Ketogenic Diets

.High fat/low carb diet could combat schizophrenia

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.

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See more;

Ketogenic diet reverses behavioral abnormalities in an acute NMDA receptor hypofunction model of schizophrenia.

Effects of a ketogenic diet on auditory gating in DBA/2 mice: A proof-of-concept study.

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Metabolic syndrome and obesity among users of second generation antipsychotics: A global challenge for modern psychopharmacology (2015)

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.

Metabolic syndrome and obesity among users of second generation antipsychotics: A global challenge for modern psychopharmacology

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


See more:

Attenuating antipsychotic-induced weight gain and metabolic side effects

Improving cognition via vegetable derived NO? Polyphenols?

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?

Here’s an interesting article:

Dietary nitrate modulates cerebral blood flow parameters and cognitive performance in humans: A double-blind, placebo-controlled, crossover investigation.

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].

See also:

Novel aspects of dietary nitrate

Psychiatric Disorders and Polyphenols: Can They Be Helpful in Therapy?

Dietary glycemic index as a modulator of behavioral and biochemical abnormalities?

Here is a recent article that is very interesting. I’d like to see more done in similar detail to investigate the effect of diet on schizophrenia.

Dietary glycemic index modulates the behavioral and biochemical abnormalities associated with autism spectrum disorder

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.”

See also: Host microbiota constantly control maturation and function of microglia in the CNS

A role for epigenetics?

“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.”

Another recent article got me interested:

A Periodic Diet that Mimics Fasting Promotes Multi-System Regeneration, Enhanced Cognitive Performance, and Healthspan

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.

Restoring a healthy gut?

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]

1. The probiotic

I’m using a clinically tested 26 billion CFU probiotic (Bifidobacterium lactis HOWARU HN019 5 billion CFU, BI-04 10.5 billion CFU; Lactobacillus acidophilus La-14 10.5 billion CFU).

“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]

Gut microbiota modulation and implications for host health: Dietary strategies to influence the gut–brain axis
Gut microbiota modulation and implications for host health: Dietary strategies to influence the gut–brain axis

2. The prebiotic

“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.

I’ll see how it goes!


See also:

A role for the microbiome in schizophrenia?

Dietary glycemic index as a modulator of behavioral and biochemical abnormalities?

Immunomodulatory Effects of Probiotic Supplementation in Schizophrenia Patients: A Randomized, Placebo-Controlled Trial.

The gut microbiota and inflammatory noncommunicable diseases: Associations and potentials for gut microbiota therapies

Gut microbiota modulation and implications for host health: Dietary strategies to influence the gut–brain axis

Host microbiota constantly control maturation and function of microglia in the CNS

Diet, metabolic syndrome and schizophrenia/ASD – a convergence on PPAR-α?

Peroxisome proliferator-activated receptor alpha plays a crucial role in behavioral repetition and cognitive flexibility in mice

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.

Attenuating antipsychotic-induced weight gain and metabolic side effects

Pharmacological strategies to counteract antipsychotic-induced weight gain and metabolic adverse effects in schizophrenia: a systematic review and meta-analysis.

  • 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”

Metformin for weight loss in schizophrenia: safe but not a panacea.

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]

Functional foods as potential therapeutic options for metabolic syndrome.

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.

High dose green tea extract is promising [link]

Saffron aqueous extract (SAE) appears to be potentially beneficial: [link]

Alpha-lipoic acid (ALA), a potent antioxidant may be helpful in reducing weight for patients taking antipsychotics:

“ALA was well tolerated and was particularly effective for individuals taking strongly antihistaminic antipsychotics” [5, 6]

Berberine shows promise in animal models [7]

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].

Figure 1
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]