Effect of herbal and nutritional products on the central ...HNP. Moreover, the antagonism of such receptors is also considered a major cause of the extrapyramidal side-effects (EPS)

JAASP http://www.aaspjournal.org

Journal of Asian Association of Schools of Pharmacy 2019; 8: 22–49 Review © 2019 The Asian Association of Schools of Pharmacy

22

Effect of herbal and nutritional products on the central nervous system effects of haloperidol: a systematic review

Rosina Yau Mok1, Sophia Yui Kau Fong1, Mengbi Yang1, Tonia Hoi-Tung Sung2, Yin Cheong Wong1, Tianjing Ren1, Cheuk Hin Chow1, Qiong Gao1 and Zhong Zuo1,*

1 School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR 2 Leslie Dan Faculty of Pharmacy, University of Toronto

Received March 20, 2019 Revised May 8, 2019 Revised June 6, 2019 Accepted June 9, 2019

ABSTRACT

Haloperidol is widely used in treatments of acute and chronic schizophrenia. Due to the narrow therapeutic window of haloperidol and the increasing popularity of herbal and nutritional products (HNPs), it is important to have comprehensive understanding on the interactions between haloperidol and HNPs. The current review is the first to provide systematic evidences from both animal and clinical studies on haloperidol-HNPs interactions. Due to the diversity of the reviewed studies, quantitative meta-analysis is not possible. Two major outcomes of haloperidol-HNPs interactions include the changes in level of catalepsy and in level of extrapyramidal side-effects. The mechanisms of these interactions remain unclear, yet factors such as modulations on oxidative stress and dopaminergic pathway were proposed. Only nine clinical trials were identified, indicating further exploration on the clinical utilization of haloperidol with HNPs is warranted. Based on the results of the current review, it is advised to monitor the potential risk of interactions between haloperidol and co-administrated HNPs in clinical practice. Key words: haloperidol, herb and nutritional products, herb-drug interactions, catalepsy, extrapyramidal side-effects, antipsychotics

* Corresponding author School of Pharmacy, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR E-mail: [email protected]

1. Background

As a part of complementary and alternative medicine, herbal and nutritional products (HNPs) are widely used around the world with escalating prevalence throughout decades (Izzo and Ernst, 2001; Kuhn, 2002; MacLennan et al., 2002; Zhang et al., 2011). They have also received increasing attention in the management of chronical conditions such as psychiatric disorders (Beaubrun and Gray, 2000; Csernansky and Schuchart, 2002; Matthews et al., 2003; Zhang et al., 2010). A survey by Grzywaczs et al. demonstrated that herbal and nutritional compounds are widely used among older adults with depression or anxiety, with a rate as high as of 82% (Grzywacz et al., 2006). In addition, the prevalence of concomitant use of Chinese medicine and antipsychotics in schizophrenic patients was reported to be around 36.4% (Zhang et al., 2011). Although the prevalence of co-administration of HNP with drugs in CNS patients is high, it is reported that 61.5% of adults in the US that was taking at least one herbal compound had not consulted or disclosed such use to their physicians (Fugh-

Berman, 2000). Such lack of guidance from healthcare professionals together with under-researched safety information of the HNPs bring out the safety concern of HNPs in combination with therapeutic drugs in psychiatric treatments (Cocka, 2015; Ernst, 1998).

As one of the first-generation antipsychotics, haloperidol was introduced in 1958 and has been widely used in western countries (Granger and Albu, 2005). This butyrophenone antipsychotic is most commonly used in treatments for both acute and chronic schizophrenia, as well as mania, autism in children, Gilles de la Tourette’s syndrome, etc (Kane et al., 2002; McIntyre et al., 2005; Perry et al., 1989; Shapiro et al., 1989; Wyosky and Baum, 1989) via intravenouse, intramuscular or oral administrations. Due to its narrow therapeutic window and large inter-individual variability of pharmacokinetics, clinical drug monitoring of haloperidol is recommended (Kudo and Ishizaki, 1999; Ulrich et al., 1998). Haloperidol is extensively metabolised in the liver with CYP3A4 and CYP2D6 being the principle enzymes (Fang et al., 1997). Glucuronidation is also reported to play a major role in haloperidol metabolism (Someya et al., 1992). The

JAASP 2019; 8: 22–49

23

blockade of dopamine receptors, specifically the D2 receptors family, was considered central to antipsychotic activity of haloperidol (Kapur and Mamo, 2003; Kapur and Remington, 2001; Saeedi et al., 2006). Such properties make it prone to interact with co-administered substances including HNP. Moreover, the antagonism of such receptors is also considered a major cause of the extrapyramidal side-effects (EPS) and therefore limits the clinical utilities of antipsychotics (Reynolds, 2004). Chronic administration of haloperidol can also induce motor dysfunction, including tardive dyskinesia (Beasley et al., 1999).

Research publications, especially review articles, are considered one of the major information resources for healthcare professionals when they are making clinical decisions regarding usage of herbal or dietary supplements (Howard et al., 2001). Although there are a few review articles on interactions between antipsychotic treatments and HNPs (Knable, 2002; Rathbone et al., 2005; Rathbone et al., 2007; Singh et al., 2010), they barely cover the details of haloperidol, suggesting that there is an evidence gap in terms of comprehensive reviews on the interactions between HNP and haloperidol. By taking a systematic approach, the current review has summarized the existing scientific evidence on interactions between haloperidol and HNPs. Studies that demonstrated information from animal models and clinical trials were identified and the potential mechanism behind it was explored, aiming to provide a more comprehensive guidance for the healthcare professionals.

2. Methodology

2.1. Literature Search Electronic computer-based search was made using the

following databases: EMBASE (1980–Jan. 2019), EMBASE Classic (1947–1979), MEDLINE (1966–Jan. 2019), OLDMEDLINE (1946–1965), PubMed (1946–Jan. 2019), Allied & Complementary Medicine (AMED) database from the Health Care Information Service of the British Library (1985–Jan. 2019), Cochrane Library (1992–Jan. 2019), Cinahl Plus (1937–Jan. 2019), SciFinder Scholar (1907–Jan. 2019), Stockley’s Herbal Medicines Interactions (1907–Jan. 2019) and Natural Medicines Comprehensive Databases (1985–Jan. 2019). Both the drug names and its brand names/ commonly used names were used as search terms of halo-peridol (“Haloperidol”, “R-1625”, “Haldol”, and “Serenace”). A comprehensive list of keywords and Medical Subject Headings (MeSH) search terms for herbs, food and dietary supplements which was previously developed were combined with the search terms of haloperidol (Table 1) (Fong et al., 2013; Fong et al., 2014).

2.2. Study Screening Articles contained data involving interactions of HNPs

with haloperidol are considered eligible for evaluation. The HNPs were categorized as “traditional Chinese medicine

(TCM)”, “food and dietary supplements” and “other herbal products”. For the TCM category, Latin names for herbs were standardized as consulted to the official compendium Pharmacopoeia of the People’s Republic of China 2015 (Chinese Pharmacopoeia) and/or Zhong Hua Ben Cao (Chinese Materia Medica). The term “food and dietary supplements” was defined by The Dietary Supplement Health and Education Act of 1994 (DSHEA). According to such act, “dietary supplement” refer to any dietary products (other than tobacco) containing one or more of the following dietary ingredients: vitamin, mineral, herb or other botanical, amino acid, a dietary substance for use by man to supplement the diet by increasing the total dietary intake. Any specific traditional food/fruit products or beverages were categorized as “food”. Relevant reports were selected and validated for their eligibility by two reviewers (Fong and Mok) independently. Due to the limited availability of clinical information, all related clinical trials were included regardless of their study characteristics. Articles on in-vivo animal studies or on clinical trials were included if they contained data involving interactions of haloperidol with TCM, herbs, food and dietary supplements. Exclusion criteria were as follows: (1) full text not available, (2) non-English language articles, (3) review and meta-analysis articles, (4) other irrelevant studies such as in-vitro studies, case reports, etc.

2.3. Quality Assessment Clinical trials were assessed by two reviewers

independently for methodological quality using the revised Cochrane risk of bias tool from the following five domains: (1) bias arising from the randomization process, (2) bias due to deviations from intended interventions, (3) bias due to missing outcome data, (4) bias in measurement of the outcome, (5) bias in selection of the reported result. A rating was given for each trial based on the three quality categories (Higgins et al., 2011). In addition, the Jadad Scale (Jadad et al., 1996) was also applied for quality assessment on clinical trials by two independent reviewers, measuring factors that impact on the quality of a trial including: (1) randomization, (2) double-blinding and (3) description on withdrawals and drop outs. A rating scale from 0 to 5 was given for each trial based on the three aspects.

2.4. Data Synthesis The current article is a systematic review on different

types of herb-drug interaction studies without meta-analysis, due to the variety of the study designs and the diversity of the clinical and pre-clinical outcomes, quantitative data synthesis is not possible, and descriptive data synthesis is conducted to summarize the pharmacokinetic and pharmacodynamic interaction between HNPs and haloperidol. Review protocol of the current study was not registered. Supplementary Table 1 showed the PRISMA checklist of the current review.

Rosina Yau Mok et al.

24

3. Results

3.1. Literature Search A total of 1700 articles were found through the initial

database searches and by scrutinizing the bibliographies of relevant literatures, within which 226 articles fulfilled the inclusion criteria and were selected for further evaluation. A final 155 articles were evaluated as eligible for full text extraction, including 145 original articles and 10 review articles. Such articles then underwent in-depth evaluations performed by 3 reviewers (Mok, Fong, Sung) independently. The current review has identified 9 clinical studies and 89 animal studies (Figure 1). The majority of studies are focusing on the haloperidol-induced catalepsy model (n = 44) and EPS related studies (n = 25). Articles exploring other outcome measure such as dopamine level, antipsychotic effect, sexual stimulating effect etc. were also included.

3.2. Risk of Bias The risk of bias of the 9 clinical studies was evaluated by

the revised Cochrane risk of bias tool, and the quality of the studies was evaluated by the Jadad scale (0–5). Among the 9 clinical studies, three studies received high Jadad scale of 4 and were categorized as low risk of bias, 1 double-blind controlled trial received Jadad scale of 3 with some concerns

of bias, 1 open-label randomized study with Jadad scale of 3 and other 4 studies with low Jadad scales (equal or less than 2) were categorized as high risk of bias.

Table 1. Keywords and MeSH search terms for herbs, food and dietary supplements.

Keywords MeSH terms

(tradition* and chines* and medic*).mp. exp Chinese drug

(drug* and chines* and herb*).mp. (TCM or CHM).tw.

exp Chinese medicine exp Chinese herb

(plant* and medic*).mp. traditional chinese.tw. (chinese adj (herb$ or drug$ or formul$ or plant$ or presri$ or remed$ or materia medica)).ab,ti,ot.

exp herbal medicine exp herbaceous agent exp plant extract

((herb$ or drug$ or formul$ or plant$ or presri$ or remed$ or materia medica) adj chinese).ab,ti,ot. exp diet supplementation 1

herbal remed$.tw. exp food drug interaction 9

(plant* and extract*).mp. exp food 910

alter* medic* exp Drugs, Chinese Herbal 17

integrative medicin$.ab,ti,ot. exp Plant Extracts 61

(phytodrug$ or phyto-drug$ or phytopharmaceutical$).tw. exp Plants, Medicinal 41

(herb or herbs or herbal).tw. Nutrition$ supplement or diet$ supplement.mp.

exp Medicine, Oriental Traditional exp Medicine, chinese traditional 6

exp Phytotherapy 32 exp Medicine, Ayurvedic 3 exp Medicine, east asian traditional

exp medicine, kampo exp medicine, korean traditional exp medicine, tibetan traditional

exp medicine, mongolian traditional

exp shamanism/

Figure 1. Study flow diagram.

Screened at title and abstract.Records fulfilled the inclusion

criteria (n=226)

Studies included (n=98):Animal studies (n=89)Clinical studies (n=9)

Records excluded due to:・ Irrelevant studies (n=47)

English full-text articlesassessed(n=145)

Records identified in database:・ Ovid (EMBASE, EMBASE Classic, Allied & Complementary

Medicine database, and Cochrane Library) (n= 510)・ Pubmed (MEDLINE and OLD MEDLINE) (n = 516)・ Cinahl Plus (n= 47)・ SciFinder Scholar (Caplus) (n= 530)・ Stockley ’s Herbal Medicines Interactions (n= 10)・ Natural Medicines Comprehensive Databases (n= 87)Total number of records identified (n=1700)

Screened at title and abstract.Records excluded due to:・ Duplicated records (n= 1042)・ Irrelevant articles (n= 432)

Records excluded due to:・ Non-English articles (n= 35)・ No full text available (n= 36)・ Review articles (n=10)

JAASP 2019; 8: 22–49

25

The risk of bias of all animal studies were relatively high compared with the clinical trials. Although all studies properly presented baseline characteristics and outcomes, none of the studies reported on allocation concealment, random housing, blinding of the caregivers, or blinding and randomization of outcome assessment. All of the animal studies were parallel design, and available information on the type of animals used in the studies, dose and duration of haloperidol, types of outcomes, and timing of outcome measurements were all summarized in the Tables 2, 3 and 5.

3.3. Effect of Herbs on Haloperidol-Induced Catalepsy Model

A total of 41 HNPs were identified in 44 articles for potential interactive effect on the haloperidol-induced catalepsy model with the catalepsy score of the studied rodent being the main outcome measure. Out of the 44 articles, 15 articles investigated the effect of TCM on the model, 24 articles investigated on other herbal products and 5 articles on food and dietary supplements (Table 2).

Among the identified 41 HNPs, 8 HNPs reported to have no significant effect on the haloperidol-induced catalepsy, including Solanum nigrum Linn., Cassia sophera Linn., Ageratum conyzoides Linn., Momordica dioica, Phyllanthus maderaspatensis Linn., Pueraria tuberosa, Randia dumetorum and Ficus Bengalensis Bark (Ghaisas et al., 2008; Maharudra et al., 2011; Nagore et al., 2009; Nirmal et al., 2009; Nirmal et al., 2012; Rao et al., 2008; Taur et al., 2007; Tote et al., 2009). Although specific mechanisms were not documented, it was believed that these HNPs do not have activities on dopaminergic transmission and hence did not show significant effect on the animals in the haloperidol-induced catalepsy model.

Among the 33 HNPs reported to have activities on the model, 11 of them reported a potentiation effect. Among which, Morus alba Linn., Acorus calamus Linn., Piper betel, Hibiscus rosa-sinensis root are reported to possess the ability to decrease dopamine level in striatum and therefore showed significant potentiation of catalepsy (Ka et al., 2009; Nade et al., 2009; Vyawahare and Bodhankar, 2007; Yadav and Nade, 2008). The mechanism for Ginkgo biloba leaf extract (EGb 761) to increase haloperidol-induced catalepsy was not clear and requires further exploration (Fontana et al., 2005). Although the specific mechanism remains unknown, Alpha-tocopherol (Vitamin C) showed potentiation effect on both rats and monkeys by producing marginal effect on dopaminergic transmission while alpha-tocopherol (Vitamin E) might potentiate catalepsy on mice by inhibiting inducible protein kinase C activity in smooth muscle cells and completely preventing glutamate induced cell death without decreasing glutamate induced accumulation of intracellular peroxides (Lazzarini et al., 2005).

Besides the non-active and potentiating HNPs, a total of 22 HNPs are found to significantly decrease the catalepsy

score. The suggested mechanisms include 1) acting as dopaminergic agonist agent or D2 receptor agonist (Boerhavia diffusa L., Nardostachys jatamansi, Trichilia catigua, anacyclus pyrethrum, Caffeine); 2) affecting dopamine level through increasing histamine level (Piper longum Linn., Anacardium occidentale L.); 3) demonstrating neuroprotective effect in stress-induced dopamine neuron degeneration (BR-16A, an herbal psychotropic preparation which contains: Bacopa monnieri, Centella asiatica, Acorus calamus, Withania somnifera, Tinospora cordifolia, Embelica officinalis, Evolvulus aisinoides, Saussurea lappa, Terminalia belerica, Terminalia chebula, Terminalia arjuna); 4) changing antioxidant enzymes level such as superoxide dismutase (SOD), glutathione peroxidase and catalase by quenching the free radicals to combat oxidative stress in brain tissue (Smilax zeylanica L., Withania somnifera, Emblica officinalis, Murraya koenigii, Alpha lipoic acid, Canscora decussate); 5) possessing CNS-depressant effect through the γ-aminobutyric acid type A (GABA-A) receptors (Bauhinia tomentosa L.) and 6) containing dopamine (mucuna pruriens). Other HNPs such as Hypericum perforatum, Rosmarimus officinalis., Triphala (An Ayurvedic herbal rasayana formula consisting of Hebulae Fructus, Terminaliae Belliricae Fructus and Phyllathus Emblica Officinalis), Smilax zeylanica L., and Carya illinoensis also showed significant protective effect against haloperidol-induced catalepsy, but specific mechanisms of such interactions were not discussed.

3.4. EPS Related Interaction As one of the most commonly seen side-effects of

antipsychotics, EPS include acute symptoms of dystonia, Parkinsonism, tardive dyskinesia (TD) and akathisia (Knable, 2002). Catalepsy tests in rodents including block test, horizontal bar test and inclined-grid test are commonly used models to evaluate the antipsychotic-induced acute parkinsonism (Fong et al., 2013). Mechanistic study has suggested that the brain mechanisms involved in the meditation of catalepsy in rats and EPS in humans might be similar. It is also reported that the behavioural deficits induced by acute administration of relatively low doses of haloperidol in rats are both analogous and homologous to the haloperidol-induced Parkinsonism symptoms in humans (Fong et al., 2014). These findings indicate that such preclinical models are feasible to assess the liability of haloperidol to induce EPS in humans. There are total 25 articles from animals (n = 16) and humans (n = 9) reported haloperidol associated EPS, among which 8 articles were on TCM, 6 articles on herbal products and 11 articles on food and dietary supplements.

In the reports from animal models (Table 3), activities including parkinsonism, locomotor activity and TD were commonly evaluated. Nardostachys jatamansi was reported to reverse haloperidol-induced Parkinsonism by up regulation of dopaminergic signalling and enhancing the

26


Tab

le 2

. Eff

ect

of H

NP

s on

Hal

oper

idol

-in

du

ced

Cat

alep

sy (

HIC

) A

nim

al M

odel

.

Typ

e P

rod

uct

M

odel

O

utc

omes

an

d f

ind

ings

R

efer

ence

M

easu

rem

ent

Mec

han

ism

E

ffic

acy

TC

M

Nar

dost

achy

s ja

tam

ansi

Adu

lt W

ista

r ra

ts

Cat

alep

sy↓,

pe

roxi

de le

vel↑

, an

tiox

idan

t lev

el↑

Ora

l adm

inis

trat

ion

of N

J al

ong

wit

h ha

lope

rido

l sig

nifi

cant

ly

rest

ored

the

pero

xide

s an

d an

tiox

idan

t lev

els

to n

ear

norm

al in

the

brai

ns o

f th

e te

st

anim

als.

Nar

dost

achy

s ja

tam

ansi

(N

J) w

as i

nves

tiga

ted

for

its

anti

cata

lept

ic e

ffec

ts i

n th

e H

IC r

at m

odel

. Rat

s (n

= 6

) re

ceiv

ed N

J at

a d

ose

of 1

00, 2

50, 5

00 m

g/kg

30

m

in b

efor

e ha

lope

rido

l (1

m

g/kg

, i.p

.) w

as a

dmin

istr

ated

to

indu

ce

cata

leps

y.

Sig

nifi

cant

re

vers

al

in

cata

leps

y w

as

obse

rved

w

ith

the

adm

inis

trat

ion

of N

J aq

ueou

s ex

trac

t. T

he m

axim

al d

ecre

ase

in c

atal

epsy

was

ob

serv

ed in

the

grou

p re

ceiv

ing

aque

ous

extr

act o

f NJ

at a

dos

e of

250

mg/

kg.

No

pron

ounc

ed r

educ

tion

in th

e ca

tale

ptic

sco

res

at a

dos

e of

500

mg/

kg.

(Ras

heed

et a

l., 2

010)

TC

M

Sol

anum

ni

grum

L.

Mal

e S

wis

s m

ice

C

atal

epsy

N

.D.

The

re w

as n

o si

gnif

ican

t re

duct

ion

in t

he d

urat

ion

of H

IC b

y th

e co

-ad

min

istr

atio

n of

S.

nigr

um b

erry

ext

ract

(50

, 10

0 an

d 20

0 m

g/kg

, i.p

.).

No

othe

r si

de e

ffec

ts o

f th

e co

ncur

rent

adm

inis

trat

ion

of H

alop

erid

ol a

nd S

. N

igru

m w

ere

men

tion

ed.

(Nir

mal

et a

l., 2

012)

TC

M

Boe

rhav

ia

diff

usa

L.

Adu

lt a

lbin

o ra

ts

Cat

alep

sy↓

The

ext

ract

was

act

ing

sim

ilar

ly

like

age

nt w

hich

is

dopa

min

ergi

c ag

onis

t or

wor

king

as

D2

rece

ptor

ago

nist

.

The

res

ult

show

ed t

hat

the

hydr

o-al

coho

lic

extr

act

of B

oerh

aavi

a di

ffus

a of

le

aves

at

a do

se 1

00 a

nd 2

00 m

g/kg

by

p.o

sign

ific

antl

y de

crea

sed

the

cata

leps

y in

duce

d by

hal

oper

idol

.

(Gad

ekar

and

Jit

ende

r,

2011

)

TC

M

Pip

er lo

ngum

L

. A

lbin

o m

ice

C

atal

epsy↓

N.D

. A

ll P

. lo

ngum

fru

it e

xtra

cts

at a

ll c

once

ntra

tion

s si

gnif

ican

tly

decr

ease

d th

e du

rati

on o

f H

IC f

or e

ach

tim

e in

terv

al. N

o ot

her

side

eff

ects

of

the

conc

urre

nt

adm

inis

trat

ion

of h

alop

erid

ol a

nd P

. Lon

gum

wer

e m

enti

oned

.

(Kau

shik

et a

l., 2

012)

TC

M

Ana

card

ium

oc

cide

ntal

e L

. M

ice

C

atal

epsy↓

N.D

. A

ll

conc

entr

atio

ns

of

A.

occi

dent

ale

extr

act

sign

ific

antl

y de

crea

sed

the

dura

tion

of

HIC

. M

axim

um p

rote

ctio

n ag

ains

t H

IC w

as o

bser

ved

at t

he A

. O

ccid

enta

le d

ose

of 3

75 m

g/kg

. N

o ot

her

side

eff

ects

of

the

conc

urre

nt

adm

inis

trat

ion

of H

alop

erid

ol a

nd A

. Occ

iden

tale

wer

e m

enti

oned

.

(Mah

ajan

et a

l., 2

011)

TC

M

Hyp

eric

um

perf

orat

um

Mal

e W

ista

r ra

ts

Cat

alep

sy↓

N.D

. T

he

com

para

tive

an

tide

pres

sant

ac

tivi

ty

of

the

extr

acts

of

H

yper

icum

pe

rfor

atum

(20

mg/

kg, p

.o.)

usi

ng H

IC m

odel

in

rats

(n

= 6

) w

as e

valu

ated

. T

he re

sult

sho

wed

a s

igni

fica

nt p

rote

ctio

n ag

ains

t HIC

com

pare

d to

con

trol

at

30 m

in a

fter

inj

ecti

on o

f ha

lope

rido

l. T

he s

tudy

rev

eale

d th

e ex

trac

ts o

f H

yper

icum

per

fora

tum

mig

ht h

ave

a pr

omis

ing

anti

depr

essa

nt p

oten

tial

.

(Moi

nudd

in e

t al.,

201

1)

TC

M

Ros

mar

imus

of

fici

nali

s

Mal

e W

ista

r ra

ts

Cat

alep

sy↓

N.D

. T

he

com

para

tive

an

tide

pres

sant

ac

tivi

ty

of

the

extr

acts

of

R

osm

arim

us

offi

cina

lis

(20

mg/

kg,

p.o.

) us

ing

HIC

mod

el i

n ra

ts (

n =

6)

was

eva

luat

ed.

The

res

ult

show

ed a

sig

nifi

cant

pro

tect

ion

agai

nst

HIC

at

60 m

in a

fter

in

ject

ion

of h

alop

erid

ol.

(Moi

nudd

in e

t al.,

201

1)

TC

M

Tri

phal

a [1

] M

ale

albi

no m

ice

C

atal

epsy↓

N.D

. T

he p

rote

ctiv

e ef

fect

of

Tri

phal

a on

HIC

was

stu

died

in

mic

e (n

= 6

).

Cat

alep

sy w

as i

nduc

ed w

ith

halo

peri

dol

(1 m

g/kg

), T

riph

ala

(2.5

, 6.

25 a

nd

12.5

mg/

kg, p

.o.)

was

adm

inis

tere

d to

thre

e gr

oups

of m

ice

resp

ecti

vely

whi

le

the

othe

r gr

oups

rec

eive

d th

e ve

hicl

e (1

0 m

l/kg

). S

ingl

e do

se o

f th

e te

st d

rug

and

vehi

cle

wer

e us

ed i

n th

e ac

ute

stud

y, a

sig

nifi

cant

dec

reas

e in

the

ca

tale

ptic

sco

re w

as o

bser

ved

at a

ll t

ime

inte

rval

s ex

cept

at

the

30 m

in

inte

rval

. In

the

chro

nic

stud

y, th

e si

ngle

dos

es w

ere

give

n on

ce a

day

for s

even

da

ys w

ith

a si

gnif

ican

t dec

reas

e in

the

cata

lept

ic s

core

obs

erve

d.

(Nar

ita

et a

l., 1

982)

27

JAASP 2019; 8: 22–49

Tab

le 2

. Eff

ect

of H

NP

s on

Hal

oper

idol

-in

du

ced

Cat

alep

sy (

HIC

) A

nim

al M

odel

(co

nti

nu

ed).

Typ

e P

rod

uct

M

odel

O

utc

omes

an

d f

ind

ings

R

efer

ence

M

easu

rem

ent

Mec

han

ism

E

ffic

acy

TC

M

Mor

us a

lba

L.

Mal

e S

wis

s al

bino

mic

e

Cat

alep

sy↑

N.D

. H

alop

erid

ol (

1 m

g/kg

, i.p

.) w

as a

dmin

istr

ated

to m

ice

(n =

6)

pre-

trea

ted

wit

h ve

hicl

e or

Mor

us a

lba

extr

act

(MA

E)

(50,

100

and

200

mg/

kg,

i.p.)

. T

he

dura

tion

of

cata

leps

y w

as m

easu

red

at 0

, 30

, 60

, 90

, 12

0, 1

50,

and

180

min

us

ing

the

bar

test

. The

res

ults

sho

wed

that

the

MA

E s

igni

fica

ntly

pot

enti

ated

H

IC a

t ea

ch t

ime

inte

rval

in

dose

dep

ende

nt m

anne

r. M

AE

at

dose

50,

100

an

d 20

0 m

g/kg

sho

wed

max

imum

cat

alep

tic

scor

e 27

5.8

± 9.

998,

290

.3 ±

5.

852

and

291.

2 ±

5.28

8 s

resp

ecti

vely

at

120

min

in

halo

peri

dol

trea

ted

anim

als.

(Yad

av a

nd N

ade,

200

8)

TC

M

Cas

sia

soph

era

Lin

n

Sw

iss

albi

no

mic

e

Cat

alep

sy

N

.D.

The

eff

ect o

f Cas

sia

soph

era

frac

tion

s on

HIC

was

stu

died

usi

ng b

ar te

st. M

ice

in te

st g

roup

s (n

= 6

) re

ceiv

ed th

e et

hano

l ext

ract

, fra

ctio

ns w

ith

chlo

rofo

rm,

ehyl

ace

tate

and

eth

anol

(75

0 m

g/kg

, p.

o.).

Hal

oper

idol

(1

mg/

kg,

s.c.

) w

as

used

to

indu

ce c

atal

epsy

and

the

dur

atio

n of

cat

alep

sy w

ere

mea

sure

d at

15,

30

, 60,

90,

120

, 150

and

180

min

. No

sign

ific

ant

decr

ease

in

the

dura

tion

of

cata

leps

y w

as s

how

ed in

the

resu

lt.

(Nag

ore

et a

l., 2

009)

TC

M

Aco

rus

cala

mus

Lin

n

Sw

iss

albi

no

mic

e

Cat

alep

sy↑

N.D

. T

he e

ffec

t of

met

hano

l (A

CM

E)

and

acet

one

(AC

AE

) ex

trac

t of

Aco

rus

cala

mus

leav

es a

gain

st H

IC h

ave

been

stu

died

in m

ice

(n =

6).

All

four

gro

ups

rece

ived

hal

oper

idol

adm

inis

trat

ion

wit

h a

dose

of

0.1

mg/

kg (

i.p.)

, A

CM

E

and

AC

AE

at

th

e do

se

of

5,

20,

50

mg/

kg

(p.o

.)

resp

ecti

vely

w

ere

adm

inis

tere

d to

all

gro

ups

exce

pt t

he c

ontr

ol g

roup

. The

res

ults

sho

wed

tha

t A

CM

E a

t th

e do

se o

f 50

mg/

kg a

nd A

CA

E a

t th

e do

se o

f 20

and

50

mg/

kg

sign

ific

antl

y po

tent

iate

d th

e ha

lope

rido

l ind

uced

cat

alep

sy.

(Ka

et a

l., 2

009)

TC

M

Age

ratu

m

cony

zoid

es

Lin

n

Sw

iss

albi

no

mic

e

Cat

alep

sy

N

.D.

The

eff

ect

of A

gera

tum

con

yzoi

des

on H

IC i

n m

ice

(n =

6)

has

been

stu

died

us

ing

the

bar

test

. A

nim

als

in 3

dif

fere

nt g

roup

s re

ceiv

ed h

ydro

alco

holi

c ex

trac

t of

Age

ratu

m c

onyz

oide

s in

dos

es 2

50,

500

and

1000

mg/

kg (

p.o.

) re

spec

tive

ly w

hile

the

oth

er g

roup

s re

ceiv

ed v

ehic

le o

r st

anda

rd d

rug.

One

ho

ur a

fter

the

dru

g ad

min

istr

atio

n, a

ll t

he g

roup

s re

ceiv

ed h

alop

erid

ol (

1 m

g/kg

, i.p

.) a

nd th

e du

rati

on o

f cat

alep

sy w

as m

easu

red

at 1

5, 3

0, 6

0, 9

0, 1

20,

150

and

180

min

. N

o si

gnif

ican

t in

hibi

tion

of

the

HIC

was

obs

erve

d in

the

te

st.

(Tot

e et

al.,

200

9)

TC

M

Pip

er b

etle

M

ale

Sw

iss

albi

no m

ice

C

atal

epsy↑

Dop

amin

e tr

ansm

issi

on m

ight

be

inhi

bite

d by

the

hydr

oalc

ohol

ic e

xtra

ct o

f P

iper

be

tel.

Hyd

roal

coho

lic

extr

act

of P

iper

bet

el (

PB

) (1

00,

200

and

400

mg/

kg)

wer

e ad

min

iste

red

to m

ice

60 m

in b

efor

e ha

lope

rido

l (1

mg/

kg, i

.p.)

. For

epaw

s of

th

e an

imal

s w

ere

then

pla

ced

on a

n el

evat

ed r

od. D

urat

ion

for

whi

ch th

e m

ice

reta

ins

the

fore

paw

s on

the

ele

vate

d ro

d w

as n

oted

dow

n. P

B (

400

mg/

kg)

trea

tmen

t sho

wed

sig

nifi

cant

pot

enti

atio

n of

epi

leps

y fr

om 3

0 to

120

min

. The

lo

wer

tw

o do

ses

of P

B (

100

and

200

mg/

kg)

did

not

show

any

sig

nifi

cant

po

tent

iati

on.

(Vya

wah

are

and

Bod

hank

ar,

2007

)

28


Tab

le 2

. Eff

ect

of H

NP

s on

Hal

oper

idol

-in

du

ced

Cat

alep

sy (

HIC

) A

nim

al M

odel

(co

nti

nu

ed).

Typ

e P

rod

uct

M

odel

O

utc

omes

an

d f

ind

ings

R

efer

ence

M

easu

rem

ent

Mec

han

ism

E

ffic

acy

TC

M

Gin

kgo

bilo

ba

L.

Sw

iss

albi

no

mic

e C

atal

epsy↑

N.D

. T

he

effe

ct

of

Gin

kgo

bilo

ba

Ext

ract

E

Gb

761

on

cata

leps

y in

duce

d by

ha

lope

rido

l w

as s

tudi

ed i

n m

ice

(n =

8–1

2).

In t

he a

cute

stu

dy,

40,

80 o

r 16

0 m

g/kg

EG

b 76

1 (p

.o.)

wer

e ad

min

iste

red

foll

owed

by

2 m

g/kg

hal

oper

idol

(i.p

.)

30 m

in la

ter.

Rep

eate

d tr

eatm

ent w

ith

EG

b 76

1 w

as p

erfo

rmed

for

5 d

ays

in th

e ch

roni

c st

udy.

Hal

oper

idol

was

adm

inis

tere

d on

day

1 a

nd d

ay 5

. A

cute

tr

eatm

ent

of E

Gb

761

wit

h H

IC t

hrou

ghou

t th

e ex

peri

men

t ex

cept

for

the

EG

b do

se o

f 80

mg/

kg a

t 10

min

. EG

b 76

1 w

ith

the

dosa

ge o

f 40

mg/

kg e

nhan

ced

the

cata

lept

ic e

ffec

t of

hal

oper

idol

at

10 m

in c

ompa

red

wit

h th

e co

ntro

l gr

oup.

R

epea

ted

adm

inis

trat

ion

of E

Gb

761

(80

mg/

kg) p

oten

tiat

ed H

IC a

t 10

min

. The

re

sult

s sh

owed

that

repe

ated

trea

tmen

t wit

h E

Gb

761

enha

nced

cat

alep

sy c

ause

d by

hal

oper

idol

.

(Fon

tana

et a

l., 2

005)

TC

M

Hib

iscu

s ro

sa-

sine

nsis

Sw

iss

albi

no

mic

e

Cat

alep

sy↑

HR

S m

ay b

e in

volv

ed in

de

crea

sing

dop

amin

ergi

c tr

ansm

issi

on

Bar

test

was

use

d to

stu

dy th

e in

tera

ctio

n be

twee

n H

ibis

cus

rosa

-sin

ensi

s (H

RS

) an

d ha

lope

rido

l. H

RS

(50

, 10

0 an

d 20

0 m

g/kg

, i.p

.) w

as a

dmin

iste

red

to t

he

anim

als

30 m

in p

rior

to

adm

inis

trat

ion

of h

alop

erid

ol (

1 m

g/kg

, i.p

.).

The

du

rati

on o

f ca

tale

psy

was

mea

sure

d at

0, 3

0, 6

0, 9

0, 1

20, 1

50 a

nd 1

80 m

in. T

he

resu

lts

show

ed th

at H

RS

sig

nifi

cant

ly p

oten

tiat

ed H

IC a

t eac

h ti

me

inte

rval

.

(Nad

e et

al.,

200

9)

HP

B

R-1

6A

(A h

erba

l ps

ycho

trop

ic

prep

arat

ion)

[2

]

Lac

a m

ice

C

atal

epsy↓

The

ant

icat

alep

tic

effe

ct o

f B

R-

16A

may

be

due

to W

itha

nia

som

nife

ra p

rese

nt in

the

form

ulat

ion.

The

eff

ect

of B

R-1

6A (

50 a

nd 1

00 m

g/kg

, p.o

.) A

gain

st h

alop

erid

ol (

1 m

g/kg

, i.p

.) in

duce

d ca

tale

psy

was

stu

died

on

mic

e. C

atal

epsy

sco

re w

as m

easu

red

for

4 h

at o

ne-h

our

inte

rval

s af

ter

halo

peri

dol.

BR

-16A

sig

nifi

cant

ly r

educ

ed

seve

rity

of

HIC

at

all

tim

e in

terv

als.

Aah

wag

andh

a (5

0 an

d 10

0 m

g/kg

, p.

o.),

th

e m

ajor

con

stit

uent

of

BR

-16A

, si

gnif

ican

tly

and

dose

dep

ende

ntly

red

uced

ca

tale

ptic

sco

re a

s co

mpa

red

to h

alop

erid

ol a

lone

trea

ted

anim

als

at 6

0, 1

20 a

nd

180

min

.

(Kum

ar a

nd K

ulka

rni,

2006

)

HP

P

uera

ria

tube

rosa

A

lbin

o ra

ts

Cat

alep

sy

A

LE

and

AQ

E e

lici

ted

sign

ific

ant n

ootr

opic

eff

ect b

y in

tera

ctin

g w

ith

chol

iner

gic,

G

AB

Ane

rgic

, adr

ener

gic

and

sero

tone

rgic

sys

tem

s. T

he

extr

acts

nei

ther

fac

ilit

ated

nor

bl

ocke

d re

leas

e of

the

dopa

min

e.

Rat

s (n

= 6

) re

ceiv

ed d

isti

lled

wat

er (

10 m

l/kg

, p.

o.)

as c

ontr

ol,

halo

peri

dol

(1m

g/kg

, i.p

.), a

lcoh

olic

ext

ract

of

P. T

uber

osa

(AL

E)

(50,

75,

100

mg/

kg, p

.o.)

an

d aq

ueou

s ex

trac

t of

P

. T

uber

osa

(AQ

E)

(100

, 20

0,

400

mg/

kg,

p.o.

) re

spec

tive

ly.

Bar

tes

t w

as u

sed

to e

valu

ate

cata

lept

ic a

ctiv

ity

at 0

, 30

, 60

, 90

, 12

0, 1

50 a

nd 1

80 m

in.

All

the

dos

es o

f A

LE

and

AQ

E n

eith

er r

educ

ed n

or

pote

ntia

ted

HIC

at a

ll ti

me

inte

rval

s.

(Rao

et a

l., 2

008)

HP

S

mil

ax

zeyl

anic

a L

.

Wis

tar

rats

G

ener

atio

n of

th

ioba

rbit

uric

aci

d re

acti

ve s

ubst

ance

s↓,

glut

athi

one↑

, ca

tale

psy↓

, SO

D

leve

ls↑

Tre

atm

ent w

ith

SZ

sig

nifi

cant

ly

incr

ease

d th

e ac

tivi

ty o

f en

zym

es b

y qu

ench

ing

the

free

ra

dica

ls a

nd r

esto

red

the

pero

xide

s an

d an

tioxi

dant

leve

ls

to n

ear

norm

al in

the

brai

ns o

f th

e te

st a

nim

als.

Sm

ilax

zey

lani

ca L

. (S

Z)

(dos

e of

100

, 250

, 500

mg/

kg)

was

adm

inis

trat

ed f

or

15 d

ays

in r

ats.

Cat

alep

sy w

as in

duce

d by

hal

oper

idol

(1

mg/

kg, i

.p.)

. The

res

ult

show

ed t

hat

HIC

was

sig

nifi

cant

ly r

ever

sed

by c

o-ad

min

istr

atio

n of

SZ

. T

he

max

imal

dec

reas

e in

cat

alep

sy w

as o

bser

ved

in t

he S

Z g

roup

at

a do

se o

f 50

0 m

g/kg

.

(Ras

heed

et a

l., 2

012)

Wis

tar

rats

C

atal

epsy↓

N.D

. H

alop

erid

ol (

1 m

g/kg

) w

as a

dmin

iste

red

to in

duce

cat

alep

sy in

rat

s. T

he e

xtra

ct

of S

Z s

igni

fica

ntly

reve

rsed

HIC

in b

ar te

st. T

he m

axim

al d

ecre

ase

was

obs

erve

d in

the

gro

up r

ecei

ving

alc

ohol

ic e

xtra

ct o

f S

Z a

t a

dose

of

500

mg/

kg.

Ora

l ad

min

istr

atio

n of

the

ext

ract

alo

ng w

ith

halo

peri

dol

sign

ific

antl

y re

stor

ed t

he

pero

xide

s an

d an

tioxi

dant

leve

ls to

nea

r no

rmal

in th

e br

ain

of th

e te

st a

nim

als.

(Sha

ik e

t al.,

201

2)

29

JAASP 2019; 8: 22–49

Tab

le 2

. Eff

ect

of H

NP

s on

Hal

oper

idol

-in

du

ced

Cat

alep

sy (

HIC

) A

nim

al M

odel

(co

nti

nu

ed).

Typ

e P

rod

uct

M

odel

O

utc

omes

an

d f

ind

ings

R

efer

ence

M

easu

rem

ent

Mec

han

ism

E

ffic

acy

HP

B

auhi

nia

tom

ento

sa L

. S

wis

s al

bino

m

ice

C

atal

epsy↓

Eth

anol

ext

ract

of

Bau

hini

a to

men

tosa

(E

EB

T)

poss

esse

d an

ti-a

nxie

ty a

nd d

epre

ssan

t ac

tivi

ty in

mic

e

Hal

oper

idol

(2

mg/

kg,

i.p.)

was

adm

inis

tere

d to

mic

e 30

min

aft

er e

than

ol

extr

act o

f EE

BT

(200

and

400

mg/

kg, p

.o.)

trea

tmen

t in

the

bar t

est.

The

resu

lt

show

ed t

hat

EE

BT

in

a do

se o

f 20

0 m

g/kg

pot

enti

ates

the

HIC

ini

tial

ly a

fter

30

m

in

of

halo

peri

dol

trea

tmen

t. H

owev

er,

the

cata

leps

y sc

ore

was

si

gnif

ican

tly

decr

ease

d af

ter

90 m

in o

f ha

lope

rido

l adm

inis

trat

ion.

EE

BT

in a

do

se o

f 400

mg/

kg d

id n

ot s

how

any

sig

nifi

cant

pot

enti

atio

n of

cat

alep

sy a

fter

30

min

but

dec

reas

ed th

e sc

ore

sign

ific

antl

y af

ter

90 m

in.

(Sat

hya

et a

l., 2

011)

HP

H

emid

esm

us

indi

cus

Rat

s C

atal

epsy↑

N.D

. T

he

aque

ous

extr

act

of

root

s of

H

emid

esm

usin

dicu

s (A

ER

HI)

w

as

adm

inis

tere

d or

ally

at

a do

se o

f 10

0, 3

00 a

nd 5

00 m

g/kg

for

a p

erio

d of

30

days

. Hal

oper

idol

indu

ced

cata

leps

y m

odel

s w

ere

used

. AE

RH

I si

gnif

ican

tly

pote

ntia

ted

the

HIC

(Mad

hu e

t al.,

201

7)

HP

D

esm

odiu

m

adsc

ende

ns

Mic

e C

atal

epsy↑

N.D

. D

esm

odiu

m a

dsce

nden

s ex

trac

t (D

AE

) di

d no

t ind

uce

any

cata

lept

ic e

vent

in

naïv

e m

ice

but o

nly

sign

ific

antl

y en

hanc

ed H

IC a

t a d

ose

of 1

000

mg/

kg.

(Am

oate

ng e

t al.,

201

7a)

HP

S

yned

rell

a no

difl

ora

Fem

ale

ICR

m

ice

Cat

alep

sy↑

Loc

omot

ion↓

N

.D.

The

cen

tral

ner

vous

sys

tem

act

ivit

ies

of S

yned

rell

a no

difl

ora

extr

act

(SN

E)

(30–

3000

mg/

kg,

p.o.

) w

ere

inve

stig

ated

. S

NE

pot

enti

ated

the

eff

ects

of

halo

peri

dol

and

chlo

rpro

maz

ine

on a

pom

orph

ine-

indu

ced

cage

cli

mbi

ng a

nd

ster

eoty

py a

ctiv

itie

s in

mic

e.

(Am

oate

ng e

t al.,

201

7b)

HP

T

rich

ilia

ca

tigu

a M

ale

Sw

iss

mic

e

Cat

alep

sy↓

T. C

atig

ua (

TC

) ex

trac

t has

st

imul

atin

g ef

fect

s up

on th

e do

pam

iner

gic

syst

em. I

t inh

ibit

s do

pam

ine

upta

ke a

nd in

crea

se

dopa

min

e re

leas

e.

The

bar

tes

t w

as u

sed

to e

valu

ate

the

effe

cts

of T

C e

xtra

ct o

n th

e ca

tale

psy

indu

ced

by h

alop

erid

ol.

Mic

e w

ere

pre-

trea

ted

wit

h T

C e

xtra

ct (

200

mg/

kg,

p.o.

) or P

BS

(10

ml/

kg, p

.o.)

foll

owed

by

halo

peri

dol a

dmin

istr

atio

n (4

mg/

kg,

i.p.)

. T

he

resu

lt

show

ed

that

ca

tale

psy

indu

ced

by

halo

peri

dol

was

si

gnif

ican

tly

decr

ease

d by

pre

-tre

atm

ent w

ith

TC

ext

ract

.

(Via

na e

t al.,

201

1)

HP

P

hyll

anth

us

mad

eras

pate

nsis

L.

Mal

e al

bino

m

ice

C

atal

epsy

Phy

llan

thus

mad

eras

pate

nsis

(P

M)

does

not

hav

e ac

tivi

ty o

n do

pam

iner

gic

tran

smis

sion

.

Bar

test

was

use

d to

stu

dy th

e in

tera

ctio

n be

twee

n aq

ueou

s ex

trac

t of

PM

and

ha

lope

rido

l. H

alop

erid

ol (

1 m

g/kg

, i.p

.) w

as i

njec

ted

to m

ice

pre-

trea

ted

30

min

bef

ore

wit

h ve

hicl

e or

aqu

eous

ext

ract

of

PM

(50

mg/

kg, i

.p.)

. The

res

ult

show

ed n

o si

gnif

ican

t aff

ect b

etw

een

PM

and

veh

icle

.

(Nir

mal

et a

l., 2

009)

HP

M

ucun

a pr

urie

ns

Mal

e m

ice

Cat

alep

sy↓

N.D

. T

he M

. pru

rien

s se

ed e

xtra

ct a

t dos

es o

f 20

0 m

g/kg

was

ora

lly

adm

inis

trat

ed.

The

cat

alep

sy o

bser

vati

on w

as p

erfo

rmed

60

min

aft

er t

he a

dmin

istr

atio

n of

ha

lope

rido

l. T

he i

nten

sity

of

the

cata

leps

y w

as m

easu

red

as t

he t

ime

of t

he

mic

e ha

ng o

n a

15 c

m h

eigh

t rod

. Cat

alep

sy te

st s

how

ed th

at e

xtra

ct w

as a

ble

to lo

wer

the

cata

leps

y in

mic

e.

(Sar

djon

o et

al.,

201

8)

Adu

lt a

lbin

o ra

ts

Cat

alep

sy↓

The

ant

icat

alep

tic

effe

ct o

f M

ucun

a pr

urie

ns (

MP

) m

ay b

e du

e to

MP

con

tain

dop

amin

e an

d 5-

HT

.

Hal

oper

idol

(1

mg/

kg, i

.p.)

was

use

d to

indu

ce c

atal

epsy

. MP

at a

dos

e of

50,

10

0 an

d 20

0 m

g/kg

was

adm

inis

tere

d or

ally

to th

ree

resp

ecti

ve g

roup

1 h

pri

or

to h

alop

erid

ol a

dmin

istr

atio

n. T

he re

sult

sho

wed

a s

igni

fica

nt re

duct

ion

in th

e ca

tale

ptic

sco

re o

f th

e st

udie

d an

imal

s.

(Cha

mpa

tisi

ngh

et a

l., 2

011)

30


Tab

le 2

. Eff

ect

of H

NP

s on

Hal

oper

idol

-in

du

ced

Cat

alep

sy (

HIC

) A

nim

al M

odel

(co

nti

nu

ed).

Typ

e P

rod

uct

M

odel

O

utc

omes

an

d f

ind

ings

R

efer

ence

M

easu

rem

ent

Mec

han

ism

E

ffic

acy

HP

W

itha

nia

som

nife

ra

Mal

e S

wis

s al

bino

mic

e C

atal

epsy↓

The

ant

ioxi

dant

pro

pert

ies

of

Wit

hani

a so

mni

fera

(W

S)

may

be

res

pons

ible

for

the

anti

cata

lept

ic e

ffec

t of

WS

. The

re

duct

ion

in S

OD

act

ivit

y in

br

ain

may

be

due

to th

e an

tiox

idan

t phy

toch

emic

al

cons

titu

ents

of

WS

The

acu

te a

nd c

hron

ic a

ntic

atal

epti

c ef

fect

of

WS

ext

ract

on

HIC

in m

ice

(n =

6)

was

eva

luat

ed. T

he a

cute

tre

atm

ent

grou

p re

ceiv

ed W

S e

xtra

ct (

1.7,

4.2

5,

8.5

mg/

kg)

30 m

in p

rior

to

halo

peri

dol

and

stan

dard

bar

tes

t w

as u

sed

to

mea

sure

cat

alep

sy. T

he c

hron

ic tr

eatm

ent g

roup

rece

ived

the

drug

s fo

r 6 d

ays.

R

esul

t sho

wed

that

WS

red

uced

cat

alep

tic

scor

e in

a d

ose

depe

nden

t man

ner,

bo

th in

the

acut

e an

d ch

roni

c st

udy.

SO

D a

ctiv

ity

was

als

o lo

wer

ed in

the

WS

(4

.25,

85

mg/

kg)

grou

p.

(Nai

r et

al.,

200

8)

Mal

e S

wis

s al

bino

mic

e C

atal

epsy↓

N.D

. V

ehic

le o

r W

S (

20-2

00 m

g/kg

, p.o

., n

= 6

) w

as a

dmin

istr

ated

to th

e m

ice

60

min

bef

ore

halo

peri

dol (

1 m

g/kg

, i.p

.). M

ice

wer

e su

bjec

ted

to th

e ba

r te

st 3

0 m

in la

ter.

WS

(20

or

50 m

g/kg

) sh

owed

insi

gnif

ican

t pro

tect

ion

agai

nst H

IC

whi

le W

S (

100

or 2

00 m

g/kg

) si

gnif

ican

tly

and

dose

dep

ende

ntly

dec

reas

ed

cata

lept

ic s

core

on

the

bar

test

as

com

pare

d to

con

trol

gro

up.

(Gir

dhar

i and

Avt

ar, 2

009)

HP

A

nacy

clus

py

reth

rum

M

ale

Sw

iss

albi

no m

ice

C

atal

epsy↓

AP

roo

t ext

ract

mig

ht p

rodu

ce

anti

depr

essa

nt e

ffec

t eit

her

by

inte

ract

ion

wit

h ad

rene

rgic

or

dopa

min

e re

cept

or.

Hal

oper

idol

(1

mg/

kg)

was

adm

inis

tere

d to

mic

e 30

min

aft

er t

he A

nacy

clus

py

reth

rum

(AP

) roo

t ext

ract

(50,

100

, 200

mg/

kg, p

.o.)

. The

resu

lt s

how

ed A

P

extr

act s

igni

fica

ntly

redu

ced

the

dura

tion

of c

atal

epsy

indu

ced

by h

alop

erid

ol.

(Bad

he e

t al.,

201

0)

HP

E

mbl

ica

offi

cina

lis

Alb

ino

mic

e

Cat

alep

sy↓

The

ant

icat

alep

tic

effe

cts

of

Em

blic

a of

fici

nali

s (E

O)

mig

ht

be d

ue to

bot

h it

s an

tich

olin

ergi

c an

d an

tiox

idan

t pr

oper

ties

. It q

uenc

hes

free

ra

dica

ls a

nd r

educ

e th

e ox

idat

ive

stre

ss in

duce

d by

ha

lope

rido

l in

the

brai

n ti

ssue

The

pro

tect

ive

effe

ct o

f the

aqu

eous

ext

ract

of

EO

on

HIC

in m

ice

(n =

6)

was

ex

amin

ed. T

he e

ffec

ts o

f E

O (

0.8,

2.0

and

4.0

mg/

kg)

and

the

stan

dard

dru

gs

scop

olam

ine

(1.0

mg/

kg)

and

onda

nset

ron

(0.5

, 1.

0 m

g/kg

) w

ere

asse

ssed

af

ter

7 da

ys, 3

0 m

ins

prio

r to

the

halo

peri

dol.

A s

tand

ard

bar

test

was

use

d to

ev

alua

te c

atal

epti

c ac

tivi

ties

at

30 m

in in

terv

als

unti

l 12

0 m

in a

nd a

t th

e en

d of

exp

erim

ent a

t 240

min

. Res

ult s

how

ed th

at th

ere

is a

sig

nifi

cant

red

uctio

n in

the

cata

lept

ic s

core

s an

d ox

idat

ive

stre

ss in

all

test

dru

g tr

eate

d gr

oup

vers

us

cont

rol.

EO

was

mor

e pr

otec

tive

aga

inst

HIC

at

dose

s 2.

0 an

d 4.

0 m

g/kg

ve

rsus

sta

ndar

d dr

ugs.

Max

imum

red

ucti

on i

n S

OD

act

ivit

y w

as s

een

at E

O

4.0

mg/

kg.

(Sud

haka

r et

al.,

200

9)

HP

R

andi

a du

met

orum

M

ale

albi

no

mic

e C

atal

epsy

The

eth

anol

ic e

xtra

ct o

f R

andi

a du

met

orum

(R

D)

frui

t doe

s no

t po

sses

s an

tido

pam

iner

gic

and

anti

-ser

oton

ergi

c ac

tivi

ty a

nd s

o do

es n

ot in

hibi

t hal

oper

idol

in

duce

d ca

tale

psy.

The

ant

icat

alep

tic

effi

cacy

of

etha

nolic

ext

ract

of

RD

fru

its

in H

IC in

mic

e (n

=

5)

w

as

eval

uate

d.

Dif

fere

nt

expe

rim

enta

l gr

oups

w

ere

adm

inis

tere

d ha

lope

rido

l (1

mg/

kg, i

.p.)

1 h

aft

er th

e tr

eatm

ent w

ith

gum

aca

cia

(1%

, p.o

.)

as v

ehic

le c

ontr

ol,

chlo

rphe

nira

min

e m

alea

te (

10 m

g/kg

, i.p

.) a

nd e

than

olic

ex

trac

t of

RD

(18

0, 3

60 a

nd 7

20 m

g/kg

, p.o

.) r

espe

ctiv

ely.

Bar

test

was

use

d to

eva

luat

e H

IC a

t 15

, 30,

60,

90,

120

, 150

and

180

min

. Res

ult

show

ed t

hat

RD

did

not

inhi

bit H

IC in

mic

e.

(Gha

isas

et a

l., 2

008)

HP

F

icus

be

ngal

ensi

s B

ark

Mal

e al

bino

m

ice

C

atal

epsy

The

ext

ract

may

not

hav

e ac

tivi

ty o

n do

pam

iner

gic

tran

smis

sion

.

The

eff

ect

of v

ario

us e

xtra

cts

of F

icus

ben

gale

nsis

Bar

k on

hal

oper

idol

-in

duce

d ca

tale

ptic

act

ivit

y w

as e

valu

ated

usi

ng a

bar

tes

t. H

alop

erid

ol (

1 m

g/kg

, i.p

.) w

as in

ject

ed to

mic

e (n

= 5

) be

fore

adm

inis

trat

ion

of v

ehic

les

or

Fic

us

beng

alen

sis

Bar

k (5

m

g/kg

. i.p

.).

The

du

rati

on

of

cata

leps

y w

as

mea

sure

d. R

esul

t sho

wed

that

non

e of

the

extr

acts

inhi

bit H

IC.

(Tau

r et

al.,

200

7)

31

JAASP 2019; 8: 22–49

Tab

le 2

. Eff

ect

of H

NP

s on

Hal

oper

idol

-in

du

ced

Cat

alep

sy (

HIC

) A

nim

al M

odel

(co

nti

nu

ed).

Typ

e P

rod

uct

M

odel

O

utc

omes

an

d f

ind

ings

R

efer

ence

M

easu

rem

ent

Mec

han

ism

E

ffic

acy

HP

N

elum

bo

nuci

fera

R

ats

Cat

alep

sy↓

Han

ging

ant

ioxi

dant

enz

ymes

le

vel s

uch

as S

OD

, glu

tath

ione

pe

roxi

dase

and

cat

alas

e by

qu

ench

ing

the

free

rad

ical

s to

co

mba

t oxi

dati

ve s

tres

s in

bra

in

tiss

ue.

Cat

alep

sy w

as i

nduc

ed b

y ad

min

istr

atio

n of

hal

oper

idol

(1

mg/

kg,

i. p.)

in

mal

e al

bino

rats

. A s

igni

fica

nt re

duct

ion

in th

e ca

tale

ptic

sco

res

wer

e ob

serv

ed

in a

ll t

he d

rug-

trea

ted

grou

ps a

s co

mpa

red

to t

he h

alop

erid

ol a

lone

tre

ated

gr

oup;

wit

h m

axim

um r

educ

tion

obs

erve

d in

the

Nel

umbo

nuc

ifer

a (2

00 a

nd

400

mg/

kg b

ody

wei

ght)

adm

inis

tere

d gr

oup.

(Red

dy a

nd S

ingh

al, 2

014)

HP

B

eta

vulg

aris

L

. R

ats

C

atal

epsy↓

The

abi

lity

of

the

drug

to

pote

ntia

te d

opam

iner

gic

tran

smis

sion

in th

e st

riat

um.

Pre

-tre

atm

ent

wit

h m

etha

nol

extr

act

of B

eta

vulg

aris

200

and

300

mg/

kg

sign

ific

antl

y re

duce

d th

e du

rati

on o

f ca

tale

psy

indu

ced

by h

alop

erid

ol a

s co

mpa

red

to h

alop

erid

ol a

lone

trea

ted

grou

p.

(Nad

e et

al.,

201

5)

HP

M

urra

ya

koen

igii

Mal

e al

bino

m

ice

C

atal

epsy↓,

SO

D,

cata

lase↑

The

ant

ioxi

dant

act

ivit

y of

M

EM

K m

ay b

e du

e to

the

pres

ence

of

flav

onoi

ds a

nd

phen

olic

com

poun

ds. M

EM

K

reve

rsed

the

chan

ges

in th

e an

tiox

idan

t enz

yme

leve

ls

(SO

D, c

atal

ase)

.

The

eff

ect

of m

etha

nol

extr

acti

on o

f M

urra

ya k

oeni

gii

(ME

MK

) on

the

HIC

w

as s

tudi

ed in

mic

e an

d a

phyt

oche

mic

al s

cree

ning

of M

EM

K w

as p

erfo

rmed

. T

hey

rece

ived

ME

MK

(30

, 10

0, 2

00 m

g/kg

, p.

o.)

at 1

h b

efor

e re

ceiv

ing

halo

peri

dol

(1 m

g/kg

, i.p

.).

Bar

tes

t w

as u

sed

to m

easu

re c

atal

epti

c ac

tivi

ty

for

3 h.

Res

ult

show

ed a

sig

nifi

cant

ly r

educ

tion

in

HIC

and

rev

erse

d th

e re

duct

ion

in th

e fo

rebr

ain

GS

H le

vels

in th

e M

EM

K-t

reat

ed g

roup

.

(Pat

il e

t al.,

201

2)

HP

P

lum

bago

ze

ylan

ica

L,

and

Cam

elli

a si

nens

is

Rat

s C

atal

epsy↓

Phy

toco

nsti

tuen

ts li

ke n

atur

al L

-do

pa, a

lkal

oids

and

pol

yphe

nols

ha

ve b

een

repo

rted

in th

is p

lant

w

hich

mig

ht b

e re

spon

sibl

e fo

r th

e ab

ove

beha

viou

ral e

ffec

ts.

Hal

oper

idol

ind

uced

a t

ime

depe

nden

t in

crea

se i

n ca

tale

ptic

sco

re i

n ra

ts, a

s co

mpa

red

to v

ehic

le t

reat

ed g

roup

s. A

ll t

he g

roup

s in

clud

ing

L-d

opa

and

carb

idop

a (S

yndo

pa),

hyd

ro-a

lcoh

olic

ext

ract

of

P.

zeyl

anic

a al

one

and

its

com

bina

tion

wit

h C

. sin

ensi

s sh

owed

sig

nifi

cant

ly l

ower

sco

res

of c

atal

epsy

at

all

tim

e pe

riod

s as

com

pare

d to

hal

oper

idol

alo

ne.

(Itt

iyav

irah

and

Rub

y, 2

014)

HP

M

omor

dica

di

oica

M

ale

albi

no

mic

e

Cat

alep

sy

N

.D.

Hal

oper

idol

(1

mg/

kg,

i.p.)

was

inj

ecte

d to

mic

e pr

e-tr

eate

d 30

min

bef

ore

wit

h ve

hicl

e, p

etro

leum

eth

er, e

thyl

ace

tate

, met

hano

l and

aqu

eous

ext

ract

s of

M

omor

dica

dio

ica

seed

(50

mg/

kg, i

.p.,

each

). N

one

of a

ll e

xtra

cts

inhi

bite

d H

IC.

(Mah

arud

ra e

t al.,

201

1)

HP

C

ansc

ora

decu

ssat

e M

ice

Cat

alep

sy↓

Han

ging

ant

ioxi

dant

enz

ymes

(S

OD

, glu

tath

ione

per

oxid

ase

and

cata

lase

) le

vel a

nd

quen

chin

g th

e fr

ee r

adic

als

to

com

bat o

xida

tive

str

ess

in b

rain

ti

ssue

.

All

thes

e as

sess

men

ts w

ere

done

on

24 m

ice

whi

ch w

ere

divi

ded

into

4 g

roup

s (n

= 6

). M

etha

nol

extr

act

of C

ansc

ora

Dec

ussa

te (

CD

) w

as a

dmin

iste

red

at

100

mg/

kg a

nd 2

00 m

g/kg

, 30

min

pri

or t

o ha

lope

rido

l tr

eatm

ent

for

7 da

ys.

CD

sig

nifi

cant

ly i

mpr

oved

the

beh

avio

ural

act

ivit

ies

and

stri

atal

ant

ioxi

dant

st

atus

in a

dos

e de

pend

ent m

anne

r.

(Tam

ilan

ban

et a

l., 2

015)

F

Caf

fein

e M

ae W

ista

r ra

ts

Cat

alep

sy↓

N.D

. T

he e

ffec

t of

chr

onic

caf

fein

e tr

eatm

ent

on H

IC w

as m

easu

red.

Rat

s w

ere

trea

ted

wit

h ca

ffei

ne o

r w

ater

for

6 m

onth

s. T

hey

wer

e ev

alua

ted

in t

he

cata

leps

y ba

r te

st f

rom

day

18–

27 a

fter

caf

fein

e w

ithd

raw

al.

Hal

oper

idol

(1

mg/

kg,

s.c.

) w

as i

njec

ted

to i

nduc

e ca

tale

psy.

Res

ult

show

ed t

hat

the

aver

age

cata

lept

ic i

mm

obil

ity

was

low

er in

the

caf

fein

e-tr

eate

d ra

ts a

nd th

ey

also

had

hig

her

cata

leps

y la

tenc

y sc

ores

com

pare

d w

ith

cont

rol r

ats.

(Nar

ita

et a

l., 1

982)

32


Tab

le 2

. Eff

ect

of H

NP

s on

Hal

oper

idol

-in

du

ced

Cat

alep

sy (

HIC

) A

nim

al M

odel

(co

nti

nu

ed).

Typ

e P

rod

uct

M

odel

O

utc

omes

an

d f

ind

ings

R

efer

ence

M

easu

rem

ent

Mec

han

ism

E

ffic

acy

F

Alp

ha li

poic

ac

id

Mal

e al

bino

W

ista

r ra

ts

TD

, cat

alep

sy↓

loco

mot

or a

ctiv

ity↑

, li

pid

oxid

atio

n↓

AL

A a

nd it

s m

etab

olit

e di

hydr

o li

poic

aci

d ha

ve a

ntio

xida

tive

pr

oper

ties

whi

ch s

cave

nge

reac

tion

oxy

gen

spec

ies

and

reac

tive

nit

roge

n sp

ecie

s.

The

eff

ect

of A

lpha

lip

oic

acid

(A

LA

) on

hal

oper

idol

ind

uced

TD

, th

eir

impa

ct o

n ox

idat

ive

stre

ss a

nd li

pid

pero

xida

tion

was

exa

min

ed. H

alop

erid

ol

(1m

g/kg

/i.p

.) w

as a

dmin

iste

red

to r

ats

for

21 d

ays

to i

nduc

e V

CM

and

ca

tale

psy.

AL

A a

t dos

es o

f 25

, 50,

100

mg/

kg p

.o. w

ere

test

ed. R

esul

t sho

wed

th

at

supp

lem

enta

tion

w

ith

AL

A

decr

ease

ha

lope

rido

l-in

duce

d T

D

(100

m

g/kg

) an

d ca

tale

psy

(dos

e-de

pend

ent)

si

gnif

ican

tly.

A

LA

re

vers

ed

the

halo

peri

dol-

indu

ced

decr

ease

in

loco

mot

or a

ctiv

ity

at a

ll d

oses

and

rev

erse

th

e ha

lope

rido

l-in

duce

d li

pid

oxid

atio

n (1

00 m

g/kg

).

(Tha

akur

and

H

umm

abin

dhu,

200

9)

F

Vit

amin

E a

nd

Vit

amin

C

Mal

e S

wis

s m

ice

Cat

alep

sy↑

Vit

amin

E in

hibi

ts in

duci

ble

prot

ein

kina

se C

act

ivit

y in

sm

ooth

mus

cle

cell

s an

d co

mpl

etel

y pr

even

ting

gl

utam

ate-

indu

ced

cell

dea

th

wit

hout

dec

reas

ing

glut

amat

e-in

duce

d ac

cum

ulat

ion

of

intr

acel

lula

r pe

roxi

des.

The

eff

ect

of v

itam

in C

and

E o

n H

IC w

as e

valu

ated

in

mic

e us

ing

the

hang

ing-

bar

test

. Mic

e w

ere

pre-

trea

ted

wit

h vi

tam

in E

(3–

100

mg/

kg, i

.p.)

or

vehi

cle,

foll

owed

by

halo

peri

dol (

1 m

g/kg

, i.p

.) 3

0 m

in la

ter.

The

resu

lt s

how

s th

at v

itam

in C

pre

-tre

atm

ent p

oten

tiat

ed th

e ca

tale

psy

indu

ced

by h

alop

erid

ol

in a

dos

e-de

pend

ent

man

ner.

The

res

ult s

how

s th

at v

itam

in E

pot

enti

ated

the

ca

tale

psy

prod

uced

by

halo

peri

dol o

nly

at th

e do

se o

f 10

0 m

g/kg

.

(Laz

zari

ni e

t al.,

200

5)

F

Car

ya

illi

noen

sis

Mal

e W

ista

r ra

ts

Cat

alep

sy↓,

OD↓

N.D

. A

queo

us e

xtra

ct o

f pe

can

nut s

hell

(A

E)

or w

ater

wer

e ad

min

iste

red

to ra

ts a

d li

bitu

m.

Aft

er 4

wee

ks o

f or

al t

reat

men

t, th

e ra

ts r

ecei

ved

eith

er v

ehic

le o

r ha

lope

rido

l (12

mg/

kg/m

l, i.m

.) o

nce

a w

eek

for 2

8 da

ys, t

otal

izin

g fo

ur d

oses

. T

he r

esul

t sho

wed

that

AE

was

abl

e to

pre

vent

OD

dev

elop

men

t com

pare

d to

th

e co

ntro

l. T

he e

ffec

t of

AE

on

the

reve

rsal

of

OD

and

HIC

was

als

o te

sted

. T

he A

E tr

eatm

ent w

as a

ble

to r

ever

se th

e O

D a

nd H

IC.

(Tre

vizo

l et a

l., 2

011)

F

Asc

orbi

c ac

id

Fem

ale

Spr

ague

D

awle

y ra

ts

Cat

alep

sy↑

Asc

orbi

c ac

id m

ight

hav

e bl

ocki

ng e

ffec

t on

dopa

min

ergi

c tr

ansm

issi

on

Rat

s w

ere

give

n as

corb

ic a

cid

(100

0 m

g/kg

, i.p

.) f

ollo

wed

in

15 m

in b

y ha

lope

rido

l (0

.2

mg/

kg,

s.c.

),

com

pare

d w

ith

cont

rol

(aci

difi

ed

sali

ne).

C

atal

epsy

was

mea

sure

d ev

ery

30 m

ins

for

up t

o 12

0 m

in. R

esul

t fo

und

that

th

e co

mbi

ned

use

in p

rogr

essi

vely

mor

e ca

tale

ptic

act

ivit

ies.

(Dor

ris

and

Dil

l, 19

86)

Adu

lt m

ale

squi

rrel

m

onke

ys

Cat

alep

sy↑

Asc

orbi

c ac

id m

ight

hav

e bl

ocki

ng e

ffec

t on

dopa

min

ergi

c tr

ansm

issi

on

Mon

keys

wer

e gi

ven

asco

rbic

aci

d (1

00 m

g/kg

, i.p

.) f

ollo

wed

in

1 h

by

halo

peri

dol (

0.1

mg/

kg, s

.c.)

. Res

ult f

ound

that

ther

e w

as in

crea

sed

cata

leps

y in

duce

d by

hal

oper

idol

whe

n co

mbi

ned

in a

scor

bic

acid

.

Not

es: [

1] C

onta

ins:

Heb

ulae

Fru

ctus

, Ter

min

alia

e be

llir

icae

Fru

ctus

, Phy

llat

hus

embl

ica

Off

icin

alis

; [2]

Con

tain

s: B

acop

a m

onni

eri,

Cen

tell

a as

iati

ca, A

coru

s ca

lam

us, W

itha

nia

som

nife

ra, T

inos

pora

cor

difo

lia,

Em

beli

ca

offi

cina

lis,

Evo

lvul

us a

isin

oide

s, S

auss

urea

lapp

a, T

erm

inal

ia b

eler

ica,

Ter

min

alia

che

bula

, Ter

min

alia

arj

una.

A

bbre

viat

ion:

N.D

: no

t de

tect

ed;

TC

M:

trad

itio

nal

Chi

nses

med

icin

e; F

: fo

od a

nd d

ieta

ry s

uppl

emen

ts;

HP

: ot

her

herb

al p

rodu

cts;

i.p

.: in

trap

erit

onea

l in

ject

ion;

p.o

.: or

al a

dmin

istr

atio

n; i

.v.:

intr

aven

ous

adm

inis

trat

ion;

s.

c.: s

ubcu

tane

ous

inje

ctio

n; i.

m.:

intr

amus

cula

r in

ject

ion

TD

: tar

dive

dys

kine

sia;

OD

: oro

faci

al d

yski

nesi

a; V

CM

: vac

uous

che

win

g m

ovem

ents

; HIC

: hal

oper

idol

-ind

uced

cat

alep

sy; S

OD

: sup

erox

ide

dism

utas

e; 5

-HT

: 5-

hydr

oxyt

rypt

amin

e.

33

JAASP 2019; 8: 22–49

Tab

le 3

. Pre

clin

ical

Stu

die

s on

Ext

rap

yram

idal

Syn

dro

me

(EP

S)

Rel

ated

Hal

oper

idol

-HN

Ps

Inte

ract

ion

s.

Typ

e P

rod

uct

M

easu

rem

ent

Ou

tcom

es a

nd

fin

din

gs

Ref

eren

ce

Mec

han

ism

E

ffec

t

TC

M

Nar

dost

achy

s ja

tam

ansi

P

arki

nson

ism↓

NJ

enha

nce

the

bioa

vail

abil

ity

of c

ircu

lati

ng d

opam

ine

by u

p re

gula

tion

of

dopa

min

ergi

c si

gnal

ling

. T

he

resu

lt

show

ed

no

sign

ific

antly

or

gan

dam

age

caus

ed

by

Nar

dost

achy

s ja

tam

ansi

(N

J) i

n ha

lope

rido

l (1

mg/

kg,

i.p.)

ind

uced

pa

rkin

soni

sm.

The

hyd

roal

coho

lic

extr

act

of N

J at

a d

ose

of 5

00

mg/

kg h

as m

ore

sign

ific

ant

effe

ct t

han

250

mg/

kg i

n th

e re

vers

al o

f ha

lope

rido

l ind

uced

par

kins

onis

m.

(Ras

heed

et a

l., 2

009)

TC

M

Hip

poph

ae

rham

noid

es L

. L

ocom

otor

act

ivit

y↑,

food

inta

ke↓

N.D

. T

he

resu

lt

show

ed

that

H

ippo

phae

rh

amno

ides

L

. (H

RL

) si

gnif

ican

tly

low

er

food

in

take

in

ra

ts

trea

ted

wit

h re

peat

ed

halo

peri

dol.

Sig

nifi

cant

inc

reas

es w

ere

obse

rved

in

rats

rep

eate

dly

trea

ted

wit

h ha

lope

rido

l plu

s or

ally

sup

plem

ente

d w

ith

HR

L. P

lasm

a tr

ypto

phan

sho

wed

no

sign

ific

ant

inte

ract

ion

betw

een

the

drug

s w

hile

bra

in tr

ypto

phan

sho

wed

sig

nifi

cant

inte

ract

ion

betw

een

HR

L

and

drug

. 5-

HT

lev

els

wer

e al

so s

igni

fica

ntly

inc

reas

ed b

y H

RL

in

halo

peri

dol i

njec

ted

rats

.

(Bat

ool e

t al.,

200

9)

TC

M

Val

eria

na

offi

cina

lis

VC

M ,

loco

mot

or a

ctiv

ity

C

o-tr

eatm

ent o

f V

O a

nd h

alop

erid

ol d

id n

ot a

lter

the

oxid

ativ

e st

ress

par

amet

ers

nor

prot

ect a

gain

st

halo

peri

dol-

indu

ced

dopa

min

e up

take

red

ucti

on in

rat

s.

The

res

ult

show

ed t

hat

Val

eria

na o

ffic

inal

is (

VO

) w

as n

ot a

ble

to

redu

ce n

eith

er t

he p

reva

lenc

e no

r th

e in

tens

ity

of V

CM

. T

he c

o-ad

min

istr

atio

n of

VO

and

hal

oper

idol

als

o fa

iled

to

prev

ent

or a

lter

th

e de

crea

se o

n lo

com

otor

act

ivit

y. V

O d

id n

ot c

ause

any

sig

nifi

cant

ch

ange

s in

the

plus

maz

e te

st c

ompa

red

to h

alop

erid

ol a

lone

trea

ted

grou

p.

(Fac

hine

tto

et a

l., 2

007)

TC

M

Mor

us a

lba

L.

VC

M↓,

TD↓,

cat

alas

e↑,

lipi

d pe

roxi

dati

on↑

MA

E m

ay h

ave

free

rad

ical

sca

veng

ing

acti

vity

, the

reby

de

crea

sing

the

lipi

d pe

roxi

dati

on le

vels

and

spa

ring

the

anti

oxid

ant e

nzym

es S

OD

and

cat

alas

e.

The

re

sult

s sh

owed

th

at

chro

nic

conc

omit

ant

adm

inis

trat

ion

of

Mor

us a

lba

extr

act

(MA

E)

sign

ific

antl

y at

tenu

ated

the

hal

oper

idol

in

duce

d V

CM

and

ton

gue

prot

rusi

ons

dose

-dep

ende

ntly

. T

he c

o-ad

min

istr

atio

n si

gnif

ican

tly

incr

ease

d ca

tala

se a

nd a

tten

uate

d li

pid

pero

xida

tion

com

pare

d w

ith

rats

trea

ted

wit

h ha

lope

rido

l onl

y.

(Nad

e et

al.,

201

0)

HP

Il

ex

para

guar

iens

is

VC

M↓,

OD↓,

mem

ory

dysf

unct

ion↓

T

he a

ntio

xida

nt p

rope

rtie

s of

IP

may

be

resp

onsi

ble

for

the

redu

ctio

n in

OD

indu

ced

by h

alop

erid

ol.

Res

ult

show

ed t

hat

co-a

dmin

istr

atio

n of

Ile

x pa

ragu

arie

nsis

(IP

) ex

trac

t an

d ha

lope

rido

l re

duce

d th

e fr

eque

ncy

of V

CM

and

sho

wed

a

sign

ific

ant i

mpr

ovem

ent i

n th

e pr

oces

s of

spa

tial

lear

ning

.

(Col

po e

t al.,

200

7)

HP

K

hat (

leav

es

and

buds

of

Cat

ha e

duli

s F

orsk

)

Hea

d tw

itch

es,

spon

tane

ous

mot

or

acti

viti

es↑

N.D

. R

esul

t sh

owed

th

at

halo

peri

dol

did

not

affe

ct

the

head

tw

itch

re

spon

se t

o K

hat

or a

mph

etam

ine

but

enha

nced

spo

ntan

eous

mot

or

acti

vity

.

(Con

nor

et a

l., 2

002)

34


Tab

le 3

. Pre

clin

ical

Stu

die

s on

Ext

rap

yram

idal

Syn

dro

me

(EP

S)

Rel

ated

Hal

oper

idol

-HN

Ps

Inte

ract

ion

s (c

onti

nu

ed).

Typ

e P

rod

uct

M

easu

rem

ent

Ou

tcom

es a

nd

fin

din

gs

Ref

eren

ce

Mec

han

ism

E

ffec

t

HP

W

itha

nia

som

nife

ra

Invo

lunt

ary

orof

acia

l m

ovem

ents↓

TD↓

The

pro

tect

ive

effe

ct o

f W

SG

fro

m n

euro

lept

ic-i

nduc

ed

TD

is p

ossi

bly

due

to it

s an

tiox

idan

t eff

ect r

athe

r th

an it

s G

AB

A-m

imet

ic a

ctio

n

Res

ult

show

ed t

hat

Gly

cow

itha

noli

des

from

Wit

hani

a so

mni

fera

(W

SG

) (1

00 a

nd 2

00 m

g, p

.o.)

, ad

min

iste

red

conc

omit

antl

y w

ith

halo

peri

dol f

or 2

8 da

ys in

hibi

ted

the

indu

ctio

n of

the

neur

olep

tic

TD

.

(Bha

ttac

hary

a et

al.,

200

2)

VC

M↓,

OD↓,

lipi

d pe

roxi

dati

on↓,

sup

er

oxid

e di

smut

ase↑

, ca

tala

se↑

WS

roo

t ext

ract

may

pos

sess

ant

ioxi

dant

act

ion

and

have

fr

ee r

adic

al s

cave

ngin

g ac

tivi

ty.

Res

ult s

how

ed th

at c

hron

ic c

o-ad

min

istr

atio

n of

Wit

hani

a S

omni

fera

(W

S)

root

ext

ract

wit

h ha

lope

rido

l doe

s-de

pend

entl

y su

ppre

ssed

the

halo

peri

dol-

indu

ced

VC

Ms

and

tong

ue p

rotr

usio

ns,

reve

rsed

the

ex

tent

of

li

pid

pero

xida

tion

an

d si

gnif

ican

tly

reve

rsed

th

e ha

lope

rido

l-in

duce

d de

crea

se i

n fo

rebr

ain

SO

D a

nd c

atal

ase.

The

re

was

no

si

gnif

ican

t ef

fect

on

ha

lope

rido

l-in

duce

d de

crea

se

in

glut

athi

one

leve

l.

(Nai

du e

t al.,

200

3)

HP

A

shw

agan

dha,

T

ulsi

and

H

aldi

[1]

TD↓

The

her

bal f

orm

ulat

ion

infl

uenc

e do

pam

ine

rece

ptor

-m

edia

ted

neur

otra

nsm

issi

on a

nd s

erot

oner

gic

rece

ptor

-m

edia

ted

neur

otra

nsm

issi

on.

The

for

mul

atio

n de

mon

stra

ted

prot

ecti

ve e

ffec

t ag

ains

t ha

lope

rido

l in

duce

d ca

tale

psy

and

brad

ykin

esia

. N

o m

orta

lity

, no

ad

vers

e ch

ange

s in

beh

avio

ur o

f an

imal

s as

wel

l as

no

abno

rmal

itie

s w

ere

dete

cted

in e

xper

imen

tal m

ice

(Pin

gale

and

Pra

bhav

alka

r,

2015

)

F

Nat

to

(Fer

men

ted

Soy

bean

)

Loc

omot

or a

ctiv

ity↓

T

he d

opam

iner

gic

path

way

pro

babl

y in

volv

es in

the

enha

ncem

ent e

ffec

t in

loco

mot

or a

ctiv

ity

indu

ced

by

Nat

to.

Hal

oper

idol

(1

m

g/kg

, i.p

.)

was

ad

min

iste

red

15

min

be

fore

lo

com

otor

act

ivit

y m

easu

rem

ent.

Res

ult

show

ed t

hat

halo

peri

dol

atte

nuat

ed th

e N

atto

-ind

uced

hyp

erlo

coti

on in

mic

e.

(Mam

iya

and

Nis

him

ura,

20

07)

F

Bra

ssic

a ol

erac

ea

lipi

d pe

roxi

dati

on↓,

TD↓

The

res

ult s

ugge

sted

the

role

of

free

rad

ical

s in

the

path

ophy

siol

ogy

of th

e ha

lope

rido

l-in

duce

d E

PS

. H

ydro

alco

holi

c ex

trac

t of

B.

oler

acea

(25

0 an

d 50

0 m

g/kg

, p.

o.)

decr

ease

d th

e el

evat

ed le

vels

of l

ipid

per

oxid

atio

n in

the

halo

peri

dol-

trea

ted

anim

als

and

elev

ated

the

cel

lula

r de

fenc

e m

echa

nism

s su

ch

as g

luta

thio

ne.

(Nag

arju

na e

t al.,

201

5)

F

Mur

raya

ko

enig

ii L

ocom

otor

act

ivit

y↑,

SO

D↑,

ca

tala

se,

glut

athi

one↑

The

trea

tmen

t of

EE

MK

and

AM

K r

ever

sed

the

halo

peri

dol-

indu

ced

decr

ease

in f

oreb

rain

SO

D a

nd

cata

lase

leve

ls.

The

res

ult

show

ed t

hat

trea

tmen

t w

ith

etha

nol

extr

act

of M

urra

ya

koen

igii

(E

EM

K)

and

aque

ous

of

Mur

raya

ko

enig

ii

(AM

K)

sign

ific

antl

y in

crea

sed

the

num

ber

of s

quar

es tr

aver

sed

and

redu

ced

the

num

ber

of

groo

min

g.

Co-

adm

inis

trat

ion

of

EE

MK

al

so

sign

ific

antl

y re

stor

ed th

e ha

lope

rido

l-in

duce

d bo

dy w

eigh

t los

t.

(Pat

il e

t al.,

201

2)

35

JAASP 2019; 8: 22–49

Tab

le 3

. Pre

clin

ical

Stu

die

s on

Ext

rap

yram

idal

Syn

dro

me

(EP

S)

Rel

ated

Hal

oper

idol

-HN

Ps

Inte

ract

ion

s (c

onti

nu

ed).

Typ

e P

rod

uct

M

easu

rem

ent

Ou

tcom

es a

nd

fin

din

gs

Ref

eren

ce

Mec

han

ism

E

ffec

t

F

Spi

ruli

na

Oxi

dati

ve s

tres

s↓,

SO

D↓,

T

D↓,

VC

M↓

Spi

ruli

na is

a c

ockt

ail o

f po

tent

ant

ioxi

dant

s, th

e en

zym

atic

and

non

-enz

ymat

ic o

xida

nts

it c

onta

ins

may

ac

t syn

ergi

stic

ally

to p

rote

ct a

gain

st h

alop

erid

ol in

duce

d ox

idat

ive

stre

ss a

nd th

ereb

y de

crea

sing

oxi

dati

ve s

tres

s in

duce

d T

D.

Spi

ruli

na (

45,

90,

180

mg/

kg)

sign

ific

antl

y de

crea

sed

dysk

inet

ic

mov

emen

ts d

evel

oped

by

halo

peri

dol

and

mai

ntai

ned

it t

ill

49th d

ay

whe

n co

mpa

red

to th

e ha

lope

rido

l alo

ne g

roup

. Spi

ruli

na a

t a d

ose

of

180

mg/

kg d

id n

ot c

ompl

etel

y re

vers

e th

e ha

lope

rido

l in

duce

d dy

skin

etic

m

ovem

ents

. T

he

decr

ease

d S

OD

ca

used

by

ch

roni

c ha

lope

rido

l w

ere

sign

ific

antl

y re

vers

ed b

y 18

0 m

g/kg

of

Spi

ruli

na.

Spi

ruli

na (

90 a

nd 1

80 m

g/kg

) si

gnif

ican

tly

reve

rsed

the

dec

reas

ed

cata

lase

lev

els.

The

tot

al a

ntio

xida

nt s

tatu

s de

crea

sed

by c

hron

ic

halo

peri

dol

was

sig

nifi

cant

ly i

ncre

ased

by

Spi

ruli

na a

t al

l th

ree

dose

s. T

he h

alop

erid

ol in

crea

sed

lipi

d pe

roxi

dati

on w

as n

ot r

ever

sed

by 4

5 an

d 90

mg/

kg o

f S

piru

lina

whe

reas

sig

nifi

cant

ly d

ecre

ased

by

180

mg/

kg o

f S

piru

lina

. In

con

clus

ion,

Spi

ruli

na t

reat

men

t at

the

do

se o

f 45

, 90

and

180

mg/

kg s

igni

fica

ntly

rev

erse

d th

e ch

roni

c ha

lope

rido

l inc

reas

ed f

requ

enci

es o

f V

CM

in r

ats.

(Tha

akur

and

Jyo

thi,

2007

)

F

Car

ya

illi

noen

sis

Cat

alep

sy↓,

OD↓

N.D

. T

he r

esul

t sh

owed

tha

t aq

ueou

s ex

trac

t of

pec

an n

ut s

hell

(A

E)

was

abl

e to

pre

vent

OD

dev

elop

men

t co

mpa

red

to t

he c

ontr

ol.

Hal

oper

idol

(12

mg/

kg/m

l, i.m

.) o

r ve

hicl

e w

ere

adm

inis

tere

d to

the

rats

onc

e a

wee

k fo

r 4

wee

ks. T

he r

ats

late

r re

ceiv

ed A

E o

r w

ater

, ad

libi

tum

, fo

r 14

day

s. T

he A

E t

reat

men

t w

as a

ble

to r

ever

se t

he O

D

and

cata

leps

y in

duce

d by

hal

oper

idol

.

(Tre

vizo

l et a

l., 2

011)

F

Ecl

ipta

alb

a E

PS

mov

emen

t di

sord

ers↓

E

clip

ta a

lba

elev

ated

the

cell

ular

def

ence

mec

hani

sm

such

as

glut

athi

one

that

pro

ves

its

anti

cata

lept

ic a

ctiv

ity.

T

he a

ntio

xida

nt p

rope

rtie

s of

Ecl

ipta

alb

a re

duce

d th

e du

rati

on o

f ca

tale

psy,

num

ber

of V

CM

, de

crea

sed

the

elev

ated

lev

els

of l

ipid

pe

roxi

dati

on in

the

halo

peri

dol t

reat

men

t gro

ups.

(Jen

a et

al.,

201

3)

F

Alp

ha li

poic

ac

id

TD↓,

cat

alep

sy↓,

lo

com

otor

act

ivit

y↑, l

ipid

ox

idat

ion↓

AL

A a

nd it

s m

etab

olit

e di

hydr

o li

poic

aci

d sc

aven

ge

reac

tion

oxy

gen

spec

ies

and

reac

tive

nit

roge

n sp

ecie

s.

Res

ult s

how

ed th

at s

uppl

emen

tati

on w

ith

AL

A d

ecre

ase

halo

peri

dol-

indu

ced

TD

(10

0 m

g/kg

) an

d ca

tale

psy

sign

ific

antl

y. A

lpha

lip

oic

acid

(A

LA

) re

vers

ed th

e ha

lope

rido

l-in

duce

d de

crea

se i

n lo

com

otor

ac

tivi

ty

at

all

dose

s an

d re

vers

e th

e ha

lope

rido

l-in

duce

d li

pid

oxid

atio

n (1

00 m

g/kg

).

(Tha

akur

and

H

umm

abin

dhu,

200

9)

Not

e: [

1] C

onta

ins:

roo

ts o

f W

itha

nia

som

nife

ra, l

eave

s of

Oci

mum

san

ctum

, and

rhi

zom

e of

Cur

cum

a lo

nga.

A

bbre

viat

ion:

N.D

: not

det

ecte

d; T

CM

: tra

diti

onal

Chi

nses

med

icin

e; F

: foo

d an

d di

etar

y su

pple

men

ts; H

P: o

ther

her

bal p

rodu

cts;

i.p.

: int

rape

rito

neal

inje

ctio

n; p

.o.:

oral

adm

inis

trat

ion;

i.v.

: int

rave

nous

adm

inis

trat

ion;

s.

c.: s

ubcu

tane

ous

inje

ctio

n; i.

m.:

intr

amus

cula

r in

ject

ion

TD

: tar

dive

dys

kine

sia;

OD

: oro

faci

al d

yski

nesi

a; V

CM

: vac

uous

che

win

g m

ovem

ents

; SO

D: s

uper

oxid

e di

smut

ase.


36

bioavailability of circulating dopamine (Rasheed et al., 2009). Hippophae rhamnoides L., Alpha lipoic acid and Murraya koenigii showed reversal effect on haloperidol-induced increase locomotor activity (Batool et al., 2009; Patil et al., 2012; Thaakur and Hummabindhu, 2009). Hippophae rhamnoides L. also showed lower food intake when co-administered with haloperidol and significantly reversed haloperidol-induced decrease in brain tryptophan and 5-HT by normalizing the level of serotonergic influence on the activity of dopaminergic neurons (Batool et al., 2009). Murraya koenigii also showed similar reversal effect on locomotion as well as the haloperidol-induced decrease in forebrain SOD (superoxide dismutase) and catalase levels, reduced the lactoperoxidase and restored the decreased glutathione level (Patil et al., 2012). Free radical scavenging was suggested as one of the possible contributing factors to such effect, and it is also responsible for the alpha lipoic acid reversal of haloperidol-induced increase in locomotor activity (Thaakur and Hummabindhu, 2009). Fermented Soybean (Natto), a traditional Japanese food was used to induce hyperlocomotion in mice; however, haloperidol administration attenuated such effect with mechanism remains unknown (Mamiya and Nishimura, 2007). The fresh leaves and buds of Catha edulis Forsk, as known as Khat, are able to induce spontaneous motor activity and head twitch responses in mice, and pre-treatment of haloperidol had no effect on the head twitch response but enhanced spontaneous motor activity by unknown mechanism (Connor et al., 2002). As TD is one of the most commonly seen EPS that can be induced by haloperidol, HNPs that contain antioxidant properties and essential fatty acids are reported to decrease the incidence of TD and oxidative stress induced by haloperidol (Mahadik and Gowda, 1996; Mahadik and Scheffer, 1996; Mahadik et al., 2001; Reddy and Yao, 1996). In the present review, spirulina maxima, pecan nut shell (Carya illinoensis), Ilex paraguariensis, Withania somnifera and Morus alba showed antioxidant potential and signifi-cantly reversed the haloperidol-induced TD (Bhattacharya et al., 2002; Colpo et al., 2007; Nade et al., 2010; Naidu et al., 2003; Trevizol et al., 2011). On the other hand, although Valeriana officinalis demonstrated anxiolytic-like effect by reversing the haloperidol-induced increase in locomotor activity on rats, it failed to show significant effect on TD (Fachinetto et al., 2007).

A total of nine clinical studies were included in the current review with schizophrenic or EPS related symptoms as outcome measure (Table 4). Out of these trials, ascorbic acid, grape fruit juice and Vitamin E showed no significant effect on schizophrenic symptoms or EPS symptoms. In a double-blind, placebo-controlled study, male chronic schizophrenia subjects receiving haloperidol (0.4 mg/kg/day) in presence and absence of ascorbic acid (4.5 g/day) showed no significant difference in psychopathology (measuring by the PSAS score) or pharmacokinetics of haloperidol (Straw et al.,

1989). In a randomized open-labelled controlled trial on twenty-four male psychosis patients receiving haloperidol 10 mg/day with or without vitamin E (3200 IU/day), vitamin E co-administration showed neither protective effect towards the haloperidol-induced EPS nor interference with the therapeutic effect of haloperidol (Eranti et al., 1998). In an open-label pilot study involved twelve female schizophrenia patients administered long-term haloperidol (6 mg bid for 3–31 weeks), and co-administered with grape fruit juice (200 ml, tid, for 7 days), the plasma concentration of haloperidol and the metabolite reduced haloperidol showed no significant change after grape fruit juice treatment, and the concentration ratios of the two remained unchanged throughout the study. The author suggested that such result might be due to the limited effect of intestinal CYP3A4 on the first-pass metabolism of haloperidol (Yasui et al., 1999).

On the other hand, three double-blind randomized control trials by Zhang et al. with high quality and low risk of bias investigated the effect of Ginkgo biloba (GB) (360 mg/day) on schizophrenic patients received a stable dose of haloperidol (0.25 mg/kg per day). The results demonstrated that GB treatment enhance the antipsychotic effect of haloperidol compared with the control group, probably due to antioxidant or free radical scavenger effect of GB and improve immune function of schizophrenia patients via the increase of CD3+, CD4+, IL-2-secreting cells as well as the CD4/CD8 ratio (Zhang et al., 2001a; Zhang et al., 2001b; Zhang et al., 2006). Yi Gan San (TCM formulae that containing Bulpeuri Radix, Poria, Chuanxiong Rhizoma, Glycyrrhizae Radix et Rhizoma, Angelicae Sinensis Radix, Uncariae Ramulus cum Uncis and Atractylodis Rhizoma) was reported to significantly reduce the psychiatric symp-toms of 34 patients in an open label study. Schizophrenic patients received a stable dose of antipsychotic medication (haloperidol included) with Yi Gan San powder (1.5 g of extract, 1–3 times per day) for 4 weeks demonstrated significant decrease of schizophrenia subscale score but not the drug-induced EPS scale score in the patients compared with the control group (Miyaoka et al., 2009). It was suggested that activities on serotonergic and glutaminergic systems might be the major contributor of the therapeutic effects of Yi Gan San. Another open-label pilot study with 17 paranoid schizophrenia patients received long-term haloperidol treatment with 1000 mg ω-3 fatty acids (eicosapentaenoic acid 180 mg + docosahexaenoic acid 120 mg, bid), vitamin E (400 IU, bid) and vitamin C (1000 mg/day) suggested that the co-administration significantly lowered the schizophrenic symptoms and EPS scores of the patients due to their anti-oxidative properties (Sivrioglu et al., 2007). In a non-interventional, observational, open-label trial using Kava special extract WS 1490 in psychiatric patients who received haloperidol treatment, the result showed significant improvement for EPS signs and symptoms with no mechanism mentioned (Boerner and Klement, 2004).

37

JAASP 2019; 8: 22–49

Tab

le 4

. Cli

nic

al S

tud

ies

on E

xtra

pyr

amid

al S

ynd

rom

e (E

PS

) R

elat

ed H

alop

erid

ol-H

NP

s In

tera

ctio

ns.

Typ

e P

rod

uct

Stu

die

s d

esig

n

Ou

tcom

es a

nd

fin

din

gs

Cou

ntr

y R

efer

ence

S

ub

ject

D

esig

n

(sam

ple

siz

e)

Jad

ad

scal

e R

isk

of

bia

s M

easu

rem

ent

Eff

ect

TC

M

Gin

kgo

bilo

ba L

. S

chiz

ophr

enic

pa

tien

ts

Dou

ble-

blin

d ra

ndom

ized

co

ntro

l (10

)

4 L

ow

Per

iphe

ral i

mm

une

func

tion↑

Sig

nifi

cant

red

ucti

on i

n br

ief

psyc

hiat

ric

rati

ng s

cale

(B

PR

S)

was

ob

serv

ed

in

both

gr

oups

. T

he

EG

b gr

oup

show

ed

sign

ific

ant

redu

ctio

n in

sca

le f

or a

sses

smen

t of

posi

tive

sym

ptom

s (S

AP

S)

and

scal

e fo

r as

sess

men

t of

nega

tive

sym

ptom

s (S

AN

S)

than

the

plac

ebo

grou

p. T

here

was

a s

igni

fica

nt c

orre

lati

on b

etw

een

the

chan

ge i

n C

D4+

cel

ls (

befo

re a

nd a

fter

tre

atm

ent)

and

the

red

ucti

on o

f B

PR

S sc

ore

in t

he w

hole

pat

ient

gro

up. T

he r

esul

t su

gges

ts t

hat

EG

b m

ay

impr

ove

the

decr

ease

d pe

riph

eral

imm

une

func

tion

s in

sch

izop

hren

ia

pati

ents

.

Chi

na

(Zha

ng e

t al.,

200

6)

Sch

izop

hren

ic

pati

ents

D

oubl

e-bl

ind

rand

omiz

ed

cont

rol (

56)

4 L

ow

Ant

i-ps

ycho

tic

effe

ct↑

The

B

PR

S,

SA

PS

, an

d S

AN

S

tota

l sc

ore

show

ed

sign

ific

ant

impr

ovem

ent

in t

he E

Gb

grou

p be

twee

n ba

seli

ne a

nd 1

2 w

eeks

of

trea

tmen

t. T

reat

men

t em

erge

nt s

ympt

om s

cale

(T

ES

S)

subs

core

1

(beh

avio

ural

tox

icity

) an

d su

bsco

re 3

(sy

mpt

oms

of n

erve

sys

tem

) w

ere

sign

ific

antl

y de

crea

sed

in t

he E

Gb

grou

p co

mpa

red

wit

h th

e pl

aceb

o gr

oup.

The

res

ults

sug

gest

tha

t E

Gb

trea

tmen

t m

ay b

e ab

le

to

incr

ease

th

e ef

fect

iven

ess

and

redu

ce

the

side

ef

fect

s of

ha

lope

rido

l.

Chi

na

(Zha

ng e

t al.,

200

1a)

Sch

izop

hren

ic

pati

ents

D

oubl

e-bl

ind

rand

omiz

ed

cont

rol (

43)

4 L

ow

Ant

i-ps

ycho

tic

effe

ct↑

Sig

nifi

cant

ly im

prov

ed S

AP

S a

nd S

AN

S sc

ore

was

obs

erve

d in

EG

b gr

oup

whi

le o

nly

sans

sco

res

wer

e im

prov

ed i

n th

e pl

aceb

o gr

oup.

T

he T

ES

S t

otal

sco

re i

n E

Gb

grou

p te

nded

to

be l

ower

tha

n th

at i

n pl

aceb

o gr

oup

(p =

0.0

8), t

he s

igni

fica

nt d

iffe

renc

es w

ere

obse

rved

in

sub

scor

e 1

and

subs

core

3.

The

ave

rage

SO

D l

evel

dec

reas

ed

sign

ific

antl

y in

pat

ient

s fr

om E

Gb

grou

p af

ter

the

trea

tmen

t

Chi

na

(Zha

ng e

t al.,

200

1b)

TC

M

Yi G

an S

an

(YG

S)

[1]

Sch

izop

hren

ic

pati

ents

O

pen-

labe

l stu

dy

(34)

3

Hig

h P

sych

iatr

ic

sym

ptom

s↓

The

ave

rage

dai

ly Y

GS

dos

age

was

6.7

± 2

.5 g

wit

h th

e hi

ghes

t pr

opor

tion

of

pati

ents

bei

ng a

dmin

iste

red

a da

ily

dosa

ge o

f 7.5

g. N

o ad

vers

e ef

fect

s w

ere

caus

ed b

y Y

GS

tre

atm

ent.

The

mea

n po

siti

ve

sym

ptom

s su

bsca

le s

core

for

tre

atm

ent

grou

p on

the

pos

itiv

e an

d ne

gati

ve s

yndr

ome

scal

e (P

AN

SS

) is

27.

7 ±

6.1

whi

le n

egat

ive

sym

ptom

s su

bsca

le s

core

is

30.4

± 5

.8 a

nd t

he g

ener

al p

sych

o-pa

thol

ogy

subs

cale

is

65.1

± 5

.4.

The

pos

itiv

e sy

mpt

oms

subs

cale

sc

ore

was

redu

ced

by 6

8.2%

at 2

wee

ks a

nd th

is re

duct

ion

prog

ress

ed

by 4

3.0%

at t

he 4

th w

eek.

The

PA

NS

S n

egat

ive

sym

ptom

s su

bsca

le

scor

e w

as

redu

ced

by

73.7

%

at

2nd

wee

k an

d th

is

redu

ctio

n pr

ogre

ssed

by

59.9

at

the

4th w

eek.

The

PA

NS

S g

ener

al p

sych

o-pa

thol

ogy

subs

cale

sco

re w

as r

educ

ed b

y 70

.5%

at 2

nd w

eek

and

this

re

duct

ion

prog

ress

ed b

y 60

.8%

at

the

4th w

eek.

No

chan

ge o

n th

e P

AN

SS

sca

les

was

obs

erve

d in

the

cont

rol g

roup

. Mil

d an

d tr

ansi

ent

adve

rse

even

ts in

clud

ing

naus

ea (2

cas

es) a

nd ti

redn

ess

(1 c

ase)

wer

e re

port

ed b

y th

e su

bjec

ts.

Japa

n (M

iyao

ka e

t al.,

20

09)


38

Tab

le 4

. Cli

nic

al S

tud

ies

on E

xtra

pyr

amid

al S

ynd

rom

e (E

PS

) R

elat

ed H

alop

erid

ol-H

NP

s In

tera

ctio

ns

(con

tin

ued

).

Typ

e P

rod

uct

Stu

die

s d

esig

n

Ou

tcom

es a

nd

fin

din

gs

Cou

ntr

y R

efer

ence

S

ub

ject

D

esig

n

(sam

ple

siz

e)

Jad

ad

scal

e R

isk

of

bia

s M

easu

rem

ent

Eff

ect

HP

K

ava

Spe

cial

E

xtra

ct (

WS

14

90)

Pat

ient

s w

ith

psyc

hiat

ric

diag

nose

s

Non

-in

terv

enti

onal

, ob

serv

atio

nal,

open

-lab

el s

tudy

(4

2)

1 H

igh

EP

S s

igns

and

sy

mpt

oms↓

P

atie

nts

(17

fem

ale,

25

mal

e) w

ere

pre-

trea

ted

by n

euro

lept

ics.

In

both

pa

tien

t an

d ph

ysic

ian

ques

tionn

aire

s as

w

ell

as

in

the

phys

icia

n’s

glob

al r

atin

gs, s

igni

fica

nt im

prov

emen

ts w

ere

foun

d fo

r al

l E

PS

sym

ptom

s re

cord

ed b

y W

S 1

490.

The

fin

ding

s of

thi

s ob

serv

atio

nal

stud

y su

gges

t th

at E

PS

of

neur

olep

tic

drug

s m

ay b

e at

tenu

ated

by

Kav

a sp

ecia

l ex

trac

t W

S 1

490.

Fiv

e ad

vers

e ev

ents

re

port

ed.

Ger

man

y (B

oern

er a

nd

Kle

men

t, 20

04)

F

Vit

amin

E

Mal

es p

atie

nts

wit

h ps

ycho

sis

R

ando

miz

ed

cont

roll

ed tr

ial

(24)

2 H

igh

EP

S s

ympt

oms

T

he re

sult

sho

wed

that

Vit

amin

E h

ad n

o pr

ophy

lact

ic e

ffec

t on

drug

-in

duce

d E

PS

. In

dia

(Era

nti e

t al.,

199

8)

F

Asc

orbi

c A

cid

Mal

e ch

roni

c sc

hizo

phre

nia

pati

ents

Dou

ble-

blin

d,

plac

ebo

cont

roll

ed

(8)

3 S

ome

conc

erns

P

SA

S s

core

The

res

ult

did

not

show

any

sig

nifi

cant

cha

nge

in p

sych

opat

holo

gy

in

pati

ents

ta

king

as

corb

ic

acid

an

d th

ere

was

no

si

gnif

ican

t ph

arm

acok

inet

ic in

tera

ctio

n w

ith

halo

peri

dol.

Uni

ted

Sta

te

(Str

aw e

t al.,

198

9)

F

Om

ega-

3 F

atty

Aci

ds,

Vit

amin

E,

Vit

amin

C,

Sup

plem

ents

Par

anoi

d sc

hizo

phre

nia

pati

ents

, tre

ated

w

ith

halo

peri

dol

for

at le

ast 3

m

onth

s

Ope

n-la

bel p

ilot

st

udy

(17)

1

Hig

h S

chiz

ophr

enic

sy

mpt

oms↓

, E

PS

sid

e ef

fect

s↓

Res

ult s

how

ed a

sig

nifi

cant

dec

reas

e in

all

the

scal

e sc

ores

and

SO

D

leve

l was

sig

nifi

cant

ly lo

wer

at t

he e

nd o

f st

udy,

sug

gest

ing

that

the

supp

lem

enta

tion

s ha

ve b

enef

icia

l ef

fect

s on

pos

itiv

e an

d ne

gati

ve

sym

ptom

s of

sch

izop

hren

ia a

nd a

lso

redu

ce th

e ha

lope

rido

l ind

uced

si

de e

ffec

ts.

Tur

key

(Siv

riog

lu e

t al.,

20

07)

F

Gra

pefr

uit

Juic

e S

chiz

ophr

enic

pa

tien

ts

Ope

n-la

bel p

ilot

st

udy

(12)

0

Hig

h S

chiz

ophr

enic

sy

mpt

oms

, sid

e ef

fect

The

BP

RS

sca

le a

nd U

KU

sid

e ef

fect

rat

ing

scal

es w

ere

used

to

asse

ss

clin

ical

sy

mpt

oms

and

side

ef

fect

s.

Res

ult

show

ed

that

gr

apef

ruit

juic

e di

d no

t alt

er th

e sc

ores

of

BP

RS

sca

le a

nd U

KU

sid

e ef

fect

rat

ing

scal

e th

roug

hout

the

stud

y.

Japa

n (Y

asui

et a

l., 1

999)

Not

e: [

1] C

onta

ins:

Bul

peur

i Rad

ix, P

oria

, Chu

anxi

ong

Rhi

zom

a, G

lycy

rrhi

zae

Rad

ix e

t Rhi

zom

a, A

ngel

icae

Sin

ensi

s R

adix

, Unc

aria

e R

amul

us c

um U

ncis

, Atr

acty

lodi

s R

hizo

ma.

A

bbre

viat

ion:

N.D

: not

det

ecte

d; T

CM

: tra

diti

onal

Chi

nses

med

icin

e; F

: foo

d an

d di

etar

y su

pple

men

ts; H

P: o

ther

her

bal p

rodu

cts;

i.p.

: int

rape

rito

neal

inje

ctio

n; p

.o.:

oral

adm

inis

trat

ion;

i.v.

: int

rave

nous

adm

inis

trat

ion;

s.

c.: s

ubcu

tane

ous

inje

ctio

n; i.

m.:

intr

amus

cula

r in

ject

ion

TD

: tar

dive

dys

kine

sia;

OD

: oro

faci

al d

yski

nesi

a; V

CM

: vac

uous

che

win

g m

ovem

ents

; SO

D: s

uper

oxid

e di

smut

ase.

39

JAASP 2019; 8: 22–49

Tab

le 5

. Mis

cell

aneo

us

Hal

oper

idol

-HN

Ps

Inte

ract

ion

s on

An

imal

Mod

els.

Typ

es

Pro

du

ct

Mod

el

Ou

tcom

es a

nd

fin

din

gs

Ref

eren

ce

Mea

sure

men

t M

ech

anis

m

Eff

ect

TC

M

Sol

anum

torv

um

Mal

e al

bino

m

ice

A

nxio

lyti

c↓

ST

mig

ht p

rodu

ce a

nxio

lyti

c ef

fect

by

inte

ract

ion

wit

h α-

adre

nerg

ic,

sero

tone

rgic

and

dop

amin

e re

cept

ors,

incr

easi

ng th

e le

vel o

f no

repi

neph

rine

, ser

oton

in a

nd

dopa

min

e in

bra

in. H

alop

erid

ol

anta

goni

zes

the

dopa

min

e D

2-re

cept

or a

nd r

ever

se th

e an

xiol

ytic

ef

fect

of

ST

.

The

eff

ect o

f a

met

hano

lic

extr

act

of S

. tor

vum

(S

T)

has

been

stu

died

in

com

bina

tion

wit

h ha

lope

rido

l in

mic

e w

ith

elev

ated

plu

s m

aze

(EP

M),

li

ght

and

dark

tra

nsit

ion

appa

ratu

s (L

DA

), h

ole

boar

d ap

para

tus

(HB

A)

and

mar

ble

bury

ing

test

(M

BT

). T

he m

etha

noli

c ex

trac

t of

ST

(30

, 10

0 m

g/kg

, i.p

.) w

ere

give

n ha

lf a

n ho

ur a

fter

adm

inis

trat

ion

of h

alop

erid

ol

(50

µg/

kg, i

.p.)

for

fou

r co

nsec

utiv

e da

ys. T

he r

esul

t sho

wed

that

ani

mal

s pr

e-tr

eate

d w

ith

halo

peri

dol

prod

uced

sig

nifi

cant

inc

reas

e in

tim

e sp

ent

and

num

ber

of e

ntri

es in

ope

n ar

m, d

ecre

ase

in ti

me

spen

t in

clos

ed a

rm

in E

PM

tes

t. In

LD

A t

est,

halo

peri

dol

com

bine

d w

ith

ST

pro

duce

d a

sign

ific

ant i

ncre

ase

in ti

me

spen

t in

ligh

t are

a an

d de

crea

se in

tim

e sp

ent

in d

ark

area

. The

com

bine

d dr

ug p

rodu

ced

sign

ific

ant i

ncre

ase

in n

umbe

r of

hea

d po

king

in H

BA

and

sig

nifi

cant

ly d

ecre

ased

the

num

ber o

f bur

ying

re

spon

se in

MB

T.

(Mom

in a

nd M

ohan

, 20

11)

TC

M

Cai

hu-S

ugan

-San

[1

] M

ale

Spr

ague

-D

awle

y ra

ts

Imm

obil

ity↑

F

erul

ic a

cid

(FA

) at

tenu

ated

de

pres

sion

via

sel

ecti

vely

in

hibi

ting

dop

amin

e re

upta

kes

in

brai

n

FA

, th

e ab

sorb

ed

com

poun

d of

C

aihu

-Sug

an-S

an,

was

st

udie

d in

co

mbi

nati

on w

ith

halo

peri

dol.

Pre

-tre

atm

ent w

ith

halo

peri

dol (

0.2

mg/

kg,

i.p.)

was

adm

inis

tere

d in

rat

s 30

min

bef

ore

FA

. The

res

ult

show

ed F

A-

indu

ced

anti

-im

mob

ilit

y ti

me

was

sig

nifi

cant

ly r

ever

sed

by t

he p

re-

trea

tmen

t. T

his

sugg

esti

ng

FA

at

tenu

ated

de

pres

sion

vi

a in

hibi

ting

do

pam

ine

reup

take

s in

bra

in.

(Zha

ng e

t al.,

201

1c)

TC

M

Cal

culu

s B

ovis

S

ativ

us

Mal

e S

prag

ue

Daw

ley

rats

A

nti-

schi

zoph

reni

a ef

fect

s↑

loco

mot

or a

ctiv

ity↓

, ce

ntra

l dis

tanc

e↑

The

enh

ance

d or

al b

ioav

aila

bili

ty

of h

alop

erid

ol w

hen

com

bine

d w

ith

Cal

culu

s B

ovis

Sat

ivus

(C

BS

) m

ight

be

attr

ibut

ed to

the

inte

ract

ion

betw

een

them

.

An

open

fie

ld te

st w

as c

ondu

cted

to v

erif

y th

e ph

arm

acod

ynam

ic e

ffec

ts

of a

com

bina

tion

trea

tmen

t of

CB

S a

nd h

alop

erid

ol o

n M

K-8

01-i

nduc

ed

schi

zoph

reni

c ra

ts. R

at p

lasm

a co

ncen

trat

ions

of

intr

agas

tric

hal

oper

idol

an

d in

trav

enou

s ha

lope

rido

l wer

e de

term

ined

aft

er o

ral a

dmin

istr

atio

n of

a

sing

le d

ose

or 1

-wee

k of

pre

trea

tmen

t w

ith

CB

S (

50 m

g/kg

). T

he

phar

mac

odyn

amic

da

ta

show

ed

a si

gnif

ican

t de

crea

se

in

loco

mot

or

acti

vity

and

an

incr

ease

in

the

perc

enta

ge o

f th

e ce

ntra

l di

stan

ce w

hen

halo

peri

dol

was

con

com

itan

tly

adm

inis

tere

d w

ith

CB

S c

ompa

red

wit

h ha

lope

rido

l adm

inis

trat

ion

alon

e.

(Lei

et a

l., 2

018)

TC

M

Aeg

le m

arm

elos

A

lbin

o m

ice

Im

mob

ilit

y↑

Blo

ckad

e of

dop

amin

e re

cept

or b

y ha

lope

rido

l inc

reas

ed d

urat

ion

of

imm

obil

ity

and

reve

rsed

an

tide

pres

sant

act

ion

of A

M.

The

eff

ect o

f m

etha

nol e

xtra

ct o

f A

egle

mar

mel

os (

AM

) ha

s be

en s

tudi

ed

in c

ombi

nati

on w

ith

halo

peri

dol

in t

ail

susp

ensi

on t

est

in m

ice

(n =

6).

P

re-t

reat

men

t of

hal

oper

idol

(0.

1 m

g/kg

) ca

used

sig

nifi

cant

inc

reas

e in

m

ean

dura

tion

of

imm

obil

ity

as c

ompa

red

to A

M (

150

mg/

kg)

alon

e. T

he

resu

lt

sugg

esti

ng

that

ha

lope

rido

l si

gnif

ican

tly

atte

nuat

ed

the

anti

depr

essa

nt e

ffec

t of

AM

.

(Kot

hari

et a

l., 2

010)

HP

H

edyo

smum

br

asil

iens

e M

ale

Sw

iss

mic

e

Imm

obil

ity↑

T

he d

opam

ine

D1

and

D2

rece

ptor

s ar

e in

volv

ed in

the

anti

-im

mob

ilit

y ac

tion

of

halo

peri

dol

in th

e m

ouse

for

ced

swim

min

g te

st.

For

ced

swim

min

g te

st w

as u

sed

to i

nves

tiga

te t

he i

nflu

ence

of

the

dopa

min

ergi

c sy

stem

on

the

anti

depr

essa

nt-l

ike

effe

ct o

f the

Hed

yosm

um

bras

ilie

nse

(HB

) ex

trac

t. H

alop

erid

ol (

0.2

mg/

kg, i

.p.)

was

adm

inis

tere

d 15

min

bef

ore

HB

(50

mg/

kg),

and

the

n te

sted

in

the

forc

ed s

wim

min

g te

st 4

5 m

in la

ter.

The

res

ult s

how

ed th

at th

e an

ti-i

mm

obil

ity

effe

ct o

f H

B

extr

act w

as s

igni

fica

ntly

pre

vent

ed b

y th

e pr

e-tr

eatm

ent o

f ha

lope

rido

l.

(Gon

çalv

es e

t al.,

20

12)


40

Tab

le 5

. Mis

cell

aneo

us

Hal

oper

idol

-HN

Ps

Inte

ract

ion

s on

An

imal

Mod

els

(con

tin

ued

).

Typ

es

Pro

du

ct

Mod

el

Ou

tcom

es a

nd

fin

din

gs

Ref

eren

ce

Mea

sure

men

t M

ech

anis

m

Eff

ect

HP

T

erns

troe

mia

pr

ingl

ei S

tand

l. A

dult

mal

e IC

R

mic

e

Sed

atio

n↑

N.D

. T

he

mic

e w

as

give

n aq

ueou

s ex

trac

t of

T

erns

troe

mia

pr

ingl

ei

and

halo

peri

dol

(0.1

–3 m

g/kg

) at

dif

fere

nt d

oses

. T

he r

esul

t sh

ows

that

co-

adm

inis

trat

ion

of

Ter

nstr

oem

ia

prin

glei

an

d ha

lope

rido

l re

sult

in

a

syne

rgis

tic

seda

tive

inte

ract

ion.

(Bal

dera

s et

al.,

200

8)

HP

S

alvi

a sc

lare

a S

prag

ue-D

awle

y ra

ts

Ant

i-de

pres

sant↓

The

ant

i-de

pres

sant

-lik

e ef

fect

of

Sal

via

scla

rea

oil i

s li

kely

m

edia

ted

via

a do

pam

iner

gic

path

way

.

The

ant

i-de

pres

sant

-lik

e ef

fect

s in

duce

d by

5%

Sal

via

scla

rea

oil

was

si

gnif

ican

tly

bloc

ked

by h

alop

erid

ol (

0.5

mg/

kg).

(S

eol e

t al.,

201

0)

HP

A

ster

acan

tha

long

ifol

ia

Sw

iss

albi

no r

ats

Ir

on d

efic

ienc

y an

aem

ia↓

N.D

. E

than

olic

ext

ract

of

Ast

erac

anth

a lo

ngif

olia

(A

L)

(100

and

200

mg/

kg,

i.p.)

was

adm

inis

trat

ed w

ith

halo

peri

dol

(0.2

mg/

kg,

i.p.)

for

4 d

ays

to

exam

ine

its

effe

ct o

n ha

lope

rido

l in

duce

d ir

on d

efic

ienc

y an

aem

ia.

The

re

sult

sho

wed

tha

t ha

lope

rido

l in

duce

d ir

on d

efic

ienc

y an

aem

ia w

as

redu

ced

in a

dos

e de

pend

ent

man

ner

by t

he t

reat

men

t of

AL

. Com

pare

d w

ith

the

cont

rol

grou

ps,

the

extr

act

trea

ted

grou

ps

dem

onst

rate

d si

gnif

ican

t inc

reas

e in

hae

mat

olog

ical

par

amet

ers.

(Paw

ar e

t al.,

201

0)

HP

V

itex

agn

us C

astu

s A

dult

Bal

b/c

mal

e m

ice

L

uten

izin

g ho

rmon

e an

d te

stos

tero

ne le

vel↓

V

AC

ext

ract

act

ivat

es th

e do

pam

iner

gic

path

way

and

in

hibi

ts h

ypot

hala

mic

–pit

uita

ry–

gona

dal a

xis

and

decr

ease

s lu

tein

izin

g ho

rmon

e an

d te

stos

tero

ne h

orm

ones

.

Vit

ex a

gnus

Cas

tus

(VA

C) e

xtra

ct (3

65 m

g/kg

) and

hal

oper

idol

(2 m

g/kg

) w

as i

.p.

inje

cted

alo

ne r

espe

ctiv

ely

or t

oget

her

once

dai

ly f

or 3

0 da

ys.

Res

ult

show

ed t

hat h

alop

erid

ol a

lone

incr

ease

d lu

tein

izin

g ho

rmon

e an

d te

stos

tero

ne l

evel

vs.

con

trol

and

sha

m g

roup

s. C

o-ad

min

istr

atio

n of

V

AC

and

hal

oper

idol

dec

reas

ed l

utei

nizi

ng h

orm

one

and

test

oste

rone

le

vel.

It w

as s

ugge

sted

tha

t V

AC

ext

ract

can

be

used

for

pat

holo

gica

l ca

ses

for

incr

easi

ng lu

tein

izin

g ho

rmon

e an

d te

stos

tero

ne.

(Nas

ri e

t al.,

200

7)

HP

A

rida

nin

(iso

late

d fr

om T

etra

pleu

ra

tetr

apet

ra)

Sw

iss

albi

no

mic

e hy

poth

erm

ic e

ffec

t

The

hyp

othe

rmic

eff

ect o

f ar

idan

in

is p

roba

bly

not m

edia

ted

by th

e do

pam

iner

gic

rece

ptor

sys

tem

.

Mic

e w

ere

pre-

trea

ted

wit

h ar

idan

in

(15

and

30

mg/

kg,

p.o.

) an

d ha

lope

rido

l (0

.1 m

g/kg

) w

as a

dmin

iste

red

afte

r. T

he r

esul

t sh

owed

tha

t ha

lope

rido

l had

no

effe

ct o

n th

e hy

poth

erm

ic a

ctiv

ity

of a

rida

nin.

(Ade

ribi

gbe

et a

l.,

2007

)

HP

D

raca

ena

arbo

rea

Mal

e W

ista

r ra

ts

Sex

ual s

tim

ulat

ing

effe

ct↓

The

sex

ual s

tim

ulat

ing

effe

ct o

ff

Dra

caen

a ar

bore

a (D

A)

may

be

med

iate

d by

the

dopa

min

ergi

c sy

stem

.

The

eff

ects

of

DA

on

the

sexu

al b

ehav

iour

of

gona

do-i

ntac

t and

cas

trat

ed

sexu

ally

exp

erie

nced

rat

s ar

e ex

amin

ed.

Mic

e w

ere

pre-

trea

ted

wit

h ha

lope

rido

l (1

0 m

g/kg

, i. p

.) a

nd w

ere

give

n a

sing

le o

ral

dose

of

the

etha

noli

c D

A e

xtra

ct (

100

mg/

kg)

to i

nduc

e pr

osex

ual

effe

ct.

Res

ult

show

ed

that

co

-adm

inis

trat

ion

of

halo

peri

dol

wit

h th

e D

A

extr

act

com

plet

ely

bloc

ked

the

sexu

al

beha

viou

r (e

rect

ion,

in

trom

issi

on,

ejac

ulat

ion)

of

the

rats

indu

ced

by D

A.

(War

cho

et a

l., 2

007)

HP

A

spid

ospe

rma

ulei

ro

ots

M

ale

Sw

iss

mic

e

Pro

-ere

ctil

e ef

fect↓

F3-

5 in

duce

d pe

nile

ere

ctio

n pr

obab

ly in

volv

e th

e do

pam

iner

gic

mec

hani

sm

The

pro

-ere

ctil

e ef

fect

of

F3-

5 (t

he i

ndol

e al

kalo

idal

ric

h fr

acti

on f

rom

A

spid

ospe

rma

ulei

roo

ts)

whe

n co

-adm

inis

tere

d w

ith

halo

peri

dol

was

ev

alua

ted.

Mic

e w

ere

pre-

trea

ted

wit

h ha

lope

rido

l (2

mg/

kg, i

.p.)

15

min

s be

fore

the

F3-

5 in

ject

ion

(25

and

50 m

g/kg

). T

he r

esul

t sh

ows

that

ha

lope

rido

l blo

ck th

e er

ecti

le e

ffec

t ind

uced

by

F3-

5.

(Cam

pos

et a

l., 2

006)

41

JAASP 2019; 8: 22–49

Tab

le 5

. Mis

cell

aneo

us

Hal

oper

idol

-HN

Ps

Inte

ract

ion

s on

An

imal

Mod

els

(con

tin

ued

).

Typ

es

Pro

du

ct

Mod

el

Ou

tcom

es a

nd

fin

din

gs

Ref

eren

ce

Mea

sure

men

t M

ech

anis

m

Eff

ect

HP

A

ster

acan

tha

long

ifol

ia

Sw

iss

albi

no r

ats

E

ryth

ropo

ieti

c ac

tivi

ty↑

The

pre

senc

e of

iron

(62

2 μg

/50

mg)

in th

e ex

trac

t may

be

cont

ribu

te to

the

eryt

hrop

oiet

ic

acti

vity

of

the

AL

ext

ract

The

ery

thro

poie

tic

acti

vity

of

Ast

erac

anth

a lo

ngif

olia

Nee

s. (

AL

) on

ha

lope

rido

l in

duce

d ir

on

defi

cien

cy

anae

mia

w

as

eval

uate

d.

The

tr

eatm

ent

grou

p w

as g

iven

hal

oper

idol

(0.

2 m

g/kg

, i.p

.) a

long

wit

h et

hano

lic

extr

act

of A

L (

100

and

200

mg/

kg,

i.p.)

for

4 d

ays.

The

n ha

lope

rido

l w

as w

ithd

raw

n fr

om a

ll t

he e

xtra

ct t

reat

ed g

roup

s an

d th

ey

wer

e tr

eate

d w

ith

thei

r re

spec

tive

ext

ract

dos

e (1

00 a

nd 2

00 m

g/kg

) co

ntin

uous

ly u

p to

15

days

. Res

ult s

how

ed th

at A

L e

xtra

ct d

emon

stra

ted

a si

gnif

ican

t in

crea

se i

n er

ythr

ocyt

e co

unt,

haem

oglo

bin

coun

t, se

rum

ir

on a

nd s

erum

pro

tein

.

(Paw

ar e

t al.,

201

0)

HP

H

U-2

10

(a c

anna

bino

id

CB

1 ag

onis

t)

Mal

e S

prag

ue-

Daw

ley

rats

Im

mob

ilit

y↑

The

ant

i-de

pres

sant

-lik

e ef

fect

of

CB

1 re

cept

or a

goni

st, H

U-2

10, i

s li

kely

med

iate

d by

the

acti

vati

on

of d

opam

ine

tran

smis

sion

The

eff

ect

of t

he h

alop

erid

ol o

n th

e an

tide

pres

sant

-lik

e ef

fect

of

CB

1 st

imul

atio

n w

as s

tudi

ed in

rats

. The

CB

1 ag

onis

t HU

-210

(0.1

mg/

kg) a

nd

halo

peri

dol

(0.2

mg/

kg)

wer

e ad

min

iste

red

befo

re t

he f

orce

d sw

imm

ing

test

. T

he r

esul

t sh

owed

tha

t ha

lope

rido

l an

tago

nize

d th

e an

tide

pres

sant

-li

ke e

ffec

t of

HU

-210

.

(Siv

riog

lu e

t al.,

200

7)

HP

W

itha

nia

som

nife

ra

Alb

ino

mic

e Im

mob

ilit

y

Dop

amin

ergi

c re

cept

ors

may

not

be

invo

lved

in th

e im

mob

ilit

y re

duci

ng e

ffec

t of

WS

The

eff

ect

of a

ntid

epre

ssan

t ac

tion

of

Wit

hani

a so

mni

fera

(W

S)

and

its

inte

ract

ion

wit

h ha

lope

rido

l was

eva

luat

ed in

mic

e. M

ice

wer

e pr

e-tr

eate

d w

ith

halo

peri

dol

(0.1

mg/

kg,

i.p.)

60

min

bef

ore

forc

ed s

wim

min

g te

st

whi

le W

S (

100

mg/

kg, i

.p.)

was

adm

inis

tere

d 30

min

s af

ter

halo

peri

dol.

A f

orce

d sw

imm

ing

test

was

use

d to

eva

luat

e th

e an

tide

pres

sant

act

ivit

y.

Res

ult s

how

ed th

at h

alop

erid

ol d

id n

ot a

ffec

t the

eff

ect o

f W

S 1

00 m

g/kg

on

dur

atio

n of

mea

n im

mob

ilit

y ti

me

(Dem

onti

s et

al.,

201

1)

HP

T

rich

ilia

cat

igua

N

on-f

aste

d m

ale

Sw

iss

mic

e Im

mob

ilit

y↓

The

eff

ects

of

TC

pro

babl

y in

volv

e th

e do

pam

iner

gic

syst

em,

it m

ay b

e li

nked

to th

e ac

tiva

tion

of

D3/

D4

rece

ptor

s si

nce

the

effe

ct is

not

mod

ifie

d by

the

sele

ctiv

e D

2 re

cept

or a

ntag

onis

t pi

moz

ide.

The

ant

i-im

mob

ilit

y ef

fect

s an

d po

ssib

le m

echa

nism

of

T.

cati

gua

(TC

) ex

trac

t was

eva

luat

ed in

mic

e. M

ice

wer

e pr

e-tr

eate

d w

ith

halo

peri

dol (

1 m

g/kg

, i.p

.) 3

0 m

ins

befo

re t

he t

reat

men

t w

ith

TC

ext

ract

(20

0 m

g/kg

, p.

o.)

6 h

befo

re t

esti

ng.

Res

ult

show

ed t

hat

the

anti

-im

mob

ilit

y ef

fect

in

duce

d by

TC

ext

ract

wer

e si

gnif

ican

tly

reve

rsed

by

halo

peri

dol

in t

he

forc

ed s

wim

min

g m

odel

in m

ice.

(Cam

pos

et a

l., 2

005)

HP

S

copo

leti

n (i

sola

ted

from

P

olyg

ala

sabu

losa

)

Fem

ale

Sw

iss

mic

e

Ant

i-de

pres

sant

eff

ect↓

T

he d

opam

iner

gic

syst

em m

ay

cont

ribu

te to

the

anti

-dep

ress

ant-

like

eff

ect o

f sc

opol

etin

.

The

ant

i-de

pres

sant

-lik

e ef

fect

of

scop

olet

in a

nd i

ts p

ossi

ble

mec

hani

sm

of a

ctio

n w

as i

nves

tiga

ted

in t

he t

ail s

uspe

nsio

n te

st i

n m

ice.

Mic

e w

ere

pre-

trea

ted

wit

h ha

lope

rido

l (0

.2 m

g/kg

, i.p

.) 3

0 m

in b

efor

e re

ceiv

ing

scop

olet

in (1

0 m

g/kg

, p.o

.) o

r veh

icle

. Tai

l sus

pens

ion

test

was

per

form

ed

60 m

in a

fter

. R

esul

t sh

owed

tha

t co

-adm

inis

trat

ion

of s

copo

leti

n w

ith

halo

peri

dol

bloc

k th

e an

tide

pres

sant

-lik

e ef

fect

of

scop

olet

in i

n th

e ta

il

susp

ensi

on te

st.

(Cap

ra e

t al.,

201

0)


42

Tab

le 5

. Mis

cell

aneo

us

Hal

oper

idol

-HN

Ps

Inte

ract

ion

s on

An

imal

Mod

els

(con

tin

ued

).

Typ

es

Pro

du

ct

Mod

el

Ou

tcom

es a

nd

fin

din

gs

Ref

eren

ce

Mea

sure

men

t M

ech

anis

m

Eff

ect

HP

N

iga-

Ichi

gosi

de F

1 (i

sola

ted

from

R

ubus

impe

rial

is)

Sw

iss

mic

e

Ant

i-no

cice

ptio

n↓

The

ant

i-no

cice

ptiv

e ef

fect

of

Nig

a-Ic

higo

side

(N

I) m

ay b

e re

late

d to

the

dopa

min

ergi

c pa

thw

ay

The

ant

i-no

cice

ptiv

e ef

fect

s of

NI w

hen

co-a

dmin

iste

red

wit

h ha

lope

rido

l w

as e

valu

ated

. M

ice

wer

e pr

e-tr

eate

d w

ith

halo

peri

dol

(0.2

mg/

kg,

i.p.)

an

d w

ere

give

n N

I (6

0 m

g/kg

, i.p

.) to

exa

min

e th

e an

tino

cice

ptiv

e ac

tion

on

for

mal

in-i

nduc

ed n

ocic

epti

on i

n m

ice.

The

tim

e sp

ent

lick

ing

the

inje

cted

paw

was

tim

ed w

hich

ser

ve a

s an

ind

icat

or o

f pa

in.

The

fir

st

phas

e m

easu

res

the

noci

cept

ive

pain

whi

ch i

s 5

min

aft

er f

orm

alin

in

ject

ion

whe

reas

th

e se

cond

ph

ase

mea

sure

s th

e ne

urog

enic

an

d in

flam

mat

ory

pain

whi

ch is

15–

30 m

in a

fter

inje

ctio

n. R

esul

t sho

wed

that

co

-adm

inis

trat

ion

of

halo

peri

dol

wit

h N

I si

gnif

ican

tly

atte

nuat

e th

e an

tino

cice

ptiv

e ef

fect

by

NI

at b

oth

phas

es.

(Ard

engh

i et a

l., 2

006)

HP

M

orin

da c

itri

foli

a L

inn.

S

prag

ue-D

awle

y m

ale

rats

C

ontr

acti

le r

espo

nse

in

isol

ated

rat

vas

de

fere

ns p

repa

rati

ons↓

Bip

hasi

c ef

fect

of

on

dopa

min

ergi

c sy

stem

T

he r

esul

ts h

ave

dem

onst

rate

d th

e bi

phas

ic e

ffec

t of

Mor

inda

Cit

rifo

lia

on d

opam

iner

gic

syst

em, w

ith

dopa

min

ergi

c an

tago

nist

ic e

ffec

t at l

ower

co

ncen

trat

ions

(<

40 m

g/m

L)

and

dopa

min

ergi

c ag

onis

tic

effe

ct a

t hig

her

conc

entr

atio

ns (

>60

mg/

mL

).

(Pan

dy e

t al.,

201

4)

HP

F

ilic

ene

(ext

ract

ed

from

Adi

antu

m

cune

atum

)

Mal

e S

wis

s m

ice

A

nti-

noci

cept

ion↓

T

he d

opam

iner

gic

syst

em m

ay

cont

ribu

te to

the

anti

-noc

icep

tive

ef

fect

of

fili

cene

. Co-

adm

inis

ter

wit

h ha

lope

rido

l, a

non-

sele

ctiv

e do

pam

iner

gic

anta

goni

st w

ill

bloc

k th

e do

pam

iner

gic

path

way

an

d re

duce

the

effe

ct o

f fi

lice

ne.

The

pos

sibl

e m

echa

nism

of

acti

on o

f th

e an

tinoc

icep

tive

pro

pert

y of

fi

lice

ne w

as in

vest

igat

ed in

mic

e. M

ice

wer

e pr

e-tr

eate

d w

ith

halo

peri

dol

(0.2

mg/

kg,

i.p.)

fol

low

ed 1

5 m

in l

ater

by

fili

cene

(30

mg/

kg,

i.p.)

or

apom

orph

ine

(1.0

mg/

kg, i

.p.)

. The

ana

lges

ic e

ffec

t was

ana

lyse

d 30

min

af

ter

trea

tmen

t w

ith

fili

cene

and

apo

mor

phin

e. R

esul

t sh

owed

tha

t pr

e-tr

eatm

ent

wit

h ha

lope

rido

l re

vers

es t

he a

ntin

ocic

epti

ve e

ffec

t ca

used

by

fi

lice

ne,

sugg

esti

ng

that

an

ti-n

ocic

epti

on

is

depe

nden

t on

th

e do

pam

iner

gic

syst

em.

(De

Sou

za e

t al.,

200

9)

HP

C

atua

ma

[2]

Wis

tar

rats

A

nti-

noci

cept

ion↓

T

he c

ompl

ete

reve

rsal

of

the

anti

-no

cice

ptiv

e ef

fect

of

Cat

uam

a by

ha

lope

rido

l sug

gest

ed th

at th

e an

ti-n

ocic

epti

ve e

ffec

t of

Cat

uam

a de

pend

s on

the

dopa

min

ergi

c re

cept

ors

or tr

adit

iona

l pat

hway

s.

The

ant

i-no

cice

ptiv

e ef

fect

s of

Cat

uam

a on

mec

hani

cal a

llod

ynia

indu

ced

by L

PS

was

eva

luat

ed. R

ats

wer

e pr

e-tr

eate

d w

ith

halo

peri

dol (

1 m

g/kg

, i.p

.),

met

hyse

rgid

e (1

m

g/kg

, i.p

.)

or

yohi

mbi

ne(1

m

g/kg

, i.p

.)

resp

ecti

vely

. C

atua

ma

(200

mg/

kg,

p.o.

) or

sal

ine

0.9%

was

giv

en 1

h

afte

r.

Res

ult

show

ed

that

an

ti-n

ocic

epti

ve

effe

ct

of

Cat

uam

a w

ere

reve

rted

by

pre-

trea

tmen

t w

ith

halo

peri

dol.

Nei

ther

met

hyse

rgid

e no

r yo

hmbi

ne s

igni

fica

ntly

aff

ect t

he a

nti-

noci

cept

ive

effe

cts

of C

atua

ma.

(Qui

ntao

et a

l., 2

008)

HP

L

ithr

ea m

olle

oide

s F

emal

e S

wis

s m

ice

Ant

i-no

cice

ptiv

e ef

fect↑

The

dop

amin

ergi

c sy

stem

may

in

volv

e in

the

antin

ocic

epti

ve

acti

on o

f L

M e

xtra

ct. T

he a

nti-

noci

cept

ion

poss

ibly

rel

ated

to th

e pr

esen

ce o

f sh

ikim

ic a

nd a

vani

llic

ac

id.

The

ant

inoc

icep

tive

eff

ect

of L

ithr

ea m

olle

oide

s (L

M)

aque

ous

extr

act

and

its

isol

ated

com

poun

ds h

as b

een

inve

stig

ated

in m

ice.

Mic

e w

ere

pre-

trea

ted

wit

h ha

lope

rido

l (1

mg/

kg,

i.p.)

30

min

s be

fore

LM

ext

ract

(10

m

g/kg

, i.p

.).

The

noc

icep

tive

res

pons

e w

as e

valu

ated

in

the

acet

ic a

cid-

indu

ced

abdo

min

al

wri

thin

g te

st.

Res

ult

show

ed

that

ha

lope

rido

l en

hanc

ed th

e an

tino

cice

ptiv

e ef

fect

of

LM

.

(Mor

ucci

et a

l., 2

012)

HP

C

edru

s at

lant

ica

Ess

enti

al O

il

Sw

iss

mic

e

Dep

leti

on o

f no

repi

neph

rine

C

AE

O a

ctiv

ated

the

desc

endi

ng

pain

mod

ulat

ion

path

way

s on

the

opio

ider

gic,

ser

oton

ergi

c,

nora

dren

ergi

c an

d do

pam

iner

gic

syst

ems.

Ced

rus

atla

ntic

a es

sent

ial

oil

(CA

EO

) al

levi

ates

pos

tope

rati

ve p

ain.

In

hala

tion

of

CA

EO

(5,

30

or 6

0 m

in)

mar

kedl

y re

duce

d m

echa

nica

l hy

pers

ensi

tivi

ty.

Hal

oper

idol

(1

m

g/kg

, i.p

.)

an

anta

goni

st

of

dopa

min

ergi

c (D

1 an

d D

2) r

ecep

tors

pre

vent

ed t

he e

ffec

t of

CA

EO

on

hype

rsen

siti

vity

.

(Mar

tins

et a

l., 2

015)

43

JAASP 2019; 8: 22–49

Tab

le 5

. Mis

cell

aneo

us

Hal

oper

idol

-HN

Ps

Inte

ract

ion

s on

An

imal

Mod

els

(con

tin

ued

).

Typ

es

Pro

du

ct

Mod

el

Ou

tcom

es a

nd

fin

din

gs

Ref

eren

ce

Mea

sure

men

t M

ech

anis

m

Eff

ect

HP

S

apog

enin

(fr

om

defa

tted

see

ds o

f C

amel

lia

olei

fera

)

Kun

min

g m

ice

Dop

amin

e le

vel i

n st

riat

um↑

Sap

ogen

in a

ctiv

ate

dopa

min

e re

cept

or r

athe

r th

an a

deno

sine

re

cept

or.

Sap

ogen

in p

rote

cted

dop

amin

e ne

uron

s th

roug

h an

ti-n

euro

infl

amm

atio

n an

d ac

tiva

tion

of

dopa

min

e re

cept

or, r

athe

r th

an a

deno

sine

rec

epto

r, a

nd

its

amin

atio

n im

prov

es it

s ph

arm

acol

ogic

al e

ffec

ts.

(Ye

et a

l., 2

014)

HP

M

unti

ngia

cal

abur

a L

eave

s m

ice

and

rat

Ant

i-no

cice

ptio

n

The

ant

i-no

cice

ptio

n ef

fect

of

met

hano

l ext

ract

of

M. c

alab

ura

(ME

MC

) w

as n

ot c

ross

talk

wit

h th

e do

pam

iner

gic

path

way

of

halo

peri

dol.

The

ME

MC

was

pre

pare

d in

the

dos

es o

f 10

0, 2

50 a

nd 5

00 m

g/kg

. The

M

EM

C,

at

all

dose

s,

dem

onst

rate

d a

sign

ific

ant

dose

-dep

ende

nt

anti

noci

cept

ive

acti

vity

in b

oth

the

brad

ykin

in-

and

phor

bol 1

2-m

yris

tate

13

-ace

tate

(P

MA

)-in

duce

d no

cice

ptio

n.

10

mg/

kg

atro

pine

(a

no

n-se

lect

ive

chol

iner

gic

rece

ptor

ant

agon

ist)

, 0.

15 m

g/kg

pra

zosi

n (a

n α1

-no

radr

ener

gic

anta

goni

st)

and

20 m

g/kg

hal

oper

idol

(a

non-

sele

ctiv

e do

pam

iner

gic

anta

goni

st)

did

not a

ffec

t the

ext

ract

's a

nti-

noci

cept

ion.

(Zak

aria

et a

l., 2

014)

F

Asc

orbi

c A

cid

Adu

lt S

wis

s m

ice

Im

mob

ilit

y↑

The

res

ult s

ugge

sted

that

the

anti

-im

mob

ilit

y ef

fect

of

asco

rbic

aci

d pr

obab

ly in

volv

es th

e do

pam

iner

gic

syst

em th

roug

h an

in

tera

ctio

n w

ith

dopa

min

e D

2 re

cept

ors.

The

ef

fect

of

as

corb

ic

acid

in

th

e ta

il

susp

ensi

on

test

an

d fo

rced

sw

imm

ing

test

and

its

int

erac

tion

wit

h th

e m

onoa

min

ergi

c sy

stem

was

in

vest

igat

ed. M

ice

wer

e pr

e-tr

eate

d w

ith

halo

peri

dol (

0.2

mg/

kg, i

.p.)

and

re

ceiv

ed e

ithe

r the

veh

icle

or a

scor

bic

acid

(0.1

mg/

kg, i

.p.)

aft

er 3

0 m

ins.

T

he r

esul

t sho

ws

that

hal

oper

idol

pre

vent

ed th

e an

ti-i

mm

obil

ity

effe

ct o

f as

corb

ic a

cid

in th

e T

ST

.

(Bin

fare

et a

l., 2

009)

F

Vit

amin

E

Mal

e ad

ult

Wis

tar

rats

D

A-s

uper

sen

siti

vity

be

havi

ours↓

The

eff

ect o

f V

itam

in E

on

tard

ive

dysk

ines

ia (

TD

) is

pos

sibl

y du

e to

it

s pr

oper

ties

as

a po

tent

fre

e ra

dica

l sca

veng

er

The

eff

ect

of v

itam

in E

on

halo

peri

dol-

indu

ced

TD

was

eva

luat

ed.

The

ra

ts w

ere

give

n ha

lope

rido

l (0

.05

mg/

kg/d

ay,

i.p.)

for

30

days

. T

he

trea

tmen

t gr

oup

rece

ived

co

ncom

itan

tly

vita

min

E

ri

ch

food

(4

00

mg/

kg/d

ay) s

tart

ed 3

wee

ks b

efor

e th

e ha

lope

rido

l tre

atm

ent u

ntil

the

end

of th

e tr

ial.

All

gro

ups

wer

e ad

min

iste

red

apom

orph

ine

(0.2

5 m

g/kg

, s.c

.).

Apo

mor

pphi

ne-i

nduc

ed

beha

viou

rs

wer

e as

sess

ed:

oral

st

ereo

typi

es,

groo

min

g an

d si

ttin

g. T

he r

esul

t sh

ows

that

Vit

amin

E s

igni

fica

ntly

de

crea

se in

ora

l ste

reot

ypie

s an

d si

ttin

g be

havi

our.

No

sign

ific

ant e

ffec

ts

wer

e ob

serv

ed in

gro

omin

g be

havi

our.

(Gat

taz

et a

l., 1

993)

F

Sac

char

um

offi

cina

rum

M

ale

Wis

tar

rats

Y

awni

ng a

nd g

enit

al

groo

min

g↓

SO

aff

ect t

he n

eura

l cir

cuit

s in

volv

ed w

ith

yaw

ning

and

gen

ital

gr

oom

ing.

Aft

er a

dmin

istr

atio

n of

the

aqu

eous

ext

ract

of

Sac

char

um o

ffic

inar

um

(AE

), t

he y

awns

and

the

gen

ital

gro

omin

g w

ere

quan

tifi

ed a

t 10

min

in

terv

als

duri

ng 1

20 m

in. S

ince

dop

amin

ergi

c an

d ch

olin

ergi

c pa

thw

ays

are

impl

ied

in t

hese

res

pons

es,

AE

wer

e ev

alua

ted

in t

he p

rese

nce

of

halo

peri

dol

0.5

mg/

kg a

nd a

trop

ine

2 m

g/kg

. AE

0.5

g/k

g in

crea

sed

the

yaw

ns, e

ffec

t tha

t was

blo

cked

bot

h by

hal

oper

idol

and

atr

opin

e.

(Gam

beri

ni e

t al.,

201

5)

F

Gre

en T

ea E

xtra

ct

Rat

s

Flu

id, f

ood

inta

ke,

grow

th r

ate↓

, se

roto

nerg

ic

met

abol

ism↑,

do

pam

ine

leve

l↓

Hal

oper

idol

indu

ced

decr

ease

d do

pam

ine

was

incr

ease

d in

the

nucl

eus

accu

mbe

nt w

hen

co-

adm

inis

ter

wit

h gr

een

tea

extr

act

(GT

E).

For

6 w

eeks

, rat

s w

ere

trea

ted

wit

h w

ater

plu

s sa

line

; G

TE

(1

g/L

, p.o

.)

plus

sal

ine;

wat

er p

lus

halo

peri

dol (

1 m

g/kg

, i.p

.); a

nd G

TE

(1

g/L

, p.o

.)

plus

hal

oper

idol

(1

mg/

kg,

i.p.)

, re

spec

tive

ly.

The

res

ults

ind

icat

e th

at

GT

E p

oten

tiat

es h

alop

erid

ol’s

eff

ects

, su

ch a

s de

crea

sed

flui

d, f

ood

inta

ke,

and

grow

th

rate

; in

crea

sed

anxi

ogen

ic

beha

viou

r;

incr

ease

d se

roto

nerg

ic m

etab

olis

m; a

nd d

ecre

ased

dop

amin

e le

vels

as

com

pare

d to

th

e w

ater

-dri

nkin

g gr

oups

. How

ever

, the

stu

dy d

oes

not i

ndic

ate

whe

ther

th

ese

find

ings

are

sta

tist

ical

ly s

igni

fica

nt.

(Mal

ik a

nd H

alee

m,

2012

)

Not

e: [

1] C

onta

ins:

Cyp

eri R

hizo

ma,

Pae

onia

e R

adix

Alb

a, B

uple

uri R

adix

, Chu

anxi

ong

Rhi

zom

a, G

lycy

rrhi

zae

Rad

ix E

t Rhi

zom

a, A

uran

tii F

ruct

us, C

itri

Ret

icul

atae

Per

icar

pium

; [2]

Con

tain

s: T

rich

ila

Cat

igua

, P

aull

inia

Cup

ana,

Pty

chop

etal

um O

laco

ides

and

Zin

gibe

r O

ffic

inal

is.

Abb

revi

atio

n: N

.D: n

ot d

etec

ted;

TC

M: t

radi

tion

al C

hins

es m

edic

ine;

F: f

ood

and

diet

ary

supp

lem

ents

; HP

: oth

er h

erba

l pro

duct

s; i.

p.: i

ntra

peri

tone

al in

ject

ion;

p.o

.: or

al a

dmin

istr

atio

n; i.

v.: i

ntra

veno

us a

dmin

istr

atio

n;

s.c.

: sub

cuta

neou

s in

ject

ion;

i.m

.: in

tram

uscu

lar

inje

ctio

n T

D: t

ardi

ve d

yski

nesi

a; O

D: o

rofa

cial

dys

kine

sia.


44

3.5. Miscellaneous Interactions Besides EPS and catalepsy related effects, there are 29

articles reported on interactions between haloperidol and TCM (4 articles), other herbal products (21 articles), and food and dietary supplements (4 articles) leading to other miscellaneous activities that were summarized in Table 5, including mainly anti-immobility effect, anti-depressant effect and other outcome measures such as sexual stimulating effect, erythropoietic activity, testosterone levels and hypothermic effect.

Administration of haloperidol significantly reversed the anti-immobility effect of ferulic acid, HU-210 (a cannabinoid CB1 agonist), Trichilia catigua, Polygala sabulosa, Salvia sclarea and ascorbic acid, suggesting that the anti-depressant like effects of these HNPs might involve the interaction with dopamine receptors (Binfare et al., 2009; Campos et al., 2005; Capra et al., 2010; Seol et al., 2010; Sivrioglu et al., 2007). On the other hand, lack of interaction with haloperidol in the immobility animal model indicates that the anti-immobility effect of Withania somnifera might not involve the activity of dopaminergic system (Demontis et al., 2011). In addition, the anti-nociceptive properties of the HNPs and their relationship with dopaminergic pathway have been examined. Three HNPs, niga-ichigoside F1 obtained from Rubus imperialis (Rosaceae), Filicene obtained from Adiantum cuneatum and Catuama (consists of hydroalcoholic extracts from Trichila catigua, Paullinia cupana, Ptychopetalum olacoides and Zingiber officinalis) demonstrated a decrease in anti-nociception after co-administration with haloperidol, suggesting such effect might depend on dopaminergic pathway (Ardenghi et al., 2006; De Souza et al., 2009; Quintao et al., 2008). On contrary, the anti-nociceptive effect of Lithrea molleoides was reported to increase with the presence of haloperidol (Morucci et al., 2012).

4. Discussion

With the aim to provide guidance for healthcare professionals to identify potential interactions between haloperidol and HNPs, the current study systematically reviewed evidence from published literature. Based on the fact that utilization of haloperidol requires therapeutic drug monitoring, together with the increased popularity of HNPs, it is important for healthcare providers as well as other clinical/preclinical researchers to acquire comprehensive information on such interactions. In the current review, for the first time, we systematically summarized up-to-date evidence of interactions between haloperidol with HNPs from both pharmacokinetics and pharmacodynamics aspects in primary literature.

We classified the included studies into three categories including haloperidol-induced catalepsy models, EPS related interactions and miscellaneous interactions. Approximately 40% of findings from the included animal studies were on the haloperidol-induced catalepsy models on rats or mice, which

focused on exploring certain properties of the studied HNPs. Another 24% of the included studies focused on EPS related interactions.

The current study only identified nine clinical trials, indicating lack of exploration of clinical utilization of haloperidol co-administration with HNPs. Among the nine clinical studies, three of them had high research qualities and low risk of bias, providing strong evidences on the enhanced antipsychotic effect of Ginkgo biloba co-treated with haloperidol. Other clinical trials, mostly open-labelled pilot studies, could also provide some hints on potential interactions between haloperidol and YGS, Kava extract WS 1490, and a supplement of ω-3 fatty acids, vitamin E and vitamin C. Other studies on herb-drug interaction with haloperidol were all pre-clinical, suggesting various mechanisms of herb-drug interaction of haloperidol. More attention should be received on these proposed mechanisms in further clinical studies.

It is observed that over 98% of the included reports are based on pharmacodynamics interactions and only two clinical trials (no animal study reported) studied the pharmacokinetics-based interactions of haloperidol. Although haloperidol is one of the anti-psychotic drugs that require careful monitoring in clinical practice, limited information was provided on changes in blood/brain concentration of haloperidol after administering HNPs. It is difficult to identify the nature of the summarized interactions without examining whether pharmacokinetic changes or pharmacodynamics interaction served as the leading role which was further illustrated as below:

Haloperidol is mainly metabolized by CYP 3A4 (and

CYP 2D6) in humans and similarly by CYP 3A in rodents (Avent et al., 2006; Igarashi et al., 1995). The CYP3A metabolism of haloperidol generates a pyridinium metabolite 4-(4-chlorophenyl)-1-[4-(4-fluorophenyl)-4-oxobutyl]pyridinium ion (HPP+) (Bloomquist et al., 1994; Eyles et al., 1994). It is suggested that HPP+ is responsible for the severe extrapyramidal side effects of haloperidol, including parkinsonism and tardive dyskinesia, by damaging neurons related to the extrapyramidal motor system (Kawashima et al., 2004; Usuki et al., 1998). The pyridinium metabolite is present in human brain, rat brain and mouse brain after administration of haloperidol and it accumulates in brain particularly after chronic administration (Crowley et al., 2013; Eyles et al., 1996; Igarashi et al., 1995). Since the HPP+ levels that observed in rodent brain overlap the range of those detected in post-mortem human brains following chronic haloperidol treatment, these data from rodent study are relevant to humans (Crowley et al., 2013). It is reported that some first-generation antipsychotic drugs and their active metabolites have slow elimination from human brain, leading to accumulation of drugs and metabolites after

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chronic treatment (Kornhuber et al., 2006). Therefore, to better understand the nature of interactions involving haloperidol, we would like to suggest that it is important to measure the blood concentrations or even brain concentrations at different brain regions relevant to the antipsychotic actions of both the parent drug haloperidol and its metabolite HPP+ in the future interaction studies.

On the other hand, haloperidol has high affinity dopamine D2-like receptors; however, it also possesses considerable affinity to other neurotransmitter receptors including sigma-1 receptor, alpha-1 adrenergic receptor and 5HT2A serotoninergic receptor (Schotte et al., 1996). Therefore, the pharmacodynamics outcome from the interactions between haloperidol with HNPs might not be solely due to the interaction at dopaminergic transmissions. In order to identify the neurotransmitter system(s) involved in the interaction, receptor occupancy should be measured. Receptor occupancy refers to the percentage of available receptors bound to the compound of interest. It can be measured by in vivo or ex vivo methods by using a tracer that selectively bound to the receptor of interest (e.g. raclopride as a specific tracer for D2 receptor). For further details on the importance and methodology of receptor occupancy measurement, readers are referred to a recent review by Schotte et al. (Schotte et al., 1996). By comparing the receptor occupancy levels in the haloperidol-alone group, HNPs group and combination group after the behavioural assessments, the receptor(s) involved in the interaction could be identified and be correlated to the behavioural scores. Moreover, receptor occupancy level could provide insights on whether the haloperidol dose used in the animal study is relevant to human dose. Dopamine D2 receptor occupancy is a translatable biomarker: a therapeutic window of 60% to 80% D2 occupancy of antipsychotics in both rodents and humans (Uchida et al., 2011). Indeed, it is suggested that in many rodent studies the doses of antipsychotics (including haloperidol) administered are not comparable to those in humans, i.e. the receptor occupancy levels achieved in the animals are not comparable to those achieved in patients receiving chronic antipsychotic treatment (Kapur et al., 2003). Most commonly used dosage of haloperidol in animal models included in the current review is 1 mg/kg for both mice and rats, which, according to the U.S. Food and Drug Administration guidance (US Food and Drug Administration, 2005), equivalent to a human dose of 0.08–0.16 mg/kg, lower than the clinical recommended dosage for patients (0.16–0.33 mg/kg assuming patient with a body weight of 60 kg). Moreover, the dosage of haloperidol in articles exploring other outcomes various from 0.05 mg/kg on mice to 12 mg/kg on rats, equivalent to human dose of 0.008–1.92 mg/kg. In addition, majority

of the animal experiments used intraperitoneal injection as the administration route while clinically haloperidol is most commonly given orally or intramuscularly. Such discrepancies in dosage and route of administration may limit the usefulness of these animal data in clinical practice. Variations in extraction methods of the herbs and lack of specific component list and dosage of each component in the studied formulae may also serve as barriers for reproducing the findings of the included articles. Thus, we would like to suggest using receptor occupancy level as guidance on future interaction study designing to provide more reflective evidence on the clinical practice. Considering the long history and popularity of both

haloperidol and HNPs, it is safe to assume that the number of articles identified by the current review is relatively small. Since the current review only covered search results from English databases, it is believed that more evidence might be found in publications in other languages. We conducted a pilot literature search of haloperidol-HNPs interactions in four Chinese databases in 2013, including Chinese BioMedical Literature Database, China Journal Net, Traditional Chinese Medical Database System, and Chinese Medical Academic Conference Database. A total 52 papers were identified in the preliminary key word search and a final of 14 papers were reviewed and considered relevant of the haloperidol-HNPs interactions, including 3 animal studies and 11 clinical trials. Among clinical studies, the haloperidol-HNPs interactions were studied in both adult and pediatric patients. Interestingly all 11 clinical studies reported beneficial effect on the combination use of haloperidol and HNPs. Among these clinical studies, ten of them were observational open-labelled studies without baseline outcome comparison reported, all with Jadad scale at 0 and high risk of bias. Only one double-blind randomized control trial (Jadad score: 4; risk of bias: some concerns) was found, reporting the beneficial effect of the artificial Calculus Bovis Sativus in the combination use with haloperidol on schizophrenic patients (Weng et al., 2010).

In order to gather as much information on the HNPs-haloperidol interaction, the current study included all identified articles regardless of the quality of the studies. However, with large numbers of animal studies and limited high-quality clinical reports identified, it is difficult to provide comprehensive clinical guidance on the haloperidol-HNPs interactions, especially potential adverse event. Other factors such as the herb authentication, extract method, dosage and dosage forms used varied among the articles also added on to the limitation of the current review. Regardless of the limitations, the current review not only is the first systematic summarizations of haloperidol-HNPS inter-actions but also provides insights and guidance in terms of future interaction study design. Both clinical healthcare


46

professionals and preclinical researchers can gather valuable information of the studied interactions from this review.

5. Conclusions

The current review is the first to provide systematically summarised evidence of interactions between haloperidol with HNPs. Such interactions were identified in both animal studies and clinical trials with major outcome measures such as change in level of catalepsy and EPS related symptoms. Healthcare professionals should be cautious while prescribing haloperidol along with HNPs, monitoring and communication with patients about the potential risk of interactions is advised. On the other hand, future preclinical interaction studies between HNPs and haloperidol should consider the pharmacokinetic and pharmacodynamic characteristics of haloperidol in order to obtain translatable information.

Acknowledgements

This study is supported by Hospital Authority of Hong Kong (Reference number: L/M (Q08-040) to HAHO(S)/P/ 45). The authors state no conflict of interest.

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Supplementary Table 1. PRISMA Checklist

Section/topic # Checklist item Reported on page #

TITLE

Title 1 Identify the report as a systematic review, meta-analysis, or both. Page 1

ABSTRACT

Structured summary 2 Provide a structured summary including, as applicable: background; objectives; data sources; study eligibility criteria, participants, and interventions; study appraisal and synthesis methods; results; limitations; conclusions and implications of key findings; systematic review registration number.

Page 2

INTRODUCTION

Rationale 3 Describe the rationale for the review in the context of what is already known. Page 3

Objectives 4 Provide an explicit statement of questions being addressed with reference to participants, interventions, comparisons, outcomes, and study design (PICOS).

Page 3

METHODS

Protocol and registration 5 Indicate if a review protocol exists, if and where it can be accessed (e.g., Web address), and, if available, provide registration information including registration number.

Page 4

Eligibility criteria 6 Specify study characteristics (e.g., PICOS, length of follow‐up) and report characteristics (e.g., years considered, language, publication status) used as criteria for eligibility, giving rationale.

Page 4

Information sources 7 Describe all information sources (e.g., databases with dates of coverage, contact with study authors to identify additional studies) in the search and date last searched.

Page 3

Search 8 Present full electronic search strategy for at least one database, including any limits used, such that it could be repeated.

Table 1

Study selection 9 State the process for selecting studies (i.e., screening, eligibility, included in systematic review, and, if applicable, included in the meta‐analysis).

Figure 1

Data collection process 10 Describe method of data extraction from reports (e.g., piloted forms, independently, in duplicate) and any processes for obtaining and confirming data from investigators.

Page 4

Data items 11 List and define all variables for which data were sought (e.g., PICOS, funding sources) and any assumptions and simplifications made.

Not applicable

Risk of bias in individual studies

12 Describe methods used for assessing risk of bias of individual studies (including specification of whether this was done at the study or outcome level), and how this information is to be used in any data synthesis.

Page 4

Summary measures 13 State the principal summary measures (e.g., risk ratio, difference in means). Not applicable

Synthesis of results 14 Describe the methods of handling data and combining results of studies, if done, including measures of consistency (e.g., I2) for each meta‐analysis.

Not applicable

Page 1 of 2

Supplementary Table 1. PRISMA Checklist (continued)

Section/topic # Checklist item Reported on page #

Risk of bias across studies 15 Specify any assessment of risk of bias that may affect the cumulative evidence (e.g., publication bias, selective reporting within studies).

Page 4

Additional analyses 16 Describe methods of additional analyses (e.g., sensitivity or subgroup analyses, meta-regression), if done, indicating which were pre‐specified.

Not applicable

RESULTS

Study selection 17 Give numbers of studies screened, assessed for eligibility, and included in the review, with reasons for exclusions at each stage, ideally with a flow diagram.

Figure 1

Study characteristics 18 For each study, present characteristics for which data were extracted (e.g., study size, PICOS, follow-up period) and provide the citations.

Page 6 Table 2-5

Risk of bias within studies 19 Present data on risk of bias of each study and, if available, any outcome level assessment (see item 12). Page 4 Table 4

Results of individual studies 20 For all outcomes considered (benefits or harms), present, for each study: (a) simple summary data for each intervention group (b) effect estimates and confidence intervals, ideally with a forest plot.

Page 4-6

Synthesis of results 21 Present results of each meta-analysis done, including confidence intervals and measures of consistency. Not applicable

Risk of bias across studies 22 Present results of any assessment of risk of bias across studies (see Item 15). Page 4 Table 4

Additional analysis 23 Give results of additional analyses, if done (e.g., sensitivity or subgroup analyses, meta-regression [see Item 16]). Not applicable

DISCUSSION

Summary of evidence 24 Summarize the main findings including the strength of evidence for each main outcome; consider their relevance to key groups (e.g., healthcare providers, users, and policy makers).

Page 7

Limitations 25 Discuss limitations at study and outcome level (e.g., risk of bias), and at review-level (e.g., incomplete retrieval of identified research, reporting bias).

Page 8

Conclusions 26 Provide a general interpretation of the results in the context of other evidence, and implications for future research. Page 8

FUNDING

Funding 27 Describe sources of funding for the systematic review and other support (e.g., supply of data); role of funders for the systematic review.

Page 8

From: Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009). Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement. PLoS Med 6(7): e1000097. doi:10.1371/journal.pmed1000097

For more information, visit: www.prisma‐statement.org.

Page 2 of 2

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