Table 1.

Antidepressant effects of marine algae examined in preclinical and clinical studies of depression

Microalgae/ Macroalgae	Algae/ Extract/ Compound	Dosage and treatment	Research model	Model establishment	Anatomical region	Behavioral outcome	Morphological/ biochemical findings	Authors
Preclinical studies
Arthrospira platensis Gomont (Spirulina platensis)	Hydrolyzed Spirulina extract by malted barley	10 ml/kg body weight/day for 2 weeks; PO	Male ICR mice	Exposure to FST	N.A.	FST: reduced immobility time	Reduced plasma levels of blood urea nitrogen and lactate dehydrogenase	(34)
	Spray-dried powder	100, 200, and 400 mg/kg body weight/day for 1 week; PO	Wistar albino rat and albino mice	Exposure to FST, TST, 5-HTP-induced head twitches, clonidine-induced aggression, L-DOPA-induced hyperactivity, and aggressive behavior	Brain	FST: reduced immobility time TST: reduced immobility time 5-HTIP-induced head twitches: increased Clonidine-induced aggression: increased L-DOPA-induced hyperactivity and aggressive behavior: increased	Increased SOD and catalase levels in the brain Toxicity at the maximum dose (2000 mg/kg) of spirulina	(52)
	Pure powder (SPM-12462016)	200 mg/kg body weight/day for 15 days; PO	Wistar female rats	Restraint stress	Basolateral amygdala	N.A.	Decreased SOD and GPx activity Increased FRAP level Decreased MDA level Increased BDNF level in amygdala Increased BDNF and TrkB mRNA expression Increased apical dendritic length and number of dendritic spines of basolateral amygdala neurons	(21)
Botryococcus braunii Kützing	Ethanol extract	100 mg/kg body weight/day for 2 weeks; PO	Male ICR mice	Exposure to FST	Cerebrum	FST: reduced immobility time	Increased ATP production Up-regulated mRNA expression of tyrosine 3-monooxygenase, pyruvate carboxylase, and BDNF Induced dopamine synthesis- and neurogenesis-related gene expression	(19)
		1/1000 (0.1%) dilution of ethanol extract for 48 h; in vitro	PC12 cells	Exposure to corticosterone	N.A.	N.A.	Increased cell viability
Chlorella vulgaris Beijerinck, M.W.	C. vulgaris powdered extract and commercialized C. vulgaris tablet	360 mg/kg body weight/day for 2 weeks; PO	Wistar rat	Chronic unpredictable mild stress	Adrenal gland	FST: reduced immobility time OFT: increased motor activity SPT: increased sucrose preference	N.A.	(53)
Haematococcus pluvialis Flotow	Astaxanthin Astaxanthin Astaxanthin Combined astaxanthin-lithium chloride	20, 40, and 80 mg/kg body weight/day for 7 days; PO	Male ICR mice	Exposure to IP injection of lipopolysaccharide	Hippocampus, prefrontal cortex	FST: reduced immobility time TST: reduced immobility time	Reduced pro-inflammatory cytokines (IL-1β, IL-6, TNF-a), inflammatory mediators (iNOS, nNOS, and COX-2 mRNA expression) Suppressed NF-κB p65 phosphorylation	(17)
		Single dose of 20, 40, and 80 mg/kg body weight; PO	Male ICR mice	Exposure to FST and IP injection of p-chlorophenylalanine and reserpine	Frontal cortex, hippocampus, hypothalamus, striatum	FST: reduced immobility time TST: reduced immobility time	Increased serotonin level in all tested brain regions Increased noradrenaline in the hippocampus Decreased indoleamine 2, 3-dioxygenase mRNA expression Reduced kynurenine/ tryptophan ratio Increased serotonin/tryptophan ratio in the hippocampus, frontal cortex, and hypothalamus	(18)
		50 mg/kg body weight/day for 4 weeks; PO Astaxanthin 50 mg/kg body weight/day for 4 weeKS; PO and lithium chloride 2 mmol/kg body weight/every other day for 4 weeks; IP	Adult male Kunming mice	Chronic exposure to organophosphorus pesticides	Hippocampus (dentate gyrus)	FST: reduced immobility time TST: reduced immobility time	Reduced neuronal damage in the hippocampus Increased p- GSK3β, p-CREB, p-P13K and p-Akt expressions in the hippocampus Activated Akt/GSK3β/CREB signaling pathway	(54)
Nizamuddinia Zanardinii (Schiffner) P.C.Silva	Methanol extract	30, 45, and 60 mg/kg body weight/day for 4 weeks; PO	Male Wistar albino rat	Exposure to FST	Brain tissues	FST: reduced immobility time	Increased brain monoamine levels (serotonin, dopamine, and noradrenaline)	(28)
Padina australis Hauck	Ethanol extract	Single dose of 0.25–0.5 mg/ml for 24 hr; in vitro	PC12 cells	Exposure to high dose corticosterone	N.A.	N.A.	Reduced lactate dehydrogenase release, intracellular reactive oxygen species, endoplasmic reticulum stress, and apoptosis Increased cell viability, endogenous glutathione, mitochondrial membrane potential, and aconitase activity	(12)
Stoechospermum marginatum (C.Agardh) Kützing	Methanol extract	30, 45, and 60 mg/kg body weight/day for 4 weeks; PO	Male Wistar albino rat	Exposure to FST	Brain tissues	FST: reduced immobility time	Increased brain monoamine levels (serotonin, dopamine, and noradrenaline)	(28)
Sargassum swartzii C. Agardh	Methanol extract	30, 45, and 60 mg/kg body weight/day for 4 weeks; PO	Male Wistar albino rat	Exposure to FST	Brain tissues	FST: reduced immobility time	Increased brain monoamine levels (serotonin, dopamine, and noradrenaline)	(28)
Solieria filiformis (Kützing) P.W. Gabrielson	Solieria filiformis lectin	Single dose of 1, 3, and 9 mg/kg body weight; IV	Male adult Swiss mice	Exposure to FST	N.A.	FST: reduced immobility time TST: reduced immobility time Interaction with the dopaminergic system possibly via D1- and D2- receptors		(55)
Ulva sp.	Hydrophilic extract (lyophilized powder) (FR 1261909)	10, 20, and 40 mg/kg body weight/day for 2 weeks; PO	Male and female Wistar rats	Exposure to FST	N.A.	FST: reduced immobility time	N.A.	(20)
Clinical studies
Chlorella vulgaris Beijerinck, M.W.	C. vulgaris extract	300 mg/tablet (ALGOMED®) 3 times/day for 6 weeks; PO	Adult patients with major depression	N.A.	N.A.	Physical and cognitive symptoms of depression: improved Anxiety symptoms: improved	N.A.	(56)
Haematococcus pluvialis Flotow	Astaxanthin	12 mg/capsule (AstaZine®)/ day for 8 weeks; PO	Healthy adults	N.A.	N.A.	Negative mood state (depression and fatigue): reduced Global mood state: improved	N. A.	(57)
Sargassum fusiforme and Pyropia yezoensis or Pyropia tenera	Whole macroalgae	Consumption ranging from at least twice/day to less than once/month; PO Portion size ranging from very small (50% or less) to very large (50% or more) of a standard portion size	Pregnant women (5 to 39 weeks pregnancy)	N.A.	N.A.	Prevalence of symptoms of depression: reduced with higher consumption of macroalgae	N.A.	(58)
Ulva Lactuca Linnaeus	Water-soluble extract	6.45 mg/kg body weight /day in the form of capsules for 12 weeks; PO	Adults with anhedonia	N.A.	N.A.	Anhedonia: reduced Sleep disorder: improved Psychomotor consequences: improved Nutrition behavior: improved	N.A.	(59)
Undaria pinnatifida and Pyropia yezoensis or Pyropia tenera	Whole macroalgae	Consumption ranging from at least twice/day to less than once/month; PO Portion size ranging from very small (50% or less) to very large (50% or more) of a standard portion size	Pregnant women (5 to 39 weeks pregnancy)	N.A.	N.A.	Prevalence of symptoms of depression: reduced with higher consumption of macroalgae	N.A.	(58)
Unnamed	Whole macroalgae	Consumption ranging from almost never/day to twice or more times/day for 3 years; PO	Adult employees	N.A.	N.A.	Incidence of symptoms of depression: reduced with higher consumption of macroalgae	N.A.	(60)

PO = per oral, IV = intravenous injection, IP = intraperitoneal injection, SOD = superoxide dismutase, GPx = glutathione peroxidase, FRAP = ferric reducing antioxidant power, MDA = malondialdehyde, BDNF = brain-derived neurotrophic factor, TrkB = tyrosine receptor kinase B, ATP = adenosine triphosphate, FST = forced swim test, TST = tail suspension test, SPT = sucrose preference test, Akt = protein kinase B, GSK3β = glycogen synthase kinase 3 beta, CREB = cAMP-response element binding protein, 5-HTP = serotonin, IL-1β = interleukin-1 beta, IL-6 = interleukin-6, TNF-α = tumor necrosis factor-alpha, iNOS = inducible nitric oxide synthase, nNOS = neuronal nitric oxide synthase, COX-2 = cyclooxygenase-2, NF-κB = nuclear factor kappa B, N.A.: Not applicable