VOL 21, NO. 3, 1995 The Epidemiology ofDrug-Induced Akathisia:Part I. Acute Akathisia

431

by Permlnder Sachdev Abstract

This article reviews the epidemi-ological data on drug-inducedacute akathisia, examining stud-ies in which akathisia was theprimary focus as well as thosein which it was one of a num-ber of drug side effects studied.The studies are diverse in meth-odology and suffer from manylimitations. Incidence rates foracute akathisia with conventionalneuroleptics vary from 8 to 76percent, with 20 to 30 percentbeing a conservative estimate;preliminary evidence suggeststhat the newer atypical antipsy-chotic drugs are less likely toproduce acute akathisia. A num-ber of nonneuroleptic drugs—inparticular the serotonin-specificreuptake inhibitors—have beenimplicated in the development ofakathisia, but the epidemiologicaldata are limited. Risk factors forneuroleptic-induced akathisia arenot completely understood. Drugdose, rate of increment of dose,and drug potency seem to be im-portant, but the role of socio-demographic factors and othertreatment-related variables ismodest. Drug-induced parkinson-ism is significantly correlatedwith akathisia. Evidence for irondeficiency as a risk factor is con-flicting, and its contribution islikely to be minor.

Schizophrenia Bulletin, 21(3):431-449, 1995.

Epidemiology, with its descriptionof the population affected by anillness and the identification ofpossible risk factors, often lies atthe heart of treatment and pre-vention programs. Drug-inducedakathisia is considered a poorlyunderstood side effect of psycho-tropic drugs and is often referred

to as the "Cinderella" of psychia-try (Stahl 1985). Since a number ofstudies have now been publishedthat examine its incidence, preva-lence, and risk factors, it is appro-priate to review these studies and,thus, the current status of the epi-demiology of akathisia. For thispurpose, we have classified akathi-sia into acute, tardive, and with-drawal subtypes (Sachdev 1994b).Part I of this review deals withacute akathisia, examined in rela-tion to both neuroleptic and non-neuroleptic drugs; the accompany-ing article, Part II, deals withchronic akathisia, tardive akathisia,and withdrawal akathisia, as wellas with akathisia in special popu-lations. Acute akathisia refers tothe onset of akathisia within hoursor days of drug initiation, increasein dose, or change in type ofdrug. For neuroleptics, the onsetis almost always within the first6 weeks (Ayd 1961), and our pro-posed criteria consider onset after3 months as a tardive onset(Sachdev 1994fc).

A review of akathisia studies en-counters the following limitations.First, most early investigationslumped akathisia together withother extrapyramidal reactions.Some early authors (e.g., Freyhan1958; Ayd 1961) did attempt todescribe akathisia separately, but itwas not until the mid-1970s thatakathisia received serious attentionin its own right, and it was in the1980s that incidence and preva-lence estimates became availablefrom well-conducted studies. Sec-ond, until recently, no definite di-agnostic criteria for akathisia had

Reprint requests should be sent toDr. P. Sachdev, Neuropsychiatric In-stitute, The Prince Henry Hospital,P.O. Box 233, Matraville, NSW 2036,Australia.

432 SCHIZOPHRENIA BULLETIN

been proposed. In many studies(e.g., Ayd 1961; Hunter et al. 1964;Kennedy et al. 1971), a clinical di-agnosis was made but the processof diagnosing was not specified.Even when rating scales wereused (e.g., Levinson et al. 1990;Rifkin et al. 1991), it was often notspecified whether both subjectiveand objective features were consid-ered necessary for the diagnosis.The reliability and validity ofmany of the scales have not beenadequately examined. One groupof investigators (Van Putten et al.1974) used a positive response toparenteral biperiden, an acetylcho-line antagonist, as the diagnosticcriterion for akathisia, but this hasnot been independently replicated.Only somewhat recently have op-erational diagnostic criteria beenproposed (Burke et al. 1987; Lang1994; Sachdev 1994b), and it ishoped that future epidemiologicalstudies will give due regard tothese criteria in arriving at inci-dence and prevalence estimates.Third, the majority of the pub-lished epidemiological studies havenot taken into consideration thevarious subtypes of akathisia. Sincethe pathophysiology, pharmacolog-ical characteristics, longitudinalcourse, and prognosis of the sub-types may be distinct (Sachdev1994b), it is necessary to considerthe epidemiological characteristicsseparately. In this review, we haveattempted to subtype the akathisiadescribed in each study accordingto the descriptions provided bythe investigators and using thedefinitions described elsewhere(Sachdev 1994b) as applicable.Where the descriptions were inad-equate, we applied a best guessand stated this in the descriptionsso that firm conclusions are notdrawn from such studies. In somecases, while it can be confidently

stated that most subjects belongedto a particular subtype, this cannotbe assumed for the entire popula-tion; such studies are included inthe section appropriate for themajority. Fourth, a distinction hasnot always been made betweenthe incidence and the prevalenceof akathisia. One difficulty in com-paring and contrasting incidenceand prevalence rates stems fromthe fact that the natural history ofakathisia is poorly understood. Itis not certain at what point acuteakathisia becomes chronic, andwhether this is different fromchronic akathisia of tardive orwithdrawal onset. Barnes andBraude (1985) attempted to distin-guish acute akathisia that tendedto persist and yet retain its phar-macological characteristics fromtardive akathisia, and they called it"acute persistent akathisia." Whilethis may be a reasonable distinc-tion to make in a longitudinalstudy, its validity in retrospectiveanalyses is questionable because ofthe difficulty in establishing thatakathisia had been continuouslypresent since its acute onset. Thepublished literature therefore pre-sents a mix of incidence and prev-alence data.

Types of Studies

The above limitations notwith-standing, the following types ofstudies that deal with the epidemi-ology of akathisia can be identi-fied.

Studies in Which Akathisia Wasthe Primary Focus of an Epide-miological Investigation. Ex-amples of this are studies by VanPutten (1975), Braude et al. (1983),Van Putten et al. (1984b), andSachdev and Kruk (1994). The

ideal design of a study to examinethe incidence of akathisia is aprospective longitudinal study ofpatients treated with a particularneuroleptic or with other psycho-tropic drugs, and of control sub-jects not treated with any suchdrugs. Since neuroleptics are usedto treat serious mental illness, anuntreated psychiatric control groupis usually not possible. Further,since akathisia is by definition adrug-induced state, a controlgroup may indeed not be neces-sary, provided a baseline examina-tion has excluded subjects withakathisia-like syndromes. Becauseneuroleptic dose and the rate ofits increment are potentially impor-tant for the development of akathi-sia, only those studies that use"clinical" doses and the usualroutes of administration are clin-ically relevant. Single-dose chal-lenge studies (e.g., Magliozzi etal. 1985) may serve the importantfunction of identifying risk factorsfor akathisia, but the incidencerates obtained from such studieshave limited clinical relevance. Re-viewing patient charts and inter-viewing patients for past historyof akathisia, as is done in retro-spective studies, are likely to bepoor epidemiological methods forthis disorder because akathisia isoften underrecognized clinicallyand patients have difficulty dis-tinguishing it from restlessness dueto other causes. Thus, a prospec-tive design is essential if pre-disposing factors to akathisia haveto be studied.

Studies That Focused on "SideEffects of Drugs," With Akathi-sia One of Many Side EffectsStudied. The classic article byAyd (1961) is an example of sucha study. The advantage of thiskind of investigation is that it can

VOL 21, NO. 3, 1995 433

place akathisia in relation to otherside effects and thus examine therelative vulnerability factors aswell as the burden. However, thelack of focus leads to a compro-mise on diagnostic rigor, and pre-disposing factors often cannot beadequately assessed.

Studies Primarily to InvestigateClinical Aspects of a Drug, WithAkathisia, to Some Extent an In-cidental Observation. Examplesare studies designed to comparedifferent doses of neuroleptics(e.g., Levinson et al. 1990; VanPutten et al. 1990; Rifkin et al.1991) or to examine the clinicalprofile of a new drug in com-parison with that of an earlierestablished one (e.g., Claghorn etal. [1987] and Cohen et al. [1991]for clozapine) or of a nonneurolep-ric drug not generally known toproduce akathisia (e.g., Goff et al.[1991] for buspirone).

Incidence and Prevalence ofAcute Akathisia

Freyhan (1957) examined for extra-pyramidal side effects (EPSE) allpatients who were treated witheither chlorpromazine or reserpineover 2 years in his hospital. Whilehe did not use the term "akathi-sia," he described patients who"complained of inner restlessnessand have at rimes an irresistibleurge to be in motion ... reminis-cent of the hyperkinetic behaviourof encephalitic patients" (p. 466).This reaction was seen in 6 to 8percent of the reserpine patientsbut in none of the chlorpromazinepatients. In another study, Freyhan(1959) made explicit the term"akathisia" and also said he be-lieved that "the various referencesto 'paradoxical reactions' or 'tur-bulent phases' are descriptions

of the syndromes of akathisia"(p. 582). He reported slightly dif-ferent prevalence rates forakathisia resulting from differentphenothiazines: trifluopromazine(sample n - 25) 12 percent; pro-chlorperazine (n = 68) 19.1 per-cent; rrifluoperazine (n = 65) 12.3percent; and perphenazine (n = 22)9.1 percent. However, equivalentdoses, as we now recognize them,for the different drugs were notused.

The largest survey of drug-induced EPSE was that of FrankAyd, Jr. (1961), who examined3,775 subjects (1,833 men and 1,942women) between the ages of 4and 88 years who had beentreated with one of seven phen-othiazines for periods rangingfrom 3 months to 6 years.Akathisia, which was described as"motor restlessness," was diag-nosed in 21.2 percent of the sub-jects (compared with parkinsonismin 15.4% and dyskinesia—largelyacute dystonia—in 2.3%). The diag-nosis was clinical, and no ratingscale was used. Akathisia devel-oped slightly before the EPSE, and90 percent of the cases occurred inthe first 72 days after initiation ofdrugs. The onset was earlier andat smaller doses as the potencyof the offending drug increased.No demographic or other drug-related vulnerability factors wereidentified.

Van Putten and his colleagueshave reported a number of studiesin which they diagnosed akathisiaif subjective restlessness was pres-ent and the subject responded tochallenges with an anticholinergicdrug. Van Putten et al. (1974) ex-amined 80 consecutive hospital ad-missions to study phenothiazine-induced exacerbations of psychosis.Nine patients (11%) had suddendecompensations, and all of them

had akathisia, sometimes subtleand evanescent, which could bereversed by an intramuscular injec-tion of biperiden—an observationthat needs independent replication.Twenty-three other patients (29%)had EPSE (akathisia, parkinsonism,or dystonia). All nine patientsbeing treated with fluphenazineenanthate had akathisia. In anotherstudy by the same author (VanPutten 1975), 110 inpatients onneuroleptics were examined. Thesubtype of akathisia was not spec-ified but presumably was largelyacute. Akathisia was diagnosed in49 inpatients (45%), with the man-ifestations being very variable.

The study by Van Putten et al.(1984a) is of interest because of itsmethodological rigor. Subjects wereacutely challenged with either5 mg haloperidol (n = 44) or0.22 mg/kg thiothixene (n •= 67)and were examined over the next6 hours for the development ofakathisia. The haloperidol groupwas then maintained on 10 mg/day and the thiothixene group on0.44 mg/kg/day of the same drugand followed up over the next 4weeks. In the haloperidol group,17 (39%) developed akathisia afterthe acute challenge (5 mild, 5moderate, 3 severe, 4 very severe),and by the seventh day of main-tenance therapy, 31 (70%) haddeveloped it. In the thiothixenegroup, 13 (20%) developed akathi-sia acutely, but if the 7 who re-ceived an anticholinergic drug fordystonia are excluded from anal-ysis, the figure becomes 22 per-cent. Over the next 4 weeks, thecumulative percentage of thosewith akathisia rose to 63 percent.

A few studies have been pub-lished that examined the develop-ment of akathisia in response toneuroleptic administration in non-psychiatric populations. Murray et

434 SCHIZOPHRENIA BULLETIN

al. (1977) performed a double-blindcrossover study of haloperidol instuttering and found that 8 out of26 patients had poor concentration,akathisia, or dystonia. WhenMagliozzi et al. (1985) adminis-tered intravenous or oral haloperi-dol to normal subjects, 8 of the 12subjects in the intravenous groupand 3 of the 9 subjects in the oralgToup developed akathisia. Noother risk factors were identified.

A number of studies whose pri-mary focus was the comparisonof different doses of neurolepticdrugs have also reported on ratesof akathisia. Only a few suchstudies that make a dear state-ment on akathisia will be men-tioned. McClelland et al. (1976)conducted a double-blind trial of 6months' duration to compare veryhigh dose (250 mg weekly) withstandard dose (12.5 mg weekly) offluphenazine decanoate in 50 pa-tients ages 18 to 60. By the 24thweek, 22 percent in the high-doseand 9 percent in the standard-dosegroups had developed akathisia.No specific akathisia rating scalewas used. The side effect wasmild, however, and only one pa-tient in the high-dose groupneeded treatment. Van Putten etal. (1990) compared three doses ofhaloperidol (5, 10, or 20 mg perday) over 4 weeks in acute or re-lapsing schizophrenia and meas-ured akathisia on a 7-point scale(May et al., unpublished manu-script 1983). Although the inci-dence of akathisia was not stated,there was a significant differencebetween the 5- and 20-mg groups,with the latter tending to havemore akathisia. Levinson et al.(1990) conducted a randomized,fixed-dose, double-blind trial oforal fluphenazine, and they used amodified version of the Simpsonand Angus (1970) rating scale to

include a rating for akathisia. Ofthe 51 patients who did not re-ceive any antiparkinsonian drugs,22 (43%) developed akathisia, typ-ically after 2 to 3 weeks of treat-ment. Patients with akathisiatended to have a worse outcomefor their psychosis. Rifkin et al.(1991) conducted a randomizedtrial to compare three doses ofhaloperidol (10, 30, and 80 mg; n— 29 in each group), again usingthe modified Simpson and Angus(1970) rating scale. Akathisiashowed a nonsignificant trend to-ward worsening over time in the10- and 80-mg groups, but thethree doses did not differ overallin the relative risks for akathisia.Any akathisia present was mild.

An important "naturalistic"study that examined the epidemi-ology and clinical features of acuteakathisia was that by Braude andcolleagues (1983). The authors sys-tematically examined at baselineand at least at weekly intervals104 patients (30 men, 74 women)who were consecutively admittedto a psychiatric ward and who re-quired antipsychotic medication.The detailed symptoms ofakathisia were rated, and a diag-nosis of akathisia was made in 25percent of the subjects. The studyhad some limitations, however.First, many patients were not drugfree at the time of admission (al-though the authors do not providefigures on this). However, onlyone patient was assessed to be"restless" at admission and wasexcluded from the final figures.Second, antiparkinsonian medica-tion was not controlled, and theauthors do not state how manypatients received anticholinergic orbeta-adrenergic antagonist drugs.This would certainly affect the in-cidence figures. But despite theselimitations, this study remains one

of the more influential studies inthis field.

Sachdev and Kruk (1994) ex-amined 100 consecutive inpatientswho had nonorganic psychotic dis-orders, were not currently on neu-roleptic or other drugs, and werefree of akathisia and related disor-ders at admission. They assessedthese patients for psychiatric statusand movement disorders at base-line and daily for 2 weeks afterthe initiation of a neuroleptic. Theauthors used different sets of diag-nostic criteria to demonstrate thatthe incidence varied with the par-ticular criteria used. When theyused a global rating, 40 percent ofthe subjects developed at leastmild akathisia and 21 percent de-veloped moderate to severe akathi-sia. When the proposed researchcriterion of a rating of 2 or moreon the sums of both the subjectiveand the objective items of theakathisia rating scale (Sachdev1994a) were used, 31 percent werediagnosed with akathisia. Thisstudy addresses some of the defi-ciencies of previous studies, withits limitation being that systematicexamination was restricted to 2weeks after drug initiation. Since85 percent of subjects in theBraude et al. (1983) study and themajority of subjects in the VanPutten et al. (1984a) study devel-oped akathisia in the first weekafter initiation of medication, theSachdev and Kruk (1994) figuresare unlikely to be a gross under-estimate. The latter authors alsoexamined a number of predispos-ing factors to acute akathisia. Thefactors that most significantly pre-dicted the development of akathi-sia were the severity of extrapy-ramidal symptoms such as rigidityand tremor, the current neurolepticdose and its rate of increment,with lesser contributions being

VOL. 21, NO. 3, 1995 435

made by the drug potency (morewith higher potency drugs) and alow serum iron level. Predictabilityof akathisia in an individual pa-tient was, however, modest.

These results and those of someother relevant studies are pre-sented in table 1.

The diversity of the studies doesnot permit a confident statementon the incidence and prevalence ofacute akathisia. The publishedrates for the conventional neuro-leptics vary from 8 percent (Mc-Creadie et aJ. 1988) to as high as76 percent (Van Purten et al.1984a). To have clinical relevance,the rates should pertain to com-monly used neuroleptic drugs atdosages and rates of incrementthat are applied in clinical practice.The incidence rates of 25 percentreported by Braude and colleagues(1983) and of 31 percent (21% to40% with different criteria) re-ported by Sachdev and Kruk(1994) are relevant in this context.When at least moderate severitywas considered, an incidence of 21percent was reported in the latterstudy. This figure is consistentwith the 21.2 percent prevalencefigure of Ayd (1961), who reportedthe largest survey, although thediagnosis of akathisia in the Aydstudy was much less rigorous. Aconservative estimate of incidenceof akathisia with classical neuro-leptics at clinical doses, therefore,is 20 to 30 percent, but as is dis-cussed later, this rate is signifi-cantly affected by treatment-relatedand other variables. For example,parenteral administration, potencyof the drug, initial dose used, etc.,will all affect the rate of akathisia.The highest rates are supported inintravenous challenge studies (VanPutten et al. 1984a; Magliozzi et al.1985). A distinction between inci-dence and prevalence rates can be

CO

CO©

CO

I(0..£

his

kat

CO

role

ptic

-indu

ced

CD

c

2

les

of

ac

ust

u

co

logi

cem

lo

a.

CD

CO

CO

»ODC

•2.

3Q

"o

Def

init

ion

cCD

Com

m

-^»

C

rou

te

m

akat

hls

l;Io

n

•

Po

pi

iors

lisia

ath

CO

tions

COO)toCD>c

£-m

rim

;

omwQ.CO

QcCDQ .

2>

CO

in

oJI

Mul

tiple

/ora

lre

-S

ubje

ctiv

e,ric

.2

Psy

cl

in

O)

utte

n 1

0 .

cCO

CD

CJCO

> *CD

P

•b"

ifie

bi-

spon

se t

o

cocCD

inpa

tiperid

in i

.v.

CO

iti

c

COCDCO

two

pha

CO

— •

Hal

oper

idol

,re

-S

ubje

ctiv

e,

^

Hea

ltal

.

OD

utte

n,

Q.

cCO

>

cCD

CDO

chal

len

i.v.

COCO

1^CO

•ffl

thio

thix

ene/

i.v.,

or

bi-

spon

se t

oct

ssu

bje

COTj-CDCJ)

CO

CDCD

Bd fo

r 4

CO3

phas

espe

ridin

i.v

.

1

CO

• " "

"5

Hal

oper

idol

/i.v.

, oi

CD

Not

sp

ecifi

Hea

lt

CO

00

ag"5)CO

?-2-CJ)

cts

subj

e

m00CJ)

co"5w

CO

*

stem

atic

co"

inC\J

o

Mul

tiple

/ora

lan

dS

ubje

ctiv

e:ri

c

.2r -

Psy

cl19

83

CO

a>

w- Q

3CO

CD

' st

udy

tic1

obje

ctiv

e

UJ

CD

inpa

ti

1

CO

oo

Cla

ssic

alan

dS

ubje

ctiv

e:ri

c

.2

Psy

cl(r

uk

.«_TJCCO

CDT3^OCO

CO

neur

olep

tics

co

vario

obje

ctiv

e (

crite

ria)

co

CD

inpati

CJ)o

COco

' c

that

in

clud

ed a

katl

IJ9U9

effe

cts

(in g

CD

-aCO

CD

indu

ele

ptic

-

2

of n

eu

COCD

tud

C

°• •CO"co

d ak

athi

Mil

oin

Flu

phen

azin

e d

ec

Clin

ical

:ric

.2

Psy

cl

CO

Han

d e

CD

:CI

\v

<D

C. .

9 pa

tien

o

anoa

tedi

agno

sis

£

patie

i

CO

r~CJ)

atm

ent

£

CMeg

CO

250

mg

wee

kly

vi

CJ)

E

12.5

m

g w

eekl

y/i.

CO

Tab

le 1

. E

pid

emlo

log

ical

st

ud

ies

of

acu

te n

euro

lep

tlc-

ind

uce

d

akat

hls

ia:

Su

mm

ary

resu

lts—

Co

nti

nu

edCO

Au

tho

rs

Mur

ray

et a

l. 19

77

Levi

nson

et

al.

1990

McC

read

ie e

t a

l.19

88

Lind

str6

m

et a

l.19

90

And

erse

n et

al.

1990

Van

P

utte

n et

al.

1990

Rifk

in e

t a

l. 19

91

Po

pu

lati

on

Stu

ttere

rs

Psy

chia

tric

patie

nts

Psy

chia

tric

patie

nts

Psy

chia

tric

patie

nts

Psy

chia

tric

patie

nts

Sch

izop

hren

iapa

tient

s

Psy

chia

tric

patie

nts

Stu

dies

of

ther

apeu

tic

drug

effe

cts,

Fre

yhan

19

59

Ayd

196

1

Van

P

utte

n et

al.

1974

Psy

chia

tric

patie

nts

Psy

chia

tric

patie

nts

Psy

chia

tric

inpa

tient

s

Def

init

ion

of

akat

hls

ia

Clin

ical

Rat

ing

scal

e

Not

st

ated

Not

st

ated

Not

st

ated

Rat

ing

scal

e

Rat

ing

scal

e

with

aka

this

ia

also

Clin

ical

diag

nosi

s

Clin

ical

diag

nosi

s

Sub

ject

ive,

re-

spon

se t

o b

i-pe

ridin

i.v

.

Dru

g(s

)/ro

ute

Hal

oper

idol

/ora

l

Flu

phen

azin

e/or

al

Thi

orid

azin

e vs

.re

mox

iprid

e/or

al

Hal

oper

idol

vs.

rem

oxip

ride/

oral

Hal

oper

idol

vs

.re

mox

iprid

e/or

al

Hal

oper

idol

5 vs

. 10

vs.

20

mg/

oral

Hal

oper

idol

10,

30

, a

nd

80 m

g

n 26 51

?

48 48 32 39

22+

38 +20 29

each

gr

oup

asse

ssed

(se

lect

ed s

tudi

es)

Tri

fluop

eraz

ine,

proc

hlor

pera

zine

,tr

ifluo

prom

azin

e,pe

rphe

nazi

ne/o

ral

7 or

al/p

heno

thia

-zi

nes

Mul

tiple

dr

ugs/

oral

65 68 25 22

3,77

5 80

Res

ult

s(%

)

< 30 43 8 57 32 68 32

1

12.3

19.1

12 9.1

21.2

> 11

Co

mm

ent

Poo

r co

ncen

trat

ion,

akat

hisi

a, a

nd d

ys-

toni

a in

clud

ed

Typ

ical

ly

afte

r 2

-3w

eeks

of

trea

tmen

t

Mor

e se

en w

ith r

e-m

oxip

ride

4%

— — Mor

e w

ith 2

0 m

g

Usu

ally

m

ild;

no

dif-

fere

nce

amon

ggr

oups

Ope

n st

udy;

"par

adox

ical

re

ac-

tions

" co

nsid

ered

to

be a

kath

isia

; dr

ugdo

ses

not

equi

vale

nt

Larg

est

open

st

udy

Phe

noth

iazi

ne-

indu

ced

exac

erba

-tio

ns

stud

ied

prim

arily

O5 o 8 m 2 W c m

VOL. 21, NO. 3, 1995 437

made in some studies, but sinceacute akathisia is of short durationin most of these studies, the dis-tinction is not of great clinical im-portance. Most investigators willagree that acute akathisia, alongwith parkinsonism, is one of themost common side effects ofneuroleptic drugs.

Akathisia Induced bySpecific Drugs

A number of published studieshave reported the prevalence ofakathisia in patients treated withspecific drugs other than conven-tional neuroleptics. A summary ofthese studies is presented in tables2 and 3. Some notable examplesare discussed here.

Akathisia Related to Newer Anti-psychotic Drugs. Studies thathave examined akathisia secondaryto the newer antipsychotics are ofparticular interest because of thedifferent pharmacological profilesof these drugs and the fact that,unlike the conventional neurolep-tics, many of these drugs are notpotent dopamine D2 receptorantagonists.

Clozapine is one such drug withan atypical profile, being a rela-tively weak D2 antagonist but amore potent serotonin 5HT2 andadrenergic a, antagonist, as wellas a D4 antagonist (Peroutka andSnyder 1980; Lee and Tang 1984;Richelson and Nelson 1984). Cloza-pine is associated with a low inci-dence and severity of EPSE (Gag-horn et al. 1987; Kane et al. 1988).The literature with regard to aka-thisia is somewhat inconsistent.Much of the earlier literature sug-gests that clozapine produces littleakathisia (Gerlach 1991) except atthe highest doses in vulnerable pa-tients (Casey 1989). Claghorn et al.

Table 2. Acute akathisia induced by specific newerantipsychotic drugs: Summary results

RateDrug and authors Comment

Clozapine

Claghorn et al. 1987Cohen et al. 1991Sandoz Pharmaceutical

Corporation 1991Safferman et al. 1992

Remoxipride

Lund Laursen and Gerlach1986

Farde et al. 1988210 mg/day420 mg/day

McCreadie et al. 1988Lindstrom et al. 1990Andersen et al. 1990

Sulpiride

Robertson et al. 1990Lepola et al. 1989Munk-Andersen et al. 1989

Amisulpiride

Mann et al. 1984

Metoclopramide

Jungmann and Schoffling 1982

6.7 Similar to chlorpromazine (5.3%)39 Usually mild

3 Product insert (n = 842)0 Akathisic patients (n = 21)

30 Median dose 600 mg/day

0 Over 4 days81

4 Comparison with thioridazine32 Comparison with haloperidol36 Comparison with haloperidol

7.9 Open study8.7 Comparison with perphenazine

44 Comparison with haloperidol

21.5 Open study

25 Single dose (10 mg i.v.) study

(1987), in a double-blind compari-son of clozapine and chlorproma-zine, reported that, contrary toexpectation, clozapine producesakathisia as frequently as chlorpro-mazine does (6.7% vs. 5.3%, re-spectively). Cohen et al. (1991), ina naturalistic study, assessed 23patients receiving clozapine forakathisia using the Chouinard etal. (1980) scale for assessment, andcompared these patients with 29control patients receiving a stand-ard neuroleptic. Using a total scoreof 3 or more (maximum possible= 9) to diagnose akathisia, theyfound that 39 percent of the cloza-pine group and 45 percent of the

control group had akathisia. Themean (standard deviation [SD])ratings for the two groups were2.17 (SD = 1.8) and 2.41 (SD -2.6), respectively. However, thosewith severe akathisia (a score of 6or more) tended to be more com-mon in the control group (14%)than in the clozapine group (9%).In this study, patients were notrandomly allocated to differenttreatments, and the dose equiva-lence of the treatments was notcertain. The package insert forclozapine reports an akathisia rateof 3 percent in 842 patients(Sandoz Pharmaceutical Corpora-tion 1991). Safferman et al. (1992)

438 SCHIZOPHRENIA BULLETIN

Table 3. Akathisia induced by nonneuroleptk drugs

Drug Authors Rate (%) Comment

Serotonin-reuptake inhibitors

Fluoxetine

Sertraline

Serotonin antagonists

CyproheptadineMethysergideBuspirone

Heterocyclic antidepressants

Tricyclics + estrogenTricyclicsAmoxapine

Anticonvulsants

Carbamazepine

Ethosuximide

Calcium channel antagonists

DiltiazemFlunarizine

Cinnarizine

Mood stabilizing drugs

Lithium carbonate

Lipinski et al. 1989

Eli-Lilly Pty. Ltd. 1993Maany and Dhopesh 1990Klee and Kronig 1993Settle 1993

Calmels et al. 1982Bemick 1988Ritchie et al. 1988Patterson 1988

Krishnan et al. 1984Zubenko et al. 1987Barton 1982Shen 1983Hullett and Levy 1983

Schwarcz et al. 1986Milne 1992Ehyai et al. 1978

Jacobs 1983Kuzuhara et al. 1989Chouza et al. 1986Meyboom et al. 1986Micheli et al. 1987Gimenez-Roldan and

Mateo 1991

Channabasavanna andGoswami 1984

Price and Zimmer 1987

9.8-25

10—150

Open study (only 20/51 systematicallyexamined)

Anxiety, nervousness, and insomnia23 patients in open studySingle case reportSingle case report

Single case reportSingle case reportSingle case reportSingle case report

3 patients reportedMultiple case reports4 cases of agitation3 cases9 cases

Single case with left temporal lobe injury2 patients2 cases with questionable akathisia

Single patient5 patients2 patientsSingle caseSingle case

Single caseSingle case

recently examined the impact ofclozapine on patients with (n •=21) and without (n - 49) akathisiaat baseline after a 2-week washoutperiod. Patients who did not haveakathisia at baseline (acute or tar-

dive) did not develop it duringthe 1 year of treatment withclozapine (mean dose = 565 mg/day). Those with akathisia, whichwas possibly a mixture of acuteand tardive akathisia and/or agita-

tion, improved considerably in thefirst 3 weeks and then continuedto improve over 3 months, eventhough the dosage of clozapinewas increasing. This finding is incontrast to findings in the

VOL. 21, NO. 3, 1995 439

Claghom et aJ. (1987) and Cohenet aJ. (1991) studies, which the au-thors argue, were deficient in notassessing akathisia adequately atbaseline in that they may have in-cluded tardive akathisia, or thecarryover effect of acute akathisia,as being caused by clozapine.Their own study, however, suf-fered from the limitation of a 50-percent dropout over the year (al-though no patients were with-drawn because of EPSE) and theuse of a modified Simpson andAngus (1970) rating scale for thediagnosis of akathisia, which isless than optimal for suchpurposes.

It is, therefore, difficult to give adefinite rate of akathisia secondaryto clozapine. The rate for the largenumber of patients enrolled in theSandoz Pharmaceutical Corporation(1991) trials, as well as the find-ings from the Safferman et al.(1992) study, suggests that akathi-sia may be relatively uncommon.The latter study also suggests thatclozapine may even permit recov-ery from chronic akathisia due toconventional neuroleptics. How-ever, the conflicting evidence pre-sented by Claghorn and associates(1987) and especially by Cohenand associates (1991) argues forfurther examination of the issue.

A number of recently introducedsubstituted benzamides are effec-tive antipsychotics but have anatypical side effects profile (LundLaursen and Gerlach 1986; An-dersen et al. 1990). Remoxipridehas been investigated with regardto akathisia. Lund Laursen andGerlach (1986) treated 10 patientswith a median dose of remoxi-pride of 600 mg/day (range: 300-1,200) and reported akathisia in 3patients, with a mean rating of 1.6on the St. Hans Hospital raringscale (rating 0-6). Farde et al.

(1988) administered remoxipride attwo dosage levels—70 and 140 mgt.i.d.—for 4 days. The drug waswell tolerated at the lower dose,but the higher dose resulted inakathisia in 7 of 8 subjects.McCreadie et al. (1988) comparedremoxipride (75-375 mg) with thio-ridazine (150-759 mg) in a double-blind study of acute schizophrenia.Although the method of assess-ment was not stated, akathisia wasdiagnosed in 8 percent of thiorida-zine patients and in 4 percent ofremoxipride patients, with the syn-drome in the latter group beingreportedly more severe. In a multi-center, double-blind comparison ofthe effects of remoxipride andhaloperidol, akathisia was noted tobe less common with the former.Lindstrom et al. (1990) reportedthat in their study (n — 48 in eachgroup), akathisia occurred in 32percent of the remoxipride patientsand 57 percent of the haloperidolpatients (p < 0.05). Andersen et al.(1990) reported a 36-percent inci-dence with remoxipride (n - 39)and a 68-percent incidence withhaloperidol (n - 32). The methodof diagnosis of akathisia was againnot specified.

Another drug from this groupthat has received increasing atten-tion is sulpiride. In an open study,Robertson et al. (1990) treated 63patients suffering from Tourette'ssyndrome with sulpiride and re-ported that 5 patients (8%) devel-oped akathisia (1 of the 26 whodiscontinued the drug and 4 ofthe 37 who continued it). Theysuggested that the drug was bettertolerated on this count than theconventional neuroleptics. In adouble-blind study, Lepola et al.(1989) compared sulpiride withperphenazine in schizophrenia.Two of 23 in the sulpiride group,and 6 of 23 in the perphenazine

group developed akathisia. The cri-teria for diagnosis were again notspecified. Munk-Andersen et al.(1989) compared sulpiride (median- 1,600 mg/day) with haloperidol(median - 12 mg/day) in adouble-blind crossover study(n — 16) and reported akathisia in8 haloperidol and 7 sulpiridepatients.

Only preliminary data on raclo-pride are available (Farde et al.1988; Cookson et al. 1989); theysuggest that it often produces dys-tonia and akathisia. In an openclinical study of amisulpiride, 3 of14 patients reportedly developedakathisia (Mann et al. 1984). Suffi-cient data on other substitutedbenzamides (e.g., emonapride) arenot available.

A benzamide that is not gener-ally used as an antipsychotic ismetoclopramide. This drug is im-portant because of its extensivenonpsychiatric usage to treat se-vere nausea, esophageal reflux,dyspepsia, neurogenic bladder,orthostatic hypotension, nonprolac-tinemic amenorrhea, hiccups; etc.Numerous reports of metodopra-mide-induced akathisia have beenpublished in the literature (e.g.,Bui et al. 1982; Allen et al. 1985;Sailer and Hellenbrecht 1985;Graham-Pole et al. 1986; Richardset al. 1986). The literature onmetoclopramide-induced movementdisorders was recently reviewedby Miller and Jankovic (1989), whorecorded 1,031 reported cases, 10percent (n = 106) of which hadakathisia (acute or tardive). Goodincidence data are unavailable.Borenstein and Bles (1965) admin-istered high doses to psychiatricpatients and reported EPSE in 25percent, but they did not specifythe rate of akathisia. Jungmannand Schoffling (1982) investigatedthe effect of an intravenous bolus

440 SCHIZOPHRENIA BULLETIN

of 10-mg metoclopramide in heal-thy volunteers and found that 25percent "complained of akathisia,"usually within 15 to 30 minutesand lasting for 3 to 4 hours. Thatthis distressing side effect is fre-quently unrecognized or ignoredhas been repeatedly highlighted(Miller and Jankovic 1989).

Risperidone is a novel benzisox-azole derivative that shows a dif-ferent side-effects profile from thatof the conventional antipsychotics.It is a potent D2, 5HT2, and <*] re-ceptor antagonist Qanssen et al.1988). A recent double-blind paral-lel group trial comparing differentfixed dosages of risperidone withhaloperidol suggests that the for-mer produces less akathisia (Jans-sen Research Foundation 1992).This difference is currently beinginvestigated in greater detail in amulticenter trial.

A number of drugs that, likerisperidone, act on D2 as well ason other receptors are currentlybeing investigated for their anti-psychotic properties and sideeffects profiles (Gerlach 1991). ICI204.636 is a dibenzothiazepine witha relatively weak D2 antagonismbut a stronger blockade of the5HT2 receptor. In a small clinicalstudy, no EPSE were observed(Fabre et al. 1990). Sertindole hasa biochemical profile like risperi-done (Skarsfeldt and Perregaard1990), but its clinical profile is stillunder investigation. Amperozide isa diphenylbutylpiperazine with anunusual biochemical profile of po-tent 5HT2 antagonism; a moderateaffinity for aa receptors; and mini-mal affinity for Dv D2, and 5HTla

receptors. In a small clinical studyof amperozide, Axelsson et al.(1991) reported no akathisia. Sa-voxepine is a novel tetracydic cya-nodibenzoxepinoacepine derivativewith strong D2 antagonistic prop-

erties, which is 10 times greaterfor the hippocampal than for thestriatal receptors (Bischoff et al.1986). Additionally, it blocks D,,5HT2, a,, and histamine Hj re-ceptors. In three open studies, sa-voxepine was found to commonlyproduce EPSE, including akathisia(Butler and Bech 1987; Moller etal. 1989; Wetzel et al. 1991).

Partial D2 agonists have recentlyaroused interest as potential anti-psychotics, and a few drugs—forexample, SDZ HDC912, terguride,roxindole, and B-HT 920—havebeen tried mostly in open clinicaltrials. EPSE, including akathisia,have been low or absent in thesetrials, but the data are preliminaryand more definitive studies areawaited (Gerlach 1991). DopamineD, antagonists have shown prom-ise as potential antipsychotics inanimal studies and may producefewer or different side effects, butclinical trials have yet to bepublished.

In conclusion, the preliminaryevidence from the use of thenewer antipsychotic drugs in re-lation to acute akathisia is encour-aging, and further systematic workis necessary. The dosages usedshould be kept in mind whenrates for different drugs are beingcompared, as it is possible thatnewer drugs are being used at rel-atively lower doses.

Serotonin-Specific ReuptakeInhibitors (SSRIs) and AcuteAkathisia. Akathisia has recentlybeen reported to occur with SSRIsused in the treatment of depres-sion and obsessive-compulsive dis-order, and its form is quite indis-tinguishable from that caused byneuroleptics. Lipinski et al. (1989)reported five cases of fluoxetine-induced akathisia. The akathisiawas rapid in onset, started within

hours up to 5 days of drug initia-tion, was mild, manifested subjec-tive and objective features, andresponded to dose reduction ortreatment with propranolol. In onepatient, akathisia continued formore than 1 year while the patientwas maintained on fluoxetine. In-terestingly, four of the reportedfive patients were young womenwith obsessive-compulsive disorder,and the fifth was a man with adepressive illness. The incidence ofakathisia with fluoxetine is uncer-tain. The Lipinski et al. (1989)cases were observed in a series of51 patients so treated, but only 20patients were systematically exam-ined; this suggests that the inci-dence could be anywhere between9.8 percent (5 of 51) and 25 per-cent (5 of 20). The product insertfor fluoxetine (Eli-Lilly Pty. Ltd.1993) describes "anxiety, nervous-ness, and insomnia" in 10 to 15percent of treated patients, leadingto drug discontinuation in 5 per-cent. It is likely that a proportionof these patients suffer fromakathisia.

The issue of fluoxetine-inducedakathisia, in spite of the above re-port, remains controversial. Maanyand Dhopesh (1990) challenged theLipinski et al. (1989) article, argu-ing that the observed side effectwas in fact not akathisia andcould be attributed to neurolepticsor trazodone. They cited their ownexperience of treating 23 patientswith fluoxetine, noting anxiety andinsomnia in 1 patient but no casesof akathisia. The criticism, how-ever, was adequately rebutted bythe authors (Lipinski et al. 1990),and it is likely that fluoxetine doesnot commonly produce akathisia atsmaller doses, which were theones used by Maany and Dhopesh(1990). The literature also suggeststhat fluoxetine-induced akathisia

VOL. 21, NO. 3, 1995 441

may be misdiagnosed or missedaltogether. Ioannou (1992) reporteda patient who developed a "horr-ible feeling inside," which was notrecognized as akathisia; rather, thesuicidal ideas this patient devel-oped subsequently were high-lighted. That suicidal ideationsometimes seen in patients treatedwith SSRIs (Teicher et al. 1990)may, at least in part, be due toakathisia has been suggested byOpler (1991), Hamilton and Opler(1992), and Wirshing et al. (1992).

Two cases (Klee and Kronig1993; Settle 1993) of akathisia haverecently been reported secondaryto sertraline, a newer SSRI. Wecould not trace any reports ofakathisia secondary to other SSRIs(e.g., paroxetine, fluvoxamine, in-dalpine, etc.). There is evidence,however, that these drugs worsenneuroleptic-induced parkinsonismor Parkinson's disease, thus sug-gesting a propensity to produceEPSE and possibly akathisia(Lipinski et al. 1990).

Other Drugs Reportedly Associ-ated With Acute Akathisia.Table 3 summarizes the publishedreports of akathisia in associationwith other nonneurolepric drugs. Itmust be emphasized that akathisiais not generally considered to be acomplication of heterocyclic antide-pressants, although a few reportshave appeared to this effect(Krishnan et al. 1984; Zubenko etal. 1987). A number of investiga-tors (Barton 1982; Hullett andLevy 1983; Ross et al. 1983; Shen1983) have recognized that the di-benzoxapine antidepressant amox-apine, which has intrinsic neu-roleptic activity Portion 1981),produces akathisia. The phenom-enon of jitteriness has been re-ported in some patients with panicdisorder who were treated with

tricyclic antidepressants (Zitrin etal. 1978; Pohl et al. 1988); thisphenomenon entailed restlessness,trouble sitting still, "shakiness in-side," insomnia, increased energy,and increased anxiety. At thisstage, however, too little is knownabout the jitteriness syndrome togroup it with drug-induced aka-thisia.

While akathisia has been re-ported in association with a num-ber of nonneurolepric drugs, aslisted in table 3, the evidence ispreliminary and larger epidemio-logical studies are necessary. Fur-ther, the clinical characteristicsshould be examined in detail todetermine if akathisia secondary toneuroleptic or nonneurolepricdrugs is similar.

Care should be taken whendrugs are used in combination—for example, lithium and halo-peridol in a patient with bipolardisorder, or a calcium antagonistand a neuroleptic drug in a hyper-tensive patient with psychosis—fora possible additive effect in thecausation of akathisia.

Risk Factors for AcuteAkathisia

In the various epidemiolo^icalstudies, the following risk factorsfor acute akathisia have beenexamined.

Sociodemographic Variables.Age. The relationship between

age and acute akathisia has notbeen adequately examined. Ayd(1961) suggested that akathisia wasmost prevalent between the ages12 and 64 years in his sample,which was in contrast to dystonia(more likely in the young) andparkinsonism (more likely in theelderly). The oldest person withakathisia in this series was 64,even though a significant propor-

tion (not stated) of subjects werein their seventies and eighties. Inthe Braude et al. (1983) study, theage range of the sample was 19 to72 years (mean - 40.6, SD = 15.0),and there was no significant dif-ference in age between the aka-thisia (n = 24) and nonakathisia(n = 23) groups. In the Sachdevand Kruk (1994) study, the akathi-sics did not differ significantlyfrom the nonakathisics in age; andon logistic regression analysis, agewas significant only at the 0.15level with an adjusted odds ratioof 1.034.

There are only a few studies ofakathisia in children, and thesegive a lower incidence and preva-lence than are found in the adultpopulations. The literature onakathisia in the elderly is evenmore scanty (see Part II Sachdev1995, this issue).

Sex. The relationship betweenakathisia and sex has also beeninadequately investigated. In hissample of 48.5 percent men and51.5 percent women, Ayd (1961)found the male:female ratio forakathisia to be 35:65. Sarwer-Foner(1960), on the other hand, statedthat "akathisia...tend[s] to prevailin men" (p. 316) but did notprovide any figures to supportthis. Most epidemiological studieshave not reported any sex differ-ences in the vulnerability to aka-thisia (Braude et al. 1983; VanPutten et al. 1984a; Sachdev andKruk 1994). An exception is thestudy by Sandyk and Kay (1990),in which a larger proportion offemale (40.6%) than male (20%)residents in a long-term unit of apsychiatric hospital were found tohave akathisia. The patients wereelderly (mean age - 63.9 years, SD» 8.9 years), and no attempt wasmade to separate acute from tar-dive akathisia.

442 SCHIZOPHRENIA BULLETIN

From the limited data available,one must conclude that sex doesnot seem to significantly determinethe occurrence of acute akathisia.However, it may possibly interactwith age as a vulnerability factorso that its importance may becomeapparent in the very young or theold. This needs to be empiricallyexamined using well-diagnosedacute akathisia populations.

Race. Akathisia has been re-ported in many racial groups(Sandyk and Kay 1990; Inada etal. 1991), although comparativestudies examining incidence havenot been published. There is nosuggestion that any particular ra-cial group is more vulnerable toacute akathisia.

Psychiatric Diagnosis. Most ofthe epidemiological studies ofacute akathisia have been per-formed in patients suffering fromschizophrenia. Some studies, how-ever, have included mixed psychi-atric populations. The Braude et al.(1983) study included patients withaffective disorder or personalitydisorder, and a few with "otherneurotic conditions" or alcoholism.There was no suggestion that anydiagnostic group was particularlyvulnerable. The Sachdev and Kruk(1994) study included 25 patientswith nonschizophrenic psychoticdisorders; psychiatric diagnosiswas again not a significant pre-dictor. The data would, therefore,suggest that the nature of the psy-chiatric disorder is probably notimportant. It must be pointed outthat neuroleptic drugs tend to beused at different doses in differentdisorders, and since akathisia isdose related, this aspect needs tobe considered in the analysis. Thereport by Galdi and Bonato (1988)is of interest, although the impli-cations of their finding are diffi-

cult to assess. While examining therelationship of adverse drug re-actions and the length of stay inhospital, they found that akathisiawas associated with an increasedhospital stay in only the schizo-phrenia patients who had a familyhistory of affective disorder.Gardos et al. (1992), who at-tempted to quantify psychomotoractivity in akathisia using ambula-tory activity monitoring, reportedthat the clinical ratings of akathi-sia tended to be higher in the de-pressed patients than in the manicand schizophrenia patients, eventhough the depressed patientswere on smaller doses of neuro-leptics. This therefore raises thepossibility that depressed patientsmay be more vulnerable to akathi-sia, as has been suggested for tar-dive dyskinesia (TD) (Khot et al.1992) and possibly for drug-induced parkinsonism (Friedman1992). This suggestion should beexamined more systematically in alarger sample. The Gardos et al.(1992) study also suggests that themotor manifestations of akathisiainteract with those of the primarypsychiatric disorder. The lattercondition should therefore betaken into consideration, par-ticularly if quantification of themovements is intended.

As already pointed out, akathisiaoften occurs in healthy individualsor in patients suffering from medi-cal or surgical illnesses when chal-lenged with neuroleptics or otherdrugs known to cause akathisia.There is no suggestion that theakathisia seen in normal individ-uals is phenomenologically differ-ent from that seen in psychiatricpatients.

Drug-Related Variables.Nature of drugs causing

akathisia. This article has already

alluded to the various drugs re-ported to cause akathisia. In sum-mary, akathisia is typically associ-ated with the classical neuroleptics,but many newer antipsychoticsand a number of other drugs havealso been reported to cause akathi-sia. These drugs share the prop-erty of directly or indirectly influ-encing the dopaminergic or theserotonergic system. Since seroto-nin has an inhibitory effect on themesolimbic and mesocortical pro-jections (Meltzer et al. 1979), thebiochemical property that bestlinks the various drugs is theirability to reduce dopamine func-tion in the central nervous system.However, the relative role of thedifferent dopamine receptors andthe brain areas that may be par-ticularly responsible for this func-tion cannot be decided from thisinformation. There are a fewdrugs—for example, anticonvul-sants on a substrate of organic im-pairments, methysergide, etc.—thatare occasionally reported to causeakathisia and that may ostensiblychallenge this hypothesis, but theevidence in their favor is weak.

Neuroleptic drug potency andakathisia. There is a general clin-ical impression that akathisia ismore likely to occur with higherpotency drugs. Ayd (1961) com-mented that akathisia developedearlier and with smaller doses asthe potency of the drug increased.Van Putten et al. (1984a) studiedsubjects treated with oral haloperi-dol (5 mg) or thiothixene (0.22mg/kg); 70 percent of the formerand 22 percent of the latter devel-oped akathisia by the seventh day.In the Sachdev and Kruk (1994)study, the effect of medicationtype was significant but small,with higher potency again associ-ated with an increased risk ofakathisia.

VOL 21, NO. 3, 1995 443

Drug dose and rate of incre-ment of dose. The positive asso-ciation of akathisia with drug doseis generally accepted. In the Mc-Clelland et aJ. (1976) study, therate of akathisia was 22 percent inthe high-dose and 9 percent in thestandard-dose groups. In the VanPutten et al. (1990) study, the20-mg haloperidol group had ahigher overall rate of akathisiathan the 5- or 10-mg groups. Inthe Sachdev and Kruk (1994)study, drug dose made a signifi-cant contribution to overall akathi-sia rates. Only the study by Rifkinet al. (1991) was at variance as itdid not find a significant differ-ence between the 10-, 30-, and80-mg haloperidol groups.

The rate of increment of dose isanother variable of some signifi-cance. Braude et al. (1983) re-ported that in patients with alarge dose increase in the first 10days after admission (log ratio ofincrease > 3.0), akathisia rates in-creased considerably. This findingwas supported by Sachdev andKruk (1994).

Clinical experience would alsosuggest that parenteral adminis-tration of the neuroleptic is morelikely to cause akathisia. This isnot supported by any research evi-dence that we are aware of, and iftrue, it may be because of any ofthe following possibilities: (1) thatneuroleptics administered paren-terally are usually of high potency;(2) that parenteral drugs are oftengiven during acute management,thus rapidly increasing the plasmalevels from nil or low baselinelevels; and (3) that bypassing thefirst-pass metabolism leads to arapid increment of levels.

Plasma levels of drugs. Pa-tients on the same dosage areknown to be at enormous variancein their plasma levels, which may

be up to a hundredfold in somecases Pahl 1986). This observationraised the hope that aberrant plas-ma levels could explain the occur-rence of side effects in some pa-tients. Overall, this hope has notbeen fulfilled. Van Putten et al.(1991) studied the relationship be-tween plasma haloperidol levelsand drug effects in 61 patients;they found that patients with lev-els above 12 ng/mL tended not todo so well and felt that this wasdue to adverse effects. Objectivelyrated akathisia and akinesia didnot show a significant relationshipwith plasma haloperidol levels.However, when side effects wererated on a Clinical Global Impres-sion scale (Guy 1976), there wasa powerful relationship betweenplasma levels and what the patientexperienced as "disabling sideeffects" (Van Putten et al. 1991,p. 204). The same authors demon-strated a significant relationshipip = 0.0008) between disabling sideeffects and plasma levels of flu-phenazine; the disabling sideeffects ratings were significantlycorrelated with the ratings ofakathisia (r = 0.6) and akinesia(r - 0.44). There is, therefore,some evidence that increasingplasma levels are associated withmore side effects—in particular,akathisia and akinesia—but moresystematic examination of this rela-tionship is necessary.

Past exposure to neurolepticdrugs and the duration of suchexposure. It has been suggestedthat patients may be more likelyto develop akathisia at the time offirst exposure to the drug, a ten-dency that may decrease with re-peated or chronic exposure. TheSachdev and Kruk (1994) studysupports this contention but sug-gests that the effect is probablysmall.

EPSE. A number of studies havepointed to an association betweenparkinsonian EPSE (generally,rigidity and resting tremor) andakathisia (Freyhan 1959; Ayd 1961;Medinar et al. 1962; Braude et al.1983; Levinson et al. 1990; Sachdevand Kruk 1994). In the Sachdevand Kruk (1994) study, the correla-tion between the EPSE and akathi-sia ratings was 0.40 (p < 0.01),and it was the most significantvariable on a logistic regressionanalysis. These findings suggestthat the two side effects oftenoccur together. Whether EPSE canbe used to predict akathisia de-pends on the time course of thetwo, and the evidence points to asimilar or slightly delayed timecourse for the development ofEPSE in comparison with akathisiafollowing a challenge with neuro-leptic medication. Therefore, EPSEmay not be very useful in predict-ing acute akathisia, but the asso-ciation probably reflects a commonvulnerability and is important forour understanding of the path-ophysiology of akathisia. It hasalso been suggested (Braude et al.1983) that akathisia associated withEPSE, with a positive response toanticholinergic medication, mayhave a different pharmacologicalprofile from the akathisia not soassociated, but this needs to be in-vestigated further (Sachdev andLoneragan 1993).

Other Variables.Iron status. The role of iron

deficiency in the pathogenesis ofakathisia has been examined in anumber of studies that have beenreviewed elsewhere (Sachdev1993). The evidence is conflicting,and the conclusion one can drawis that most patients who developakathisia do not have iron defi-ciency and that the overall contri-

444 SCHIZOPHRENIA BULLETIN

bution of iron to the developmentof akathisia, if indeed significant,is likely to be small. Further, he-matological and serum biochemicalmeasures are inadequate in assess-ing iron function in the brain invivo. Magnetic resonance imagingshows promise in this area, butfurther delineation of appropriatemeasures to assess brain iron isnecessary.

Organic brain disease. Akathi-sia has been described in relationto a number of neurological disor-ders, such as encephalitis lethar-gica (Jelliffe 1932), Parkinson's dis-ease (Lang and Johnson 1987),traumatic brain lesions (Stewart1989), and brain abscess involvingthe subthalamus and basal ganglia(Carrazana et al. 1989). A featurecommon to these disorders is theinvolvement of the basal ganglia.Since this article deals specificallywith drug-induced akathisia, wewill not discuss "akathisia due togeneral medical condition" in anydetail except to emphasize that thepresence of any such disorder islikely to increase the propensityfor the drug-induced syndrome.

Alcohol. Case reports have ap-peared in which the ingestion ofalcohol was temporally associatedwith the development of akathisiain patients being treated with neu-roleptics (Lutz 1976) or amoxapine(Shen 1984). The exact mechanismis not known, but the finding isnot inconsistent with the dopaminehypothesis of akathisia (Lai et al.1978).

Smoking. Menza et al. (1991)reported that in their patients withchronic psychiatric illness, femalesmokers had more objective, butnot subjective, akathisia. One pos-sible interpretation of this findingis that their patients had tardiveakathisia rather than acute akathi-sia, and one can predict that the

finding for tardive akathisia wouldbe similar to that for TD. Ofcourse, the study is an isolatedone and needs replication. Further,the smokers in this study hadhigher levels of neuroleptics, andthis could account for the higherrates of akathisia quite independ-ent of the status of smoking.

Diabetes mellitus. The re-ported association between glucoseintolerance and TD (Mukherjee etal. 1985), as well as the effect ofglucose on striatal dopaminergicactivity (Sailer and Chiodo 1980),prompted Sandyk et al. (1991) toexamine 68 chronic schizophreniapatients referred to the movementdisorder clinic of a large urbanpsychiatric hospital for an associa-tion between diabetes mellitus andakathisia. Sixteen of their patients(23.5%) had diabetes on retrospec-tive chart review, and the akathi-sia ratings in the diabetics weremore than twice those in the non-diabetics. This study had manymethodological limitations, whichwe will not discuss in detail, butit does draw attention to a hith-erto unexplored risk factor.

Conclusions

The factors that predispose an in-dividual to the development ofakathisia are incompletely under-stood. The high rates of akathisiareported in some studies (e.g., the76-percent incidence reported byVan Putten and colleagues [1984<J])suggest that most individuals willdevelop akathisia under some cir-cumstances. It is uncertain whethereveryone is vulnerable to the de-velopment of akathisia if chal-lenged with very high doses ofneuroleptics. As our review sug-gests, we have limited informationon the factors that increase vul-nerability to acute akathisia, and

even this information is restrictedto neuroleptic-induced akathisia.Drug-related factors—in particular,drug dose, rate of increment ofdose, and drug potency—areclearly important. Further, thedevelopment of parkinsonism alsopredicts the development of aka-thisia, although akathisia may oc-cur first or concurrently in manycases. The role of sociodemo-graphic factors and other treat-ment-related variables is modest.The evidence for iron deficiency asa risk factor is conflicting, but thecontribution of iron deficiency islikely to be minor. As is apparent,a significant proportion of the sus-ceptibility to akathisia is unex-plained (Sachdev and Kruk 1994).

References

Allen, J.C.; Gralla, R.; Reilly, L.;Kellick, M.; and Young, C. Meto-clopramide: Dose-related toxicityand preliminary antiemetic studiesin children receiving cancer che-motherapy, journal of Clinical On-cology, 3:1136-1141, 1985.

Andersen, J.; Korner, A.; Oster-gaard, P.; Fensbo, C; Birket Smith,M.; Thiesen, S.; Hansen, N.R.;Fogh, M.; Kristensen, M.; and Mol-ler Nielsen, E.M. A double-blindcomparative multicentre study ofremoxipride and haloperidol inschizophrenia. Ada PsychiatricaScandinavica, 358(Suppl.):104-107,1990.

Axelsson, R.; Nilsson, A.; Chris-tensson, E.; and Bjork, A. Effectsof amperizode in schizophrenia:An open study of a potent 5-HT2

receptor antagonist. Psychophar-macology, 104(3):287-292, 1991.

Ayd, F., Jr. A survey of drug-induced extrapyramidal reactions.Journal of the American Medical As-sociation, 175:1054-1060, 1961.

VOL. 21, NO. 3, 1995 445

Barnes, T.R., and Braude, W.M.Akathisia variants and tardive dys-kinesia. Archives of General Psychia-try, 42:874-878, 1985.Barton, J.L. Amoxapine-inducedagitation among bipolar depressedpatients. [Letter] American journalof Psychiatry, 139:87, 1982.

Bernick, C. Methysergide-inducedakathisia. Clinical Neuropharmacol-ogy, 11:87-89, 1988.

Bischoff, S.; Vassout, A.; Delina-Stula, A.; and Waldmeier, P. Inter-actions of cipazoxapine, citatepine,eresepine, and maroxepine withcentral dopamine (DA) receptors:Effects of in vivo [3H]spiperonebinding, DA metabolism, and be-havioral parameters. Pharmacopsy-chiatry, 19:306-307, 1986.

Borenstein, P., and Bles, G. Effectsclinques et electroencephalographi-ques du metoclopramide en psy-chiatrie. Therapie, 29:975-995, 1965.

Braude, W.M.; Barnes, T.R.; andGore, S.M. Clinical characteristicsof akathisia: A systematic inves-tigation of acute psychiatric inpa-tient admissions. British Journal ofPsychiatry, 143:139-150, 1983.

Bui, N.B.; Marit, G.; Albin, H.; Du-rand, M.; Mauriac, L.; and Hoerni,B. High dose metoclopramide dur-ing cancer chemotherapy: Phase IIstudy in 80 consecutive patients.Bulletin du Cancer, 69:330-335,1982.

Burke, R.E.; Kang, U.J.; and Fahn,S. Tardive akathisia: Motor phe-nomena and treatment. Neurology,37(Suppl. 1):124-125, 1987.

Butler, B., and Bech, P. Neurolep-tic profile of cipazoxapine (savox-epine), a new tetracyclic dopamineantagonist: Clinical validation ofthe hippocampus versus striatumratio model of dopamine receptorsin animals. Psychopharmacopsychia-try, 20:122-126, 1987.

Calmels, J.P.; Sorbette, F.; Mon-tastruc, J.L.; and Albarade, J.L.Latrogenic hyperkinetic syndromecaused by an antihistaminic. [Let-ter] Nouvelle Presse Medicale,ll(30):2296-2297, 1982.

Carrazana, E.; Rossitch, E., Jr.; andMartinez, J. Unilateral "akathisia"in a patient with AIDS and a tox-oplasmosis subthalamic abscess.Neurology, 39:449-450, 1989.

Casey, D.E. Clozapine: Neuroleptic-induced EPS and tardive dys-kinesia. Psychopharmacology, 99(Suppl.):S47-S53, 1989.

Channabasavanna, S.M., and Gos-wami, U. Akathisia during lithiumprophylaxis. British Journal of Psy-chiatry, 144:555-556, 1984.

Chouinard, G.; Ross-Chouinard, A.;Annable, L.; and Jones, B.D. Extra-pyramidal rating scale. [Abstract]Canadian Journal of NeurologicalSciences, 1:233, 1980.

Chouza, C; Caamano, J.L.; Al-janati, R.; Scaramelli, A.; Medina,O.; and Romero, S. Parkinsonism,tardive dyskinesia, akathisia, anddepression induced by flunarizine.Lancet, 1:1303-1304, 1986.

Claghom, J.; Honigfeld, G.;Abuzzahab, F.S.; Wang, R.; Stein-book, R.; Tuason, V.; and Klerman,G. The risks and benefits of cloza-pine versus chlorpromazine. Journalof Clinical Psychopharmacology,7:377-384, 1987.

Cohen, B.M.; Keck, P.E.; Satlin, A.;and Cole, J.O. Prevalence and se-verity of akathisia in patients onclozapine. Biological Psychiatry,29:1215-1219, 1991.

Cookson, J.C.; Natorf, B.; Hunt, N.;Silverstone, T.; and Uppfeldt, G.Efficacy, safety, and tolerability ofraclopride, a specific D2 receptorblocker, in acute schizophrenia: Anopen trial. International ClinicalPsychopharmacology, 4:61-70, 1989.

Dahl, S.G. Plasma level monitoringof antipsychotic drugs. ClinicalPharmacokinetics, 11:36-61, 1986.

Donlon, P.T. Amoxapine: A newlymarketed tricyclic antidepressant.Psychiatric Annals, 11:379-383, 1981.

Ehyai, A.; Kilroy, A.W.; andFenichel, G.M. Dyskinesia andakathisia induced by ethosuximide.American Journal of Diseases ofChildren, 132:527-528, 1978.

Eli Lilly Pry. Ltd. Fluoxetine Hydro-chloride: Approved Product Informa-tion. West Ryde, New SouthWales, Australia: Eli Lilly Pty.Ltd., 1993.

Fabre, L.; Slotnick, V.; Jones, V.;Murray, G.; and Malick, J. "ICI204.636, A Novel Atypical Antipsy-chotic: Early Indications for Safetyand Efficacy in Man." Presented atthe 17th Congress of the Collegi-um Internationale Neuro-Psycho-pharmacologium (CINP), Kyoto,Japan, 1990.

Farde, L.; Grind, M.; Nilsson, M.I.;Ogenstad, S.; and Sedvall, G. Re-moxipride—A new potential anti-psychotic drug: Pharmacologicaleffects and pharmacokinetics fol-lowing repeated oral administrationin male volunteers. Psychophar-macology, 95:157-161, 1988.

Freyhan, F.A. Psychomotility andparkinsonism in treatment withneuroleptic drugs. Archives ofNeurology and Psychiatry, 78:465-472, 1957.

Freyhan, F.A. Extrapyramidal Symp-toms and Other Side Effects in Tri-fluoperazine—Clinical and Pharmaco-logical Aspects. Philadelphia, PA:Lea & Febiger, 1958.

Freyhan, F.A. Therapeutic implica-tions of differential effects of newphenothiazine compounds. Ameri-can Journal of Psychiatry, 115:577-585, 1959.

446 SCHIZOPHRENIA BULLETIN

Friedman, J.H. Drug-induced par-kinsonism. In: Lang, A.E., andWeiner, W.J., eds. Drug-InducedMovement Disorders. New York,NY: Futura Publishing Company,1992. pp. 41-83.Galdi, J., and Bonato, R.R. Rela-tionship of adverse drug reactionsto length of hospital stay in genet-ically subgrouped schizophrenics.Canadian Journal of Psychiatry,33:816-818, 1988.

Gardos, G.; Teicher, M.H.; Lipinski,J.F., Jr.; Matthews, J.D.; Morrison,L.; Conley, C; and Cole, J.O.Quantitative assessment of psy-chomotor activity in patients withneuroleptic-induced akathisia.Progress in Neuro-Psychopharma-cology and Biological Psychiatry,16:27-37, 1992.

Gerlach, J. New antipsychotics:Classification, efficacy, and adverseeffects. Schizophrenia Bulletin,17(2):289-309, 1991.

Gimenez-Roldan, S., and Matea, D.Cinnarizine-induced parkinsonism:Susceptibility related to aging andessential tremor. Clinical Neurophar-macology, 14:156-164, 1991.Goff, D.C.; Midha, K.K.; Brotman,A.W.; McCormick, S.; Waites, M.;and Amico, E.T. An open trial ofbuspirone added to neuroleptics inschizophrenic patients. Journal ofClinical Psychopharmacology, 11:193—197, 1991.

Graham-Pole, J.; Weare, J.; Engel,S.; Gardner, R.; Mehta, P.; andGross, S. Antiemetics in childrenreceiving cancer chemotherapy: Adouble-blind prospective random-ized study comparing metoclopra-mide with chlorpromazine. Journalof Clinical Oncology, 4:1110-1113,1986.

Guy, W., ed. ECDEU AssessmentManual for Psychopharmacology, re-vised. Rockville, MD: National In-

stitute of Mental Health, DHEWPublication No. (ADM) 76-338,1976.

Hamilton, M.S., and Opler, L.A.Akathisia, suicidality, and fluoxe-tine. Journal of Clinical Psychiatry,53:401-406, 1992.

Hullert, F.J., and Levy, A.B. Amox-apine-induced akathisia. [Letter]American Journal of Psychiatry,140(6):820, 1983.

Hunter, R.; Earl, C.J.; and Thomi-croff, S. An apparently irreversiblesyndrome of abnormal movementsfollowing phenothiazine medica-tion. Proceedings of the Royal So-ciety of Medicine, 57:758-762, 1964.

Inada, T.; Yagi, G.; Kaijima, K.;Ohnishi, K.; Kamisada, M.; andRockhold, R.W. Clinical variants oftardive dyskinesia in Japan. Jap-anese Journal of Psychiatry andNeurology, 45:67-71, 1991.

Ioannou, C. Media coverage versusfluoxetine as the cause of suicidalideation. [Letter] American Journalof Psychiatry, 149(4):572, 1992.

Jacobs, M.B. Diltiazem and akathi-sia. Annals of Internal Medicine,99:794-795, 1983.

Janssen, P.A.J.; Niemegeers, C.J.E.;Awouters, F.; Schellekens, K.H.L.;Megens, A.A.H.P.; and Meert, T.F.Pharmacology of risperidone (R 64766): A new antipsychotic withserotonin-S2 and dopamine-D2 an-tagonistic properties. Journal ofPharmacology and ExperimentalTherapeutics, 244:685-693, 1988.

Janssen Research Foundation."Risperidone in the Treatment ofChronic Schizophrenic Patients: AnInternational Multicentre Double-Blind Parallel-Group ComparativeStudy Versus Haloperidol." Un-published Clinical Research Report,RIS-INT-2, Janssen Research Foun-dation, Beerse, Belgium, 1992.

Jelliffe, S.C. Psychopathology ofForced Movements and the Oculo-gyric Crises of Lethargic Encephali-tis. Washington, DC: Nervous &Mental Disease Publishing Com-pany, 1932.

Jungmann, E., and Schoffling, K.Akathisia and metoclopramide.[Letter] Lancet, 11:221, 1982.

Kane, J.; Honigfeld, G.; Singer, J.;and Meltzer, H. Clozapine for thetreatment-resistant schizophrenic: Adouble-blind comparison withchlorpromazine. Archives of GeneralPsychiatry, 45:789-7%, 1988.

Kennedy, P.F.; Hershon, H.I.; andMcCruire, R.J. Extrapyramidal dis-orders after prolonged phenothia-zine therapy. British Journal of Psy-chiatry, 118:509-518, 1971.

Khot, V.; Egan, M.F.; Hyde, T.M.;and Wyatt, R.J. Neuroleptics andclassic tardive dyskinesia. In: Lang,A.E., and Weiner, W.J., eds. Drug-Induced Movement Disorders. NewYork, NY: Futura Publishing Com-pany, 1992. pp. 121-166.

Klee, B., and Kronig, M.H. Casereport of probable sertraline-induced akathisia. [Letter] AmericanJournal of Psychiatry, 150:986-987,1993.

Krishnan, K.R.; France, R.D.; andEllinwood, E.H., Jr. Tricyclic-induced akathisia in patients tak-ing conjugated estrogens. AmericanJournal of Psychiatry, 141:696-697,1984.Kuzuhara, S.; Kohara, N.; Ohkawa,Y.; Fuse, S.; and Yamanouchi, H.Parkinsonism, depression and aka-thisia induced by flunarizine, acalcium entry blocken Reportof 31 cases. Rinsho Shinkeigaku,29:681-686, 1989.

Lai, H.; Carino, M.A.; and Horito,A. Effects of ethanol on centraldopamine functions. Life Sciences,27:19-28, 1978.

VOL. 21, NO. 3, 1995 447

Lang, A.E. Withdrawal akathisia:Case reports and a proposed clas-sification of chronic akathisia.Movement Disorders, 9(2):188-192,1994.

Lang, A.E., and Johnson, K. Aka-thisia in idiopathic Parkinson's dis-ease. Neurology, 37:477-481, 1987.

Lee, T., and Tang, S.W. Loxapineand clozapine decrease serotonin(S2) but do not elevate dopamine(D2) receptor numbers in the ratbrain. Psychiatry Research, 12:277-285, 1984.

Lepola, U.; Koskinen, T.; Rimon,R.; Salo, H.; and Gordin, A. Sul-piride and perphenazine in schizo-phrenia: A double-blind clinicaltrial. Acta Psychiatrica Scandinavica,80:92-96, 1989.

Levinson, D.F.; Simpson, G.M.;Singh, H.; Yadalam, K.; Jain, A.;Stephanos, M.J.; and Silver, P.Fluphenazine dose, clinical re-sponse, and exrrapyramidal symp-toms during acute treatment. Ar-chives of General Psychiatry, 47:761-768, 1990.

Lindstrom, L.H.; Wieselgren, I.M.;Struwe, G.; Kristjansson, E.; Ak-selson, S.; Arthur, H.; Andersen,T.; Lindgren, S.; Norman, O.; andNaimell, L. A double-blind com-parative mulricentre study of re-moxipride and haloperidol inschizophrenia. Acta PsychiatricaScandinavica, 358(Suppl.):130-135,1990.

Lipinski, J.F., Jr.; Mallya, G.; Zim-merman, P.; and Pope, H.G., Jr.Fluoxetine-induced akathisia: Clini-cal and theoretical implications.Journal of Clinical Psychiatry,50:339-342, 1989.

Lipinski, J.F., Jr.; Mallya, G.; Zim-merman, P.; and Pope, H.G., Jr.Akathisia and fluoxetine: Reply.[Letter] Journal of Clinical Psychia-try, 51:211-212, 1990.

Lund Laursen, A., and Gerlach, J.Antipsychotic effect of remoxipride,a new substituted benzamide withselective antidopaminergic activity.Acta Psychiatrica Scandinavica,73:17-21, 1986.

Lutz, E.G. Neuroleptic-inducedakathisia and dystonia triggeredby alcohol. Journal of the AmericanMedical Association, 236:2422-2423,1976.

Maany, I. and Dhopesh, V. Akathi-sia and fluoxetine. [Letter] Journalof Clinical Psychiatry, 51:210-212,1990.

Magliozzi, J.R.; Gillespie, H.;Lombrozo, L.; and Hollister, L.E.Mood alteration following oral andintravenous haloperidol and rela-tionship to drug concentration innormal subjects. Journal of ClinicalPharmacology, 25:285-290, 1985.

Mann, K.; Bartels, M.; Bauer, H.;and Gaertner, H.J. Amisulpiride:An open clinical study of a newbenzamide in schizophrenic pa-tients. Pharmacovsychiatry, 17:111-115, 1984.

May, P.R.A.; Lee, M.; and Baron,R. "Handbook for InstrumentMeasurement of ExtrapyramidalSymptoms and Involuntary Move-ments." Unpublished manuscript,University of California, Los An-geles, 1983.

McClelland, H.A.; Farquarson, R.G.;Leyburn, P.; Furness, J.A.; andSchiff, A.A. Very high dosefluphenazine decanoate: A con-trolled trial in chronic schizophre-nia. Archives of General Psychiatry,33:1435-1439, 1976.

McCreadie, R.G.; Todd, N.; Living-stone, M.; Eccleston, D.; Watt,J.A.G.; Tait, D.; Crocket, G.;Mitchell M.J.; and Huitfeldt, B.A double blind comparative studyof remoxipride and thioridazine inthe acute phase of schizophrenia.

Acta Psychiatrica Scandinavica,78:49-56, 1988.

Medinar, C; Kramer, M.D.; andKurland, A.A. Biperidin in thetreatment of phenothiazine-inducedextrapyramidal reactions. Journal ofthe American Medical Association,182:1127-1128, 1962.

Meltzer, H.; Young, M.; Metz, J.;Fang, V.S.; Schyve, P.M.; andArora, R.C. Extrapyramidal sideeffects and increased serum prolac-tin following fluoxetine, a newantidepressant. Journal of NeuralTransmission, 45:165-175, 1979.

Menza, M.A.; Grossman, N.; VanHorn, M.; Cody, R.; and Forman,N. Smoking and movement disor-ders in psychiatric patients. Biolog-ical Psychiatry, 30:109-115, 1991.

Meyboom, R.H.; Ferrari, M.D.; andDieleman, B.P. Parkinsonism, tar-dive dyskinesia, akathisia, and de-pression induced by flunarizine.[Letter] Lancet, 11:292, 1986.

Micheli, F.; Pardal, M.F.; Gatto, M.;Torres, M.; Paradiso, G.; Parera,C; and Giannaula, R. Flunarizine-and cinnarizine-induced ex-trapyramidal reactions. Neurology,37:881-884, 1987.

Miller, L.G., and Jankovic, J.Metoclopramide-induced movementdisorders: Clinical findings with areview of the literature. Archives ofInternal Medicine, 149:2486-2492,1989.

Milne, I.K. Akathisia associatedwith carbamazepine therapy. [Let-ter] New Zealand Medical Journal,105:182, 1992.

Moller, H.J.; Kissling, W.; Dietz-felbinger, T.; Stoll, K.-D.; andWendt, G. Efficacy and tolerabilityof a new antipsychotic compound(savoxepine): Results of a pilotstudy. Pharmacopsychiatry, 22:38-41,1989.

448 SCHIZOPHRENIA BULLETIN

Mukherjee, S.; Wisniewski, A.;Bilder, R.; and Sackeim, H.A. Pos-sible association between tardivedyskinesia and altered carbohy-drate metabolism. [Letter] Archivesof General Psychiatry, 42(2)1205,1985.

Munk-Andersen, E.; Behnke, K.;Heltberg, J.; Nielsen, H.; andGerlach, J. Sulpiride versus halo-peridol, a clinical trial in schiz-ophrenia. A preliminary report.Acta Psychiatrica Scandinavica,311(Suppl.):31-41, 1989.Murray, T.J.; Kelly, P.; Campbell,L.; and Stefanik, K. Haloperidol inthe treatment of stuttering. BritishJournal of Psychiatry, 130:370-373,1977.

Opler, L.A. Akathisia and suicide.[Letter] American Journal of Psychi-atry, 148:1259, 1991.

Patterson, J.F. Akathisia associatedwith buspirone. Journal of ClinicalPsychopharmacology, 8:296-297, 1988.

Peroutka, S.J., and Snyder, S.H.Relationship of neuroleptic drugeffects at brain dopamine, seroto-nin, alpha-adrenergic, and hista-mine receptors to clinical potency.American Journal of Psychiatry,137:1518-1522, 1980.

Pohl, R.; Yeragani, V.K.; Balon, R.;and Lycaki, H. The jitteriness syn-drome in panic disorder patientswith antidepressants. Journal ofClinical Psychiatry, 49:100-104,1988.

Price, W.A., and Zimmer, B.Lithium-induced akathisia. [Letter]Journal of Clinical Psychiatry, 48:81,1987.

Richards, P.D.; Flaum, M.A.; Bate-man, M.; and Kardinal, C.G. Theanti-emetic efficacy of secobarbitaland chlorpromazine compared tometodopramide, diphenhydramine,and dexamethasone. Cancer,58:959-962, 1986.

Richelson, E., and Nelson, A. An-tagonism by neuroleptics of neuro-transmitter receptors of normalhuman brain in vitro. EuropeanJournal of Pharmacology, 103:197-204, 1984.

Rifkin, A.; Doddi, S.; Karajgi, B.;Borenstein, M.; and Wachspress,M. Dosage of haloperidol forschizophrenia. Archives of GeneralPsychiatry, 48:166-170, 1991.Ritchie, E.C.; Bridenbaugh, R.H.;and Jabbari, B. Acute generalizedmyoclonus following buspirone ad-ministration. Journal of Clinical Psy-chiatry, 49:242-243, 1988.

Robertson, M.M.; Schneiden, V.;and Lees, W.J. Management ofGilles de la Tourette syndromeusing sulpiride. Clinical Neuro-pharmacology, 13(3):229-235, 1990.

Ross, D.R.; Walker, J.I.; and Peter-son, J. Akathisia induced by amox-apine. American Journal of Psychia-try, 140:115-116, 1983.Sachdev, P. The neuropsychiatry ofbrain iron. Journal of Neuropsychia-try and Clincial Neurosciences, 5:18-29, 1993.Sachdev, P. A rating scale fordrug-induced akathisia: Develop-ment, reliability and validity. Bio-logical Psychiatry, 35(4):263-271,1994a.Sachdev, P. Research diagnosticcriteria for drug-induced akathisia:Conceptualization, rationale, andproposal. Psychopharmacology,114:181-186, 19946.Sachdev, P. The epidemiology ofdrug-induced akathisia: Part II.Chronic, tardive, and withdrawalakathisias. Schizophrenia Bulletin,21(3):451-461, 1995.Sachdev, P., and Kruk, J. Clinicalcharacteristics and predisposingfactors in acute drug-induced aka-thisia. Archives of General Psychia-try, 51(12):963-974, 1994.

Sachdev, P., and Loneragan, C.Intravenous challenges of benzrro-pine and propranolol in acute neu-roleptic-induced akathisia. ClinicalNeuropharmacology, 16:324-331,1993.

Safferman, A.Z.; Lieberman, J.A.;Pollack, S.; and Kane, J.M. Cloza-pine and akathisia. Biological Psy-chiatry, 31:753-754, 1992.

Sailer, C.F., and Chiodo, L.A.Glucose suppresses basal firingand haloperidol-induced increasein firing rate of central dopamin-ergic neurons. Science, 210:1269-1271, 1980.

Sailer, R., and Hellenbrecht, D.Comparison of the antiemetic effi-cacy of two high-dose benzamides,metoclopramide and alizapride,against cisplatin-induced emesis.Cancer Treatment Reports, 69:1301-1303, 1985.

Sandoz Pharmaceutical Corpora-tion. Hospital Pharmacist's Guide tothe Clozaril Patient ManagementSystem. East Rutherford, NJ:Sandoz, 1991.

Sandyk, R., and Kay, S.R. Relation-ship of neuroleptic-induced akathi-sia to drug-induced parkinsonism.Italian Journal of Neurological Sci-ences, 11:439-442, 1990.

Sandyk, R.; Kay, S.R.; Awerbuch,G.I.; and Iacono, R.P. Risk factorsfor neuroleptic-induced movementdisorders. International Journal ofNeuroscience, 61:149-188, 1991.

Sarwer-Foner, G.J. Recognition andmanagement of drug-induced ex-trapyramidal reactions and "para-doxical" behavioral reactions inpsychiatry. Canadian Medical Asso-ciation Journal, 83:312-318, 1960.

Schwarcz, G.; Gosenfeld, L.; Gil-derman. A.; Jiwesh, ].; and Ripple,R.E. Akathisia associated with car-bamazepine therapy. [Letter] Amer-

VOL. 21, NO. 3, 1995 449

ican Journal of Psychiatry, 143:1190-1191, 1986.Settle, E.C. Akathisia and sertra-line. [Letter] Journal of Clinical Psy-chiatry, 54:321, 1993.

Shen, W.VV. The management ofamoxapine-induced akathisia.American Journal of Psychiatry,140:1102-1103, 1983.

Shen, W.W. Alcohol, amoxapine,and akathisia. Biological Psychiatry,19:929-930, 1984.

Simpson, G.M., and Angus, J.W.S.A rating sale for extrapyramidalside-effects. Ada Psychiatrica Scan-dinavica, 213:11-19, 1970.

Skarsfeldt, T., and Perregaard, J.Sertindole, a new neuroleptic withextreme selectivity on A10 versusA9 dopamine neurons in the rat.European Journal of Pharmacology,182:613-^14, 1990.

Stahl, S.M. Akathisia and tardivedyskinesia: Changing concepts. Ar-chives of General Psychiatry, 42:915-917, 1985.

Stewart, J.T. Akathisia followingtraumatic brain injury: Treatmentwith bromocriptine. Journal ofNeurology, Neurosurgery and Psychi-atry, 52:1200-1201, 1989.

Teicher, M.H.; Glod, C; and Cole,J.O. Emergence of intense suicidalpreoccupation during fluoxetinetreatment. American Journal of Psy-chiatry, 147:207-210, 1990.

Van Putten, T. The many faces ofakathisia. Comprehensive Psychiatry,16:43-47, 1975.

Van Putten, T.; Marder, S.R.; andMintz, J. A controlled dose com-parison of haloperidol in newlyadmitted schizophrenic patients.Archives of General Psychiatry,47:754-758, 1990.Van Putten, T.; Marder, S.R.;Wirshing, W.C.; Aravagiri, M.; andChabert, N. Neuroleptic plasmalevels. Schizophrenia Bulletin,17(1):197-216, 1991.

Van Putten, T.; May, P.R.; andMarder, S.R. Akathisia with halo-peridol and thiothixene. Archives ofGeneral Psychiatry, 41:1036-1039,1984a.

Van Putten, T.; May, P.R.; andMarder, S.R. Akathisia with halo-peridol and thiothixene. Psycho-pharmacology Bulletin, 20(l):114-117,1984b.

Van Putten, T.; Mutalipassi, L.R.;and Malkin, M.D. Phenothiazineinduced decompensation. Archivesof General Psychiatry, 30:13-19,1974.

Wetzel, H.; Wiedemann, K.;Holsboer, F.; and Benkert, O.Savoxepine: Invalidation of an"atypical" neuroleptic responsepattern predicted by animal mod-els in an open clinical trial withschizophrenic patients. Psychophar-macology, 103:280-283, 1991.

Wirshing, W.C.; Van Putten, T.;Rosenberg, J.; Marder, S.; Ames,D.; and Hicks-Gray, T. Fluoxetine,akathisia, and suicidality: Is therea causal connection? Archives ofGeneral Psychiatry, 49:580-581,1992.

Zitrin, CM.; Klein, D.F.; andWoerner, M.G. Behavior therapy,supportive psychotherapy, imipra-mine and phobias. Archives of Gen-eral Psychiatry, 35:307-316, 1978.

Zubenko, G.S.; Cohen, B.M.; andLipinski, J.F., Jr. Antidepressant-related akathisia. Journal of ClinicalPsychopharmacology, 7:254-257, 1987.

Acknowledgments

This study was supported by agrant from the National Healthand Research Council of Australia.The author is grateful to JaneKruk and Doreen Hanlon for theirinvaluable assistance.

The Author

Perminder Sachdev, M.D., Ph.D.,F.R.A.N.Z.C.P., is Associate Pro-fessor of Neuropsychiatry, Univer-sity of New South Wales, Schoolof Psychiatry, and Clinical Direc-tor, Neuropsychiarric Institute, ThePrince Henry Hospital, Sydney,Australia.