Diet Overall and Hypocaloric Diets Are Associated With Improvements in Depression but Not Anxiety in People With Metabolic Conditions: A Systematic Review and Meta-Analysis

The risk of depression and anxiety is higher in people with metabolic conditions, but whether dietary approaches, which are central to the management of metabolic conditions, can also improve depression and anxiety is uncertain. The primary aim of this systematic review and meta-analysis was to evaluate the effects of dietary interventions on depression and anxiety in adults with metabolic conditions. The secondary aim was to evaluate the effects of hypocaloric and isocaloric dietary interventions on these outcomes. Four databases (MEDLINE, PsychINFO, EMBASE, and CINAHL) were searched from inception to March 2023. Randomized controlled trials (RCTs) including dietary interventions in adults with metabolic conditions (type 2 diabetes mellitus, hyperlipidemia, hypertension, and/or overweight/obesity) that assessed depression and/or anxiety as outcomes were included. Overall, 13 RCTs were included in the systematic review, ≤13 of which were included in the meta-analysis. Estimates were pooled using random-effect meta-analysis for dietary interventions compared with controls. Improvements in depression scores were found in meta-analytic models including all dietary interventions [pooled estimate for the standardized mean difference (SMD) = −0.20 (95% CI: −0.35, −0.05); P = 0.007] and hypocaloric only diets [SMD = −0.27 (95% CI: −0.44, −0.10); P = 0.002]. There were no improvements in depression scores with isocaloric dietary interventions only [SMD = −0.14 (95% CI: −0.38, 0.10); P = 0.27]. In addition, there were no significant effects of any dietary interventions on anxiety scores. In adults with metabolic conditions, all dietary interventions and hypocaloric diets improved depression, but not anxiety. These findings suggest that dietary interventions including hypocaloric diets can play an important role in the management of depression in people with metabolic conditions. This systematic review and meta-analysis has been registered with PROSPERO (CRD42021252307).


Introduction
There are an estimated 264 and 322 million people living with anxiety and depression globally, respectively, which have been linked to reduced quality of life [1].Primary treatment includes psychotherapy and medication, but these treatments do not target other known risk factors such as physical inactivity and poor-quality diet which are common in these individuals [2,3].Hence, there is a need to include lifestyle strategies to improve the management of depression and anxiety symptoms as well as target-related risk factors such as obesity, which is commonly associated with these mood disorders [4][5][6].
Metabolic conditions including abdominal or visceral obesity, hypertension, dyslipidemia, and/or glucose dysregulation are estimated to affect 20%-25% of adults globally [7][8][9][10] and have been identified as risk factors for both depression and anxiety, with a bidirectional association being implicated [11].Social factors such as weight stigma, limits to health care access, and low socioeconomic status are also risk factors in the relationship between metabolic conditions and depression and anxiety [12,13].Those with depression and anxiety have higher rates of metabolic conditions [14,15] and vice versa [16][17][18].Multiple interrelated factors have been proposed to underpin the link between these mood disorders and metabolic conditions, including chronic, low-grade systemic inflammation and oxidative stress [19], which are exacerbated by both poor dietary habits and physical inactivity [20][21][22][23][24][25].Indeed, there is high-level of evidence that isocaloric and hypocaloric dietary approaches such as low-fat, low-carbohydrate, and the Mediterranean diet can play a role in the management of metabolic conditions [26][27][28][29].Similarly, there is emerging evidence that various dietary patterns (e.g., Mediterranean diet) and some dietary interventions (e.g., low-carbohydrate diet), can help reduce risk and symptoms of depression and anxiety [4,5,[30][31][32][33][34]. Whether dietary approaches alone, specifically including hypocaloric or isocaloric dietary interventions, can reduce risk and symptoms of depression and anxiety in those at higher risk with metabolic conditions is unknown.
The primary aim of this systematic review and meta-analysis was to evaluate the effects of dietary interventions on depression and anxiety in adults with metabolic conditions.The secondary aims were to evaluate the effects of isocaloric and hypocaloric dietary interventions separately on depression and anxiety in adults with metabolic conditions.

Methods
This systematic review was performed based on the PRISMA statement [35] and was registered in the PROSPERO database (CRD42021252307).Several changes were made to the systematic review and meta-analysis after registering with PROS-PERO.The aim was expanded from individuals with metabolic syndrome to include those with components of metabolic syndrome given there were insufficient studies with metabolic syndrome only.Additional coauthors (SS, CLF, and GA) were added to assist with specific areas of the review.The inclusion criteria were narrowed to include only randomized controlled trials (RCTs) as there were an extensive number of RCTs identified in the search, and this study design provides a higher level of evidence based on the National Health and Medical Research Council Evidence hierarchy [36].Regarding "mood," the outcomes changed to depression and anxiety only.Therefore, the title has been changed along with the primary and secondary aims to specifically reflect that we included adults with metabolic syndrome, or its components, and the focus was specifically on dietary interventions with depression and/or anxiety as outcomes.Additional outcomes extracted include changes in weight to help identify whether improvements were influenced by changes in weight (e.g., weight loss).A meta-analysis was conducted by pooling estimates using random-effect models with subgroup analyses to determine the effects of 1) hypocaloric and 2) isocaloric dietary interventions separately on depression and anxiety outcomes.

Data source
A detailed search was conducted using MEDLINE, PsycINFO, EMBASE, and CINAHL databases from inception to 1 March 2023.English language, humans, and peer-reviewed article filters were applied at the end of each database search.Additional publications were also identified from reference lists of systematic reviews and relevant articles.Details of the search terms used for all the 4 databases can be found in Supplemental Figures 1-4.

Types of studies
Only RCTs were included.Prospective cohort studies, onearm pilot studies, case-control, cross-sectional, and case-series studies and reviews, letters, editorials, commentaries, animal studies, and duplicate studies were excluded as these study designs do not allow a comparison of the effects of a dietary intervention compared with control.

Participants
Studies with participants aged 18 y or older with metabolic conditions, which included metabolic syndrome (defined as 3 of the 5 criteria: obesity, hyperglycemia, dyslipidemia, hypertension) [37], and/or overweight or obesity (BMI ! 25 kg/m 2 ), and/or prediabetes or type 2 diabetes mellitus (T2DM), and/or hypertension, and/or hyperlipidemia, and/or steatosis, and/or metabolic associated fatty liver disease, and/or nonalcoholic steatohepatitis were included.These metabolic conditions were diagnosed based on the criteria outlined in the respective studies.Participants did not have to be formally diagnosed with clinical depression and/or anxiety to be included.Studies were excluded if they only included healthy weight participants with no metabolic comorbidities, were residents at aged care facilities, inpatients at psychiatric hospitals, or if the study population involved participants with other psychiatric diseases and mental disorders, including schizophrenia, bipolar disorder, post-traumatic stress disorder, eating disorders, attention-deficit/hyperactivity disorder, and obsessive-compulsive disorder.

Interventions
Interventions that evaluated the effects of any type of dietary intervention described in sufficient detail were included.Sufficient detail was defined as a "whole of diet approach," including the main components of the diet such as energy intake and/or food groups and/or macronutrients or interventions with individual or group dietary counseling or nutrition education.All RCTs required a dietary intervention and a control comparison group.Dietary interventions with a combined intervention (e.g., with exercise, stress management, additional dietary supplement(s), cognitive behavioral therapy, pharmaceutical, psychotherapy) were included but only if they contained a diet-only arm and a control group.The control group could include participants following their habitual lifestyle or general information (e.g., a leaflet) about a healthy diet with no prescribed energy recommendations or basic range-of-motion stretches and calisthenic movement.

Outcome measures
The primary outcome measures were depression and/or anxiety scores, which were derived from validated surveys.Data were extracted if depression and/or anxiety values at baseline and postintervention or mean pre-post change scores or between-group differences in change scores were reported.Authors of relevant studies were contacted (if after reading the full text) baseline and/or postintervention values or mean pre-post change scores were not reported.If these data could not be obtained, the study was excluded.

Study selection
Publications resulting from the database searches were imported and duplicates were removed using Endnote and Covidence.Screening of title, abstract, and full text were completed using Covidence by 2 independent reviewers (TP and CLF).Studies included after the first screen were read in full, independently by the 2 reviewers (TP and SS) and assessed for eligibility based on the inclusion criteria.Conflicts between reviewers were resolved by a third reviewer (ESG).

Data extraction and data items
Data extraction for each article in the systematic review was done manually by 1 independent reviewer (TP), which was checked by a second reviewer (SS).Other authors were consulted for clarification on data and outcomes as needed.Data extraction included the following: 1) participant characteristics (number of participants, sex, study population, age, and the demographic location of the study); 2) the duration of the intervention and details of the dietary intervention and control group(s); 3) the method of assessment for depression and/or anxiety scores; 4) between-group differences in depression and/or anxiety scores and weight with statistical analyses; and 5) within-group differences in depression and/or anxiety scores and weight with statistical analyses.

Risk of bias and study methodological quality assessment
The Cochrane Risk of Bias Tool was used to assess risk of bias (high risk, low risk, and unclear) and the studies' overall quality rating.The Risk of Bias tool version 2.0 [38] assesses bias under the following domains: sequence generation (selection bias), allocation concealment (selection bias), blinding of participants and personnel (performance bias), blinding of outcome assessors (detection bias), incomplete outcome data (attrition bias), selective outcome reporting (reporting bias), and other sources of bias.Risk of bias in all included studies was completed independently by 2 reviewers (TP and SS) for each study.If there were conflicts a third reviewer (ESG) was consulted for an outcome.

Statistical analysis
For both depression and anxiety, the intervention and control groups were compared on the mean changes from baseline to postintervention for each study.For the primary aim, we included dietary interventions for depression and anxiety separately in adults with metabolic conditions.For the secondary aims, we compared the effect of 1) only isocaloric dietary interventions on depression and anxiety separately in participants with metabolic conditions, and 2) only hypocaloric dietary interventions on depression and anxiety in participants with metabolic conditions.Therefore, a total of 6 meta-analyses were conducted.Pooled data were analyzed using a random-effects model in ReviewManager 5. We used random-effects models given that there was no common fixed parameter, studies estimated different parameters, and the interventions were different [39].Heterogeneity was assessed with the standard Chi-square (significance level: 0.1) and I-squared statistics (70%-100% interpreted as considerable heterogeneity, 69%-40% moderate heterogeneity, <40% minor heterogeneity) [40].Results are presented as standardized mean differences (SMD) with 95% CIs and shown in forest plots.Possible publication bias was examined through visual inspection of funnel plots for all studies in all meta-analyses combined and by technique, the regression-based Egger test for small-study effects, and nonparametric trim-and-fill analysis using Stata/BE 17.0.

Study selection
Four databases (MEDLINE, psychINFO, EMBASE, CINAHL) were searched resulting in a total of 20,687 studies.After removing duplicates 15,954 articles were screened based on title and abstract, from which 219 remained for full-text screening.One study was excluded as the authors only reported baseline depression scores and not postintervention or mean pre-post change score data for depression and did not respond when contacted [41].Overall, 13 RCTs met the eligibility criteria and were included in the meta-analyses [42][43][44][45][46][47][48][49][50][51][52][53][54].Full PRISMA flow chart of database searches and included studies in the systematic review and meta-analysis are shown in Figure 1.

Dietary intervention group characteristics
Dietary interventions differed across all the included studies.Four studies provided nutrition education and counseling [42,43,53,54], with topics including following a low-fat vegan diet [42], a plant-based diet [43], high-fiber foods and nutrients for the microbiome [53], or a Mediterranean Dietary Approaches to Stop Hypertension (DASH) for neurodegenerative delay [54].The DASH diet promotes sodium restriction and an increase in potassium intake, increasing fruits, vegetables, whole grains, low-fat dairy, lower saturated and total fat with a Mediterranean diet high in olive oil, green vegetables, fruits, moderate fish and other meats, cereals, nuts, legumes, dairy products, low intake of eggs, red wine, and sweets [54].

Control group characteristics
Five of the 13 control groups had participants who continued their habitual lifestyle [42,45,47,[52][53][54].Two studies had control participants continuing their habitual lifestyle with a placebo, one with wheat starch and additives [44] and the other with corn oil [43].One provided an advice leaflet based on the Arthritis Research Campaign (United Kingdom) leaflet for osteoarthritis of the knee, (information related to the intervention removed) and home visits conducted every 4 mo where participants were asked about their general wellbeing and lifestyle, with additional support via phone calls between home visits FIGURE 1. PRISMA flow diagram for the screening, inclusion, and exclusion of studies in this systematic review and meta-analysis.

TABLE 1
Study characteristics and changes in depression scores, anxiety scores, and weight for the 13 dietary intervention studies included in this review and meta-analysis.Abbreviations: BDI, Beck's Depression Inventory; BSI-18, Brief Symptom Inventory-18; CHO, carbohydrates; CES-D, Centre for Epidemiologic Studies Depression; DASH, dietary approaches to stop hypertension; E, energy; FA, fatty acids; FFQ, food frequency questionnaire; GDS, geriatric depression scale; GI, glycemic index; HADS, hospital anxiety and depression rating scale; HTN, hypertension; ITT, intention-to-treat; PO, orally by mouth; POMS, profile of mood states; RCT, randomized controlled trials; SF-36, Short Form-36; STAI, State-Trait Anxiety Inventory; T2DM, type 2 diabetes mellitus.[46].Another did not receive lifestyle advice or participate in the diet and exercise intervention group regimes and were given general information about a healthy diet during monthly visits with researchers [48].One prescribed 45-min sessions of stretching 4 d/wk and range-of-motion calisthenic exercises to keep heart rate below 100 beats/min [49], whereas another had participants track their daily steps [50], and one study followed the same healthy food and ratio of each component as per the dietary group without calorie restriction [51].

Dietary adherence and/or dietary intake
Dietary adherence and/or dietary intake methods and results varied considerably across all studies.Three of the 13 studies did not report dietary adherence and/or intake [46,48,51].In 8 of the 13 studies that reported dietary intake, the dietary intervention group overall showed reductions in energy [45,47,49,50,52], fat, SFA, and cholesterol [43][44][45]47,50], CHO [50], PUFA [50], MUFA [43], protein [50], and increases in fiber [43,44,53], CHO [43], dairy [53], vegetables [53], vitamins [44,52], PUFA [43,44], and MUFA [44] intake.One of 10 studies defined adherence to the vegan low-fat diet as 35% of the total energy intake from fat and cholesterol intake of 75 mg/d, with 85% of the dietary group and 21% of the control group as adherent to the vegan component (P < 0.001) and 86% of the dietary group compared with 40% of the control group as adherent to the low-fat component of the diet (P < 0.001) [42].One of the 10 studies used the Mediterranean DASH intervention for neurodegenerative delay score at baseline and after the intervention, with a maximum score of 15 indicating the highest level of adherence [54].The mean score significantly increased by 3.8 in the dietary group, with baseline and postintervention scores not reported [54].
Specific details regarding dietary adherence and/or dietary intake in each included study in the systematic review and metaanalysis can be found in Supplemental Table 1.
Results represented by þ ¼ significantly decreased (improvement) in the intervention relative to controls, -¼ significantly increased (worsened) in the intervention relative to controls, ↔ ¼ no significant difference in the intervention relative to controls.
1 Adjusted for sex, cluster, medications, and baseline values in univariate analysis.Adjusting for the baseline scores and covariates (depression: medication use, anxiety: medication use). 5 Adjusted means are changes in psychological factors adjusted for baseline scores and covariates (e.g., age, baseline BMI, marital status, anxiolytics, and antidepressant use). 6 Controlling for baseline values. 7 Adjusted for energy intake as a covariate.
Three of the 7 studies reported no significant between-group difference in depression change scores [45,48,49].The length of the intervention ranged between 3 mo and a set hypocaloric dietary intervention of 1200-1330 kcal/d [49] to 1 y [45,48] with a total daily energy intake of 1200-2000 kcal/d based on baseline weight [45] and a 500-700 kcal/d calorie deficit based on calculated calorie requirements [48].Two of the 7 studies reported significant differences between groups in favor of the dietary group for depression change scores [50,51], with the length of the interventions being a 3-mo hypocaloric dietary intervention calculated for each participant using the Scholfield equation [50] and a 6-mo 1200 kcal/d hypocaloric dietary intervention [51].One of 7 studies did not report data on differences between groups in depression change score, yet reported a significant within-group decrease in depression change score in the dietary group after a 2-y hypocaloric dietary intervention deficit of 2.5 MJ/d based on calculated requirements [46].One of 7 studies reported no significant between-group differences in depression change score, yet there was a significant within-group difference in depression change score in the dietary group after a 6-mo hypocaloric dietary intervention with a deficit of 300-500 kcal/d based on energy requirements [52].
Of the 6 studies with isocaloric dietary interventions [42-44, 47,53,54], 2 reported a significant difference in weight loss between the groups in favor of the dietary group [47,53], with only 1 study showing significant group differences for depression change scores in favor of the dietary group (a 2-mo education on food and nutrients for the microbiome intervention) [53]; the other study did not report group differences in depression change score, however, there was no significant within-group improvement in depression change score in the dietary group after a 1-y low-fat, SFA, and cholesterol dietary intervention [47].One study did not report data on weight but reported a significant group difference in depression change scores in favor of the dietary group after 4 and a half months of a low-fat vegan dietary intervention [42].One study reported no significant difference between groups in depression change score and weight loss, however, there was a significant within-group increase (worsening) in depression change score after a 3-y plant-based counseling intervention [43].One study reported no significant within or between-group differences for changes in weight or depression scores after a 1 mo Mediterranean DASH dietary intervention [54], and 1 study did not report data for the between-group differences for changes in weight or depression score, however, there was no significant within-group differences for changes in weight or depression scores after the 6-mo Mediterranean dietary intervention [44].
Of the 5 isocaloric dietary interventions, 1 study reported (after a 1-y low-fat, SFA, and cholesterol dietary intervention) that there was a significant between-group difference for weight loss favoring the dietary group, but no significant within-group difference for anxiety change score, as between-group data were not reported [47].One of 5 studies did not report data on weight after a 4-and-a-half month low-fat vegan dietary intervention, however, there was a significant between-group difference in anxiety change score favoring the dietary intervention [42].One of 5 studies reported no significant between-and within-group differences in weight loss and anxiety change scores after a 1-mo Mediterranean DASH dietary intervention [54].One of 5 studies reported no significant between-group difference weight loss and anxiety change scores, however, there was a significant within-group increase (worsening) in anxiety change scores and no change in weight after a 3-y plant-based dietary counseling intervention [43].One study reported no significant within-group differences in weight loss and anxiety change scores in a 6-mo Mediterranean dietary intervention, as data for between-group differences were not reported [44].

Risk of bias
Figure 8 shows risk of bias assessment for all 13 studies with risk of bias graph included in Supplemental Figure 5.Using the Cochrane Risk of Bias Tool Version 2 [38], 10 studies obtained an overall result of "poor quality," which was due to >2 criteria scoring "high risk" or "unclear" [42-47, 49,50,52,53].Three studies obtained an overall result of "fair quality" because they scored "unclear"/"high risk" on 2 criteria [48,51,54].Potential publication bias was first checked via examination of funnel plots.Funnel plot asymmetry was not evident.
The regression-based Eggers test produced nonsignificant results for all meta-analyses, indicating little evidence of smallstudy effects.However, the trim-and-fill analyses indicated potential publication bias in 3 of the meta-analyses examining: 1) dietary interventions on depression scores, 2) hypocaloric dietary interventions on anxiety scores, and 3) isocaloric dietary interventions on depression scores, with pooled estimates including imputed studies showing a statistically significant difference in the original pooled estimate compared with the trim-and-fill analysis.Full analysis of all funnel plots and trimand-fill analyses for each meta-analysis is reported in Supplemental Figures 6-11.

Discussion
This systematic review and meta-analysis is the first to our knowledge, to comprehensively evaluate the effects of dietary interventions on depression and anxiety in adults with common metabolic conditions.Our findings indicate that there was a beneficial effect of all dietary interventions, including only hypocaloric diets, on depression but not anxiety in adults with various metabolic conditions.In contrast, isocaloric dietary interventions only were not associated with a beneficial effect on either depression or anxiety scores.
The key finding from this meta-analysis was that dietary interventions overall, had beneficial effects on depression scores in adults without clinical depression with various metabolic conditions.This outcome is in line with observational evidence, which  has suggested that dietary interventions can improve depression in a range of participants, including high-risk populations with metabolic conditions [4,5,31].A meta-analysis of 15 RCTs (45,826 participants) including healthy adults as well as those with comorbidities all without reported clinical depression, showed that all types of dietary interventions including improving nutrition (e.g., reducing SFA intake, increasing plant-based foods), reducing fat intake, and weight loss diets had significant beneficial effects on depression scores (hedges ¼ 0.246; 95% CI: 0.07, 0.423, P ¼ 0.006) [31].This meta-analysis applied no restrictions on diagnosis of depression or any other clinical or demographic characteristics, which provides further evidence to support our findings that dietary approaches can improve depression across a wide spectrum of the population.It is also worth noting that the small albeit significant effect size (SMD ¼ À0.20) in our meta-analysis in those with metabolic conditions, was comparable with this previous meta-analysis in a broader, healthy population that reverse-coded the effects (hedges ¼ 0.246), where a positive hedges score represents a beneficial intervention effect [31].For our study, we cannot determine which dietary recommendations are most effective for improving depression in adults with metabolic conditions as the studies included heterogenous dietary recommendations.However, the general aim and intent of most dietary interventions hold common features including increasing plant-based foods such as vegetables and fruits; increasing healthy fats; and reducing intake of takeaway foods, refined CHO, and SFAs from "junk" food.Plant-based foods and healthy fats contain bioactive compounds (e.g., vitamins, minerals, fiber, polyphenols, and fatty acids), which are recommended to improve metabolic pathways including inflammation, insulin resistance, mitochondrial dysfunction, and oxidative stress, all of which have been linked with lower rates of depression and metabolic conditions [3,[55][56][57][58].However, 7 of these 13 studies in our primary meta-analysis were hypocaloric, which implies that they were targeting weight loss that is known to have a positive effect on depression.
Weight loss (mainly from lifestyle interventions) has demonstrated the benefits for depression in adults with obesity [59][60][61], however, there is limited research looking at only hypocaloric diets on depression [30,31].Another important finding from our meta-analyses was that in those who had metabolic conditions, hypocaloric diets designed and aiming to elicit weight loss significantly improved depression scores.There appeared to be a small yet significant additional benefit with hypocaloric dietary interventions compared with all dietary interventions (SMD ¼ À0.27 compared with À0.20).Therefore, weight loss from hypocaloric diets may have been driving and mediating the overall relationship between all dietary interventions and depression.Of the 7 hypocaloric diet studies in our meta-analysis, half of which reported a significant improvement in depression scores [46,[50][51][52], all reported significant weight loss in favor of the dietary intervention, with the magnitude of benefits ranging from a mean within-group loss of 1.1-9.7 kg in 5 studies [45,[48][49][50]52], 3.3 kg/m 2 for BMI in another trial [51], and a mean difference in weight loss between groups of 2.95 kg [46].This is in line with a previous systematic review (no meta-analysis) of 16 studies, which reported that calorie-restricted diets (10 of which had reported and led to a within-group mean weight loss ranging from 1.1 to 13.7 kg) were associated with improvements (effect size between %0.2 and %0.6) in depressive symptoms in participants who were overweight or obese [30].Although loss of total body weight outcomes were not investigated in our results, research has shown that a 5%-10% loss in total body weight can improve metabolic risk factors (e.g., T2DM and hypertriglyceridemia) [62,63].These improvements are hypothesized to be a consequence of improved inflammation, oxidative stress, and mitochondrial dysfunction [64,65], all factors which are also known to influence depression [3,56,[66][67][68]. Terefore, although weight loss has been shown to improve depression, the exact magnitude of loss required to elicit improvements has not yet been established.Besides improvements in metabolic pathways, improvements in social factors, for example, weight-based stigma, may have also played a role in improving depression [69].Although weight-based stigma outcomes were not reported in our results, a prior meta-analysis with 30 studies reported an association with depression and anxiety [69].Therefore, it is plausible that weight loss may have improved weight-based stigma, which may have played a positive role in depression.Our results suggest that although dietary interventions overall are beneficial for depression outcomes, hypocaloric diets tended to result in a slightly more favorable effect as weight loss may have been the mediator driving the positive relationship in overall dietary interventions on depression.
Our findings also demonstrated that when isocaloric diets were assessed in isolation in adults with metabolic conditions, there were no beneficial effects on depression scores, which seems to conflict with existing literature from RCTs looking at plant-based diets (e.g., Mediterranean diet) aimed at improving depression in those with clinical depression [70][71][72][73].It is difficult to isolate the main reason to explain conflicting findings between our findings and current research.However, there may be several reasons such as there were many differences between each of the 6 included studies in the dietary interventions, length of intervention, and primary aims and results which is demonstrated by the I 2 result of 69% defined as moderate heterogeneity between studies found to be a significant result (P ¼ 0.004).Existing literature exploring isocaloric diets has mostly been conducted and reported positive findings in studies where depression was the primary aim [70][71][72][73].Only 2 of 6 studies in our meta-analysis had depression as the primary outcome and found significant between-group differences in depression in favor of the dietary intervention group [42,53].There were also a large variety of dietary intervention topics (e.g., the Mediterranean diet [44]; low-fat, SFA, and cholesterol [47]; low-fat vegan [42]; food and nutrients for the microbiome [53]; Mediterranean DASH diet [54], and following a plant-based diet [43]), with the duration of studies ranging between 1-mo [54] and 3 y [43], contact time with the dietitian ranging between weekly [42,54] to 6 mo [43], and differences in the assessment and definition of dietary adherence and/or intake to the dietary intervention (e.g., Mediterranean DASH intervention for neurodegenerative delay score [54], 3-d food diary [49], 24-h recall [50]), to determine what had the greatest impact on depression.Therefore, further clinical trials that are adequately powered and with similar methodology are required to establish whether isocaloric dietary interventions are effective at improving depression.
Previous research demonstrates that those with clinical anxiety experience improvements in anxiety scores with improved diet quality (e.g., increasing vegetables, oily fish, fruit, whole grains) and reduced intake of discretionary foods (e.g., high-fat and sugar and processed foods) [55,74].The findings from our meta-analyses show that that all dietary interventions, including isolating only hypocaloric and isocaloric interventions had no beneficial effect on anxiety scores in adults with metabolic conditions.We had a small number of studies (n ¼ 7), 2 of which were hypocaloric and 5 of which were isocaloric included in our meta-analyses, which may explain the very small effect sizes (À0.05,À0.06, and À0.04, respectively) and no beneficial effect on anxiety.Our findings are consistent with 3 previous meta-analyses in nonclinical cases of anxiety that found that all dietary interventions (n ¼ 11; hedges ¼ 0.100, 95% CI: À0.04, 0.24, P ¼ 0.148), weight loss (n ¼ 4; hedges ¼ 0.058, 95% CI: À0.067, 0.183, P ¼ 0.366) and isocaloric-only diets (n ¼ 6; hedges ¼ 0.397, 95% CI: À0.173, 0.967, P ¼ 0.173) were not effective at improving anxiety [31].Multimodal lifestyle interventions (e.g., diet, exercise, and stress management) may be required rather than diet alone, to have a greater impact on anxiety outcomes.Although no studies to date have assessed whether multimodal lifestyle interventions are superior to diet alone for anxiety outcomes, evidence shows that lifestyle interventions do improve anxiety outcomes [60,75,76].For instance, a meta-analysis of 4 RCTs assessing the effect of lifestyle interventions compared with a control group on anxiety levels among 148 females, reported a pooled estimate (SMD ¼ À1.74; 95% CI: À2.62, À0.87, P < 0.001), which compared with our pooled result of À0.05, suggests there may be a superior effect of lifestyle compared with dietary-only interventions [59].Therefore, further adequately powered clinical trials with well-designed, comprehensive, and tailored dietary interventions are required to determine if dietary interventions are effective at improving anxiety in adults with metabolic conditions.
There are multiple strengths in this systematic review and meta-analysis.The study design was comprehensive with the review conducted in line with the most current PRISMA guidelines [35].The eligibility was robustly designed to capture dietary interventions alone to answer the research question.Furthermore, there were several meta-analyses conducted that enabled us to answer our primary aim of assessing the effect of dietary interventions on depression and anxiety in people who have metabolic conditions, as well as determine the effects of hypo-and isocaloric diets in isolation.
Despite its strengths there are several limitations that need to be acknowledged in this systematic review and meta-analysis and also in this field of research as it is poorly investigated.First, depression and anxiety were secondary outcomes for most of the included studies, and therefore studies were not powered to detect changes or group differences in depression and anxiety.Furthermore, studies did not recruit participants with depression and anxiety at baseline and thus it is likely that there was limited capacity for improvement as low baseline levels reduce the scope for change.Furthermore, based on risk of bias assessment, 10 studies obtained an overall result of "poor quality" and 3 studies obtained "fair quality," which could impact the validity of the results.Furthermore, depression and anxiety symptoms were measured with a variety of questionnaires, making comparison of results inherently challenging.Although all the studies used validated tools to measure depression and anxiety, they were not validated within populations with metabolic conditions, which is a further limitation.There was also a moderate level of heterogeneity measured using the I 2 statistic in the meta-analyses assessing all dietary and only isocaloric in depression and anxiety outcomes, and there was a large variation in the type of dietary interventions, contact time with dietitians/researchers, and length of the interventions.However, due to the small number of studies included, it was not considered appropriate to explore sources of heterogeneity using meta-regression analysis.Finally, studies lacked the ability to define dietary adherence, whereas other studies had different methods to measure dietary intake and others did not even report dietary intake.
In conclusion, our findings suggest that dietary interventions overall and hypocaloric diets only, can improve depression but not anxiety in people with metabolic conditions.In contrast, there were no beneficial effects of isocaloric dietary interventions on either depression or anxiety.This suggests that dietary interventions may be an effective strategy for managing depression in adults with metabolic conditions.Caution is warranted when interpreting results due to the overall low quality and small effect size of the studies included.Future clinical trials should consider depression and anxiety as the primary outcome, measure and define dietary adherence, use validated tools in participants with metabolic conditions, and also explore specific dietary patterns including isocaloric and/or hypocaloric diets that are comprehensively designed and measured.

2
In the study byEinvik et al., 2010 [43], the Oslo diet and Antismoking Study from 1972 to 1977 where all participants that received traditional lifestyle advice, including advice on cessation of smoking, and half the participants were randomly assigned to dietary counseling (dietary counseling n ¼ 604 compared with no diet counseling n ¼ 628).The study relevant to this review is the 25-y follow-up (DOIT) study with n ¼ 505 male participants from 1997 to 2003.3 Analysis of covariance with adjustment for baseline values examining independent effects of diet.4

FIGURE 3 .
FIGURE 3. Forest plot assessing differences in change in anxiety score between baseline and postintervention between the dietary intervention and control group.CI, confidence interval; df, degrees of freedom; Std, standardized.

FIGURE 4 .
FIGURE 4. Forest plot assessing differences in change in depression score between baseline and postintervention between the hypocaloric diet intervention and control group.CI, confidence interval; df, degrees of freedom; Std, standardized.

FIGURE 5 .
FIGURE 5. Forest plot assessing differences in change in anxiety score between baseline and postintervention between the hypocaloric diet intervention and control group.CI, confidence interval; df, degrees of freedom, Std; standardized.

FIGURE 2 .
FIGURE 2. Forest plot assessing differences in change in depression score between baseline and postintervention between the dietary intervention and control group.CI, confidence interval; df, degrees of freedom; Std, standardized.

FIGURE 6 .
FIGURE 6. Forest plot assessing differences in change in depression score between baseline and postintervention between the isocaloric diet intervention and control group.CI, confidence interval; df, degrees of freedom; Std, standardized.

FIGURE 7 .
FIGURE 7. Forest plot assessing differences in change in anxiety score between baseline and postintervention between the isocaloric diet intervention and control group.CI, confidence interval; df, degrees of freedom; Std, standardized.

FIGURE 8 .
FIGURE 8. Risk of bias assessment using the Cochrane Risk of Bias Tool Version 2 for all included studies in this systematic review.Green, low risk; yellow, unclear risk; red, high risk.

TABLE 1
2) with knee pain, > 45 y old Age (mean and SD):Factorial study with 4 groups; diet, diet þ exercise, exercise, and a control group Diet group: n ¼ 122