Feeding the mood: The role of macronutrients in depression prevention and treatment

Abstract

Depression is a complex mental health disorder that significantly impairs quality of life and affects millions globally. Emerging evidence underscores a potential link between macronutrient imbalances and depression onset or progression. This review explores how macronutrients—carbohydrates, fats, and proteins—may influence depressive symptoms. For example, excessive sugar consumption is associated with heightened depressive risk, likely due to its effects on insulin resistance and inflammation. Conversely, sufficient protein intake appears to mitigate depression risk, with studies reporting that a 10% increase in caloric intake from protein correlates with a significant reduction in depression prevalence. However, diets rich in saturated fats and proteins may slightly elevate depressive risk. This review emphasizes the critical importance of dietary balance in promoting mental health. Although some studies have suggested that maintaining specific macronutrient ratios may be associated with a reduced risk of depression, given the diversity of evidence and contradictory findings among studies, further research is needed to clarify the exact effects. Future research should aim to elucidate the molecular mechanisms underlying these associations, providing a robust foundation for dietary interventions in the prevention and treatment of depression.

Key Words: Macronutrients; Depression; Mental health; Dietary interventions; Clinical evidence

Core Tip: Depression is a global health problem that seriously affects quality of life. Emerging evidence suggests that macronutrient imbalance may be closely related to the occurrence and development of depression. This review examines how carbohydrates, fats, and proteins affect depressive symptoms by regulating physiological processes such as neurotransmitter activity, inflammation, and oxidative stress. Studies have found that patients with depression often present with metabolic changes and that appropriate protein intake can reduce the risk of depression. Future studies are needed to further reveal the molecular mechanisms of these associations and provide a scientific basis for dietary intervention.

INTRODUCTION

Historically, depression has been a stigmatized illness, initially considered as demonic possession or heresy, with primary treatments involving exorcism rituals conducted by various priests and clergy. Medical descriptions of its behavioral characteristics can be traced back to the Hippocratic era, where the term melancholia was used, defined as prolonged fear (phobos) or distress (dysthymia). Based on the theory of the four humors, treatments such as bloodletting were developed for melancholia, though with limited effectiveness[1]. With the long-term development of natural sciences, melancholia gradually shed its mystical characteristics and came to be regarded as a mental state worthy of observation and research. By the late 18^th century, William Cullen classified melancholia as a nervous disorder[2]. In 1806, Pinel[3] provided a significant descriptive characterization of melancholia: it manifested solely as abnormalities in emotional levels (including emotional calmness, lack of fluctuation, or an insurmountable aversion to life), while higher cognitive functions, such as understanding, remained intact. By the mid-19^th century, Guislain[4] further defined melancholia as a purely emotional disorder, primarily involving sadness, grief, anxiety, fear, and terror. This development distanced melancholia from the categories of nervous system disorders or primary intellectual disabilities, marking an important beginning for the modern concept of depression. By the late 19^th century, melancholia was defined purely as mental depression, and the term melancholia was eventually replaced by depression, which has been used since[5-7].

With the definition of depression clarified, the Patient Health Questionnaire-9 has rapidly gained recognition and widespread adoption among psychiatric researchers. Its critical significance lies in its ability to quantify depression as a measurable indicator, thereby establishing a relatively objective standardized global framework for patients, physicians, and researchers to assess diagnosis, treatment, and prognostic follow-up[8].

In 2012, the World Health Organization stated that depression results from a complex interaction of social, psychological, and biological factors[9]. As a modifiable factor, diet is a key means of antidepressant treatment. In recent years, the relationship between diet and depression has garnered considerable interest, particularly as dietary interventions are associated with lower economic and social burdens compared to pharmacological treatments[10]. Multiple nutrients have been reported to relate to the prevention and treatment of depressive disorders[11,12].

General and specific nutrient intakes and inadequate food intake are inversely associated with depression[13]. In animal studies, macronutrients have been protective against depression, and several amino acids that comprise protein have been shown to be beneficial for mental function[9]. Meta-analysis has suggested that a Mediterranean diet is associated with a reduced risk of depression[14]. A systematic review conducted by Swainson et al[15] reported improvements in mood following dietary intervention compared to the comparison group. These studies underscore the potential importance of nutritional strategies in managing depressive symptoms.

As pivotal components of diet, the three macronutrients—sugar, fat, and protein—exhibit a particularly strong association with depression. A study of diet and mood in 38 college students showed that the proportion of macronutrients in one’s diet affected long-term mood. A higher proportion of protein was associated with higher levels of depression, and a higher proportion of carbohydrates was associated with higher energy and lower levels of depression.

Thus, these studies suggest that different macronutrients have different effects on mood and food intake[16]. A considerable body of research has elucidated the relationship between macronutrients and depression[9,13]. Both an excess and deficiency of macronutrient elements are reported to elevate depression risk[13]. Numerous studies have demonstrated that excessive consumption of sweets, sugar-sweetened beverages, and candies increases depression risk[14,15], while high-fat diets are considered a risk factor for depression[16]. Furthermore, an investigation in the United States has indicated that increased protein intake is linked to a decreased risk of depression among men but correlates with an increased risk of depression in women[17].

This minireview mainly summarizes the clinical research to understand the roles for dietary macronutrient intervention in the treatment of depression.

METHODOLOGY

A search was conducted on PubMed using the search terms "(carbohydrates) AND (depression)", "(fat) AND (depression)", and "(protein) AND (depression)". The timeframe was set from 1990 to the present, and the document type was limited to "Clinical trial". Carbohydrates, fats, and proteins were all considered food-derived components. However, studies involving proteins primarily focused on mechanisms related to depression-associated proteins and pathways rather than food-derived proteins and were therefore excluded without further elaboration.

Based on the PICOS framework, studies were included in the preliminary analysis if their outcomes involved the occurrence of depression or changes in depression levels and if the intervention or comparator included differences in dietary components. Subsequently, the studies were categorized by population (male, female, or other specific groups). If randomized controlled trials (RCTs) existed for a specific population, studies with lower levels of evidence were not considered. If no RCTs existed for a specific population, only the study with the largest sample size was analyzed. For studies with inconsistent findings within the same population group, all were included for discussion.

As this is a descriptive review rather than a systematic review, no quality or bias analysis was performed on the included literature. Instead, the limitations of the studies are discussed.

CARBOHYDRATES

As early as the 1980-1990s, there were studies linking carbohydrate intake and depression. An observational study by de Castro[18] reported significant inverse associations between depression symptoms and carbohydrate intake among free-living individuals. However, this study was conducted quite a long time ago, with a small sample size, short follow-up period, and lacked effective scales for assessing depression, which may have led to inaccurate results. In 1991, Brezezinski et al[19] conducted a study on 17 women that focused on premenstrual depression by examining the effects of d-Fenfluramine (a drug that releases serotonin and blocks its reuptake). They found that d-Fenfluramine could suppress excessive calorie, carbohydrate, and fat intake and alleviate premenstrual depression. This study only demonstrated that with pharmacological treatment, women suffering from premenstrual syndrome consumed fewer carbohydrates and experienced reduced depressive symptoms, but it did not delve into the cause-and-effect relationship between depression and reduced carbohydrate intake. The conclusions of the two studies are in direct opposition: Does carbohydrate intake exacerbate or alleviate depressive symptoms? Although these studies were conducted over 30 years ago, they still laid the foundation for research on carbohydrates and depression, establishing it as a highly controversial topic worthy of exploration.

The link between carbohydrates, neurological function and mood was based on the fat that glucose is the primary energy source of the brain, high-carbohydrate diets increase serum tryptophan concentrations and serotonin synthesis, and that carbohydrate cravings have been reported in people with depression. Carbohydrates are also linked to inflammatory mediators, increase the hypothalamic–pituitary–adrenal axis activity and increase serum cortisol concentrations[20].

Some studies focusing on high carbohydrate intake primarily include high-glycemic load (high-GL) and high-glycemic index (high-GI). Depression usually co-exists with other diseases. For depressed patients with different underlying diseases, the role of carbohydrates is also distinct. For example, obese patients may consume more carbohydrates, further aggravating obesity. Cheatham et al[21] noted that for obese patients, high-carbohydrate and high-GL diets reported negative effects on mood compared to low-carbohydrate and low-glycemic load (low-GL) diets. Another RCT proposed that a high-GL diet resulted in a higher score for depressive symptoms compared to a low-GL diet. Meanwhile, subgroup analysis showed that overweight/obese participants had severe depressive symptoms compared to healthy weight participants[22]. The first study[21] included 42 overweight adults [age 35 ± 5 years; body mass index (BMI) 27.8 ± 1.6 kg/m²], while the second study[22] recruited 82 healthy weight and overweight/obese adults aged 18–45 years [healthy weight (BMI > 18.5 to < 25.0 kg/m²) and overweight/obese (BMI ≥ 28.0–40.0 kg/m²)]. The intervention in both studies involved either a high-GL or low-GL diet, with the second study specifying the energy proportions (55% energy from carbohydrates, 30% energy from fat, and 15% energy from protein). These studies focused on the relationship between obesity and depression and suggested that a high-carbohydrate, high-GL diet had adverse effects on depression. However, these studies both had small sample sizes and primarily emphasized glycemic load, with no focus on calorie proportions of carbohydrates. Therefore, further investigations need to be refined and expanded.

The glycemic index of carbohydrates is also important. Gangwisch et al[23] found a progressively higher dietary glycemic index to be associated with increasing odds of depression incidence and suggested that high-GI diets could be a risk factor for depression in postmenopausal women. Furthermore, a cross-sectional analysis by Gopinath et al[24] showed that participants in the highest tertile of dietary glycemic index intake had increased likelihood of having depressive symptoms compared to those in the lowest tertile. The first study[23] was a prospective cohort study that included 87618 postmenopausal women, while the second[24] was a cross-sectional study involving more than 4000 elderly individuals. Although different scales were used to assess depression, both studies revealed an association between high glycemic index and depression incidence. These two studies had relatively large sample sizes, but their focus was on glycemic index, with no elaboration or exploration of the impact of the proportion of carbohydrate-derived energy on depression.

However, a high carbohydrate diet is not necessarily detrimental and may have no effect or even benefit. Another example is that people with seasonal affective disorder may be inclined to ease their depression by eating more carbohydrates. However, Danilenko et al[25] found that in patients with seasonal affective disorder, neither a carbohydrate-rich diet at breakfast nor in the evening demonstrated any clinical improvement of winter depressive state. This study only examined 22 patients with depression who also had seasonal affective disorder, making the sample size relatively small. The study lasted just 9 days and only specified the total calorie intake (a minimum of 1600 kcal). Although it claimed to investigate a carbohydrate-rich diet, 1600 kcal is relatively low for adult patients with depression. The study did not specifically calculate the total amount of carbohydrates in the carbohydrate-rich diet or the proportion of energy derived from carbohydrates.

A clinical study by Lemmens et al[26] showed that neither a high-protein meal (En% P/C/F 65/5/30) nor a high-carbohydrate meal (En% P/C/F) 6/64/30) affected depressive symptoms. This study included 19 women and 19 men with BMIs ranging between 18.9-30.5 kg/m². Encouragingly, this study explored the impact of a high-carbohydrate proportion on depression, although the results were negative. This may be related to the small sample size and short follow-up period. Nevertheless, it prompts us to consider: What would the results be if the proportion of carbohydrates were altered?

For binge eating disorder combined with depression, researchers divided patients into three groups. Group 1 received a 1700-kcal diet (21% proteins, 27% lipids, 52% carbohydrate), cognitive-behavioral therapy (CBT), sertraline and topiramate. Group 2 received the same diet, CBT and sertraline. After a 6-month intervention, ‘depression’ significantly improved only in group 2 patients, which excluded specific diet and sertraline administration as the cause of the difference[27].

In a dietary intervention for refugees suffering from depression, there was no improvement in depression or insulin resistance[28]. This may be due to the fact that the intervention in this study only replaced milled rice with brown rice, but did not limit the total calories or alter the carbohydrate caloric ratio. Moreover, the intervention measures in this study included a combination of factors such as diet, exercise, sleep, and medication. The lifestyle factors were difficult to control, and there were many confounding variables.

Meanwhile, for malnourished elderly patients, a randomized controlled study found that increased carbohydrate and protein intake showed significant improvements in cognitive function and depressive symptoms[29]. For such patients, carbohydrates are beneficial. It suggests that we should pay attention to the underlying diseases when studying the relationship between carbohydrates and depression. At the same time, further studies should focus on the calorie changes of carbohydrates before and after nutritional interventions.

On the other hand, biological sex should be considered. In a study of 211 low-income African Americans with diabetes, females had a higher percentage of daily carbohydrate consumption and a higher incidence of severe depression compared to males[30]. But these data were only baseline characteristics, and the study did not definitively suggest whether a correlation exists between carbohydrates and depression.

Because high carbohydrates seemed to cause controversy and confusion, researchers have wondered whether dietary interventions to reduce carbohydrates would make a difference. The relationship between depression and carbohydrate consumption is likely bidirectional. There have been studies on reducing carbohydrate intake, but the results varied depending on the status of underlying diseases. Unfortunately, most studies have only focused on reducing the total amount of carbohydrates without investigating the effects of reducing the proportion of energy derived from carbohydrates.

A low-calorie diet (including 50%-60% carbohydrates, 15%-20% protein, 20%-35% fat, and 25 g of fiber/day plus a restriction of 500-1000 kcal/day) helped reduce body weight, BMI, insulin resistance, inflammatory markers, and depression scores in postmenopausal women[31]. In this study, the BMI of 60 postmenopausal women was 35.93 ± 2.67 kg/m², classifying them as obese. A low-calorie diet was beneficial for them, and the results indeed showed an improvement in depression scores. However, there was bias in participant selection.

Meanwhile, dietary therapy combined with exercise improved perimenopausal depression symptoms. A randomized controlled study showed that after 12 weeks of intervention, the intake of cereal, meat, fats and oils of the intervention group was significantly lower compared to baseline. The total Kupperman Menopause Index (KMI) score, as well as the individual KMI scores for depression of the intervention group were significantly lower compared to the control group[32]. This study highlighted the diet pattern and restricted proportion of energy: Carbohydrate 55%-65%; fat 20%-30%; protein 10%-15%. However, this study did not separately explore the impact of carbohydrates, proteins or fats on depression scores. The intervention also included exercise, which impacted the results.

The National Health and Nutrition Examination Survey (NHANES) is a meticulously designed nationwide survey collecting representative data from general individuals within residential communities. It includes demographic data, physical exam results, lab tests, dietary information, and survey responses. Tan et al[33] conducted a cross-sectional study utilizing NHANES data spanning 2005–2020 and suggested that a higher caloric ratio of carbohydrate intake is significantly associated with an increased likelihood of depressive symptoms among United States adults. Oh et al[34] analyzed the NHANES datasets of the United States (NHANES, 2005 to 2016) and South Korea (K-NHANES, 2014 and 2016) and identified an association between carbohydrate intake and the prevalence of depression in the United States but not in South Korea.

The definitions of "high-carbohydrate" and "low-carbohydrate" remain unclear, and most studies do not restrict the proportion of energy contributed by the three macronutrients. The terms "high" and "low" are relative concepts used to describe the experimental and control groups in studies (including high total energy and high energy contribution). The purpose of our research is to determine the distinction between "high" and "low" when possible, providing guidance for clinical practice. The correlation between carbohydrates and depression is an area of active research.

Taken together, the above studies suggest that increased carbohydrate intake does not ameliorate depression. Different underlying diseases, different genders, different carbohydrate caloric ratios, different study duration and assessment scales (i.e., screening tools and diagnostic tools) all have an impact on research results. Carbohydrate intake should be limited to a reasonable range, and particular focus should be put on the caloric ratio of carbohydrates. In addition, more studies are required to determine the cause-and-effect relationship between high carbohydrate intake and depression. Compared to other macronutrients, research on carbohydrates is more comprehensive (Table 1), likely due to the ease of controlling variables and better compliance of patients with dietary restrictions on carbohydrates. In addition to exploring potential underlying mechanisms, future studies should focus on clearly defining study populations, specific categories of carbohydrates, and effectively adjusting for the influence of other nutrients. This will help advance research in this field and provide more detailed dietary guidance.

Table 1 The outline of clinical researches on the relation between depression and carbohydrates.

Ref.	Research type	Country	Population (P)	Intervention (I)	Comparison (C)	Duration	Assessment scales	Outcome	Limitations
de Castro[18], 1987	Observational study	United States	8 male and 30 female undergraduate students	-	-	9 days	7 point mood rating scales	High proportionate carbohydrate intake correlated with energy and negatively with depression	Observational study; small sample size; insufficient follow-up time; lack of sensitivity in assessment scales
Brezezinski et al[19], 1991	RCT	United States	17 women with premenstrual syndrome	D-fenfluramine	Placebo	The luteal phases of six menstrual cycles	Hamilton Rating Scale for Depression and its Addendum	D-fenfluramine decreased premenstrual Hamilton Rating Scale for Depression and Addendum scores by 62%. Kilocalorie, carbohydrate, and fat intakes suppressed	Small sample size
Cheatham et al[21], 2009	RCT	United States	42 overweight adults aged 35 ± 5 years	High-GL diet	Low-GL diet	6 months	POMS questionnaire	High-GL diet was associated with a poorer mood outcome for depression at the sub-clinical level compared to the low-GL diet	Small sample size; without investigating the energy contribution ratio of carbohydrates
Breymeyer et al[22], 2016	RCS	United States	82 healthy weight and overweight adults aged 18-45 years	High-GL diet	Low-GL diet	Two 28-days	POMS subscales; CES-D scale	High-GL diet resulted in a 38% higher score for depressive. Symptoms on the CES-D compared to the low-GL diet. The overweight/obese participants had 40% higher scores on the CES-D scale compared to healthy weight participants	Small sample size; insufficient follow-up time; without investigating the energy contribution ratio of carbohydrates
Gangwisch et al[23], 2015	Prospective cohort study	United States	87618 postmenopausal women aged 50-79 years	High-GI diet	Low-GI diet	3 years	the Burnam 8-item scale	High-GI diets could be a risk factor for depression in postmenopausal women	Without investigating the energy contribution ratio of carbohydrates
Gopinath et al[24], 2016	ross-sectional study	Australia	2334 participants aged 55+ years and 1952 participants aged 60+ years	Dietary information was collected using a semi-quantitative FFQ	-	-	Mental Health Index scale and antidepressant use and CES-D-10 scale	Dietary glycemic index is associated with the prevalence of depressive symptoms	Cross-sectional study; without investigating the energy contribution ratio of carbohydrates
Danilenko et al[25], 2008	RCT	Russia	22 unmedicated, DSM-IV-diagnosed depressed women with seasonal affective disorder aged 19-63 years	Morning carbohydrate-rich diet, evening carbohydrate-rich diet, or evening protein-rich diet (1600 kcal)	-	9 days	DSM-IV and SIGH-SAD score	None of the three nine-day diets had a selective mood-elevating effect upon winter depression	Small sample size; insufficient follow-up time; without investigating the energy contribution ratio of carbohydrates
Lemmens et al[26], 2011	RCS	The Netherlands	38 Caucasian subjects aged 18-51 years	A high-protein meal (En% P/C/F 65/5/30)	A high-carbohydrate meal (En% P/C/F 6/64/30)	4 times in a fasted state between 08: 00 and 9: 00 AM	POMS and STAI questionnaires	Consumption of the high-protein vs high-carbohydrate meal did not affect feelings of depression	Small sample size; insufficient follow-up time; without investigating the energy contribution ratio of carbohydrates
Brambilla et al[27], 2009	RCT	Italy	30 BED patients	Three treatment groups: A 1700-kcal diet, CBT, Sertraline and topiramate; or the same diet, CBT, sertraline; or nutritional counselling and CBT	-	6 months	the SCL-90-R and the PDQ-4-R	Group 2 patients improved on the SCL-90-R subitems ‘depression’	Small sample size
Wagner et al[28], 2023	RCT	United States	188 participants, aged 35–75 years	lifestyle intervention called EWS; EWS plus medication therapy management	Social services	12 months	Unclear	No health behavior changes were associated with improved depression	Lifestyle is difficult to control; many confounding factors
Endevelt et al[29], 2011	RCT	Israel	127 eligible participants aged < 75 years	Dietetic Intervention treatment	Non-randomized “untreated nutrition”	6 months	The geriatric depression Screening Scale	The dietetic intervention treatment group showed a significant improvement in intake of carbohydrates and protein, and showed significant improvement in cognitive function and depression score	The underlying condition is malnutrition, and dietary habits were not considered
Lynch et al[30], 2017	RCT	United States	211 Low-income African Americans	Females	Males	18 months	Incidence of depression	Males consumed more daily calories, but females consumed a greater proportion of carbohydrates. Females were found to have a higher incidence of severe depression compared with males	Dietary habits were not considered
Elsayed et al[31], 2022	RCT	Egypt	60 postmenopausal women aged 66.61 ± 4.80 years	Laser biostimulation and low-calorie diet (50%-60% carbohydrates, 15%-20% protein, 20%-35% fat, 500-1000 kcal/day)	Low-calorie diet	12 weeks	HAMD-17	Both experimental group and control group showed a reduction in the body weight, BMI, IR, inflammatory markers, and depression scores	Small sample size; insufficient follow-up time
Xi et al[32], 2017	RCT	China	60 patients with perimenopausal syndrome	Health education, diet supervision and exercise supervision twice a week	As normal	12 weeks	KMI score	The total KMI score and the individual KMI scores for depression were significantly lower in experimental group compared with the control group	Small sample size; Insufficient follow-up time

RCT: Randomized controlled trial; High-GL: High-glycemic load; Low-GL: Low-glycemic load ; POMS: Profile of Mood States; CES-D: Center for Epidemiological Studies - Depression; RCS: Cross-sectional study; FFQ: Food Frequency Questionnaire; STAI: State Trait Anxiety Inventory; BED: Binge-eating disorder; CBT: Cognitive-behavioral therapy; SCL-90-R: Symptoms Check List-90-Revised; PDQ-4-R: Personality Diagnostic Questionnaire-4-Revised; EWS: Eat, Walk, Sleep; HAMD: Hamilton Depression Rating Scale; BMI: Body mass index; IR: Insulin resistance; KMI: Kupperman Menopause Index.

FATTY ACIDS

The role of fatty acids in depression is still controversial. Fatty acids consist of saturated fatty acids and unsaturated fatty acids (monounsaturated fatty acids and polyunsaturated fatty acids). The fatty acid family is vast, and so far, only omega-3 fatty acids have been studied. Fatty acids are primarily obtained from meat and fish, which encompass diverse types of food. Thus, the research on fatty acids are relatively complicated.

For females, omega-3 fatty acids are beneficial for preventing postpartum depression. Epidemiological studies have shown associations between a greater annual fish intake and lower depression rates[35]. But another cross-sectional study came to the opposite conclusion, showing that vegetarians had a better mood than omnivores, even though their intakes of both omega-3 and omega-6 fatty acids were lower. Another two-week RCT by the same research team found that depression improved with the restricted consumption of meat, fish, and poultry[36]. However, the latter study was short in duration and did not specify the caloric ratios of different fatty acids.

There were also some studies of omega-3 fatty acids in patients with cancer and depression. For example, researchers attempted to study whether supplementation with long-chain omega-3 polyunsaturated fatty acids improved quality of life in prostate cancer patients with depression[37]. Researchers also studied whether reducing the fat-caloric ratio of breast cancer patients to less than 25% had an effect on depression[38]. However, the above two studies were protocols and the results have not yet been published.

The NHANES database analyzed by Jihoon Oh et al[34] showed that fat intake was not significantly associated with depression in either the United States or South Korea.

PROTEINS

Because of the wide variety of proteins, it is not easy to study the correlation between proteins and depression. Clinical studies of dietary proteins primarily focused on some amino acids and peptides. Lemmens et al[38] showed that a protein-rich meal increased cortisol levels. However, consumption of a high-protein meal appears to have limited impact on stress-related eating behavior compared to a high-carbohydrate meal[39].

A study by Firk and Markus[40] showed that intake of tryptophan-rich hydrolyzed protein increased positive mood to acute stress. Dietary tyrosine supplementation may serve as a dietary prevention strategy to protect against postpartum depression. Notably, it did not increase the total amount of tyrosine in breast milk and has little effect on breastfeeding[41].

In addition, the blood level of acetyl-L-carnitine is significantly lower in patients with depression than in healthy persons, and supplementation with acetyl-L-carnitine decreased the depressive symptoms in several clinical studies[42].

Besides amino acids, peptides are also an important area of research. Studies have shown that decapeptides from whey protein can significantly improve depression[43]. Peptides from soy protein, rice protein, casein, or whey from milk-derived proteins have been shown to have antidepressant or anxiolytic effects[44-46]. Among them, oligopeptide from β-conglycinin in soy protein or rice endosperm protein have been confirmed to improve negative emotions in humans[47].

The role of dairy product consumption in mental disorders (i.e., depression and anxiety) has been the focus of increased research interest. A protocol to assess the potential effects of consumption of A2 beta casein only vs conventional dairy containing both A1 and A2 beta-casein on symptoms of depression has been published[48].

Using the NHANES database, Oh et al[34] suggested that a 10% increase in proportion of caloric intake by protein significantly decreased the prevalence of depression in both the United States and South Korea.

DISCUSSION

Current research may yield different results due to depression being associated with various underlying conditions. Studies on carbohydrates have primarily focused on specific populations, including healthy individuals, obese individuals, and postmenopausal women. A high total carbohydrate intake and a high carbohydrate energy proportion may have negative effects; however, due to varying intervention measures, increasing carbohydrate intake in populations with binge eating disorder, refugees, or individuals with malnutrition and depression may have little impact. Most studies have only focused on the total amount of carbohydrates without investigating the energy contribution proportion of carbohydrates.

As the most accessible and adjustable components of daily diet, macronutrients play a significant role in the development, progression, and treatment of depression. Macronutrients may influence the development of depression through the following mechanisms:

Carbohydrates (Sugar): A high-sugar diet can affect 5-hydroxytryptamine (5-HT) levels in the brain, with reductions in 5-HT being a key factor implicated in the pathogenesis of depression. Animal studies have demonstrated that a high-sugar diet reduces the activity of dendritic 5-HT-1A receptors, potentially disrupting the feedback control of serotonin synthesis and release in the hypothalamus. This disruption can lead to decreased 5-HT levels, which leads to depression[49]. Although studies have shown that a high-sugar diet reduces the activity of dendritic 5-HT-1A receptors, it remains unclear which specific cell types or brain regions are most affected. Additionally, whether other types of 5-HT receptors are involved in this process warrants further investigation. The precise mechanism by which high sugar interferes with the feedback control of serotonin synthesis and release is not fully understood, especially regarding potential regional differences within the brain.

Elevated glucose levels may contribute to depression onset by inducing inflammatory responses, characterized by increased levels of IL-6, TNF-α, IL-13, and IL-12. As an inflammatory inducer, lipopolysaccharide (LPS) activates monocytes, macrophages, endothelial cells, and epithelial cells, thereby triggering cell signaling pathways and leading to increased levels of various cytokines and inflammatory mediators[50]. These peripheral inflammatory signals cross the blood-brain barrier via endothelial cells or second messengers, reaching the central nervous system (CNS) and inducing neuroinflammation. Consequently, both peripheral and central administration of LPS can activate microglia and trigger a series of inflammatory responses, ultimately leading to the development of depression[51]. While LPS is known to induce neuroinflammation and depressive-like behaviors, the exact mechanisms linking peripheral inflammation to CNS dysfunction remain incompletely understood. The interplay between various signaling pathways, cytokines, and neural circuits requires further exploration. While significant progress has been made in understanding how LPS induces depression through inflammatory pathways, there are still several challenges that need to be addressed to fully translate these findings into clinical practice. Continued research will be essential for developing more effective treatments for inflammation-associated depression.

These elevated glucose levels may also contribute to depression by reducing serum levels of brain-derived neurotrophic factor (BDNF)[52]. BDNF is one of several endogenous proteins that plays a crucial role in the survival, maintenance, and growth of brain and peripheral neurons, and there is an association between low serum BDNF levels and major depressive disorder (MDD). Plasma BDNF concentrations were significantly reduced in suicidal patients[53]. Although low serum levels of BDNF are associated with MDD and significantly reduced BDNF concentrations have been observed in suicidal patients, most current studies are observational. There is a lack of direct evidence to determine whether reduced BDNF levels cause depression or are merely a consequence of the condition.

In conclusion, although existing research provides important clues about the role of high-sugar diets and inflammation in the pathogenesis of depression, many unknown areas need to be explored before these findings can be translated into clinical applications. These include the differences between animal models and human diseases, the elucidation of specific molecular mechanisms, and the impact of individual variability. Continued research will be essential for developing more effective antidepressant therapies.

Fats: Dietary fats are metabolized and absorbed by the body, and are subsequently converted into total cholesterol (TC). High-density lipoprotein, a major component of TC, has been linked to depression via neural signaling pathways. Chronic consumption of a high-fat diet has been associated with decreased 5-HT concentrations, reduced expression of AMPA receptors (GlutA2) and GABA receptors (GAD65), as well as downregulation of GLT-1 at synaptic sites, all of which are closely related to the development of depression[54,55].

The specific mechanism of lipid metabolism and its effect on neural signaling are not fully understood. Whether these changes directly cause depression or are a secondary effect of other physiological disorders is unclear. In addition, the downstream effects of specific brain regions and cell types are poorly understood, which poses a challenge for the development of effective therapeutic strategies.

Proteins: The precise mechanisms by which dietary protein influences depression remain insufficiently understood. However, evidence suggests that the intake of tryptophan—an essential amino acid derived from dietary proteins—may increase serotonin levels in the brain, offering potential therapeutic benefits for depression. This highlights the role of protein intake in modulating mood and its potential significance in the prevention and management of depressive disorders[56].

Novelty and limitations

Previous studies on carbohydrates have not emphasized the impact of carbohydrate energy contribution ratios on the occurrence of depression under different disease conditions. On one hand, we revisited and summarized prior research, highlighted its shortcomings, and hope to provide guidance for future investigations. On the other hand, we propose that future studies should focus not only on total carbohydrate intake but also on the energy contribution ratio of carbohydrates.

Although these studies provide valuable insights, the definition of "high-carbohydrate" remains unclear, posing challenges for consistency in subsequent research. This may help explain inconsistencies between different studies. For instance, a study by Professor Tan on carbohydrate proportion found a rapid increase in depression risk when carbohydrate intake exceeded 45% of total energy[33]. Therefore, in further exploration of this topic, providing data on carbohydrate proportions and referencing appropriate thresholds to define "high-carbohydrate" may be necessary.

Table 1 summarizes research on the relationship between dietary carbohydrates and depression. However, differences in underlying diseases, study durations, and small sample sizes have influenced the results.

First, many studies have relatively small sample sizes, limiting the generalizability of their findings. Second, although the majority of studies are interventional, the intervention measures and assessment scales vary significantly, making it difficult to establish causality. Additionally, there is variability in dietary assessment methods across studies, which may introduce bias. Finally, many studies do not adequately control for potential confounding factors, such as lifestyle habits and comorbidities.

CONCLUSION

Although substantial biological evidence regarding depression has been established, effective clinical evidence remains somewhat limited. The primary challenges may include the vast variety of dietary types, differences in underlying diseases among populations, and the combined effects of multiple factors. In the current studies, the investigation of carbohydrate intake are relatively comprehensive, but variables still need to be controlled in subsequent studies. Due to the diverse variety of fatty acids and proteins, it is difficult to strictly control variables and reveal the correlations. Moreover, the underlying diseases involved in the existing research are still limited. Further studies regarding the general population to provide public health guidance are needed. Additionally, prospective studies in large populations remain a huge challenge.