Table 3.

Studies assessing OTC products used for depression

Study ID Country, N recruited Comorbidities	Product details and duration	Comparator	Depression outcome(s)	Effective on ≥ 1 depression outcome?	Safety
Dietary supplements
Rondanelli et al., 2011 [53] Italy N = 226	Omega-3 long chain polyunsaturated fatty acids (1.67 g EPA and 0.83 g DHA), 2.5 g/day 8 weeks	Placebo (paraffin oil)	GDS	Yes	No side effects.
Rondanelli et al., 2010 [55] Italy N = 271	Omega-3 long chain polyunsaturated fatty acids, 2.5 g/day 8 weeks	Placebo (paraffin oil)	GDS	Yes	No serious adverse events
Chang et al., 2020 [84] Taiwan N = 237 Comorbidity- Chronic heart disease	Omega-3 long chain polyunsaturated fatty acids (2 g EPA + 1 g DHA)/day 2 weeks	Placebo (soybean oil 3 g/day)	HAM-D BDI	No	Not reported
Pomponi et al., 2014 [83] Italy N = 96 Comorbidity-Parkinson’s disease	Omega-3 fatty acid (800 mg/d DHA and 290 mg/d EPA) 6 months	Placebo (vegetable oil)	HAM-D	Yes	Not reported
Rizzo et al. 2012 [54] Italy N = 46	Omega-3 oil (1 tbsp or 2.5 g) 1/day 2 months	Placebo (1 tbsp paraffin oil with similar lemony taste)	HAM-D SDS CGI	Yes	No side effects
Tajalizadekhoob et al., 2011 [50] Iran N = 66 Comorbidity-dementia	Fish oil (1 g cod liver oil, glycerol, and water; 180 mg EPA and 120 mg DHA) 6 months	Placebo (gelatin capsule containing medium-chain triglycerides, glycerol, and water)	GDS	Yes	Mild effects (gastrointestinal disturbances), settled after a month.
Da Silva et al., 2008 [82] Brazil N = 250 Comorbidity- Parkinson’s disease	1. Fish oil capsules (180 mg EPA, 120 mg DHA and tocopherol) 4/day 2. Fish oil plus antidepressant 3 months	1. Placebo x 2 (mineral oil) 2. Placebo plus antidepressant	MADRS CGI BDI	Yes	Not reported
Alavi et al., 2019 [46] Iran N = 255	Vitamin D3 50,000 IU weekly at mealtime. 8 weeks	Placebo	GDS	Yes	No side effects were noted.
Koning et al. 2019 [88] Netherlands N = 155	Vitamin D3 (400 IU cholecalciferol) 3/day + advice to consume ≥ 3 dairy/day or 500 mg/day calcium tablet for 8 weeks 12 months	Placebo	CES-D MDD incidence (CIDI)	No	No serious adverse effects.
Almeida et al., 2014 [86] Australia N = 153 Some comorbidities in sample	Vitamin B (0.5 mg B12, 2 mg folic acid, 25 mg B6) 1 capsule + citalopram 52 weeks	Citalopram + placebo	MDD relapse (DSM-IV) MADRS	Did not enhance, antidepressant treatment, but antidepressant response sustained over 1 year.	No differences in adverse events between study groups
Walker et al., 2012 [77] Australia N = 909 2 × 2 × 2 factorial design	1. Vitamin B (400 µg folic acid and 100 µg vitamin B-12) 1/day. After safety review, protocol changed to 2 daily doses (200 µg FA + 50 µg vitamin B-12 each) + physical activity + mental health literacy 2. Supplement + physical activity and pain information 3. Supplement + nutritional information + mental health literacy 4. Supplement + nutritional information + pain information 24 months	4 groups include placebo + other interventions	PHQ-9	Yes	Not reported
Bersani et al., 2013 [59] Italy N = 80	L-acetylcarnitine, 1 g, 3/day 7 weeks	Fluoxetine 20 mg/day	HAM-D CGI BDI	Yes	Lesser side effects were noted for L-acetylcarnitine compared to fluoxetine.
Garzya et al., 1990 [57] Italy N = 28	L-acetyl-carnitine, 500 mg, 3/day 60 days	Placebo	HAM-D BDI SCAG	Yes	No statistical difference in side effects between groups
Passen et al., 1993 [58] Italy N = 120 Comorbidity-dementia	5’-Methyltetrahydrofolic acid 50 mg/day (1 tablet in the morning) 8 weeks	Trazodone 100 mg/day (2 tablets)	HAM-D	Yes	No side effects were noted.
Herbal products
Meleppurakkal et al., 2021 [79] India N = 75	1. Ashwagandha (Withania somnifera (Linn) Dunal) 3.75 g + Vacha (Acorus calamus L.) 250 mg, 4 g powder 2/day with water 2. Yoga + Ashwagandha and Vacha 30 days	Yoga alone	HAM-D	Yes (most significant in group plus yoga)	Not reported
Liang et al., 2019 [65] China N = 93 Comorbidity- Ischaemic stroke	Ginkgo (Gingko biloba L.) 40 mg, 3/day + venlafaxine 75 mg/day 8 weeks	Venlafaxine 75 mg/day only	HAM-D SDS	Yes	Fewer adverse events in experimental group
Tiwari et al., 2011 [80] India N = 60	Saraswata Churna (preparation involved Kustha, Ashwagandha, Ajmmoda, Sweta and Krisna Jiraka, Sunthi, Marich, Pipali, Patha, Sankhpuspi, and Vacha powder) 1.5 g, 2/day with 1tsp (5 ml) ghrita & 0.5tsp (2.5 ml) honey, after meals 3 months	Citalopram 20 mg once a day	HAM-D	Yes	No side effects were noted.
Bazrafshan et al., 2020 [49] Iran N = 114	Lavender tea (2 g teabag, genus and species not reported) steeped for 10–15 min in 300 mL hot water, 2/day 2 weeks	No treatment	BDI	Yes	No side effects were noted.
Harrer et al., 1999 [70] Germany & Austria N = 161	St John’s Wort (Hypericum perforatum L. dry extract, LoHyp-57) 200 mg, 2/day 6 weeks	5.6 mg of fluoxetine hydrochloride (equivalent to 5 mg fluoxetine)	HAM-D SDS CGI	St John’s Wort was non-inferior to fluoxetine.	12 adverse drug reactions in LoHyp-57 (6 abandoned treatment) and 17 in fluoxetine (8 abandoned treatment)
Steger et al., 1985 [72] Germany N = 100	St John’s Wort (Hypericum perforatum L., 90-100 mg standardised to 0.05 mg hypericin) and Valerian (Valeriana officinalis L. 50 mg 6:1 extract) extract Sedariston Konzentrat® 6 weeks	Desipramin hydrochloride 25 mg	CGI D-S	Yes	Occasionally tiredness, dizziness, tachycardia dry mouth - all minor complaints

BDI Beck Depression Inventory, CES-D Centre for Epidemiological Studies Depression Scale, CGI Clinical global impression, CIDI Composite International Diagnostic Interview, DHA Docosahexaenoic Acid, D-S Depressivitäts-Skala, DSM-IV Diagnostic and Statistical Manual of Mental Disorders IV, EPA Eicosapentaenoic acid, GDS Geriatric Depression Scale, HAM-D Hamilton Depression Rating Scale, MADRS Montgomery-Asberg Depression Rating Scale, MDD major depressive disorder, IU international units, PHQ-9  9-item Patient Health Questionnaire, SCAG Sandoz Clinical Assessment – Geriatric, SDS self-rating depression rating scale, tsp teaspoon