TABLE 1.

Antipsychotic potential of phytochemicals in non-clinical studies.

Chemical Class	Phytochemical	Source	Assay/Test	Animal/ Cell Type	Doses	Method	Mechanism	Result	References
Alkaloids	Arecoline	Areca catechu	Y-maze Behavioral test	cuprizone induced mouse model	0, 2.5, or 5 mg/kg/Day	Recorded spontaneous alternation behavior	Preventing white matter injury, prevented memory impairment	Attenuated spatial working memory impairment, increased the expression of myelin basic protein in the frontal cortex	Xu, Adilijiang, Wang, You, Lin, Li and He (2019)
	Stepholidine	Stephania intermedia	Paw test Pre-pulse inhibition	Male Wistar rats	4–16 mg/kg	Determined limb retraction time and	D1 receptor agonist and D2 receptor antagonist	Increased hind limb retraction time Reverse apomorphine induced disruption	Ellenbroek, ZHANG and JIN (2006)
	Galantamine	Galanthus caucasicus	Dopamine receptor agonism by apomorphine, NMDA antagonism by MK-801, muscarinic receptor antagonism by scopolamine	Wistar rats	0.3, 1.0 and 3.0 mg/kg	Apomorphine agonism, NMDA and Ach antagonism models	Increase in cholinergic activity	Pre-pulse inhibition was improved	Hohnadel et al. (2007)
	Corymine	Hunter zeylancia	2 electrode voltage clamp technique	cDNA clones of NR1a and NR2b OF Xenopus	100 µM	Potentiating effect of corymine was induced in presence of glycine	Potentiation on NMDA response	Potentiates the NMDA induced currents and can be used for schizophrenia	Leewanich et al. (2005)
	Reticuline	Ocotea duckei	Amphetamine induced hyper-motility	Swiss albino mice	50–100 mg/kg	Number of steps recorded	Dopamine antagonist activity	Reduced hyper-motility	Morais, Barbosa-Filho and Almeida (1998)
	Geissoschizine methyl ether	Uncariae ramulus	Cell based Calcium imaging analysis	Human cell line and mouse brain tissue		Inhibited dopamine induced calcium response	Partial agonist/antagonist at D2, partial antagonist at 5HT receptors	Inhibited calcium induced serotonin current	Ueda et al. (2011)
	Psychollatine	Psychotria umbellata	Male adult mice	a) Apomorphine induced climbing b)MK-801 induced hyperactivity	100 mg/kg	Climbing behavior and locomotion determined	Interference with DA, 5HT and NMDA receptors	Attenuated the climbing and locomotion	Costa-Campos, Lara, Nunes and Elisabetsky (1998)
	Alstonine	Picralima nitida	Male albino mice Male Wistar rats	a)Apomorphine induced stereotypy, b)haloperidol induced catatonia	0.5 to 2 mg/kg	Determined behavioral score and catatonic time	Modulating the DA uptake and serotonin receptors	Reduction in behavioral score, diminished catatonic time	Costa-Campos, Lara, Nunes and Elisabetsky (1998)
	Physostigmine	Physostigma venenosum	Conditioned emotional response	Male Wistar rats	0.5 mg/kg	Pre-exposure and in conditioning response is measured	Induced Latent inhibition disruption	Reverse the cognitive impairment in schizophrenia	Barak and Weiner (2010)
Amino acid and derivatives	Leucine	Cucurbeta pepo	Apomorphine induced stereotypy. Haloperidol induced catalepsy	Wistar rats	0.7 mg/kg	Stereotypy, catalepsy	Anti-dopaminergic effect	Decreased stereotypy, potentiated catalepsy	Suresh and Raju (2013)
	Betaine	Beta vulgaris	PPI, NOR	Male ICR mice	O, 30, 100 mg/kg	%PPI, recognition index %	Modulation of NMDA R glycine site	Attenuated ketamine induced disruption in PPI, improved novel recognition	Lin et al. (2016)
Bioflavonoids/ Polyphenols	Quercetin-3- rutoside	Fagopyrum esculentum	PCR-RFLP method	Human brain	10 µmol	Hetero-plasmic sequence variation determined	reduced oxidative stress	Quench the superoxide production	Marchbanks et al. (2003)
	Scopoletin	Morinda citrifolia	a) Apomorphine induced Cage climbing, b) Amphetamine induced stereotypy	Male ICR mice	0.1 mg/kg	Climbing and stereotypy determined	Anti-dopaminergic effect	Reduction in climbing and stereotypy	Pandy and VijeePallam (2017)
	Quercitin	Lonchocarpus cyanescens	Novel object recognition (NOR)	Balb-C mice	25 and 50 mg/kg	Memory impairment model by ketamine used	Antioxidant potential	Improves cognitive deficit	Mert, Turgut, Arslanbas, Gungor and Kara (2019)
	Myricitrin	Eugenia uniflora	Apomorphine induced stereotypy, catalepsy and paw test	Swiss albino mice Wistar rats	5,10 and 30 mg/kg	Stereotypy, climbing, limbs retraction and catalepsy noted	Nitric oxide and Protein kinase C inhibitor	Blocked stereotypy, climbing, impaired retraction time of limbs, increased catalepsy	Moore and Martin (1957); Pereira et al. (2011)
Cannabinoids	Cannabidiol	Cannabis sativa L	Apomorphine induced stereotypy	Male Wistar rats	15–480 mg/kg	Stereotypy and prolactin secretion were measured	Blockade of serotonin reuptake or increased GABAergic activity	Attenuated the stereotypy and increase in prolactin	Zuardi et al. (1991)
Carotenoids	Crocin	Crocus sativus L	MK-801 induced Rotarod test, open field test	Neonatal Sprague Dawley rats	25,50 mg/kg	Balance, motor coordination and locomotion	regulations of SIRT1 and downstream BDNF expression in the hippocampus	Improved motor coordination, balance and locomotion deficit	Sun, Zhao, Xie and Wan (2020)
Cholesterols	Hydroxytyrosol	Olea europaea	Prenatal restraint stress model	Sprague dawley rats	10 and 50 mg/kg/day	Spontaneous alteration performance, Morris water maze test performed	Antioxidant, anti-inflammatory and brain protecting	Improves cognitive functions and Might be used for schizophrenia	Young et al. (2008); Calabrese et al. (2017)
	hydroxytyrosol	Olea europaea	Determination of DNA strand breakage (comet assay)	IMR-32 cell line; histiocytic lymphoma U937 cell line		extent of H2O2-induced DNA damage	Decrease DNA damage	Neuroprotective efficacy, might be useful for schizophrenia
Flavonoids/ Polyphenols	Naringin	Citrus paradisi	Locomotor activity, PPI	Male Wistar rats	100 mg/kg	Counts per 5 min, %PPI	targeting Wnt/β-catenin together with Akt/GSK-3β pathways	Increased locomotor activity, increased %PPI	George et al. (2020)
	Nobiletin	Citrus depressa	MK-801 induced learning impairment	ddY mice	2–50 mg/kg	Step-through Passive-Avoidance Task	Improves hypo-function of NMDA receptor-ERK signaling	Improvement of cognitive symptoms, might be beneficial for schizophrenia	Naka et al. (2007)
Glycosides	Bacosides A and B	Bacopa monnieri	Novel object recognition test	Rat		Discrimination ratio was obtained	Increasing VGLUT2 density to normal level	Increase in Discrimination Ratio score	Wetchateng and Piyabhan (2014)
	sulforaphane	Brassica oleracea	Locomotor activity, Pre-pulse inhibition	Male mice	30 mg/kg	Hyper-locomotion and PPI deficits were examined	An antioxidant protects against dopaminergic neurotoxicity by increasing Nrf2 expression	Attenuated PCP-induced hyper locomotion and PPI deficits	Shirai et al. (2012)
	Hypericin	Hypericum perfolatum					Inhibit D3/D4	Might be used for schizophrenia	Butterweck et al. (2002)
	Emodin	Rheum rhabarbarum	Acoustic startle response, Methamphetamine induced hyper-locomotion	Sprague dawley rats	50 mg/kg	Startle response and locomotor activity	Targets ErbB signaling alters dopamine and serotonin metabolism	Suppressed acoustic startle response and hyper-locomotion	Mizuno et al. (2008); Mizuno et al. (2010)
	cardenolides	Nerium oleander		NMRI male albino mice				Might be used for schizophrenia	Zhang (2004)
	Polygalasaponins	Polygala tenuifolia		a) Female TO mice	25–500mg/kg	Animal’s movements, behavioral patterns and hyperactivity measured	Dopamine and serotonin antagonist activity	Reduction in climbing, stereotypy and hyperactivity	Chung et al. (2002)
b) Male lister hooded rats
	Diosmin	Scrophularia nodosa	Apomorphine induced stereotypy, catalepsy	Swiss male mice	25, 50, 100 mg/kg	Stereotypy scoring, cataleptic behavior	Enhancement of GABAergic neurotransmission	Attenuated stereotypy, devoid of cat	Eneni et al. (2020)
	Picroside II, wedelolactone, 7-o-methylwogonin and isoformononetin	Picrorhiza scrophulariiflora		In vitro studies		Docking studies	Interaction with NMDA receptor	Good docking score	Bagchi and Somashekhar (2014)
Polyphenols	Resveratrol	Vitis vinifera	a) Apomorphine induced stereotypy	Swiss albino mice	200 and 400 mg/kg	Stereotypy and grooming determined	D1 receptor antagonistic effect	Decreased climbing and swim induced grooming	Magaji et al. (2017)
	b) Swim induced grooming
	Kaempferol	Lonchocarpus cyanescens	a) Amphetamine induced-stereotype	Wistar rats albino mice	50–400 mg/kg (i.p)	Stereotypy was measured, Spontaneous motor activity was measured		Suppressed stereotyped behavior. Reduction in spontaneous motor activity	Sonibare et al. (2012)
	b) Open field test
	Rutin	Morinda citrifolia	a) Apomorphine induced Cage climbing	Male ICR mice	0.1 mg/kg	Climbing and stereotypy determined	Inhibition of D2 receptors	Reduction in climbing and stereotypy	Pandy and VijeePallam, (2017)
			b) Amphetamine induced stereotypy
	Curcumin	Curcuma lona	Assay based on tietze method	Mice	10 and 50 µM	Oxidized and reduced GSH level determined	Antioxidant action	Increased GSL and GSH level in astrocytes and neurons	Lavoie et al. (2009)
	Genistein	Genista tinctoria L	Locomotor activity, forced swim test, active avoidance	rats	50 mg/kg	Hyperactivity, immobility, avoidance	Anti-dopaminergic activity due to increased estrogen	Hyperactivity, enhanced immobility and decreased avoidance	Kalpana, Raju and Merugu (2014)
	Gallic acid	Camellia sinensis	ketamine-induced psychosis	Swiss albino mice	50, 100 and 200 mg/kg	Stereotypy, locomotor activity	enhancement of NMDA receptor function	Stereotypy improved and locomotor activity increased	Yadav et al. (2018a)
	Morin	Allium cepa	Open field, apomorphine-induced stereotypy, ketamine-induced stereotypy	Male Swiss mice	50 and 100 mg/kg	Locomotor activity, stereotypy	Might be enhancement of GABA activity	reduced spontaneous locomotor activity. Also, morin suppressed apomorphine-induced stereotypy and ketamine induced stereotypy	Ben-Azu et al. (2018)
Polypropanoid	Alpha (α)—asarone	Acorus calamus	Apomorphine-induced stereotypy	Swiss albino mice	30 and 50 mg/kg	Climbing time and climbing behavior determined	Anti-dopaminergic property	Decrease in the cage climbing time and climbing behavior	Pandy and Vijeepallam (2016)
Sesquiterpene	Tutin	Coriaria ruscifolia	Ca2+ transients& CREB analysis	Mouse spinal cord neurons	1, 3, 5 and 8 mg/kg		Inhibit GABA A receptor	Might be used or schizophrenia	Fuentealba et al. (2007)
Steroids	Anaferine, Beta-Sitosterol, Withaferin A, Withanolide A, Withanolide B and Withanolide D	Withania somnifera		Molecular docking			Inhibition of GluN2B-containing NMDARs	Might be useful for schizophrenia	Kumar and Patnaik (2016)
Sterol	Stigmasterol	Akebia quinata	Ketamine induced stereotypy	Swiss albino mice	50mg/kg	Stereotypy and hyperlocomotion measured	Antioxidant action and increase in GABA and decrease in dopamine and acetylcholine	Decrease in stereotypy and locomotion	Yadav et al. (2018b)
Terpenoid	1,8-cineole	Hyptis martiusii	haloperidol-induced catalepsy, and ketamine-induced hyperkinesia	female Swiss mice	50 mg/kg	Catalepsy and hyperkinesis	Possible modulation of dopaminergic and glutamatergic systems	potentiated haloperidol-induced catalepsy and reduced ketamine-induced hyperkinesia	Monteiro et al. (2019)
Xanthone/ Polyphenol	α-mangostin	Garcinia mangostana L	Pre-pulse inhibition (PPI) test, open field test (OFT), forced swim test (FST)	Sprague Dawley dams and offsprings	20 mg/kg	Sensorimotor gating, locomotor activity and depressive behavior determine	antioxidant	%PPI, locomotor hyperactivity and depressive like behavior were reversed	Lotter (2018)
	Magniferin	Magnifera indica	Open field test	Swiss mice, Wistar rat	50 mg/k g	Locomotor behavioral changes	Antioxidant, anti-inflammatory effect	Overcome grooming and stereotypy	Rao et al. (2012)