrenia-spectrum disorders in our study. This was comparable with that reported in a similar study in a hospital sample in South-East Asia which showed that 36.4 per cent of patients with schizophrenia had thyroid dysfunction.” (Radhakrishnan R, et al., 2013)

Insufficient energy availability when stress is high, impacts upon HPA axis function, increasing cortisol, and this can create conditions that are known to promote the things that interfere with thyroid energy metabolism, causing symptoms associated with schizophrenia.

“Increasing evidence suggests that within those at risk for psychosis, higher levels of cortisol is associated with…psychotic symptoms…the onset of psychosis is characterized by HPA axis hyperactivity, as supported by findings of high cortisol levels…” (Borges S, et al., 2013)

“Dysfunction in energy metabolism is one of the most consistent scientific findings associated with these disorders…The presence of metabolic alterations related to energy pathways have been recurrently implied as one of the physiological features of SCZ [schizophrenia]…” (Zuccoli GS, et al., 2017)

The idea is to find the metabolic, biochemical links in the chain leading to worsening symptoms, and then use that information to build a holistic therapeutic response, so that you can work on improving overall function of metabolism from as many angles as possible.

Symptoms of schizophrenia can worsen a great deal (and fluctuate significantly) over time, so there is every reason to believe that an awareness of the different measures of metabolism connected to worsening symptoms (and knowledge regarding different stressors that have a negative impact) will be able to make a big difference in relation to disease progression.

Stress wastes glycogen stores leading to an increase in cortisol, and this promotes other biochemical changes associated with HPA axis dysfunction and schizophrenia. Rising levels of the stress substances are encouraged by a hypo-metabolic state, together with increased free fatty acid release, often polyunsaturated. These factors combined can cause a downward spiraling vicious circle of stress and metabolic suppression.

The breakdown products of the polyunsaturated fats (PUFAs) promote ‘oxidative stress’, inflammation and mitochondrial dysfunction, all of which are associated with thyroid energy production issues, and are known to be involved in the development of schizophrenia.

“Oxidative stress is a part of the pathology in schizophrenia and appears as a promising field to develop new therapeutic strategies. Considerable attention has been focused on the determination of biomarkers of lipid peroxidation in schizophrenia. PUFAs peroxidation is a chain reaction with a large number of intermediates and end point molecules.” (Bošković M, et al., 2011)

“The vulnerability-stress-inflammation model may help to explain the role of inflammation in schizophrenia because stress can increase pro-inflammatory cytokines and may even contribute to a chronic pro-inflammatory state…the benefit of anti-inflammatory medications found in some studies…provide further support for the role of inflammation in this debilitating disease…” (Müller N. et al., 2018)

“Mitochondrial deficit, altered redox balance and chronic low-grade inflammation are evident in schizophrenia. It is hypothesized that oxidative/nitrosative stress responses due to mitochondrial dysfunctions might activate immuno-inflammatory pathways and subsequently lead to neuroprogressive changes in schizophrenia…” (Rajasekaran A, et al., 2015)

“Mitochondria are key players in the generation and regulation of cellular bioenergetics, producing the majority of adenosine triphosphate [ATP] molecules by the oxidative phosphorylation system (OXPHOS)…One consistent pathological finding implicated in SCZ is abnormal brain energy metabolism…Mitochondria…portray various deficits in SCZ…malfunctioning of the OXPHOS, source of ATP production…main driving force of various mitochondrial-related cellular functions.” (Bergman O, et al., 2016)

An under active metabolism resulting from stress, tends to go hand in hand with a sluggish, irritated and inflamed digestive system. Intestinal interference plays a significant part in the advancement of metabolic issues, including the disorders of the mind.

When digestion is slow, bacteria can grow in number and move further up the intestine promoting an increase in the release of bacterial toxins such as endotoxin. Endotoxin is involved in the promotion of inflammation and elevation of numerous stress substances associated with schizophrenia and other mood related issues.

“Neuropsychiatric disorders (e.g., autism, schizophrenia) are partially characterized by social cognitive deficits, including impairments in the ability to perceive others’ emotional states…endotoxin-induced inflammation led to significant decreases in performance…” (Moieni M, et al., 2015)

“Endotoxin…caused a profound transient physiological response with dose-related…increases in plasma interleukin (IL)-6, IL-10, tumor necrosis factor (TNF)-α and IL-1 receptor antagonist (IL-1ra), salivary and plasma cortisol, and plasma norepinephrine. These changes were accompanied by dose-related decreased mood and increased anxiety levels…there is growing experimental and clinical evidence implicating systemic inflammation to be involved in the pathophysiology of neuropsychiatric diseases such as depression and schizophrenia…” (Grigoleit JS, et al., 2011)

Endotoxin promotes serotonin, estrogen and nitric oxide, and all of these things can interfere with mitochondria, reduce intestinal barrier function, and lead to an increase in absorption of toxins into the main system. This results in greater circulation of stress substances (including estrogen and cortisol), worsening inflammation, and further disruption of thyroid systems, impacting on the brain, encouraging symptoms of schizophrenia.

“Nitric oxide (NO) has been proposed to act as an intracellular messenger in the brain and its overproduction is associated with schizophrenia…data show that the iNOS inhibitor…may be efficacious in attenuating memory impairments often observed in schizophrenia patients.” (Lafioniatis A, et al., 2016)

“Because the considerable evidence base showing that alterations of activity of NO are active in pathogenesis of schizophrenia, recent attempts have been undertaken to develop the therapy correcting disturbances of the synthesis and release of nitric oxide. Minocycline, semisynthetic tetracycline of the second generation, inhibiting enzyme iNOS and preventing development of microglial inflammatory process has been quite well studied.” (Nasyrova RF, et al., 2015)

“Chronic widespread stress-induced serotonergic overdrive in the cerebral cortex in schizophrenia…is the basic cause of the disease….Disruption of glutamate signalling by serotonergic overdrive leads to neuronal hypometabolism and ultimately synaptic atrophy and grey matter loss according to principles of brain plasticity.” (Eggers AE, et al., 2013)

Metabolic suppression resulting from stress, intensifies the bacteria promoting effects of hard to digest foods (like beans, grains, legumes, and other starchy and fibrous things), increasing the quantity of inflammatory substances which pass through the intestine, placing a greater load upon the liver.

Stress has more impact upon metabolic function when the liver is damaged, and this can then suppress thyroid metabolism even further. The provision of enough protein, sugar and certain vitamins and minerals, play a crucial role in liver function, as well as protection from metabolic dysfunction and schizophrenia progression.

“…certain vitamins and minerals may be effective for improving symptomatic outcomes of schizophrenia, by restoring nutritional deficits, reducing oxidative stress, or modulating neurological pathways….vitamin B supplementation…reduced psychiatric symptoms significantly more than control conditions…” (Firth J, et al., 2017)

“Average vitamin D values were deficient for FEP [first episode psychosis] patients, especially those 22 with a final diagnosis of schizophrenia.” (Salavert J, et al., 2017)

Continuously running down glycogen stores can mean that the stress substances become chronically high, and this is an important factor implicated in the progression of schizophrenia and other brain and mood related disorders and metabolic illness in general.

Chronic or acute stress and persistently low glycogen stores, lead to an increase in the release of the polyunsaturated free fatty acids, directly promoting inflammation, and impeding thyroid energy systems, promoting blood sugar dysregulation and insulin resistance. It is probably not a coincidence that schizophrenia and diabetes often go together.

“It has been reported in the earlier literature that many patients with psychoses had abnormalities in glucose metabolism as revealed by glucose tolerance testing…the schizophrenic population appears to have…a 2–3-fold increased risk for…diabetes…Because glucose is essential for energy metabolism in neurons, any change in…levels in brain…may have significant clinical implications.” (Dwyer DS, et al., 2001)

“Schizophrenia is associated with increased risk for type 2 diabetes mellitus, resulting in elevated cardiovascular risk and limited life expectancy, translated into a weighted average of 14.5 years of potential life lost and an overall weighted average life expectancy of 64.7 years. The exact prevalence of type 2 diabetes among people with schizophrenia…ranges 2-5fold higher than in the general population…” (Mamakou V, et al., 2018)

Stress, blood sugar dysregulation and high levels of PUFAs in the blood, promote further increases in cortisol and adrenaline, interfering with sleep, energy provision, cellular regeneration and optimal brain function.

“Previous studies have indicated that schizophrenia is linked to abnormal lipid metabolism. Free fatty acids (FFAs) in peripheral blood can reflect the status of lipid metabolism in human body…Monounsaturated fatty acids (MUFAs) and ω-6 polyunsaturated fatty acids (ω-6 PUFAs) were significantly increased in SCZs [schizophrenia] compared with HCs [healthy controls]…” (Yang X, et al., 2017)

Too much exposure to PUFAs can feed a vicious circle of serotonin, estrogen and nitric oxide dominance, fueling systemic inflammation and exacerbating many symptoms which are biologically connected to the development of schizophrenia.

“In agreement with previous findings, we show that the schizophrenia group exhibits significantly higher levels of MDA [malondialdehyde, breakdown product of PUFA] and NO [nitric oxide]…” (Gonzalez-Liencres C, et al., 2014)

One thing impacts upon another, and so rising stress substance exposure, lack of sugar, and excessive circulation of PUFAs, can promote dysregulation in almost every biological system, creating the potential for a gradually worsening degree of symptom seriousness, and yet the same information can be utilized for prevention or treatment.

“Deregulations of the pituitary-TH axis continue to be of interest given the interaction between the pituitary-thyroid axis and the dopaminergic, serotonergic, glutamatergic, and GABAergic systems, together with relationships with myelination and proinflammatory response, which are strongly implicated in schizophrenia.” (Santos NC, et al., 2012)

Sugar avoidance in combination with stress, excess PUFAs and exposure to endotoxin, interfere with pregnenolone production and can lead to an estrogen dominant (progesterone or testosterone deficient) state, similar to those seen post menopause as well as in breast cancer.

Although it is popular to suggest (as a means to explaining increased occurrence of schizophrenia in men) that estrogen is protective, this is contradicted by the fact that schizophrenia in women is associated with an increased risk of breast cancer and is more common post menopause, where tissue levels of estrogen are significantly increased, and progesterone is reduced. High testosterone has been shown to have protective effects against schizophrenia in men. Some other conditions which happen more regularly with schizophrenia, and are connected to estrogen dominance, include MS and epilepsy.

Another possible explanation for higher rates of schizophrenia in men, is the fact that women are better protected from iron accumulation pre-menopause. Interaction between accumulated iron, PUFAs and endotoxin, has been shown to promote iron dysregulation, and iron issues are involved in inflammation and oxidative stress, and have been demonstrated to play a role in the development of diseases like cancer and diabetes, as well as brain disorders including schizophrenia.

If you look at changing levels of individual stress hormones, as well as inflammation or thyroid dysfunction, as though they were all unrelated (genetically predetermined) issues, it’s easy to think then, that there isn’t that much known about the development or potential treatment of schizophrenia, and often co-occurring diseases such as cancer and diabetes.

“High levels of pro-inflammatory substances such as cytokines have been described in the blood and cerebrospinal fluid of schizophrenia patients…stress may increase pro-inflammatory cytokines and…contribute to a lasting pro-inflammatory state…” (Müller N, et al., 2015)

“Typical alterations of dopaminergic, serotonergic, noradrenergic, and glutamatergic neurotransmission described in schizophrenia have….been found in low-level neuroinflammation and consequently may be key factors in the generation of schizophrenia symptoms.” (Müller N. 2018)

If you are unaware of the potential impact of excessive exposure to PUFAs, and ongoing sugar restriction (and other nutritional factors), on all of the above conditions and on stress and metabolic function in general, it’s easy to disregard diet as a powerful causative or preventative element.

It’s not surprising that official dietary guidelines are unhelpful (at best), and sadly the ‘healthy diet’ paradigm is almost never questioned by practitioners, but rather it tends to be obediently and blindly recommended.

The ubiquitous nature of anti-sugar and salt, pro-PUFAs propaganda, means that the power of real nutrition as a means to fueling metabolism and protecting against stress, is no longer harnessed therapeutically.

Popularly prescribed anti-psychotic medications, whilst sometimes working at least for a while to suppress the so called ‘positive symptoms’ of schizophrenia, have been shown to gradually worsen metabolic function and lead to the progression of many symptoms often considered unrelated or irrelevant.

“Treatment with the new atypical antipsychotics has a much lower risk of movement disorders; however, weight gain, hyperglycemia, and diabetes are emerging as significant side effects.” (Dwyer DS, et al., 2001)

Some other known ‘side-effects’ of the anti-psychotic medications include movement disorders, heart problems, sexual dysfunction, suicidal depression and suicide. It has been suggested that failure to stay on these medications (because of their unpleasant effects) explains poor treatment success rates. Or it could be that they damage overall metabolic function, explaining lack of long term success.

I’m not a doctor or a scientist, and I’m no expert on the subject of schizophrenia. I don’t believe that we have the power to fix every health issue, but it seems to me that there is a lot that is known that can help people who are suffering from schizophrenia, and if I’m able to know a bit about it, then what exactly am I missing here? Perhaps healing is not the priority.

The first generation anti-histamine cyproheptadine (Periactin), is one example of a drug which has been shown over time to safely and effectively treat symptoms of schizophrenia. It has anti-serotonergic, anti-estrogenic, anti-cortisol, pro-metabolic effects, protects against the substances of stress and inflammation (including endotoxin, nitric oxide and PUFAs) and is generally thyroid supportive and stress protective.

“We conclude that cyproheptadine 16 mg/day is as effective as propranolol for the treatment of acute NIA [neuroleptic-induced akathisia]. The antiakathisic effect of cyproheptadine may be mostly attributable to its serotonin antagonistic activity.” (Fischel T, et al., 2001)

Other pro-metabolism, anti-stress things which have been shown to improve symptoms of schizophrenia include glycine, pregnenolone, progesterone, DHEA, thyroid hormone, the anti-histamine famotidine, aspirin, theanine, lysine, methylene blue, and certain antibiotics.

“The beneficial effects of short-term glycine administration in chronic schizophrenic subjects have been shown to persist after discontinuation for at least 8 weeks…” (Woods SW, et al., 2013)

“Treatment with…pregnenolone significantly decreased negative symptoms in patients with schizophrenia or schizoaffective disorder…and elevations in pregnenolone…post-treatment…were correlated with cognitive improvements.” (Marx CE, et al., 2011)

“Pregnenolone and L-Theanine have shown ameliorative effects on various schizophrenia symptoms…” (Kardashev A, et al., 2018)

The therapeutic application of red light, as well as techniques which look at the relationship between eye function, vestibular issues, and nervous system performance, have potential in relation to brain function and mood issues.

“The brain suffers from many different disorders…traumatic events…degenerative diseases…and psychiatric disorders…There is some evidence that all these seemingly diverse conditions can be beneficially affected by applying light to the head.” (Hamblin MR. 2016)

“…visual abnormalities in children in the general population are more strongly associated with the later development of schizophrenia than any other form of sensory impairment…Given this, and the fact that vision is the most studied and best understood function in neuroscience, why is vision such an understudied area in schizophrenia research?” (Silverstein S, et al., 2015)

A metabolism enhancing diet, removing PUFAs and limiting difficult to digest starches and fibers, whilst including sufficient protein from milk, cheese and gelatin, and plenty of sugar from sweet ripe fruits, fruit juice and white sugar, is one possible approach to protecting against symptoms of schizophrenia.

Relapses into psychosis are commonly blamed on ‘genetics’, on brain defects, or on a failure to adhere to drug therapy regimens. What tends to be disregarded, are the effects of changes in levels of exposure to biological stress in general (including dietary stress), and the cumulative damage from long-term exposure to numerous metabolically suppressive and harmful things.