VOL 21, NO. 4, 1995 Clozapine: Efficacyand Safety

579

by Robert W. Buchanan Abstract

Clozapine (Clozaril) representsthe first major advance in thepharmacological treatment ofschizophrenia since the introduc-tion of antipsychotics into clini-cal practice in the 1950s. Studiesconsistently support its efficacyfor reducing positive symptomsin acutely psychotic patients andin treatment-resistant patients,for preventing positive symptomexacerbations as a maintenancetreatment, and for reducingsymptoms of hostility and vio-lence. There is evidence to sug-gest that clozapine may improvesocial and occupational function-ing and quality of life and mayreduce affective symptoms, hos-pitalizations, secondary negativesymptoms, and tardive dys-kinesia. Its most significant sideeffects include agranulocytosis,seizures, weight gain, hypoten-sion and tachycardia, sedation,and perhaps rebound psychosis(with abrupt discontinuation ofmedication).

Schizophrenia Bulletin, 21(4):579-591, 1995.

Clozapine (Clozaril) represents thefirst major advance in the pharma-cological treatment of schizophre-nia since the introduction of anti-psychotics into clinical practice inthe 1950s. The introduction ofclozapine and further research re-garding its novel clinical effectshave stimulated renewed interestin drug development and fosteredseveral hypotheses regarding waysin which the efficacy or adverseeffects profile of antipsychoticdrugs might be improved.

First manufactured in 1959,clozapine is a dibenzodiazepine

derivative with unique preclinicaland clinical characteristics. In pre-clinical studies, clozapine, likeother antipsychotic drugs, blocksconditioned avoidance behaviors, ameasure that is considered predic-tive of antipsychotic activity (Fittonand Heel 1990). However, unlikeother antipsychotic drugs, cloza-pine does not cause catalepsy,block apomorphine- or ampheta-mine-induced stereotyped be-haviors, elevate serum prolactin, orcause dopamine receptor hypersen-sitivity in laboratory animals (Fit-ton and Heel 1990). Clozapine isfurther distinguished from otherantipsychotic drugs by its rela-tively higher affinity for D, thanfor D2 dopaminergic receptors, itshigher affinity for 5-HT2a seroto-nergic than'for D2 dopaminergicreceptors, and its strong affinityfor the D4 dopaminergic receptor(Baldessarini and Frankenburg1991; Jann 1991; Meltzer 1993).Clozapine is also highly anti-cholinergic and has significant al-phaj and alpha2 antiadrenergicproperties (Baldessarini and Fran-kenburg 1991; Jann 1991). In clini-cal studies, clozapine has beenshown to have differential clinicalefficacy for treatment-resistantschizophrenia patients and to beassociated with a low incidence ofextrapyramidal side effects (EPS)(Kane et al. 1988). The combina-tion of these preclinical and clini-cal characteristics has led clozapineto be termed an "atypical antipsy-chotic" (Kane et al. 1988).

This review addresses the fol-lowing questions:

Reprint requests should be sent toDr. R.W. Buchanan, Maryland Psychi-atric Research Center, P.O. Box 21247,Baltimore, MD 21228

580 SCHIZOPHRENIA BULLETIN

1. What is the efficacy (vs.placebo and/or conventional anti-psychotics) of clozapine duringacute symptom episodes for reduc-tion of positive symptoms,negative/deficit symptoms (i.e.,primary, enduring negative symp-toms), and other outcomes?

2. What is the efficacy (vs.placebo and/or conventional anti-psychotics) of clozapine duringmaintenance treatment for reductionof positive symptoms, negative/deficit symptoms, and otheroutcomes?

3. Is clozapine efficacious forschizophrenia patients who fail torespond to conventional anti-psychotics?

4. What are the side effects andrisks associated with clozapine?

Methods

Computerized searches of MED-LINE, MEDLARS, and PSYCLITdata bases were conducted back to1966. In addition, the references inarticles obtained from the comput-erized searches were checked toensure that relevant articles nototherwise identified were included.Conference abstracts, book chap-ters, and unpublished data are notincluded in this review.

The inclusion and exclusion cri-teria used to select studies varyfor the different review questions,reflecting the different levels ofprogress in the investigation ofdifferent outcome measures, andthe different levels of feasibility inthe conduct of methodologicallyrigorous studies for each outcome.The clinical efficacy of clozapinefor two outcomes, positive andnegative symptoms, in acutely psy-chotic patients and in treatment-resistant schizophrenia patients hasbeen most extensively studied.

Therefore, the selection criteria forprimary articles addressing thesetwo outcomes in these two popu-lations are the most rigorous: (1)the study must have been a ran-domized, double-blind trial; (2) thestudy must have used standard-ized, structured rating instrumentsto measure positive and negativesymptoms; and (3) the article mustbe in English.

The studies examining the useof clozapine as a maintenancetreatment are not as methodologi-cally rigorous as those examiningthe drug's clinical efficacy inacutely psychotic or treatment-resistant patients. This is largelyowing to the difficulty in conduct-ing long-term prospective double-blind trials of maintenance treat-ment. Therefore, the selection crite-ria studies addressing this issuewere expanded to include open-labeled, retrospective, and prospec-tive followup studies that ex-amined clozapine's efficacy as amaintenance treatment. And be-cause the literature evaluatingclozapine's efficacy for other out-come measures (i.e., violent be-havior and affective symptoms) isnot as extensive as that in otherareas, the selection criteria forthose studies were expanded to in-clude open-labeled studies andcase reports that use standardized,structured rating instruments (ifapplicable), in addition to double-blind studies. All articles and let-ters that provide primary informa-tion on clozapine's side effects andare written in English were in-cluded. The rationale for usingsuch broad criteria is the inherentnature of side effects (i.e., theymay be rare in occurrence), whichmeans that management strategiesfor treating serious or life-threatening side effects often can-

not be evaluated in a method-ologically rigorous manner.

Findings

What Is the Efficacy (vs. Placeboand/or Conventional Antipsy-chotics) of Clozapine DuringAcute Symptom Episodes for Re-duction of Positive Symptoms,Negative/Deficit Symptoms, andOther Outcomes? Nine studies ofthe efficacy of clozapine foracutely psychotic patients met thereview criteria and are sum-marized in table 1. Most of thesestudies found clozapine to beequally or more effective than tra-ditional neuroleptics (Ekblom andHaggstrom 1974; Gerlach et al.1974; Singer and Law 1974; Chiuet al. 1976; Guirguis et al. 1977;Gelenberg and Doller 1979; Shop-sin et al. 1979; Claghom et al.1987). Only the study by Fischer-Cornelssen and Ferner (1976) failedto find clozapine to be at least aseffective as traditional neuroleptics.Specifically, these authors reporttrifluoperazine to be more effectivethan clozapine but note that thismay have been related to meth-odological problems surroundingthe dosage schedule for clozapine.The uniformity of these findingssuggests that clozapine is at leastas effective as traditional neurolep-tics for the treatment of acutely illschizophrenia patients. However,these studies are characterized bysmall sample sizes or by the useof low dosages of either clozapineor chlorpromazine. These meth-odological limitations preclude adefinitive conclusion that clozapineis more effective than traditionalneuroleptics for acutely ill schizo-phrenia patients, and leave openthe highly unlikely possibility thatclozapine is less effective.

Tab

le

1.

Eff

icac

y of

clo

zap

ine

for

acu

te

psy

cho

sis

o

Stu

dy

Ch

arac

teri

stic

s:d

esig

n,

loca

tio

n,

du

rati

on

,sa

mp

le

size

Ou

tco

mes

re

sult

s

Co

mp

aris

on

trea

tmen

tsP

osi

tive

sym

pto

ms

Neg

ativ

esy

mp

tom

sS

ide

effe

cts

Oth

er

Ekb

lom

an

d D

oubl

e-bl

ind,

par

alle

l C

hlor

prom

azin

e N

ot

sign

ifica

ntH

aggs

trom

gr

oups

; in

patie

nt;

40

(CP

Z)

(NS

)(1

974)

da

ys;

n =

41

Ger

lach

et

al.

(197

4)D

oubl

e-bl

ind,

cro

ss-

ove

r; i

npat

ient

; 8

wee

ks;

n =

20

Hal

oper

idol

(HD

L)C

LZ =

HD

L fo

rB

PR

S

psyc

hotic

sym

ptom

s;

CLZ

>

HD

L fo

rB

PR

S

conc

ep-

tual

dis

orga

niza

-tio

n

Clo

zapi

ne

(CLZ

)>

C

PZ

on

BP

RS

em

otio

nal

with

draw

al

CLZ

= H

DL

for

BP

RS

an

ergi

a

No

extr

apyr

ami-

dal

side

ef

fect

s(E

PS

) in

eith

ergr

oup

CLZ

<

H

DL

for

EP

S

Not

as

sess

ed(N

A)

CLZ

>

H

DL

for

BP

RS

an

xiet

y

CO

CO

O1

Sin

ger

and

Law

(1

974)

Chi

u et

al.

(197

6)

Fis

cher

-C

omel

ssen

an

d F

erne

r(1

976)

Gui

rgui

s et

al.

(197

7)

Gel

enbe

rgan

d D

olle

r(1

979)

Sho

psin

et

al.

(197

9)

Cla

ghor

n et

al.

(198

7)

Dou

ble-

blin

d, p

aral

lel

grou

ps;

inpa

tient

; 40

days

; n

= 3

8D

oubl

e-bl

ind,

pa

ralle

lgr

oups

; in

patie

nt;

6w

eeks

; n

= 6

4D

oubl

e-bl

ind,

pa

ralle

lgr

oups

; in

patie

nt(m

ultic

ente

r);

7w

eeks

; n

= 7

23D

oubl

e-bl

ind,

pa

ralle

lgr

oups

; in

patie

nt;

7w

eeks

; n

= 5

0D

oubl

e-bl

ind,

pa

ralle

lgr

oups

; in

patie

nt;

4-8

w

eeks

; n

= 1

5D

oubl

e-bl

ind,

pa

ralle

lgr

oups

; in

patie

nt;

5w

eeks

; n

= 3

1D

oubl

e-bl

ind,

pa

ralle

lgr

oups

; in

patie

nt;

in-

patie

nt

(mul

ticen

ter)

;2

8-5

6 da

ys;

n =

151

CP

Z

CP

Z

CP

Z,

HD

L, t

ri-

fluop

eraz

ine,

clop

enth

ixol

CP

Z

CP

Z

CP

Z,

plac

ebo

CP

Z

NS

NS

CLZ

>

H

DL

NS

CLZ

>

C

PZ

on

BP

RS

th

ough

tdi

sord

erN

S

CLZ

>

C

PZ

on

BP

RS

th

ough

tdi

sord

er

NS

NS

CLZ

>

CLZ

>

BP

RS

CLZ

>

BP

RS

NS

CLZ

>

BP

RS

HD

L

CP

Z o

nan

ergi

a

CP

Z o

nan

ergi

a

CP

Z o

nan

ergi

a

NA

NA

NS

NA

NA

NA

CLZ

<

C

PZ

for

EP

S

NA

NA

NA

NA

NA

CLZ

>

C

PZ

on

BP

RS

de

pres

sion

CLZ

>

C

PZ

on

BP

RS

ho

stili

ty/

susp

icio

usne

ss

Not

e.—

BP

RS

=

B

rief

Psy

chia

tric

R

atin

g S

cale

(O

vera

ll an

d G

orha

m

1962

).

oo

582 SCHIZOPHRENIA BULLETIN

None of the studies used spe-cific assessments of negative symp-toms, and there was no attempt todifferentiate the effect of clozapineon deficit versus secondary nega-tive symptoms. Therefore, defini-tive statements about clozapine'sefficacy for negative symptoms inacutely psychotic patients are notpossible.

Clozapine was observed to beeffective in reducing symptoms ofirritability, hostility, and sus-piciousness (Chiu et al. 1976;Gelenberg and Doller 1979;Claghorn et al. 1987) and of anx-iety and depression (Gerlach et al.1974; Gelenberg and Doller 1979;Shopsin et al. 1979; Claghorn et al.1987). However, none of the stud-ies examined how clozapine's sed-ative actions or its decreased likeli-hood of inducing EPS relate to itstherapeutic effect on these out-comes. Several studies found it tohave a more rapid onset of action,with differences emerging betweenclozapine and the comparison drugby 2 weeks (Ekblom and Hagg-strom 1974; Singer and Law 1974;Claghorn et al. 1987).

What Is the Efficacy (vs. Placeboand/or Conventional Antipsy-chotics) of Clozapine DuringMaintenance Treatment for Re-duction of Positive Symptoms,Negative/Deficit Symptoms, andOther Outcomes? The characteris-tics and findings from the 11 stud-ies that examined clozapine as amaintenance treatment and met re-view criteria are shown in table 2.A number of general limitationsapply to most, if not all, of thesestudies. Specifically, all the retro-spective studies are limited bytheir dependence on medical rec-ords as the major source of infor-mation; their lack of objective

symptom ratings, which precludesthe specific evaluation of positiveand negative symptom response toclozapine treatment; and theirfailure to use objective criteria todefine treatment response. Theprospective studies are charac-terized by small sample sizes andthe lack of nonblind ratings ofoutcome measures. All the retro-spective and prospective studies,except Leon (1979), are limited bythe lack of comparison treatmentgroups, which makes it impossibleto definitively ascribe changes inclinical status to clozapine treat-ment. As a result, definitive con-clusions about the efficacy ofclozapine as a maintenance treat-ment await further study.

The data from these studies thusprovide the following qualifiedconclusions. First, most of the pa-tients included in these studieshad not experienced adequatetreatment responses to traditionalneuroleptics. Therefore, the resultsof these studies provide furthersupport for the proposition thatclozapine has differential efficacyfor schizophrenia patients whodo not respond to traditionalneuroleptics.

Second, the studies provide con-flicting data on the efficacy ofclozapine for negative symptoms.Two studies report a positiveeffect; however, one used a proxymeasure composed of mainly de-pressive symptoms (Meltzer 1992),and the other found negativesymptom change related to changein positive and extrapyramidalsymptoms (Lieberman et al. 1994).The latter finding is similar to ob-servations from uncontrolled short-term treatment studies (Tandon etal. 1993; Miller et al. 1994). Thus,the data suggest that clozapine'seffect on negative symptoms may

be limited. None of the studiesthat examined this effect differenti-ated deficit from secondary nega-tive symptoms.

Third, clozapine treatment ap-pears to be effective in preventingexacerbations of psychotic symp-toms and is associated with de-creased rates of hospitalization(Leon 1979; Meltzer et al. 1990;Breier et al. 1993). However, it isunclear if this advantage exists inpatients who are not treatment re-sistant, nor is it known to whatextent the weekly monitoring re-quired for clozapine treatment maybe related to the decrease in hos-pitalizations that occurs withtreatment.

Fourth, long-term clozapinetreatment is associated with im-proved social and occupationalfunctioning and quality of life.Fifth, clozapine treatment is associ-ated with a significant decrease insuicidal behavior (Meltzer andOkayli 1995). Sixth, the major rea-sons for discontinuing clozapinetreatment are lack of adequatetreatment response, noncompliance,and severe side effects.

Is Clozapine Efficacious forSchizophrenia Patients Who Failto Respond to Conventional An-tipsychotics? Selected characteris-tics and study samples of thethree studies that examined theefficacy of clozapine in treatment-resistant schizophrenia patients andmet review criteria are presentedin table 3. Two studies examinedthe efficacy of clozapine in hospi-talized treatment-resistant patients(Kane et al. 1988; Pickar et al.1992), and one study examined itin treatment-resistant outpatients(Breier et al. 1994). These studies,primarily Kane et al. (1988) andBreier et al. (1994), provide strong

Tab

le 2

. E

ffic

acy

of c

loza

pin

e fo

r m

ain

ten

ance

tr

eatm

ent

Stu

dy

Leon

(197

9)

Juul

-P

ouls

en e

tal

. (1

985)

Kuh

a an

dM

ietti

nen

(198

6)

Lind

stro

m(1

988)

Lepp

ig e

tal

. (1

989)

Mat

tes

(198

9)

Mel

tzer

et

al.

(199

0);

Mel

tzer

(199

2)

Dav

ies

etal

. (1

991)

Ch

arac

teri

stic

s:d

esig

n,

loca

tio

n,

du

rati

on

,sa

mp

le

size

Ret

rosp

ectiv

e ch

art

revi

ew;

loca

tion

not

spec

ified

; 3

-4

year

s;n

=

31

-37

Ret

rosp

ectiv

e ch

art

revi

ew;

inpa

tient

; up

to

12 y

ears

; n

=21

6

Ret

rosp

ectiv

e fo

llow

-up

; in

patie

nt

and

outp

atie

nt;

30

da

ys-

7 ye

ars;

n

= 1

08

Ret

rosp

ectiv

e fo

l-lo

wup

; in

patie

nt

an

dou

tpat

ient

; m

ean

=44

mon

ths;

n =

96

Ret

rosp

ectiv

e ch

art

revi

ew;

outp

atie

nt;

mea

n =

21

mon

ths;

n =

12

1

Cas

e re

port

s, o

pen

tria

l; in

patie

nt

an

dou

tpat

ient

; va

riabl

efo

llow

up;

n =

14

Pro

spec

tive

open

tria

l; in

patie

nt;

6m

onth

s; n

= 3

8

Pro

spec

tive

open

tria

l; in

patie

nt

and

outp

atie

nt;

1 ye

ar;

n =

24

Co

mp

aris

on

trea

tmen

t

Chl

orpr

omaz

ine

(CP

Z)

Prio

r tr

eatm

ent

with

con

ven-

tiona

l an

tipsy

-ch

otic

s

Prio

r tr

eatm

ent

with

con

ven-

tiona

l an

tipsy

-ch

otic

sP

rior

trea

tmen

tw

ith c

on

ven

-tio

nal

antip

sy-

chot

ics

Prio

r tr

eatm

ent

with

con

ven-

tiona

l an

tipsy

-ch

otic

s

Prio

r tr

eatm

ent

with

con

ven-

tiona

l an

tipsy

-ch

otic

s

Prio

r tr

eatm

ent

with

con

ven-

tiona

l an

tipsy

-ch

otic

s

Prio

r tr

eatm

ent

with

con

ven-

tiona

l an

tipsy

-ch

otic

s

Po

siti

vesy

mp

tom

s

Clo

zapi

ne(C

LZ)

>

CP

Z

NA

30%

m

arke

dre

duct

ion;

36

%m

odes

t re

duc-

tion

NA

Dec

reas

ed d

e-lu

sion

s an

d in

-co

here

nce

Dec

reas

edB

PR

S p

sy-

chos

is

Dec

reas

edB

PR

S

psy-

chos

is

NA

Ou

tco

mes

re

sult

s

Neg

ativ

esy

mp

tom

s

Not

as

sess

ed(N

A)

NA

NA

NA

Dec

reas

edan

ergi

a

Dec

reas

edB

PR

S e

mo-

tiona

l w

ith-

draw

al

Dec

reas

edB

PR

S

aner

gia

NA

Glo

bal

NA

Com

pare

d w

ithpr

ior

trea

tmen

ton

co

nven

tiona

lan

tipsy

chot

ics:

51

%

bette

r,47

% u

n-ch

ange

d, 2

%w

orse

NA

43%

glo

bal

im-

prov

emen

t; 3

8%

mod

erat

e im

-pr

ovem

ent

12%

co

mpl

ete

rem

issi

on;

57

%m

arke

dly

im-

prov

ed;

24

%m

ildly

im

prov

edN

A

NA

Ove

rall

sym

p-to

m

redu

ctio

n(t

ype

not

spec

-ifi

ed)

Oth

er

CLZ

>

C

PZ

for

hosp

italiz

atio

nre

duct

ion

NA

NA

Em

ploy

men

t ra

tein

crea

sed

from

3% t

o 3

8%

Dec

reas

ed d

e-pr

essi

on

NA

Impr

oved

qu

ality

of

life;

enh

ance

dem

ploy

men

t; 8

3%

decr

ease

in

hos

pi-

taliz

atio

n

NA

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584 SCHIZOPHRENIA BULLETIN

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support for the proposition thatclozapine exhibits differentialefficacy for treatment-resistantschizophrenia patients, especiallyinpatients. The relatively smallsample in the Breier et al. (1994)study precludes definitive conclu-sions on this score, but the study'sresults, when combined with theresults from the maintenance stud-ies, provide strong presumptiveevidence.

Clozapine was found to beeffective for both positive andnegative symptoms. Its effect onnegative symptoms is restricted tosecondary negative symptoms, andthis effect is related to its en-hanced efficacy for positive symp-toms and the decreased incidenceof EPS. In the only study that ex-amined clozapine's effect on deficitsymptoms, Breier et al. (1994) re-port no effect.

Both Kane et al. (1988) andBreier et al. (1994) found clozapineto be effective for reducing symp-toms of hostility but not ofanxiety/depression. The findings ofclozapine's efficacy for hostilitysymptoms are similar to the find-ings from the studies examiningthe effect of clozapine in acutelypsychotic patients. Kane et al.(1988) note that clozapine exhibitsits differential efficacy by the firstweek of treatment. Breier et al.(1994) do not report any time-of-onset data.

What Are the Side Effects andRisks Associated With Clozapine?Clozapine treatment is associatedwith a broad range of side effects,yet it offers the advantage oflower rates of EPS than those ob-served with conventional anti-psychotics. The most serious ofclozapine's side effects is agranulo-cytosis. Other important side

VOL. 21, NO. 4, 1995 585

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effects include orthostatic hypoten-sion and tachycardia, sedation, sei-zures, weight gain, and reboundpsychosis.

Agranulocytosis. Clozapinetreatment is associated with thedevelopment of agranulocytosis(granulocyte count < 500/mm3),neutropenia (granulocyte count <1,500/mm3), and/or leukopenia(white blood cell count [WBC] of< 3,500/mm3) (Safferman et al.1991). The severity of clozapine'seffect on the bone marrow is di-rectly related to how quickly ab-normalities in bone marrow func-tion are detected. Estimates of thecumulative incidence of clozapine-induced agranulocytosis rangefrom 0.05 to 2.0 percent; neu-tropenia is estimated to occur in2.8 percent of patients, and leuko-penia is estimated to occur in atleast 0.3 percent of patients (Fittonand Heel 1990; Stephens 1990; Bal-dessarini and Frankenburg 1991;Safferman et al. 1991; Krupp andBarnes 1992). The range of inci-dence rates for agranulocytosismay be related to differences inpatient characteristics, dosage regi-mens, and treatment duration (Fit-ton and Heel 1990). The risk ofdeveloping agranulocytosis withclozapine treatment is 10 timesgreater than that with traditionalneuroleptics (Fitton and Heel 1990;Meltzer 1993). Clozapine-inducedagranulocytosis is most likely tooccur within the first 6 months oftreatment, with 75 to 80 percent ofall cases occurring within the first4 to 18 weeks (Baldessarini andFrankenburg 1991; Safferman et al.1991; Krupp and Barnes 1992;Meltzer 1993). The peak of newcases occurs at 10 weeks (Kruppand Barnes 1992). The drop inWBC may be precipitous or grad-ual (Meltzer 1993).

586 SCHIZOPHRENIA BULLETIN

Hypotension and tachycardia.Clozapine treatment is commonlyassociated with orthostatic hypo-tension (secondary to clozapine'salpha-adrenergic antagonism; rateof occurrence: 8%-13%) andtachycardia (secondary to cloza-pine's anticholinergic activity; rateof occurrence: 12%-25%) (Borisonand Diamond 1990; Baldessariniand Frankenburg 1991; Saffermanet al. 1991; Meltzer 1993), andboth are dosage dependent. Pa-tients tend to develop tolerance tothese side effects with time (Fittonand Heel 1990; Jann 1991).

Sedation. Sedation, the mostcommon side effect (20%-50%), isprobably related to clozapine'santihistaminergic and anti-alpha]-adrenergic properties (Grohmannet al. 1989; Leppig et al. 1989;Borison and Diamond 1990; Ste-phens 1990; Safferman et al. 1991).Sedation occurs early in treatment,and patients typically become tol-erant to it (Fitton and Heel 1990;Baldessarini and Frankenburg1991).

Seizures. Clozapine treatment,as compared with traditional neu-roleptic treatment, is associatedwith a relatively high risk ofgrand mal seizures (l%-10%) (Fit-ton and Heel 1990; Stephens 1990;Baldessarini and Frankenburg 1991;Devinsky et al. 1991; Liukkonen etal. 1992). There are also reports ofmyoclonic and atonic activity and/or seizures with clozapine treat-ment (Lemus et al. 1989; Chiles etal. 1990; Gouzoulis et al. 1991; Saf-ferman et al. 1991; Berman et al.1992; Szarek and Goethe 1992).The presence of myoclonic jerksmay presage the development offuture grand mal seizures (Bermanet al. 1992). Seizure activity is apotential complication of clozapineoverdoses (Jann 1991); concurrent

neuroleptic treatment may increasethe risk of seizures (Liukkonen etal. 1992).

Electroencephalogram changesand seizures appear to be dosagerelated (Simpson and Cooper 1978;Leppig et al. 1989; Fitton and Heel1990; Haller and Binder 1990; Ste-phens 1990; Baker and Conley1991; Jann 1991; Safferman et al.1991; Meltzer 1993). Devinsky etal. (1991) conducted a retrospectivechart review of 1,418 clozapine-treated patients to examine the re-lationship between clozapine dos-age and seizures. They report thefollowing frequency rates: cloza-pine dosage below 300 mg perday (1%); clozapine dosage below600 mg per day (2.7%); andclozapine dosage above 600 mgper day (4.4%). They also notethat rapid upward titration andthe use of concurrent medicationsthat lower the seizure thresholdwere associated with an increasedlikelihood of developing seizures.

Weight gain. Significant weightgain is commonly observed withclozapine treatment (13%-23%)(Leppig et al. 1989; Carson andForbes 1990; Cohen et al. 1990; Fit-ton and Heel 1990; Leadbetter andVieweg 1990; Baldessarini andFrankenburg 1991; Safferman et al.1991; Lamberti 1992; Leadbetter etal. 1992; Meltzer 1993). The weightgain may be related to clozapine'sserotonergic antagonist actions,since serotonin agonists have beennoted to suppress appetite (Lead-better et al. 1992). Weight gain hasbeen associated with clinical re-sponse; patients who exhibit thegreatest weight gain also exhibitthe best clinical response (Leadbet-ter and Vieweg 1990; Lamberti1992; Leadbetter et al. 1992).

Rebound psychosis. Therehave been reports of rapid deterio-

ration and the onset of new psy-chotic symptoms with abruptclozapine withdrawal (Simpson etal. 1978; Ekblom et al. 1984; Pe-renyi et al. 1985; Eklund 1987;Borison et al. 1988; Stephens 1990;Alphs and Lee 1991; Safferman etal. 1991; Parsa et al. 1993). Thefrequency of this phenomenon isunknown, but patients with higherbaseline symptom levels (Borisonet al. 1988) or longer duration ofclozapine treatment may be morelikely to exhibit the phenomenon.Exacerbations of psychosis follow-ing clozapine withdrawal havebeen shown to be associated withincreased tardive dyskinesia (TD)(Alphs and Lee 1991), suggestingthe possibility that supersensitivityof dopaminergic receptors may un-derlie this phenomenon.

Other side effects. Amongother side effects of clozapine arenausea, vomiting, and constipation(Baldessarini and Frankenburg1991; Safferman et al. 1991); eleva-tion of liver enzymes (up to 10%)(Kirkegaard and Jensen 1979; Ste-phens 1990; Safferman et al. 1991);hypersalivation (12%-40%) (Stephens1990; Baldessarini and Frankenburg1991; Safferman et al. 1991; Meltzer1993); confusion or delirium (3%)(Schuster et al. 1977; Banki andVojnik 1978; Grohmann et al. 1989;Fitton and Heel 1990; Stephens1990; Baldessarini and Frankenburg1991; Safferman et al. 1991); inconti-nence, frequency/urgency, hesi-tancy, urinary retention, or impo-tence (6%) (Safferman et al. 1991;Meltzer 1993); benign hyperthermia(5%-15%) (Fitton and Heel 1990;Stephens 1990; Baldessarini andFrankenburg 1991; Meltzer 1993);and development or exacerbationof obsessive-compulsive symptoms(Baker et al. 1992; Patil 1992;Meltzer 1993). This last phenome-

VOL 21, NO. 4, 1995 587

non may be related to clozapine'santiserotonergic properties (Baker etal. 1992; Patil 1992). There are noknown teratogenic effects of cloza-pine (Meltzer 1993; Waldman andSafferman 1993).

Side effects of other antipsy-chotics less commonly seen withclozapine. Clozapine is associatedwith lower rates of certain sideeffects than are typically observedwith conventional antipsychotics.The incidence of EPS is low (4%-7%) (Casey 1989; Fitton and Heel1990; Stephens 1990; Baldessariniand Frankenburg 1991; Saffermanet al. 1991; Meltzer 1993). Cloza-pine is also associated with alower risk of neuroleptic malignantsyndrome (NMS) (Borison and Di-amond 1990; Fitton and Heel 1990;Safferman et al. 1991; Meltzer1993). Although clozapine has beenclaimed not to cause NMS, thereare case reports of clozapine-induced NMS in patients receivingonly clozapine treatment (Nopouloset al. 1990; Anderson and Powers1991; Miller et al. 1991; Goatesand Escobar 1992). In contrast,there are also case reports ofclozapine being successfully usedin patients with previous historiesof NMS (Stoudemire and Clayton1989; Windhager et al. 1990; Bur-rell et al. 1991; Weller andKomhuber 1992), suggesting thatclozapine may be a viable alterna-tive for patients who developNMS on traditional neuroleptics.

It is unclear if clozapine cancause TD (Kane et al. 1993). Sev-eral authors claim that there areno confirmed cases of clozapine-related TD (Casey 1989; Fitton andHeel 1990; Stephens 1990; Saffer-man et al. 1991; Meltzer 1993), butthere are several case reports ofclozapine exacerbation of TD andclozapine-induced TD (de Leon et

al. 1991; Jann 1991; Kane et al.1993). If clozapine causes TD, itappears that the incidence of TDwith clozapine treatment is mark-edly less than that with traditionalneuroleptics.

There have been several case re-ports and studies examining thepotential therapeutic effect ofclozapine for TD, with some stud-ies documenting the therapeuticvalue of clozapine for diminishingTD (Simpson et al. 1978; Meltzerand Luchins 1984; Small et al.1987; Van Putten et al. 1990;Lieberman et al. 1991; Bajulaiyeand Addonizio 1992; Littrell andMagill 1993; Tamminga et al.1994); however, others have notfound evidence supporting thiseffect (Gerlach et al. 1975; Carrollet al. 1977; Caine et al. 1979;Wirshing et al. 1990).

Discussion

The quality of the studies evaluat-ing clozapine's clinical efficacy forpositive and negative symptoms inacutely psychotic and in treatment-resistant schizophrenia patients,and as a maintenance treatmentfor positive and negative symp-toms, varies widely within eacharea. Multiple double-blind studieshave been conducted examiningthe efficacy of clozapine for thetreatment of acutely ill schizophre-nia patients; however, most ofthese studies are characterized bysmall sample sizes or the use oflow dosages of either clozapine orthe comparison drug. Only threedouble-blind studies have ex-amined the efficacy of clozapine intreatment-resistant schizophreniapatients. The majority of studiesexamining clozapine's efficacy as amaintenance treatment are retro-spective. These studies are limited

by their dependence on medicalrecords as their major source ofinformation, their lack of objectivesymptom ratings, and their failureto use objective criteria to definetreatment response. The prospec-tive studies are characterized bysmall sample sizes and lack ofnonblind ratings of outcomemeasures.

The general quality issue withrespect to the studies examiningthe effect of clozapine on otheroutcome measures is that none ofthe studies are double-blind. Inaddition, there is a relative paucityof literature in each of the areas,especially that of clozapine's effecton cognitive impairments (not re-viewed in this article).

With regard to clozapine'sefficacy for the active symptoms ofschizophrenia, it can be said withsubstantial confidence that it is (1)as effective as traditional neurolep-tics for the reduction of positivesymptoms in acutely psychotic pa-tients, (2) an effective treatment forreducing psychotic symptoms in 30to 60 percent of schizophrenia pa-tients who fail to respond to ade-quate trials of traditional neurolep-tics, (3) an effective maintenancetreatment for positive symptoms,and (4) an effective treatment forhostility.

There is suggestive evidence thatclozapine (1) improves social andoccupational functioning, (2) im-proves patients' quality of life, (3)decreases the rate and length ofhospitalizations, (4) reduces affec-tive symptoms, (5) reduces second-ary negative symptoms, and (6) re-duces TD.

As to clozapine's side effect pro-file, there is substantial evidencethat clozapine is associated withan increased risk for agranulocy-tosis and seizures; that it is associ-

588 SCHIZOPHRENIA BULLETIN

ated with a reduced likelihood ofdeveloping EPS, NMS, and TD;and that it may cause reboundpsychosis if abruptly discontinued.

Needs for Future Research

Several measurement issues needto be addressed in future studies.The first is assessment of negativesymptoms. There has been a gen-eral lack of attention paid to dif-ferentiation of deficit from othernegative symptoms. Future studiesneed to incorporate assessments ofdeficit symptoms (Kirkpatrick et al.1989) in order to be able to evalu-ate the effect of clozapine on thesesymptoms. Second, future studiesshould use instruments that pro-vide detailed evaluations of rolefunctioning, quality of life, andfamily burden. Third, the evalua-tions of clozapine's effect oncognitive functions should beorganized according to specificcognitive functions observed to beabnormal in schizophrenia patients,with detailed evaluations of eachfunction included in the neuropsy-chological assessment battery.

Future investigations shouldfocus on the following areas ofsubstantive interest:

1. Double-blind studies to ex-amine clozapine's efficacy (1) fornegative symptoms, includingwhether such efficacy includesboth deficit and secondary nega-tive symptoms and, if limited tosecondary negative symptoms,what the underlying mechanismsare for this beneficial effect; (2) forcognitive impairments; (3) forquality of life, social and occupa-tional role functioning, and familyburden; and (4) as a maintenancetreatment, including its effect onrelapse and hospitalization rates.

2. Double-blind studies to evalu-ate what constitutes an optimalclozapine treatment trial and whoshould be eligible for clozapinetreatment; that is, what is the op-erational definition of treatmentresistance?

3. Double-blind studies to evalu-ate pharmacological augmentationstrategies for patients who do nothave an adequate response toclozapine.

4. The interaction betweenclozapine treatment and nonphar-macological treatment interventions.

5. The effectiveness of clozapinein nonresearch settings, includingevaluations of factors affecting thepatient's acceptance of or non-compliance with clozapine treat-ment, and factors affecting thephysician's clozapine prescriptionpractices.

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The Author

Robert W. Buchanan, M.D., is As-sociate Professor of Psychiatry,University of Maryland School ofMedicine, and Chief of the Outpa-tient Program of the MarylandPsychiatric Research Center, Bal-timore, MD.