Current state of nutritional psychiatry: A scoping review of randomized controlled trials

Abstract

BACKGROUND

Nutritional psychiatry is a rapidly expanding field of research, with mounting evidence suggesting that nutritional factors may play a role in the development of psychiatric disorders.

AIM

To examine the level of evidence for nutritional psychiatry.

METHODS

A scoping review was conducted to assess the current state of nutritional psychiatry, including a search for randomized controlled trials (RCTs).

RESULTS

The review identified a total of seven papers, with many concentrating on the relationship between depression and the gut microbiome. A salient issue that emerged from this review was the paucity of sample size in many studies. The inherent complexity of nutritional studies, characterized by a multitude of potential factors and exposures that often act as confounders, poses significant challenges to the development of effective RCT designs. The analysis revealed that probiotics, though demonstrating efficacy, exhibited a modest effect size.

CONCLUSION

Conducting RCTs with effective markers is imperative from these studies. The implementation of Mendelian randomization and the investigation of mechanisms in basic research are essential complementary approaches.

Key Words: Nutritional psychiatry; Randomized controlled trial; Mendelian randomization; Fundamental research; Probiotics; Gut microbiota

Core Tip: The number and quality of randomized controlled trials (RCTs) in the field of nutritional psychiatry remain inadequate. The relationship between nutrition and psychiatric disorders is challenging to demonstrate causally in RCTs due to the multitude of confounding factors and the relatively modest effect sizes observed. To enhance the evidence base in nutritional psychiatry, it would be beneficial to utilize not only RCTs but also data from Mendelian randomization studies and fundamental research, with the aim of elucidating the underlying mechanisms.

INTRODUCTION

Nutrition psychiatry is a field of scientific inquiry that seeks to understand the impact of dietary and nutritional factors on brain function and mental health[1]. There are several reasons why the field of nutrition psychiatry is receiving increased attention. One factor contributing to the growing interest in nutrition psychiatry is the observed increase in mental illnesses. In recent years, there has been a notable rise in the prevalence of conditions such as depression and anxiety disorders, underscoring the need for a deeper understanding of their underlying causes and the development of novel therapeutic approaches[2]. Second, the relationship between diet and health has attracted attention[3]. It is becoming increasingly clear that diet is deeply involved not only in physical health but also in mental health. Given the brain's capacity for plasticity, whereby it can adapt in response to experience and environment, it is reasonable to posit that dietary factors may exert a beneficial influence on brain function. Nutritional psychiatry encompasses research into a number of different areas including neurotransmitters, gut microbiota, and inflammation[4]. Neurotransmitters such as serotonin, dopamine, and norepinephrine play a pivotal role in emotional regulation and motivation[5]. Dietary modifications can influence the synthesis and secretion of these neurotransmitters, thereby impacting mental state. Gut microbiota is not only involved in the synthesis of neurotransmitters such as serotonin and dopamine, but also affects mental state through the gut-brain axis. It has been demonstrated that chronic inflammation increases the risk of developing mental illnesses such as depression and anxiety disorders[6]. In addition, dietary therapy has been shown to have the effect of suppressing inflammatory responses[7]. However, nutritional psychiatry is a relatively new field, and the evidence base supporting its claims has yet to be fully established. The relationship between nutrients and mental function is primarily based on observational studies, which may be subject to bias.

Therefore, the present paper provides a review of the currently available randomized controlled trials (RCTs) in the field of nutritional psychiatry, which have a higher level of evidence than observational studies, and provides suggestions for future research methods.

MATERIALS AND METHODS

A comprehensive electronic search of the PubMed and J-STAGE databases was conducted for articles published in English up to December 2024. The search terms employed were "nutritional psychiatry," "randomized controlled trial," "gut microbiota," and "mental function." The abstracts of the retrieved articles were reviewed, and only those that described either diet, probiotics, or nutrients were included in the subsequent analysis. The screening and selection process was conducted by the author. A flow diagram illustrating the review process, including details of the databases and registers searched, is presented in Figure 1.

Figure 1 Flow diagram for the review, which included searches of databases and registers. RCTs: Randomized controlled trials.

RESULTS

A preliminary evaluation of 76 abstracts revealed that only a small number of studies met the criteria of the present study. The preponderance of studies in the domain of nutritional psychiatry were of an observational or case report nature, with a modest number classified as RCTs. The screening process identified 13 RCTs; however, only 7 of these studies had mental function as an outcome. Six studies that investigated non-psychiatric outcomes or mental health without nutritional intervention were excluded from the analysis.

A comprehensive analysis of seven studies revealed that the predominant themes were depression and obesity, with probiotics identified as the most prevalent intervention. The observation period ranged from 8 weeks to 12 weeks, with the majority of the studies focusing on short-term effects. A comprehensive list of the RCTs that were incorporated into the review is provided in Table 1[8-14]. A synthesis of the results revealed that probiotics exhibited a modest effect on cognition, while prebiotics demonstrated minimal impact. The following section presents an overview of the included studies.

Table 1 List of articles included in the analysis.

Ref.	Sample size	Study design	Outcome assessment	Conclusions
Rudzki et al[8], 2019	Patients with depression were randomized to receive either the probiotic Lactobacillus Plantarum 299v plus an SSRI (n = 30) or placebo plus an SSRI (n = 30) for 8 weeks	Psychiatric symptoms were assessed using the Hamilton Depression Rating Scale, Symptom Checklist and Perceived Stress Scale. Cognitive function was assessed using the Attention and Perceptivity Test, Stroop Test. Biochemical markers measured included tryptophan, kynurenine	There was a significant decrease in kynurenine concentration in the Lactobacillus Plantarum 299v group compared to the placebo group. Results of post hoc analysis did not reach statistical significance in neither probiotic nor placebo group. There were no significant changes of TNF-α, IL-6, and IL-1β and cortisol concentrations in neither probiotic nor placebo groups	Augmentation of SSRI treatment with probiotic bacteria Lactobacillus Plantarum 299v improved cognitive performance and decreased kynurenine concentration
Lee et al[14], 2022	The study involved 17 subjects with major depressive disorder (aged 60 years or older, 41.2% female) and received levomirasipran or placebo for 12 weeks	To determine if changes in gut microbiota occur with remission in geriatric depression	Baseline enrichment of Faecalibacterium, Agathobacter, and Roseburia relative to a reference frame was associated with treatment outcome of remission	Fecal microbiota as a potential predictor of treatment response in geriatric depression
Vaghef-Mehrabani et al[13], 2023	45 women with obesity and major depression	Patients were assigned to consume either inulin or maltodextrin at a dose of 10 g per day for 8 weeks. All patients also consumed a healthy calorie-restricted diet. Anthropometric measurements, food intake, depression, lipopolysaccharide, inflammatory biomarkers (TNF-α, IL-10, monocyte chemoattractant protein-1, Toll-like receptor-4, high-sensitivity C-reactive protein), and BDNF were measured	Weight loss and Hamilton Depression Rating Scale scores decreased in both groups, with non-significant between-group differences at the end of the study	In a short-term study, prebiotic supplementation had no significant beneficial effects on depressive symptoms, intestinal permeability, or inflammatory biomarkers in obese and depressed women
Badrfam et al[11], 2024	60 hospitalized patients with a history of methamphetamine use for 3 years or more	Brief Psychiatric Rating Scale, Beck Anxiety Inventory, Pittsburgh Sleep Quality Index were evaluated under treatment with Probiotic Lactobacillus acidophilus with risperidone	Patients who took probiotics had better quality sleep, increased appetite, and a higher BMI, but there were no statistically significant differences between the two groups when it came to improvement in psychiatric and anxiety symptoms	The use of probiotics was associated with improved sleep quality, increased appetite, and increased BMI in patients with chronic methamphetamine use
Sevillano-Jiménez et al[39], 2022	A randomized clinical trial of a group of 50 people diagnosed with schizophrenia spectrum disorder during the severe acute respiratory syndrome-coronavirus 2 restriction period	Assessment of cardiovascular event risk factors in a personalized nutrition education program rich in prebiotics and probiotics (e.g., dairy products, fermented foods, green leafy vegetables, high-fiber fruits, and whole grains)	A 27.4% reduction in the prevalence of metabolic syndrome risk factors in all its components was evidenced, leading to a clinically significant improvement (decrease in cardiovascular risk) in the intervention group at 6 months	The development of a nutritional program focused on increasing the dietary content of prebiotics and probiotics effectively improves the cardio-metabolic profile in schizophrenia spectrum disorders
Hwang et al[10], 2019	A 12-week intervention for 100 patients with mild cognitive impairment	Lactobacillus plantarum C29 fermented soy (DW2009) was administered as a dietary supplement for cognitive enhancement, and the composite score of cognitive function related to memory and attention measured by computerized neurocognitive testing and BDNF levels were measured	DW2009 group showed greater improvements in the combined cognitive functions, especially in the attention domain. Cognitive improvement was associated with increased serum BDNF levels	DW2009 can be safely administered to enhance cognitive function in individuals with MCI. Increased serum BDNF levels after administering DW2009 may provide preliminary insight into the underlying effects of cognitive improvement, which suggests the importance of the gut-brain axis in ameliorating cognitive deficits in MCI
Freijy et al[12], 2024	An 8-week trial of probiotics and prebiotics in 118 depressed adults	At baseline and 8 weeks, the Cogstate Brief Battery was administered, testing processing speed, attention, visual learning, and working memory. Data were analyzed using Bayesian linear regression	Weak evidence that the probiotic improved working memory. For the other treatments, there was little or no evidence of cognitive improvement. Weak evidence that the prebiotic diet impaired processing speed	A probiotic-induced improvement in working memory, and prebiotic-induced impairment in processing speed. However, the evidence remains inconclusive regarding any cognitive benefit or harm induced by the probiotic, prebiotic diet, or synbiotic treatments

BDNF: Brain-derived neurotrophic factor; BMI: Body mass index; IL: Interleukin; MCI: Mild cognitive impairment; SSRI: Selective serotonin reuptake inhibitor; TNF-α: Tumor necrosis factor alpha.

In an RCT that examined the effects of combining probiotics (LP299v) with selective serotonin reuptake inhibitors for depression, no enhancement of the antidepressant effect was observed. However, cognitive function measured by the Stroop Test and other methods improved compared to placebo[8]. The RCT comprised 30 patients in each of the probiotic and placebo groups, with a treatment period spanning 8 weeks. Tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), and IL-1β, which were measured as inflammatory markers, remained unchanged. However, a significant reduction in blood kynurenine concentrations was observed in the probiotic group, which correlated with improved cognitive function. Kynurenine, a substance produced during the metabolism of the essential amino acid tryptophan in the body, is a notable component of this pathway. Tryptophan is also a raw material for the neurotransmitter serotonin, and its metabolism is related to mental function and plays an important role in mood and sleep. In patients diagnosed with depression, the pathway that metabolizes tryptophan to kynurenine is overactivated[15]. This overactivation has been linked to the conversion of kynurenine into neurotoxic substances that can damage nerve cells. The potential for probiotics to enhance tryptophan metabolism and reduce kynurenine levels in the intestinal environment is a promising avenue for further research. However, this effect did not result in an increase in clinical antidepressant effects.

In an RCT that involved 100 individuals with mild cognitive impairment (MCI), cognitive function was evaluated over a 12-week period using computerized neurocognitive function tests. The participants were administered either a plant-derived probiotic, Lactobacillus plantarum C29 fermented soy (DW2009), or a placebo. The results showed that the attention domain of cognitive function exhibited significant improvement[10]. Serum brain-derived neurotrophic factor (BDNF) levels were found to be associated with the observed enhancement in cognitive function. The potential for probiotics derived from fermented foods to enhance cognitive functions in MCI patients is a promising avenue for further research.

In an RCT involving 60 inpatients with a history of more than 3 years of methamphetamine use, probiotic capsules or placebo were administered for a period of 8 weeks in conjunction with risperidone. The psychiatric symptoms, sleep, and appetite of the participants were measured using the Brief Psychiatric Rating Scale (BPRS). The Beck Anxiety Inventory (BAI), Pittsburgh Sleep Quality Index, and Simple Appetite Nutritional Questionnaire were used to assess psychiatric symptoms, sleep quality, and appetite, respectively. The results indicated that the probiotic group exhibited enhancements in sleep quality, heightened appetite, and an augmented body mass index[11]. However, no alterations were observed in the BPRS or BAI. The study's findings indicate that probiotics did not improve psychiatric or anxiety symptoms in methamphetamine users, yet they did enhance sleep quality and physical well-being.

In an RCT that examined the effects of prebiotics and probiotics on cognitive function, probiotics were found to improve cognitive function[12]. This RCT involved 118 adults with low mood, and four groups were compared, each receiving a combination of two of the following three interventions: (1) A probiotic supplement; (2) A high-prebiotic diet; and (3) Placebo. The treatment period spanned 8 weeks, and cognitive function was measured using the Cogstate Brief Battery. The probiotic supplement demonstrated a significant enhancement in working memory. Conversely, the high-prebiotic diet exhibited a detrimental effect on processing speed. The synbiotic group, which received a combination of a probiotic supplement and a high-prebiotic diet, exhibited no alterations in cognitive function. In adults experiencing low mood, probiotics exhibited a mild effect, while synbiotics in combination with a high-prebiotic diet demonstrated no significant impact. Consequently, these findings indicate that, in contrast to probiotics, the administration of prebiotics exerts minimal influence on enhancing cognitive function. In a similar vein, the administration of prebiotics in isolation has demonstrated minimal antidepressant efficacy. In an RCT investigating the efficacy of prebiotics in treating depression associated with obesity, the effect was comparable to that of a placebo[13]. In this study, 45 obese women with major depression were randomly assigned to receive either 10 g of the prebiotic inulin or 10 g of placebo maltodextrin per day for 8 weeks. All patients adhered to a nutritionally balanced diet that was calorie-restricted, and serum levels of zonulin, lipopolysaccharide, inflammatory biomarkers (TNF-α, IL-10, monocyte chemoattractant protein-1, Toll-like receptor-4, and high-sensitivity C-reactive protein), and BDNF were measured before and after the intervention. The results indicated that both prebiotics and placebo led to a mild reduction in weight and antidepressant effects. However, these effects were comparable between the two groups, and no significant differences were observed in inflammatory marker levels. It is noteworthy that prebiotics do not exert a direct influence on the gut microbiota, in contrast to the action of probiotics, which may diminish their efficacy.

In an RCT that compared the response of 17 depressed patients aged 60 years or older to levomilacipran or placebo over a 12-week period, the fecal microbiota of the group in remission from depression exhibited higher levels of Faecalibacterium, Agathobacter, and Roseburia prior to the intervention[14]. Differential abundance analysis revealed significant changes at the genus level from baseline to post-treatment in patients in remission from depression, but no changes were observed in non-remission patients. The alterations in the composition of the gut microbiota appear to be closely associated with the response to antidepressant treatment. The emergence of an antidepressant effect is contingent on the presence of specific bacterial taxa within the gut microbiota prior to intervention, along with a subsequent shift in the composition of the gut microbiota following intervention.

DISCUSSION

Current status of RCTs in nutritional psychiatry

Nutrition, akin to lifestyle habits, is a modifiable factor that can be addressed through intervention. Nutritional psychiatry, a relatively recent field of study, utilizes dietary modifications and supplements to address mental health concerns. Deficiencies in specific nutritional elements have been demonstrated to impair cognitive function and have been linked to the emergence of various mental health conditions. For instance, deficiencies in vitamin D and omega-3 fatty acids have been linked to an increased risk of depression, while vitamin B₁₂ deficiency has been associated with impaired memory and reduced cognitive ability. Magnesium deficiency has been linked to increased anxiety and irritability[16]. However, the evidence on the aforementioned nutritional factors and mental function is predominantly derived from observational studies, which hinders the ability to eliminate confounding factors and elucidate the causal relationship.

RCTs have been demonstrated to minimize the influence of confounding factors and demonstrate a causal relationship. Consequently, a scoping review of RCTs in the domain of nutritional psychiatry research was conducted. The findings revealed a paucity of evidence from RCTs concerning the relationship between nutrients and mental function. The majority of RCTs were grounded in interventions targeting the gut microbiota, employing probiotics and prebiotics. Probiotic interventions have been demonstrated to enhance specific domains of cognitive function, including working memory and attention. However, these interventions have not yielded improvements in psychiatric symptoms. As biomarkers, interventions with nutritional factors such as probiotics have been shown to alter the gut microbiota. In individuals with depression, there has been a decrease in kynurenine and an increase in BDNF, but no improvement has been confirmed in intestinal permeability or various inflammatory markers that affect psychiatric symptoms. The biological pathways through which nutritional factors may induce psychiatric symptoms include inflammation, oxidative stress, epigenetic changes, and neuroplasticity, often mediated through the microbiota-gut-brain axis[17-19]. However, the efficacy of short-term nutritional interventions in modulating these biological pathways remains to be elucidated.

RCTs in the field of nutritional psychiatry are characterized by the presence of numerous potential factors, confounding exposures, and relatively modest individual effect sizes. Consequently, these RCTs are unable to reach the same conclusions as RCTs in conventional pharmacological studies. Nevertheless, the inability to preclude false negative outcomes due to inadequate statistical power and false positive results attributable to biased designs persists in RCTs of nutritional psychiatry.

Mendelian randomization trials as a complement to RCTs

In instances where it is challenging to draw conclusions from RCTs, the advent of genetic research has led to the utilization of Mendelian randomization (MR) trials as a means to estimate causal relationships[20]. RCTs and MR studies represent two research designs that provide randomized evidence in the realm of human biological and medical research. MR utilizes genetic markers that are reliably associated with specific, potentially modifiable exposures as instrumental variables to assess the relationship between exposure and outcome. A key advantage of MR is its ability to reduce bias, as alleles are randomly assigned at conception, thereby ensuring the independence of the outcome variable from confounding factors.

MR studies are currently being conducted to ascertain whether nutritional factors, including vitamin D, folate, serum magnesium, copper, triglycerides, and glucose metabolic pathways, are associated with the emergence of psychiatric symptoms. For instance, Alzheimer's disease and vitamin D, schizophrenia and vitamin B₆, and mood disorders and trace elements have been examined using MR trials[21-23]. However, the causal relationship between these nutritional factors and the development of psychiatric symptoms remains unclear. A primary reason for this is that many nutritional factors do not demonstrate a linear relationship between exposure and outcome. Consequently, the inferential process of determining causation through conventional MR analysis necessitates a linear relationship between exposure and outcome. However, the relationship between cognitive function and vitamin D is not linear, as both deficiency and excess have been demonstrated to be deleterious[24].

Although MR is not a substitute for RCTs in detecting causal relationships, it can be a useful method to estimate whether dietary factors are causally related to psychiatric symptoms in nutritional psychiatry, where it is difficult to design effective RCTs due to potential confounding factors[25]. Consequently, the development of novel MR research methodologies that address nonlinearity, such as the fractional polynomial method and the piecewise linear method, is of paramount importance in the nutritional psychiatry research.

Exploring mechanisms in fundamental research

To enhance the precision of RCTs, it is imperative to elucidate the mechanism of action of nutritional factors through fundamental research. The elucidation of the mechanism of action of nutritional factors through fundamental research is instrumental in the development of an effective RCT design.

This review of RCTs also indicates that probiotics may be effective in improving cognitive function, but no significant impact on psychiatric symptoms. However, case reports have demonstrated that probiotics can significantly improve the psychiatric symptoms associated with schizophrenia in some patients. A case study that administered a probiotic containing three different bacterial strains to patients with schizophrenia and gut dysbiosis (gastrointestinal symptoms), intestinal barrier dysfunction (history of bacterial translocation), and central dopamine nervous system dysfunction (e.g., cognitive dysfunction) found that the probiotic improved psychiatric symptoms in parallel with changes in gut microbiota patterns[26]. Given our knowledge of the specific bacterial strain, we can investigate the underlying mechanism by which probiotic colonization of germ-free mice leads to the alleviation of psychiatric symptoms. The probiotic strains utilized in this study were Bacillus subtilis TO-A, Enterococcus faecium T-110, and Clostridium butyricum TO-A[27]. The colonization of germ-free mice with these bacteria resulted in an augmentation of neural stem cells, in comparison to the number observed in specific pathogen-free mice raised under standard conditions[28]. The augmentation in neural stem cells serves as a model for adult neurogenesis, a process implicated in memory and emotional regulation[29]. In a metabolomics analysis, 16 metabolites, including theanine, carnosine, and 3-hydroxybutyric acid, were identified in the blood of mice colonized with the three types of probiotics compared to germ-free mice. Subsequent administration of theanine, carnosine, and 3-hydroxybutyric acid to human-derived neural stem cells resulted in the promotion of neural stem cell differentiation into neurons. These findings from basic research suggest that the three types of probiotics induce adult neurogenesis through their metabolites[28]. While probiotics do not directly enhance brain function, they do so by facilitating neurogenesis through various mediators. If the mediators are predicted through fundamental research, then when assembling an RCT with the probiotics, a more accurate RCT can be designed by adding measurements of the mediators. The findings of fundamental research provide indispensable information for the effective design of RCTs (Figure 2).

Figure 2  Schematic diagram of mechanisms and research methods in nutritional psychiatry.

Therefore, gut microbiota plays a crucial role in mental health. The gut-brain axis, a complex communication network between the gut and brain, highlights this connection. An imbalance in gut microbiota, known as dysbiosis, has been linked to mental health issues like anxiety, depression, and even neurodevelopmental conditions. Gut microbiota produces neurotransmitters, chemical messengers that regulate mood, emotions, and cognition. Gut microbiota ferments fiber, producing short-chain fatty acids (SCFAs) that have anti-inflammatory and gut-protective properties. SCFAs can also influence brain function and mood. Moreover, gut microbiota influences the immune system, reducing inflammation and oxidative stress that can negatively impact brain function. To summarize the above and show a conceptual diagram of the current state of nutritional psychiatry, RCTs on healthy diets, probiotics, prebiotics, and nutrient interventions are still insufficient to build evidence, and it is important to plan effective RCTs using the results of Mendelian randomized trials and basic research.

Effective RCTs of nutritional psychiatry are scarce, but the need for them is growing. In the 21^st century, there has been a marked increase in public interest in mental health[30]. Mental illness exerts a substantial influence on individuals' lives, concurrently imposing a considerable socioeconomic burden[31]. The low response rate and adverse effects associated with drug therapy in the field of psychopharmacology have impeded the reduction of this socioeconomic burden. This underscores the imperative for novel intervention methods that do not rely on drug therapy for addressing mental illness. In 2015, the World Psychiatry organization advanced the theory of nutritional psychiatry, which posits the notion of leveraging nutritional interventions to prevent and treat mental illness[32]. This theory underscores the necessity to develop customized nutritional intervention programs tailored to individual patients. While the factors that determine mental health are complex, there is a strong association between an unhealthy diet and the worsening of mood disorders, such as anxiety and depression, and other neuropsychiatric disorders. However, the study noted that, despite the 2015 recommendation by World Psychiatry organization, there is a paucity of effective RCTs in nutritional psychiatry with sufficient detection power. There is an absence of compelling evidence to support the notion that interventions tailored to specific nutritional factors exert a favorable influence on mental health. The heterogeneity of study results and variation in the quality of evidence pose challenges for study planning and clinical decision-making. Consequently, a comprehensive and systematic understanding of nutrition and psychiatric disorders remains elusive.

The necessity for high-quality, adequately powered RCTs is evident to establish a robust evidence base for nutritional psychiatry. Observational and basic research have demonstrated that inflammation, oxidative stress, gut microbiota, mitochondrial dysfunction, and neuroplasticity are potential mechanisms by which nutritional factors affect psychiatry[33-35]. The design of RCTs should be informed by these hypothesized mechanisms to ensure the relevance and validity of the research findings. The design of RCTs using such markers is crucial for substantiating the efficacy of nutritional interventions in psychiatry. The utilization of evidence derived from valid RCTs has the potential to contribute to the prevention and treatment of psychiatric disorders, thereby reducing the socioeconomic burden associated with these conditions.

Current dietary strategies and origins of the idea of nutritional psychiatry

Dietary strategies can be a valuable tool in the treatment of mental illness. People with mental illness should be screened for nutritional deficiencies. This can be done using a variety of methods, such as a dietary questionnaire or a blood test. A detailed dietary history should be obtained from all patients. This should include information about the patient's usual food intake, as well as any food allergies or intolerances. An assessment of gut health may also be helpful. This can be done using a variety of methods, such as a stool test or a breath test. Thus, individuals with mental illness should be provided with individualized dietary counseling. This should include education about the importance of a healthy diet for mental health, as well as specific recommendations for dietary changes. In some cases, nutritional supplementation may be necessary to correct nutritional deficiencies. Probiotics may be helpful for improving gut health and cognitive function. Individuals with mental illness could be encouraged to make dietary changes that are sustainable and easy to adhere to, such as eating a variety of fruits, vegetables, and whole grains[36]. Outcome measures, such as mood scales and cognitive tests, can be used to assess the effectiveness of the dietary intervention. Specific dietary recommendations for mental illness include below. For depression, a diet rich in omega-3 fatty acids, B vitamins, and vitamin D may be helpful for improving mood and reducing symptoms of depression. For anxiety, a diet that is low in processed foods and high in fruits, vegetables, and whole grains may be helpful for reducing anxiety symptoms. For bipolar disorder, a diet that is low in processed foods and high in fruits, vegetables, and whole grains may be helpful for stabilizing mood. For schizophrenia, a diet that is low in processed foods and high in fruits, vegetables, and whole grains may be helpful for improving cognitive function and reducing symptoms of schizophrenia. For attention-deficit hyperactivity disorder, a diet that is low in processed foods and high in fruits, vegetables, and whole grains may be helpful for improving attention and reducing hyperactivity. For autism spectrum disorder, a gluten-free and casein-free diet may be helpful for some children with autism spectrum disorder[37].

The idea of nutritional psychiatry owes its origins to the work of two great men named Rudolf. The human body is incapable of sustaining its functions without a constant infusion of nutritional elements. As posited by the German theoretical physicist Rudolf Clausius, the natural world is governed by the law of increasing entropy. To maintain function, energy must be continuously infused to reduce entropy[38]. In adults, the infused energy is replaced by elements that comprise the body's proteins, in addition to energy, as demonstrated by the experiments of Rudolph Schoenheimer. Schoenheimer's experiments demonstrated that when adult mice were fed food containing nitrogen-15-labeled leucine, only 29.6% of the nitrogen-15 administered was excreted in urine and feces, while more than half, 56.5%, was incorporated into the proteins that make up the body[39]. It is noteworthy that approximately half of the proteins comprising a mouse's entire body are replaced with new proteins over a period of 3 days. The necessity for organisms to undergo constant change at the elemental level through nutrition to ensure survival and functionality is underscored by this observation. This underscores the significance of nutrients at a molecular level in preserving bodily functions. Evidence-based nutritional factor interventions should be considered as cost-effective mental health measure. However, as demonstrated in this scoping review, there is currently a paucity of established evidence in the field of nutritional psychiatry. Consequently, there is a pressing need to devise and validate novel RCT protocols through the refinement of measurement factors, informed by the findings of MR research, fundamental research, and epidemiological research.

Limitations of the study

This study had several limitations. First, the fact that no rigorous RCTs on diet were found in nutritional psychiatry research is a major limitation of this review. Second, this scoping review employed the search term "nutritional psychiatry," which resulted in the exclusion of articles that did not include this term. A concept analogous to nutritional psychiatry is psychobiotics, and it is imperative to augment the number of analogous search terms and conduct further investigations. Finally, no search was conducted for ongoing clinical trials. Although the search did result in registered RCTs and protocol-level articles, these were not included in this review as the results are not yet available.

CONCLUSION

A review of RCTs in nutritional psychiatry has demonstrated that probiotics have been shown to modify gut microbiota patterns and enhance cognitive function via the microbiota-gut-brain axis. There has been minimal improvement in the psychiatric symptoms observed; however, the quality and quantity of RCTs in nutritional psychiatry are inadequate. The challenge in conducting effective RCTs in this field is believed to stem from the presence of numerous confounding factors, including lifestyle influences, and the relatively modest effect sizes of specific nutritional factors on mental status. To bolster the evidence in nutritional psychiatry, it would be advantageous to disseminate the findings of nonlinear MR studies and fundamental research into the development of effective RCTs.