*3.2. Ramadan Studies*

Ramadan study (Figure 2) characteristics are presented in Table 1 and study quality in Supplementary Table S1. Overall, five studies (1009 participants) [19,22,23,26,28] were included in the Ramadan studies. Two studies were carried out in Iran [22,23], one in Germany [19], one in Turkey [26], and one in Kuwait [28]. One study [22] was carried out in hospital nurses, one in a type II diabetes mellitus population [28], and the others in healthy volunteers [23].

**Figure 1.** Flow chart.

**Figure 2.** Forests plots of Ramadan studies for stress, anxiety and depression.

Overall, Ramadan was associated with improved stress (b = −0.222 [−0.323;−0.121], *p* < 0.0001, I2 = 0), improved anxiety (b = −0.387 [−0.689;−0.084], *p* = 0.012, I2 = 87.79) and improved depression (b = −0.618 [−0.977;−0.258], *p* = 0.001, I2 = 95.32).

Four studies were classified with moderate risk of bias [19,23,26,28] and one with high risk of bias [22] (Supplementary Table S1). Removing this study did not change our results. The moderate risk of bias was due to studies using self-reported questionnaires and participants being aware of the exposure, as for all nutritional intervention studies.

Funnel plots for Ramadan studies are presented in Supplementary Figure S1. We found no publication bias (Egger's tests > 0.05 for anxiety and depression).

The observational Ramadan studies did not report fasting's adverse events [22,23,26,28]. Fatigue was reported only in the controlled study [19]. Ramadan was associated with increased fatigue during the first week but decreased fatigue during week 2 to 4 and decreased sleepiness during the whole of Ramadan. No study reported dropout due to inability to follow Ramadan.

#### *3.3. Fasting Controlled Trials*

Fasting controlled trials (Figure 3) characteristics are presented in Table 1 and study quality in Supplementary Table S2. Seven studies (452 participants, 264 receiving fasting intervention, 188 being controls) were included (five randomized controlled trials [17,20,21,24,25] and two controlled trials [19,27]). The two studies carried out in Malaysia assessed the effectiveness of a 12-week, 300–500 kCal daily caloric restriction associated with 2 days a week of Sunnah Muslim fasting [20,21]. One study carried out in the Czech Republic studied the effects of 12 weeks of caloric restriction with or without 14 h/day intermittent fasting in a diabetes population [17]. One US study measured the effects of 104 weeks of 25% caloric restriction [24]. Among the three studies carried out in Germany, one studied the effects of Ramadan [19], one the effects of 12 weeks of an 800 Cal/day low calorie diet [25] and one the effects of 8 weeks of one day per week fasting, totaling 24 h a week [27].



14


**Table 1.** *Cont.*


#### *Nutrients* **2021**, *13*, 3947

**Table 1.** *Cont.*

#### All studies

#### Sensitivity analysis: Randomized controlled studies only

Anxiety


**Figure 3.** Forest plots of fasting intervention controlled studies for anxiety, depression and body mass index.

Overall, the fasting groups were not found to have lower anxiety or depression levels compared to control groups at the end of fasting (*p* > 0.05, Figure 3), but they were found to have lower body mass index (b = −1.446[−2.677;−0.274], *p* = 0.021).

After removing the two non-randomized controlled trials [19,27], fasting groups were found to have lower anxiety and depression levels (respectively, b = −0.508[−0.988;−0.028], *p* = 0.038, I2 = 0 and b = −0.281[−0.502;−0.061], *p* = 0.012, I2 = 0).

Four randomized controlled trials were evaluated to have low risk of bias [17,20,21,24], one with intermediate risk of bias [25] and the two controlled trials were evaluated to have a high risk of bias [19,27].

There was no publication bias for anxiety and depression (Egger's tests > 0.05) but a publication bias for body mass index (Egger's test = 0.01). Funnel plots are presented in Supplementary Figure S2.

Fatigue was measured in four studies [19,21,24,27]. The fasting groups were not found to have lower or increased fatigue levels at the end of fasting compared to control groups (*p* > 0.05, data not shown). Limiting the analysis to randomized controlled trials [21,24] did not change our results.

Overall, 42 (15.4%) dropouts were reported in fasting groups and 20 (10.2%) in control groups (*p* > 0.05). Among dropouts of fasting interventions, two diabetic patients reported a lack of motivation for 2 meals a day [17], two participants were unable to follow the two days/week fasting combined with caloric restriction for 12 weeks [20] and three participants were removed for safety reasons for 104 weeks of 25% caloric restriction [24]. The other dropouts were for reasons not related to fasting or for unknown reasons.

Only one study reported detailed adverse events for 1 day/week fasting [27]. These adverse events were: headache, migraine, nausea, ravenousness, circulatory disturbance, hunger, general feeling of weakness, tiredness, stomach ache, meteorism, heartburn, and cold sensations in the body.

#### **4. Discussion**

In our meta-analysis including 11 studies and 1436 participants, we found that post-Ramadan scores for stress, anxiety and depression were lower compared to those before Ramadan. In fasting controlled trials, we found no significant effect of fasting on anxiety and depression when analyzing all studies. However, we found that fasting groups had

lower anxiety and depression levels compared to control groups when limiting the analyses to randomized controlled trials. Fasting was associated with decreased body mass index in all studies without increased fatigue in fasting groups compared to controls. Adverse events were only reported for 1 day/week fasting.

First, we found a positive effect of Ramadan on stress, anxiety and depression. Ramadan is a religious fasting, i.e., including a spiritual and social dimension that may be missing in other forms of fasting. One may hypothesize that depression improvement may not be only due to fasting but also to other lifestyle modifications. For example, Ramadan fasting includes tobacco abstinence, and tobacco abstinence has been associated with improved depressive symptoms [29]. As Ramadan is a dry fasting between sunrise and sunset, the Ramadan fasters may wake up earlier in the morning to feed before sunrise and may therefore reduce their sleep duration. Sleep reduction has been associated with depression improvement [30] and may also play a role in the observed results. Despite its significance, we found heterogeneous results across Ramadan studies for anxiety and depression. We have identified the following factors that may explain this heterogeneity: country/cultural context, clinical (diabetes) vs. non clinical populations, various delay between end of Ramadan and first endpoint evaluation (from 0 to 6 weeks), various scales to assess stress, anxiety and depressive symptoms, various ages and sex ratios. These variables could not be tested due to the small number of studies. Other uncaptured data, such as socioeconomic environment, addictive behaviors, sleep, diet, physical activity and physical comorbidities, including overweight/obesity, may also contribute to heterogeneity. For example, the German study included only healthy male students [19] and the effect of Ramadan on anxiety was much higher in this study compared to the others. However, the results were still significant after removing this study. It should be underlined that all scales to evaluate stress, anxiety or depression were self-reported, and that clinician-rated scales could be useful to confirm these results.

The second major finding is the result of fasting controlled trials. Our overall results were not significant (with a trend toward significance for anxiety, *p* = 0.07). However, after removing two studies with a high risk of bias, the results became significant with low heterogeneity. These results are encouraging to pursue research on fasting intervention effects on mental health, especially in psychiatric samples that have been untested thus far. It should be underlined that the mean stress/anxiety/depression scores were mostly under the pathological rank at baseline, suggesting that fasting interventions are effective for moving from a "healthy" to "even healthier" mood. Despite this fact, the effect sizes indicated a mild effect for depression and moderate effect for anxiety when limited to randomized controlled trials. As most interventions are most effective in patients with more severe baseline symptoms, we believe that fasting interventions should therefore be effective in psychiatric samples. Moreover, we found that patients receiving these interventions benefited from body mass index reduction. Obesity is common in patients with major depression and may influence psychiatric trajectory [31,32]. Intentional weight loss improves the symptoms of depression [10]. However, no study explored if fasting interventions were more effective in overweight participants and it remains to be determined if body mass index is correlated with depressive symptoms. It remains also to be determined if overeating is conversely associated with impaired mood and the direction of the causal relationship [33]. Animal studies also suggest that fasting improves oxidative stress [34]. Further studies should explore if the improvement of oxidative stress parameters would be associated with improved anxiety/depression in humans.

Adverse events were poorly reported. The only study reporting adverse events was those exploring the effects of 24 h/week fasting. Daily intermittent fasting may be effective in limiting these adverse events. The absence of significant dropout rate differences between fasting and control groups is encouraging for the acceptability of fasting interventions. It should be underlined that two meals/day associated with caloric restriction appeared as a safe intervention in patients with diabetes. No hypoglycemia was reported in this study. Metabolic disorders are frequent in psychiatric populations and should therefore not be a

limitation to test fasting interventions in psychiatry. Additional data are needed to confirm these preliminary results.

Strengths. We used the most recent meta-analysis standards to carry out the present meta-analysis. A comprehensive search following PRISMA criteria has been carried out, and we used leave-1-out analyses and quality evaluations to determine the risk of bias. The present work therefore adds important knowledge in the field.

Limitations. Our results must be interpreted with caution. Only 11 studies with relatively small sample sizes were included. Four Ramadan studies were observational and two fasting controlled trials were not randomized. The small number of studies did not enable us to carry out sensitivity analyses. An important limitation and direction for future research is that our results were insufficient to determine if caloric restriction is the true effective intervention to improve anxiety or depression, or if intermittent fasting (time-restricted feeding) may have a specific effect. Lastly, although visual inspection of funnel plots did not suggest publication bias, definitive confidence in excluding publication bias was limited by the small number of studies included in our funnel plots. Very lowcalorie interventions could not be included in the quantitative analyses. However, most of them reported mood improvement after these interventions. Further trials are therefore warranted to explore their effectiveness.

#### **5. Conclusions**

Preliminary evidence suggests that fasting interventions may have a positive effect on anxiety, depression and body mass index reduction without increasing fatigue. It remains unknown if caloric restriction is the true effective component of fasting or if intermittent fasting may increase its effectiveness on stress, anxiety and depressive symptoms. A 12 week intermittent fasting associated with caloric restriction appears as a safe and acceptable intervention, even in patients with diabetes. Further randomized controlled trials are warranted to strengthen these results, especially in psychiatric populations that have not been tested thus far.

**Supplementary Materials:** The following are available online at https://www.mdpi.com/article/10 .3390/nu13113947/s1, Figure S1: Funnel plots of Ramadan studies; Figure S2: Funnel plots of fasting controlled trials; Table S1: Study quality for Ramadan studies, Table S2: Study quality for fasting controlled trials.

**Author Contributions:** Conceptualization, G.F. and L.B.; methodology, L.B.; software, L.B.; validation, L.B.; formal analysis, L.B.; investigation, E.B. and G.F.; resources, E.B. and G.F.; data curation, G.F.; writing—original draft preparation, E.B. and G.F.; writing—review and editing, D.E.-E., D.T., C.L., G.F. and L.B.; supervision, G.F. and L.B. All authors have read and agreed to the published version of the manuscript.

**Funding:** This work received no funding. No drug manufacturing company was involved in the study design, the data collection, the data analysis, the data interpretation, the writing of the report, or the decision to submit the report for publication.

**Institutional Review Board Statement:** Not applicable.

**Informed Consent Statement:** Not applicable.

**Conflicts of Interest:** The authors declare no conflict of interest.

#### **References**

