Dietary Supplementations and Depression

Figures & data

Figure 1 Literature search results.

Table 1 Study Characteristics

Characteristics/Country of Study	Number of Studies (%)
Iran	26 (41.3)
Australia	6 (9.5)
America	5 (7.9)
Netherlands	5 (7.9)
France	3 (4.8)
China	3 (4.8)
Brazil	2 (3.2)
Japan	2 (3.2)
Denmark	1 (1.6)
Nigeria	1 (1.6)
Norway	1 (1.6)
Italy	1 (1.6)
Taiwan	1 (1.6)
Korea	1 (1.6)
Austria	1 (1.6)
Ghana	1 (1.6)
Sweden	1 (1.6)
Poland	1 (1.6)
Spain	1 (1.6)
Vietnam	1 (1.6)
Age of Subject Studied
<18 years old	1 (1.6)
≥18 years old	62 (98.4)
The type of Supplementation Studied
PUFA	17 (26.9)
Vitamin D	15 (23.8)
Probiotic	8 (12.7)
Combination of vitamins and nutrients	6 (9.5)
Vitamin B	4 (6.3)
Vitamin E	3 (4.8)
Zinc	2 (3.2)
Curcumin	2 (3.2)
Nanocurcumin	1 (1.6)
Vitamin A	1 (1.6)
Vitamin C	1 (1.6)
ALA (Alpha-lipoic acid)	1 (1.6)
Ferrous sulfate	1 (1.6)
Magnesium oxide	1 (1.6)
Melatonin	1 (1.6)
Myo-inositol	1 (1.6)
Sumac (Rhus coriaria L)	1 (1.6)
Zinc sulfate	1 (1.6)
Caffeine	1 (1.6)
Carnitine	1 (1.6)
Coenzyme Q10	1 (1.6)
Scale of Depression
Beck Depression Inventory (BDI, BDI-II)	30 (47.6)
Hamilton Depression Rating Scale (HDRS, HDRS-17)	9 (14.3)
Geriatric Depression Scale (GDS, GDS-15)	7 (11.1)
Depression Anxiety Stress Scale (DASS, DASS-21	6 (9.5)
Personal Health Questionnaire (PHQ-8, PHQ-9)	5 (7.9)
Edinburgh Postnatal Depression Scale (EPDS)	5 (7.9)
Center for Epidemiologic Studies Depression (CES-D)	4 (6.3)
Hospital Anxiety and Depression Scale (HADS)	3 (4.8)
Montgomery-Asberg Depression Rating Scale (MADRS)	3 (4.8)
Global Seasonality Score (GSS)	1 (1.6)
Children’s Depression Rating Scale (CDRS)	1 (1.6)
Child PTSD Symptom Scale (CPSS)	1 (1.6)
Profile of Mood State (PMOS)	1 (1.6)
State-Trait Personality Inventory (STPI)	1 (1.6)

Table 2 Effects of Using PUFA Supplements for Treating Depression

Author	Year	Country	Dosage	Duration	Scale of Depression	Result
Nishi et al^Citation23	2019	Japan and Taiwan	134 mg EPA + 67.7 mg DHA (9 times daily)	12 weeks	HDRS, EPDS, and BDI-II	Had beneficial effects, decreased overall score by 59.5%
Ravi et al^Citation27	2016	Iran	1 capsule = 360 mg EPA + 240 mg DHA (twice daily)	8 weeks	BDI-II, HADS, and PHQ-9	Had beneficial effects, decreased overall score by 47.86%
Gharekhani et al^Citation85	2014	Iran	180 mg EPA + 120 mg DHA (6 times daily)	16 weeks	BDI	Had beneficial effects, decreased BDI score by 42.86%
McNamara et al^Citation22	2016	America	Group 1: 1.6 g EPA + 0.8 g DHA (4 capsules/day) Group 2: 10.8 g EPA + 5.4 g DHA (2 tbsp/day)	10 weeks	CDRS	Had beneficial effects, decreased CDRS score by 40%
Keshavarz et al^Citation86	2018	Iran	1 capsule contains 180 mg EPA + 120 mg DHA (6 capsule/day)	12 weeks	BDI	Had beneficial effects, decreased BDI score by 32.48%
Rizzo et al^Citation87	2012	Italy	2.5 g (with EPA:DHA 2:1) per day	8 weeks	GDS	Had beneficial effects, decreased GDS score by 32.16%
Jiang et al^Citation88	2018	America	Group 1: 400 mg EPA + 200 mg DHA Group 2: 500 mg EPA (4 times daily)	12 weeks	HDRS and BDI-II	Had beneficial effects, decreased overall score by 28.35%
Ginty et al^Citation29	2015	America	1000 mg EPA + 400 mg DHA per day	21 days	BDI	Had beneficial effects, 67% of the subject no longer met criteria of depression
Vaz et al^Citation89	2017	Brazil	1.08 g EPA + 0.72 g DHA per day	16 weeks	EPDS	No significant effect
Antypa et al^Citation90	2012	Netherlands	1.74 g EPA + 0.25g DHA per day	4 weeks	BDI-II	No significant effect
Maltais et al^Citation91	2019	France	400 mg DHA + 112.5 mg EPA, twice a day	3 years	GDS	No significant effect
Park et al^Citation26	2015	Korea	1140 mg EPA + 600 mg DHA (3 times daily)	12 weeks	CES-D and HDRS	No significant effect

Abbreviations: BDI, beck depression inventory; EPDS, Edinburgh postnatal depression scale; HDRS, Hamilton depression rating scale; GDS, geriatric depression scale; CES-D, center for epidemiologic studies depression; HADS, hospital anxiety and depression scale; PHQ, personal health questionnaire depression scale; CDRS, children’s depression rating scale.

Figure 2 The proposed mechanism of EPA in inhibiting phospholipase A2 and preventing depression.

Table 3 Effects of Combined PUFA Supplementations for Treating Depression

Author	Year	Country	Combination	Dosage	Duration	Scale of Depression	Result
Jamilian M et al^Citation30	2018	Iran	PUFA and vitamin E	1000-mg of PUFA + 400 IU vitamin E per day	12 weeks	BDI	Had beneficial effects decreased BDI score by 13.33%
Giltay et al^Citation92	2011	America	PUFA and ALA	400 mg EPA-DHA/day, 2 g ALA/day, or both combination EPA-DHA and ALA	40 months	GDS	No significant effect
Kuszewski et al^Citation93	2020	Australia	PUFA and Curcumin	400 mg EPA + 2000 mg DHA/day + 160 mg curcumin/day	16 weeks	PMOS	No significant effect
Meyer et al^Citation94	2013	Australia	PUFA and vitamin E	2 g DHA + 0.6 g EPA + 10 mg vitamin E (8 x 1 g capsules per day)	16 weeks	HDRS	No significant effect
Andreeva et al^Citation95	2012	France	PUFA and vitamin B	Vitamin B [5-methyl-tetrahydrofolate (0.56 mg) and vitamins B-6 (3 mg) and B-12 (0.02 mg)] + PUFAs [600 mg EPA and DHA in a 2:1 ratio] in 2 capsules per day	5 years	GDS	No significant effect

Abbreviations: GDS, geriatric depression scale; PMOS, profile of mood states; BDI, beck depression inventory; HDRS, Hamilton depression rating scale.

Table 4 Effects of Vitamin D Supplementation on Depression

Author	Year	Country	Dosage	Duration	Scale of Depression	Result
Sepehrmanesh Z et al^Citation96	2016	Iran	50 kIU/week	8 weeks	BDI	Had beneficial effects, decreased score by 31.75%
Vaziri F et al^Citation97	2016	Iran	2000 IU/day	±15 weeks	EPDS	Had beneficial effects, decreased score by 50.36%
Kjærgaard M et al^Citation98	2012	Norway	20,000 IU/week	6 months	1. BDI-II 2. HADS 3. MADRS 4. GSS	Had beneficial effects, decreased score by 25%
Zheng S et al^Citation99	2018	Australia	50,000 IU/month	24 months	PHQ-9	Had beneficial effects, decreased score by 14.71%
Sharifi A et al^Citation100	2018	Iran	300,000 IU (injection one time)	3 months	BDI	Had beneficial effects, decreased score by 33.59%
Omidian M et al^Citation101	2019	Iran	4000 IU/day	12 weeks	BDI-II	Had beneficial effects, decreased score by 35.53%
Raygan F et al^Citation31	2018	Iran	Every two weeks: Vit. D: 50,000 IU + Probiotic: 8×10^9 CFU/g	12 weeks	BDI	Had beneficial effects, decreased score by 12.07%
Yosaee S et al^Citation32	2019	Iran	Group: 1. 2000 IU/day Vit. D + daily zinc placebo 2. 30 mg zinc gluconate/day + placebo Vit.D/day 3. Vit. D 2000 IU/day + 30 mg/day zinc gluconate 4. Identical matching placebos for vitamin D and zinc	12 weeks	BDI-II	Had beneficial effects. Change in BDI-II: a) Zinc: −7.02 b) Vitamin D: −3.87 c) Zinc+Vitamin D: −7.62
Alavi NM et al^Citation102	2018	Nigeria	● 50,000 IU/week	8 weeks	GDS-15	Had beneficial effects, decreased score by 19.14%
Hansen JP et al^Citation103	2019	Denmark	● 2800 IU/day	12 weeks	HDRS17	No significant effect
Okereke OI et al^Citation104	2020	America	● 2000 IU/day	5.3 years	PHQ-8	No significant effect
De Koning EJ et al^Citation105	2019	Netherlands	● 1200 IU/day	12 months	CES-D	No significant effect
Rolf L et al^Citation106	2017	Netherlands	● 7000 IU/day (first four weeks) ● 14,000 IU/day (up to 48 weeks)	48 weeks	HADS	No significant effect
Mousa A et al^Citation107	2017	Australia	● 100,000 IU followed by 4,000 IU daily	16 weeks	BDI	No significant effect
Wang Y et al^Citation108	2016	China	● 50,000 IU/week	52 weeks	BDI-II	No significant effect

Abbreviations: HDRS, Hamilton depression rating scale; PHQ, personal health questionnaire depression scale; CES-D, center for epidemiologic studies depression; HADS, hospital anxiety and depression scale; GDS, geriatric depression scale; BDI, beck depression inventory; EPDS, Edinburgh postnatal depression scale; HADS, hospital anxiety and depression scale; MADRS, Montgomery-asberg depression rating scale; GSS, global seasonality score.

Table 5 Dietary Supplementation Permissible Levels

Dietary Supplementation	Description
Vitamin D	>50,000 IU/day (Toxic level of Vitamin D)^Citation45
PUFA: Omega-3 fatty acids, mainly the combination of Docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA)	Daily intake of EPA and DHA higher than 2 g is not recommended^Citation121
Caffeine	Recommended daily intake is low dose 60 mg/day but Not recommended at high dose intake (>120 mg)^Citation116
Carnitine	Recommended daily intake around 250 mg–2000 mg per day^Citation60
Coenzyme Q10 (CoQ10)	Recommended doses from previous study around 150–1200 mg per day^Citation61,Citation122
Nanocurcumin	Recommended doses from previous study is 80 mg per day^Citation62,Citation65
Curcumin	Recommended dose based previous clinical trials is around 250–1000 mg/day^Citation62
Magnesium oxide	Recommended dose from previous study was around 125–500 mg/day^Citation68
Melatonin	Recommended doses based previous study around 5–10 mg/day^Citation117
Myo-inositol	Recommended doses from previous study around 2 gram per day^Citation60
Sumac (Rhus coriaria L)	Recommended doses from previous study around 1000–3000 gram per day^Citation73
Vitamin A (retinyl palmitate)	Tolerable Upper Intake Level (UL) for Vitamin A is 3000 μg per day for >18 years^Citation123
Vitamin B12	No tolerable upper intake level have been determined. Recommended Dietary Allowances 2.4 μg per day for >18 years^Citation123
Folic acid	Tolerable upper intake level for folic acid was at 1000 μg per day^Citation124
Zinc	Recommended Dietary Intake around 8–12 mg per day. Tolerable Upper Intake Level (UL) for Zinc is 40 mg per day for >18 years^Citation123
Vitamin C and Vitamin E	Tolerable Upper Intake Level (UL) for Vitamin C is 2000 mg/day for >18 years and 1000 mg Vitamin E per day for >18 years^Citation123
Iron	Tolerable Upper Intake Level (UL) for Iron is 45 mg/day^Citation125

Figure 3 The proposed vitamin D pathway to prevent depression.

Table 6 Effects of Probiotic Supplementation for Treating Depression

Author	Year	Country	Species, Dosage	Duration	Scale of Depression	Result
Moludi et al^Citation109	2019	Iran	L. rhamnosus 1.6×10^9 CFU per capsule per day	12 weeks	BDI	Had beneficial effects, decreased BDI score by 28.36%
Inoue et al^Citation110	2018	Japan	Various Bifidobacteria species, each 1.25×10^10 CFU per sachet per day	12 weeks	PHQ-9	Had beneficial effects, decreased PHQ-9 score by 26.92%
Mohammadi et al^Citation111	2016	Iran	Group 1 100 g/day probiotic yogurt with L. acidophilus and B. lactis 1×10^7 CFU + one placebo capsule Group 2 100 g/day conventional yogurt with S. thermophilus and L. bulgaricus + one probiotic capsule Group 3 100 g/day conventional yogurt + one placebo capsule The probiotic capsule contained Lactobacillus casei 3 × 10^3, L. acidophilus 3 × 10^7, L. rhamnosus 7 × 10^9, L. bulgaricus 5 × 10^8, Bifidobacterium breve 2 × 10^10, B. longum 1 × 10^9, S. thermophilus 3×10^8 CFU/g	6 weeks	DASS	Had beneficial effects with DASS score decreased by 8.83 for overall intervention group.
Kouchaki et al^Citation112	2017	Iran	One capsule containing Lactobacillus acidophilus, Lactobacillus casei, Bifidobacterium bifidum, and Lactobacillus fermentum each 2×10^9 CFU/g per day	12 weeks	BDI	Had beneficial effects with BDI score decreased by 5.5±0.8
Akkasheh et al^Citation113	2016	Iran	One capsule daily containing Lactobacillus acidophilus (2×10^9 CFU/g) Lactobacillus casei (2×10^9 CFU/g) Bifidobacterium bifidum (2×10^9 CFU/g)	8 weeks	BDI	Had beneficial effects with BDI score decreased by 5.3±1.2
Louzada et al^Citation49	2020	Brazil	L. paracasei 10^9–10^8 CFU + L. rhamnosus 10^9–10^8 CFU + L. acidophilus 10^9–10^8 CFU + B. lactis 10^9–10^8 CFU consumed orally twice a day	24 weeks	GDS-15	No significant effect
Kazemi et al^Citation17	2018	Iran	Probiotic Groups: Lactobacillus helveticus and Bifidobacterium longum Prebiotic: Galactooligosaccharide Dosage: ⩾10 × 10^9 CFU per 5 g sachet consumed orally per day	8 weeks	BDI	No significant effect
Reininghaus et al^Citation114	2020	Austria	Probiotic oral supplement that contains nine bacterial strains at least 7.5 billion organisms per 1 sachet (3g). Also contains 125 mg vitamin B7 + 30 mg horsetail + 30 mg fish collagen + 30 mg keratin, consumed once daily.	4 weeks	HDRS and BDI-II	No significant effect

Abbreviations: BDI, beck depression inventory; PHQ, personal health questionnaire depression scale; HDRS, Hamilton depression rating scale; DASS, depression anxiety stress scales; GDS, geriatric depression scale.

Table 7 Effects of Combining Vitamins and Nutrient Supplementation as Depression Treatments

Author	Year	Country	Supplementation	Dosage	Duration	Scale of Depression	Result
Nguyen et al^Citation50	2017	Vietnam	Pre-pregnancy: 1. Multiple micronutrients 2. Iron and folic acid 3. Folic acid During pregnancy: iron+ folic acid	Pre-Pregnancy Group: Group 1: 2800 μg folic acid Group 2: 2800 μg folic acid + 60 mg iron Group 3: 15 micronutrients including 2800 μg folic acid + 60 mg iron During Pregnancy: 60 mg iron + 400 μcg folic acid	Pre-pregnancy: weekly until conception During pregnancy: daily until delivery	Preconception: CES-D During Pregnancy and 3 Months Postpartum: EPDS	Had beneficial effects, decreased EPDS score during first and second trisemester in group 1 and 2 compare to group 3 (p<0.05)
Berens et al^Citation51	2018	Sweden	Nutritional supplementation	119mL nutritional supplementation (150 kcal 20 g whey protein 800 IU vitamin D Combination of vitamins and minerals) daily	6 months	CES-D	Had beneficial effects, decreased CES-D score by 26.80%
Oliver-Baxter et al^Citation52	2018	Australia	Supplements containing 12 vitamins, minerals, and herbs	1 tablet/day	8 weeks	STPI	Had beneficial effects, decreased STPI score by 16.66%
Harris et al^Citation53	2011	Australia	Supplements containing 53 vitamins, minerals, antioxidants, and herbs	One tablet after meal	8 weeks	DASS	Had beneficial effects, decreased DASS score by 50%
Bot et al^Citation115	2019	Netherlands	PUFA, selenium, folic acid, vitamin D3 coupled with calcium	1412 mg PUFA, 30 μg selenium, 400 μg of folic acid, 20 μg of vitamin D3 coupled with 100-mg calcium (2 pills/day)	1 year	PHQ-9	No significant effect
Okronipa et al^Citation56	2018	Ghana	1. Iron 2. Folic acid 3. Calcium 4. Multiple micronutrient capsule (MMN) 5. SQ-LNS supplement (contained similar as the MMN capsule, plus other four minerals (Ca, P, K, Mg) and essential fatty acids	Group 1: 60 mg iron and 400 μg folic acid capsule daily during pregnancy with calcium (Ca) for the first six months postpartum Group 2: Multiple micronutrient capsules (18 vitamins and 20 mg iron daily) daily during pregnancy and the first six months postpartum Group 3: 20 g SQ-LNS during pregnancy and the first six months postpartum	6 months postpartum	EPDS	No significant effect

Abbreviations: PHQ, personal health questionnaire depression scale; EPDS, Edinburgh postnatal depression scale; CES-D, center for epidemiologic studies depression; STPI, state-trait personality inventory; DASS, depression anxiety stress scales.

Table 8 Effects of Other Supplements in Treating Depression

Author	Year	Country	Supplementation	Dosage	Duration	Scale of Depression	Result
Liu et al^Citation116	2017	China	Caffeine	Group 1: 60 mg caffeine daily Group 2: 120 mg caffeine daily	4 weeks	HDRS-17 and MADRS	Had beneficial effects, 60 mg caffeine decreased HDRS-17 score by 25.2% and MADRS score by 20.61%, 120 mg caffeine did not result any beneficial effects
Jamilian et al^Citation60	2017	Iran	Carnitine	250 mg/day	12 weeks	BDI and DASS	Had beneficial effects, decreased BDI score by 19.85% and DASS score by 9.27%
Sanoobar et al^Citation61	2015	Iran	Coenzyme Q10 (CoQ10)	500mg/day	12 weeks	BDI	Had beneficial effects, decreased BDI score by 28.18%
Asadi et al^Citation62	2020	Iran	Nanocurcumin	One capsule of nanocurcumin, 80 mg daily	8 weeks	DASS-21	Had beneficial effects, decreased DASS-21 score by 8.38%
Yu et al^Citation63	2015	China	Curcumin	Two capsules of curcumin, 1000 mg daily with escitalopram orally, 5–15 mg daily	6 weeks	HDRS-17 and MADRS	Had beneficial effects, decreased HDRS-17 score by 4.52 (3.17) and MADRS score by 6.26 (4.03)
Rajizadeh et al^Citation68	2017	Iran	Magnesium Oxide	250 mg magnesium oxide twice daily	8 weeks	BDI-II	Had beneficial effects, decreased BDI-II score by 58.14%
Shabani et al^Citation117	2019	Iran	Melatonin	10-mg melatonin daily	12 weeks	BDI	Had beneficial effects, decreased BDI score by 23.53%
Jamilian et al^Citation72	2018	Iran	Myo-inositol	2 g Myo-inositol + 200 microgram folate twice daily	12 weeks	BDI and DASS	Had beneficial effects, decreased BDI score by 6.4% and DASS score by 4.3%
Hariri et al^Citation73	2020	Iran	Sumac (Rhus coriaria L)	Three capsules of sumac, 1 gram/capsule daily	12 weeks	BDI-II	Had beneficial effects, decreased BDI-II score by 41.1%
Bitarafan et al^Citation76	2016	Iran	Vitamin A (retinyl palmitate)	25,000 IU/day for six months and continued by 10,000 IU/day for six months	12 months	BDI-II	Had beneficial effects, decreased BDI-11 score by 95.41%
de Koning et al^Citation118	2016	Netherlands	Vitamin B (B12 and folic acid)	500 µg vitamin B12 and 400 µg folic acid daily	Two years	GDS-15	Had beneficial effects, resulted logistic regression intervention result by 112 (8.6)
Bochyńska et al^Citation119	2012	Poland	Vitamin B	0.4 mg folate, magnesium with 50 mg vitamin B6, and 100 mg vitamin B12 daily	1 year	BDI	Had beneficial effects, decreased BDI score by 24.17% for all patients
Loria-Kohen et al^Citation120	2013	Spain	Vitamin B (folic acid)	10 mg daily	6 months	BDI	Had beneficial effects, decreased BDI score by 33.62%
Solati et al^Citation79	2015	Iran	Zinc	30 mg daily	12 weeks	BDI-II	Had beneficial effects, decreased BDI-II score by 30.5%
Ranjbar et al^Citation80	2014	Iran	Zinc Sulfate	25 mg zinc sulfate/day with citalopram20–60 mg/day or fluoxetine 20–60 mg/day	12 weeks	HDRS	Had beneficial effects, statistically significant difference with p<0.05 compared to placebo
Mazloom et al^Citation58	2013	Iran	Vitamin C & vitamin E	Group 1: one vitamin C capsule, 1000 mg daily Group 2: one vitamin E capsule, 400 IU daily	6 weeks	DASS-21	No significant effect
Vaucher et al^Citation59	2012	France	Ferrous Sulfate	80 mg/day prolonged-release ferrous sulfate for women who had a ferritin level less than 50 ug/L and	12 weeks	CPSS	No significant effect

Abbreviations: DAS, depression anxiety stress scales; HDRS, Hamilton depression rating scale; MADRS, Montgomery-asberg depression rating scale; BDI, beck depression inventory; CPSS, child PTSD symptom scale; GDS, geriatric depression scale.

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