An Overview of Side Effects

Caused by Typical Antipsychotics

.

George W. Arana, M.D.

Typical anlipsycholics often combine efficacy in treating antipsychotic illnesses with a side effect
profile that can affect every system of the body and range from the annoying-photosensitivity and

jaundice, for example-to the disabling-seizures and blindness, among others-to the potentially
r,Hul-agranulocytosis und neuroleptic malignant syndrome. The siJe effects of conventional anlipsychOLics arc associateu with clTccts al eNS transmission and receptor sites and appear in relation 10
dose levels and potency of the drug. Characteristics of palienls-induuing gender, age, and cDmorbiLi
medical illncss-ci.lll make thCl1l1110re or less susceptible to particular antipsychotic side effects. Side
effects influence patient quality of life and affect patient compliance with medications. This article
will consider the physiolugiL: syslems alTecled by conventional ncurolepties, the sexual anu reprodLlc~
tive side effects of typical anti psychotics, and the ccntral nervous sidc effects of the conventional
neuroleptics in the light of these concerns.
(1 Clin Psychiatry 2000;61{Sllppl Bj:5-11)

ypical antipsychotics have been a potent weapon in

the psychiatrist's annamentariulll against psychotic
illnesses, but the side effect prolile of these medications
is troubling. Adverse evenls can arfecl every system of
the body and range from the annoying-photosensitivity
and jaundice, for example-to the disabling-seizures
and blindness, among others-to the pO!entially fatalagranulocylosis and neuroleptic malignanl syndrome. The
side effects of conventional antipsychotics are associated
with crrects at CNS transmission and receptor sites and
appear in relation to dose levels and potency of the drug.
Patient characteristics-including gender, age, and comorbid illness-can inJ-luence susceptibility to panicular antipsychotic side effects. Side elTects affect subjective and
objective assessments of patielll quality of life, inl1uencing patient compliance with medication.
-Most physiologic systems are adversely affected by
typical anti psychotics. In particular, those side effects affect the CNS, including movement disorders, sedation,
and seizures, and certain other side effects can be particularly troublesome for patients such as those affecting
sexual and reproductive function.

From the DlfpartmenllJrPsJjchiatry. MelhcallJniversity or

South Carolina. Nalph H .Johnson E4 Medical Centel;
Charlestun.
Presented at the planning roundtable "Side Effects of
AlllliJ.~ychoticMedications: Physician s Choice ofMedicatioll
lind Pat;lfnt COmplimlCl!, ,. hehl.Jmwary 22, 1!J9!J, i/l Dallas.
Texas. and sJlonsored by an rmreslricled educational grant
(rom Jallssen Plwrmaceutica, L.P.
Reprint requests to: Geol:qe Il~ Arana, M.D., Director.
Menial Health Service, Ralph H. Johnson E4t11C, l09 Bee
Street. Charleston, SC 294()/.

J Clin Psychiatry 2000;lil (sLlppl 8)

PHYSIOLOGIC HEACTIONS
The physiologic systems affected by typical neuroleptics provide an apt system for organizing side effects
(Table 1).

Autonomic and Cardiovascular

Potentially the most dangerous side effects of lypical
antipsychotics are the autonomic and cardiovascular
effects, which can include ileus, ralls, arrhythmi<is, and
seizures. Cardiac effects may be direct or follow from hypotension and anticholinergic-induced tachycardia that indirectly alfect the cardiovascular system. Postural hypotension, possibly related to a-adrenergic blockade or Ca++
channel blockac~e, can be a serious problem in elderly pa. tients who are treated with low-potency anti psychotics.
This side effect also may contribute to hip fractures when
low-potency antipsychotics are used in geriatric populations. Palients sometimes develop tolerance to orthostasis;
gradually increasing the dose m.ay reduce the risk of hypotension. Less dangerous but troublesome anticholinergic effecLs include dry mouth, constipation, and tachycardia.
These are usually benign but may sometimes be clinically
significant, as, for example, in a patient with a compromised cardiovascular system.
In addition La the autonomic and cardiovascular cl"fects
of conventionul antipsycholics, quinidine-like ch<lnges
crln be observed on electrocardiographs in some patients. l
These quinidine-like effects include QT prolongation, abnormal T-wave morphology, and widening of the QRS
complex. Patients receiving antipsychotic medications are
at particular risk for lorsade de poimes arrhythmia,2 which

George W. Arana

Table I. Physiologic Systems Affected by Typical Antip!\)'chotic Compounds

System
Autollomic and
c,mlinvasclilar

Errect
Anticholinergic: xcrosltllllin, constipation
a-Adrenergic: p{)~lllml hypotension, nrlhostasis

Danger
IlcllS, (:Ills, nrrhylhmias

Falls. arrhythmias

Endocrinologic

Ca++ channel blockade: rClrogmde cjaculalion:

postural hypotension
Quinidine-like: lwt!vc flal/incrcascd QR inlcl"','3)
Tolerallce. prnbahly 10 anticholinergic effect
llypcrprnlnclincmia: :lmcl1llrrhca, galactorrhea.

High risl:: lnw potency. eg. thioridazine. ehlmprnmazinc:

low-mcdiulIl risk: I11cdiullll1l1tCllCY. eg. pCrphCIl:17.illC.
thinlhiXCllc. lm;apillc. trifluuperazine
Thinridazinc. Illcsnrillazine. and others

Arrh)'lhmias
Withdrawal. seizUl'cs
Pituilary adelloma

All. mmtly Inw potency. increased :lOtichnlinCT!!il'

All

Ohesity

All

i\.'!ctahnlic

Hcmatlllul;.ic

Hepatil:

Alle!]ic

Dermatologil:
Ophthalmologic

gync(,:fll11:lstia. impotellce
Weighl gain: > 5 kg g:lin within 2 mil in
:l\'cr:lg.c patient
Temperature clysrcgul:llion: hypcrpyrcxi;l. hyp(lpylcxi;,
Leukocytosis ;mllicukopcnin: transienl high or
Inw while cell culln!; usually within 3-f1 wk
or slarting trealmcnt
Liver [ulll:tioll te.~t elevnlion: transicnt.
soon arler initiating treatment
Jaundice (cholest:ltic-likc): early in treatment idiosyncr.ltic rever. right upper quauTllnt pain. chills
M;ICulop:lpular ra.~h. erythema multironne.
gencr:llized urticaria
Photosensitivity: .~kin hyperpigmenlalion
Corne:ll/lcnticular changes: granular deposits
nnt impairing \'jsion
Acute ,lllgle-c!osurc glaucoma: can be treated
and nllt contrainuicatioll
Pigmentary rclinupallly

Mo.~t

Ileat slmke. hypolhen11iOl

Agranulocytosis
(1/Ill.Oflll pt)
Nonc

None

All

Angioedema:
exfoliali\'e dermatitis
Nonc
Nilne

All

OIindness

High doscs, chronic lise, moslly chlorpromazine

Chiorprlllmlzinc. trinunpcr:tzine, pcrphcn;\zinc.
thiorillazine, nUphclIal.ine. chlorprolhixcllc
All

Illinllness

> ROO mglllihinridal.inc; m:c:lsiunally chlllrprtlll1:l;ojnc

is potentially lethal due to sudden onset of ;'Iction,

difficulty in treating, and potential to convert to a Iifethreatcning ventricular fibrillntion. Standard nntinrrhylhmic agents that cause QT prolongation cannot be IIsed because the prolonged QT interval sets the stage for this
disorder, Torsade dc pointcs can be treated with isoproterenol or cardiac pacing. Clinicians should be aware of this
risk, which Illay dcvclop wiLh many commonly used antipsychotics, including thioridazine, pimozide, haloperidol,
and chlorpromazine.
Endocrinologic and Metabolic
Neuroleptic side effects affecting the endocrinologic
system-amenorrhea, galactorrhea, gynecomastia, and
impotence-arise from hyperprolaclillemia, which has
been considered an unavoidable side effect in most patients treated with therapeutic doses of traditional antipsychotics and may even be a clinical marker of response.
Marken el aL' suggesled thal lypical neuroleplics may
block dopamine receptorfi in the pituitary prolactinsecreting cells, preventing dopamine~induced reduction of
prolactin release. The resulting hyperprolactinemia can result in amenorrhea in women and impotence in men.
Windga"en el aI.' found a prevalence rale of 19% for galactorrhea in 150 neurQleptic.trea,tcd ~chizophrenic patients. Hamner and Arana5 studied the available literature
and identified risk factors for galactorr;hea as use of a depot antipsycholic. traditional antipsychotic therapy (especially long-term). prior pregnancy. use of oral contraceptives, and a history of antipsychotic-induced galactorrhea.

Compound

Sustained prolactin elevations arc less likely to ocnlr with

the use of atypical anti psychotics, so atypicals are lreat~
ment options in patients with neuroleptic-induced hyperprol aClincmia.
Hyperprolactincmia is defincd as a prolactin levcl
above 20 ~Lg/L. but clinically significant symptoms arc unlikely to occur until the level reaches 30 to (10 ~Lg/L or
higher. Thus. hyperprolactincmia '1lone is not a rc'lson (0
prescribe therapeutic interventions unless adverse effects
are troublesome for the palient. Education and rcassurance
may allay concerns about symptoms such as galactorrhea.
If symptoms become clinically significant and the pnlient
is unable to reduce the dose of or change antipsychotics,
treatment with an agent such as bromocriptinc, which lowers prolactin levels, may be tried. In rare cases, hyperpro1.lctinemia is a sign of pituitary adenoma.
A weight gain or mOl:e than 5 kg within 2 1110nths is an
adverse event of antipsychotics acting on the metabolic
system in many patients. When chlorpromazine was introduced, the large majority of palicnts gained considerable
amounts of weight, and similar problems have occurred to
varying degrees with all antipsychotics. Excessive weight
gain places the antipsychotic-treated p<ltient at risk for the
obesity-associated illnesses that affecl the general population such as non-illslilin dependent diabetes mellitus and
cardiovascular
disease.
Weight gain is 'ulso
often a factor

I
in noncompliance with treatment. Since weight gain is
likely to be a concern for most patients taking antipsychotl
ic agents, it is important to stress behavioral and educational strategies La help prevent weight. increases.
J Clin Psychiatry 2000;61 (suppl 8)

Side Effects of'l'ypic,1 Antipsychotics

Othcr metabolic sidc effccts of ncuroleptics include hyperpyrexia and hypopyrexia. The slighl lemperalure decrease in most antipsychotic-treated patients is unlikely to
be,clinically significant. Heat stroke was marc likely [Q be
problcmatic in the days before air conditioning became
common.
~"
Hematologic and Hepatic
Neurolcptic side effects affecting the hematologic sys~
((:111 include leukocytosis and leukopenia, Vlhich usually
occur within the !irst 3 lo 6 weeks after antipsychotic
treatmenl is started. Although agranulocytosis, a pOlentially fatal ad\'cr~c ..m.:ct, ha~ hccn mo~t frcquently linked
'i.jlh the fir~t iJ.t:-pit:aJ a.rltip~::t:h'Jtil: dCJz.apirl(:. it t:arl aheJ
l,L:CUr uitlJ all)' "i Ill\:; l::i)iLal afJ\iv.. )Lhr,liL~..
Li \'cr I unctil)fJ abnf,fuJi.l.litit:-. during i.l.Iltip-,:: Lthtic.:
Ut~...tr..lll.

t [,t-t"'J u.J';.t.j .:.:.:::

\;;:.g

~ <:.rllip~:~r.:iA..i.:;:

rJ..i::.,.t:

been ill u~t. but art ~tiul.J:iI1 a I=.a~u:u i'}I iiJ~g ii.~:':'II;~r,!':.....
tion. Mild-lO-modenne increases in tran~amina~e enzyme
levels are sometimes discovered in routine laboratory
analyses, usually early in treatment; these increases are
unlikely to result in serious liver damage. Some patients
experience cholest3tic-like jaundice wilh idiosyncratic fever, ahdolllinal pain, ami chills early in (remment. Cholest:lsis al"fccts I % to 1% of p.Hicnts who lake.: chlurprunHIzine, indepenuent of dose, and orten during the lirst 4
weeks or treatment I; it has also been reported with haloperidol. 6 Antipsychotic trealment should be discontinued
and a thorough hepatic evaluation performed in palients
who are symptomatic or who have large elevations in liver
enzyme levels.
Allergic, Dermatologic, and Ophthalmologic
Allergic siLie effects include maculopapular rash,
erylhema l11ultiformc, and generalized urticaria. Urticaria
is among the most coml11on allergic reactions LO lhe administration of psychotropic medications. Photocontact
unicmia hns been observed during chlorpromazinc trealment,1 but ullergic reactions can occur with all typical
agents. The most seriolls allergic adverse effects are '.lI1giol.;l!cma and cxl'olialivc dcnnalilis.
Anlipsycholic adverse events affecting the dermalOlogic system include photosensitivily and skin hyperpig
IllcllIatioll. If lhe photosensitivity is an allergic reaction, it
should Occur aftcr an incubation period and should be corrclat~d with dose. Patienls should be warned about this
possihJc side elTecl so they c<.ln take piccaulions by avoiding exposure .lnd using sun blocks. Skin hyperpigmentalion seems lO OCClir m;.linly in patients treated chronically
with high uoscs of l,;hlorpromazine. l Pathophysiologic
mechanisms that may be responsible for this include an
inllaJ11lllatory response to chlorpromazine lhm causes increased melanin deposition or l11ebnin acting as a scavenger uf purple- LO blue-colored free radicals formed by
ultraviolellighl acting on chlorpromazinc,

J elin Psychiatry 2000;G! Isuppl S)

Ophthalmologic side effects, which sometimes involve

cutaneous structures or pigmentary changes, are often considered to be related to the dermalologic effecls, although
the palhophysiologic mechanisms may differ. Ocular
effects range from the inconvenient cornc<.Il/lcnticular
changes to the vision-threatening acute angle-closure
glaucoma and pigmentary retinopathy. Acute angleclosurc glaucoma: which occurs when pupils are dilated in
patients wilh physiologically narrow anterior chamber
angles, is a grealer risk for patients taking medications with
slrong anticholinergic effecls. tI Symptoms include blurred
vision, pain, lacrimation, lill edema, and such syslemic
effects as nausea and vomiting. To prevent permanent
ICJi.!o> 'If ',i~i"n from
incn::a.",eu intraot:ular prc~surc:,
tith::r ~ufgL:;al ir,h:r.t:fltirJn rJr treatment ;,ith teJpical ...ntichlJlirl::~.U::ri.:.~ dilU r~~n:... ~rrlrJ<:.t~JrJr(,irr.:::ti~ drug~ mu;,t tx:
imrrldiiat. Sir,:;c il.!.:UU:: a.(,~lt ...dcJ-~urC ;fb.w:;f'm.... can be
i:-t:~i. ~i i.~ ....JO: C:. vx.::.r;.i;..:i:':"S{~rl r:.r c:-.r.i~,,:~(.r:f,ti.c u..~c.
Pigmtllla.r) rtUIJulJi:.Lu(. b ;i.J:J~i !J.L:::J ... iJ i';~;":":' ~l:-.6
more than 800 mglday of thioridazine, but has been reported with lower doses of othcr '.JOtipsychotics.'J It occurs
when pigment is deposited, spreading from the periphery
to the celllntl retina. Patients first lose peripheral vision,
then night vision decreases, and scotoma may develop;
evenlually blindness C.111 follow. Visual acuity may improve
if pigmentary relinopathy is discovered early and i.lI1lipsychOlic therapy is stopped, but thc pigmcnlary changes arc
thoughl to be permanent and may progress even after treatment discontinuation. To minimize ophthalmologic side
effects, patients who are being.treated wilh typical alllipsychotics should be encouraged to seek routine eye care and
asked regularly about vision changes.
SEXUAL AND REPRODUCTlVE SIDE EFFECTS
Alllraditional anlipsychotic medications have been llSsociated with sexual dysfunction (Table 1). Men may experience ejaculatory disturbances related to Ca++ channel
blockade and/or adrenergic effecls. Impotence, decreased
libido, and changes in the quality of orgasm may be duc to
reduced teslosterone or hyperprolaclinemia. Women may
experience org<lsmic dysfunction ami reduced libido possibly due to a-adrenergic aClivity anu/or C.I++ channel
blockade.
Prolonged creciion, which can I~au iO priapism, is possibly related to the a.-adrenergic aClivity. AbOllt 20% of all
cases of medication~induccd priapism are <!uribuled to
cOllvention..i1 anlipsycholics, but priapism has nOl been
relmcd to dose, length of trealment, or potency of the antipsychotic. 1Il Priapism should be treated as .. urologic emergency since cl'fcctive ireatmcnl within the first 4 to 6 hours
should minimize lhe need for invasive procedures and lhe
possibility of permanent impotence.
Although sexual side effects can make conventional
<LniipsychOlics intolerable La Illany patients, c1iniciilns 01'-

George W. Arana

Table 2. Sexual and ReproducLive Side Effects of Typical Antipsychotic Compounds

Clas.o:;ilicalioll
SexuOlll1ysfllllcliull
".Iell

Woinell
Teratogcnicity
Risk to ncollntcs
Brca.~lfeeding

Effect

COIllpnullll

Ejaculatory disturbances: Ca++ channel bltlCkOldc

Ollld/or adrenergic effecls
Impotence, deCleased libido, ChOlll!!C in quality of orga.~lll:
reducctitesiOSIerone or hyperprolaetinemia
Prolonged erecliun: plIs.~ible a-adrenergic activity

NOlle

Orgasmic dysfunclion. rnlucctl lihido: possihle

n-atlrel1ergic anti/or C:I++ ch;umcl hlockade
FirM-lrimester exposure: nonspecific congenilal defccls:
minimizc wilh low-umc. high-potcllcy agen!
Neonatal hepiltic dy.~fllnclilm. >Illticholincrgic ,!;ide effccls.
extmpyramid;J!sioe effcct,!;
Drugs secretcd in milk nwy callsc Ileurologie
;:Illd olher side cffcC!,!;

NOllC

Chlorproma7.inc. chillrprothilicllC. lluphcna7.inc. haloperidol.

llle$orid:l7.ine. lhiolhixcnc. thinrida7inc. trilllltlllCr<l7ine
ChlorprolilOlZilll:. flllllhcn:J7.ine tlecallll;\lc.
hahlpcridllJ. pimn7.itlc. Ihitlrida7.inc. Ihinlhixcllc
Chlorpn1l1wzinc, nuphcnazinc. h'l!l)pcridol. l1le.~oridil7il\c.
rnnlimlone. pcrphrna7.inc. Ihiorida7.inc. thinlhixenc
FllIphcllOlzinc. Illc~(lrida7.ille. thillrida7inc. trillllollL'ra7.ine

Birth defeels

All

ten fail to ask about sexual function and patients do not reporI sexual problems voluntarily. Aizenberg et al. tl studied
122 male patients-20 drug-free schizophrenic patients,
51 neuroleptic-treated patients, and 51 healthy controlsto quantitatively and qualitatively assess sexual function
with a detailed structured interview. The researchers found
thaI, although a high frequency of sexual dysfunction was
reported by both !'ichizophrenic groups of patients, impairments in arousal (erection) iJnd orgasm during sex were
reported mainly by the lrcated patients, who also disclosed
dissatisfaction with their sex.ual function. The authurs
noted thaI, while neuroleptic treatment was associated
with restoration of desire in schizophrenic patients, it
can lead to problems with erection, orgasm, and sexual
satisfaction.
Ternlogcnicity, risk to neonates, and risk from ingesting
breast milk arc also concerns with the typical antipsychotics, which cross thc placenta and are secrcted in breast milk.
First-trimester ex.posure should be avoided when possible
to avoid nonspecific congenital defects. The risk can be
minimized with the use of a low-dose, high-potency agent.
In neonates whose mothers were treated with conventional
antipsycholics, the risk can include hepatic dysfunction,
anticholinergic side effects, and extrapyramidal side efrects. Handal et al." reported on a 2-week-old girl wilh
symptoms resembling those of tardive dyskinesia. Her
mother had received perphenazine decanoate during the
second ami third trimesters of pregnancy.
Typical antipsychotics ingested by breastfeeding
mothers can be secreted in milk and cause neurologic and
other side drecls in inrants. Yoshida el al. 13 studied 12
mothers who were prescribed haloperidol, chlorpromazine, or trifluoperazine and breast-fed their infants. Clinical and developmental evaluations of the infants continued until they were 30 months old. Eigllteen bOltle-red
infants whose mothers also took anti psychotics or moodstabilil.ing mcdic<ltions sctved as controls. Inl'nnts were
found to bc ingcsting up to 3% of the maternal daily dose
per kg body weigh!. Although 2 inFants had plasma con-

O;JlIger

NOlle
Priapism

Cl1Illplicalcd
childbirth
None

Ali
Chlorpromazine. Irinllllrcra7.inc, rrnchlorpcfa7.ine,
Ihioriuaz:inc. haloperidol. lllcsorida1.inc

centrations of haloperidol at the adult level, adverse

events were not found. However, 3 other breastfcd infants
showed a decline in developmental scores between first
and second <lssessmenls. The researchers advised c<llltion
if breastfeeding mothers take neuroleptic drugs ilt the upper end of the recommended range.

CNS SIDE EFFECTS

The eNS side effects of antips)'chotics include movement disorders such as tardive dyskinesia and acute extrapyramidal symptoms (EPS), akathisia, akinesia, and dystonia; the neuroleptic malignant syndrome, which may be
a variant of acute EPS; seizures; and sedation and other
cognitive effects (Table 3). Most patients who receive conventional anti psychotics experience movement disorders.
which nol only can be troublesome to paticnts hut also
concern caregivers. The neuroleptic malignant syndrome
is particularly worrisome because of its potential for morbidity and mortalit)'. Some physicians limit the usc of antipsychotic mcdications because of the risk of seizures.
which are generally manageable with dose and tlrug ndjustments. Sedation and olhcr cognitive effects onen
bother paticnts and may limit compliance.

I
.,

Tardive Dyskinesia
Tardive dyskinesia, a syndrolne of choreoathetotic
movements that occurs after the chronic usc of antipsychotic medications, is one of the most troubling side effects nrising from conventional neuroleptic use, in parI because it is disfig~ring and contrihutes to the stigma of
schizophrenia. Elderly patients, women, and people with
diabetes seem to present tile grealest risk for the dcvelopment of targive dyskinesin. which can be irreversible and
may. interfere with the normal activities of daily living. P.
The overall incidence rate ~al1ges from 32% aflcr 5 years .~.
of neuroleptic exposure to 68% after 25 years of exposure.'" Tardive dyskinesia may develop in as many as 53%
elderly patients after 3 years of cumulative exposure to

or

J Clin P5ychialry 2000;61 (suppl 8)

I

.tt

Side Effects of Typical Antipsychotics

Table 3. CNS Side Effects of Typical Antipsychotic Compoonds'

Effect
Tardive dyskinesia (TO)
','

Acute extrapyramidal
~Ylllplorns

Key Features
Irreversible

Comments

io ulllny pmicllts; interferes with ADL;

. disfiguri]lg, cOnlributcs to stigma

Vcry uncomfortable for patients; CUIIIll3.sk clinical

Akatllisia

depression; illlcrfcn: with writing and ADL

Vcry uncomfortable for patients; CUll rcscmbh:

Akinesia

ps}'chOlic >lgitiltion, anxiety; oflen leads to

increased dosing
Mimics negative symptoms of schizophrenia

Risk of TD vs COSI reduclion will be foclIs of debate

over usc uf atypical anlipsychotics '
Anlicholinergics urc quite effective
/i-Bl(lckers, ullticholinergics, bcnztluiuzcpines ,Ire
effective; twice as likely to develop in womcn

MAO-B promising for lfeatmcnt

or psychomotor rClunJation of depression
Laryngeal spasm is life-threatening; frightening to
Mosl common in younger mcn; prophylaxis
DyslOliia
patients; interferes wilh compliullce; r..Irc aftcr
and ucute treattnenllllethods are effective
1 wk of trcalmenl
Life-threatening (about 15% mortality); ullpn.:dict:lblc.
Neuroleplic malign'lllt
Early recognilion is key; mortalily rate decreased
syndrome
occurs in n.ol %-1 % of psychiatric adl11issioll~;
from 75% bcfore 197010 15% in I ~~O
reduces option 10 usc high doses
All drugs reduce seizure threshold; an early
Seizures
Risk fllr.:turs include preexisting sci7.un:s, CNS
complic:Hioll of treatlllcl1t; manageable with
pathology, abnormal EEG, mpid im;n:asc of dosage
dose-drug manipulati01l
Sedlltitll\
Interferes with rehabilitatiol\; mistaken
Likely effect of histamine b1.ockade
for cuntrary behavior
Cognitive impairmclll
No signilicanl posilive or negalive effects 011 memory;
App,lrenl cognitive ilnpainnellt probably EPS-relaled
may inlerfere with allenlioll or response time
aAbbn.::\,jations: ADL = aclivilies
daily living; EPS - cxtrapyramidlll symplOms; MAO - monoamine oxidase.

or

typi<.:al antipsychotics. 15 Medication should be changed

whenever signs of tardive uyskincsi<l arc ohserved.
Clinicians sometimes try to avoid the use of conventional anlipsychotics because of concern about the legal liability of tardive dyskinesia. Since the risk of tardive dyskinesia increases in proportion to the length of treatment,
and there nre emerging data thm indicate a lower incidence
of treatment-emergent tardive dyskinesia with the use of
thc morc cxpcnsive atypical unlipsychotics,lf' the risk
of tardive dyskinesia versus cost of treatment is likely to
hecomc an issue in medication selection over the next
several yeiJrs.
Acute Extrapyramidal Symptoms
The incidence of acule EPS-ukathisia, akinesia, and
dystonia-associated with traditional antipsycholics varies,
but most researchers agree that neuroleptic-induced EPS
occur in 50% (0 75% of patients who take typical antipsychotics. 17 For the typical neuroleptics, EPS can bc placed
on a scale of potency. High-potency drugs can be administen~d ..It lower doses and are associateu with higher rates of
EPS but Icss sedation, hypotcnsion, and anticholincrgic
dr~cts. Low-potency urugs arc associated with fcwer EPS
but higher rates of sedation, hypotension, and anticholinergic cITcCIS. 1
Routine monitoring for EPS is essential, and scales
such as the Simpson-Angus Neurologic Rating Scale, the
EXlrnpyramidal Symplom RUling Scale, and the Barnes
Rating Scale for Drag-Induced Akathisia offer the best
tools for documenting and objectively qual1lifying longitudinal changes. Patients should be assessed for the presence of EPS when treatment with conventional <lntipsychotics begins and regularly thereafter.

J Clin PsychiatlY 2000;61 (soppl 8)

Akatl,is;l'. About 250/0 of patients treated with a conventional neuroleptic will develop akathisia, a side effect characterized by a sense or inner restlessness and a compulsion
to move accompanied by restless motion. JI( This symptom
is probably the 1110st intolerable of those that develop early
in treatment. Fidgety Illotion of the legs when sitting and
inability to stand in one place are the most common observable symptoms. Patients Inight complain of feeling restless,
tense, jittery, or anxious.
Akathisia, which can resemble psychotic agitation, is
associated with higher doses of medication, and may
coexist with other EPS. Women arc twice as likely as men
to experience akalhisia. While some investigators have
noted lhat akathisia occurs Illore onen when highpotency antipsychotics are used, Sachdev and Kruk" did
not find this factor significant. The most effective treatment for akathisia is a decrease in the dose of amipsychotic or the use of a ~-adrenergic blocking agent. Anticholinergic agents and benzodiazepines are also effective.
Atypical i.intipsychotics, which generally have less risk of
acute EPS, may be a reasonable alternative for patients
who cannot tolerate akalhisia.
Akitw!iia. Over 509(, of patients treated with conventional anlipsychotics may experience akinesia, and 90% of
the cases are reported within 3 months of" starting treatmcnt.~11 Akinesia, which mimics tile negative symptoms
of schizophrenia or the psychomotor retardation of depression, involves (I) slowed motor activity with difficulty initiating and susw.ining behaviors, (2) anhedonia
with depressed mood and natlcned affect, and (3) cognitive impairment. Thus, distinguishing akinesia from negalive symplol1u.lIology or depression can be difficult, but
has obvious implications in terms of treatment. The rela9

George W. Arana

tionship between akinesia and negative symptoms is complex amI gives rise to the t1irficully in t1istinguishing between primary and secondary negative symptoms.
Prophylactic anliparkinsonian agents for akinesia are not
recommended. although monoamine oxidnse inhibitor-B
has shuwn promise for treatment. As with i.Iki.lthisii.l, i.lkincsia should be treated by lowering the ~1I1tipsycholjc dose, if
possible, or changing llcurolcptics. If neither strategy is SllCcessful, i.llltiparkinsonian treatmcnt should be tricd.
Dystonia. Dystonia is another disturbing side effect of
typical neuroleptic therapy, which usually occurs during
the first week of trcaLJnent or shortly after a dose increase.
The involuntary contractions or muscle spasms, which are
fright.ening to patients, Illay occur within hours of initiating treatment; the laryngeal spasm can be life-threatening.
During contraclion, the afTected bOtly part may appear to
move in a moderately slow, writhing fashion. A sustained
contraction may stop temporarily before starting again.
Other problems, such as temporomandibular joint dislocation. Illay develop secondary to the muscle spasms. Thc
pain, surprise, <lnd bizurre quality of acule dystonia may
cause fUlUre noncompliance.
Dystonic reactions generally respond rapidly to anticholinergic medications such as benztropinc. and prophylactic anticholinergic treatment is lIseful for patients at
high risk such as young men who are receiving highpolency anlipsychotics. I \hen my colleagues and f!' reviewed data from 9 studies that compnred the incidence of
drug-induced acute dystonia with and without the concomilant anticholinergic therapy, we found that the rate of
dystonia was decreased almost 2-fold in those taking concomitant anlicholinergics.
Neuroleptic Malignant Syndrome
Neuroleptic malignant syndrome (NMSl, like agranulocytosis, is a potenlially fatal side effect of neuroleptic
treatment characterized by hyperthermia, severe EPS, autonomic nervous system instability, and clouding of consciousness. The incidence of NMS ranges from 0.01% to
1%,22 and the risk is increascd in agitated men who have
received intramuscular injections of anlipsychotic medications in high and rapidly escalating doses. Early detection
and nppropriate interventions are important in 31neliorating the course and outcome of NMS; the mortality rate
from NMS has decreased from 75% before 1970 to 15% in
1990.
Muiliple factors probnbly contribute to the occurrence
of NMS. The fact that patients can be reehallenged with
antipsycholic medications without a recurrence of NMS 23
means some factors. e.g., comorbid medical conditions,
dehydr<1tion. <1git~ltion, must be transienl.
Seizures
Typical <1ntipsychotics in general reduce the sei7.ure
threshold, making seizures a potential early complication

10

of antipsychotic treatment. The practical risk of sei7.ures,

which occur in 0.5% to 0.9% of patients taking conventional nntipsychotic:-i,l is low. Rapid upw:lrd titration is a
risk factor for seizures, which can generally be managed
with dose and drug adjustments. Other risk f;lclors include
a history of seizures, eNS pathology, and ahnormal electroencephalognlph results. Since seizures can be minimized through careful medication selection. dosage reduction, and use of :Int iconvulsallts, the uccurrence of seizures
is not a cOlltraindicalion to treatment.
Sedation
Conventional i.1lltipsycholics arc sedating, a likely effect of histamine blockade. While sedation may seem ben
eficial initially in the treatment of highly agitated psy
chotic patients, over the long lenll. it is oneil mistaken for
contrary behavior and interfcres wilh rehahilitalion. In
general, high-milligram, low-potency :I11tipsychotics produce more sedatiol1 tl1<111 low-milligram, high-potency
agents. Sedation can be dirricuh to distinguish from the
mental slowing of cognitive impairment.
Cognitive Impairment
The effects of conventional neuroleptics on cognition
are not well understood. Reviews of the literilture reveal
contradictory fin.dings. Cassells ct al.,~1 for eX:lI11ple. reported that the acute administralion of conventional antipsychotics impairs perform:lnce on some, but not all, tasks
requiring vigilance and allention and on some tasks requiring motor bclmvior. The effects of conventional antipsychoties all cognition arc confounded by the fact that many
antipsycholic.treatcd patienl.'i are also taking allticho
lincrgic medication. Spuhn allll Str:lllSs~5 found ncuroleptic therapy was associated with limited normalization on
many psychological mensurcs, where:ls anticllOlinergics
were associated with disruption of memory. Apparent cognitive impairment, thus, may be related to the administration of anticholinergic medication or with EPS-Iike akinesia that cause cognitive dulling. Jeste et al.,26 in a review of
humLin and animal studies of adverse neurobiologic:ll effeelS arising from long-lerm usc of typical ncuroleptics,
noted that persistent cognitive impairment associated with
long-term use has not been well documented.

IMPACT 01' SIDE EFFECTS

ON QUALITY OF LIFE
All of lhese side effects affect the patient's quality of
life and contribute to noncompliance. Awad and 1-log311 27
reported that subjective response to neuroleptics can predict compliance, therapc)Jlic outco'me, and suicidal behavior. While conventionaJ'neuroleptics '8re effective in the
treatmenl of psychotic illness, they have' pdverse side effect profiles that can affeel every physiologic system.
Some of these effects slich <1S dystonia and allergic reac-

J elin Psychiall,' 2000;61 (,uppl 8)

\ i1.'

Side Effects of Typical Antipsychotic,

Figure I. Side Effects Thai Impact Quality of Life'

Time From Initiation 01 Treatment

Acule
Side Effects

NMS
Dystonia
Endocrine
Aile/gil:

Ca,diovascular b
Aulonomlc b

(0--14 days)

Subacule
(2-10 wk)

Maintenance
(3+mo)

.'

EXlrapyramidal b

..

Weight gain

Oermatologic
Sexualb
Tardive dyskinesia

"Abbreviation: NMS = neuroleptic nHilignunt syndrome.

"h'lany can be medically managed.

lions occur wilhin the firs[ few days of starting tre<Hmenl

while others such as Lanlive dyskinesia may not emerge
for months or years (Figure I). Many of these adverse effects, such as cardiovascular and extnJpyramidal symplams, can be managed medically.
Side effects influence the patient's daily life in a variety
of ways that extend from the merely annoying to the life
threatening. There is a wide varinbilily in the susceptibility of pUlients for the develoment of the side effecls reviewed in this article. Side effects are evident' both in the
subjective and objective assessmcnls or patient quality of
life, sometimes intlucncing patient compliance with medication. Hence, the clinicians must carefully consider the
impact of side effects when a conventional neuroleptic is
prescribcd.

I.

Dmg IWllles: LJenztropine lCocntin and others), bromocriplinc (Parlo

del), chlorpromazinc (Thurazinc and others), chlorprothixcne (TaracIan), cloz'lpinc (Cluzaril), Ouphcl\<lzinc (Prulixin ;llld OIhcrs), haloperidol (Haldol and uthcrs), isoprotcrenol (lsuprcl hydrochloride), loxapinc
ILoxitanel, Illcsoridnzinc (Sercntil), mulindone (Moban), pcrphcnazinc
ITrilafoll), pimozidc (Or'I], ]Jrochlorperazille (Comp.rline), thioridazine (t.lell'lril and uthers), thiuthixenc (Nnvilne), anu tril1uoperazine
(SlClazine).

Disc/o.wr/! (lJ oJf-Il/hl!! lI.wg/!: The author of this ilrlielc has d~h.:nnil\cd
that, til the best of his knuwledgc, Ill) investigatiullal infurlllatioll about
phanllal,:elllieill i1gelll~ h,,~ been prcsentcd herein that is outside U.S.
Fund and Drug AUlllinislralitlll-apprnved lahcling.

REFERENCES
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Uulll()()7:2J:567-5K2
2. Tholilas SilL. DI'Il!!~. QT interval ahnorlllalitics 'll1U ventricular arrhytillnias. r"\u",else Dmg Rcactiolls Tosienl Rev 11)9..4; 13:77-102

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3. l\-'larken PA. Haykill RF. Fisher IN. Managemcnt of psychotropic-induced

hypcrprolactincinia. Clin PhannacoI1992;ll:851-856
4. Winugasscn K, Wcssclmalill U, Schulze Monking H. Galactorrhea and
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tf
5. Halllner MB, Aruml GW. Hypcrprolilctinclllia in i1l1tipsychotic-trc'IICd
padl,.'"llb: guidelincs fur avoidance anu managemcnt. CNS Drugs 199H;IO:
201J-222,
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6. Dinc!'>Oy HP, Sac1inger DA. Haloperidol-induced c\loleslatic liver disease.
Gastmcnterology 1982;83:69+-700
7. Lowell CR, Cnll1in E, Rhlldcs EL. Ph(lllX.'unlael uJ1icaria rrol.lI chlorpromllzinc. Conlacl Dermatitis 1986;14:290-291
8. Oshika T. Ocular adverse cfii:cts of neuropsychiatric agents. Drug Saf
1995; 12:256-263
9. Mitchell AC, Brown KW. Chlorpromazine-induced retinopathy (letler). Br
J Psychiatry 1995; 166:812-823
10. Gitlin MJ. PsychOlropic medic:Jtions mnl their crreels Oil sexual function:
diagnosis, biology, and treatmcnt approaches. J Clill Ps)'chialry 1994;55:
406--413
II. Aizcnbcrg 0, Zcmishlany Z, Dorfman-Etrog P, ct a!' Sl:xua[ dysfunction in
lIlale schizophrenic patil:nls. J CUn P~ychialr)' I ()95;56: 137-141
12. Handill M, Matheson I, Bcchensh:l:ll AG. et al. Antipsychotic agcnts and
pregnant WOlllen:.l casc rcportllelterl. Tidsskr Nor L:legdoren 1995:115:
2539-2540
13. Yoshida K, Smilh 13, Craggs M, et al. Neuroleptic umgs in breaSHnilk:
a sludy of jlharmacokillctics and of po~sible ;Idvcr~e effects in breast-fcd
infittlb. Psyehul Mcd 1998;28:81-1J1
11. Glazer WM, Morgcllstcm 1-1, Dnuccile JT. Predicting the long-tcon risk nf
lardive dyskinesia in Ollipaticnl.~ maintained nn neuroleplic llledil;alinJ1S.
J Clin P.~ychiiltry 1993;54:133-131)
15. Wocrner MG, Alvir JMJ, Saltz ilL, ct al. Prospeclive llludy of tardive dys
kinesia in the elderly: mlc."i and risk fur.:tnrs. Alii J Psychiatry 1998;155:
1511-1528
16. Tollefson GO, Beasley CMJ, T<lllllJrJ RN, cl nl. Blind, conlrollcd, longleon study of the t:tllllp<lr:ltive incidencc of treatment-emergent t<lrdi,c
dyskinesia with olnnwpinc or haloperidol. Am J Psychiatry 1997;154:
1248-1254
17. Collabonuivc Working Groop on Clinical Trial Evaluations. Asse~sl11ent or
EPS nmJ tardive dyskincsia in clinic:!t trials. J Ctill Psychialry 199H;5!.l
(suppl 12):23-27
18. Habteatl SM, Bames TRE, Speller JC. Akalhisia: pn:valence and associ;lIed dysphoria in an in-piltient population with chronic schizophrcnia. Dr
J Psychiatry 11)94;164:177-183
IIJ. Sachde\' P, Kruk J. Clinical charm;teriSlics and Ill"edisposing factors in aClite
dmg-induced :lk:lthisia. Arch Gen P:>ychi:llry 1994;51:963-1)74
20. Rcmingloll G, Kapur S. NCl.lrolcplic~illduccd cxtmpyr,unida1 symptoms
anu the rolc of combined serotonin/dopamine antagonism. J Clin Psychiatry MOllograph 1996;14(1):14-24
2 I. Amua GW. GolT DC, Baldcssarini RJ, el al. Eflic;lcy ur antit:holillcrgic prophylaxis fur neuroleptic-induced :Jcule dyl>tonia. Am J Psychiatry 1988;
145:993-996
22. Casey DE. TIle relutionship of pharmacolugy to .~idc crfecls. J Clin Psythi
atry 19()7;58(suppl 10):55-62
23. Pope HG Jr, AizJey HG, Keck PE Jr, et :II. Neuroleptic malignanl
syndrome: long-term follow-up of 2U C;l~es. J Clin Psychi'ltry 1\)91;52:
208-212
2'-1. Cassens a,lnglis AK, Appelbaum PS, et al. Ncurulcptics: erfects on neuropsychological functioll in chmnic schizophrenic.: paticllls. St.:hiwphr l3ull
1990;16:477-199
15. Spohn HE, Str.IIISS ME. Relation of nCllnJlcptic ilud anticholincrgic lllcdi
cation III cognitivc fUllt:tillllS in schizophrenia. J Abnonn P.~ychol 1989;98:
367-380
2(). Jellte DV, Lohr JB, E."thillll JH, ct OIl. Adverse neurobiological effccts of
Inng-term lise or ncumlepties: hllllliln anll animal studies. J Psychiatr Rc"
1998;32:201-214
27. Awad AG. Hogan 1'1'. Subjcctivc re~Jlllmc lU nCliroleptics and the tlllillily uf
life: implicalinlls for tn:<Ilmen{ (IulctllllC. A'l:l Ps)'chialr St.:;JllO 1994;80
(Sllppt 380):27-32

11

Discussion

An Overview of Side Effects

Caused by Typical Antipsychotics
Dr. Conley: The effect of schizophrenia on qnality of
life has been tremendollsly ulHlercmphasil.cd. Some outcome studies I and Illy colleagues have done in Maryland
have demonstrated the superiority of aLypicnl antipsychotics over lypical ncuroleplics; the difference in recidivism
rates between patients taking typical alllipsycholics and
those taking novel anti psychotics is remarkable. These improved oUlcomes arc due largely to compliance. Persistent
medication compliance is a phenomenon rarely willlcssed
with patients taking lypical anlipsychotics. The dysphoria
accompanying the use of traditional 3ntips)'cholics has received little attention.
Dr. Mcllzcr: First-episode patients' responscs to
dystonias and extrapyramidal symptoms (EPS) in gcnerul
arfct:t long-term cOlllpliant:c. In addition, the costeffectiveness of atypical anti psychotics has important implications for the ullimate cost of treating schizophrenic
patients who are noncompliant.
Dr. Arnna: Quality of life is a great problem in patients taking the typical anti psychotics. Families may be
happier than they were before lrentlllcnt because patients /
iJrc 110 longer hearing voices, but the patients still lie il:J
bed all day. They arc suffering.
Dr. Meltzer: I have done a lot of work with quality
of life. Of chronic illnesses, schizophrenia ranks among
the lowest-with AIDS-in quality of life. We have not
been able accurately to determine how much of the poor
quality of life associated with schizophrenia is related to
the side effects of medici.ltions and how much is due to
the limits of their efficacy. 1 relate poor quality of life in
particular to problcms of cognition, work functioning,
and negative symptoms. I would not expect quality of life
to improve drastically if medication side effects were
eliminated.
.
Dr. Masand: When patients are asked why they are
noncompliant with medications, the number one reason
. cited is side effects. When asked about their perception of
distressing EPS, which are the most common side effect,
the chief aspect of EPS cited for noncompliance has been
low motivation, which raises the whole issuc of primary
versus secondary negative symptoms. Is low motivation
a result of secondary ncgative symptoms, or arc these
symptoms a primary part of the illness? Nobody has made
this distinction in terms of compliance. No one has asked,
for example, whether primary negative symptoms or secondary negative symptoms due to EPS are causing non-

12

compliance in patients, bCCi.lUSe there is no Will' to differentiate them in a clinical setting. After low motivation, the
second Illost common EPS cited by patients as a rcason for
noncompliance has been akalhisia. followed by tremulousness and tardivc dyskinesia. Tardive dyskinesia bothers clinicians much more than i1 bothers patients. only 5%
of whom have cited grimacing and posturing as a reason
for noncompliance. There is often this disparity between
reasons for noncompliance given by the patient and the
physician.
Dr. BJncklJUrn: Quality of life is beginning to be
addressed by physicians. Singer et aJ. [lAMA 1999;281:
163-168J address quality-of-life issues in end-of-life care.
They found that paticnls' perspectives were often different
from those or physicians.
Dr. Meltzer: Dr. Arana, you raised the issuc or higher
risk of tardive dyskinesia with the low-cost typical antipsychotics versus lower risk with the marc expensive
atypical agents and ciled the incidence of tardive dyskinesii1 as I in 4 patients t:lking typici.ll anti psychotics. The ratc
of agranulocytosis pCI' patient for the phellothiazines is
closer 10 I in 2000, while it may be much lowcr ror haloperidol. When c10zapine treatment is carefully monitorcd,
the death rate is I in 10,000 1000.
Dr. Arnnn: I agree. The problem of agranulocytosis antcdates c1ozapine. For example, the risk of developing
agranulocytosis in chlorpromazine users is Illllch greater
than we realized.
Dr. Conic,)': On my recent trip (0 China, where c1ozapine is the drug of choice, particularly in chronic, hospitalized patients, I found that monitoring was not performed
on a regular bl.lsis. I assumed, therefore, that the death rate
from agranulocytosis \Vas very high, but it wus nOI. Thc
Chinese monitor the patient's medical condition. They regard chlorpromazine unsafe from the standpoint of secondary infections.
I
Dr. Meltzer: Sandoz originally dictated our approach
to monitoring c1ozapine. But weekly monitoring is rare
elsewhere in the world. I have encountered those who cite
a 100-(0-1 difference between the cost afan atypical anlipsychotic andnhe cost of atypical Il.euroleptic, a difference
I question. There are probably many !circumstanccs in
which much more is paid. even for'the"lypical antipsychot-'
ics. Dr. Garver. do you have any statistics?
Dr. Gnrver: The Veterans Administration (VA) purchases haloperidol for less than $10 a year per patient.

J elin Psychiatry 2000;61 (suppl 8)

Discllssion

Dr. Arana: Represenlatives of the VA cile a 100-fold

difference every lime Ihey call me to ask, "Are you sure
thaI you want 10 Sl1cnd this much money on olanzapine?"
Dr. Masand: The depot formulation of haloperidol
costs $1,000 a year, bUllhe oral form COSIS Ihe VA, at the
mosl, From $ I 010 $30 a year.
i
Dr. Meltzer: Whal happens to the patient who is filling
a prescription aL a reli.lil pharmacy?
Dr. IVlasand: At a retail pharmacy there is ilbout a
70- to 100-fold difference in the cost of generic chlorpromazine or haloperidol and risperidone; the difference is
grc<lter for olanzapillc.
Dr. l\IIiIIer: At OIlC retail pharmacy I checked, the cost
of haloperidol was between $10 and $20 a month.
Dr. I'vlcltzcr: That price lncans that haloperidol costs
1110s1 p<Hit..:nls aboul $240 a year. Altha! ralc, the cost or an
alypical anlipsychotic is 15 times the cost of haloperidol.
I want to examine the ethical issues around tardive dyskinesia, which can appear quickly, be severe, and be irreversihle in a smull number of people.
Dr. Zarate: Tardivc dyskinesia can occur panicularly
in rirst-episode paLients, in whom the cumulative incid~llcC is about 5% per year and Can increase (0 20% to
25% after 5 years or trealment with traditional antipsychotic drugs. SOll1~ studies suggcst a risk for tardive dyskincsia up tn 13 times greater with the traditional antipsychotic drugs than with novel neuroleptics. Given these
disparities, it is unethical today to expose a first-episode
patient to a traditional antipsychotic drug. We should consider atypical antipsychOlics as first-line medications in

I.

I
I

schizuphr~nia.

Ur. iVlellzer: What is different about a chronic

patient? I r the palient is 27 years old and has had 3 psychotic breaks while being treLiteLi with typical neuroleptics, why proceed any differently than one would with the
21-year-old, I1rst-episodc pilli~nt?
~
Dr. Zarate: The ethical issues :ne similar for both
groups of palienls (lirst and multiple episode patients).
The only difference is that some chronic patients who have
been exposed to neuroleptics for many years (with little or
no cvidence of tardive dyskinesia) and ar~ relatively stable
may not be the best candidates to consider switching. In
this case, the risk of switching (from a tYljicalto an atypical antipsychotic drug) may be greater than the risk of developing tmdive dyskinesia (especially if there is no eviLi~nce of it :lfler many y~ars of neurolcptic exposure).
Howcv~r, unfortunntdy many clinicians continue to resist
switching to atypical antipsychotics despitc clear bcnel1ts

i
I

I'

of these drugs especially in patients \,..ho continue functionally or cognitively impair~d, or have tardive dyskinesia. For first-episode psycholid patiems, we will do a great
service to our patients by ne~r exposing them to typical
nntipsychotic drugs.
Dr. Masand: The risk is probably the grealesl in lhe
first 7 years, and then it lends to level off. A patient who
has been taking a typical antipsychotic for 13 years will
not incur the 5% risk a year that Dr. Zarale mentioned.
The case for using atypical antipsycholics is as strong
for somebody who has been exposed to conventional neuroleptics for 1 or 2 years and has had 2 or 3 psychotic
episodes as it is for the first-episode patient. The risk of
tardive dyskinesia with cumulative exposure to typic<ll
ulllipsychotics is the same for the first 7 or 10 yenrs as it
would be for somebody with first-episode schizophrenia.
Who makes the decision as to what side effect should be
acceptilble to patients and what costs should be assigned to
each side effect? The psychiatric palient is unfairly targeted to endure more side effects than the average medical
patient. If patients with diabetes or hypertension had a
choice of 2 drugs-one that produced tardive dyskinesia
and one that did not but cost 100 times more-there would
be a great hue ilnd cry lhat the <lv,erage diabetic patient was
being exposed to tardive dyskinesia. The cost/performance
trade-olT for lypical and atypical anlipsychotics would not
even be considered for a patient with a medical illness.
There is absolutely no reason, from an economic standpoint, to justify even a 200-fold cost savings by exposing
somebody to an irreversible neurologic side effect that is
traumatic for both the patient and the family members.
Dr. Meltzer: I regularly clu.:ounter-particularly in VA
hospitals-patients who are determined to remain with the
drug they have been taking all along. They can have tardive dyskinesia, they can have severe EPS, bUl they. have
been laking haloperidol for 13 years, and no mailer what
they are told about the benefits of olher medications. they
refuse 10 change. First-episode patients often imprint on
their initial medications.
Dr. Garver: How does the risk of tardive dyskinesia in
somcone who has been tLlking typical nl.:uroleptics for 13
years compare with that in the uninitiated palient'!
Dr. Zarate: The risk of developing tardive dyskincsia
when taking a convcntionul antipsychotic is greatest in the
earlier years, then the risk levels oil aftcr the l1rst Liecade.
There Inight bc a second peak (increascd risk of developing wrdive dyskinesia) in the elderly. There arc however.
spontaneous dyskinesia that may occur in this age group.

I,

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J Clin Psychiatry 2000;G! (sLlppl 8)

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13