discussion
night nurse
currentapproachestotreatmentsforschizophrenia.pdf
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Open Access Full Text Article
http://dx.doi.org/10.2147/NDT.S37485
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Current approaches to treatments for schizophrenia spectrum disorders, part i: an overview and medical treatments
wai Tong Chien Annie LK Yip School of Nursing, Faculty of Health and Social Sciences, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong
Correspondence: wai Tong Chien School of Nursing, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong Tel +852 2766 5648 Fax +852 2334 1124 email [email protected]
Abstract: During the last three decades, an increasing understanding of the etiology,
psychopathology, and clinical manifestations of schizophrenia spectrum disorders, in addition to
the introduction of second-generation antipsychotics, has optimized the potential for recovery from
the illness. Continued development of various models of psychosocial intervention promotes the
goal of schizophrenia treatment from one of symptom control and social adaptation to an optimal
restoration of functioning and/or recovery. However, it is still questionable whether these new
treatment approaches can address the patients’ needs for treatment and services and contribute
to better patient outcomes. This article provides an overview of different treatment approaches
currently used in schizophrenia spectrum disorders to address complex health problems and a wide
range of abnormalities and impairments resulting from the illness. There are different treatment
strategies and targets for patients at different stages of the illness, ranging from prophylactic
antipsychotics and cognitive–behavioral therapy in the premorbid stage to various psychosocial
interventions in addition to antipsychotics for relapse prevention and rehabilitation in the later
stages of the illness. The use of antipsychotics alone as the main treatment modality may be
limited not only in being unable to tackle the frequently occurring negative symptoms and
cognitive impairments but also in producing a wide variety of adverse effects to the body or organ
functioning. Because of varied pharmacokinetics and treatment responsiveness across agents,
the medication regimen should be determined on an individual basis to ensure an optimal effect
in its long-term use. This review also highlights that the recent practice guidelines and standards
have recommended that a combination of treatment modalities be adopted to meet the complex
health needs of people with schizophrenia spectrum disorders. In view of the heterogeneity of
the risk factors and the illness progression of individual patients, the use of multifaceted illness
management programs consisting of different combinations of physical, psychological, and social
interventions might be efficient and effective in improving recovery.
Keywords: schizophrenia, schizophrenia spectrum disorders, treatment, psychosocial interven-
tion, pharmacology, antipsychotics
Introduction Schizophrenia and its spectrum disorders (all falling under the term “schizophrenia” in
this article) are chronic remitting and disruptive disorders associated with significant
abnormalities and the progressive deterioration of a wide variety of cognitive, psycho-
social, vocational, and behavioral functioning. The fourth edition of the Diagnostic
and Statistical Manual of Mental Disorders (DSM-IV) defines schizophrenia as a
syndrome characterized by long duration, high relapse rate (.70%), bizarre delusions
and behaviors, negative symptoms, and sometimes a few mood problems.1 The onset
of symptoms typically occurs in adolescence and young adulthood, with a worldwide
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estimate of its lifetime prevalence and incidence of 1.4–4.6
and 0.16–0.42 per 1,000 persons annually, respectively.2,3
A recent systematic review indicated that patients diagnosed
with this disorder have a shorter lifespan than the average
general population and are particularly at risk for suicide,
increased physical risk (eg, limited exercise, poor diet,
and obesity), and reduced access to medical treatment and
healthcare services.4 In addition, 5%–8% of healthy people
indicate an attenuated form of schizoid personality and
schizophrenia-like symptoms, such as paranoid delusional
thinking and auditory hallucination.5
Because of the complex health problems and wide range
of abnormalities and impairments concerning schizophrenia,
comprehensive and multimodal treatment approaches are
considered and tested in different combinations, with the
goal of reducing patients’ illness episodes and symptoms,
as well as improving their functioning and quality of life
in the longer term. Antipsychotic medications have been
recommended consistently and continuously as the main-
stream and standard treatment for nearly all patients with
schizophrenia, to provide them with a safe and therapeutic
environment and effective symptom control since the intro-
duction of chlorpromazine (the first antipsychotic) in the
1960s. In the last three to four decades, physical treatments
such as electroconvulsive therapy (ECT; in the 1930s) and
different approaches to psychosocial interventions such as
psychoanalysis (in the 1950s), family therapy (in the 1960s),
psychoeducation (in the 1980s), cognitive–behavioral ther-
apy (in the 1990s), and cognitive remediation (in the 2000s)
have been introduced successively,7–14 and their comparative
or combined efficacies for schizophrenia treatment have
been increasingly evaluated in various clinical trials.8,10,12,13
Recent systematic reviews and practice guidelines have
recommended that as an adjunct to psychopharmacological
treatment, psychosocial interventions designed to support
both people with schizophrenia and their families should
also be used to improve their rehabilitation, reintegration into
the community, and recovery from the illness.6,15 Different
modalities and combinations of psychosocial programs are
recommended to address the complex individualized needs
of these patients for multimodal care, particularly regarding
relapse prevention, management of negative symptoms and
cognitive dysfunction, and medication adherence.14,16 Despite
increased recognition and demands for an individualized
treatment plan and the integration of different intervention
approaches to optimize patient outcomes, current psychiat-
ric treatments and services still involve practicing the same
set of treatment approaches for each patient group in the
course of illness. More clinical trials are recommended to
examine the active ingredients of unimodal or integrated
psychosocial interventions for schizophrenia that can be
effective in enhancing recovery and other patient outcomes.
There has also been increasing attention and demand for
cost-effectiveness analyses of these interventions.
To gain a more in-depth and focused understanding of
the effects and benefits of recent approaches to treatments
for schizophrenia, we performed a comparative review, sum-
marized here, of the efficacy, safety, and tolerability of the
current pharmacological and other medical treatments for
these patients. In another article, we also performed a com-
parative review of the efficacy of approaches to psychosocial
interventions for schizophrenia and a critical discussion about
patient-focused perspectives of acceptance, benefits, and
satisfaction in psychiatric care. Recommendations for best
practices for continuity of schizophrenia care are also made.
This article also provides an overview of the approaches to
treatments across different stages of schizophrenia and the
future direction of treatments for this illness.
Review of current approaches to medical treatments for schizophrenia During the last two decades, the mainstream of medical treat-
ment for schizophrenia has remained the use of antipsychotics
and/or other psychotropic medications. With increasing
initiatives and evidence of the effectiveness of psychosocial
interventions for schizophrenia, the highly structured or
manualized (eg, cognitive–behavioral and psychoeducation
programs) and a few integrated programs (eg, the Schizo-
phrenia Patient Outcomes Research Team Programs and the
Recovery After an Initial Schizophrenia Episode Early Treat-
ment Program in the United States),17,18 used as an adjunct to
antipsychotics, have indicated positive patient outcomes. On
the basis of several large-scale randomized controlled trials,
single and multiple types of antipsychotics, or polypharmacy
in combination with other psychotropic drugs, are consid-
ered useful in schizophrenia treatment. The introduction of
second-generation antipsychotics has further improved the
desired effects of these medications for schizophrenia care
and, more important, reduced their undesirable effects such
as extrapyramidal adverse effects, mortality, and metabolic
disorder. Before exploring the recent changes or improve-
ments needed in schizophrenia treatment and rehabilitation, it
is important to review and understand the current knowledge
about pharmacological and other medical treatments for
schizophrenia sufferers.
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Current treatments for schizophrenia spectrum disorders
Pharmacological treatment First- and second-generation antipsychotics More than 70 antipsychotics have been introduced. They are
mainly categorized into first- and second-generation agents
and share a similar pharmacological mechanism in blocking
the dopamine D-2 receptors.19 Their blocking mechanisms
or actions are linked to their efficacy against positive and
disorganization symptoms of schizophrenia.11–13
The first-generation antipsychotics (FGAs), or typi-
cal antipsychotics (eg, chlorpromazine, fluphenazine, and
haloperidol, included in the World Health Organization’s
list of Essential Medications in 2009),20 were first intro-
duced for the treatment of schizophrenia in the 1950s. The
second- generation (atypical) antipsychotics (eg, clozapine,
olanzapine, and risperidone) introduced in the last three
decades were believed to be more efficacious and toler-
able than the FGAs, and a few have progressively replaced
the older FGAs to become the first-line prescription or the
standard of care. To capture the research evidence or drug
trials on antipsychotics, full-text articles published in English
between 1966 and 2010 were searched for in CINAHL,
MEDLINE, EMBASE, The Cochrane Library, Cochrane
Schizophrenia Group’s Register, Biological Abstracts,
Sociological Abstracts, Sociofile, and PsycLIT. Participants
included people with schizophrenia, schizophrenia-like
psychoses such as schizophreniform and schizoaffective dis-
orders, and psychotic disorders such as delusional disorder,
nonaffective psychosis, or dual diagnosis. The main out-
comes identified from the reviewed articles mainly involved
mental state, global functioning, and adverse events.
Thirteen systematic reviews on the efficacy of FGAs
using a randomized controlled trial design were found
(Table 1). With similar intended outcomes, several outcome
measurement tools were commonly used, including the
Clinical Global Impression, Global Assessment Scale, and
Global Assessment of Functioning scale for patients’ global
functioning; the Brief Psychiatric Rating Scale, Positive
and Negative Syndrome Scale, Scale for the Assessment
of Negative Symptoms, and Scale for the Assessment of
Positive Symptoms for their mental state or symptom sever-
ity; and the Involuntary Movement Scale, Extrapyramidal
Symptom Rating Scale, Extrapyramidal Rating Scale, and
Simpson and Angus Scale for the adverse effects of medi-
cation used. Most of the clinical trials (.70%) evaluated
the medication effects over a short period of time (eg, up
to 12 weeks), whereas a few (,10%) involved a long-term
follow-up (eg, .1 year).
The first FGA invented – chlorpromazine, has become
the well-established and benchmark treatment for people
with schizophrenia to facilitate their deinstitutionalization21
and has been used for more than 40 years. Nevertheless,
the reviewed literature showed that the incidence and
average dose of chlorpromazine prescribed to people with
schizophrenia has been decreasing.22 Other commonly
used FGAs such as trifluoperazine, thioridazine, sulpiride,
pimozide, perphenazine, and fluphenazine were tested
and confirmed to have similar and satisfactory efficacy in
symptom reduction – mainly for positive symptoms (eg,
delusions and hallucinations).23–28 However, there was
limited evidence to support their efficacy at lower doses or
in short-term treatment.28–31 Major adverse events induced
by FGAs generally include sedation, movement disorders,
endocrine disturbance, and metabolic and electrocardiogram
changes.24,25,28,32
Most of all, FGAs are a relatively low-cost treatment and
commonly used medication; however, there is little evidence
to support their efficacy in reducing negative symptoms
(eg, anhedonia, loss of volition, and social withdrawal) and
cognitive functioning, which may contribute much to the
functional disability of people with schizophrenia.26,29,33 It is
generally concluded that there is similar satisfactory clini-
cal efficacy in terms of mental state and global functioning
across the FGAs and second-generation antipsychotics.34–37
However, a few trials indicate the superiority of individual
second-generation agents over the FGAs in specific illness
condition or patient outcomes.29,33,37,38 In two meta-analyses
of placebo-controlled trials,39,40 haloperidol was reported
to be less effective in reducing symptoms and/or relapse
than certain second-generation agents (eg, clozapine and
olanzapine).
Second-generation (or atypical) antipsychotics were
believed to have good antipsychotic properties and minimal
adverse effects compared with those noted with the use of
FGAs. Some of them have been shown to be more efficacious
and less problematic in terms of sedative and neurologi-
cal effects than FGAs.41,42 Using the same databases and a
similar procedure as the literature search on FGAs presented
earlier, 12 systematic reviews (between 1966 and 2010)
have been conducted to compare the effects among second-
generation antipsychotics and the effects between these
second-generation agents and FGAs or a placebo (Table 2). In
addition to the main patient outcomes used (ie, mental state,
global functioning, and relapse), several other psychosocial
outcomes were usually compared across studies, including
level of depression, acceptability of treatment (eg, dropout
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T ab
le 1
S um
m ar
y of
r ev
ie w
s on
fi rs
t- ge
ne ra
tio n
an tip
sy ch
ot ic
s fo
r sc
hi zo
ph re
ni a
A ut
ho rs
C lin
ic al
t ri
al s
re vi
ew ed
, N In
te rv
en ti
on s
Sa m
pl e
si ze
a nd
st
ud y
se tt
in g
Le ng
th o
f s tu
dy
or fo
llo w
-u pa
Su m
m ar
y of
m ai
n fin
di ng
s C
on cl
us io
n
A da
m s
et a
l21 50
C hl
or pr
om az
in e
(o
ra l o
r by
in je
ct io
n)
vs p
la ce
bo
N =
1 ,3
95 ; m
ai nl
y
ho sp
ita l-b
as ed
; a
fe w
c on
du ct
ed
in t
he c
om m
un ity
24 h
ou rs
t o
5
ye ar
s; fo
llo w
-u p
in
o nl
y 22
s ho
rt -
te rm
s tu
di es
, 20
m ed
iu m
-t er
m
st ud
ie s,
a nd
e ig
ht
lo ng
-t er
m s
tu di
es
• Si
x of
5 0
co nt
ro lle
d tr
ial s
fo un
d th
at
ch lo
rp ro
m az
in e
co ul
d re
du ce
r el
ap se
in a
sh
or t-
to m
ed iu
m -t
er m
fo llo
w -u
p; th
re e
w er
e in
a
lo ng
-t er
m fo
llo w
-u p
(6 m
on th
s to
2 y
ea rs
); an
d
tw o
in a
m uc
h lo
ng er
-t er
m fo
llo w
-u p
(2 –5
y ea
rs ).
• T
w en
ty -fo
ur o
f t he
t ri
al s
fo un
d th
at
an tip
sy ch
ot ic
s co
ul d
in du
ce g
lo ba
l im
pr ov
em en
ts in
p os
iti ve
s ym
pt om
s an
d
fu nc
tio ni
ng in
a s
ho rt
- to
m ed
iu m
-t er
m
(u p
to 6
m on
th s)
fo llo
w -u
p. •
N ot
s ur
pr is
in gl
y, a
r an
ge o
f a dv
er se
e ffe
ct s
su ch
a s
ex tr
ap yr
am id
al s
ym pt
om s,
s ed
at io
n,
di zz
in es
s, a
nd w
ei gh
t ga
in w
as fo
un d.
• FG
A s
su ch
a s
ch lo
rp ro
m az
in e
ca
n be
t he
b en
ch m
ar k
of
tr ea
tm en
t fo
r sc
hi zo
ph re
ni a.
• it
is w
el l-e
st ab
lis he
d bu
t
im pe
rf ec
t tr
ea tm
en t.
M os
t
ev id
en ce
o n
th ei
r si
gn ifi
ca nt
ef
fe ct
s ha
s be
en fo
un d
in
ho sp
ita ls
, a nd
r el
at iv
el y
lit tle
w
as a
pp lic
ab le
t o
pa tie
nt s
in
c om
m un
ity c
ar e.
Fe nt
on e
t al
24 42
T hi
or id
az in
e vs
F G
A s,
se
co nd
-g en
er at
io n
an
tip sy
ch ot
ic s,
an
d/ or
p la
ce bo
N =
3 ,4
98 ; m
ai nl
y
ho sp
ita l-b
as ed
; t hr
ee
tr ia
ls c
on du
ct ed
in
ou tp
at ie
nt s
et tin
gs
Fo llo
w -u
p:
30 s
ho rt
- te
rm , t
en m
ed iu
m -
te rm
, a nd
t w
o
lo ng
-t er
m t
ri al
s
• A
s co
m pa
re d
w ith
t he
p la
ce bo
c on
tr ol
s, t
hr ee
R
C T
s fa
vo re
d th
io ri
da zi
ne in
t er
m s
of g
lo ba
l fu
nc tio
ni ng
a fte
r lo
ng er
-t er
m fo
llo w
-u p
(ie , u
p
to 6
m on
th s)
, a nd
a no
th er
t hr
ee R
C T
s fo
un d
it
se da
tin g,
b ut
it w
as n
ot g
en er
al ly
fo un
d to
ca
us e
m ov
em en
t di
so rd
er s.
• C
om pa
re d
w ith
F G
A s,
1 1
sm al
l a nd
t hr
ee
m ed
iu m
R C
T s
fo un
d no
d iff
er en
ce in
g lo
ba l
fu nc
tio ni
ng ; 1
9 sm
al l R
C T
s fo
un d
no
di ffe
re nc
e in
e ar
ly a
tt ri
tio n
or d
ef au
lts ; a
nd
se ve
n R
C T
s fo
un d
th io
ri da
zi ne
t o
ha ve
fe w
er
ex tr
ap yr
am id
al a
dv er
se e
ve nt
s, b
ut t
hr ee
R
C T
s re
po rt
ed it
w as
a ss
oc ia
te d
w ith
ca
rd ia
c ad
ve rs
e ef
fe ct
s.
• T
hi or
id az
in e
in di
ca te
d no
si
gn ifi
ca nt
d iff
er en
ce in
c lin
ic al
ef
fic ac
y w
he n
co m
pa re
d
w ith
o th
er c
om m
on ly
u se
d
an tip
sy ch
ot ic
s in
t er
m s
of g
lo ba
l fu
nc tio
ni ng
. •
T he
r es
ea rc
he rs
s ug
ge st
ed
co ns
id er
in g
ot he
r al
te rn
at iv
es
w he
n pa
tie nt
s di
d no
t re
sp on
d
w el
l t o
th io
ri da
zi ne
.
H ar
tu ng
e t
al 26
25 Pe
rp he
na zi
ne v
s
pl ac
eb o
an d
ot he
r
an tip
sy ch
ot ic
s
N =
2 ,4
78
(2 ,2
85 r
an do
m iz
ed );
al
l c on
du ct
ed in
ho
sp ita
ls o
r
ou tp
at ie
nt s
et tin
gs
T w
o sh
or t-
te rm
, tw
o m
ed iu
m -t
er m
tr
ia ls
• T
w en
ty R
C T
s fo
un d
pe rp
he na
zi ne
a s
ef fe
ct iv
e
as o
th er
a nt
ip sy
ch ot
ic s
in t
er m
s of
s af
et y,
ill
ne ss
b eh
av io
r, a
nd t
ol er
ab ili
ty .
• Po
or d
at a
re po
rt in
g an
d th
e us
e of
v ar
io us
co
m pa
ra to
rs li
m ite
d th
e va
lid ity
o f t
he r
ev ie
w .
• it
w as
n ot
p os
si bl
e to
d ra
w
cl ea
r co
nc lu
si on
s; p
er ph
en az
in e
in
di ca
te d
si m
ila r
de si
ra bl
e an
d
ad ve
rs e
ev en
ts t
o ot
he r
dr ug
s. •
H ow
ev er
, i t
is r
el at
iv el
y
lo w
-c os
t, an
d th
us m
or e
fr
eq ue
nt ly
u se
d. ir
vi ng
e t
al 31
21 H
al op
er id
ol (
or al
)
vs p
la ce
bo N
= 1
,5 19
; a ll
co
nd uc
te d
in
ho sp
ita l o
r ou
tp at
ie nt
se
tt in
gs ; u
su al
ly
m ul
tic en
te r
de si
gn
el ev
en s
ho rt
-t er
m
an d
te n
m ed
iu m
- te
rm tr
ia ls
• T
hr ee
R C
T s
fo un
d th
at h
al op
er id
ol p
ro du
ce d
im
pr ov
em en
t in
g lo
ba l f
un ct
io ni
ng d
ur in
g th
e
fir st
6 w
ee ks
o f f
ol lo
w -u
p; e
ig ht
R C
T s
fa vo
re d
th
e dr
ug a
t 6–
24 w
ee ks
.
• it
w as
s ug
ge st
ed t
ha t
pr es
cr ib
in g
al te
rn at
iv e
dr ug
s an
d ha
lo pe
ri do
l sh
ou ld
n ot
b e
an o
pt io
n fo
r
a ra
nd om
iz ed
c on
tr ol
le d
tr ia
l.
it is
, h ow
ev er
, s til
l s ur
pr is
in gl
y
w id
el y
us ed
.
N
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ps yc
hi at
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is ea
se a
nd T
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t d ow
nl oa
de d
fr om
h ttp
s: //w
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.d ov
ep re
ss .c
om / b
y 16
5. 21
5. 20
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ay -2
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p er
so na
l u se
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1315
Current treatments for schizophrenia spectrum disorders
• A
bo ut
h al
f f ai
le d
to c
om pl
et e
th e
sh or
t- te
rm
fo llo
w -u
p (0
–6 w
ee ks
), an
d el
ev en
s tu
di es
fo un
d
th at
t he
o ut
co m
e di
ffe re
nc e
on ly
m ar
gi na
lly
fa vo
re d
ha lo
pe ri
do l.
• H
al op
er id
ol is
a p
ot en
t c au
se o
f m ov
em en
t di
so rd
er s
in th
e sh
or t-
te rm
; a s
ig ni
fic an
t n um
be r
of
p eo
pl e
su ffe
re d
fr om
s le
ep in
es s,
an d
a fe
w
ad ve
rs e
ef fe
ct s
su ch
a s
pa rk
in so
ni sm
, a ka
th isi
a
an d
ac ut
e dy
st on
ia w
er e
fo un
d in
e le
ve n
RC Ts
. K
um ar
a nd
St
re ch
30
18 Z
uc lo
pe nt
hi xo
l di
hy dr
oc hl
or id
e vs
pl
ac eb
o, F
G A
s, a
nd /
or s
ec on
d- ge
ne ra
tio n
an
tip sy
ch ot
ic s
N =
1 ,5
78 ; m
ai nl
y
co nd
uc te
d in
in pa
tie nt
or
o ut
pa tie
nt s
et tin
gs ;
a fe
w s
et tin
gs w
er e
no
t ab
le t
o be
id
en tifi
ed
18 s
ho rt
-t er
m
st ud
ie s
• T
w o
R C
T s
di d
no t
re po
rt t
he fi
nd in
gs o
f g lo
ba l
or m
en ta
l s ta
te o
ut co
m es
, b ut
a n
in cr
ea se
d
ri sk
o f e
xp er
ie nc
in g
ex tr
ap yr
am id
al a
dv er
se
ef fe
ct s
w as
fo un
d. •
C om
pa re
d w
ith F
G A
s, se
ve n
RC Ts
s ho
w ed
th
at z
uc lo
pe nt
hi xo
l d ec
re as
ed th
e ris
k of
n o
ch
an ge
o r
a w
or se
ni ng
o f t
he il
ln es
s; ni
ne R
C Ts
sh
ow ed
n o
di ffe
re nc
e in
te rm
s of
a dv
er se
e ffe
ct s.
• A
s co
m pa
re d
w ith
s ec
on d-
ge ne
ra tio
n
an tip
sy ch
ot ic
s, t
w o
R C
T s
sh ow
ed n
o di
ffe re
nc e
in
t er
m s
of g
lo ba
l s ta
te a
nd w
ei gh
t ga
in w
ith
ri sp
er id
on e,
b ut
o ne
fo un
d th
at m
or e
an
ti- Pa
rk in
so ni
an m
ed ic
at io
ns w
er e
pr es
cr ib
ed
in p
eo pl
e ta
ki ng
z uc
lo pe
nt hi
xo l.
• So
m e
cl in
ic al
a dv
an ta
ge s
of
zu cl
op en
th ix
ol d
ih yd
ro ch
lo ri
de
in t
he s
ho rt
-t er
m , s
uc h
as
si gn
ifi ca
nt im
pr ov
em en
ts
in g
lo ba
l s ta
te .
• M
or e
m ov
em en
t di
so rd
er s
w
er e
fo un
d th
an w
ith t
he
ne w
er g
en er
at io
n of
d ru
gs .
• T
he re
is n
o cl
ea r
an d
ad eq
ua te
in
fo rm
at io
n ab
ou t
se rv
ic e
us
e, fu
nc tio
na l a
nd b
eh av
io ra
l ou
tc om
es , a
nd r
el ap
se
pr ev
en tio
n.
Le uc
ht e
t al
32 14
H al
op er
id ol
v s
ch
lo rp
ro m
az in
e
(o ra
l a nd
in tr
am us
cu la
r
ro ut
e)
N =
7 94
; t en
s tu
di es
co
nd uc
te d
in in
pa tie
nt
se tt
in gs
a nd
fo ur
in
no ni
de nt
ifi ed
s et
tin gs
Fo llo
w -u
p:
48 h
ou rs
to
3 y
ea rs
, m os
tly
sh or
t- te
rm
• N
in e
R C
T s
fa vo
re d
ha lo
pe ri
do l,
ev en
t ho
ug h
th
e di
ffe re
nc e
w as
n ot
s ta
tis tic
al ly
s ig
ni fic
an t.
• Si
x R
C T
s re
po rt
ed t
ha t
m ov
em en
t di
so rd
er s
w
ith h
al op
er id
ol w
er e
m or
e fr
eq ue
nt , a
nd
fiv e
fo un
d th
at h
yp ot
en si
on w
as a
ss oc
ia te
d
w ith
c hl
or pr
om az
in e.
• N
o di
ffe re
nc e
w as
fo un
d be
tw ee
n in
tr am
us cu
la r
an
d or
al a
dm in
is tr
at io
n.
• Fe
w er
t ha
n 80
0 pe
op le
w er
e
ra nd
om iz
ed , a
nd r
ep or
tin g
on
th e
m ai
n re
su lts
w as
in co
m pl
et e.
• H
al op
er id
ol in
di ca
te d
st at
is tic
al ly
no
ns ig
ni fic
an t
ef fic
ac y
in t
er m
s
of v
ar io
us p
at ie
nt o
ut co
m es
, th
us m
ak in
g it
di ffi
cu lt
to d
ra w
co
nc lu
si on
s. Le
uc ht
a nd
H
ar tu
ng 28
Si x
Pe ra
zi ne
v s
ot he
r
FG A
s an
d/ or
p la
ce bo
N =
2 88
; fi ve
co
nd uc
te d
in in
pa tie
nt s
et tin
gs
an d
on e
in a
no
ni de
nt ifi
ed s
et tin
g
Si x
sh or
t- te
rm
tr ia
ls •
O ne
R C
T w
ith a
5 -w
ee k
fo llo
w -u
p fo
un d
th
at p
er az
in e
w as
s up
er io
r to
t he
p la
ce bo
on
im pr
ov em
en t
in g
lo ba
l f un
ct io
ni ng
b ut
m
ad e
no s
ig ni
fic an
t di
ffe re
nc e
to m
en ta
l s ta
te .
• Si
m ila
r ad
ve rs
e ef
fe ct
s w
er e
fo un
d am
on g
th
e m
ed ic
at io
ns u
se d
an d
co m
pa re
d; m
os t
pa
rt ic
ip an
ts r
ec ei
ve d
at le
as t
on e
do se
of
a nt
i-P ar
ki ns
on ia
n m
ed ic
at io
n. •
Fi ve
R C
Ts p
ro vi
de d
in su
ffi ci
en t i
nf or
m at
io n
of
o ut
co m
es to
d ra
w c
on cl
us io
n, a
nd th
re e
RC
Ts s
ho w
ed th
e dr
ug in
di ca
te d
sim ila
r ris
ks
of e
xt ra
py ra
m id
al a
dv er
se e
ffe ct
s to
o th
er d
ru gs
.
• T
he re
w as
n o
st at
is tic
al ly
si
gn ifi
ca nt
d iff
er en
ce in
m os
t
cl in
ic al
o ut
co m
es , a
nd li
m ite
d
ev id
en ce
t o
dr aw
c on
cl us
io ns
.
(C on
tin ue
d )
N
eu ro
ps yc
hi at
ric D
is ea
se a
nd T
re at
m en
t d ow
nl oa
de d
fr om
h ttp
s: //w
w w
.d ov
ep re
ss .c
om / b
y 16
5. 21
5. 20
9. 15
o n
11 -M
ay -2
01 9
F or
p er
so na
l u se
o nl
y.
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1316
Chien and Yip
T ab
le 1
(C on
tin ue
d)
A ut
ho rs
C lin
ic al
t ri
al s
re vi
ew ed
, N In
te rv
en ti
on s
Sa m
pl e
si ze
a nd
st
ud y
se tt
in g
Le ng
th o
f s tu
dy
or fo
llo w
-u p
Su m
m ar
y of
m ai
n fin
di ng
s C
on cl
us io
n
Li u
an d
D e
H
aa n22
Fo ur
C hl
or pr
om az
in e
vs
p la
ce bo
N =
1 ,0
12 ; m
ai nl
y
co nd
uc te
d in
h os
pi ta
l se
tt in
gs
Fo ur
s ho
rt -t
er m
tr
ia ls
• Tw
o RC
Ts fo
un d
fe w
er e
xt ra
py ra
m id
al a
dv er
se
ef fe
ct s
in a
lo w
-d os
e gr
ou p
of c
hl or
pr om
az in
e,
fa ci
lit at
in g
a be
tt er
q ua
lit y
of li
fe .
• O
ne R
C T
fa vo
re d
th e
hi gh
-d os
e gr
ou p
w
ith m
uc h
be tt
er fu
nc tio
ni ng
, e ve
n th
ou gh
th
ey in
di ca
te d
m or
e ad
ve rs
e ef
fe ct
s.
Bo th
g ro
up s
ex pe
ri en
ce d
ak at
hi si
a.
• Th
e do
se o
f c hl
or pr
om az
in e
gi
ve n
de cl
in ed
a cr
os s
tim e,
th
us c
on tr
ib ut
in g
to fa
vo ra
bl e
ou
tc om
es a
nd le
ss a
dv er
se e
ffe ct
s. •
it is
e xt
en si
ve ly
u se
d in
de
ve lo
pi ng
c ou
nt ri
es .
M ar
qu es
et
a l23
50 T
ri flu
op er
az in
e vs
pl
ac eb
o, o
th er
F G
A s,
an
d/ or
s ec
on d-
ge ne
ra tio
n
an tip
sy ch
ot ic
s
N =
2 ,5
83 ; 4
4 st
ud ie
s
co nd
uc te
d in
h os
pi ta
l se
tt in
gs
28 s
ho rt
-t er
m , s
ix
m ed
iu m
-t er
m , a
nd
on e
lo ng
-t er
m t
ri al
• w
he n
co m
pa re
d w
ith t
he p
la ce
bo , t
hr ee
sm
al l-s
ca le
s ho
rt -t
er m
R C
T s
fa vo
re d
tr
ifl uo
pe ra
zi ne
in t
er m
s of
g lo
ba l i
m pr
ov em
en ts
, fo
ur fo
un d
th at
m or
e pe
op le
a llo
ca te
d to
tr
ifl uo
pe ra
zi ne
u se
d an
ti- Pa
rk in
so ni
an d
ru gs
, an
d se
ve n
re po
rt ed
1 2%
a tt
ri tio
ns in
b ot
h
gr ou
ps a
t fo
llo w
-u ps
. •
w he
n co
m pa
re d
w ith
th e
FG A
s, 22
R C
Ts fo
un d
no
d iff
er en
ce in
te rm
s of
g lo
ba l i
m pr
ov em
en t
be tw
ee n
gr ou
ps , 1
4 fo
un d
th at
s im
ila r
nu m
be r
of
p ar
tic ip
an ts
r ep
or te
d at
le as
t o ne
a dv
er se
ef
fe ct
, a nd
th re
e fo
un d
tr ifl
uo pe
ra zi
ne m
os t l
ik el
y
ca us
ed e
xt ra
py ra
m id
al a
dv er
se e
ffe ct
s. •
O ne
s m
al l-s
ca le
R C
T fo
un d
no d
iff er
en ce
be
tw ee
n tr
ifl uo
pe ra
zi ne
a nd
s ec
on d-
ge ne
ra tio
n
an tip
sy ch
ot ic
s on
p at
ie nt
o ut
co m
es .
• Si
m ila
r ef
fic ac
y an
d ad
ve rs
e
ev en
ts a
re fo
un d
be tw
ee n
tr
ifl uo
pe ra
zi ne
a nd
t he
o th
er
co m
m on
ly u
se d
an tip
sy ch
ot ic
s. •
T ri
flu op
er az
in e
is a
p ot
en t
FG
A , i
ne xp
en si
ve a
nd w
id el
y
ac ce
ss ib
le , b
ut it
s su
pe ri
or ity
is
in co
nc lu
si ve
w he
n co
m pa
re d
w
ith s
ec on
d- ge
ne ra
tio n
an
tip sy
ch ot
ic s.
M at
ar , A
lm er
ie
an d
Sa m
ps on
27
Se ve
n Fl
up he
na zi
ne (
or al
)
vs p
la ce
bo N
= 4
39 ; m
ai nl
y in
ho
sp ita
l o r
co m
m un
ity
se tt
in gs
M os
t sh
or t-
te
rm (
6) •
T w
o R
C T
s fo
un d
no d
iff er
en ce
o n
gl ob
al
st at
es b
et w
ee n
flu ph
en az
in e
an d
pl ac
eb o
gr
ou p
in t
he s
ho rt
-t er
m .
• Fo
ur r
ep or
te d
flu ph
en az
in e
gr ou
p tr
ia l
in di
ca te
d a
hi gh
er r
is k
of d
ev el
op in
g
ad ve
rs e
ef fe
ct s
in t
he s
ho rt
-t er
m .
• Fl
up he
na zi
ne is
a n
ef fe
ct iv
e
bu t
im pe
rf ec
t tr
ea tm
en t;
it is
in
ex pe
ns iv
e an
d ac
ce ss
ib le
. •
T he
r es
ea rc
he rs
p re
fe r
to u
se
ot he
r al
te rn
at iv
es w
ith fe
w er
ad
ve rs
e ef
fe ct
s. R
at hb
on e
an d
M
cM on
ag 25
35 (
27 r
an do
m iz
ed ;
ei gh
t do
ub le
-b lin
d) Pi
m oz
id e
vs p
la ce
bo N
= 1
,3 48
; m ai
nl y
co
nd uc
te d
in in
pa tie
nt
or o
ut pa
tie nt
s et
tin gs
Fo llo
w -u
p: fr
om
28 d
ay s
(s ho
rt -
te rm
) t o
3 ye
ar s
(lo
ng -t
er m
)
• T
w o
R C
T s
su gg
es te
d pi
m oz
id e
co ul
d be
tt er
pr
ev en
t re
la ps
e w
he n
co m
pa re
d w
ith p
la ce
bo .
• Si
x fo
un d
th e
dr ug
h ad
s im
ila r
ef fic
ac y
an d
di d
no t
ha ve
a h
ig he
r m
or ta
lit y
ra te
th an
o th
er F
G A
s, bu
t m
or e
lik el
y ca
us ed
li m
b tr
em or
in th
e sh
or t-
te rm
. •
H ow
ev er
, fi ve
in di
ca te
d th
e dr
ug w
as le
ss li
ke ly
to
c au
se s
ed at
io n
in m
ed iu
m -t
er m
. •
Fo ur
in di
ca te
d an
ti- Pa
rk in
so ni
an m
ed ic
at io
n
sh ou
ld b
e ne
ed ed
.
• M
os t
st ud
ie s
ca nn
ot b
e us
ef ul
to
c om
m en
t on
e ffi
ca cy
o f
pi m
oz id
e fo
r pe
op le
w ith
de
lu si
on al
d is
or de
rs .
• It
sh ow
s si
m ila
r ef
fic ac
y to
ot
he r
FG A
s.
N
eu ro
ps yc
hi at
ric D
is ea
se a
nd T
re at
m en
t d ow
nl oa
de d
fr om
h ttp
s: //w
w w
.d ov
ep re
ss .c
om / b
y 16
5. 21
5. 20
9. 15
o n
11 -M
ay -2
01 9
F or
p er
so na
l u se
o nl
y.
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1317
Current treatments for schizophrenia spectrum disorders
rate and patient dissatisfaction), inability to work, family
burden, and social and cognitive functioning. Therefore,
there are a wider variety of outcome measurements than
used in previous studies, such as depression (eg, the Calgary
Depression Scale, the Hamilton Rating Scale for Depres-
sion, or the Montgomery Asberg Depression Rating Scale),
quality of life (eg, the Quality of Life Scale, the Schizo-
phrenia Quality of Life Scale, the Subjective Well-being
on Neuroleptics [Antipsychotics] Scale, or the Personal and
Social Performance Scale), and patient satisfaction (eg, the
Nurses Observational Scale Inpatients Evaluation) measures.
Similar to those receiving FGAs, most of the clinical trials
evaluated the short-term effects (up to 12 weeks) of the
second-generation antipsychotics, even though a few long-
term evaluations appear promising.39,40
A few systematic reviews also indicated that the con-
trolled trials of second-generation antipsychotics have mainly
tested only a few kinds, including risperidone, olanzapine,
quetiapine, loxapine, sertindole, aripiprazole, and amisul-
pride, and mostly compared them with placebo controls.43–50
The reviews concluded that second-generation antipsychotics
had similar effects to FGAs in terms of reduction of positive
symptoms. The treatment efficacy of both FGAs and second-
generation antipsychotics varies in terms of stages of the
illness, with first-episode schizophrenia responding faster
and better than at later illness stages.35,41,51 Nevertheless, most
of the second-generation antipsychotics had comparatively
fewer and lower levels of adverse effects such as movement
disorders and cardiac and sedative problems than FGAs.
Clozapine, the first second-generation antipsychotic, has
been found to be particularly effective in treating refractory
patients and reducing suicidality.36,41 A recent meta-analysis
comparing nine second-generation antipsychotics with the
FGAs (eg, chlorpromazine, fluphenazine and haloperidol)
for overall efficacy concluded that four second-generation
antipsychotics (namely, amisulpride, clozapine, olanzapine,
and risperidone) were better than the FGAs, with small
to medium effect sizes (ie, 0.13–0.52).37 The four second-
generation antipsychotics have been shown to induce fewer
extrapyramidal adverse effects than the low-potency FGAs.
Although olanzapine can induce more weight gain and pro-
duction of prolactin, it is shown to exert a persistent treatment
effect over other second-generation antipsychotics in chronic
schizophrenia.37,52
A recent Cochrane’s systematic review was published on
nine randomized, placebo-controlled trials of aripiprazole,
which is one of the newer second-generation antipsychotics.
Its main results indicated that aripiprazole can significantly So ar
es e
t al
29 18
Su lp
ir id
e vs
p la
ce bo
, FG
A s,
a nd
/o r
se
co nd
-g en
er at
io n
an
tip sy
ch ot
ic s
N .
9 00
; 1 4
st ud
ie s
co
nd uc
te d
in h
os pi
ta l
se tt
in gs
a nd
o ne
in t
he
co m
m un
ity ; t
hr ee
in
no ni
de nt
ifi ed
s et
tin gs
M os
t f ol
lo w
-u p
ov
er 8
w ee
ks
(s ho
rt -t
er m
).
• Su
lp ir
id e
in di
ca te
d fe
w er
a dv
er se
e ffe
ct s,
an
d lit
tle d
iff er
en ce
w as
fo un
d be
tw ee
n th
e
dr ug
a nd
o th
er a
nt ip
sy ch
ot ic
s. •
N o
fin di
ng s
of n
eg at
iv e
sy m
pt om
s w
er e
sh ow
n.
• in
g en
er al
, s m
al l-s
ca le
a nd
p oo
r-
qu al
ity s
tu di
es w
er e
fo un
d. •
it m
ay b
e ef
fe ct
iv e
an d
ha ve
fe
w er
a dv
er se
e ffe
ct s
at lo
w
do se
s, b
ut t
he re
w as
in su
ffi ci
en t
ev id
en ce
. •
T he
re w
er e
lim ite
d re
su lts
on
n eg
at iv
e sy
m pt
om s.
So ar
es a
nd
Si lv
a de
L im
a33
27 (
el ev
en s
tu di
es
ra nd
om iz
ed )
Pe nfl
ur id
ol v
s FG
A s,
de
po t
in je
ct io
ns ,
an d/
or p
la ce
bo
N =
1 ,0
24 ; m
ai nl
y
co nd
uc te
d in
h os
pi ta
l or
o ut
pa tie
nt s
et tin
gs ;
fo ur
w ith
n on
id en
tifi ed
se
tt in
gs
Fi ve
s ho
rt -t
er m
an
d 22
m ed
iu m
- te
rm tr
ia ls
• Fo
ur m
ed iu
m -t
er m
R C
T s
fo un
d pe
nfl ur
id ol
su
pe ri
or t
o pl
ac eb
o in
t er
m s
of g
lo ba
l fu
nc tio
ni ng
, w he
re as
a no
th er
fi ve
R C
T s
sh
ow ed
t ha
t a
co m
bi na
tio n
of a
nt ip
sy ch
ot ic
s
w as
c on
si de
re d
ne ce
ss ar
y. •
T en
s ho
w ed
n o
di ffe
re nc
e be
tw ee
n pe
nfl ur
id ol
an
d ot
he r
FG A
s in
t er
m s
of g
lo ba
l s ta
te
ov er
3 –6
m on
th s.
• Fi
ve fo
un d
th at
t he
d ru
g w
as s
up er
io r
in
k ee
pi ng
p at
ie nt
s in
t re
at m
en t.
• Ef
fic ac
y an
d ad
ve rs
e ef
fe ct
pr
ofi le
s ar
e si
m ila
r am
on g
FG
A s,
n o
m at
te r
w he
th er
by
o ra
l o r
de po
t ro
ut e.
• Pe
nfl ur
id ol
is a
n op
tio n
fo r
ch
ro ni
c ill
ne ss
w ith
r es
id ua
l ps
yc ho
tic s
ym pt
om s
an d
is
c on
si de
re d
a lo
w -c
os t
in
te rv
en tio
n.
N ot
es : a D
ur at
io n
of s
tu dy
o r
fo llo
w -u
p, w
ith t
ri al
s ra
ng in
g fr
om s
ho rt
-t er
m , u
p to
1 2
w ee
ks , t
o m
ed iu
m -t
er m
, 1 3–
24 w
ee ks
, t o
lo ng
-t er
m , m
or e
th an
2 4
w ee
ks .
A bb
re vi
at io
ns : F
G A
s, fi
rs t-
ge ne
ra tio
n an
tip sy
ch ot
ic s;
R C
T s,
r an
do m
iz ed
c on
tr ol
le d
tr ia
ls ; v
s, v
er su
s.
N
eu ro
ps yc
hi at
ric D
is ea
se a
nd T
re at
m en
t d ow
nl oa
de d
fr om
h ttp
s: //w
w w
.d ov
ep re
ss .c
om / b
y 16
5. 21
5. 20
9. 15
o n
11 -M
ay -2
01 9
F or
p er
so na
l u se
o nl
y.
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1318
Chien and Yip
T ab
le 2
S um
m ar
y of
r ev
ie w
s on
s ec
on d-
ge ne
ra tio
n an
tip sy
ch ot
ic s
fo r
sc hi
zo ph
re ni
a
A ut
ho rs
C lin
ic al
t ri
al s
re vi
ew ed
, N In
te rv
en ti
on s
Sa m
pl e
si ze
a nd
st
ud y
se tt
in g
Le ng
th o
f s tu
dy
or fo
llo w
-u pa
Su m
m ar
y of
m ai
n fin
di ng
s C
on cl
us io
n
A lp
te ki
n et
a l34
O ne
R C
T a
nd
a fe
w w
ith
no nr
an do
m iz
ed
co m
pa ri
so n
gr
ou ps
d es
ig n
O la
nz ap
in e,
ri
sp er
id on
e or
ha
lo pe
ri do
l v s
zi pr
as id
on e
N =
2 87
; m ul
tic en
te r
tr
ia ls
in a
h os
pi ta
l or
o ut
pa tie
nt s
et tin
g
Fo llo
w -u
p: u
p
to 1
2 w
ee ks
(s
ho rt
-t er
m )
• Z
ip ra
si do
ne s
ho w
ed s
ig ni
fic an
t ef
fe ct
s on
im pr
ov em
en t
in
m en
ta l s
ta te
a nd
c og
ni tiv
e fu
nc tio
ni ng
. •
It ha
s a
co m
pa ra
tiv el
y ne
ut ra
l m et
ab ol
ic p
ro fil
e an
d
is c
lin ic
al ly
v al
ua bl
e w
he n
ta ke
n w
ith fo
od .
• T
he fi
nd in
gs c
on fir
m t
he
ef fe
ct iv
en es
s of
z ip
ra si
do ne
as
a n
ap pr
op ri
at e
ch oi
ce fo
r
sw itc
hi ng
o f d
ru gs
w he
ne ve
r
ne ed
ed .
Be lg
am w
ar a
nd
el -S
ay eh
48
N in
e A
ri pi
pr az
ol e
vs
pl ac
eb o
N =
2 ,5
85 ; m
ai nl
y
co nd
uc te
d in
a
ho sp
ita l o
r
ou tp
at ie
nt s
et tin
g
ei gh
t sh
or t-
te rm
an
d tw
o m
ed iu
m -
te rm
t ri
al s
• O
ne R
C T
w ith
le ss
t ha
n 3
m on
th s
fo llo
w -u
p fo
un d
th
at a
ri pi
pr az
ol e
si gn
ifi ca
nt ly
r ed
uc ed
r el
ap se
. •
ei gh
t R
C T
s sh
ow ed
b et
te r
m ed
ic at
io n
co m
pl ia
nc e,
an
d tw
o sh
ow ed
lo w
er r
is ks
o f r
ai se
d pr
ol ac
tin
an d
pr ol
on ga
tio n
of t
he c
or re
ct ed
Q T
in te
rv al
o f e
C G
(r
ep re
se nt
s th
e de
po la
ri za
tio n
an d
re po
la ri
za tio
n of
t he
le
ft an
d ri
gh t
ve nt
ri cl
es o
r ve
nt ri
cu la
r ar
rh yt
hm ia
s) .
• M
os t
w er
e un
ab le
t o
ex tr
ac t
an y
us ab
le d
at a
on
m or
ta lit
y, s
er vi
ce u
til iz
at io
n an
d sa
tis fa
ct io
n,
an d
co gn
iti ve
fu nc
tio ni
ng .
• A
ri pi
pr az
ol e
ca n
be e
ffe ct
iv e
in
t he
s ho
rt -
to m
ed iu
m -t
er m
of
t re
at m
en t.
• T
he re
w as
h ig
h at
tr iti
on in
al
l s tu
di es
( .
30 %
).
C ha
kr ab
ar ti
et
a l47
41 Lo
xa pi
ne v
s pl
ac eb
o,
se co
nd -g
en er
at io
n
an tip
sy ch
ot ic
s,
an d/
or F
G A
s
N =
2 ,3
81 ; a
ll
co nd
uc te
d in
ho
sp ita
ls
Fo llo
w -u
p: fr
om
72 h
ou rs
( sh
or t-
te
rm )
to 6
m on
th s
(lo
ng -t
er m
)
• T
hi rt
ee n
sh or
t- te
rm R
C T
s fo
un d
lo xa
pi ne
a s
ef fe
ct iv
e
as o
th er
F G
A s,
w he
re as
s ix
lo ng
er -t
er m
R C
T s
re po
rt ed
it
w as
a s
ef fe
ct iv
e as
s ec
on d-
ge ne
ra tio
n an
tip sy
ch ot
ic s
in
t er
m s
of r
el ap
se a
nd a
fe w
p at
ie nt
o ut
co m
es .
• Fo
ur fo
un d
th e
dr ug
h ad
s im
ila r
ad ve
rs e
ef fe
ct s
to
o th
er F
G A
s an
d th
at t
he y
w er
e m
or e
se ve
re
th an
t ho
se o
f s ec
on d-
ge ne
ra tio
n an
tip sy
ch ot
ic s.
• Lo
xa pi
ne c
an b
e ef
fe ct
iv e
fr om
sh
or t-
t o
lo ng
-t er
m t
re at
m en
t
in s
ch iz
op hr
en ia
, b ut
w ith
s im
ila r
ef
fic ac
y to
a fe
w o
th er
F G
A s
an d
se
co nd
-g en
er at
io n
an tip
sy ch
ot ic
s. •
it m
ay c
au se
m or
e ex
tr ap
yr am
id al
ad
ve rs
e ef
fe ct
s w
he n
co m
pa re
d
w ith
o th
er s
ec on
d- ge
ne ra
tio n
an
tip sy
ch ot
ic s.
C itr
om e35
32 Lu
ra si
do ne
v s
pl
ac eb
o N
= 8
,0 71
; m os
t
se tt
in gs
n ot
sp
ec ifi
ed
Fo llo
w -u
p: fr
om
7 da
ys (
sh or
t- te
rm )
to
1 8
m on
th s
(lo
ng -t
er m
)
• Lu
ra si
do ne
w as
s ho
w n
to b
e ef
fic ac
io us
a nd
t ol
er ab
le
w ith
fo od
a nd
h ad
a h
ig hl
y fa
vo ra
bl e
m et
ab ol
ic p
ro fil
e. •
A ka
th is
ia o
r Pa
rk in
so ni
sm w
as r
ep or
te d
in m
os t
R C
T s.
• A
dd iti
on al
d at
a w
er e
ne ce
ss ar
y
to s
up po
rt it
s lo
ng -t
er m
e ffi
ca cy
as
a m
ai nt
en an
ce t
re at
m en
t.
D ug
ga n
et a
l46 56
O la
nz ap
in e
vs F
G A
s,
se co
nd -g
en er
at io
n
an tip
sy ch
ot ic
s,
an d/
or p
la ce
bo
N .
1 0,
00 0;
m
ai nl
y co
nd uc
te d
in
t he
h os
pi ta
l o r
ou
tp at
ie nt
s et
tin g;
el
ev en
c on
du ct
ed
in n
on id
en tifi
ed
se tt
in gs
31 s
ho rt
-t er
m ,
23 m
ed iu
m -t
er m
, an
d tw
o lo
ng -t
er m
tr
ia ls
• Si
xt ee
n R
C T
s sh
ow ed
h ig
h at
tr iti
on b
y 6
w ee
ks
in b
ot h
ol an
za pi
ne a
nd p
la ce
bo /F
G A
s; fo
ur fo
un d
th
e dr
ug a
s ef
fe ct
iv e
as F
G A
s. •
Fo ur
fo un
d ol
an za
pi ne
t o
ca us
e fe
w er
m ov
em en
t
di so
rd er
s bu
t m
or e
w ei
gh t
ga in
fr om
3 t
o 12
m on
th s
of
t re
at m
en t.
• el
ev en
r ec
or de
d th
at 2
3% o
f p eo
pl e
in t
ri al
s of
ol
an za
pi ne
a nd
o th
er s
ec on
d- ge
ne ra
tio n
an tip
sy ch
ot ic
s
le ft
by 8
w ee
ks , a
nd 4
8% b
y 3
to 1
2 m
on th
s.
• M
os t
st ud
ie s
re po
rt ed
v er
y hi
gh
at tr
iti on
in b
ot h
ol an
za pi
ne
an d
pl ac
eb o/
FG A
/o th
er s
ec on
d-
ge ne
ra tio
n an
tip sy
ch ot
ic g
ro up
s,
ra ng
in g
fr om
. 30
% b
y 6
w ee
ks
to 5
0% b
y 12
m on
th s.
• T
he re
w as
s im
ila r
ef fic
ac y
to
o th
er s
ec on
d- ge
ne ra
tio n
an
tip sy
ch ot
ic s
in r
el ap
se
pr ev
en tio
n an
d re
du ct
io n
of
p os
iti ve
s ym
pt om
s, b
ut
no n
ot ab
le b
en efi
t in
n eg
at iv
e
sy m
pt om
s.
N
eu ro
ps yc
hi at
ric D
is ea
se a
nd T
re at
m en
t d ow
nl oa
de d
fr om
h ttp
s: //w
w w
.d ov
ep re
ss .c
om / b
y 16
5. 21
5. 20
9. 15
o n
11 -M
ay -2
01 9
F or
p er
so na
l u se
o nl
y.
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1319
Current treatments for schizophrenia spectrum disorders
el -S
ay eh
a nd
M
or ga
nt i49
15 A
ri pi
pr az
ol e
vs F
G A
s,
se co
nd -g
en er
at io
n
an tip
sy ch
ot ic
s,
an d/
or p
la ce
bo
N =
7 ,1
10 ; e
ig ht
co
nd uc
te d
in
ho sp
ita l s
et tin
g an
d
tw o
in o
ut pa
tie nt
se
tt in
g; fi
ve w
ith
no ni
de nt
ifi ed
se
tt in
gs
T en
s ho
rt -t
er m
, th
re e
m ed
iu m
-t er
m ,
an d
tw o
lo ng
-t er
m
tr ia
ls
• O
ne R
C T
s ho
w ed
t ha
t ar
ip ip
ra zo
le c
ou ld
s ig
ni fic
an tly
de
cr ea
se r
el ap
se in
s ho
rt -
an d
m ed
iu m
-t er
m fo
llo w
-u p.
• ei
gh t
R C
T s
fo un
d th
at t
he d
ru g
pr od
uc ed
b et
te r
co
m pl
ia nc
e; s
ev en
r ep
or te
d th
at it
p ro
du ce
d a
lo w
er
ri sk
o f a
ka th
is ia
w he
n co
m pa
re d
w ith
F G
A s
an d
le ss
ri
sk o
f m et
ab ol
ic a
nd c
ar di
ac e
ve nt
s w
he n
co m
pa re
d
w ith
o th
er s
ec on
d ge
ne ra
tio n
an tip
sy ch
ot ic
s. •
it w
as n
ot p
os si
bl e
to e
xt ra
ct a
ny u
sa bl
e da
ta
on m
or ta
lit y,
s er
vi ce
u se
a nd
s at
is fa
ct io
n, a
nd g
en er
al
an d
co gn
iti ve
fu nc
tio ni
ng .
• M
os t
R C
T s
re po
rt ed
h ig
h
at tr
iti on
r at
es (
30 %
–5 0%
). •
A ri
pi pr
az ol
e ca
n be
e ffe
ct iv
e
in m
ed iu
m -t
er m
t re
at m
en t,
w
ith s
im ila
r ef
fic ac
y to
o th
er
se co
nd -g
en er
at io
n an
tip sy
ch ot
ic s
an d
m os
t FG
A s
in r
el ap
se
pr ev
en tio
n an
d re
du ct
io n
of
p os
iti ve
s ym
pt om
s. •
its p
re sc
ri pt
io n
as r
ou tin
e
or u
su al
p ra
ct ic
e ca
nn ot
b e
co
nfi rm
ed .
K ar
ay al
e t
al 54
A n
op en
-la be
l,
fle xi
bl e-
do se
tr
ia l
Sw itc
hi ng
fr om
qu
et ia
pi ne
t o
zi
pr as
id on
e
N =
2 41
; c on
du ct
ed
in a
n ou
tp at
ie nt
se
tt in
g
A ll
pa rt
ic ip
an ts
w
er e
fo llo
w ed
-u p
ov
er 3
m on
th s
(m
ed iu
m -t
er m
)
• T
he R
C T
s ho
w ed
t ha
t sw
itc hi
ng t
o zi
pr as
id on
e
co ul
d pr
od uc
e a
si gn
ifi ca
nt d
ec re
as e
in w
ei gh
t
an d
im pr
ov em
en ts
in m
en ta
l s ta
te a
nd c
og ni
tiv e
fu
nc tio
ni ng
, w ith
a n
eu tr
al m
et ab
ol ic
p ro
fil e.
• it
w as
r ec
om m
en de
d to
b e
ta ke
n w
ith fo
od .
• Z
ip ra
si do
ne s
ho w
s si
gn ifi
ca nt
be
ne fit
s in
o ve
ra ll
m en
ta l
st at
e an
d fu
nc tio
ni ng
in t
he
m ed
iu m
-t er
m .
• Pa
tie nt
s ta
ki ng
t hi
s dr
ug s
ho w
ed
sa tis
fa ct
or y
to le
ra bi
lit y
an d
sa
fe ty
; t he
re fo
re , i
t is
a g
oo d
ch
oi ce
fo r
th e
sw itc
hi ng
o f
se co
nd -g
en er
at io
n an
tip sy
ch ot
ic s.
Le w
is e
t al
69 T
hr ee
Se rt
in do
le v
s
pl ac
eb o
or
ha lo
pe ri
do l
N =
1 ,1
04 ; m
ai nl
y
co nd
uc te
d in
th
e ho
sp ita
l o r
ou
tp at
ie nt
s et
tin g
O ne
s ho
rt -t
er m
, on
e m
ed iu
m -t
er m
, an
d on
e lo
ng -t
er m
tr
ia l
• W
he n
co m
pa re
d w
ith t
he p
la ce
bo , n
o si
gn ifi
ca nt
di
ffe re
nc e
w as
fo un
d w
ith a
d os
e of
m or
e th
an
12 m
g da
ily , b
ut a
m ar
gi na
lly s
ig ni
fic an
t di
ffe re
nc e
w
as fo
un d
w he
n ta
ki ng
2 0
m g
da ily
. •
T he
re w
as n
o si
gn ifi
ca nt
d iff
er en
ce b
et w
ee n
lo w
a nd
hi
gh d
os es
o f s
er tin
do le
in t
er m
s of
m os
t ad
ve rs
e
ev en
ts ; c
ar di
ov as
cu la
r ad
ve rs
e ef
fe ct
s sh
ow ed
si
gn ifi
ca nt
d iff
er en
ce b
et w
ee n
gr ou
ps a
t al
l d os
es
by 8
w ee
ks , w
he re
as w
ei gh
t ga
in w
as s
ig ni
fic an
tly
hi gh
er w
ith a
h ig
h do
se o
f s er
tin do
le .
• w
he n
co m
pa re
d w
ith h
al op
er id
ol , s
er tin
do le
in du
ce d
m
or e
ca rd
ia c
pr ob
le m
s, r
hi ni
tis , a
nd w
ei gh
t ga
in ,
bu t
fe w
er m
ov em
en t
di so
rd er
s an
d le
ss s
ex ua
l dy
sf un
ct io
n an
d se
da tio
n th
an h
al op
er id
ol .
• Se
rt in
do le
a pp
ea rs
t o
ha ve
s im
ila r
ef fic
ac y
bu t
to b
e m
or e
to le
ra bl
e
th an
h al
op er
id ol
. •
Se rt
in do
le 1
6 m
g/ da
y is
s ug
ge st
ed
to b
e th
e m
os t
op tim
al d
os e.
N us
sb au
m a
nd
St ro
up 45
ei gh
t Pa
lip er
id on
e (o
ra l
an d
in tr
am us
cu la
r)
vs p
la ce
bo o
r
se co
nd -g
en er
at io
n
an tip
sy ch
ot ic
s
N =
2 ,5
62 ; m
ai nl
y
co nd
uc te
d in
a
ho sp
ita l o
r
ou tp
at ie
nt s
et tin
g;
a fe
w n
ot s
pe ci
fie d
A ll
fo llo
w ed
u p
in
sh or
t- te
rm •
w he
n co
m pa
re d
w ith
p la
ce bo
s, s
ev en
R C
T s
in
di ca
te d
th at
fe w
er p
eo pl
e ra
nd om
ly a
ss ig
ne d
to t
he
pa lip
er id
on e
gr ou
p le
ft th
e st
ud ie
s an
d th
at le
ss r
el ap
se
w as
r ep
or te
d; fo
ur fo
un d
th at
t he
d ru
g pr
od uc
ed
si gn
ifi ca
nt im
pr ov
em en
t in
g lo
ba l f
un ct
io ni
ng , b
ut m
os t
R
C T
s in
di ca
te d
th at
t hi
s dr
ug c
au se
d ad
ve rs
e ev
en ts
su
ch a
s ta
ch yc
ar di
a an
d ex
tr ap
yr am
id al
s yn
dr om
e.
• Pa
lip er
id on
e ap
pe ar
s to
b e
ef
fe ct
iv e
in r
el ap
se p
re ve
nt io
n,
al th
ou gh
n o
fir m
c on
cl us
io ns
w er
e dr
aw n
as to
it s
lo ng
-t er
m e
ffe ct
s. •
T he
re a
re s
im ila
r le
ve ls
o f
ad ve
rs e
ef fe
ct s
w he
n it
is
co m
pa re
d w
ith o
th er
s ec
on d-
ge
ne ra
tio n
an tip
sy ch
ot ic
s.
(C on
tin ue
d )
N
eu ro
ps yc
hi at
ric D
is ea
se a
nd T
re at
m en
t d ow
nl oa
de d
fr om
h ttp
s: //w
w w
.d ov
ep re
ss .c
om / b
y 16
5. 21
5. 20
9. 15
o n
11 -M
ay -2
01 9
F or
p er
so na
l u se
o nl
y.
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1320
Chien and Yip
T ab
le 2
( Co
nt in
ue d)
A ut
ho rs
C lin
ic al
t ri
al s
re vi
ew ed
, N In
te rv
en ti
on s
Sa m
pl e
si ze
a nd
st
ud y
se tt
in g
Le ng
th o
f s tu
dy
or fo
llo w
-u pa
Su m
m ar
y of
m ai
n fin
di ng
s C
on cl
us io
n
• w
he n
co m
pa re
d w
ith o
th er
s ec
on d-
ge ne
ra tio
n
an tip
sy ch
ot ic
s, t
hr ee
R C
T s
in di
ca te
d no
d iff
er en
ce
in e
ffi ca
cy b
et w
ee n
pa lip
er id
on e
an d
ol an
za pi
ne
in t
he s
ho rt
t er
m ; a
no th
er t
hr ee
fa vo
re d
th e
dr ug
in
t er
m s
of r
el ap
se p
re ve
nt io
n an
d w
ei gh
t ch
an ge
, an
d al
l r es
ul ts
fa vo
re d
th e
dr ug
fo r
ca us
in g
fe w
er
m ov
em en
t di
so rd
er s.
• N
o da
ta w
er e
fo un
d on
s er
vi ce
u se
, q ua
lit y
of li
fe ,
be ha
vi or
c ha
ng es
, s at
is fa
ct io
n w
ith t
re at
m en
t re
ce iv
ed ,
co gn
iti ve
fu nc
tio ni
ng , a
nd c
os t-
be ne
fit .
R at
te ha
lli
Ja ya
ra m
a nd
Sm
ith 43
T en
R is
pe ri
do ne
vs
p la
ce bo
N =
2 4–
30 3;
m
ai nl
y co
nd uc
te d
in
a h
os pi
ta l o
r
ou tp
at ie
nt s
et tin
g;
fo ur
s tu
di es
w ith
no
ni de
nt ifi
ed
se tt
in gs
A ll
fo llo
w ed
-u p
in
s ho
rt -t
er m
• T
en R
C T
s sh
ow ed
h ig
h at
tr iti
on (
60 %
) in
p la
ce bo
gr
ou ps
b y
6 w
ee ks
. •
T hr
ee R
C T
s fo
un d
no d
iff er
en ce
b et
w ee
n ri
sp er
id on
e
an d
a pl
ac eb
o in
t er
m s
of g
lo ba
l f un
ct io
ni ng
, w he
re as
se
ve n
sh ow
ed t
ha t
ri sp
er id
on e
pr od
uc ed
s ig
ni fic
an t
im
pr ov
em en
ts in
m en
ta l s
ta te
. •
Fi ve
t ri
al s
re po
rt ed
a fe
w a
dv er
se e
ffe ct
s in
t he
m
ed iu
m -t
er m
, m ai
nl y
in t
er m
s of
m et
ab ol
ic
an d
ca rd
ia c
pr ofi
le s.
• Be
ca us
e of
h ig
h at
tr iti
on r
at es
, ri
sp er
id on
e is
s ug
ge st
ed t
o
ha ve
m od
er at
e bi
as es
in t
he
in te
rp re
ta tio
n of
t he
fi nd
in gs
, th
us d
ra w
in g
no fi
rm c
on cl
us io
ns
ab ou
t its
e ffi
ca cy
a nd
a dv
er se
ev
en ts
. •
T he
re w
er e
m ar
gi na
l b en
efi ts
in
t er
m s
of a
fe w
p at
ie nt
ou
tc om
es b
y th
e fir
st fe
w w
ee ks
, su
ch a
s im
pr ov
em en
ts in
m
en ta
l s ta
te a
nd g
lo ba
l fu
nc tio
ni ng
. Si
lv ei
ra d
a
M ot
a et
a l50
19 A
m is
ul pr
id e
vs
pl ac
eb o,
F G
A s,
an
d/ or
s ec
on d-
ge
ne ra
tio n
an
tip sy
ch ot
ic s
N =
2 ,4
43 ; m
ai nl
y
co nd
uc te
d in
a
ho sp
ita l o
r
ou tp
at ie
nt s
et tin
g;
fo ur
s tu
di es
w ith
no
ni de
nt ifi
ed
se tt
in gs
M os
t fo
llo w
ed -u
p
in s
ho rt
-t er
m (
17 );
tw
o in
m ed
iu m
- te
rm
• w
he n
co m
pa re
d w
ith a
p la
ce bo
, f ou
r R
C T
s
fa vo
re d
a lo
w d
os e
of a
m is
ul pr
id e
in t
er m
s of
gl
ob al
fu nc
tio ni
ng a
nd n
eg at
iv e
sy m
pt om
s; t
w o
sh
ow ed
t ha
t am
is ul
pr id
e ca
us ed
m or
e ad
ve rs
e
ef fe
ct s.
• W
he n
co m
pa re
d w
ith F
G A
s, 1
4 R
C T
s co
nfi rm
ed
th e
dr ug
a s
be in
g m
or e
ef fe
ct iv
e in
t er
m s
of g
lo ba
l fu
nc tio
ni ng
, m en
ta l s
ta te
, a nd
n eg
at iv
e
sy m
pt om
s. •
O ne
R C
T c
om pa
re d
th e
ef fic
ac y
of t
he d
ru g
w ith
th
at o
f r is
pe ri
do ne
a nd
fo un
d no
d iff
er en
ce
in m
os t
pa tie
nt o
ut co
m es
. •
D at
a on
s er
vi ce
u se
, f am
ily b
ur de
n, a
nd q
ua lit
y
of li
fe w
er e
no t
th or
ou gh
ly e
va lu
at ed
.
• M
or e
pa tie
nt b
en efi
ts w
er e
fo
un d
in t
ho se
w ith
lo w
d os
es
of a
m is
ul pr
id e
w he
n co
m pa
re d
w
ith F
G A
s. S
im ila
r ef
fic ac
y
w ith
o th
er s
ec on
d- ge
ne ra
tio n
an
tip sy
ch ot
ic s
w as
n ot
ed .
• A
m is
ul pr
id e
ca n
be a
n ef
fe ct
iv e
al
te rn
at iv
e to
o th
er s
ec on
d-
ge ne
ra tio
n an
tip sy
ch ot
ic s.
N
eu ro
ps yc
hi at
ric D
is ea
se a
nd T
re at
m en
t d ow
nl oa
de d
fr om
h ttp
s: //w
w w
.d ov
ep re
ss .c
om / b
y 16
5. 21
5. 20
9. 15
o n
11 -M
ay -2
01 9
F or
p er
so na
l u se
o nl
y.
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1321
Current treatments for schizophrenia spectrum disorders
Sr is
ur ap
an on
t
et a
l44
12 Q
ue tia
pi ne
v s
pl
ac eb
o, F
G A
s,
an d/
or s
ec on
d-
ge ne
ra tio
n
an tip
sy ch
ot ic
s
N =
3 ,4
43 ; m
os t
st
ud y
se tt
in gs
n ot
re
po rt
ed
T en
s ho
rt -t
er m
, tw
o m
ed iu
m -t
er m
tr
ia ls
• Fo
ur R
C T
s re
po rt
ed t
ha t
th e
qu et
ia pi
ne g
ro up
s
in di
ca te
d hi
gh er
a tt
ri tio
n (.
50 %
in s
ho rt
-t er
m
fo llo
w -u
ps )
th an
t he
p la
ce bo
; o ne
R C
T
re po
rt ed
t w
o de
at hs
in t
he g
ro up
w ith
h ig
he r
do se
s
of q
ue tia
pi ne
. •
w he
n co
m pa
re d
w ith
F G
A s,
s ix
R C
T s
fo un
d th
at t
he
qu et
ia pi
ne g
ro up
s in
di ca
te d
36 %
d ro
po ut
s in
t he
sh
or t-
te rm
; fi ve
in di
ca te
d th
at q
ue tia
pi ne
p ro
du ce
d
m od
er at
e ch
an ge
s in
g lo
ba l f
un ct
io ni
ng a
nd m
en ta
l st
at e
in t
he s
ho rt
-t er
m ; a
nd s
ev er
e ad
ve rs
e
ef fe
ct s
w er
e fo
un d
in fi
ve R
C T
s, w
he re
as fo
ur
re po
rt ed
t ha
t it
pr od
uc ed
fe w
er m
ov em
en t
di
so rd
er s.
• w
he n
co m
pa re
d w
ith r
is pe
ri do
ne , 3
0% o
f p eo
pl e
le
ft th
e st
ud y
in o
ne R
C T
, a nd
a no
th er
r ep
or te
d
th at
fo ur
p eo
pl e
di ed
d ur
in g
th e
st ud
y. •
O ne
R C
T fo
un d
fe w
er p
eo pl
e re
ce iv
in g
qu et
ia pi
ne
pr es
en tin
g w
ith e
xt ra
py ra
m id
al a
dv er
se e
ffe ct
s;
fo ur
s tu
di es
fo un
d th
at t
he d
ru g
pr od
uc ed
a lo
w er
ri
sk fo
r m
ov em
en t
di so
rd er
s bu
t hi
gh er
r is
ks
fo r
di zz
in es
s, d
ry m
ou th
, a nd
s le
ep in
es s.
• Li
m ite
d da
ta w
er e
fo un
d on
s er
vi ce
u se
, ec
on om
ic o
ut co
m es
, s oc
ia l f
un ct
io n,
a nd
q ua
lit y
of
li fe
.
• A
lth ou
gh p
ot en
tia l b
ia se
s
m ay
o cc
ur b
ec au
se o
f h ig
he r
at
tr iti
on r
at es
a m
on g
th e
st ud
ie s,
qu
et ia
pi ne
c an
b e
eq ua
lly
ef fe
ct iv
e in
im pr
ov in
g pa
tie nt
s’
m en
ta l s
ta te
a nd
g lo
ba l
fu nc
tio ni
ng a
s th
e FG
A s
an d
ot
he r
ty pi
ca l a
ge nt
s, b
ut w
ith
fe w
er e
xt ra
py ra
m id
al a
dv er
se
ef fe
ct s
an d
m ov
em en
t di
so rd
er s.
• H
ow ev
er , m
or e
re se
ar ch
ev
id en
ce o
f t he
lo ng
er -t
er m
ef
fic ac
y of
t hi
s dr
ug w
ith lo
w
at tr
iti on
r at
es is
n ee
de d.
N ot
e: a D
ur at
io n
of s
tu dy
o r
fo llo
w -u
p, w
ith t
ri al
s ra
ng in
g fr
om s
ho rt
-t er
m , u
p to
1 2
w ee
ks , t
o m
ed iu
m -t
er m
, 1 3–
24 w
ee ks
, t o
lo ng
-t er
m , m
or e
th an
2 4
w ee
ks .
A bb
re vi
at io
ns : F
G A
s, fi
rs t-
ge ne
ra tio
n an
tip sy
ch ot
ic s;
R C
T s,
r an
do m
iz ed
c on
tr ol
le d
tr ia
ls .
N
eu ro
ps yc
hi at
ric D
is ea
se a
nd T
re at
m en
t d ow
nl oa
de d
fr om
h ttp
s: //w
w w
.d ov
ep re
ss .c
om / b
y 16
5. 21
5. 20
9. 15
o n
11 -M
ay -2
01 9
F or
p er
so na
l u se
o nl
y.
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1322
Chien and Yip
decrease relapse in both the short-term (,3 months; n = 310;
risk ratio, 0.59 [95% confidence interval, 0.45–0.77]) and
medium-term (3–6 months; n = 310; risk ratio, 0.66 [95%
confidence interval, 0.53–0.81]) when compared with pla-
cebo controls.48 Aripiprazole can also produce less attrition
and better compliance with study protocol (n = 2,275; risk
ratio, 0.74 [95% confidence interval, 0.59–0.93]), and lower
risk for raised prolactin level than that expected from the
placebo (n = 305; risk ratio, 0.21 [95% confidence interval,
0.11–0.37]).
Apart from oral medication, inhaled loxapine is consid-
ered a well-tolerated and rapid acute treatment for agitation
but needs further longer-term controlled trials to verify
its efficacy.53 Studies on relatively new second-generation
antipsychotics such as ziprasidone have shown that their
efficacy on positive symptoms is much better than that of
other second-generation antipsychotics, whereas ziprasidone
and lurasidone are clinically valuable and suggested to be
taken with food.34,54
Most of the reviews appear not only to be concerned
with their clinical efficacy and tolerability but also to pay
more attention to psychosocial functioning and cognitive
performance in activities of daily living. Among few sys-
tematic reviews/meta-analyses of the effect of FGAs on
cognition in schizophrenia, one meta-analysis by Mishara
and Goldberg55 included 34 randomized, placebo-controlled
trials and suggested that most FGAs can provide modest to
moderate benefits (ie, effect sizes ranged from 0.13 to 0.29)
in multiple cognitive domains, whereas motor function was
affected negatively. Although most of the newest second-
generation antipsychotics have shown similar treatment
efficacy in improving mental state and general functioning,
they have not yet shown significant differences or consis-
tent effects on reducing negative symptoms or cognitive
dysfunction.36,56–60 Although one review reported that social
functioning was better for people with schizophrenia tak-
ing the newer second-generation antipsychotics,36 most
of the controlled trials only evaluated their efficacy over
3–6 months, and very high attrition rates and limited long-
term effects on cognitive functioning, quality of life, service
use and satisfaction, and other psychosocial functioning and
behaviors were noted.36,57–62 Therefore, it is difficult to draw
conclusions with regard to these second-generation antipsy-
chotics, both on most patient outcomes, particularly in the
longer-term, or on their cost benefits.46,49,63 Nevertheless, it
is noteworthy that a recent population-based cohort study
in Finland with 11 years of follow-up indicated decreased
rates of mortality with perphenazine when compared with
the other FGAs and a few second-generation antipsychotics
and that only the use of clozapine was associated with lower
rates of overall mortality.64
In conclusion, FGAs and second-generation antipsychot-
ics are found to be similar and robust in treatment efficacy
among acute and sometimes chronic schizophrenia, par-
ticularly against positive and disorganization symptoms.65
Their efficacy varies according to the course or stage of the
illness; people with first-episode schizophrenia can respond
faster and better to antipsychotics than those at later stages
of the illness. In contrast, neither is effective in reducing
negative symptoms, and they can even worsen the negative
symptoms associated with extrapyramidal adverse effects
(eg, antipsychotic-induced dysphoria).66 The efficacy of
FGAs and second-generation antipsychotics on cognitive
and social functioning, as well as other longer-term effects
such as mortality and quality of life, are inconsistent.
However, individual antipsychotics have shown significant
differential efficacy in particular illness conditions and
related problems, as well as different adverse effects. All
of them reveal their onset of action within a few days and
achieve optimal antipsychotic effect over the course of sev-
eral weeks. Although antipsychotics substantially decrease
patients’ relapse from schizophrenia, it is not possible to
ensure medication or other treatment compliance; thus, long-
term injectable antipsychotics (eg, oil-based fluphenazine
decanoate) may be considered. In view of the significantly
varied pharmacokinetics of and treatment responses to
antipsychotics among people with schizophrenia, it is rec-
ommended not only to examine the overall efficacy within
and across patient groups but also to consider the efficacy
of each antipsychotic medication for each individual patient
when it is prescribed.67,68
Safety and tolerability of antipsychotics Antipsychotics, particularly FGAs, can have a wide range of
undesirable and adverse effects on patients, mainly includ-
ing neurological, metabolic, cardiovascular, hematological,
endocrine, and genitourinary disturbances. In addition, they
differ from one to another in the levels and nature of these
adverse effects. Although a few had less-extreme adverse
effects (eg, perphenazine and sulpiride),26,29 all of the reviews
indicated that the profile of adverse events concerning these
adverse effects found in most FGAs (eg, acute extrapyramidal
symptoms and tardive dyskinesia) is substantial and of major
concern, thus reducing patients’ medication compliance and
treatment efficacy.23,24,26–30,33
N
eu ro
ps yc
hi at
ric D
is ea
se a
nd T
re at
m en
t d ow
nl oa
de d
fr om
h ttp
s: //w
w w
.d ov
ep re
ss .c
om / b
y 16
5. 21
5. 20
9. 15
o n
11 -M
ay -2
01 9
F or
p er
so na
l u se
o nl
y.
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1323
Current treatments for schizophrenia spectrum disorders
Nevertheless, most second-generation antipsychotics
have comparatively fewer and lower levels of adverse effects
such as movement disorder, increased prolactin, and cardiac
and sedative problems, than FGAs. In contrast, there may be
higher risks for dizziness, sedation, weight gain, substantial
increases in serum prolactin, and tachycardia for individual
second-generation antipsychotics.44–48,69 However, there has
not been any systematic work or classification to categorize
or distinguish the risks of these adverse effects between antip-
sychotics, particularly the second-generation antipsychotics.
As these adverse effects may affect aspects of patients’ lives
and treatment adherence and satisfaction, more work on
such classification of antipsychotics in terms of their types
or levels of adverse effects should be considered.
Clozapine, the first second-generation antipsychotic, does
not show any extrapyramidal effects or tardive dyskinesia,
but other serious adverse effects such as agranulocytosis
and metabolic syndrome have limited its utility. In contrast,
Tiihonen et al64 reported that clozapine was associated with
a significantly lower mortality rate than other antipsychot-
ics and also concluded that a lower mortality rate could
be associated with a longer-term use of antipsychotics.
Although clozapine is expected to have higher risks of a few
adverse effects, inducing increased mortality, the researchers
explained it has been shown to demonstrate very positive
effects on symptom reduction and treatment compliance.
Studies on relatively new second-generation antipsychotics
such as ziprasidone have shown that they had fewer adverse
effects in terms of metabolic profile (eg, metabolic distur-
bance and weight gain) and cognitive functioning and that
their effects on positive symptoms are much better than those
of other second-generation antipsychotics.34,44 Lurasidone
has also indicated a highly favorable metabolic profile but
is still not free from adverse events such as akathisia and
Parkinson’s syndrome.35
A large, 25-year cohort study measuring the mortality
of 370 people with schizophrenia in Southampton, United
Kingdom, reported that the cohort had an all-cause stan-
dardized mortality ratio of 289 (95% confidential interval,
247–337), indicating small and nonsignificant changes
between 1981 and 2006 but falling sharply from 376
(1981–1986) to 264 (1986–1991) in the first 10 years.70 This
considerable reduction of mortality rate in the 1980s was
mainly a result of a significant fall in unnatural deaths over
the period (ie, the mortality ratio of suicide decreased from
6,110 in 1981–1986 to 0 in 1986–1991). In addition, the
findings of the study support previous findings that people
with schizophrenia have a mortality between two and three
times that of the general populations,74 as well as raise con-
cern about the cardiovascular mortality of schizophrenia,
which has significantly increased during the past 25 years.80
Nevertheless, the effects of clozapine and other second-
generation antipsychotics on mortality and treatment compli-
ance among patients with schizophrenia reveal the difficulties
in linking medium- or long-term patient outcomes with
short-term drug effects; that is, whether symptom reduction
can be mainly explained by the efficacy of antipsychotic use.
It is therefore recommended that more longitudinal research
be conducted with longer-term follow-up on predictors or
mediators of patient outcomes in schizophrenia in relation
to antipsychotic use.
Patterns in medication use: mono- and polypharmacy Treatment of people with schizophrenia who are resistant
to treatment and have persistent cognitive and negative
symptoms remains a challenge to most clinicians. Many
controlled trials of antipsychotics and their combined use
with other psychotropic drugs (eg, acetylcholinesterase
inhibitors, glutamatergic agents, antidepressants, benzo-
diazepines, and anticonvulsants) have been carried out in
people with treatment-resistant and chronic schizophrenia,
particularly on the means for improvement of negative
symptoms, quality of life, and social function. However,
very limited and weak evidence has been shown to confirm
whether a particular antipsychotic medication or any of the
combination strategies used could be efficacious in main
patient outcomes and/or superior to the others in the treat-
ment of schizophrenia,71–76 and none can be considered a
robust treatment or prevention prescription for schizophrenia
care.77–84 Nevertheless, psychosocial interventions, together
with pharmacological treatment, are recommended to be the
most effective strategies in the treatment and rehabilitation
of people with schizophrenia.85
Despite such inconclusive and weak evidence on
pharmacological agents to control negative symptoms or
treatment-resistant cases, some combinations of medica-
tion use have indicated modest to satisfactory benefits in
targeting specific psychotic symptoms.71,86–88 For instance,
anticonvulsants such as valproic acid and carbamazepine are
found to be useful as adjuncts to antipsychotics in treating
aggression and impulsivity in schizophrenia,75,76 and adjunc-
tive antidepressants can be useful in treating depression and
anxiety symptoms and in reducing craving in comorbid
substance use.83,84,89 Interestingly, a double-blinded, multi-
center randomized placebo-controlled trial on the effects
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1324
Chien and Yip
of a Warm- Supplementing Kidney Yang capsule containing
13 traditional Chinese herbs indicated that the capsule had
demonstrated significant improvements in quality of life
and social function, as well as in depression symptoms, in
200 patients with schizophrenia at a 4-week follow-up.90
Depot injections have also been used extensively for con-
trolling treatment noncompliance and long-term maintenance
therapy, thus reducing the risk of relapse.91–93 Reviews on
second-generation antipsychotic or FGA depots (eg, bro-
mperidol decanoate, haloperidol depot, risperidone depot,
and fluphenazine decanoate) versus oral antipsychotic drugs
and placebo indicated that patients with FGA depots had few
relapses and fewer oral medications, even though the differ-
ence did not reach statistical significance.94–96 Together with
similar levels of adverse effects found in depot medications,
it was also difficult to conclude that a particular depot was
no better than any other depot or oral medication.96 Despite
showing similar clinical efficacy between oral and depot
medications, depot injections can avoid frequent regular
administration of and nonadherence to oral medication,
rendering them more desirable for maintenance or compli-
ance therapy.
Pharmacological treatment used in different developmental stages of life During the last decade, there have been an increasing number
of randomized controlled trials of the efficacy and safety
of the FGAs and secondary-generation antipsychotics in
children and adolescents with schizophrenia, involving
double-blind, placebo-controlled, or open-labeled design and
short- to medium-term follow-up (ie, 4–8 weeks).97–103 Those
aged 12–17 years were usually included in the controlled
trials, and a wide variety of second-generation antipsychot-
ics such as quetapine,97 risperidone,98 paliperidone,99 and
olanzapine100 were tested. A few main patient outcomes were
commonly used, including global functioning, symptom
severity, and quality-of-life assessment; however, few of the
studies involved any long-term follow-up (ie, .8 weeks).97–103
In addition, a few types of treatment-emergent adverse events
specifically for the second-generation antipsychotic used
were observed (eg, metabolic and endocrine abnormalities
for olanzapine and somnolence, agitation and electrocardio-
gram (ECG) and ophthalmic abnormalities for quetiapine).
Similar to other age groups, most of the antipsychotics have
had positive benefits for adolescents on reducing psychotic
symptoms and global functioning, and the treatment was
well- tolerated with acceptable levels of adverse events in low
and medium dosages. None of the FGAs or second-genera-
tion antipsychotics has shown its superiority over the others,
and the benefits of polypharmacy to any psychotic symptoms
and comorbidities such as mood disorders for adolescents
are also inconclusive.102,103 Nonetheless, it is suggested that
antipsychotics are generally better tolerated and more effec-
tive in early psychosis.
Interestingly, a case study on a 17-year-old patient with
intractable catatonic schizophrenia showed moderate effects
in the resumption of spontaneous movement as a result of
ECT as an adjunct to clozapine treatment.104 The researchers
suggested that appropriate combinations of antipsychotic
medication and other treatment modalities could also be con-
sidered in young patients, although it would be unusual.
It is estimated globally that about 23% of hospitalized
patients with schizophrenia are older than 40 years and that
more than 0.1% of elderly people have a diagnosis of late-
onset schizophrenia.105 Very few studies have been done on
those aged more than 65 years, and thus there are inadequate
data and evidence to support any guidelines for treatment
of late-onset schizophrenia or to serve these older patients’
quality of life, functioning, and service use.105,106
ECT and other treatments ECT, in which clonic seizure is electrically induced in anes-
thetized patients for therapeutic effects such as improved
mood and volition, was commonly used in the 1930s–1970s.
One of the major patient groups for this treatment com-
prised those with schizophrenia or schizoaffective disorder.
Although recent research findings are limited, ECT is con-
sidered an alternative treatment for those with unfavorable
responses to antipsychotics alone after receiving different
courses of medical or psychological treatment, and/or those
with very strong suicidality and catatonic features.107,108 It
is an effective adjunct to clozapine in treating refractory
schizophrenia.104 There is certainly no strong or conclu-
sive evidence to suggest that ECT alone or as an adjunct
to antipsychotics is superior to antipsychotics alone or
to any combination of different treatment modalities for
schizophrenia. In addition, ECT may cause short-term, or
occasionally long-term, memory impairment and leaves
many unanswered questions about its role and mechanisms
in the treatment of schizophrenia.108 Similarly, transcranial
magnetic stimulation (a procedure that uses magnetic fields
to stimulate the depolarization or hyperpolarization of the
neuron cells in the cortical regions of the brain) has shown
preliminary positive evidence in treating refractory negative
symptoms and auditory hallucinations.109,110
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Current treatments for schizophrenia spectrum disorders
It is also believed that Chinese herbal medicine pro-
duces progressive positive changes in physiological and
mental state and fewer adverse effects when compared with
Western medicine. The adverse effects of antipsychotics-
induced psycho- and physiopathological changes (eg,
dysfunctions of the body organs and sleep–wake cycle) in
the body can be treated with such herbal medicine, which is
considered to promote the Yin–Yang balance and maintain a
homeostatic environment of the internal bodily condition.111
Electroacupuncture for schizophrenia sufferers with auditory
hallucination who were partially or fully nonresponsive to
risperidone monotherapy was studied with a small-sized
sample. The results showed that there was no significance
difference between the two treatment modalities in terms of
adverse effects, whereas electroacupuncture could induce
a satisfactory improvement in auditory hallucination and a
few other positive symptoms.112 Nevertheless, no conclusions
were drawn on the potential efficacy of traditional Chinese
medicine in treating schizophrenia, because of the very
limited empirical evidence on this topic.
Approaches to treatment for schizophrenia from prodromal to later stages of illness Various pharmacological treatments and psychosocial inter-
ventions for people with schizophrenia have been developed
and evaluated over the last four decades. Although these
innovative treatments and interventions have aroused much
attention and accelerated deinstitutionalization, moderately
low improvements in recovery, community-based rehabili-
tation, and quality of life among people with schizophrenia
have been the result. The modest nature of these improve-
ments may be because of the limited accessibility and
availability of different alternatives or combined treatments
and/or very advanced pathological and severe symptoms of
patients when they present to and seek treatments from the
mental healthcare system.66 More important, current treat-
ments demonstrate that fairly positive patient outcomes in
schizophrenia can be explained by the fact that most treat-
ment plans do not vary across the course of the illness, even
though different psychopathological processes are closely
linked with different stages of schizophrenia. The three
main stages of schizophrenia can include the premorbid and
prodromal stage, the first onset or episode of acute illness,
and the later stages of ongoing management, rehabilitation,
and recovery.
To better understand the common treatment modali-
ties, their main purposes, and their levels of effectiveness
and reproducibility, a summary of current approaches to
treatments for schizophrenia specific to the three stages of
schizophrenia mentioned earlier is presented in Table 3. In
the summary of the current body of knowledge about phase-
specific treatment approaches (Table 3), it is essential to note
that the mainstay treatments and management strategies of
schizophrenia seem to have evolved at a slow pace and are
highly reliant on antipsychotic agents as the basic treatment
for all schizophrenia sufferers. The effectiveness and/or cost-
benefit analysis of most psychosocial interventions used, as
well as their superiority and therapeutic components, are
somewhat inconsistent and inconclusive.
Throughout the course of schizophrenia, more than 70 types
of antipsychotic agents classified into first- and second-
generation groups can be useful for symptom management.
Nearly all antipsychotics share similar properties to block the
dopamine D-2 receptor in terms of different potencies relating
to their affinity for the receptor.19 They show no major differ-
ences in clinical efficacy for the overall schizophrenia group
in meta-analyses of recent placebo-controlled studies.40,66,113
Although antipsychotics are found to significantly reduce a
wide range of psychotic symptoms, and thus relapses, their
effects on psychosocial functioning, cognitive and vocational
skills, and longer-term community living skills in schizo-
phrenia are vague and inadequately studied.114,115 It is also
essential to point out that this similar overall efficacy reported
in schizophrenia is not equal to and does not signify the same
desirability or adverse effects, safety, tolerance, and/or other
clinical responses in each individual patient.
Nevertheless, new pharmacological treatments for schizo-
phrenia have been merging as a result of better understanding
of its etiology and pathophysiology and the specific targeting
of individual symptom domains.114 For instance, N-methyl-
D-aspartate glutamate receptor agonists and glycine site ago-
nists have been used in combination with antipsychotics, or
the activating agents of the metabotropic glutamate 2/3 recep-
tors, and can be successful in reducing negative symptoms.115
Alpha 7 nicotinic receptor agonists, dopamine 1 receptor
agonists, and modulators of glutamatergic aminomethyl-
phosphonic acid (AMPA) receptors have been found to be
useful in reducing cognitive impairments in schizophrenia.116
Therefore, different pharmacological treatment plans can
be designed to target different pathophysiological processes
relevant to different stages of schizophrenia.
For the premorbid phase (Table 3), most people with
psychotic features experience a lengthy prodromal period
of nonspecific symptoms and slowly progressive functional
impairments before the full emergence of the diagnostic
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1326
Chien and Yip
T ab
le 3
A pp
ro ac
he s
to c
on tin
ui ty
o f c
ar e
fo r
pe op
le w
ith s
ch iz
op hr
en ia
in t
hr ee
s ta
ge s
of il
ln es
s
P ha
se o
f i lln
es s
A pp
ro ac
he s
to c
ar e
Le ve
l o f e
vi de
nc e
D ur
at io
n A
pp lic
ab ili
ty
Pr em
or bi
d or
p ro
dr om
al
ph as
e C
om m
un ity
-b as
ed a
pp ro
ac he
s to
c ar
e, t
ar ge
te d
at p
re ve
nt io
n an
d ea
rl y
in te
rv en
tio ns
o f t
he il
ln es
s. 1.
P op
ul at
io n-
ba se
d or
s el
ec te
d at
-r is
k gr
ou p
ill ne
ss p
re ve
nt io
n pr
og ra
m s
re co
gn iz
e ea
rl ie
r
th e
ri sk
fa ct
or s
fo r
sc hi
zo ph
re ni
a an
d re
du ce
t he
d ev
el op
m en
t of
b eh
av io
ra l a
nd c
og ni
tiv e
pa
th ol
og y
w ith
t ar
ge t
m ed
ic at
io ns
a nd
t re
at m
en t
ap pr
oa ch
es .
* *
*
2. L
ow d
os ag
e of
p ro
ph yl
ac tic
a nt
ip sy
ch ot
ic s
an d/
or a
nt id
ep re
ss an
ts c
an e
xe rt
o pt
im al
e ffe
ct s
on
s ym
pt om
r ed
uc tio
n w
ith in
1 –2
w ee
ks .
** **
**
3. i
n th
e pr
od ro
m al
p ha
se , c
og ni
tiv e
th er
ap y
as a
n ad
ju nc
t to
a lo
w d
os e
of a
nt ip
sy ch
ot ic
s ca
n pr
ev en
t
tr an
si tio
n to
p sy
ch ot
ic d
is or
de rs
a nd
r ed
uc e
m ed
ic at
io n
us e
an d
th e
se ve
ri ty
o f s
ub cl
in ic
al s
ym pt
om s.
* **
**
4. A
ss er
tiv e
ou tr
ea ch
s er
vi ce
w ith
e vi
de nc
e- ba
se d
in te
rv en
tio ns
a da
pt ed
t o
th e
ne ed
s of
in di
vi du
al s
w
ith s
ub cl
in ic
al o
r pr
od ro
m al
s ym
pt om
s, in
cl ud
in g
lo w
-d os
e an
tip sy
ch ot
ic s,
c og
ni tiv
e th
er ap
y, fa
m ily
co
un se
lin g,
a nd
v oc
at io
na l t
ra in
in g.
* *
*
A cu
te p
ha se
o r
fir st
-e pi
so de
Ef fe
ct iv
e tr
ea tm
en t
an d
ca re
a re
p ro
vi de
d in
t he
a cu
te p
ha se
o f t
he il
ln es
s fo
r ac
tiv e
an d
ef fic
ie nt
in
te rv
en tio
ns t
o co
nt ro
l s ev
er e
sy m
pt om
s an
d pr
ep ar
e fo
r lo
ng er
-t er
m il
ln es
s m
an ag
em en
t.
A nt
ip sy
ch ot
ic s
pr od
uc e
si gn
ifi ca
nt p
os iti
ve e
ffe ct
s on
t he
s ho
rt -t
er m
c lin
ic al
o ut
co m
es o
f a cu
te
sc hi
zo ph
re ni
a; fo
r ex
am pl
e, s
ym pt
om r
ed uc
tio n
an d
re la
ps e
an d
su ic
id e
pr ev
en tio
n. 1.
P sy
ch ot
ro pi
c dr
ug s
ar e
pr es
cr ib
ed fo
r ef
fic ie
nt c
on tr
ol o
f a cu
te p
sy ch
ia tr
ic s
ym pt
om s:
•
A nt
ip sy
ch ot
ic s
(b ot
h th
e fir
st a
nd s
ec on
d ge
ne ra
tio n)
a re
t he
m os
t ef
fe ct
iv e
fo r
po si
tiv e
sy m
pt om
s
an d
at te
nt io
n (b
ut h
av e
lim ite
d ef
fe ct
s fo
r co
gn iti
ve a
nd n
eg at
iv e
sy m
pt om
s) .
•
C lo
za pi
ne is
r el
at iv
el y
m or
e ef
fe ct
iv e
th an
o th
er a
nt ip
sy ch
ot ic
s in
r ef
ra ct
or y
sc hi
zo ph
re ni
a an
d su
ic id
al ity
.
• A
nt id
ep re
ss an
ts a
re e
ffe ct
iv e
in t
re at
in g
de pr
es si
ve a
nd a
nx ie
ty s
ym pt
om s
in s
om e
pa tie
nt s
w
ith le
ss -p
ro m
in en
t po
si tiv
e sy
m pt
om s.
•
A nt
ic on
vu ls
an ts
s uc
h as
c ar
ba m
az ep
in e
an d
va lp
ro ic
a ci
d, a
s ad
ju nc
ts t
o an
tip sy
ch ot
ic s,
ca
n tr
ea t
ag gr
es si
on a
nd im
pu ls
iv ity
.
** *
**
**
*
** *
* * *
** *
**
**
**
2. e
le ct
ro co
nv ul
si ve
t he
ra py
c an
b e
ef fe
ct iv
e in
t re
at in
g ve
ry s
ev er
e ps
yc ho
tic a
nd c
at at
on ic
s ym
pt om
s.
T hi
s th
er ap
y, t
og et
he r
w ith
c lo
za pi
ne , c
an a
ls o
be u
se d
fo r
tr ea
tin g
re fr
ac to
ry s
ch iz
op hr
en ia
. **
** *
**
3. T
ra ns
cr an
ia l m
ag ne
tic s
tim ul
at io
n de
m on
st ra
te s
ef fe
ct s
in t
re at
in g
ne ga
tiv e
sy m
pt om
s
an d
au di
to ry
h al
lu ci
na tio
ns .
* **
*
4. F
am ily
p sy
ch oe
du ca
tio n
(6 –9
m on
th s)
c on
si st
in g
of e
du ca
tio n
ab ou
t th
e ill
ne ss
a nd
it s
tr ea
tm en
t,
pr ob
le m
-s ol
vi ng
s ki
lls , a
nd c
ri si
s in
te rv
en tio
n ca
n re
du ce
r el
ap se
r at
es , f
am ily
b ur
de n,
an
d tr
ea tm
en t
ad he
re nc
e.
** *
**
La te
r st
ag es
o f i
lln es
s w
id e
va ri
et ie
s of
a pp
ro ac
he s
to t
re at
m en
t an
d ca
re a
re a
im ed
a t
en ha
nc in
g th
e co
nt in
ui ty
a nd
qu
al ity
o f o
ng oi
ng il
ln es
s m
an ag
em en
t, ps
yc ho
so ci
al r
eh ab
ili ta
tio n,
a nd
r el
ap se
p re
ve nt
io n.
1. A
nt ip
sy ch
ot ic
a ge
nt s
ar e
ef fe
ct iv
e in
t he
p er
si st
en t
co nt
ro l a
nd r
ed uc
tio n
of p
sy ch
ot ic
sy
m pt
om s
in v
ar io
us il
ln es
s co
nd iti
on s:
•
A fe
w s
ec on
d- ge
ne ra
tio n
an tip
sy ch
ot ic
s su
ch a
s ol
an za
pi ne
in di
ca te
p er
si st
en t
tr ea
tm en
t ef
fe ct
s
in s
ym pt
om r
ed uc
tio n,
a s
w el
l a s
fe w
er e
xt ra
py ra
m id
al a
dv er
se e
ffe ct
s an
d an
tic ho
lin er
gi c
ac tiv
ity .
•
L on
g- ac
tin g
in je
ct io
n of
a nt
ip sy
ch ot
ic s
as a
t re
at m
en t
re gi
m en
in di
ca te
s so
m e
ad va
nt ag
es o
ve r
or
al m
ed ic
at io
n in
c om
m un
ity c
ar e
an d
re du
ci ng
n on
ad he
re nc
e an
d re
la ps
e.
• H
ow ev
er , p
eo pl
e w
ith la
te r
st ag
es o
f s ch
iz op
hr en
ia h
av e
be en
s ho
w n
to b
e le
ss r
es po
ns iv
e
to a
nt ip
sy ch
ot ic
a ge
nt s.
**
**
**
* **
*
* **
*
N
eu ro
ps yc
hi at
ric D
is ea
se a
nd T
re at
m en
t d ow
nl oa
de d
fr om
h ttp
s: //w
w w
.d ov
ep re
ss .c
om / b
y 16
5. 21
5. 20
9. 15
o n
11 -M
ay -2
01 9
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p er
so na
l u se
o nl
y.
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1327
Current treatments for schizophrenia spectrum disorders
2. P
sy ch
os oc
ia l i
nt er
ve nt
io ns
a re
u se
d in
c om
bi na
tio n
w ith
a nt
ip sy
ch ot
ic s
to h
el p
in r
ed uc
in g
sy m
pt om
s
an d
im pr
ov in
g tr
ea tm
en t
ad he
re nc
e, s
oc ia
l a nd
c og
ni tiv
e fu
nc tio
ns , a
nd q
ua lit
y of
li fe
.
• P
at ie
nt a
nd fa
m ily
p sy
ch oe
du ca
tio n
pr og
ra m
s ar
e ef
fe ct
iv e
in p
ro vi
di ng
il ln
es s-
re la
te d
in fo
rm at
io n
an
d ps
yc ho
so ci
al s
up po
rt , a
s w
el l a
s ef
fe ct
iv e
co pi
ng s
tr at
eg ie
s an
d pr
ob le
m -s
ol vi
ng s
ki lls
.
• C
og ni
tiv e-
be ha
vi or
al t
he ra
py d
em on
st ra
te s
si gn
ifi ca
nt e
ffe ct
s in
r ed
uc in
g po
si tiv
e sy
m pt
om s
an
d di
so rg
an iz
ed t
ho ug
ht s
in t
ho se
w ith
p er
si st
en t
an d
re si
du al
p sy
ch ot
ic s
ym pt
om s.
•
C og
ni tiv
e re
m ed
ia tio
n is
e ffe
ct iv
e in
t re
at in
g im
pa ir
ed c
og ni
tio n
(e g,
a tt
en tio
n, w
or ki
ng m
em or
y,
ex ec
ut iv
e fu
nc tio
n, a
nd s
oc ia
l c og
ni tio
n) a
nd is
a ss
oc ia
te d
w ith
im pr
ov em
en ts
in
p sy
ch os
oc ia
l f un
ct io
ni ng
.
• S
oc ia
l s ki
lls t
ra in
in g
ca n
im pr
ov e
pe rf
or m
an ce
-b as
ed s
oc ia
l a nd
c om
m un
ity fu
nc tio
ni ng
b ut
h as
lit
tle e
ffe ct
o n
sy m
pt om
c on
tr ol
a nd
r el
ap se
p re
ve nt
io n.
•
S up
po rt
iv e
em pl
oy m
en t
w ith
w or
k sk
ill s
tr ai
ni ng
is t
ai lo
re d
to t
ho se
w ho
n ee
d jo
b pl
ac em
en t
or
v oc
at io
na l t
ra in
in g
an d
is e
ffe ct
iv e
in h
el pi
ng p
at ie
nt s
ob ta
in a
nd m
ai nt
ai n
op en
c om
pe tit
iv e
em
pl oy
m en
t. H
ow ev
er , t
he re
is li
m ite
d ev
id en
ce o
n lo
ng er
-t er
m e
m pl
oy m
en t
ou tc
om es
s uc
h
as jo
b re
te nt
io n
an d
ec on
om ic
in de
pe nd
en ce
.
** *
**
* **
*
**
**
* **
**
** *
** *
* **
**
3. P
ee r-
le d
pa tie
nt a
nd fa
m ily
s up
po rt
g ro
up p
ro gr
am s
pr ov
id e
fle xi
bl e
an d
no nh
ie ra
rc hi
ca l p
sy ch
os oc
ia l
su pp
or t
to p
at ie
nt s
an d/
or t
he ir
fa m
ily m
em be
rs a
nd h
av e
an e
ffe ct
o n
re du
ci ng
p at
ie nt
r el
ap se
, im
pr ov
in g
fa m
ily a
nd s
oc ia
l s up
po rt
, e nh
an ci
ng m
ed ic
at io
n ad
he re
nc e,
a nd
im pr
ov in
g co
pi ng
s ki
lls .
* *
**
4. A
ss er
tiv e
co m
m un
ity t
re at
m en
t of
fe rs
a m
ul tid
is ci
pl in
ar y
ap pr
oa ch
t o
in te
ns iv
e pa
tie nt
c ar
e, s
up po
rt
an d
co nt
ac ts
in t
he c
om m
un ity
, o r
in a
h om
el es
s si
tu at
io n
is e
ffe ct
iv e
in r
ed uc
in g
ho sp
ita liz
at io
ns a
nd
im pr
ov in
g so
ci al
in te
gr at
io n
fo r
th os
e w
ho a
re t
re at
m en
t- re
si st
an t
an d
pr on
e to
h ig
h re
ad m
is si
on r
at es
.
* **
**
5. M
ul tif
ac et
ed il
ln es
s m
an ag
em en
t pr
og ra
m s,
in cl
ud in
g so
ci al
s ki
lls t
ra in
in g,
m ed
ic at
io n
ad he
re nc
e
th er
ap y,
p ro
bl em
-s ol
vi ng
a nd
c om
m un
ic at
io n
sk ill
s tr
ai ni
ng , s
up po
rt ed
e m
pl oy
m en
t,
an d
ev en
fa m
ily b
eh av
io ra
l a nd
c as
e m
an ag
em en
t, ca
n im
pr ov
e pa
tie nt
s’ r
ec ov
er y,
t re
at m
en t
co
m pl
ia nc
e, a
nd s
oc ia
l r ei
nt eg
ra tio
n.
* *
**
N ot
es : “
Le ve
l o f e
vi de
nc e”
d en
ot es
th e
th re
e le
ve ls
o f e
vi de
nc e
on th
e ap
pr oa
ch es
to c
ar in
g fo
r sc
hi zo
ph re
ni a
in te
rm s
of th
e am
ou nt
a nd
c on
si st
en cy
o f t
he r
es ea
rc h
ev id
en ce
: * **
, v er
y m
uc h
co ns
is te
nt a
nd c
on cl
us iv
e, p
os iti
ve fi
nd in
gs ;
** , s
at is
fa ct
or y
co ns
is te
nc y
an d
re pl
ic ab
ili ty
w ith
a fe
w n
on si
gn ifi
ca nt
o r
ne ga
tiv e
fin di
ng s;
a nd
* , f
ew o
r in
co ns
is te
nt fi
nd in
gs . “
D ur
at io
n” in
di ca
te s
th e
du ra
tio n
of th
e re
se ar
ch e
vi de
nc e
on th
e ap
pr oa
ch es
to c
ar e
id en
tifi ed
in th
e lit
er at
ur e,
in
cl ud
in g
** *,
e vi
de nc
e no
te d
fo r
m or
e th
an 2
0 ye
ar s;
* *,
e vi
de nc
e no
te d
fo r
10 –2
0 ye
ar s;
a nd
* , e
vi de
nc e
no te
d fo
r no
t m or
e th
an 1
0 ye
ar s.
“ A
pp lic
ab ili
ty ”
de no
te s
th e
le ve
ls o
f f ea
si bi
lit y
an d
ap pl
ic ab
ili ty
fo r
th e
in te
rv en
tio n
to b
e ap
pl ie
d to
m en
ta l h
ea lth
ca re
p ra
ct ic
e: *
** , v
er y
fle xi
bl e
an d
ap pl
ic ab
le t
o fie
ld p
ra ct
ic e;
* *,
s at
is fa
ct or
y ap
pl ic
ab ili
ty t
o pr
ac tic
e; a
nd *
, n ot
e as
ily o
r co
m m
on ly
a pp
lie d
to p
ra ct
ic e.
N
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ric D
is ea
se a
nd T
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nl oa
de d
fr om
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s: //w
w w
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ss .c
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5. 21
5. 20
9. 15
o n
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ay -2
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p er
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l u se
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Chien and Yip
psychotic symptoms. The development of higher levels
of dysfunction and disability during the prodromal period
creates major inhibitory factors influencing recovery, thus
providing very strong rationale for premorbid assessment
and interventions. To promote accurate and valid assess-
ment of high-risk individuals or groups, specific scales are
being developed, such as the Bonn Scale for the Assessment
of Basic Symptoms and the Comprehensive Assessment of
At-Risk Mental State, as well as the Scale of Prodromal
Symptoms.117,118 Without any of the strategies currently used,
specific population-based prevention and assessment efforts
should be made, targeting high-risk groups with mild early
psychotic symptoms. Most important, identification of risk
factors and symptomatic indicators is critical for accurately
selecting at-risk persons and matching them to the most
appropriate preventive treatment. As suggested by Birch-
wood, Todd, and Jackson’s hypothesis of critical periods
of onset and early intervention of psychosis,119 therapeutic
interventions such as cognitive–behavioral therapy and asser-
tive outreach services are most effective if they are offered
at the earliest possible moment during the most vulnerable
periods of illness onset.120,121 Research evidence suggesting
that these cognitive and behavioral interventions can help
people in the prodromal stage of schizophrenia is emerging,
but is as yet inconclusive.122
In acute-episode or first-onset schizophrenia, the use of
different antipsychotic agents is found to be crucial and effec-
tive in symptom reduction, especially for positive symptoms
and attention. Second-generation (atypical) antipsychotics
showing less risk for extrapyramidal adverse effects and tar-
dive dyskinesia can be considered as the first-line treatment
for acute psychosis. The second-generation antipsychotic
clozapine is more effective in treating refractory schizo-
phrenia and suicidality.123 Other psychotropic drugs such as
antidepressants and anticonvulsants can be used as an adjunct
to antipsychotics to control specific psychiatric symptoms
such as depression, anxiety, aggression, and impulsivity.
Physical treatments, especially ECT, are found effective
in controlling a few treatment-resistive symptoms such as
catatonic state, strongly depressive and suicidal ideation, and
some negative symptoms.107 Repetitive transcranial magnetic
stimulation studies have demonstrated some promise in
the treatment of schizophrenia, particularly for those with
treatment-resistant auditory hallucinations and severe mood
problems.124 Family psychoeducation (6–9 months) can reduce
relapse rates, family burden, and treatment adherence.7
For ongoing management and later-stage schizophre-
nia, a variety of psychosocial interventions are found
useful in reducing patients’ relapses and rehospitalizations,
enhancing their functioning and medication adherence, and
facilitating their rehabilitation and recovery. As indicated
in Table 3, the more conclusive and consistent therapeutic
interventions with moderate to large effect sizes in symp-
tom control, relapse prevention, and levels of psychosocial
functioning included patient and/or family psychoeducation
programs,125 cognitive–behavioral therapy,126 and an inte-
grated program with antipsychotics and different approaches
to psychosocial care.127,128 Although small effect sizes to
relapse prevention were found, a few commonly used
approaches to psychosocial intervention for schizophrenia
show increasingly consistent effects on specific patient out-
comes, such as patients’ social and community functioning
being improved by social and vocational skills and short-
term competitive employment being enhanced by supported
employment with work skills training.65,129
Similar to Amsterdam’s first-aid service in the 1970s,
crisis intervention models for people with schizophrenia
and other serious mental illnesses have at times emerged,
aimed at treating psychiatric crises in the community and
reducing relapses and/or the number of hospitalizations.129
Multidisciplinary, around-the-clock crisis intervention ser-
vices advocate prompt detection of symptom exacerbation
and immediate intensive treatments as needed (eg, psychotro-
pic agents, individual and family counseling, psychological
therapies, and practical assistance in activities of daily living)
in both community and home settings. Programs in Australia
and the United States, such as mobile crisis teams, crisis units
in hospitals, crisis day treatment centers, and crisis residential
programs, have been integrated into routine mental healthcare
services.64,130 Nevertheless, recent clinical trials suggested
that about half of the crisis intervention groups indicated
nonsignificant effects on improvements in mental state or
reducing hospitalization during the treatment period, as well
as lacking evidence of their long-term benefits in terms of
patient outcomes.131 In addition, recent research has also
evaluated the effectiveness of multifaceted illness manage-
ment programs consisting of a wide variety of biological/
physical, psychological, and social interventions and sug-
gested these programs might efficiently and effectively
improve patient recovery and social reintegration.65,127,131
Conclusion Antipsychotics (first- and/or second-generation antipsychot-
ics) are shown to be effective in reducing overall psychotic
symptoms and relapse in patients with schizophrenia. It is
therefore recommended in most of the literature as first-line
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Current treatments for schizophrenia spectrum disorders
treatment for people with schizophrenia, at least in the
short-term or at the acute stage of illness. However, the use
of antipsychotics alone as the main treatment modality may
be limited not only by their inability to tackle the frequently
occurring negative symptoms and cognitive impairments but
also by producing a wide variety of adverse effects in the
internal body or organ functioning. The FGAs and second-
generation antipsychotics are two distinct classes of antipsy-
chotics with quite different potency and adverse effects, but
these two classes do not have any definitive categorization
between them in terms of efficacy, safety, and tolerability or
in their clinical outcomes. However, because of the varied
pharmacokinetics and patients’ treatment responsiveness
across different agents, the medication regimen should be
determined on an individual basis to ensure optimal effect in
their long-term use. Other medical and psychological treat-
ments should be considered as an adjunct to antipsychotic
agents. However, many of these alternative treatments are
not strongly evidenced or conclusive in producing specific
therapeutic effects in treating schizophrenia. More con-
trolled trials are recommended to enhance understanding
about their efficacy as a monotherapy or in combined use
with antipsychotics, other medication, and/or psychosocial
interventions.
Many patients with schizophrenia often have unresolved
life events and psychological distress, as well as illness-
related or drug-induced problems, which significantly affect
their normalcy of daily life. In the last few decades, various
models of psychosocial intervention have been developed and
implemented as an adjunct to the pharmacological or other
medical treatments at different stages of schizophrenia. The
main purpose of these approaches to treatment is to provide
these patients (and their family members) with adequate
knowledge of and skills in this illness and its treatment
and care, emotional support, problem-solving and coping
skills, and/or enhancing cognitive and functional recovery.
The current models commonly used for schizophrenia care
include cognitive–behavioral therapy, psychoeducation,
family intervention, social skills training, and cognitive
remediation therapy. These psychosocial interventions and
their comparative efficacy in treating people with schizophre-
nia will be discussed in another article. Recent systematic
reviews on psychosocial interventions for schizophrenia
have indicated significant positive medium-term (up to
18 months) effects of a few approaches (eg, psychoeducation
and cognitive–behavioral therapy) integrated or embedded
into routine care (and medication use) in people with acute
or chronic schizophrenia. To overcome the shortcomings
of antipsychotics in the treatment of schizophrenia, clinical
guidelines and standards of practice have recommended that
a combination of treatment methods or modalities be adopted
to meet the complex psychiatric and other health needs of
people with schizophrenia. We are assured of and also highly
recommend more research in the clinical efficacy of differ-
ent existing and new models of psychosocial interventions,
together with antipsychotics or other psychotropic drugs, to
ascertain a treatment approach for people with schizophre-
nia with the highest possible levels of efficacy, safety, and
acceptability.
Disclosure The authors report no conflicts of interest in this work.
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