Research by James Cook University scientists has found a diet favoured by body-builders may be effective in treating schizophrenia.
Associate Professor Zoltan Sarnyai and his research group from JCU’s Australian Institute of Tropical Health and Medicine (AITHM) have discovered that feeding mice a ketogenic diet, which is high on fat but very low on carbohydrates (sugars), leads to fewer animal behaviours that resemble schizophrenia.
The ketogenic diet has been used since the 1920s to manage epilepsy in children and more recently as a weight loss diet preferred by some body builders.
Dr Sarnyai believes the diet may work by providing alternative energy sources in the form of so-called ketone bodies (products of fat breakdown) and by helping to circumvent abnormally functioning cellular energy pathways in the brains of schizophrenics.
“Most of a person’s energy would come from fat. So the diet would consist of butter, cheese, salmon, etc. Initially it would be used in addition to medication in an in-patient setting where the patient’s diet could be controlled,” he said.
Schizophrenia is a devastating, chronic mental illness that affects nearly one per cent of people worldwide. There is no cure and medications used to alleviate it can produce side effects such as movement disorder, weight gain and cardiovascular disease.
But if the research findings can be translated into the effective management of schizophrenia they may offer a secondary benefit too.
The group’s paper, published online in the leading journal Schizophrenia Research, also shows mice on a ketogenic diet weigh less and have lower blood glucose levels than mice fed a normal diet.
“It’s another advantage that it works against the weight gain, cardiovascular issues and type-two diabetes we see as common side-effects of drugs given to control schizophrenia,” said Dr Sarnyai.
The JCU researchers will now test their findings in other animal schizophrenia models as they explore a possible clinical trial.
Having experienced weight gain side effects from clozapine, it’s nice to see some progress being made towards ameliorating them… I’m particularly impressed by the authors in depth discussion of the potential use of phytochemicals. I’ve included some highlights.
Second generation antipsychotics (SGAs), such as clozapine, olanzapine, risperidone and quetiapine, are among the most effective therapies to stabilize symptoms schizophrenia (SZ) spectrum disorders. In fact, clozapine, olanzapine and risperidone have improved the quality of life of billions SZ patients worldwide. Based on the broad spectrum of efficacy and low risk of extrapyramidal symptoms displayed by SGAs, some regulatory agencies approved the use of SGAs in non-schizophrenic adults, children and adolescents suffering from a range of neuropsychiatric disorders. However, increasing number of reports have shown that SGAs are strongly associated with accelerated weight gain, insulin resistance, diabetes, dyslipidemia, and increased the cardiovascular risk. These metabolic alterations can develop in as short as six months after the initiation of pharmacotherapy, which is now a controversial fact in public disclosure. Although the percentage of schizophrenic patients, the main target group of SGAs, is estimated in only 1% of the population, during the past ten years there was an exponential increase in the number of SGAs users, including millions of non-SZ patients. The scientific bases of SGAs metabolic side effects are not yet elucidated, but the evidence shows that the activation of transcriptional factor SRBP1c, the D1/D2 dopamine, GABA2 and 5HT neurotransmitions are implicated in the SGAs cardiovascular toxicity. Polypharmacological interventions are either non- or modestly effective in maintaining low cardiovascular risk in SGAs users. In this review we critically discuss the clinical and molecular evidence on metabolic alterations induced by SGAs, the evidence on the efficacy of classical antidiabetic drugs and the emerging concept of antidiabetic polyphenols as potential coadjutants in SGA-induced metabolic disorders.
“…we summarized the results of 20 clinical studies and three preclinical studies, assessing the efficacy of pharmacological interventions (i.e. metformin, nizatadine, orlistat, ranitidine, topiramate, etc.) against SGA-induced metabolic side effects. This summarized evidence shows that one out of five studies with metformin resulted in negative results. The other four positive studies concluded that weight gain, insulin resistance can be efficiently controlled, but lipid profile may even worsen. Metformin reduced body weight in clozapine-treated patients, but its beneficial effects disappeared after discontinuing this medication. Orlistat in overweight/obese clozapine-or olanzapine-treated patients failed to prevent obesity and lipid accumulation, which suggest that the intestinally absorbed lipids may not be relevant for SGAs-induced obesity. Atomoxetine, a selective norepinepherine reuptake inhibitor with appetite suppressant activity, was not effective in preventing obesity in patients treated with olanzapine and clozapine.”
With respect to the serotoninergic hypothesis, the interventions with fluoxetine also failed. The use of sertraline in clozpaine-induced weight gain resulted in cardiac death in rodents.
Tetradecylthioacetic acid (TTA), a modified fatty acid, recently showed a minor protective effect against hypertriglyceridemia, but failed to prevent weight gain induced by clozapine in rodents.
Berberine, a natural alkaloid, inhibited in vitro adipogenesis and SREBP-1 overexpression induced by clozapine and risperidone in 3T3 adipocytes: “Berberine is an example of an antidiabetic phytochemical with potential protective effect against lipid accumulation induced by clozapine.”
Resveratrol and green tea, showed some efficacy in decreasing weight gain and fat mass accumulation induced by olanzapine in rodents.
“Our group and others have demonstrated that specific polyphenols from dietary sources ameliorate insulin resistance, inflammation and obesity.”
Anthocyanins, a family polyphenols, have shown significant clinical effect in improving insulin sensitivity in obese, nondiabetic, insulin-resistant patients.
“Polyphenols are family of polar compounds found in fruits and vegetables, they have been popular for their potent antioxidant effect, but in the past 5 years increasing evidence has shown that, anthocyanins, a specific category of polyphenols, are effective in ameliorating obesity and insulin resistance.
The mode of action and pharmacokinetic profile of these compounds is not yet fully elucidated and their bioavailability after oral administration is a matter of continuous controversy. However, there is robust evidence on their efficacy in cardiometabolic problems. Kurimoto et al. reported that anthocyanins from black soy bean increased insulin sensitivity via the activation of AMP-activated protein kinase (AMPK) in skeletal muscle and liver of in type 2 diabetic mice. AMPK, a regulator of glucose and lipid metabolism in liver and muscle cells, is inhibited by olanzapine, which may contribute to the olanzapine-induced hepatic lipid accumulation. Anthocyanins also display insulin-like effects even after intestinal biotransformation.
We have previously demonstrated that anthocyanins ameliorate signs of diabetes and metabolic syndrome in obese mice fed with a high fat diet have. Delphinidin 3-sambubioside-5-glucoside (D3S5G), an anthocyanin from Aristotelia chilensis, is as potent as Metformin in decreasing glucose production in liver cells, and it displays insulin-like effect in liver and muscle cells. The anti-diabetic mode of action of anthocyanins have been associated with the transcriptional down-regulation of the enzymes PEPCK and G6P gene in hepatocytes. Prevention of adipogenesis is also another reported mechanmis for some anthocyanins from Aristotelia chilensis. Anthocyanins also induce significant increase in circulating levels of adiponectin in murine models of MetS. This is relevant, since adiponectin is reduced in clozapine-treated patients and weight reduction is associated with higher circulating levels of adiponectin. In a recent study Roopchand et al., demonstrated that blueberry anthocyanins are as potent as metformin in correcting hyperglycemia and obesity in obese hyperglyceminc mice. Dietary anthocyanins have also proven efficacy in decreasing les of the inflammatory mediators PAI-1 and retinol binding protein 4 in obesity and type 2 diabetes . Recent medical and nutritional studies suggest that anthocyanins from diverse dietary sources are potent anti-diabetic, anti-obesity and cardioprotective molecules. Another fact that makes anthocyanins candidates for preventing clozapine-induced lipogenesis is that they are capable of suppressing the inflammatory response through targeting the phospholipase A2, PI3K/Akt and NF-kappaB pathways. These pre-clinical findings were corroborated by clinical evidence showing the dietary anthocyanins from blueberries improve insulin resistance in young obese, non-diabetic adults. The clinical efficacy of polyphenols in SGAs-induced MetS has not yet been established, but a recent pre-clinical demonstrated that, resveratrol, a polyphenol found in grapes, decreases olanzapine-induced weight gain.”
Some polyphenols showing positive outcomes for diabetes, obesity and metabolic syndrome [see article for more information]:
Purified anthocyanins 160 mg twice a day
Cinnamon extract 250 mg, twice a day
Whole blueberries 22.5 g twice a day
Resveratrol 150 mg
Pomegranate juice 1.5 mL/Kg
Raisins (Vitis vinifera) 36 g/day
Green tea extract 375 mg (270mg catechins) per day
Intravenous sodium nitroprusside (acting as a NO donor) shows impressive antipsychotic potential. I wonder if dietary nitrate supplementation (vegetables rich in nitrate include spinach, lettuce, broccoli and beetroot) can provide both antipsychotic and cognitive benefits for people with schizophrenia via improved function of the PFC?
Nitrate derived from vegetables is consumed as part of a normal diet and is reduced endogenously via nitrite to nitric oxide. It has been shown to improve endothelial function, reduce blood pressure and the oxygen cost of sub-maximal exercise, and increase regional perfusion in the brain. The current study assessed the effects of dietary nitrate on cognitive performance and prefrontal cortex cerebral blood-flow (CBF) parameters in healthy adults. In this randomised, double-blind, placebo-controlled, parallel-groups study, 40 healthy adults received either placebo or 450ml beetroot juice (~5.5mmol nitrate). Following a 90minute drink/absorption period, participants performed a selection of cognitive tasks that activate the frontal cortex for 54min. Near-Infrared Spectroscopy (NIRS) was used to monitor CBF and hemodynamics, as indexed by concentration changes in oxygenated and deoxygenated-haemoglobin, in the frontal cortex throughout. The bioconversion of nitrate to nitrite was confirmed in plasma by ozone-based chemi-luminescence. Dietary nitrate modulated the hemodynamic response to task performance, with an initial increase in CBF at the start of the task period, followed by consistent reductions during the least demanding of the three tasks utilised. Cognitive performance was improved on the serial 3s subtraction task. These results show that single doses of dietary nitrate can modulate the CBF response to task performance and potentially improve cognitive performance, and suggest one possible mechanism by which vegetable consumption may have beneficial effects on brain function.
•Dietary nitrate is reduced endogenously via nitrite to nitric oxide.
•The effects of nitrate rich beetroot juice on frontal cerebral blood-flow were tested.
•Nitrate modulated the hemodynamic response to task performance in the frontal cortex.
•Performance on one of three tasks (serial 3s subtractions) was improved.
•Plasma nitrite was increased.
“The ingestion of nitrate, including from dietary sources, is associated with a number of effects consistent with increased levels of endogenous NO synthesis, including reductions in blood pressure. This effect has been demonstrated as early as 3 h after a single dose of nitrate rich beetroot juice, with a concomitant protection of forearm endothelial function and in vitro inhibition of platelet aggregation. Dietary nitrate has also been shown to reduce the overall oxygen cost of sub-maximal exercise 2.5 h after ingestion and after three or more days of administration. Similarly, an increase in peak power and work-rate, a speeding of VO2 mean response time in healthy 60–70 year olds and delayed time to task failure during severe exercise have also been reported following the consumption of nitrate rich beetroot juice consumed daily for 4 to 15 days. Nitrate related reductions have also been demonstrated with regard to the rate of adenosine-5′-triphosphate (ATP) turnover using magnetic resonance spectroscopy, whilst improved oxygenation has been confirmed directly in the muscle during exercise using Near-Infrared Spectroscopy (NIRS).
NO plays a pivotal role in cerebral vasodilation and the neurovascular coupling of local neural activity and blood-flow. Several studies have probed the effects of dietary nitrate derived from beetroot or spinach on brain function, including three studies that have included some form of cognitive testing either as an additional measure, or as the primary focus of the project. Whilst these studies demonstrated modulation of a number of physiological parameters they did not provide evidence of cognitive improvements, possibly due to comparatively small sample sizes and other methodological factors. Two studies have also investigated the effects of dietary nitrate on cerebral blood-flow parameters. In the first of these, Presley et al. demonstrated, using arterial spin labelling magnetic resonance imaging (MRI), that a diet high in nitrate consumed for 24 h increased regional white matter perfusion in elderly humans, but with this effect restricted to areas of the frontal cortex. More recently, Aamand et al., investigated the effects of 3 days of administration of dietary nitrate (sodium nitrate) on the haemodynamic response in the visual cortex elicited by visual stimuli, as assessed by functional MRI (fMRI). They demonstrated a faster, smaller and less variable blood-oxygen-level dependent (BOLD) response following nitrate, which they interpreted as indicating an enhanced neurovascular coupling of local CBF to neuronal activity. As the BOLD response simply reflects the contrasting magnetic signals of oxygenated and deoxygenated haemoglobin (with increased activity imputed from an assumed relative decrease in deoxyhemoglobin as local activation engenders a greater influx of blood borne oxygenated -Hb), it cannot disentangle the contributions of changes in blood-flow and changes in oxygen consumption to the overall signal. The current study therefore utilised Near-Infrared Spectroscopy (NIRS), a brain imaging technique that has the advantage over fMRI BOLD in that it measures both concentration changes in deoxy-Hb and overall local CBF (changes in oxy-Hb and deoxy-Hb combined).”
Previous research suggests that NO exerts a number of effects that might also impact on overall cellular energy consumption in the brain. These include the inhibition of mitochondrial respiration and therefore oxygen consumption, including via inhibition of cytochrome c oxidase, and enhancement of the efficiency of oxidative phosphorylation by decreasing slipping of the proton pumps
“It is important to note that beetroot contains a plethora of other, potentially bioactive, phytochemicals including the nitrogenous betalains, a range of phenolics, including multiple flavonoids and flavonols and folates. Given the ability of similar phytochemicals to modulate peripheral endothelial function, CBF parameters and cognitive function the possibility that any effects are related to high levels of these other compounds cannot be ruled out. It is also notable that the NO3−/NO2−/NO pathway is reported to be most prevalent during hypoxic conditions and in the presence of reducing agents such as vitamin C and polyphenols. Having said this, recent evidence from a study directly comparing nitrate rich beetroot juice to nitrate depleted (but otherwise identical) beetroot juice suggests that the effects seen on blood pressure and the O2 cost of exercise are directly attributable to the nitrate content of the juice rather than to any other bioactive components (although synergies cannot be ruled out). Given the potential for multifarious phytochemicals to impact on CBF, an extension of the current study using these nitrate rich and depleted interventions may be able to resolve the question of the direct contribution of nitrate to the cognitive and CBF effects seen here.”
To conclude:
“…the findings here suggest that supplementation with dietary nitrate can directly modulate important physiological aspects of brain function and improve performance on a cognitive task that is intrinsically related to prefrontal cortex function. Taken alongside a previous demonstration of increased prefrontal cortex perfusion in elderly humans following consumption of a high nitrate diet for ~ 36 h, the results here suggest both a specific food component and physiological mechanisms that may contribute to epidemiological observations of relationships between the consumption of a diet rich in vegetables and polyphenols (which naturally co-occur with nitrate in vegetables) and preserved cognitive function in later life. Of particular importance, the results here were demonstrated in young humans, who can be assumed to be close to their optimum in terms of brain function, and hint at the potential benefits of a healthy, vegetable rich diet across the lifespan.
In summary, dietary nitrate, administered as beetroot juice, modulated CBF in the prefrontal cortex during the performance of cognitive tasks that activate this brain region, with this effect most consistently seen as reduced CBF during the easiest of three tasks (RVIP). Cognitive performance was improved on a further task, serial 3s subtractions. These results suggest that a single dose of dietary nitrate can modify brain function, and that this is likely to be as a result of increased NO synthesis leading to an exaggerated neurovascular response to activity or improved efficiency of cellular metabolism”
Dietary intake of cocoa flavanols is also associated with benefits for cognitive performance [1].
Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder of unknown etiology, but very likely resulting from both genetic and environmental factors. There is good evidence for immune system dysregulation in individuals with ASD. However, the contribution of insults such as dietary factors that can also activate the immune system have not been explored in the context of ASD. In this paper, we show that the dietary glycemic index has a significant impact on the ASD phenotype. By using BTBR mice, an inbred strain that displays behavioral traits that reflect the diagnostic symptoms of human ASD, we found that the diet modulates plasma metabolites, neuroinflammation and brain markers of neurogenesis in a manner that is highly reflective of ASD in humans. Overall, the manuscript supports the idea that ASD results from gene–environment interactions and that in the presence of a genetic predisposition to ASD, diet can make a large difference in the expression of the condition.
“The main finding from these studies is that diet can significantly alter the phenotypic characteristics of BTBR mice, an inbred strain that models all the three behavioral characteristics of human ASD. The diet-mediated changes in behavior are paralleled by changes in markers of inflammation as well as neurogenesis and synaptic function, all of which are also altered in human ASD. Although only a limited number of studies have been carried out on the brains from human ASD subjects, several clear differences have emerged. Overall, the ASD brains show increases in neuroinflammation as well as multiregional dysregulation of neurogenesis and neuronal migration and maturation. Functional magnetic resonance imaging suggests that these anatomical changes result in deficits in functional connectivity. Together, these data suggest that there is an intimate connection between inflammation, neurogenesis and neuronal maturation, which when disturbed can lead to ASD. However, what gives rise to those disturbances is still unclear. Our results provide strong support for the idea that it is a combination of genetic and environmental factors, in this case diet, that promote inflammation and the ASD phenotype.”
“…Since ASD is thought to result from changes in brain development that occur both before and after birth, the BTBR mice were exposed to the different diets both pre- and postnatally. Thus, our data do not allow us to distinguish between prenatal and postnatal effects of diet on the autistic phenotype. Future studies will be designed to address this question. Consistent with our hypothesis that diet-induced inflammation plays a key role in ASD, we found increased levels of CRP, a marker of chronic systemic inflammation, in the plasma of the mice exposed to/fed the high-GI diet relative to those fed the low-GI diet. In addition, we also saw increased levels of AGE- and MG-modified proteins in both the blood and brains of the mice fed the high-GI diet as compared to mice fed the low-GI diet, indicating that the high-GI diet specifically increased non-enzymatic protein glycation as reported in an earlier study on aging mice. We believe that the increases in CRP and AGEs are linked…”
A role for microglia?
“One way in which inflammation could influence brain development and function is via effects on microglia. Microglia play a critical role in synaptic pruning during brain development and a transient loss of microglia during brain development in mice is associated with structural and behavioral alterations. similar to those seen in human ASD subjects. Furthermore, analysis of brain samples from ASD subjects showed marked increases in microglial activation. We found that the microglia in the brains of the low-GI diet-fed mice were much more ramified consistent with healthy, unactivated microglia. In contrast, microglia in the brains of the mice fed the high-GI diet had shorter processes more similar to those observed in activated microglia.”
A role for the microbiome?
“…the metabolomics study indicated that the two diets have distinct effects on the gut microbiota. Large differences between the two diets were seen in the plasma levels of several compounds with known gut microbiome metabolic origin or contribution, including a variety of amino acid metabolites. The low-GI diet, whose major starch is amylose, has higher levels of resistant fiber as compared with the high-GI diet. Resistant fiber promotes changes in the gut ecosystem since it is entirely digested in the large intestine. A very recent study showed that MIA in mice could alter the gut microbiota in the offspring. Interestingly, a tyrosine metabolite related to phenol sulfate was increased in the plasma of these mice and contributed to some of their ASD-like behavioral changes. Furthermore, oral treatment of the offspring with Bacteroides fragilis reduced some of the ASD-associated behavioral deficits. However, B. fragilis did not affect the reduction in social interaction in the MIA offspring. Thus, some of the effects of the low-GI diet could be mediated through modulation of the gut microbiota. Further studies will be needed to clarify this point.”
“Importantly, the metabolomics analysis of the plasma of the mice fed the two different diets showed a number of differences that have been noted in comparative analyses between control and human ASD subjects. For example, a number of human studies have shown lower levels of sulfur-containing amino acids, including methionine and taurine, in the blood and urine of ASD subjects as compared to normal controls. These differences are thought to be a reflection of the metabolic changes that contribute to the ASD phenotype. Similarly, the mice fed the high-GI diet show lower plasma levels of methionine and taurine as well as the related compounds N-acetylmethionine and hypotaurine. Since methionine is an essential precursor for DNA methylation, these results suggest that there may be epigenetic changes associated with the two different diets that could contribute to some of the behavioral and/or biochemical differences. Further studies will be needed to address this question.”
Therapeutic potential of a ketogenic diet?
“…a recent study using the BTBR mouse model showed that a ketogenic diet could reduce some of the ASD-like behaviors in these mice. Interestingly, in our study, a significantly higher level of 3-hydroxybutyrate, a fatty acid metabolite that is increased by a ketogenic diet, was seen in the plasma of the mice fed the low-GI diet as compared to the mice fed the high-GI diet. This finding suggests that there may be overlap with regard to the physiological consequences of a ketogenic diet and low-GI diet.”
To conclude:
“…our study strongly supports the hypothesis that ASD arises from a combination of genetic susceptibility factors and environmental insults. In this case, the genetic predisposition of BTBR mice to display behavioral and biochemical characteristics of ASD was modified by lowering the GI of their diet. This diet also altered the levels of AGEs and other inflammatory markers in the plasma and in the brain, suggesting a mechanism underlying these effects. Importantly, a number of the metabolic changes associated with the ASD-promoting high-GI diet are also seen in human ASD subjects. Together these data might suggest that a similar dietary modification in humans would have the potential to eventually be translated, if these findings are confirmed by the necessary clinical trials, into novel interventions for ASD.”
Prolonged fasting (PF) promotes stress resistance, but its effects on longevity are poorly understood. We show that alternating PF and nutrient-rich medium extended yeast lifespan independently of established pro-longevity genes. In mice, 4 days of a diet that mimics fasting (FMD), developed to minimize the burden of PF, decreased the size of multiple organs/systems, an effect followed upon re-feeding by an elevated number of progenitor and stem cells and regeneration. Bi-monthly FMD cycles started at middle age extended longevity, lowered visceral fat, reduced cancer incidence and skin lesions, rejuvenated the immune system, and retarded bone mineral density loss. In old mice, FMD cycles promoted hippocampal neurogenesis, lowered IGF-1 levels and PKA activity, elevated NeuroD1, and improved cognitive performance. In a pilot clinical trial, three FMD cycles decreased risk factors/biomarkers for aging, diabetes, cardiovascular disease, and cancer without major adverse effects, providing support for the use of FMDs to promote healthspan.
“The components and levels of micro- and macro-nutrients in the human FMD were selected based on their ability to reduce IGF-1, increase IGFBP-1, reduce glucose, increase ketone bodies, maximize nourishment, and minimize adverse effects in agreement with the FMD’s effects in mice. The development of the human diet took into account feasibility (e.g., high adherence to the dietary protocol) and therefore was designed to last 5 days every month and to provide between 34% and 54% of the normal caloric intake with a composition of at least 9%–10% proteins, 34%–47% carbohydrates, and 44%–56% fat.”
“The human fasting mimicking diet (FMD) program is a plant-based diet program designed to attain fasting-like effects while providing micronutrient nourishment (vitamins, minerals, etc.) and minimize the burden of fasting. It comprises proprietary vegetable-based soups, energy bars, energy drinks, chip snacks, chamomile flower tea, and a vegetable supplement formula tablet. The human FMD diet consists of a 5 day regimen: day 1 of the diet supplies ∼1,090 kcal (10% protein, 56% fat, 34% carbohydrate), days 2–5 are identical in formulation and provide 725 kcal (9% protein, 44% fat, 47% carbohydrate)”
Also, it’s interesting to see how diet [a high protein one in particular] can worsen or precipitate a secondary psychosis that is induced by metabolic disorders [2]
Acute fasting increases somatodendritic DA release [3]:
“Fasting and food restriction alter the activity of the mesolimbic dopamine system to affect multiple reward-related behaviors. Food restriction decreases baseline dopamine levels in efferent target sites and enhances dopamine release in response to rewards such as food and drugs. In addition to releasing dopamine from axon terminals, dopamine neurons in the ventral tegmental area (VTA) also release dopamine from their soma and dendrites, and this somatodendritic dopamine release acts as an auto-inhibitory signal to inhibit neighboring VTA dopamine neurons. …fasting caused a change in the properties of somatodendritic dopamine release, possibly by increasing dopamine release, and that this increased release can be sustained under conditions where dopamine neurons are highly active.”
Western diets high in fat and refined sugar are associated with increased levels of brain BDNF and tryptophan and decreased exploratory and anxiety-like behaviour [4].
Dampened mesolimbic dopamine function and signaling by saturated but not monounsaturated dietary lipids has been reported: “…saturated lipids can suppress DA signaling apart from increases in body weight and adiposity-related signals known to affect mesolimbic DA function, in part by diminishing D1 receptor signaling, and that equivalent intake of monounsaturated dietary fat protects against such changes” [5].
Relationships between diet-related changes in the gut microbiome and cognitive flexibility have been investigated [6].
I have noticed how much diet plays a role in how I feel. If I eat too much bread and lots of other carbohydrates, I feel crap. If I snack on foods rich in simple carbohydrates, that’s a recipe for really feeling bad. On protein, I feel much better. Add some quality oils and fats (I like a good dose of fish oil rich in omega-3’s) and I’m much better. Periodic fasting is good for feeling uplifted but my sanity starts to suffer. Doing things in balance is not something I’m great at so I tend to drift towards extremes in diets, something I’m working on improving. The human fasting mimicking diet sounds like something novel enough to keep me interested!
I’m going to try and keep some notes so I can correlate my diet with how ‘autistic’ and ‘psychotic’ I’m getting (‘autistic’ being generally detectable by a long post of citations and links on here, while I’ll take the intensity of my auditory verbal hallucinations as a measure of how ‘psychotic’)… once my medications are stabilised, that is.
It’s becoming more apparent that my gastrointestinal system is about as healthy as my mental health. Clozapine has worsened already problematic constipation and the high protein diet that I’m using to combat weight gain certainly hasn’t helped that, nor the excessive (highly malodourous) flatulence. A month on a general probiotic initially seemed promising but it seems I need to further modify my diet. Even on the high protein diet, once again, I’m gaining weight. Food cravings are extreme and I wake up in the middle of the night – essentially on autopilot aka ‘clozapined’ – to eat…
I would say I’ve never really had a well functioning GI system and with all the research pointing to the role of the microbiome and brain-gut axis in health and illness, it’s time to see if I can change that with some simple and safe dietary modifications.
Basically, I’m considering continuing the probiotic and adding prebiotics, additional soluble fibre and enriching my diet with polyphenols to align with a more ancient and traditional one:
“Comparisons of the modern Western-style diet (WSD) with more ancient and traditional diets are helping to redefine the paradigm of malnutrition. Malnutrition is no longer restricted to the lack of certain essential nutrients, but also encompasses over nutrition and aberrant nutrient ratios and profiles. The WSD is typified by altered fat profiles with elevated saturated fats and synthetic trans-fatty acids compared to essential fatty acids and unsaturated fatty acids (mono- and polyunsaturated) and low availability of saturated fats in more traditional diets. The WSD is also defined by high levels of refined carbohydrates or sugars as opposed to traditional diets where foods enriched with complex, lowly digestible highly fermentable carbohydrates (e.g., fiber and prebiotics) form staples and support a saccharolytic, SCFA-producing gut microbiota. For proteins too, major differences occur between WSD and more traditional diets and foods, with amino acid composition and profile of foods being altered by industrial food-processing technologies. The WSD has largely replaced plant polyphenols as preservatives and to a lesser extent flavorings with chemical substitutes and finally, modern foods have substituted the phylogenetically diverse and numerically dense microbial food passengers found on traditional fermented and raw foods with monocultures of strains selected for technological purposes or more commonly, with sterility. Within the human “super-organism,” nowhere are the metabolic consequences of this altered nutritional environment more obvious than in the interactions between the gut microbiome and host energy metabolism and brain function. We have known for a while now that the gut microbiome and its interactions with diet plays a critical role in energy homeostasis and immune tolerance. We have linked aberrant gut microbiota profiles with diseases of immune function or autoimmune diseases and metabolic diseases like obesity, diabetes and non-alcoholic fatty liver disease. However, only very recently has altered brain development been considered a consequence of our closely co-evolved gut microbiome being out of step with our modern diet.” [1]
“There are some studies showing effects of probiotics on brain function in healthy humans. For example, women who had taken a fermented milk product containing four probiotics (Bifidobacterium animalis subsp. lactis, Streptococcus thermophiles, Lactobacillus bulgaricus, and Lactococcus lactis subsp. lactis) showed reductions in brain responses to an emotional task, particularly in sensory and interoceptive regions that were measured with functional magnetic resonance imaging. Moreover, in another study, global psychological distress and anxiety symptoms, as measured by the Hospital Anxiety and Depression Scale, were improved in the group taking a Lactobacillus and Bifidobacterium-containing probiotic compared with those taking a matched control product. Importantly, probiotic supplementation of the mother during and after pregnancy has been shown to alter the infant’s microbiota. There is a need for future trials focusing on the best combinations of probiotic strains, the timing of administration, and whether these probiotics are more efficacious in conjunction with prebiotics. Also the mechanisms of action of probiotics are understudied and further investigating why certain bacterial strains have positive effects on brain health will be an important area into the future.” [1]
Recently, a randomized controlled trial to test the effect of multispecies probiotics on cognitive reactivity to sad mood provided “…the first evidence that the intake of probiotics may help reduce negative thoughts associated with sad mood” [2]
“Prebiotics are nondigestible food ingredients that selectively stimulate the growth of probiotic bacteria such as Lactobacilli and Bifidobacteria in the gut. Increasing the proportion of these bacteria with prebiotics such as galactooligosaccharides or fructooligosaccharides has many beneficial effects on the gut, the immune system, and on brain function, specifically, increased BDNF expression and NMDA receptor signaling, providing initial support for further investigations of the utility of prebiotics in mental health and potential treatment of psychiatric disorders. Recently, a human study has shown that subjects supplemented with galactooligosaccharides displayed a suppression of the neuroendocrine stress response and an increase in the processing of positive versus negative attentional vigilance, showing an early anxiolytic-like profile. Inulin-type fructans and lactulose modulate gut transit, decrease putrefactive activity within the gut lumen, prevent GI infections, and mitigate inflammatory responses” [3]
I’m using inulin:
“Inulin and oligofructose are considered as functional food ingredients since they affect the physiological and biochemical processes in rats and human beings, resulting in better health and reduction in the risk of many diseases. Experimental studies have shown their use as bifidogenic agents, stimulating the immune system of the body, decreasing the pathogenic bacteria in the intestine, relieving constipation, decreasing the risk of osteoporosis by increasing mineral absorption, especially of calcium, reducing the risk of atherosclerosis by lowering the synthesis of triglycerides and fatty acids in the liver and decreasing their level in serum. These fructans modulate the hormonal level of insulin and glucagon, thereby regulating carbohydrate and lipid metabolism by lowering the blood glucose levels; they are also effective in lowering the blood urea and uric acid levels, thereby maintaining the nitrogen balance. Inulin and oligofructose also reduce the incidence of colon cancer.” [4]
Even at doses as low as 2.5 g twice a day, inulin can exert a prebiotic effect in healthy volunteers by stimulating bifidobacteria growth. [5] Doses of 5-40g have been used for therapeutic purposes: 10 g per day for lowering triglycerides to upward of 40 g per day for relieving constipation. It has been reported that prehistoric foragers in the Chihuahuan Desert ate a diet which contained upward of 135 grams of inulin-like fructans [6].
“An inulin dose of 5–8 g/d should be sufficient to elicit a positive effect on the gut microbiota. One possible side effect of prebiotic intake is intestinal discomfort from gas production. However, bifidobacteria and lactobacilli cannot produce gas as part of their metabolic process. Therefore, at a rational dose of up to 20 g/d, gas distension should not occur. If gas is being generated, then the carbohydrate is not acting as an authentic prebiotic. This is perhaps because dosage is too high and the prebiotic effect is being compromised, i.e., bacteria other than the target organisms are becoming involved in the fermentation.” [7]
In overweight adults, treatment with galactooligosaccharides induced “favorable” changes in gut microbial composition, increased secretory IgA levels, and reduced inflammation and measures of the metabolic syndrome [8]
10g of inulin tastes fine mixed in with a protein shake.
3. Polyphenols etc:
I’m using raw cocoa [cacao] powder. It is known to be rich in polyphenols, such as catechin, epicatechin, procyanidin B2 (dimer), procyanidin C1 (trimer), cinnamtannin A2 (tetramer), and other oligometric procyanidins [9] It has numerous health benefits and provides caffeine and theobromine [10]. I’m using a dose of 30g/day [380kJ, 6.4g protein, 7.6g carbohydrate]
“Cocoa is a food relatively rich in polyphenols, which makes it a potent antioxidant. Due to its activity as an antioxidant, as well as through other mechanisms, cocoa consumption has been reported to be beneficial for cardiovascular health, brain functions, and cancer prevention. Furthermore, cocoa influences the immune system, in particular the inflammatory innate response and the systemic and intestinal adaptive immune response. Preclinical studies have demonstrated that a cocoa-enriched diet modifies T cell functions that conduce to a modulation of the synthesis of systemic and gut antibodies. In this regard, it seems that a cocoa diet in rats produces changes in the lymphocyte composition of secondary lymphoid tissues and the cytokines secreted by T cells. These results suggest that it is possible that cocoa could inhibit the function of T helper type 2 cells, and in line with this, the preventive effect of cocoa on IgE synthesis in a rat allergy model has been reported, which opens up new perspectives when considering the beneficial effects of cocoa compounds. On the other hand, cocoa intake modifies the functionality of gut-associated lymphoid tissue by means of modulating IgA secretion and intestinal microbiota.” [11]
4. Supplemental dietary fibre
NOTE: In case of medication-induced constipation, caution is required when increasing fibre intake.
“Dietary fibers pass through the upper intestine and are fermented by large-bowel anaerobic microbiota to produce SCFAs. SCFAs promote gut epithelial integrity and exert immune effects, including stimulation of G protein–coupled receptors, promotion of innate (Toll-like receptor 2) immune responses, and induction of regulatory T cells” [8]
I’m sticking with psyllium husk in divided doses. I’ve found it has better effects for alleviating constipation when it’s mixed with water and a macrogol 3350 sachet.
Nuclear peroxisome proliferator activated receptor-α (PPAR-α) plays a fundamental role in the regulation of lipid homeostasis and is the target of medications used to treat dyslipidemia. However, little is known about the role of PPAR-α in mouse behavior.
Methods
To investigate the function of Ppar-α in cognitive functions, a behavioral phenotype analysis of mice with a targeted genetic disruption of Ppar-α was performed in combination with neuroanatomical, biochemical and pharmacological manipulations. The therapeutic exploitability of PPAR-α was probed in mice using a pharmacological model of psychosis and a genetic model (BTBR T + tf/J) exhibiting a high rate of repetitive behavior.
Results
An unexpected role for brain Ppar-α in the regulation of cognitive behavior in mice was revealed. Specifically, we observed that Ppar-α genetic perturbation promotes rewiring of cortical and hippocampal regions and a behavioral phenotype of cognitive inflexibility, perseveration and blunted responses to psychomimetic drugs. Furthermore, we demonstrate that the antipsychotic and autism spectrum disorder (ASD) medication risperidone ameliorates the behavioral profile of Ppar-α deficient mice. Importantly, we reveal that pharmacological PPAR-α agonist treatment in mice improves behavior in a pharmacological model of ketamine-induced behavioral dysinhibition and repetitive behavior in BTBR T + tf/J mice.
Conclusion
Our data indicate that Ppar-α is required for normal cognitive function and that pharmacological stimulation of PPAR-α improves cognitive function in pharmacological and genetic models of impaired cognitive function in mice. These results thereby reveal an unforeseen therapeutic application for a class of drugs currently in human use.
“In rodents, Ppar-α has been linked to brain dopamine function, a neurotransmitter system that is a target of some antipsychotic and autism spectrum disorder (ASD) medications. Specifically, Ppar-α activation improves antipsychotic medication adverse event oral tardive dyskinesia and indirectly reduces the activity of dopamine cells in the ventral tegmental area in rodents. In humans, dyslipidemia is more prevalent in individuals with schizophrenia and ASD compared to the general population.
…genetic inactivation of Ppar-α resembles a behavioral and cognitive phenotype consistent with preclinical models of schizophrenia and ASD. In an effort to elucidate the mechanism through which this phenotype is mediated, we analyzed the brain. We observed that the genetic prevention of Ppar-α activity produced a reduction in cortical PV + GABAergic interneurons, consistent with post-mortem analyses of brains from patients with schizophrenia. We also report that the behavioral profile of Ppar-α null mice was improved with antipsychotic risperidone treatment. Thus, Ppar-α deficient mice may represent a new preclinical model to investigate the etiology and/or treatment of schizophrenia. The behavioral profile of Ppar-α null mice also shows similarities with ASD mouse model BTBR, which displayed an improved repetitive behavior with PPAR-α agonist treatment. Furthermore, risperidone is also used to alleviate hyperactivity, self-injurious, and repetitive behavior symptoms in humans suffering with ASD. Together, these results highlight PPAR-α as a potential point of commonality between schizophrenia and ASD worthy of further investigation.
Considering that repetitive behaviors can arise from a disruption in the direct cortico-striatal circuit, it is possible that PPAR-α plays an instrumental role in the organization and orchestration of PV + interneuron-pyramidal neuron cortical microcircuitry, and the absence of this regulation contributes to a net increase in cortical firing and output onto striatal structures. Supporting this possibility, GABAergic interneurons are crucial for synchronization of network activity, Ppar-α −/− mice exhibit abnormal EEG waves, and Ppar-α −/− mice are resistant to the behavioral disinhibition caused by the administration of NMDA receptor antagonists, which inhibit the activity of cortical PV + interneurons.
Given our observation that PPAR-α agonist treatment improves behavior in a pharmacological model of psychosis (ketamine) and a mouse model that displays face validity for ASD (BTBR), our research suggests that patients with schizophrenia and ASD co-prescribed fibrates to improve dyslipidemia may show a greater benefit in cognitive symptom amelioration. This possibility warrants further investigation in patient populations. Moreover, it is possible that at least a subset of these patients may receive direct therapeutic benefit from fibrates. If this were the case, it would have the added benefit of overcoming the metabolic disturbance associated with many current antipsychotic medications. Of interest, loss of function of Ppar-α results in middle age-onset obesity/weight gain in mice. Thus, increasing the activity of PPAR-α with compounds such as fibrates in patients may serve a further metabolic-protective role.
In conclusion, our findings disclose a previously unknown role for Ppar-α in cognitive function in mice. In addition to highlighting a neurological phenotype resulting from the loss of function of Ppar-α, our findings also suggest that this receptor may represent a target for the pharmacological amelioration of neurological conditions associated with behavioral perseveration/repetition. This is a particularly attractive prospect given that naturally occurring and synthetic PPAR-α agonists are currently used in clinical practice.”
Recent research has revealed that metabolic syndrome may be linked to sensory gating deficit in patients with schizophrenia and that the relationship between neurocognitive function and sensory gating deficits could be affected by the metabolic status of the patients [1]. Similarly, medical treatment of certain components of the metabolic syndrome could affect cognitive performance in patients with schizophrenia [2]. Weinstein et al. [3] recently found that hyperglycemia is associated with subtle brain injury and impaired attention and memory even in young adults, indicating that brain injury is an early manifestation of impaired glucose metabolism. Labouesse et al. [4] found that chronic consumption of a high-fat diet impairs sensorimotor gating in mice and this impairment was related to neural circuitry abnormalities, in particular to the striatal dopaminergic circuit: “It has been suggested that metabolic syndrome could affect the integrity of striatal dopaminergic circuits through the effect of metabolic circulating factors such as glucose, insulin or leptin”
Dietary interventions?
Peroxisome proliferator-activated receptors (PPARs) are transcription factors that belong to the superfamily of nuclear hormone receptors and regulate the expression of several genes involved in metabolic processes that are potentially linked to the development of some diseases such as hyperlipidemia, diabetes, and obesity. One type of PPAR, PPAR-α, is a transcription factor that regulates the metabolism of lipids, carbohydrates, and amino acids and is activated by ligands such as polyunsaturated fatty acids and drugs used to treat dyslipidemias. PPAR-α acts as a key nutritional and environmental sensor for metabolic adaptation [5]
Natural ligands such as PUFAs are provided by the diet (linoleic, α-linolenic, γ-linolenic, and arachidonic acids) and bind to PPAR-α at physiologic concentrations
The beneficial effects of fish oil are thought to be, in part, mediated by activation of the nuclear receptor PPAR-α by omega-3 polyunsaturated fatty acids and the resulting upregulation of lipid catabolism [6]
It is well-known that dietary PUFAs have effects on diverse biological processes such as insulin action, cardiovascular function, neural development, and immune function, some of them mediated via PPARα.
Other natural compounds such as polyphenols have been described as ligands of PPAR-α: resveratrol, a natural polyphenol found in grapes, peanuts, and berries, and some of its derivatives and analogs, activate PPAR-α, resulting in brain protection against stroke. Genistein, another polyphenol that is the main soy isoflavone, induced the expression of PPAR-α at both messenger RNA (mRNA) and protein levels and enhanced expression of genes involved in fatty acid catabolism through activation of PPAR-α. Additional PPAR-α ligands from diet with hypolipidemic activity have been reported, such as the natural carotenoid abundant in seafood, astaxanthin, and the active compound extracted from the tomato, 9-oxo-10(E),12(E)-octadecadienoic acid. It has been demonstrated that phytanic acid, a branched-chain fatty acid generated from phytol present in dairy products, is also a natural ligand of PPAR-α.
Linalool is another orally active PPAR-α agonist [7]
Intriguingly, PPAR-α activation may stimulate allopregnanolone synthesis [8]
A recent study [9] found that autistic children exhibit decreased levels of essential fatty acids in red blood cells and increased levels of PUFA-derived metabolites such as prostaglandin E2.
Metformin was the most extensively studied drug in regard to body weight, the mean difference amounting to -3.17 kg (95% CI: -4.44 to -1.90 kg) compared to placebo.
Topiramate, sibutramine, aripiprazole, and reboxetine were also more effective than placebo.
Metformin and rosiglitazone improved insulin resistance, while aripiprazole, metformin, and sibutramine decreased blood lipids.
“…literature supports the use of concomitant metformin as first choice among pharmacological interventions to counteract antipsychotic-induced weight gain and other metabolic adversities in schizophrenia.”
“Metformin could be considered an adjunctive therapy with clozapine to prevent metabolic syndrome in schizophrenic patients”
On the contrary, a recent systematic review and meta-analysis of agents for reducing olanzapine and clozapine-induced weight gain in schizophrenia concluded: “topiramate and aripiprazole are more efficacious than other medications in regard to weight reduction and less burden of critical adverse effects as well as being beneficial for clinical improvement.”
In clozapine treated patients:
“Aripiprazole, fluvoxamine, metformin, and topiramate appear to be beneficial; however, available data are limited to between one and three randomized controlled trials per intervention. Orlistat shows beneficial effects, but in males only. Behavioral and nutritional interventions also show modest effects on decreasing clozapine-associated weight gain, although only a small number of such studies exist.” [1]
Use of melatonin is a promising strategy:
“Our results show that melatonin is effective in attenuating SGAs’ adverse metabolic effects, particularly in bipolar disorder. The clinical findings allow us to propose that SGAs may disturb a centrally mediated metabolic balance that causes adverse metabolic effects and that nightly administration of melatonin helps to restore. Melatonin could become a safe and cost-effective therapeutic option to attenuate or prevent SGA metabolic effects.” [2]
“…in patients treated with olanzapine, short-term melatonin treatment attenuates weight gain, abdominal obesity, and hypertriglyceridemia. It might also provide additional benefit for treatment of psychosis.” [3]
Melatonin is appropriate to consider for any patient who will be started on a psychotropic drug that is potentially associated with weight gain or other adverse metabolic effects [link]
Obesity as part of metabolic syndrome is a major lifestyle disorder throughout the world. Current drug treatments for obesity produce small and usually unsustainable decreases in body weight with the risk of major adverse effects. Surgery has been the only treatment producing successful long-term weight loss. As a different but complementary approach, lifestyle modification including the use of functional foods could produce a reliable decrease in obesity with decreased comorbidities. Functional foods may include fruits such as berries, vegetables, fibre-enriched grains and beverages such as tea and coffee. Although health improvements continue to be reported for these functional foods in rodent studies, further evidence showing the translation of these results into humans is required. Thus, the concept that these fruits and vegetables will act as functional foods in humans to reduce obesity and thereby improve health remains intuitive and possible rather than proven.
Vitamin D deficiency exacerbates atypical antipsychotic-induced metabolic side effects in rats [8] and vitamin D supplementation may be promising in the prevention and treatment of metabolic disorders caused by antipsychotic medications.
Dehydroepiandrosterone (DHEA) supplementation “results in stabilization of BMI, waist circumference and fasting glycaemia values in schizophrenic patients treated with olanzapine” [8]
It has recently shown that the microbiota plays a critical role in olanzapine-induced weight gain in rats (Davey et al., 2013 and Davey et al., 2012) which has been confirmed in germ-free mice study (Morgan et al., 2014) [9].
Managing cardiovascular disease risk in patients treated with antipsychotics: a multidisciplinary approach.
My weight loss journey started with the addition of 10mg aripiprazole per day to clozapine (300mg) and venlafaxine (375mg). Aripiprazole augmentation of clozapine has been demonstrated to have beneficial effects on weight [10].
In addition, morning and lunch meals were replaced with a 30g high protein/no carbohydrate meal (Whey Protein Isolate, mixed in water)
I increased my daily exercise to 1 x 45min brisk walk in the morning and a 20min walk later in the day.
I managed to lose ~25kg and have reached a healthy BMI
A systematic review found:
“Psychiatric symptoms were significantly reduced by interventions using around 90 min of moderate-to-vigorous exercise per week (standardized mean difference: 0.72, 95% confidence interval -1.14 to -0.29). This amount of exercise was also reported to significantly improve functioning, co-morbid disorders and neurocognition.” [11]
To conclude:
“The management of weight gain and obesity in patients with schizophrenia centers on behavioural interventions using caloric intake reduction, dietary restructuring, and moderate-intensity physical activity. The decision to switch antipsychotics to lower-liability medications should be individualized, and metformin may be considered for adjunctive therapy, given its favorable risk-benefit profile.” [12]
Recent studies indicate that individuals with schizophrenia have evidence of immune activation that may contribute to disease pathogenesis. The source of this immune activation has not been identified but is likely to be related to both genetic and environmental components. Recently it has become apparent that the composition of microbes on mucosal surfaces, termed the microbiome, represents an important modulator of the immune response in humans and in experimental animals. The microbiome has been linked to the generation of an aberrant immune response and alsobeen shown to modulate brain development and behavior in animal model systems. We employed high throughput sequencing to characterize the complete oro-pharyngeal microbiome of 41 individuals with schizophrenia and 32 controls without a psychiatric disorder. We also examined the role of probiotics in modulating the microbiome.Interim analysis indicates that there are large differences between case and control individuals in terms of bacterial, viral, and fungal composition. Individuals with schizophrenia had increased levels of lactic acid bacteria including Lactobacillus casei, Lactobacillus salivarias, Lactobacillus lactis, and Streptococcus thermophilius as well as several other species of streptococci including S mitis and S mutans. Several of these bacteria have been associated with altered Th2 immune responses, an immunological change also noted in schizophrenia. On the other hand individuals with schizophrenia had decreased levels of many non-pathogenic bacteria such as strains of Neisseria, Haemophilus, Prochlorococcus, and Shwanella. Within the group of individuals with schizophrenia, altered levels of microorganisms were associated with an increased prevalence of the deficit syndrome as well as increased levels of intestinal immune activation as indicated by antibodies to food and intestinal antigens. In terms of fungi, individuals with schizophrenia had higher levels of pathogenic yeasts such as Candida glabrata and Candida tropicalis, but lower levels of the relatively less pathogenic Candida albicans. We also characterized a number of known human viruses such as Herpesviruses and Papillomaviruses, as well as bacteriophages and novel viruses. The microbiome was significantly altered by probiotic therapy, with a tendency towards normalization following treatment. Furthermore, many of the species which are increased in the oral microbiome of individuals with schizophrenia, such as streptococci, are modifiable by the administration of antibiotic medications. These studies indicate that the oral microbiome is altered in individuals with schizophrenia and that the microbiome is a potential target for novel therapies.
This schematic represents the putative modulatory capability of diet, especially dietary extremes, represented by the Mediterranean-style diet, rich in components which support the gut microbiota, and the Western-style diet, with high fat and animal protein which mediate a detrimental impact on the gut microbiota and their metabolic output, on the gut:brain axis. Key intermediaries in this communication highway are the metabolites produced/regulated by the gut microbiota [e.g., serotonin/5-hydroxytryptamine (5-HT), gamma-amino butyric acid (GABA), glutamate (Glu), Phenylalanine (Phe), Tryptophan (Trp), tyrosine (Tyr), Carnosine, short-chain fatty acids (SCFA), Threonine (Thr), Alanine (Ala), Lysine (Lys), Glycine (Gly), Serine (Ser), aspartic acid (Asp), Ammonia, gut hormone/incretin production], microbial regulation of barrier integrity (both within the gut and at the blood brain barrier, BBB), and nutrient absorption at the mucosal surface, which is itself controlled in part by gut bacteria. These activities have the potential to impact on neurotransmission, inflammation, redox potential and epigenetic regulation of developmental processes, as well as neurological function, probably through the vagus nerve or in certain cases, may mediate direct effects on the brain [Source]Loss of contact with “old friends” and increased inflammatory conditions in the modern world. In populations adequately exposed to old friends, such as many societies in the developing world, priming of regulatory T cells (Treg) is sufficient to maintain an appropriate balance of Treg to effector T cells (Teff), with the result that inappropriate inflammation is generally constrained. When contact with the old friends is disrupted as a result of modern cultural practices (e.g. sanitation, water and food treatment, modern medicines), priming of Treg is inadequate, with the result that the ratio of Treg to Teff is low. In this situation, the population as a whole is at risk for a variety of syndromes attributable to inadequate termination of inflammatory responses to any of a range of environmental stimuli. Consistent with this, although the prevalence of serious infections is significantly reduced in the industrialized world, rates of chronic inflammatory conditions (e.g. autoimmune diseases, allergies, asthma, and cardiovascular disease) have been shown in many studies to be much higher than in the developing world. Some individuals have a genetic background and/or immunological history that places them at risk for disorders, such as multiple sclerosis (MS), inflammatory bowel disease (IBD) and type 1 diabetes mellitus (DM), characterized by overactive/uncontrolled T helper (Th) type 1 and/or Th17 activity. In other individuals, Th2 responses are more liable to inadequate control, resulting in asthma and allergic disorders. While not developing gross immune-related pathology, a further group of individuals with inadequate termination of either Th1 or Th2 inflammatory responses is susceptible to CNS effects of cytokines, including major depressive disorder (MDD). It should be noted, however, that conditions associated with Th1/Th17 and Th2 dysregulation are highly comorbid with MDD. IL-10: interleukin-10; TGF-β: transforming growth factor-β [source]The ‘‘psychomicrobiotic’’: Targeting microbiota in major psychiatric disorders: Asystematic review.:
The term ‘‘dysbiosis’’ refers to situations where microbial composition and functions are shifted from their normal beneficial state to another that is deleterious to the host’s health. The microbiota dysbiosis may negatively impact CNS functioning through various intertwined pathways that collectively form the ‘‘brain-gut axis’’. These pathways can be described as follows:
modification of intestinal permeability that allows entry of endotoxins in the systemic blood flow. The lipopolysaccharide (LPS) is a potent pro-inflammatory endotoxin of the cell walls of gram-negative bacteria that can alter neuronal activity in the limbic system (e.g. increased amygdala activity) and also activate microglia, thus potentially contributing to chronic inflammation in the host’s CNS. Leakage of LPS from the intestine might be a trigger for peripheral inflammatory responses that lead to de novo production of cytokines in the brain. Improving the epithelial barrier may reduce traffic of bacteria and their byproducts and hence be a way to stop the inflammatory response;
neuropeptides synthesis;
modulation of local and peripheral inflammation. The gut microbiota regulates the development of lymphoid structures and modulates the differentiation of immune cell subsets thus maintaining homeostatic interactions between the host and the gut microbiota. Certain specific bacteria, including members of the Enterobacteriaceae family, appear to be better equipped for survival under the prevailing conditions in the inflamed gut than are the anaerobic commensals dominant in healthy individuals. Given the postulated anti-inflammatory effects of butyrate, it is possible that depletion in butyrate producing bacteria in dysbiosis may contribute to inflammation. Major depressive disorder, bipolar disorder and schizophrenia are associated with a dysregulation of immune responses as reflected by the observed abnormal profiles of circulating pro- and anti-inflammatory cytokines in affected subjects;
decrease in absorption of beneficial and essential nutrients (e.g. essential amino acids, vitamins, polyunsaturated fatty acids), increase of deleterious compound synthesis (ammonia, phenols, indoles, sulphide and amines), reduction of the antioxidant status and increase in lipid peroxidation, increase of carbohydrate malabsorption;
activation/deactivation of the autonomic nervous system that is directly connected to the nucleus tractus solitarius. This nucleus in turn issues direct noradrenergic ascending projections to brain areas involved in anxiety regulation (namely amygdala, basal forebrain cholinergic system and cortex);
modulation of brain-derived neurotrophic factor;
increase of small intestinal bacterial overgrowth and/or gastric/instestinal pathogens (e.g. Helicobacter pylori)
Schizophrenia and bipolar disorders
Severance et al. recently measured serological surrogate markers of bacterial translocation (soluble CD14 (sCD14) and lipopolysaccharide binding protein (LBP)) in bipolar subjects (n = 38) and schizophrenia subjects (n = 141) compared to controls. sCD14 seropositivity conferred a 3.1-fold increased odds of association with schizophrenia (OR = 3.09, P < 0.0001) compared to controls. Case–control differences in sCD14 were not matched by LBP. Quantitative levels of LBP, but not sCD14, correlated with BMI in schizophrenia (r2 = 0.21, P < 0.0001). sCD14 and LBP also exhibited some congruency in schizophrenia with both significantly correlated with CRP (P < 0.0001). Antipsychotic treatment generally did not impact sCD14 or LBP levels except for significant correlations, especially sCD14, with gluten antibodies in antipsychotic-naıve schizophrenia (r2 = 0.27, P < 0.0001). In bipolar disorder, sCD14 levels were significantly correlated with anti-tissue transglutaminase IgG (r2 = 0.37, P < 0.001). The authors concluded that these bacterial translocation markers produced discordant patterns of activity that may reflect an imbalanced, activated innate immune state. Whereas both markers may upregulate following systemic exposure to Gram-negative bacteria, autoimmunity, non-lipopolysaccharide-based monocyte activation and metabolic dysfunction may also contribute to the observed marker profiles.
Conclusion
Research on the role of the human intestinal microbiota in the genesis and/or maintenance of psychiatric disorders is in its infancy but appears as one of the most promising avenues of research in psychiatry. While rodent models suggest that the microbiota plays a fundamental role in the genesis of the HPA axis, the serotoninergic system and the immuno-inflammatory system, and that the microbiota can affect the CNS through multiple pathways, few studies have been carried out on humans. Today, autism is the psychiatric disorder in which the role of the microbiota has been the most studied. Some therapeutic opportunities targeting potential microbiota dysbiosis have already been explored such as probiotic administration or diet modifications, with inconsistent results. Further studies are warranted to determine which patients may benefit from microbiota-oriented therapies.
“The findings from clinical studies demonstrate an upregulated immune and inflammatory status in patients with schizophrenia (Song et al., 2013) and a correlation between the level of inflammatory markers and severity of clinical symptoms (Hope et al., 2013). It has been suggested that the uncontrolled neuroinflammation by proinflammatory cytokines is involved in the pathogenesis of schizophrenia (Dennison et al., 2012 and Nemani et al., 2014). Chronic macrophage activation and secretion of interleukin-2 and interleukin-2 receptors has been proposed as the basic biological mechanism of schizophrenia in earlier papers (Smith, 1991 and Smith, 1992). For example, the protozoa Toxoplasma gondii is known to cause major perturbation to the gut microbiota and is a recognized environmental risk factor for schizophrenia ( Bhadra et al., 2013 and Molloy et al., 2013). More recently a chlorovirus (family Phycodnaviridae) has been identified in humans that affects cognitive function relevant to schizophrenia in animal models ( Yolken et al., 2014).
NMDA receptor hypofunction is believed to be central to the pathophysiology of schizophrenia, as NMDA receptor antagonists produce schizophrenia-like symptoms while agents that enhance NMDA receptor function reduce negative symptoms and improve cognition (Coyle, 2012). Variation in BDNF expression is believed to play a role in the molecular mechanism underlying cognitive dysfunction in schizophrenia (Nieto, Kukuljan, & Silva, 2013). Given that normal development of the microbiota is necessary to stimulate brain plasticity through the appropriate expression of BDNF and NMDA receptors, it is possible that altered microbiota may contribute to the NMDA receptor dysfunction seen in schizophrenia (Dinan et al., 2014 and Nemani et al., 2015). In animal model of schizophrenia (chronic NMDA antagonist treatment), it has been shown that the gut microbiota profile correlated to memory performance, suggesting an influence of the microbiota on cognition in the model, which was supported by restoration of cognition through oral ampicillin administration (Pyndt Jorgensen et al., 2014).
Evidence showing possible microbiota alteration in schizophrenia includes structural damage to the GI tract, a heightened immune response to infectious pathogens and food antigens, and known differences in the microbiome in other neuropsychiatric disorders (Nemani et al., 2014). Further investigation into the microbiota and how the gut–brain axis may mediate the link between neuropsychiatric disease and the immune system is needed.
It is also worth noting that one of the most important side effects of treatments for schizophrenia is weight gain and metabolic syndrome. We have recently shown that the microbiota plays a critical role in olanzapine-induced weight gain in rats (Davey et al., 2013 and Davey et al., 2012) which has been confirmed in germ-free mice study (Morgan et al., 2014)”
“Considering the gut’s multifaceted capacity to communicate with the CNS, it is plausible that the gut and its components are playing a crucial role in resultant mood and behaviors. Some therapeutic opportunities targeting potential microbiota dysbiosis have already been explored such as probiotic administration, fecal transplantation, or diet modifications, with inconsistent results. Exciting evidence from animal studies has provided the rationale to warrant further exploration in humans, both in health and disease. Future research should focus on delineating the relative contributions of immune, neural, and endocrine pathways through which the gut microbiota communicates with the brain. A better understanding of these pathways will improve our knowledge about the role of gut microbiota play in a range of neurological disorders, including neuropsychiatric diseases”
“The composition of the microbiome in schizophrenia has yet to be investigated, but there are several therapeutic interventions on the horizon which have less potential for toxicity than traditional treatment and may exert their influence through altering the microbiota.
Dietary interventions
Dietary changes affect both the composition and function of the gut microbial communities, which in turn can alter the innate and adaptive immune system (Vieira et al., 2014). Seven clinical trials have been published that examine the effects of a gluten-free diet on schizophrenia symptoms (Kalaydjian et al., 2006). These early studies included schizophrenia patients not tested for antibodies and had variable results. The resolution of schizophrenia symptoms after initiation of a gluten-free diet has been described in case reports (De Santis et al., 1997, Jackson et al., 2012, Jansson et al., 1984 and Kraft and Westman, 2009), and there are at least two current trials underway that are investigating the effects of gluten removal on schizophrenia symptoms in AGA-positive individuals. Data from these trials and future studies are needed to determine the impact of gluten-free diet on the subpopulation of people with schizophrenia who are sensitive to gluten.
While a study conducted in 1973 showed earlier discharge from the hospital in relapsed schizophrenia patients after a cereal-free, milk-free diet (Dohan and Grasberger, 1973), the impact of a casein-free diet in isolation on schizophrenia has yet to be investigated.
Antimicrobials
Alteration of the gut commensal microbiota with antibiotics has been shown to modify the susceptibility to autoimmune demyelinating processes of the central nervous system, such as that seen in multiple sclerosis (Ochoa-Repáraz et al., 2009). The protection afforded antimicrobials is associated with a shift in the immune response from Th1/Th17 toward anti-inflammatory Th2-type responses (Ochoa-Repáraz et al., 2010). Minocycline, a second generation tetracycline, is currently under investigation as an adjunct treatment in schizophrenia and there has been some early evidence of its efficacy in treating negative symptoms (Jhamnani et al., 2013, Khodaie-Ardakani et al., 2014 and Liu et al., 2014) and treatment-resistant schizophrenia (Qurashi et al., 2014). While tetracycline is believed to have a neuroprotective effect due to its anti-inflammatory action and ability to enhance glutamate neurotransmission (Liu et al., 2014), its immunomodulatory properties as mediated by gut microbiota have yet to be investigated and may play a role.
Probiotics
There is promising clinical evidence to support a role of probiotic interventions in reducing anxiety, decreasing the stress response, and improving mood in both animals (Arseneault-Bréard et al., 2012, Bravo et al., 2011 and Messaoudi et al., 2011) and humans (Logan and Katzman, 2005, Messaoudi et al., 2011 and Rao et al., 2009). The mechanism responsible for these effects is not known, but it has been hypothesized that it may be related to a reduction in the effects of pro-inflammatory cytokines as well as modification in nutritional status through direct effects on B vitamins, omega-3 fatty acids, and minerals (Cryan and O’Mahony, 2011 and Logan and Katzman, 2005). Probiotics have also been found to improve lactose digestion and potentially reduce the interference that high intestinal lactose concentration may have with serotonin availability through l-tryptophan metabolism (Ledochowski et al., 1998). As patients with schizophrenia often suffer from an increased stress response, compromised nutritional status, increased inflammatory status, and lactose sensitivity, probiotic interventions have promising therapeutic potential.
Probiotic interventions have also been shown to improve obesity-associated dyslipidemia and insulin resistance in animal models (Yu et al., 2013) and reduce weight gain and fat mass (Ji et al., 2012). Oral administration of Lactobacillus gasseri SBT2055 in healthy overweight humans has been found to reduce abdominal visceral and subcutaneous fat ( Kadooka et al., 2010). The anti-obesity effects of probiotics may have therapeutic potential for patients with schizophrenia given their higher risk metabolic profile. A recent study in rats reported that co-administration of antibiotics attenuated olanzapine-induced alteration in microbiota, as well as olanzapine-induced metabolic disturbances including weight gain, visceral fat deposition, elevated plasma free fatty acids, and macrophage infiltration of adipose tissue ( Davey et al., 2013). These findings suggest that microbiota might be a novel treatment target for metabolic comorbidity in patients with schizophrenia.
Fecal microbiota transplantation
While probiotics and antibiotics may be the best known and commercially available options to treat gastrointestinal dysbiosis, fecal microbiota transplantation is an old procedure that has been rediscovered as a cutting-edge option for the restoration of gut microbiota. There has been growing interest in the use of fecal microbiota for the treatment of patients with chronic gastrointestinal infections and inflammatory bowel diseases. Lately, there has also been interest in its therapeutic potential for extraintestinal conditions including cardiometabolic disease and autoimmune disorders (Smits et al., 2013). A better understanding of the microbiome in schizophrenia needs to be gained before the therapeutic potential of fecal transplantation can be explored.”
Evidence that patients with schizophrenia may have altered microbiota:
1. Changes in the microbiota seen in neuropsychiatric disorders
2. Structural damage to the GI tract in schizophrenia
3. Abnormal response to infectious pathogens in schizophrenia
4. Abnormal response to food antigens in schizophrenia
5. Sensitivity to gluten and bovine casein
“Several risk factors for the development of schizophrenia can be linked through a common pathway in the intestinal tract. A growing body of research emphasizes the role of the microbiota in regulating brain development, immune function, and metabolism but the composition of the microbiome in individuals with schizophrenia has yet to be investigated. Evidence that indicates possible microbiota alteration in schizophrenia includes structural damage to the GI tract, a heightened immune response to infectious pathogens and food antigens, and known differences in the microbiome in other neuropsychiatric disorders. A significant subgroup of patients may benefit from the initiation of a gluten and casein-free diet, and the therapeutic potential of antimicrobial and probiotic interventions will be elucidated by further research. Further investigation into the microbiome and how the gut may mediate the link between neuropsychiatric disease and the immune system is needed.”
Although peripheral immune system abnormalities have been linked to schizophrenia pathophysiology, standard antipsychotic drugs show limited immunological effects. Thus, more effective treatment approaches are required. Probiotics are microorganisms that modulate the immune response of the host and, therefore, may be beneficial to schizophrenia patients. The aim of this study was to examine the possible immunomodulatory effects of probiotic supplementation in chronic schizophrenia patients. The concentrations of 47 immune-related serum proteins were measured using multiplexed immunoassays in samples collected from patients before and after 14 weeks of adjuvant treatment with probiotics (Lactobacillus rhamnosus strain GG and Bifidobacterium animalis subsp. lactis strain Bb12; n = 31) or placebo (n = 27). Probiotic add-on treatment significantly reduced levels of von Willebrand factor (vWF) and increased levels of monocyte chemotactic protein-1 (MCP-1), brain-derived neurotrophic factor (BDNF), RANTES, and macrophage inflammatory protein-1 beta (MIP-1) beta with borderline significance (P ≤ 0.08). In silico pathway analysis revealed that probiotic-induced alterations are related to regulation of immune and intestinal epithelial cells through the IL-17 family of cytokines. We hypothesize that supplementation of probiotics to schizophrenia patients may improve control of gastrointestinal leakage.
The gut microbiome has been shown to regulate the development and functions of the enteric and central nervous systems. Its involvement in the regulation of behavior has attracted particular attention because of its potential translational importance in clinical disorders, however little is known about the pathways involved. We previously have demonstrated that administration of Lactobacillus rhamnosus (JB-1) to healthy male BALB/c mice, promotes consistent changes in GABA-A and -B receptor sub-types in specific brain regions, accompanied by reductions in anxiety and depression-related behaviors. In the present study, using magnetic resonance spectroscopy (MRS), we quantitatively assessed two clinically validated biomarkers of brain activity and function, glutamate+glutamine (Glx) and total N-acetyl aspartate+N-acetylaspartylglutamic acid (tNAA), as well as GABA, the chief brain inhibitory neurotransmitter. Mice received 10(9) JB-1 per day for 28days and were subjected to MRS weekly and again 4weeks after cessation of treatment to ascertain temporal changes in these neurometabolites. Baseline concentrations for Glx, tNAA and GABA were equal to 10.4±0.3mM, 8.7±0.1mM, and 1.2±0.1mM, respectively. Delayed increases were first seen for Glx (~10%) and NAA (~37%) at 2weeks which persisted only to the end of treatment. However, Glx was still elevated 4weeks after treatment had ceased. Significantly elevated GABA (~25%) was only seen at 4weeks. These results suggest specific metabolic pathways in our pursuit of mechanisms of action of psychoactive bacteria. They also offer through application of standard clinical neurodiagnostic techniques, translational opportunities to assess biomarkers accompanying behavioral changes induced by alterations in the gut microbiome.
Ingestion of specific probiotics, namely “psychobiotics”, produces psychotropic effects on behavior and affects the hypothalamic-pituitary-adrenal axis and neurochemicals in the brain. We examined the psychotropic effects of a potential psychobiotic bacterium, Lactobacillus plantarum strain PS128 (PS128), on mice subjected to early life stress (ELS) and on naïve adult mice. Behavioral tests revealed that chronic ingestion of PS128 increased the locomotor activities in both ELS and naïve adult mice in the open field test. In the elevated plus maze, PS128 significantly reduced the anxiety-like behaviors in naïve adult mice but not in the ELS mice; whereas the depression-like behaviors were reduced in ELS mice but not in naïve mice in forced swimming test and sucrose preference test. PS128 administration also reduced ELS-induced elevation of serum corticosterone under both basal and stressed states but had no effect on naïve mice. In addition, PS128 reduced inflammatory cytokine levels and increased anti-inflammatory cytokine level in the serum of ELS mice. Furthermore, the dopamine level in the prefrontal cortex (PFC) was significantly increased in PS128 treated ELS and naïve adult mice whereas serotonin (5-HT) level was increased only in the naïve adult mice. These results suggest that chronic ingestion of PS128 could ameliorate anxiety- and depression-like behaviors and modulate neurochemicals related to affective disorders. Thus PS128 shows psychotropic properties and has great potential for improving stress-related symptoms
Subchronic phencyclidine (subPCP) treatment induces schizophrenic-like behavior in rodents, including cognitive deficits and increased locomotor sensitivity towards acute administration of PCP. Evidence is accumulating that the gut microbiota (GM) influences behavior through modulation of the microbiota–gut–brain axis, and hence, part of the variation within this animal model may derive from variation in the GM. The aims of this study was to investigate first, the duration of subPCP-induced cognitive impairment in the novel object recognition test, and second, the possible effect of subchronic PCP-treatment on the GM, and the association between the GM and the behavioral parameters. The association was further investigated by antibiotic reduction of the GM. Male Lister Hooded rats were dosed twice daily i.p. with either 5 mg/kg PCP or sterile isotonic saline for seven days followed by a seven-day washout period. Rats were tested in the novel object recognition and the locomotor activity assays immediately after, three weeks after, or six weeks after washout, and the fecal GM was analyzed by high throughput sequencing. Antibiotic- and control-treated rats were tested in the same manner following washout. In conclusion, subPCP-treatment impaired novel object recognition up to three weeks after washout, whereas locomotor sensitivity was increased for at least six weeks after washout. Differences in the core gut microbiome immediately after washout suggested subPCP treatment to alter the GM. GM profiles correlated to memory performance. Administration of ampicillin abolished the subPCP-induced memory deficit. It thus seems reasonable to speculate that the GM influences memory performance, contributing to variation within the model.
“The core gut microbiome of subPCP rats differed significantly from that of vehicle-treated rats immediately after washout, suggesting a PCP-induced stress-modulation of the GM. However, this cannot be fully concluded based on the setup of the study, where rats were co-housed. Single housing was not preferred, as single housing previously has been shown to impact rodent memory performance. Thus, the core gut microbiome was compared in an attempt to overcome a possible effect of the cage-factor on the GM. By this approach only bacteria which were present in at least 50% of the samples were included in the analysis, thereby eliminating the effect of bacteria only being present in a single cage. No difference was seen between treatment groups when assessed at three weeks after washout, suggesting stabilization within three weeks after washout. The GM of SubPCP rats tended to contain increased abundance of the genera Roseburia, Dorea, and Odoribacter immediately after washout compared to vehicle-treated rats. Roseburia spp. and Dorea spp. have previously been shown to be affected by stress induced by social defeat in mice, where time between the stress factor and fecal sampling seemed to be an important factor affecting the abundance of especially Roseburia spp. Moreover, we have also reported an increase in Odoribacter as a consequence of stress exposure in mice. The present observations are in line with the previous ones, thus, supporting the hypothesis that subPCP administration induces stress-related changes in the GM. However, the relevance and the influence of these bacteria on behavior are not clear, and consequently, further investigations into this should be conducted to clarify the relevance of the observations. Three weeks after washout the GM of SubPCP rats tended to contain increased abundance of an unclassified genus from the S24-7 family compared to vehicle-treated rats. A previous study found increased abundance of an unclassified genus of this family to be associated with improved spatial memory performance. This is in contradiction to the present finding, where SubPCP rats display decreased memory performance. However, it can be speculated whether the tendency towards an increase in abundance of this genus reflects the initial phase of a rise in abundance, contributing in restoring memory formation, and so, studies addressing this would be interesting to perform.
The GM profiles correlated significantly to memory performance immediately after washout, and showed a tendency towards the same three weeks after washout, suggesting an additive influence from the GM on the behavior observed in the model. Based on this, it is proposed that variation within the GM contributes to the variation observed in memory performance within the model. However, additional studies addressing this association need to be performed for further conclusion. Therefore, the second study was set up, in which the GM was substantially reduced by oral ampicillin-administration throughout the whole study period, in order to investigate whether a modulation of the GM would affect behavior in the model.
Administration of ampicillin to SubPCP rats restored the memory performance, but did not affect locomotor activity. This observation supports the correlation between the GM and memory formation found in the first study, suggesting an association between the GM and memory performance in the model, in which the commensal GM seems to be important for induction of the PCP-induced deficits. Some β-lactam antibiotics, to which ampicillin belongs, have been demonstrated to be able to increase expression of the glutamate transporter GLT-1 protein in the central synapses. Upregulation of GLT-1 reduces synaptic glutamate, thus contributing to decreased activation of the NMDA receptor, which enhances the effect of the NMDA receptor antagonist PCP. The effect of this does not seem to be of importance in the present study, in which the negative effect of PCP on cognition was abolished in ampicillin-treated rats, whereas the locomotor activity was not affected in either treatment groups.
Mimicking the NMDA receptor hypofunction hypothesis, administration of the NMDA receptor antagonist PCP affects the inhibitory GABA interneuron signaling, which is thought to be involved in the pathogenesis of schizophrenia. Reduced expression of hippocampal parvalbumin containing GABA neurons has been demonstrated six weeks after subPCP treatment. Habitants of the gut are able to affect levels of central neurotransmitters and receptors, as reviewed by Collins. As an example, administration of the commensal Lactobacillus rhamnosus has been shown to influence central GABA receptor expression in mice, which coincided with reduced stress-induced corticosterone levels and relief of depression- and anxiety-like behavior, where vagotomy inhibited the effect on brain and behavior. It can be speculated that altering the GM through antibiotic treatment in the present study may influence the level of specific GABA receptors, secondly impacting behavior. Another factor involved in brain plasticity and cognition is brain-derived neurotrophic factor (BDNF). Several studies demonstrate the ability of the GM to modulate central levels of BDNF. It can be speculated whether this neurotrophic factor is involved in restoration of the subPCP-induced brain neurochemical changes. Thus, it can be suggested that an ampicillin-induced alteration of the GM may affect cognition of SubPCP rats through modulation of BDNF levels in the present study. M. Gareau et al. demonstrated reduced levels of hippocampal BDNF and impaired memory in the NOR test of germ-free mice when compared to SPF mice, which illustrates the impact of the presence of the GM on brain development and memory formation. Demonstrating the impact of the composition of the GM, memory deficits in the NOR were abolished by probiotic treatment of stress exposed SPF mice. Furthermore, Bercik et al. found oral antibiotic treatment of SPF mice to decrease anxiety behavior and increase central BDNF levels. Neither intraperitoneal antibiotic treatment of SPF mice nor oral antibiotic treatment of germ-free mice had an effect on behavior, thus, demonstrating the impact of the GM on behavior and the brain. Vagotomy or chemical sympathectomy did not affect the impact of the GM, and neither was local intestinal inflammation found to be involved, and consequently, they proposed GM metabolites to be involved in the communication between the gut and the brain. Unfortunately, the effect of intraperitoneal antibiotic administration on central BDNF levels was not addressed. The studies support the results of the present study demonstrating oral antibiotic modulation of the GM to relieve subPCP-induced cognitive deficits, suggesting influence from the gut commensals to be through modulation of brain receptors, neurotransmitters, and BDNF. Hence, it seems plausible to speculate that the GM affects behavior in the subchronic PCP-induced animal model of schizophrenia. However, future studies should clarify whether an unknown, direct central effect of ampicillin is involved in restoring cognition before final conclusions on the present observations can be drawn.”
“GM analysis suggested the gut microbiome to be affected by subchronic PCP-treatment immediately after washout, with restoration within three weeks. The GM profile correlated to memory performance in the NOR, suggesting an influence of the GM on cognition in the model, which was supported by restoration of cognition in SubPCP rats through oral ampicillin administration. Further studies are needed to conclude more on this. In perspective, if the GM impacts memory performance, as the study suggests, this knowledge may be used to refine the animal model.”
Psychiatry is at an important juncture, with the current pharmacologically focused model having achieved modest benefits in addressing the burden of poor mental health worldwide. Although the determinants of mental health are complex, the emerging and compelling evidence for nutrition as a crucial factor in the high prevalence and incidence of mental disorders suggests that diet is as important to psychiatry as it is to cardiology, endocrinology, and gastroenterology. Evidence is steadily growing for the relation between dietary quality (and potential nutritional deficiencies) and mental health, and for the select use of nutrient-based supplements to address deficiencies, or as monotherapies or augmentation therapies. We present a viewpoint from an international collaboration of academics (members of the International Society for Nutritional Psychiatry Research), in which we provide a context and overview of the current evidence in this emerging field of research, and discuss the future direction. We advocate recognition of diet and nutrition as central determinants of both physical and mental health.
We live in a transformational moment for understanding the etiology of mental disorders. The previous leap in understanding occurred 60 years ago, which led us to incorporate psychopharmacology into our curricula to address the chemical basis of neurotransmitter function, especially as explained through the then-popular catecholamine hypothesis. The current revolution is broader, consisting of the rapidly accumulating knowledge of how inflammation, microbiome imbalance (gut dysbiosis), oxidative stress, and impaired mitochondrial output affect brain function. Suitable interventions for fighting inflammation, restoring normal gut function, reducing oxidative stress, and improving mitochondrial metabolism incorporate lifestyle variables, including nutrients and probiotics. This article invites readers to stay abreast of this emerging model of the biological basis of mental illness, given that it has particular relevance for those readers interested in alleviating the suffering of individuals with mental disorders. This overview describes the basis for a new field in mental health: nutritional psychiatry/psychology
Pregnenolone has a plethora of pharmacological properties that validate its use in the augmentation of antipsychotics [1, 2,3]
DHEA (also via its sulfate) shows pro-neurogenic, neuroprotective, sigma-1 receptor agonism, anti-glucocorticoid, NMDAR enhancing, catecholaminergic, antioxidant, anti-inflammatory and immunomodulating activity amongst other promising activities, similarly implicating it as a potential therapy for negative, depressive and anxiety symptoms in schizophrenia [4, 5, 6, 7]
Omega-3 fatty acids initially demonstrated beneficial effects. More recent studies attempting to prevent the transition to psychosis in at-risk patients have been less encouraging [Update: but notable in another- see: Longer-term outcome in the prevention of psychotic disorders by the Vienna omega-3 study] but animal models are uncovering a broad range of prophylactic and restorative benefits. Widely available and with few side effects, use of omega-3 PUFAs at an anti-inflammatory dose [2.7 grams or more of omega-3 (EPA + DHA)] is personally encouraged as a simple dietary measure.
Omega-3 fatty acids have shown promise as an adjunctive treatment for schizophrenia. However, efficacy across studies has been inconsistent. We conducted a meta-analysis of published controlled studies with the goal of detecting different efficacy profiles at various stages of schizophrenia. An online search was conducted for randomized, double-blind, placebo-controlled clinical trials, and a meta-analysis was conducted. Ten studies met the criteria for inclusion. Among patients in the prodromal phase of schizophrenia, omega-3 supplementation reduced psychotic symptom severity and lowered conversion rates to first-episode psychosis. In patients with first-episode schizophrenia, omega-3 decreased nonpsychotic symptoms, required lower antipsychotic medication dosages, and improved early treatment response rates. Omega-3 had mixed results in patients with stable chronic schizophrenia, with only some patients experiencing significant benefits. Among patients with chronic schizophrenia, use of omega-3 fatty acids both by those experiencing acute exacerbations and those who had discontinued antipsychotic medications resulted in worsening of psychotic symptoms. The data suggest that omega-3 fatty acids may be efficacious in reducing clinical symptoms for patients in the earlier stages of schizophrenia (prodrome and first episode), while producing mixed results for patients in the chronic stages. Based on these results, omega-3 fatty acids would not be recommended for acute exacerbations in patients with chronic schizophrenia nor for relapse prevention after discontinuation of antipsychotics.
PUFAs can modulate many signal transduction mechanisms in neuronal membranes and the synapse. As serotonin (5-HT1 and 5-HT4), beta-adrenergic and dopamine (D1 and D2) receptors are all coupled to the cAMP messenger system, PUFAs can influence them by increasing adenylate cyclase (Murphy, 1985 and Nicolas et al., 1991) and protein kinase A (Speizer et al., 1991) activity. Animal studies, in piglets (de la Presa Owens and Innis, 1999) and in two generations of rats (Zimmer et al., 1999 and Zimmer et al., 2000b) fed n-3 PUFA deficient diets identify many effects on dopaminergic systems, including lower levels of dopamine (de la Presa Owens and Innis, 1999 and Zimmer et al., 2000b), D2 receptors, D2 receptor mRNA and dopaminergic presynaptic vesicles (Zimmer et al., 2000b), and increased breakdown of dopamine (Zimmer et al., 1998), in the prefrontal cortex. Experimental n-3 PUFA deficiency in rat dams shortly after conception also results in offspring with decreased tyrosine hydroxylase (Kuperstein et al., 2008), the rate-limiting enzyme in dopamine synthesis; fewer detectable dopaminergic neurons in the substantia nigra and ventral tegmentum (Ahmad et al., 2008); and elevated postnatal expression of dopamine receptor genes in rat pups (Kuperstein et al., 2005). After two generations of n-3 PUFA deficiency, rats also exhibit higher dopamine levels, D2 receptor mRNA, D2 receptors, and less release and breakdown of dopamine in the nucleus accumbens (Zimmer et al., 2000a). Conversely, two generations of a high-n-3 PUFA diet increases dopamine levels in rat prefrontal cortex by 40% and elevates D2 receptor binding, while lowering monoamine oxidase B activity in prefrontal cortex and D2 receptor binding in striatum (Chalon et al., 1998). PUFA associations with dopamine also have been implicated in clinical depression (Sublette et al., 2014). Less has been reported concerning dietary PUFA effects on serotonin (5-HT), although, compared with normally fed animals, rats with low brain DHA had decreased 5-HT levels and turnover in frontal cortex (nulliparous females) and higher density of hippocampal 5-HT1A receptors (parous dams) (Levant et al., 2008). Also, in 2-month old male rats, stimulated 5-HT release in the hippocampus was lower in rats fed an n-3 PUFA deficient diet for two generations, and the ability of diet alteration to reverse this deficiency decreased over time after parturition (Chalon, 2006a). However, in adult male mice, n-3 PUFA supplementation was effective in reversing 5-HT levels that had declined by 40–65% as a result of unpredictable chronic mild stress (Vancassel et al., 2008). On the other hand, in one study comparing high saturated fat, high n-3 PUFA, and high n-6 PUFA diets, 5-HT2A receptor and 5-HT transporter binding were most strongly affected by the n-6 PUFA diet (Dubois et al., 2006).
PUFAs also can interact with the phosphoinositide signaling pathway by exerting effects on phospholipase C (Irvine et al., 1979) and protein kinase C (McPhail et al., 1984a and McPhail et al., 1984b), both of which are involved in 5-HT2 and alpha-1 adrenergic mediated signal transduction.
Neurotransmitters affect PUFA turnover, as PLA2 is activated by multiple receptor types – dopamine D2 (Vial and Piomelli, 1995), serotonin 5-HT2 (Berg et al., 1996), glutamate (Tence et al., 1995), and muscarinic acetylcholine (Jones et al., 1996) – to liberate fatty acids from the sn-2 position of phospholipids. In turn, PUFAs also regulate the activity, mRNA expression, and protein levels of multiple PLA2 isoforms (Downes and Currie, 1998, Lister et al., 1988 and Rao et al., 2007a).
Fatty acids that are not recycled back into phospholipids can be metabolized through several pathways, e.g. cyclooxygenase (COX)-2 ( O’Banion, 1999) acts on AA, EPA and DHA ( Serhan et al., 2002) to produce prostanoids (prostaglandins [PGE] and thromboxanes) ( Chang and Karin, 2001 and Kozak et al., 2001), while lipoxygenases produce leukotrienes and lipoxins. PGEs occur in 3 families which have different effects through interactions with specific signaling systems: the PGE-2 family transduces signals via a Gs protein, elevating cAMP levels, whereas the PGE-3 family uses a Gi protein, lowering cAMP, and the PGE-1 family acts through a phosphoinositide signaling system ( Smith, 1992). Eicosanoids, 20-carbon n-6 compounds, and docosanoids, 22-carbon n-3 compounds that include resolvins or neuroprotectins, can have opposing effects on signal transduction and inflammatory processes ( Calder, 2006 and Piomelli, 1994).
Release of neurotransmitters from synaptic vesicles by activation of Ca2+/calmodulin-dependent protein kinase is affected by PUFAs (Piomelli et al., 1989), and Ca-ATPase in neuronal membranes is inhibited by DHA and EPA.
Neuroinflammation
The balance between n-6 and n-3 PUFAs thus can have profound effects on neuroinflammation. For example, as n-3 and n-6 LC-PUFAs compete for membrane insertion, an n-3 PUFA-enriched diet increases production of anti-inflammatory docosanoids and decreases the n-6 content of glial cell membranes, resulting in less substrate available for AA-derived eicosanoid synthesis (Calder, 2006). Some examples with clinical relevance include rodent models of metabolic and behavioral responses to traumatic brain injury, in which n-3 PUFA deficiency states worsened post-injury anxiety-like behavior (Agrawal et al., 2014) and sensorimotor impairments (Russell et al., 2013), and resulted in lower levels of anxiolytic neuropeptide Y1 receptor (Agrawal et al., 2014) and mRNA expression of tissue inhibitor of matrix metalloproteinase-1 (Timp1) (Russell et al., 2013). Supplementation with n-3 PUFAs in the diet prior to experimental injury mitigated the usual sequelae of abnormal levels of brain-derived neurotrophic factor (BDNF), synapsin I, and cAMP responsive element-binding protein (CREB) (Wu et al., 2004), as well as axonal injury, apoptosis (Mills et al., 2011), and cognitive impairments (Mills et al., 2011 and Wu et al., 2004). Moreover, in a mouse model, even after experimental brain injury, an inhibitor of fatty acid amide hydrolase (FAAH) reduced breakdown of the PUFA metabolite anandamide, and thereby mitigated fine motor and working memory impairments and anxiety-like behaviors, concomitantly reducing neurodegeneration and amyloid precursor protein, and upregulating stress-responsive growth factors and heat shock proteins (Tchantchou et al., 2014).
PUFAs as regulators of brain energy
DHA also has been identified as an important regulator of brain energy metabolism, having effects on both glucose uptake and on the density of glucose transporter-1 (GLUT1) in endothelial cell cultures (Pifferi et al., 2007) and in cerebral cortex from rat brain (Pifferi et al., 2005). Neuroimaging in humans with [18F]-fluoro-2-deoxyglucose positron emission tomography (FDG-PET) has identified correlations between plasma PUFA levels and cerebral metabolic rates for glucose (rCMRglu) in specific brain regions (Sublette et al., 2009).
PUFAs and neuroprotection
The benefits of n-3 LC-PUFAs to neuropsychiatric health are likely afforded, in part, by their neuroprotective properties. DHA and its metabolite NPD1 alter the expression of pro- and anti-apoptotic genes, including Bcl-2, Akt, and Bfl-1 (Akbar and Kim, 2002, Akbar et al., 2005 and Bazan, 2007), positively affecting neuronal survival. Resolvins, too, protect the brain from ischemia (Marcheselli et al., 2003). Dietary DHA also confers neuroprotection by specifically reducing β-amyloid in a mouse model of Alzheimer’s disease (Lim et al., 2005a) and in cytokine-stressed human neural cells (Lukiw et al., 2005), while in an in vivo human study, elevated AA brain uptake was seen with PET, in patients with Alzheimer’s disease compared to healthy volunteers ( Esposito et al., 2007). Conversely, in vivo DHA depletion has been shown to result in decreased brain-derived neurotrophic factor (BDNF) in rodents ( Rao et al., 2007b) and increased neuronal cell death in cell cultures ( Akbar et al., 2005).
“…we propose mechanisms by which serotonin synthesis, release, and function in the brain are modulated by vitamin D and the 2 marine omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Brain serotonin is synthesized from tryptophan by tryptophan hydroxylase 2, which is transcriptionally activated by vitamin D hormone. Inadequate levels of vitamin D (∼70% of the population) and omega-3 fatty acids are common, suggesting that brain serotonin synthesis is not optimal. We propose mechanisms by which EPA increases serotonin release from presynaptic neurons by reducing E2 series prostaglandins and DHA influences serotonin receptor action by increasing cell membrane fluidity in postsynaptic neurons. We propose a model whereby insufficient levels of vitamin D, EPA, or DHA, in combination with genetic factors and at key periods during development, would lead to dysfunctional serotonin activation and function and may be one underlying mechanism that contributes to neuropsychiatric disorders and depression. This model suggests that optimizing vitamin D and marine omega-3 fatty acid intake may help prevent and modulate the severity of brain dysfunction”
Folate plus vitamin B12 supplementation can improve negative symptoms of schizophrenia, but treatment response is influenced by genetic variation in folate absorption [8]. L-methylfolate is undergoing clinical trials [9]
Vitamin D may play a role in the pathogenesis of psychiatric illness [10]. Multiple relevant neurotransmitter pathways, immune function and inflammation are all influenced by vitamin D status [11] Developmentally vitamin D deficient animals show increased behavioural deficits in a NMDA antagonist model of schizophrenia and “a transient vitamin D deficiency has a long-lasting effect on NMDA-mediated signalling in the rodent brain and may be a plausible candidate risk factor for schizophrenia and other neuropsychiatric disorders. [12] Clinical trials are underway to determine if antipsychotic induced weight gain may be related to a vitamin D deficiency [13]
1,25(OH)2D3 has a direct effect on neural stem cell proliferation, survival, and neuron/oligodendrocyte differentiation, thus representing a novel mechanism underlying its remyelinating and neuroprotective effect.
Despite some limitations – particularly related to bioavailability – supplementation with curcumin may be of benefit. A clinical trial is underway to determine if curcumin nanoparticles will improve behavioral measures and biomarkers of cognition and neuroplasticity in patients with schizophrenia.
A diet composed of zinc, melatonin, curcumin, piperine, eicosapentaenoic acid (EPA, 20:5, n-3), docosahexaenoic acid (DHA, 22:6, n-3), uridine and choline may target multiple relevant pathways and thus provide a broad-spectrum nutraceutical approach to symptom reduction in neurodegenerative conditions [14].
Clinical trials demonstrated beneficial effects of N-acetylcysteine and omega-3 fatty acids and and vitamins E and C in the treatment of schizophrenia. Furthermore, these studies seem to suggest that antioxidant treatment supports positive outcomes in the early stage of schizophrenia.
a-Lipoic acid, a liphophilic anti-oxidant, shows potential in animal models. [15 , 16] N-acetylcysteine is a readily available and potentially effective agent. [17, 18, 19] Actions at mGluR2/3 receptors [20] add to its intriguing pharmacology. [21, 22]
Melatonin displays neurotrophic activity. Administration of melatonin, which also attenuates stress induced changes to the HPA-axis and hippocampus, helps to entrain circadian rhythms and attenuates antipsychotic induced metabolic side-effects [23] is a benign approach to potential symptom reduction.
Acetyl-L-carnitine administered intravenously has been shown to promote rapid antidepressant responses by acetylation of histone proteins that control the transcription of BDNF and metabotropic glutamate 2 (mGlu2) receptors in the hippocampus and prefrontal cortex [24]. It is also a potent antioxidant. Clinical trials are currently underway (using small doses of 500mg) with the hope of improving cognitive and negative symptom domains.
OTHERS
Adjunctive L-carnosine produced improvements in executive functions, memory, attention, and motor speed over placebo. [25]
6g/day of L-lysine added to risperidone has shown superiority over placebo [26] Large doses can deplete intra-cellular L-arginine stores, leading to a reduction in NO [more here]. Actions as a 5-HT4 partial antagonist may also play a role. High doses have demonstrated an anxiolytic effect in humans
Creatine [examine.com]: “Dechent et al (1999) studied the effect of oral creatine supplementation for 4 wk demonstrating a statistically significant increase of mean concentration of total creatine across brain regions. These findings suggest the possibility of using oral creatine supplementation to modify brain high-energy phosphate metabolism in subjects with various brain disorders, including schizophrenia and major depression. Recently, Rae et al (2003) reported that creatine supplementation for 6 weeks had a significant positive effect on both working memory and Raven matrices. Several independent lines of evidence suggest the possible involvement of altered cerebral energy metabolism in schizophrenia.
We are performing a double blind cross-over study of creatine in schizophrenia.” [27]
A pilot open study of long term high dose creatine augmentation in patients with treatment resistant negative symptoms schizophrenia found only “mild positive effects on the patients’ symptomatology and behavior” but concluded it “might have beneficial effect on tardive parkinsonism” [28]
Zinc may be an effective augmentation strategy [29]
Zinc can modulate fast-excitatory transmission, facilitate the release of amino butyric acid and potentiate nicotinic acetylcholine receptors. There are also emerging evidences discussing the implication of these neurotransmitters in pathophysiology of schizophrenia. The purpose of this study was to evaluate the efficacy of Zn sulfate as an add-on therapy in the treatment of schizophrenia in a 6-week, double-blind and placebo-controlled trial. Eligible participants were 30 inpatients with schizophrenia according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision criteria. Patients were randomly allocated into two equal groups; one group of patients received risperidone 6 mg/day plus capsules of Zn sulfate (each containing 50 mg elemental Zn) three times a day and another group received risperidone 6 mg/day plus placebo. The Positive and Negative Syndrome Scale (PANSS) was applied to assess the psychotic symptoms and aggression risk at baseline, week 2, 4, and 6 of the study. The results of this study showed that both protocols significantly decreased the scores on all subscales of the PANSS and supplemental aggression risk subscale as well as PANSS total score over the study. However, this improvement was significantly higher in Zn sulfate receiving group compared to the placebo group. No major clinical side-effects were detected. It may be concluded that Zn is an effective adjuvant agent in the management of patients with schizophrenia.
advancingschizophreniatherapeutics 