1. Introduction

2. Materials and Methods

3. The Gut-Brain Axis in the Pathogenesis of Schizophrenia

3.7. SCFAs and BDNF

In the process of enteric fermentation, bacteria produce short-chain fatty acids (SCFAs) i.e. butyrate, propionate, acetate, and valerate [72]. SCFAs are recognized as primary molecules responsible for the communication of the gut microbiome with the host[73]. SCFAs can cross the blood-brain barrier, where they stimulate cytokine production, modulate microglial activity, and exert an influence on CNS function [74]. Some research suggests that alterations in gut microbiota composition and SCFA production could influence brain function and behavior through the gut-brain axis [75].

Peng et al. indicated decreased concentrations of various SCFAs in SCZ-diagnosed patients and individuals in ultra-high-risk compared to healthy controls (HC) [76]. On the other hand, Li et al. did not observe significant differences in SCFA levels between patients with SCZ and HC. However, scientists reported that treatment with risperidone for 24 weeks led to increased serum levels of butyric acid. This increase was correlated with reductions in positive symptoms and PANSS scores in the drug-naive, first-episode patients [77].

Moreover, butyrate can promote the production of brain-derived neurotrophic factor (BDNF), which enhances neurotransmitter production through the vagus nerve [75]. BDNF is a neurotrophic factor crucial for neurodevelopment, neuroprotection, and the plasticity of glutamatergic and GABAergic synapses. It plays a significant role in neuronal differentiation and exerts influence on serotonergic and dopaminergic neurotransmission [78]. Studies have indicated that individuals diagnosed with schizophrenia exhibit reduced blood levels of BDNF compared to healthy controls [79].

There is an apparent relationship between gut microflora and behavioral phenotype. Traditionally used probiotics include bacteria such as Lactobacilli and Bifidobacteria in their composition. A groundbreaking 2018 study by Berkley Luk et al.[80] showed that colonization of gnotobiotic mice with a complex gut microflora that included four species of infant-type Bifidobacterium prevented behavioral disorders in mice. Adult mice lacking the microbiome were observed to have memory problems, anxiety-like behavior, and impaired motor skills. These disorders were not present in the behavior of mice colonized with Bifidobacterium spp. additionally showed improved memory in colonized individuals. The study also shows that the administration of Bifidobacterium effectively modifies the intestinal microflora and increases the production of short-chain fatty acids (SCFAs). SCFAs such as butyric acid can in turn act as a secondary messenger and prevent cognitive dysfunction [75]. Species such as Roseburia and Faecalibacterium, whose reduced levels have been found in people with schizophrenia, are responsible for butyrate production [81].

Dysbiosis in gut microbiota among SCZ-diagnosed patients could potentially affect SCFA production and, in turn, influence brain function [75]. However, the exact mechanisms linking SCFAs to schizophrenia pathogenesis remain unclear and require further investigation.

Scheme 1. Pathways of Microbiota-Gut-Brain Communication. The diagram illustrates pathways through which the gastrointestinal tract and gut microbiota interact with the brain, highlighting the most significant mechanisms: the neural pathway, the immunological pathway, the endocrine pathway, and products of microbial metabolism. Gut dysbiosis impacts neuropsychiatric health by disrupting the key pathways of the microbiota-gut-brain axis. GABA - gamma-aminobutyric acid; 5-HT - serotonin; DA - dopamine; NA - noradrenaline; Ach - acetylcholine; IL - interleukin; TNF-a - Tumour Necrosis Factor-alpha; SCFAs - short chain fatty acids; the HPA axis - the hypothalamic–pituitary–adrenal axis.

Scheme 1. Pathways of Microbiota-Gut-Brain Communication. The diagram illustrates pathways through which the gastrointestinal tract and gut microbiota interact with the brain, highlighting the most significant mechanisms: the neural pathway, the immunological pathway, the endocrine pathway, and products of microbial metabolism. Gut dysbiosis impacts neuropsychiatric health by disrupting the key pathways of the microbiota-gut-brain axis. GABA - gamma-aminobutyric acid; 5-HT - serotonin; DA - dopamine; NA - noradrenaline; Ach - acetylcholine; IL - interleukin; TNF-a - Tumour Necrosis Factor-alpha; SCFAs - short chain fatty acids; the HPA axis - the hypothalamic–pituitary–adrenal axis.

3.9. The Kynurenic Acid (KYNA)

In the pathogenesis of schizophrenia (SCZ), activation of the brain immune system manifests through elevated concentrations of kynurenic acid (KYNA) and proinflammatory cytokines in the brain and cerebrospinal fluid (CSF). KYNA acts as an antagonist of N-methyl-D-aspartate (NMDA) and α7 nicotinic acetylcholine receptors and is derived from astrocytes in the tryptophan degradation pathway [88]. Studies conducted on patients diagnosed with schizophrenia have revealed an elevated kynurenine/tryptophan ratio in the prefrontal cortex, indicating disruptions in serotoninergic transmission [89]. Furthermore, while the exact mechanism by which KYNA influences the central nervous system (CNS) remains unclear, it is hypothesized to modulate dopaminergic and glutaminergic transmission [90].

Scheme 2. Production of Kynurenic Acid, Increase in KYNA levels and the pathogenesis of schizophrenia. Tryptophan is converted into serotonin (SER - in ~ 5%) and kynurenine (KYN ~ 95%). Kynurenine can then be metabolized into kynurenic acid (KYNA) and other metabolites. Proinflammatory cytokines stimulate circulating macrophages to produce more kynurenine, which astrocytes can later convert into KYNA(Scheme 2.1). As an N-methyl-D-aspartate (NMDA) receptor antagonist, increased levels of KYNA can lead to NMDA receptor hypofunction in GABA interneurons, resulting in increased glutamatergic activity of pyramidal neurons. This hyperactivity can over-activate the mesolimbic dopamine pathway, causing excessive dopamine release into the ventral striatum and potentially leading to psychosis(Scheme 2.2) [91].

Scheme 2. Production of Kynurenic Acid, Increase in KYNA levels and the pathogenesis of schizophrenia. Tryptophan is converted into serotonin (SER - in ~ 5%) and kynurenine (KYN ~ 95%). Kynurenine can then be metabolized into kynurenic acid (KYNA) and other metabolites. Proinflammatory cytokines stimulate circulating macrophages to produce more kynurenine, which astrocytes can later convert into KYNA(Scheme 2.1). As an N-methyl-D-aspartate (NMDA) receptor antagonist, increased levels of KYNA can lead to NMDA receptor hypofunction in GABA interneurons, resulting in increased glutamatergic activity of pyramidal neurons. This hyperactivity can over-activate the mesolimbic dopamine pathway, causing excessive dopamine release into the ventral striatum and potentially leading to psychosis(Scheme 2.2) [91].

Zhu et al. conducted a study in which male mice were transplanted with fecal microbiota from drug-free patients diagnosed with schizophrenia. The animals exhibited altered behavior, including psychomotor hyperactivity, and showed impairments in learning and memory. Furthermore, an increase in the kynurenine–kynurenic acid pathway of tryptophan degradation was observed peripherally and in these mice’s brains. Additionally, basal extracellular dopamine levels in the prefrontal cortex and serotonin (5-HT) levels in the hippocampus were found to be elevated compared to mice receiving transplants from healthy controls [92]. Despite understanding gaps in KYNA’s role in the pathogenesis of schizophrenia, this area holds promise for further research and potential therapeutic interventions.

Table 1. The influence of the gut microbiota on brain function and psychiatric symptomes.

Table 1. The influence of the gut microbiota on brain function and psychiatric symptomes.

4. Diets

Table 2. Effects of diet on schizophrenia: key factors and their effects.

Table 2. Effects of diet on schizophrenia: key factors and their effects.

4.3. The Ketogenic Diet

The ketogenic diet is used not only for weight loss but also for the improvement of the patient’s lipid profile, as the body is put into a state of ketosis. This state leads to a decrease in glucose levels, resulting in the production of ketone bodies. The presence of ketone bodies is an exponent of the effectiveness of the diet. This diet plan includes 1 gram of protein per kilogram of body weight, 10-15 grams of carbohydrates per day, with the remaining calories coming from fats [100]. This diet increases the risk of heart disease, and atherosclerosis by decreasing glycated hemoglobin, and increasing low-density lipoprotein (LDL) [101].

The ketogenic diet reverses impaired glucose metabolism, inflammatory response, oxidative stress and dysregulation of neurotransmitter homeostasis. Some studies also suggest improvements in monoaminergic systems and the hypothalamic-pituitary-adrenal axis. These are systems that are often implicated in psychiatric disorders[102].

The mechanism by which glucose metabolism may have an impact on brain function in people with schizophrenia has long been the subject of research interest. One theory to explain this mechanism is that of bioenergetic dysfunction. According to this hypothesis, abnormalities in glucose metabolism lead to disrupted energy supply to brain cells, resulting in dysfunction of the nervous system. The brain is an organ that is highly susceptible to energy deprivation, consuming about 20% of the body’s energy while making up only 2% of our body weight[103]. Abnormalities in glucose metabolism may therefore lead to a reduction in energy use by brain cells, which may have an impact on the changes in cognitive function observed in people with schizophrenia. The existence of a link between glucose metabolism, and brain function in people with schizophrenia is an area of research that needs further observation to fully understand the pathophysiological mechanisms of this disease [104].

Scheme 3. Beginning with lipolysis, triglycerides in adipose tissue are hydrolyzed by lipase to free fatty acids (FFAs) and glycerol that then enter the bloodstream and get transported to the liver. Subsequently, in the process of beta-oxidation, free fatty acids (FFAs) are converted to acetyl-CoA, NADH, and FADH2 through a series of oxidative reactions in the mitochondria of cells in the target tissue. Acetyl-CoA is used to produce ketone bodies in ketogenesis. In the first step, two acetyl-CoA molecules combine to form acetoacetyl-CoA, which is then converted to acetoacetate and β-hydroxybutyrate. In the final step, known as ketolysis, ketones such as acetoacetate and beta-hydroxybutyrate are transported to extrahepatic tissues, where they may be reconverted to acetyl-CoA and used as a substrate in the tricarboxylic acid cycle for energy production.

Scheme 3. Beginning with lipolysis, triglycerides in adipose tissue are hydrolyzed by lipase to free fatty acids (FFAs) and glycerol that then enter the bloodstream and get transported to the liver. Subsequently, in the process of beta-oxidation, free fatty acids (FFAs) are converted to acetyl-CoA, NADH, and FADH2 through a series of oxidative reactions in the mitochondria of cells in the target tissue. Acetyl-CoA is used to produce ketone bodies in ketogenesis. In the first step, two acetyl-CoA molecules combine to form acetoacetyl-CoA, which is then converted to acetoacetate and β-hydroxybutyrate. In the final step, known as ketolysis, ketones such as acetoacetate and beta-hydroxybutyrate are transported to extrahepatic tissues, where they may be reconverted to acetyl-CoA and used as a substrate in the tricarboxylic acid cycle for energy production.

Adult patients with severe, treatment-resistant psychiatric disorders (major depressive disorder, bipolar disorder, and schizoaffective disorder) were studied in a retrospective clinical trial. Patients with schizophrenia have been on a restrictive ketogenic diet during their stay in a psychiatric hospital. The measure of improvement was the Positive and Negative Syndrome Scale (PANSS). Significant improvements in metabolic parameters were observed. These included weight loss, normalization of blood pressure, and regulation of blood glucose, and triglyceride levels [105]. The study therefore suggests that a restrictive ketogenic diet may be an effective therapy for patients with refractory psychiatric disorders, including schizophrenia. It is associated with improvements in metabolic parameters, and symptom scores on the PANSS scale.

Dietcha et al. found a potentially beneficial effect of a ketogenic diet on anxiety disorders in patients diagnosed with schizophrenia. It should be noted, however, that this was not high-quality evidence [106].

In conclusion, current evidence on the efficacy of the ketogenic diet for the treatment of psychiatric disorders is inconclusive. It is still unclear whether a ketogenic diet on its own or in combination with a low-carbohydrate diet is the best way to achieve therapeutic effects. In addition, a thorough characterisation of the adverse effects and the potential for recurrence of symptoms after discontinuation of the diet is crucial.

4.5. Gluten and Schizophrenia

Celiac disease is twice as common in patients with schizophrenia as in the general population, according to epidemiological studies[121].

The elimination of gluten from the diet may be beneficial for patients with a diagnosis of schizophrenia [122]. As early as World War II, observations by Joseph Dohan revealed an important association between average annual wheat consumption and an increase in first hospitalizations for schizophrenia in women [123]. In addition, the same psychiatrist noted that a lower incidence of schizophrenia was observed in places where wheat consumption was considered limited, compared to areas of the world where gluten-rich products were more accessible [124].

A case has been described in which single-photon computed tomography (SPECT) showed prefrontal cortex dysfunction in a patient with celiac disease, and a diagnosis of schizophrenia, which disappeared after the introduction of a gluten-free diet. Hypoperfusion of the left frontal lobe without visible structural changes was found on a SPECT scan. Atrophy and anti-endomysial antibodies were found on intestinal biopsy. Resolution of psychiatric symptoms, and standardization of histologic, and SPECT findings were achieved by initiating a gluten-free diet without adjunctive psychiatric pharmacotherapy. Previous neuroleptic pharmacotherapy was discontinued. There was no recurrence of schizophrenia symptoms in the patient on the gluten-free diet after discontinuation of pharmacological treatment. Therefore, it can be concluded that the gluten-free diet was the only therapy that led to improvements in his psychiatric, and physical condition[125].

The efficacy of the gluten-free diet (GFD) was studied in two schizophrenia-positive patients with tissue transglutaminase (tTG) or antiglandin (AGA) antibodies. Both patients experienced improvements in psychiatric symptoms. These included anxiety, hallucinations, delusions, and disorganized thinking. Negative, and extrapyramidal symptoms also decreased. The results suggest that a gluten-free diet may be beneficial for people who have been diagnosed with schizophrenia, particularly those who have antibodies to tTG, and AGA [126].

Genois et al. describe the case of a 23-year-old woman with long-standing visual, and auditory hallucinations that improved completely with the introduction of a gluten-free diet. However, symptoms returned after accidental ingestion of gluten. TTG antibody tests were negative. Therefore, it is not clear whether the patient had a visceral disease or a hypersensitivity to gluten. Nevertheless, the elimination of gluten proved to be effective, and safe in alleviating his psychotic symptoms. This confirms the beneficial effect of the gluten-free diet in schizophrenia [127].

A systematic review by Aranburu et al. found that gluten avoidance may improve cognitive function in schizophrenia [128]. The study included 16 schizophrenic or schizoaffective patients without celiac disease but with high levels of antigliadin IgG. The participants who were on a gluten-free diet were divided into two groups: one group was given additional milk cocktails with gluten flour, and the other group with rice flour. There was no improvement in positive symptoms in patients receiving the rice flour cocktail. However, an improvement in negative symptoms was observed. SANS (Scale for the Assessment of Negative Symptoms) scores showed improvements in five domains: affective impairment, alogy, abulia/apathy, anhedonia, frustration, and attention deficit [128].

Gluten consumption can cause inflammatory reactions in the brain. This increases the permeability of the blood-brain barrier. In patients with schizophrenia, this can increase the penetration of haptoglobin-2, and worsen symptoms. Due to the increased permeability of the blood-brain barrier caused by the inflammatory process, the concentration of this peptide is increased in schizophrenia patients [129]. Studies have shown that the effect of a gluten-free diet on schizophrenia symptoms is either positive or neutral. Based on these data, it can be concluded that a gluten-free diet is well tolerated and can be used to treat schizophrenia. However, since the diagnosis, and treatment of celiac disease in the presence of coexisting conditions appears to significantly improve patient prognosis, attention should be paid to gastric symptoms suggestive of celiac disease in clinical practice.

4.6. Diet in Diabetic Patients

Diabetes is a serious concern for people with schizophrenia, as they are at an increased risk of developing the disease when compared to the general population. A study analyzed data from both the World Health Organization and the Food and Agriculture Organization (FAO). It was found that a more severe course of schizophrenia, as manifested by the overall poor health of the patients, was associated with the consumption of products rich in saturated fatty acids relative to those rich in polyunsaturated fatty acids. This means that a higher percentage of fat, lower indicators of diet quality, and a higher intake of unhealthy products such as full-fat creams, and sweetened beverages were found in schizophrenia patients who preferred such a diet. There is an association between these poor dietary habits and poorer health outcomes in patients with schizophrenia. However, these outcomes may also be influenced by other factors, such as medications and overall health [130].

In light of the epidemiologic studies conducted by Stokes et al., an important association between sugar intake, and the severity of schizophrenia symptoms was confirmed, particularly in the context of drug treatment, with a focus on the use of clozapine. In addition, a secondary analysis suggested a possible association between the intake of polyunsaturated fatty acids, and the worsening of the symptoms of schizophrenia, independent of the pharmacological treatment [131].

Insulin resistance has been diagnosed in patients with schizophrenia, and type II diabetes, both in those on medication, and in untreated patients [132]. Furthermore, the importance of the risk of developing type II diabetes is underscored by the meta-analysis by Philinger et al. who suggested that glucose homeostasis is impaired from the first psychotic episode in people with schizophrenia [133]. In addition, the study by Huang et al. showed that the incidence of type II diabetes in schizophrenics is significantly higher than in the general population, especially in people under the age of 60. This may indicate that it is not related to a decrease in metabolic rate with age [134].

Scheme 4. The schematic representation of glucose metabolism, and energy production in the cell includes the following processes. Glucose is taken up by glucose transporters, and converted by the restriction enzyme hexokinase to glucose-6-phosphate (G6P). Two molecules of ATP (adenosine triphosphate) are produced and used as an energy substrate. Lactate, and pyruvate are the end products of glycolysis. The pentose phosphate (PPP) pathway provides ribose for the construction of ribosomal RNA, and DNA. It also provides NADH (Nicotinamide adenine dinucleotide), which regulates free radicals generated during ATP synthesis in the mitochondria. During periods of intense synaptic excitability, lactate can be used for energy production. Pyruvate enters the mitochondria where it is metabolized to acetyl-CoA, which is used in the citric acid cycle (CAC) for the production of precursors of certain amino acids, such as the excitatory neurotransmitter glutamate, which can be converted to the inhibitory neurotransmitter GABA (gamma-aminobutyric acid), and the reducing factor NADH, which is introduced into the oxidative phosphorylation pathway (OXPHOS). This leads to the synthesis of ATP (30-36 molecules) by the enzyme ATP synthase. These processes are critical for normal brain function. They may be important in the context of schizophrenia, where there are abnormalities in glucose metabolism that can lead to changes in cognitive function (31192814).

Scheme 4. The schematic representation of glucose metabolism, and energy production in the cell includes the following processes. Glucose is taken up by glucose transporters, and converted by the restriction enzyme hexokinase to glucose-6-phosphate (G6P). Two molecules of ATP (adenosine triphosphate) are produced and used as an energy substrate. Lactate, and pyruvate are the end products of glycolysis. The pentose phosphate (PPP) pathway provides ribose for the construction of ribosomal RNA, and DNA. It also provides NADH (Nicotinamide adenine dinucleotide), which regulates free radicals generated during ATP synthesis in the mitochondria. During periods of intense synaptic excitability, lactate can be used for energy production. Pyruvate enters the mitochondria where it is metabolized to acetyl-CoA, which is used in the citric acid cycle (CAC) for the production of precursors of certain amino acids, such as the excitatory neurotransmitter glutamate, which can be converted to the inhibitory neurotransmitter GABA (gamma-aminobutyric acid), and the reducing factor NADH, which is introduced into the oxidative phosphorylation pathway (OXPHOS). This leads to the synthesis of ATP (30-36 molecules) by the enzyme ATP synthase. These processes are critical for normal brain function. They may be important in the context of schizophrenia, where there are abnormalities in glucose metabolism that can lead to changes in cognitive function (31192814).

Furthermore, Upadhyaya et al. suggest structural abnormalities in the first psychotic episode [135], and Leticia-González-Blanco et al. show prolactin dysregulation in schizophrenia [136]. This hormone can therefore be used as a hormone marker prognostic schizophrenia [137].

Some components of the diet, i.e., simple sugars, and saturated/trans fats, can impair glucose, and insulin metabolism, which indirectly affects pituitary function, and may lead to increased cortisol secretion. (van den Brink et al., 2018) Glucocorticoids increase glucose production in the liver and decrease glucose uptake in other tissues. Prolonged use of glucocorticoids leads to hyperglycaemia and insulin resistance [138].

Eating more artificial foods was found to have a significant effect on the expression of genes associated with pituitary function, including those responsible for glycemic control, and glucose metabolism, in studies of the effects of diet on pituitary, and neuroendocrine regulation in patients with schizophrenia [75]. A diet high in saturated fat, and carbohydrates may be detrimental to the prognosis of these patients. It may increase the risk of insulin resistance, and metabolic syndrome. In contrast, glycemic control, and pituitary function may be improved with a diet low in saturated fat, high in fiber, and low glycemic index products. Because glucose homeostasis is impaired in schizophrenia patients from the first psychotic episode, the study emphasizes the need to monitor glycemic levels in schizophrenia patients and recommends further research on the effects of diet on pituitary neuroendocrine regulation in these patients.

5. Supplementation

6. How Eating Habits Affect Schizophrenia?

7. Metabolic Impact of Antipsychotics in Schizophrenia

7.1. Glucose Metabolism and Neuroleptics Treatment

Of the atypical antipsychotics, clozapine and olanzapine are associated with the highest risk of weight gain, type 2 diabetes, and dyslipidemia. In contrast, risperidone and quetiapine can cause intermediate weight gain and varied metabolic changes, but additional results were inconclusive on the incidence of diabetes and dyslipidemia. Aripiprazole and ziprasidone showed the least weight gain, and there is no evidence of a risk of diabetes or dyslipidemia during or after their use [226]. It is worth noting that a study by Casey et al. shows that changing the treatment of patients previously taking olanzapine or risperidone to aripiprazole or ziprasidone resulted in a significant reduction in weight over 6 to 8 weeks compared to the weight of patients before treatment [228].

Table 3. Neuroleptics used to treat schizophrenia can have negative effects such as weight gain, type 2 diabetes and dyslipidemia. The most serious side effects are seen with clozapine and olanzapine, while aripiprazole and ziprasidone show the least side effects.

Table 3. Neuroleptics used to treat schizophrenia can have negative effects such as weight gain, type 2 diabetes and dyslipidemia. The most serious side effects are seen with clozapine and olanzapine, while aripiprazole and ziprasidone show the least side effects.

The pathomechanisms involved in the occurrence of metabolic diseases are not fully understood, but it is assumed that weight gain occurs secondary to a central increase in appetite. This theory stems from the fact that histamine can inhibit the mesolimbic dopamine pathway, which controls the intake of palatable food via the H3 autoreceptor while activating it via the histamine H1 receptor [229]. A study by Kroeze et al. showed that the binding affinity of atypical antipsychotics to the histamine H1 receptor is a relevant predictor of weight gain mediated by group of atypical antipsychotic drugs [230].

The results of the study indicate that olanzapine, which is associated with weight gain, causes a significant increase in postprandial insulin, glucagon-like peptide 1 (GLP-1) and glucagon levels, which co-occurs with insulin resistance compared to placebo. In contrast, aripiprazole, considered less metabolically damaging, induces insulin resistance, but has no effect on postprandial hormones. In addition, atypical antipsychotics, here olanzapine and aripiprazole, have been shown to directly affect tissues, i.e.: postprandial glucose and hormone levels, as well as glucose metabolism and insulin resistance. The changes occur regardless of dietary mechanisms, as metabolic changes were seen in patients who showed no weight gain or increased food intake [231].

8. Conclusion

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