NDT 37485 Current Approaches to Treatments for Schizophrenia Part i 091013

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Currnt approachs to tratmntsfor schzophrna spctrum dsordrs,part i: an or and mdcal tratmnts

wa Tong Chn

Ann LK Yp

School of Nursng, Faculty of Halthand Socal Scncs, Th Hong Kong

Polytchnc Unrsty, Hung Hom,Koloon, Hong Kong

Corrspondnc: wa Tong ChnSchool of Nursng, Th Hong KongPolytchnc Unrsty, Hung Hom,Koloon, Hong KongTl +852 2766 5648Fax +852 2334 1124emal [email protected]

Abstract: During the last three decades, an increasing understanding o the etiology,

psychopathology, and clinical maniestations o schizophrenia spectrum disorders, in addition to

the introduction o second-generation antipsychotics, has optimized the potential or recovery rom

the illness. Continued development o various models o psychosocial intervention promotes the

goal o schizophrenia treatment rom one o symptom control and social adaptation to an optimalrestoration o unctioning and/or recovery. However, it is still questionable whether these new

treatment approaches can address the patients needs or treatment and services and contribute

to better patient outcomes. This article provides an overview o dierent treatment approaches

currently used in schizophrenia spectrum disorders to address complex health problems and a wide

range o abnormalities and impairments resulting rom the illness. There are dierent treatment

strategies and targets or patients at dierent stages o the illness, ranging rom prophylactic

antipsychotics and cognitivebehavioral therapy in the premorbid stage to various psychosocial

interventions in addition to antipsychotics or relapse prevention and rehabilitation in the later

stages o the illness. The use o antipsychotics alone as the main treatment modality may be

limited not only in being unable to tackle the requently occurring negative symptoms and

cognitive impairments but also in producing a wide variety o adverse eects to the body or organ

unctioning. Because o varied pharmacokinetics and treatment responsiveness across agents,

the medication regimen should be determined on an individual basis to ensure an optimal eect

in its long-term use. This review also highlights that the recent practice guidelines and standards

have recommended that a combination o treatment modalities be adopted to meet the complex

health needs o people with schizophrenia spectrum disorders. In view o the heterogeneity o

the risk actors and the illness progression o individual patients, the use o multiaceted illness

management programs consisting o dierent combinations o physical, psychological, and social

interventions might be ecient and eective in improving recovery.

Keywords: schizophrenia, schizophrenia spectrum disorders, treatment, psychosocial interven-

tion, pharmacology, antipsychotics

IntroductionSchizophrenia and its spectrum disorders (all alling under the term schizophrenia in

this article) are chronic remitting and disruptive disorders associated with signicant

abnormalities and the progressive deterioration o a wide variety o cognitive, psycho-

social, vocational, and behavioral unctioning. The ourth edition o the Diagnostic

and Statistical Manual of Mental Disorders (DSM-IV) denes schizophrenia as a

syndrome characterized by long duration, high relapse rate (.70%), bizarre delusions

and behaviors, negative symptoms, and sometimes a ew mood problems.1 The onset

o symptoms typically occurs in adolescence and young adulthood, with a worldwide

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Chn and Yp

estimate o its lietime prevalence and incidence o 1.44.6

and 0.160.42 per 1,000 persons annually, respectively.2,3

A recent systematic review indicated that patients diagnosed

with this disorder have a shorter liespan than the average

general population and are particularly at risk or 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% o healthy people

indicate an attenuated orm o schizoid personality and

schizophrenia-like symptoms, such as paranoid delusional

thinking and auditory hallucination.5

Because o the complex health problems and wide range

o abnormalities and impairments concerning schizophrenia,

comprehensive and multimodal treatment approaches are

considered and tested in dierent combinations, with the

goal o reducing patients illness episodes and symptoms,

as well as improving their unctioning and quality o lie

in the longer term. Antipsychotic medications have been

recommended consistently and continuously as the main-

stream and standard treatment or nearly all patients with

schizophrenia, to provide them with a sae and therapeutic

environment and eective symptom control since the intro-

duction o chlorpromazine (the rst antipsychotic) in the

1960s. In the last three to our decades, physical treatments

such as electroconvulsive therapy (ECT; in the 1930s) and

dierent approaches to psychosocial interventions such as

psychoanalysis (in the 1950s), amily therapy (in the 1960s),

psychoeducation (in the 1980s), cognitivebehavioral ther-

apy (in the 1990s), and cognitive remediation (in the 2000s)

have been introduced successively,714 and their comparative

or combined ecacies or 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 amilies should

also be used to improve their rehabilitation, reintegration into

the community, and recovery rom the illness.6,15 Dierent

modalities and combinations o psychosocial programs are

recommended to address the complex individualized needs

o these patients or multimodal care, particularly regarding

relapse prevention, management o negative symptoms and

cognitive dysunction, and medication adherence.14,16 Despite

increased recognition and demands or an individualized

treatment plan and the integration o dierent intervention

approaches to optimize patient outcomes, current psychiat-

ric treatments and services still involve practicing the same

set o treatment approaches or each patient group in the

course o illness. More clinical trials are recommended to

examine the active ingredients o unimodal or integrated

psychosocial interventions or schizophrenia that can be

eective in enhancing recovery and other patient outcomes.

There has also been increasing attention and demand or

cost-eectiveness analyses o these interventions.

To gain a more in-depth and ocused understanding o

the eects and benets o recent approaches to treatments

or schizophrenia, we perormed a comparative review, sum-

marized here, o the ecacy, saety, and tolerability o the

current pharmacological and other medical treatments or

these patients. In another article, we also perormed a com-

parative review o the ecacy o approaches to psychosocial

interventions or schizophrenia and a critical discussion about

patient-ocused perspectives o acceptance, benets, and

satisaction in psychiatric care. Recommendations or best

practices or continuity o schizophrenia care are also made.

This article also provides an overview o the approaches to

treatments across dierent stages o schizophrenia and the

uture direction o treatments or this illness.

Review of current approachesto medical treatmentsfor schizophreniaDuring the last two decades, the mainstream o medical treat-

ment or schizophrenia has remained the use o antipsychotics

and/or other psychotropic medications. With increasing

initiatives and evidence o the eectiveness o psychosocial

interventions or schizophrenia, the highly structured or

manualized (eg, cognitivebehavioral and psychoeducation

programs) and a ew integrated programs (eg, the Schizo-

phrenia Patient Outcomes Research Team Programs and the

Recovery Ater 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 o several large-scale randomized controlled trials,

single and multiple types o antipsychotics, or polypharmacy

in combination with other psychotropic drugs, are consid-

ered useul in schizophrenia treatment. The introduction o

second-generation antipsychotics has urther improved the

desired eects o these medications or schizophrenia care

and, more important, reduced their undesirable eects such

as extrapyramidal adverse eects, mortality, and metabolic

disorder. Beore 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 or

schizophrenia suerers.
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Currnt tratmnts for schzophrna spctrum dsordrs

Pharmacological treatmentFrst- and scond-gnratonantpsychotcsMore than 70 antipsychotics have been introduced. They are

mainly categorized into rst- 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 ecacy against positive and

disorganization symptoms o schizophrenia.1113

The rst-generation antipsychotics (FGAs), or typi-

cal antipsychotics (eg, chlorpromazine, fuphenazine, and

haloperidol, included in the World Health Organizations

list o Essential Medications in 2009),20 were rst intro-

duced or the treatment o 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 ecacious and toler-

able than the FGAs, and a ew have progressively replaced

the older FGAs to become the rst-line prescription or the

standard o care. To capture the research evidence or drug

trials on antipsychotics, ull-text articles published in English

between 1966 and 2010 were searched or in CINAHL,

MEDLINE, EMBASE, The Cochrane Library, Cochrane

Schizophrenia Groups Register, Biological Abstracts,

Sociological Abstracts, Sociole, and PsycLIT. Participants

included people with schizophrenia, schizophrenia-like

psychoses such as schizophreniorm and schizoaective dis-

orders, and psychotic disorders such as delusional disorder,

nonaective psychosis, or dual diagnosis. The main out-

comes identied rom the reviewed articles mainly involved

mental state, global unctioning, and adverse events.

Thirteen systematic reviews on the ecacy o FGAs

using a randomized controlled trial design were ound

(Table 1). With similar intended outcomes, several outcome

measurement tools were commonly used, including the

Clinical Global Impression, Global Assessment Scale, and

Global Assessment o Functioning scale or patients global

unctioning; the Brie Psychiatric Rating Scale, Positive

and Negative Syndrome Scale, Scale or the Assessment

o Negative Symptoms, and Scale or the Assessment o

Positive Symptoms or their mental state or symptom sever-

ity; and the Involuntary Movement Scale, Extrapyramidal

Symptom Rating Scale, Extrapyramidal Rating Scale, and

Simpson and Angus Scale or the adverse eects o medi-

cation used. Most o the clinical trials (.70%) evaluated

the medication eects over a short period o time (eg, up

to 12 weeks), whereas a ew (,10%) involved a long-term

ollow-up (eg,.1 year).

The rst FGA invented chlorpromazine, has become

the well-established and benchmark treatment or people

with schizophrenia to acilitate their deinstitutionalization21

and has been used or more than 40 years. Nevertheless,

the reviewed literature showed that the incidence and

average dose o chlorpromazine prescribed to people with

schizophrenia has been decreasing.22 Other commonly

used FGAs such as trifuoperazine, thioridazine, sulpiride,

pimozide, perphenazine, and luphenazine were tested

and conrmed to have similar and satisactory ecacy in

symptom reduction mainly or positive symptoms (eg,

delusions and hallucinations).2328 However, there was

limited evidence to support their ecacy at lower doses or

in short-term treatment.2831 Major adverse events induced

by FGAs generally include sedation, movement disorders,

endocrine disturbance, and metabolic and electrocardiogram

changes.24,25,28,32

Most o all, FGAs are a relatively low-cost treatment and

commonly used medication; however, there is little evidence

to support their ecacy in reducing negative symptoms

(eg, anhedonia, loss o volition, and social withdrawal) and

cognitive unctioning, which may contribute much to the

unctional disability o people with schizophrenia.26,29,33 It is

generally concluded that there is similar satisactory clini-

cal ecacy in terms o mental state and global unctioning

across the FGAs and second-generation antipsychotics.3437

However, a ew trials indicate the superiority o individual

second-generation agents over the FGAs in specic illness

condition or patient outcomes.29,33,37,38 In two meta-analyses

o placebo-controlled trials,39,40 haloperidol was reported

to be less eective 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 eects compared with those noted with the use o

FGAs. Some o them have been shown to be more ecacious

and less problematic in terms o sedative and neurologi-

cal eects 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 eects among second-

generation antipsychotics and the eects between these

second-generation agents and FGAs or a placebo (Table 2). In

addition to the main patient outcomes used (ie, mental state,

global unctioning, and relapse), several other psychosocial

outcomes were usually compared across studies, including

level o depression, acceptability o treatment (eg, dropout


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rate and patient dissatisaction), inability to work, amily

burden, and social and cognitive unctioning. Thereore,

there are a wider variety o outcome measurements than

used in previous studies, such as depression (eg, the Calgary

Depression Scale, the Hamilton Rating Scale or Depres-

sion, or the Montgomery Asberg Depression Rating Scale),

quality o lie (eg, the Quality o Lie Scale, the Schizo-

phrenia Quality o Lie Scale, the Subjective Well-being

on Neuroleptics [Antipsychotics] Scale, or the Personal and

Social Perormance Scale), and patient satisaction (eg, the

Nurses Observational Scale Inpatients Evaluation) measures.

Similar to those receiving FGAs, most o the clinical trials

evaluated the short-term eects (up to 12 weeks) o the

second-generation antipsychotics, even though a ew long-

term evaluations appear promising.39,40

A ew systematic reviews also indicated that the con-

trolled trials o second-generation antipsychotics have mainly

tested only a ew kinds, including risperidone, olanzapine,

quetiapine, loxapine, sertindole, aripiprazole, and amisul-

pride, and mostly compared them with placebo controls.4350

The reviews concluded that second-generation antipsychotics

had similar eects to FGAs in terms o reduction o positive

symptoms. The treatment ecacy o both FGAs and second-

generation antipsychotics varies in terms o stages o the

illness, with rst-episode schizophrenia responding aster

and better than at later illness stages.35,41,51 Nevertheless, most

o the second-generation antipsychotics had comparatively

ewer and lower levels o adverse eects such as movement

disorders and cardiac and sedative problems than FGAs.

Clozapine, the rst second-generation antipsychotic, has

been ound to be particularly eective in treating reractory

patients and reducing suicidality.36,41 A recent meta-analysis

comparing nine second-generation antipsychotics with the

FGAs (eg, chlorpromazine, fuphenazine and haloperidol)

or overall ecacy concluded that our second-generation

antipsychotics (namely, amisulpride, clozapine, olanzapine,

and risperidone) were better than the FGAs, with small

to medium eect sizes (ie, 0.130.52).37 The our second-

generation antipsychotics have been shown to induce ewer

extrapyramidal adverse eects than the low-potency FGAs.

Although olanzapine can induce more weight gain and pro-

duction o prolactin, it is shown to exert a persistent treatment

eect over other second-generation antipsychotics in chronic

schizophrenia.37,52

A recent Cochranes systematic review was published on

nine randomized, placebo-controlled trials o aripiprazole,

which is one o the newer second-generation antipsychotics.

Its main results indicated that aripiprazole can signicantlySoarstal29

18

Sulprdvsplacbo,

FGAs,and/or

scond-gnraton

antpsychotcs

N.9

00;14

studs

conductdn

hosptal

sttngsandonnth

communty;thrn

nonidentied

settings

Mostfollo-up

ovr8ks

(short-trm).

Sulprdndcatdfradvrsffcts,

andlttldffrncasfoundbtnth

drugandothrantpsychotcs.

Nondin

gsofnegativesymptomswereshown.

ing

nral,small-scalandpoor-

qua

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itm

aybffctvandhav

f

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vdnc.

Thrrlmtdrsults

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Soarsand

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randomzd)

PenuridolvsFGAs,

dpotnjctons,

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N=1,024;m

anly

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oroutpatntsttngs;

fourwithnonidentied

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Fvshort-trm

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Fourmed

ium-termRCTsfoundpenuridol

suprortoplacbontrmsofglobal

functionin

g,whereasanotherveRCTs

shodthatacombnatonofantpsychotcs

asconsdrdncssary.

Tenshow

ednodifferencebetweenpenuridol

andothr

FGAsntrmsofglobalstat

ovr36

months.

Fvfoundthatthdrugassupror

nkpngpatntsntratmnt.

Efcacyandadverseeffect

pro

lesaresimilaramong

FGAs,nomattrhthr

byoralordpotrout.

Pen

uridolisanoptionfor

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psychotcsymptomsand

sconsdrdalo-cost

nt

rvnton.

Notes:aDuratonofstudyorfollo-up,thtralsrangngfromshort-trm,upto12ks,tomdum-trm,1324ks,tolong-trm,morthan24ks.

Abbreviations:FGAs,rst-generationantipsychotics;RCTs,randomizedcontrolledtrials;vs,versus.


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Srsurapanont

tal44

12

Qutapnvs

placbo,FGAs,

and/orscond-

gnraton

antpsychotcs

N=3,443;most

studysttngsnot

rportd

Tnshort-trm,

tomdum-trm

trals

FourRCTsrportdthatthqutapngroups

ndcatdhghrattrton(.50%nshort-trm

follo-ups)thanth

placbo;onRCT

rportdtodathsnthgroupthhghrdoss

ofqutapn.

whncompard

thFGAs,sxRCTsfoundthatth

qutapngroupsndcatd36%dropoutsnth

short-term;veindicatedthatquetiapineproduced

modratchangs

nglobalfunctonngandmntal

statnthshort-trm;andsvradvrs

effectswerefound

inveRCTs,whereasfour

rportdthattpr

oducdfrmovmnt

dsordrs.

whncompard

thrsprdon,30%ofpopl

lftthstudynon

RCT,andanothrrportd

thatfourpopldddurngthstudy.

OnRCTfoundf

rpoplrcvngqutapn

prsntngthx

trapyramdaladvrsffcts;

fourstudsfound

thatthdrugproducdalor

rskformovmntdsordrsbuthghrrsks

fordzznss,drym

outh,andslpnss.

Lmtddatar

foundonsrvcus,

conomcoutcoms,socalfuncton,andqualty

oflf.

Althoughpotntalbass

may

occurbcausofhghr

attrtonratsamongthstuds,

qutapncanbqually

ffc

tvnmprovngpatnts

mn

talstatandglobal

functonngasthFGAsand

oth

rtypcalagnts,butth

f

rxtrapyramdaladvrs

ffc

tsandmovmntdsordrs.

Ho

vr,morrsarch

vdncofthlongr-trm

efcacyofthisdrugwithlow

attrtonratssndd.

Note:aDuratonofstudyorfollo-up,thtralsrangngfromshort-trm,upto12ks,

tomdum-trm,1324ks,tolong-trm,morth

an24ks.

Abbreviations:FGAs,rst-generationantipsychotics;RCTs,randomizedcontrolledtrials.


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Chn and Yp

decrease relapse in both the short-term (,3 months; n = 310;

risk ratio, 0.59 [95% condence interval, 0.450.77]) and

medium-term (36 months; n = 310; risk ratio, 0.66 [95%

condence interval, 0.530.81]) 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% condence interval, 0.590.93]), and lower

risk or raised prolactin level than that expected rom the

placebo (n = 305; risk ratio, 0.21 [95% condence interval,

0.110.37]).

Apart rom oral medication, inhaled loxapine is consid-

ered a well-tolerated and rapid acute treatment or agitation

but needs urther longer-term controlled trials to veriy

its ecacy.53 Studies on relatively new second-generation

antipsychotics such as ziprasidone have shown that their

ecacy on positive symptoms is much better than that o

other second-generation antipsychotics, whereas ziprasidone

and lurasidone are clinically valuable and suggested to be

taken with ood.34,54

Most o the reviews appear not only to be concerned

with their clinical ecacy and tolerability but also to pay

more attention to psychosocial unctioning and cognitive

perormance in activities o daily living. Among ew sys-

tematic reviews/meta-analyses o the eect o 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 benets (ie, eect sizes ranged rom 0.13 to 0.29)

in multiple cognitive domains, whereas motor unction was

aected negatively. Although most o the newest second-

generation antipsychotics have shown similar treatment

ecacy in improving mental state and general unctioning,

they have not yet shown signicant dierences or consis-

tent eects on reducing negative symptoms or cognitive

dysunction.36,5660 Although one review reported that social

unctioning was better or people with schizophrenia tak-

ing the newer second-generation antipsychotics,36 most

o the controlled trials only evaluated their ecacy over

36 months, and very high attrition rates and limited long-

term eects on cognitive unctioning, quality o lie, service

use and satisaction, and other psychosocial unctioning and

behaviors were noted.36,5762 Thereore, it is dicult 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 benets.46,49,63 Nevertheless, it

is noteworthy that a recent population-based cohort study

in Finland with 11 years o ollow-up indicated decreased

rates o mortality with perphenazine when compared with

the other FGAs and a ew second-generation antipsychotics

and that only the use o clozapine was associated with lower

rates o overall mortality.64

In conclusion, FGAs and second-generation antipsychot-

ics are ound to be similar and robust in treatment ecacy

among acute and sometimes chronic schizophrenia, par-

ticularly against positive and disorganization symptoms.65

Their ecacy varies according to the course or stage o the

illness; people with rst-episode schizophrenia can respond

aster and better to antipsychotics than those at later stages

o the illness. In contrast, neither is eective in reducing

negative symptoms, and they can even worsen the negative

symptoms associated with extrapyramidal adverse eects

(eg, antipsychotic-induced dysphoria).66 The ecacy o

FGAs and second-generation antipsychotics on cognitive

and social unctioning, as well as other longer-term eects

such as mortality and quality o lie, are inconsistent.

However, individual antipsychotics have shown signicant

dierential ecacy in particular illness conditions and

related problems, as well as dierent adverse eects. All

o them reveal their onset o action within a ew days and

achieve optimal antipsychotic eect over the course o sev-

eral weeks. Although antipsychotics substantially decrease

patients relapse rom schizophrenia, it is not possible to

ensure medication or other treatment compliance; thus, long-

term injectable antipsychotics (eg, oil-based fuphenazine

decanoate) may be considered. In view o the signicantly

varied pharmacokinetics o and treatment responses to

antipsychotics among people with schizophrenia, it is rec-

ommended not only to examine the overall ecacy within

and across patient groups but also to consider the ecacy

o each antipsychotic medication or each individual patient

when it is prescribed.67,68

Safety and tolerabilityof antipsychoticsAntipsychotics, particularly FGAs, can have a wide range o

undesirable and adverse eects on patients, mainly includ-

ing neurological, metabolic, cardiovascular, hematological,

endocrine, and genitourinary disturbances. In addition, they

dier rom one to another in the levels and nature o these

adverse eects. Although a ew had less-extreme adverse

eects (eg, perphenazine and sulpiride),26,29 all o the reviews

indicated that the prole o adverse events concerning these

adverse eects ound in most FGAs (eg, acute extrapyramidal

symptoms and tardive dyskinesia) is substantial and o major

concern, thus reducing patients medication compliance and

treatment ecacy.23,24,2630,33


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Nevertheless, most second-generation antipsychotics

have comparatively ewer and lower levels o adverse eects

such as movement disorder, increased prolactin, and cardiac

and sedative problems, than FGAs. In contrast, there may be

higher risks or dizziness, sedation, weight gain, substantial

increases in serum prolactin, and tachycardia or individual

second-generation antipsychotics.4448,69 However, there has

not been any systematic work or classication to categorize

or distinguish the risks o these adverse eects between antip-

sychotics, particularly the second-generation antipsychotics.

As these adverse eects may aect aspects o patients lives

and treatment adherence and satisaction, more work on

such classication o antipsychotics in terms o their types

or levels o adverse eects should be considered.

Clozapine, the rst second-generation antipsychotic, does

not show any extrapyramidal eects or tardive dyskinesia,

but other serious adverse eects such as agranulocytosis

and metabolic syndrome have limited its utility. In contrast,

Tiihonen et al64 reported that clozapine was associated with

a signicantly lower mortality rate than other antipsychot-

ics and also concluded that a lower mortality rate could

be associated with a longer-term use o antipsychotics.

Although clozapine is expected to have higher risks o a ew

adverse eects, inducing increased mortality, the researchers

explained it has been shown to demonstrate very positive

eects on symptom reduction and treatment compliance.

Studies on relatively new second-generation antipsychotics

such as ziprasidone have shown that they had ewer adverse

eects in terms o metabolic prole (eg, metabolic distur-

bance and weight gain) and cognitive unctioning and that

their eects on positive symptoms are much better than those

o other second-generation antipsychotics.34,44 Lurasidone

has also indicated a highly avorable metabolic prole but

is still not ree rom adverse events such as akathisia and

Parkinsons syndrome.35

A large, 25-year cohort study measuring the mortality

o 370 people with schizophrenia in Southampton, United

Kingdom, reported that the cohort had an all-cause stan-

dardized mortality ratio o 289 (95% condential interval,

247337), indicating small and nonsigniicant changes

between 1981 and 2006 but alling sharply rom 376

(19811986) to 264 (19861991) in the rst 10 years.70 This

considerable reduction o mortality rate in the 1980s was

mainly a result o a signicant all in unnatural deaths over

the period (ie, the mortality ratio o suicide decreased rom

6,110 in 19811986 to 0 in 19861991). In addition, the

ndings o the study support previous ndings that people

with schizophrenia have a mortality between two and three

times that o the general populations,74 as well as raise con-

cern about the cardiovascular mortality o schizophrenia,

which has signicantly increased during the past 25 years.80

Nevertheless, the eects o clozapine and other second-

generation antipsychotics on mortality and treatment compli-

ance among patients with schizophrenia reveal the diculties

in linking medium- or long-term patient outcomes with

short-term drug eects; that is, whether symptom reduction

can be mainly explained by the ecacy o antipsychotic use.

It is thereore recommended that more longitudinal research

be conducted with longer-term ollow-up on predictors or

mediators o patient outcomes in schizophrenia in relation

to antipsychotic use.

Patterns in medication use:mono- and polypharmacyTreatment o people with schizophrenia who are resistant

to treatment and have persistent cognitive and negative

symptoms remains a challenge to most clinicians. Many

controlled trials o 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 or improvement o negative

symptoms, quality o lie, and social unction. However,

very limited and weak evidence has been shown to conrm

whether a particular antipsychotic medication or any o the

combination strategies used could be ecacious in main

patient outcomes and/or superior to the others in the treat-

ment o schizophrenia,7176 and none can be considered a

robust treatment or prevention prescription or schizophrenia

care.7784 Nevertheless, psychosocial interventions, together

with pharmacological treatment, are recommended to be the

most eective strategies in the treatment and rehabilitation

o people with schizophrenia.85

Despite such inconclusive and weak evidence on

pharmacological agents to control negative symptoms or

treatment-resistant cases, some combinations o medica-

tion use have indicated modest to satisactory benets in

targeting specic psychotic symptoms.71,8688 For instance,

anticonvulsants such as valproic acid and carbamazepine are

ound to be useul as adjuncts to antipsychotics in treating

aggression and impulsivity in schizophrenia,75,76 and adjunc-

tive antidepressants can be useul 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 eects


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o a Warm-Supplementing Kidney Yang capsule containing

13 traditional Chinese herbs indicated that the capsule had

demonstrated signicant improvements in quality o lie

and social unction, as well as in depression symptoms, in

200 patients with schizophrenia at a 4-week ollow-up.90

Depot injections have also been used extensively or con-

trolling treatment noncompliance and long-term maintenance

therapy, thus reducing the risk o relapse.9193 Reviews on

second-generation antipsychotic or FGA depots (eg, bro-

mperidol decanoate, haloperidol depot, risperidone depot,

and fuphenazine decanoate) versus oral antipsychotic drugs

and placebo indicated that patients with FGA depots had ew

relapses and ewer oral medications, even though the dier-

ence did not reach statistical signicance.9496 Together with

similar levels o adverse eects ound in depot medications,

it was also dicult to conclude that a particular depot was

no better than any other depot or oral medication.96 Despite

showing similar clinical ecacy between oral and depot

medications, depot injections can avoid requent regular

administration o and nonadherence to oral medication,

rendering them more desirable or maintenance or compli-

ance therapy.

Pharmacological treatmentused in different developmentalstages of lifeDuring the last decade, there have been an increasing number

o randomized controlled trials o the ecacy and saety

o 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 ollow-up (ie, 48 weeks).97103 Those

aged 1217 years were usually included in the controlled

trials, and a wide variety o second-generation antipsychot-

ics such as quetapine,97 risperidone,98 paliperidone,99 and

olanzapine100 were tested. A ew main patient outcomes were

commonly used, including global unctioning, symptom

severity, and quality-o-lie assessment; however, ew o the

studies involved any long-term ollow-up (ie,.8 weeks).97103

In addition, a ew types o treatment-emergent adverse events

specically or the second-generation antipsychotic used

were observed (eg, metabolic and endocrine abnormalities

or olanzapine and somnolence, agitation and electrocardio-

gram (ECG) and ophthalmic abnormalities or quetiapine).

Similar to other age groups, most o the antipsychotics have

had positive benets or adolescents on reducing psychotic

symptoms and global unctioning, and the treatment was

well-tolerated with acceptable levels o adverse events in low

and medium dosages. None o the FGAs or second-genera-

tion antipsychotics has shown its superiority over the others,

and the benets o polypharmacy to any psychotic symptoms

and comorbidities such as mood disorders or adolescents

are also inconclusive.102,103 Nonetheless, it is suggested that

antipsychotics are generally better tolerated and more eec-

tive in early psychosis.

Interestingly, a case study on a 17-year-old patient with

intractable catatonic schizophrenia showed moderate eects

in the resumption o spontaneous movement as a result o

ECT as an adjunct to clozapine treatment.104 The researchers

suggested that appropriate combinations o 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% o hospitalized

patients with schizophrenia are older than 40 years and that

more than 0.1% o elderly people have a diagnosis o late-

onset schizophrenia.105 Very ew studies have been done on

those aged more than 65 years, and thus there are inadequate

data and evidence to support any guidelines or treatment

o late-onset schizophrenia or to serve these older patients

quality o lie, unctioning, and service use.105,106

ECT and other treatmentsECT, in which clonic seizure is electrically induced in anes-

thetized patients or therapeutic eects such as improved

mood and volition, was commonly used in the 1930s1970s.

One o the major patient groups or this treatment com-

prised those with schizophrenia or schizoaective disorder.

Although recent research ndings are limited, ECT is con-

sidered an alternative treatment or those with unavorable

responses to antipsychotics alone ater receiving dierent

courses o medical or psychological treatment, and/or those

with very strong suicidality and catatonic eatures.107,108 It

is an eective adjunct to clozapine in treating reractory

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 o dierent treatment modalities or

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 o schizophrenia.108 Similarly, transcranial

magnetic stimulation (a procedure that uses magnetic elds

to stimulate the depolarization or hyperpolarization o the

neuron cells in the cortical regions o the brain) has shown

preliminary positive evidence in treating reractory negative

symptoms and auditory hallucinations.109,110


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It is also believed that Chinese herbal medicine pro-

duces progressive positive changes in physiological and

mental state and ewer adverse eects when compared with

Western medicine. The adverse eects o antipsychotics-

induced psycho- and physiopathological changes (eg,

dysunctions o the body organs and sleepwake cycle) in

the body can be treated with such herbal medicine, which is

considered to promote the YinYang balance and maintain a

homeostatic environment o the internal bodily condition.111

Electroacupuncture or schizophrenia suerers with auditory

hallucination who were partially or ully nonresponsive to

risperidone monotherapy was studied with a small-sized

sample. The results showed that there was no signicance

dierence between the two treatment modalities in terms o

adverse eects, whereas electroacupuncture could induce

a satisactory improvement in auditory hallucination and a

ew other positive symptoms.112 Nevertheless, no conclusions

were drawn on the potential ecacy o traditional Chinese

medicine in treating schizophrenia, because o the very

limited empirical evidence on this topic.

Approaches to treatmentfor schizophrenia from prodromalto later stages of illnessVarious pharmacological treatments and psychosocial inter-

ventions or people with schizophrenia have been developed

and evaluated over the last our 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 o lie among people with schizophrenia

have been the result. The modest nature o these improve-

ments may be because o the limited accessibility and

availability o dierent alternatives or combined treatments

and/or very advanced pathological and severe symptoms o

patients when they present to and seek treatments rom the

mental healthcare system.66 More important, current treat-

ments demonstrate that airly positive patient outcomes in

schizophrenia can be explained by the act that most treat-

ment plans do not vary across the course o the illness, even

though dierent psychopathological processes are closely

linked with dierent stages o schizophrenia. The three

main stages o schizophrenia can include the premorbid and

prodromal stage, the rst onset or episode o acute illness,

and the later stages o ongoing management, rehabilitation,

and recovery.

To better understand the common treatment modali-

ties, their main purposes, and their levels o eectiveness

and reproducibility, a summary o current approaches to

treatments or schizophrenia specic to the three stages o

schizophrenia mentioned earlier is presented in Table 3. In

the summary o the current body o knowledge about phase-

specic treatment approaches (Table 3), it is essential to note

that the mainstay treatments and management strategies o

schizophrenia seem to have evolved at a slow pace and are

highly reliant on antipsychotic agents as the basic treatment

or all schizophrenia suerers. The eectiveness and/or cost-

benet analysis o most psychosocial interventions used, as

well as their superiority and therapeutic components, are

somewhat inconsistent and inconclusive.

Throughout the course o schizophrenia, more than 70 types

o antipsychotic agents classiied into irst- and second-

generation groups can be useul or symptom management.

Nearly all antipsychotics share similar properties to block the

dopamine D-2 receptor in terms o dierent potencies relating

to their anity or the receptor.19 They show no major dier-

ences in clinical ecacy or the overall schizophrenia group

in meta-analyses o recent placebo-controlled studies.40,66,113

Although antipsychotics are ound to signicantly reduce a

wide range o psychotic symptoms, and thus relapses, their

eects on psychosocial unctioning, 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 ecacy reported

in schizophrenia is not equal to and does not signiy the same

desirability or adverse eects, saety, tolerance, and/or other

clinical responses in each individual patient.

Nevertheless, new pharmacological treatments or schizo-

phrenia have been merging as a result o better understanding

o its etiology and pathophysiology and the specic targeting

o 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 o the metabotropic glutamate 2/3 recep-

tors, and can be successul in reducing negative symptoms.115

Alpha 7 nicotinic receptor agonists, dopamine 1 receptor

agonists, and modulators o glutamatergic aminomethyl-

phosphonic acid (AMPA) receptors have been ound to be

useul in reducing cognitive impairments in schizophrenia.116

Thereore, dierent pharmacological treatment plans can

be designed to target dierent pathophysiological processes

relevant to dierent stages o schizophrenia.

For the premorbid phase (Table 3), most people with

psychotic eatures experience a lengthy prodromal period

o nonspecic symptoms and slowly progressive unctional

impairments beore the ull emergence o the diagnostic


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psychotic symptoms. The development o higher levels

o dysunction and disability during the prodromal period

creates major inhibitory actors infuencing recovery, thus

providing very strong rationale or premorbid assessment

and interventions. To promote accurate and valid assess-

ment o high-risk individuals or groups, specic scales are

being developed, such as the Bonn Scale or the Assessment

o Basic Symptoms and the Comprehensive Assessment o

At-Risk Mental State, as well as the Scale o Prodromal

Symptoms.117,118Without any o the strategies currently used,

specic population-based prevention and assessment eorts

should be made, targeting high-risk groups with mild early

psychotic symptoms. Most important, identication o risk

actors and symptomatic indicators is critical or accurately

selecting at-risk persons and matching them to the most

appropriate preventive treatment. As suggested by Birch-

wood, Todd, and Jacksons hypothesis o critical periods

o onset and early intervention o psychosis,119 therapeutic

interventions such as cognitivebehavioral therapy and asser-

tive outreach services are most eective i they are oered

at the earliest possible moment during the most vulnerable

periods o illness onset.120,121 Research evidence suggesting

that these cognitive and behavioral interventions can help

people in the prodromal stage o schizophrenia is emerging,

but is as yet inconclusive.122

In acute-episode or rst-onset schizophrenia, the use o

dierent antipsychotic agents is ound to be crucial and eec-

tive in symptom reduction, especially or positive symptoms

and attention. Second-generation (atypical) antipsychotics

showing less risk or extrapyramidal adverse eects and tar-

dive dyskinesia can be considered as the rst-line treatment

or acute psychosis. The second-generation antipsychotic

clozapine is more eective in treating reractory schizo-

phrenia and suicidality.123 Other psychotropic drugs such as

antidepressants and anticonvulsants can be used as an adjunct

to antipsychotics to control specic psychiatric symptoms

such as depression, anxiety, aggression, and impulsivity.

Physical treatments, especially ECT, are ound eective

in controlling a ew 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 o schizophrenia, particularly or those with

treatment-resistant auditory hallucinations and severe mood

problems.124 Family psychoeducation (69 months) can reduce

relapse rates, amily burden, and treatment adherence.7

For ongoing management and later-stage schizophre-

nia, a variety o psychosocial interventions are ound

useul in reducing patients relapses and rehospitalizations,

enhancing their unctioning and medication adherence, and

acilitating their rehabilitation and recovery. As indicated

in Table 3, the more conclusive and consistent therapeutic

interventions with moderate to large eect sizes in symp-

tom control, relapse prevention, and levels o psychosocial

unctioning included patient and/or amily psychoeducation

programs,125 cognitivebehavioral therapy,126 and an inte-

grated program with antipsychotics and dierent approaches

to psychosocial care.127,128 Although small eect sizes to

relapse prevention were ound, a ew commonly used

approaches to psychosocial intervention or schizophrenia

show increasingly consistent eects on specic patient out-

comes, such as patients social and community unctioning

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 Amsterdams rst-aid service in the 1970s,

crisis intervention models or 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 o hospitalizations.129

Multidisciplinary, around-the-clock crisis intervention ser-

vices advocate prompt detection o symptom exacerbation

and immediate intensive treatments as needed (eg, psychotro-

pic agents, individual and amily counseling, psychological

therapies, and practical assistance in activities o 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 hal o the crisis intervention groups indicated

nonsignicant eects on improvements in mental state or

reducing hospitalization during the treatment period, as well

as lacking evidence o their long-term benets in terms o

patient outcomes.131 In addition, recent research has also

evaluated the eectiveness o multiaceted illness manage-

ment programs consisting o a wide variety o biological/

physical, psychological, and social interventions and sug-

gested these programs might eciently and eectively

improve patient recovery and social reintegration.65,127,131

ConclusionAntipsychotics (rst- and/or second-generation antipsychot-

ics) are shown to be eective in reducing overall psychotic

symptoms and relapse in patients with schizophrenia. It is

thereore recommended in most o the literature as rst-line


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treatment or people with schizophrenia, at least in the

short-term or at the acute stage o illness. However, the use

o antipsychotics alone as the main treatment modality may

be limited not only by their inability to tackle the requently

occurring negative symptoms and cognitive impairments but

also by producing a wide variety o adverse eects in the

internal body or organ unctioning. The FGAs and second-

generation antipsychotics are two distinct classes o antipsy-

chotics with quite dierent potency and adverse eects, but

these two classes do not have any denitive categorization

between them in terms o ecacy, saety, and tolerability or

in their clinical outcomes. However, because o the varied

pharmacokinetics and patients treatment responsiveness

across dierent agents, the medication regimen should be

determined on an individual basis to ensure optimal eect in

their long-term use. Other medical and psychological treat-

ments should be considered as an adjunct to antipsychotic

agents. However, many o these alternative treatments are

not strongly evidenced or conclusive in producing specic

therapeutic eects in treating schizophrenia. More con-

trolled trials are recommended to enhance understanding

about their ecacy as a monotherapy or in combined use

with antipsychotics, other medication, and/or psychosocial

interventions.

Many patients with schizophrenia oten have unresolved

lie events and psychological distress, as well as illness-

related or drug-induced problems, which signicantly aect

their normalcy o daily lie. In the last ew decades, various

models o psychosocial intervention have been developed and

implemented as an adjunct to the pharmacological or other

medical treatments at dierent stages o schizophrenia. The

main purpose o these approaches to treatment is to provide

these patients (and their amily members) with adequate

knowledge o and skills in this illness and its treatment

and care, emotional support, problem-solving and coping

skills, and/or enhancing cognitive and unctional recovery.

The current models commonly used or schizophrenia care

include cognitivebehavioral therapy, psychoeducation,

amily intervention, social skills training, and cognitive

remediation therapy. These psychosocial interventions and

their comparative ecacy in treating people with schizophre-

nia will be discussed in another article. Recent systematic

reviews on psychosocial interventions or schizophrenia

have indicated signicant positive medium-term (up to

18 months) eects o a ew approaches (eg, psychoeducation

and cognitivebehavioral therapy) integrated or embedded

into routine care (and medication use) in people with acute

or chronic schizophrenia. To overcome the shortcomings

o antipsychotics in the treatment o schizophrenia, clinical

guidelines and standards o practice have recommended that

a combination o treatment methods or modalities be adopted

to meet the complex psychiatric and other health needs o

people with schizophrenia. We are assured o and also highly

recommend more research in the clinical ecacy o dier-

ent existing and new models o psychosocial interventions,

together with antipsychotics or other psychotropic drugs, to

ascertain a treatment approach or people with schizophre-

nia with the highest possible levels o ecacy, saety, and

acceptability.

DisclosureThe authors report no conficts o interest in this work.

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NDT 37485 Current Approaches to Treatments for Schizophrenia Part i 091013