Available online at www.sciencedirect.

com

Schizophrenia Research 100 (2008) 20 38

www.elsevier.com/locate/schres

World Psychiatric Association Pharmacopsychiatry Section statement

on comparative effectiveness of antipsychotics
in the treatment of schizophrenia
Rajiv Tandon a,, R.H. Belmaker c , Wagner F. Gattaz d , Juan J. Lopez-Ibor Jr. e ,
Ahmed Okasha f , Bruce Singh g , Dan J. Stein h , Jean-Pierre Olie i ,
W. Wolfang Fleischhacker j , Hans-Juergen Moeller b
for the Section of Pharmacopsychiatry, World Psychiatric Association
a
University of Florida, Tallahassee, USA
Department of Psychiatry, University of Munich, Munich, Germany
c
Department of Psychiatry, Ben Gurion University of the Negev, Beersheva, Israel
d
Institute of Psychiatry, University of Sao Paulo, Sao Paulo, Brazil
e
Institute of Psychiatry, Complutense University, Madrid, Spain
f
Institute of Psychiatry, Ain Shams University, Cairo, Egypt
g
Department of Psychiatry, University of Melbourne, Melbourne, Australia
h
Department of Psychiatry, University of Cape Town, Cape Town, South Africa
i
Department of Psychiatry, Centre-Hospitale Saint-Anne, Paris, France
j
Department of Biological Psychiatry, University of Innsbruck, Innsbruck, Austria
b

Received 16 April 2007; received in revised form 30 October 2007; accepted 20 November 2007
Available online 19 February 2008

Abstract
Data from two major government-funded studies of comparative antipsychotic effectiveness in schizophrenia contradict the
widely prevalent belief that the newer second-generation medications are vastly superior to the older first-generation drugs. This
has caused uncertainty among patients, clinicians and policy-makers about the relative utility of first- and second- generation
antipsychotic agents in its treatment. To reduce confusion and provide a contextual understanding of the new data, the World
Psychiatry Association Section on Pharmacopsychiatry comprehensively reviewed the literature on the comparative effectiveness
of different antipsychotic treatments for schizophrenia and developed this update. Utilizing data from the approximately 1,600
randomized controlled trials of antipsychotic treatment in schizophrenia, we applied the two indirect and one direct method to
comparing the effectiveness of 62 currently-available antipsychotic agents. The subclasses of 51 first-generation and 11 secondgeneration antipsychotics were both found to be very heterogeneous, with substantial differences in side-effect profiles among
members. Second-generation antipsychotic agents were found to be inconsistently more effective than first-generation agents in
alleviating negative, cognitive, and depressive symptoms and had a lower liability to cause tardive dyskinesia; these modest
benefits were principally driven by the ability of second-generation antipsychotics to provide equivalent improvement in positive
symptoms along with a lower risk of causing extrapyramidal side-effects. Clozapine was found to be more efficacious than other
agents in treatment-refractory schizophrenia. There were no consistent differences in efficacy among other second-generation

Corresponding author. 3706 Glin Circle, Tallahassee, FL 32309, USA. Tel.: +1 850 766 6535.
E-mail address: rtandon@umich.edu (R. Tandon).
0920-9964/$ - see front matter 2007 Elsevier B.V. All rights reserved.
doi:10.1016/j.schres.2007.11.033

R. Tandon et al. / Schizophrenia Research 100 (2008) 2038

21

antipsychotic agents; if such differences exist, they are likely small in magnitude. Dosing was found to be a key variable in
optimizing effectiveness of both first- and second- generation antipsychotic agents. There was enormous individual variability in
antipsychotic response and vulnerability to various adverse effects. In contrast to their relatively similar efficacy in treating positive
symptoms, there were substantial differences among both first- and second- generation antipsychotic agents with regard to their
propensity to cause extrapyramidal, metabolic and other adverse effects; second-generation agents have a lower liability to cause
acute extrapyramidal symptoms and tardive dyskinesia along with a tendency to cause greater metabolic side-effects than firstgeneration agents. Based on these data about the comparative effectiveness of different antipsychotic treatment options, we
summarize elements of current best antipsychotic practice for the treatment of schizophrenia and discuss the role of government
and the pharmaceutical industry in obtaining and disseminating information which can facilitate best practice.
2007 Elsevier B.V. All rights reserved.

1. Introduction
The past decade witnessed major changes in the
practice of antipsychotic therapy around the world. The
sequential introduction of eleven atypical or secondgeneration antipsychotics (clozapine, amisulpride, zotepine, risperidone, olanzapine, quetiapine, sertindole, ziprasidone, aripiprazole, perospirone, and paliperidone),
led to increased optimism among physicians and
patients about what can be achieved with effective
antipsychotic therapy in schizophrenia. Like the 51
older typical or conventional first-generation antipsychotics (FGAs) (Table 1), the eleven newer atypical second-generation antipsychotics (SGAs) are at
least as effective in reducing the delusional thinking,

hallucinatory experiences, and thought disorganization

that are the hallmarks of psychosis (positive symptoms).
Compared to the older FGAs, however, this new generation of SGAs has a lower liability for inducing extrapyramidal side effects (EPS) resulting in their being
termed atypical (Moller, 2000; Kapur and Remington,
2001; Meltzer, 2004; Tandon, 2007). SGAs were considered by practitioners to be more effective than FGAs
in terms of possessing a broader spectrum of efficacy
(particularly with regard to negative, cognitive, and
mood symptoms) and having a lower liability to cause
acute and long-term motor side-effects. Consequently,
expert panels and professional organizations around the
world uniformly recommended the use of these newer
agents in preference to the older ones (World Psychiatric

Table 1
List of approved antipsychotics around the world, 2007
Typical or conventional or first-generation antipsychotics (FGAs) N = 51
Phenothiazines (N = 23)
Acetophenazine
Cyamemazine
Methotrimeprazine
Piperacetazine
Propericiazine
Thioproperazine

Butaperazine
Dixyrazine
Perazine
Pipoptiazine
Sulforidazine
Trifluoperazine

Chlorproethazine
Fluphenazine
Periciazine
Prochlorperazine
Thioridazine
Triflupromazine

Chlorpromazine
Mesoridazine
Perphenazine
Promazine
Thiopropazate

Non-Phenothiazines (N = 28)
Benperidol
Clopenthixol
Flupenthixol
Melperone
Nemonapride
Pipamperone
Tiapride

Bromperidol
Clothiapine
Fluspirilene
Molindone
Oxypertine
Sulpiride
Timiperone

Chlorprothixene
Droperidol
Haloperidol
Moperone
Penfluridol
Sultopride
Trifluperidol

Clocapramine
Fluanisone
Loxapine
Mosapramine
Pimozide
Thiothixene
Zuclopenthixol

Clozapine
Quetiapine
Zotepine

Olanzapine
Risperidone

ATYPICAL OR SECOND GENERATION ANTIPSYCHOTICS (SGAs) N = 11

Amisulpride
Paliperidone
Sertindole

Aripiprazole
Perospirone
Ziprasidone

22

R. Tandon et al. / Schizophrenia Research 100 (2008) 2038

Associations, 2002; Kane et al., 2003; Miller et al.,

2004; American Psychiatric Association, 2004; Falkai
et al., 2005).
Amidst this enthusiasm, governments became concerned about the rapidly escalating costs for this class of
medications as global direct expenditures on antipsychotic medications multiplied over 20-fold over the past
decade from approximately $ 0.5 billion/year to more
than $ 15 billion/year (Hoenberg and Goetz, 2006). This
increase was principally driven by the proportionately
greater use of the 5-30 fold more costly SGAs at the
expense of the older FGAs. Even as many experts
believed that SGAs are substantially better than FGAs,
some questioned any such advantage. Governments and
clinicians also became increasingly skeptical about
available comparative information about antipsychotic
agents, much of which was derived from pharmaceutical
industry-sponsored trials (Melander et al., 2003; Perlis
et al., 2005; Lexchin et al., 2003; Montgomery et al.,
2004; Heres et al., 2006). It was consequently hoped that
results of two large government-sponsored studies
[Clinical Antipsychotic Trial of Intervention Effectiveness in schizophrenia in the U.S.A. (CATIE, Lieberman
et al., 2005; McEvoy et al., 2006; Stroup et al., 2006a)
and Cost Utility of the Latest Antipsychotics in Severe
Schizophrenia in the U.K. (CUtLASS, Lewis et al.,
2006a,b; Jones et al., 2006)] would provide definitive
answers. Both these trials found SGAs to be neither
more effective nor less likely to cause EPS than FGAs
(Lieberman et al., 2005; Jones et al., 2006), clozapine to
be more effective than other SGAs in refractory
schizophrenia (McEvoy et al., 2006; Lewis et al.,
2006b), and FGAs to be more cost-effective than SGAs
(Rosenheck et al., 2006; Davies et al., 2007). Instead of
resolving the controversy about the comparative effectiveness of older and newer antipsychotics, however,
findings of CATIE and CUtLASS further fueled disagreement in the field about how SGAs compare to
FGAs. While primary investigators of these studies interpreted the results to establish FGAs as being clinically equivalent to SGAs, other experts pointed to study
sample and design constraints and suggested the need
for caution in interpreting findings of CATIE and
CUtLASS. Whereas critics opined that SGAs are clearly superior to FGAs and described these studies as
fundamentally flawed and adding little of value, proponents suggested that failure to accept the finality of
their conclusion that FGAs are at least as effective and
safe as SGAs reflected an inability to face the truth.
In view of this resulting confusion, the Section of
Pharmacopsychiatry in the World Psychiatry Association developed this comprehensive position statement

on the comparative effectiveness of different antipsychotic treatments for schizophrenia. The Chairman of
the section (HJM) engaged its forty other members from
22 countries over two years in the construction of
the statement. Anticipating uncertainty and controversy
following the initial publication of CATIE findings in
September, 2005 (Lieberman et al., 2005), the Section
membership resolved to develop a precise consensus
statement about comparative effectiveness of antipsychotics in the treatment of schizophrenia. An initial draft
of the paper was distributed in December 2005. Following comments received from Section members, the
statement was very substantially revised and a new
draft was distributed in June, 2006. Between JuneDecember, 2006, there was an electronic dialogue among
members of the Section that led to progressive refinements in the statement. In view of the difficulty in
integrating disparate opinions among 41 psychopharmacology experts from around the world, presentation
of a majority and minority report was considered; the
Section membership uniformly felt, however, that presentation of divergent opinions would only add to confusion and assiduously labored to resolve significant
areas of disagreement and develop a statement that
all the members could sign on to. As new results
from CATIE and CUtLASS continued to be published
through 2007 and other findings became available, these
were incorporated. The manuscript was revised by the
authors in response to the initial editorial review and the
updated statement was reviewed by the entire Section
membership with additional appropriate changes being
made based on input. All members formally approved
the final overall statement; a substantial majority approved the entire wording, with four members dissenting on some individual points of emphasis [two of the
41 members of the section felt that the EPS advantage of
SGAs over FGAs should have been further emphasized
whereas two other members felt that the metabolic
disadvantages of SGAs versus FGAs needed additional
emphasis]. In addition to providing a unified expert
perspective on the comparative effectiveness of antipsychotic treatments, the renewed emphasis on optimal
recovery in the context of individualized treatment of
schizophrenia (Anthony, 1993) also makes this update
timely.
2. Comparing effectiveness of different antipsychotic
agents in the treatment of schizophrenia
Although pharmacological findings derived from animal studies and receptor imaging can be useful, only
data from clinical trials in schizophrenia can directly

R. Tandon et al. / Schizophrenia Research 100 (2008) 2038

provide information about the comparative effectiveness

of antipsychotic agents in its treatment. Randomized
patient assignment to parallel treatment arms allows one
to attribute confidently observed differences in effectiveness between these arms to the effects of the treatments; therefore, well-conducted randomized controlled
trials [RCT's] represent the gold standard of clinical
information (McAlister et al., 1999; Pocock and
Elbourne, 2000). Study findings need to be replicated
for both accuracy and generalizability and therefore,
multiple RCTs comparing every pair of antipsychotic
agents in large samples of schizophrenia patients at
various stages of illness across diverse populations
would be ideal. The fact that this is not feasible necessitates application of both direct and indirect methods to RCT data in order to elucidate comparative
effectiveness of different antipsychotic agents in the
treatment of schizophrenia. Utilizing data from the
approximately 1,600 RCTs of antipsychotic treatment of
schizophrenia (Gilbody et al., 2002; Tharyan, 2005), the
three broad approaches (Glenny et al., 2005) include:
(i) direct comparison within head-head RCT's. Since
this approach retains all the benefits of randomization, it provides the most robust comparison
between therapeutic agents and is only limited by
design biases within individual studies (Heres
et al., 2006; Tandon and Fleischhacker, 2005)
and the paucity (or absence) of studies addressing specific questions in particular populations
(Pocock and Elbourne, 2000; Rothwell, 2005).
(ii) refined or adjusted indirect comparison across
RCTs of individual agents. In this approach, the
effects of therapeutic agents are adjusted by the
results of their comparison against a common
control group in the RCTs. Improvements seen in
patients treated with different agents after subtracting a common comparator (placebo or specified active agent) are averaged across studies and
then compared. This approach thus partially uses
the strength of randomization.
(iii) naive or unadjusted indirect comparison across
RCTs of individual agents. In this approach, the
effects of therapeutic agents are not adjusted by
subtracting a common comparator. Improvements
seen in patients treated with different agents are
pooled across RCTs and the weighted averages are
compared. Although data from RCTs are utilized,
this approach does not utilize the strengths of
randomization and therefore warrants careful
examination of whether like is being compared
with like. Even this indirect approach using RCT

23

data, however, provides less biased information

than direct comparisons from non-randomized
trials (Glenny et al., 2005; Song et al., 2003).
Medical literature published in any language on
RCTs of antipsychotic treatment of schizophrenia was
identified using MEDLINE and EMBASE, supplemented by the reference lists of published articles. Search
terms included randomized controlled trial, clinical trial,
schizophrenia, antipsychotic, neuroleptic, and generic
names of the 62 antipsychotic agents (Table 1). We
decided to consider only published studies because they
have been subjected to peer-review, are of higher quality, and provide more complete information than meeting abstracts (Dundar et al., 2006; Scherer et al., 2007).
We also decided not to seek additional information
about unpublished studies from manufacturers of individual antipsychotic agents for the same reason and
because of the likely greater retrieval bias in the collection and pooling of such data. We believe the rigor
and transparency advantages of this method substantially outweigh the constraint of publication bias (Texier
et al., 2007; Martin et al., 2005). We do recognize the
significant potential distortions produced by publication
bias, however, and in the final section of this report, we
discuss strategies to reduce such bias.
3. Meta-analysis
Meta-analysis is a powerful averaging technique
that pools data from several clinical trials and then
provides a quantitative estimate of treatment effect size.
It can be applied to each of the above approaches, but
requires the studies whose data are pooled to be similar
with sufficient information available from each primary
study in order to compute a pooled treatment effect size.
Common problems affecting meta-analyses include
small sample sizes, inadequate power, study heterogeneity, lack of extractable data, lack of interchangeable
measurement instruments and definitions of outcomes,
and other differences in the design of studies whose data
are pooled. This results in multiple tensions between the
competing needs of being comprehensive versus preserving the integrity of the meta-analytic method:
(i) using data from the largest possible number of
disparate studies versus the need for pooling data
only from essentially identical studies [in terms of
study population, design, duration, measurement
instruments used, only those published, etc];
(ii) identifying studies to be analyzed using a broad
range of methods versus the requirement for

24

R. Tandon et al. / Schizophrenia Research 100 (2008) 2038

utilizing a very strict, replicable, protocol-driven

approach; and
(iii) imputing data in order to maximize the number of
studies in the meta-analysis versus the need to
be methodologically rigorous and including only
those studies which explicitly provide the data that
are to be extracted.
Necessary compromises made to resolve these competing needs detract from the internal validity and/or
generalizability of the treatment effect size generated by
the meta-analysis (Noble, 2006; Mismetti et al., 2007).
4. Applying the indirect method to randomized
controlled clinical trials of antipsychotic treatment
of schizophrenia
There are approximately 1600 RCTs of antipsychotic
treatment in patients with schizophrenia. For the purpose
of registration in different countries, all antipsychotic
agents have to be studied over a 48 week period among
patients with schizophrenia and schizoaffective disorder
during an acute psychotic exacerbation, using a randomized, parallel-group design with double-blind assessment; usually the Brief Psychiatric Rating Scale (BPRS,
Overall and Gorham, 1962; Guy, 1976) or the Positive
and Negative Symptoms Scale (PANSS, Kay et al., 1987)
is utilized for symptom assessment. Consequently, studies
with the above characteristics provide the best data for the
application of indirect approaches to comparing the
efficacy of different antipsychotic agents in schizophrenia. Total BPRS and PANSS scores provide reliable
measures of overall psychopathology and their positive
and negative symptom subscale scores provide reliable
measures of positive and negative symptom severity,
respectively. This indirect approach can be applied in two
ways: (i) naively, by comparing change scores for
different agents, without subtracting effects of a common
comparator; and (ii) after adjustment, comparing
change scores after subtracting the effects of a common
comparator such as placebo or another common agent
utilized across studies.
The principal advantage of the naive indirect method of
comparing efficacy is that it allows the unbiased pooling
of the largest amount of RCT data without the need for
data transformation. Since this method does not involve
averaging of a difference from control effect, all RCT's
with specified common criteria can be included, regardless
of the nature of the control group (placebo, haloperidol,
other). As this allows for a larger pool of RCTs to be
available for analysis, greater rigor can be employed in
specifying common RCT inclusion characteristics (since

using more rigorous inclusion/exclusion criteria reduces

the number of studies available for pooled comparison).
Pooling estimates of mean change from baseline to
endpoint across different agents (without subtracting a
common control effect) also represents the major
shortcoming of this method as it necessitates the
assumption that there were no systematic variations in
studies across the different agents.
5. Applying the crude or naive indirect method
Utilizing the PANSS as the assessment instrument,
studies find an average reduction of 1420 points in the
total PANSS score across the various agents over a 4
8 week period; FGAs and SGAs are found to produce a
similar range of improvement. In one such analysis
(Tandon and Jibson, 2005), the average improvement
among approximately 5000 patients across 22 studies of
risperidone, olanzapine, and quetiapine was compared.
This analysis discovered that while there was considerable variation in the degree of improvement with
a particular agent across its different studies, average
improvement across agents was similar for all efficacy
parameters considered (18.118.5 point total PANSS
reduction across agents; 5.15.7 point PANSS positive
score reduction across agents; and 4.44.5 point PANSS
negative score reduction across agents). When data from
amisulpride, sertindole, zotepine, and paliperidone studies were similarly analyzed, average improvements in
PANSS total, positive symptom, and negative symptom
scores were found to be similar. When data from all the
aripiprazole studies are analyzed, a smaller improvement
is noted (14.1 points on the PANSS total, 4.2 points on the
PANSS positive and 3.2 points on the PANSS negative);
similarly, when data from ziprasidone studies are
analyzed, improvements of 15.4 points on the PANSS
total, 4.4 points on the PANSS positive and 3.7 points on
the PANSS negative subscales are noted. Most of these
data are, however, derived from 4-week studies; controlling for the duration of trial, no significant difference in
mean improvement is noted across agents (Tandon and
Fleischhacker, 2005). The only FGA with an adequate
amount of relevant PANSS data is haloperidol; average
improvements of 15.6 on the PANSS total, 4.7 on the
PANSS positive and 3.2 on the PANSS negative subscales
are noted over a 48 week period.
Utilizing the BPRS as the assessment instrument,
studies find an average reduction of 1017 points in the
total BPRS score across the various agents over a 4
8 week period; again, FGAs and SGAs are found to
produce a similar range of improvement. The studies that
provide the data for such analyses were conducted over a

R. Tandon et al. / Schizophrenia Research 100 (2008) 2038

40-year period and consequently are even more heterogeneous than the ones using the PANSS.
6. Applying the refined or adjusted indirect method
Subtracting effects of a common comparator, three
major meta-analytic comparisons of the efficacy of FGAs
versus SGAs have been published (Leucht et al., 1999;
Geddes et al., 2000; Davis et al., 2003). Leucht et al.
(1999) conducted a meta-analysis of 21 randomized,
controlled clinical trials, comparing olanzapine, quetiapine, risperidone, and sertindole to haloperidol and
placebo. They observed that all antipsychotics were
about equally more effective than placebo. Additionally, risperidone and olanzapine (but not sertindole or
quetiapine) were found to be slightly more effective than
haloperidol. Comparing the efficacy of these antipsychotics based on relative effect size versus haloperidol
appears valid except that the haloperidol dose with which
the different agents were compared to was not the same.
Higher comparator doses of haloperidol were employed
in many risperidone and olanzapine studies (1520 mg/
day) than in many quetiapine and sertindole studies (10
12 mg/day). Higher doses of haloperidol cause more EPS
(Zimbroff et al., 1997; Hugenholtz et al., 2006; Tandon
and Nasrallah, 2006) and earlier drop-out from the study,
leading to a reduced estimate of efficacy. An examination
of the effects of haloperidol in the Leucht analysis
indicates that the suggested differences in efficacy among
risperidone, olanzapine, quetiapine, and sertindole based
on different effect sizes versus haloperidol were, in fact,
due to differences in the effects of haloperidol in these
comparisons (Tandon and Fleischhacker, 2005).
In a more comprehensive meta-analysis of 52 RCTs
of antipsychotic efficacy in schizophrenia (Geddes et al.,
2000), atypical antipsychotics were found to be marginally superior to conventional antipsychotics in the
treatment of schizophrenia but the apparent benefits of
SGAs over haloperidol diminished when comparator
doses of b 12 mg/day of haloperidol were considered.
It needs to be emphasized that an advantage for the
atypical class (albeit smaller) was noted even when
compared to b 12 mg/day of haloperidol. Geddes and
co-workers further noted that indirect comparison in
meta-regression models did not identify any individual
atypical antipsychotic as more or less effective when
dose of comparator drug was taken into account.
In the most comprehensive meta-analysis to-date
(Davis et al., 2003), Davis et al. utilized data from 124
RCTs comparing one of 10 second generation antipsychotics (SGAs) (amisulpride, aripiprazole, clozapine, olanzapine, remoxipride, risperidone, quetiapine,

25

sertindole, ziprasidone, and zotepine) to a first-generation antipsychotic (FGA). Based on their analysis, the
authors concluded that there are two groups of SGAs:
group 1 (comprised of amisulpride, clozapine, olanzapine, and risperidone) more efficacious than FGAs;
and group 2 (comprised of the other six) not differently
efficacious than FGAs. This conclusion is weakened by
the fact that the doses of various SGAs that the authors
stipulate as equivalent for use in their analyses are
questionable (Kane et al., 2003), there were differences
in the cohorts of patients who participated in studies of
the newer versus the older SGAs, and higher comparator
doses of haloperidol were utilized against group 1 than
against group 2 SGAs (Tandon and Fleischhacker, 2005;
Hugenholtz et al., 2006). Sensitivity analyses performed
by the authors (Tandon and Nasrallah, 2006) did not
adequately address these limitations.
Whereas these analyses are direct comparisons of
FGAs versus SGAs, they provide an adjusted indirect
comparison between different SGAs. Comparing FGAs
to SGAs, these analyses suggest a modest advantage for
SGAs, which diminishes with optimal FGA dosing.
With regard to the issue of comparative efficacy among
various SGAs, these indirect RCT meta-analyses do not
provide undisputed evidence of differential efficacy
(Tandon and Fleischhacker, 2005; Motlova et al., 2007).
7. Applying the direct method: head to head
randomized controlled clinical trials
7.1. First-generation (FGAs) versus second-generation
antipsychotics (SGAs)
The direct head-to-head RCT method was applied to
the comparison of FGAs versus SGAs in the above
section. Collectively, these meta-analytic comparisons
indicate that SGAs are modestly (though not consistently)
more effective than FGAs in the treatment of schizophrenia. While FGAs and SGAs appear to have similar
efficacy with regard to positive symptoms, SGAs are
associated with a variable and modestly greater average
improvement in negative symptoms, cognition and
depression/anxiety. Differences in occurrence of extrapyramidal side-effects (EPS) appear to be significantly
responsible for this perceived greater effectiveness of the
SGAs (Kapur and Remington, 2001; Meltzer, 2004;
Tandon, 2007). Although data from path-analytic studies
indicate that these greater beneficial effects of SGAs
versus FGAs with reference to negative, cognitive and
depressive symptoms are not fully explained by their EPS
advantage (Moller, 2003; Tollefson et al., 1998; Harvey
and Keefe, 2001), an additional direct benefit of SGAs

26

R. Tandon et al. / Schizophrenia Research 100 (2008) 2038

Table 2
Description of CATIE phase-1 and CUtLASS band-1 studies
CUtLASS Band 1

CATIE

Single-phase study

Three-phase study

SETTING
SUBJECTS
Number
Diagnosis
Mean age
Gender
Mental illness duration
First episode patients
Baseline antipsychotic
Baseline PANSS total

14 NHS trusts in the UK

57 sites across the USA

227 subjects
75% schizophrenia
41 years
68% male
14 years
Included (13% of total)
82% on FGA
72.2

1,460 subjects
100% Schizophrenia
41 years
74% male
16 years
Excluded (0% of total)
15% on FGA
75.7

METHODS
When conducted
Study duration
Randomized assignment to

19992003
12 months
FGA or SGA Class (50% FGA)

20012004
18 months
One of 5 agents (4 SGAs, 1 FGA)
(20% FGA) in Phase 1
15% continued on same agent 57%
actually switched agents 28% started new agent
Five Antipsychotic Arms
All-Cause Antipsychotic Discontinuation
Medication blinded to raters, patients and physicians

Antipsychotic switching
Comparison groups
Primary outcome measure
Clinical care and primary outcome assessment

All patients switched agents 49%

switched class 51% stayed in same class
FGA versus SGA Arms
Quality of Life (QOL)
Medication blinded to raters but not to
patients and physicians

has been questioned (Carpenter and Gold, 2002; Erhart

et al., 2006). These data imply that EPS avoidance while
maximizing efficacy is one key to optimizing antipsychotic effectiveness. Judicious use of SGAs or use of low
doses of FGAs are two strategies that can be utilized
towards this end, although it should be noted that even
low-dose haloperidol causes more EPS than SGAs
(Zimbroff et al., 1997). Use of modest doses of lowpotency FGAs can also minimize the risk of EPS, but
optimal efficacy may be compromised by this strategy
(Leucht et al., 2003) and there is a greater risk of
metabolic and cardiovascular adverse effects when using
low-potency FGAs in comparison to high-potency FGAs
(Allison et al., 1999).
7.2. CUtLASS
CUtLASS (Cost Utility of the Latest Antipsychotics in
Severe Schizophrenia) was a large multi-center government-sponsored pragmatic trial conducted in the United
Kingdom to compare the effectiveness of SGAs versus
FGAs (Lewis et al., 2006a,b; Jones et al., 2006). In band 1
of the study (Jones et al., 2006, Table 2), 227 individuals
with schizophrenia poorly responsive to or intolerant of
current antipsychotic treatment were randomized to
receive either an FGA (any one of 11, including four
long-acting preparations, chosen by the treating clinician)

or an SGA (either risperidone, olanzapine, quetiapine, or

amisulpride, chosen by the clinician) and quality of life
was evaluated over one year. No significant differences in
quality of life or symptoms were observed among patients
assigned to the two groups. Furthermore, FGAs were
found to be more cost-effective than SGAs because they
were both less costly and more effective in terms of
quality-adjusted life-years (Davies et al., 2007).
At the time the study was conducted, comparing entire
classes of FGA versus SGA antipsychotics may have
seemed useful; in retrospect, the significant heterogeneity
among both FGAs and SGAs likely lessened power and
reduced the interpretability of the findings (Tandon et al.,
2007; Moller, 2007). Furthermore, in CUtLASS-1, individuals assigned to an FGA could receive either oral or longacting injectable antipsychotic medication in contrast to
those assigned to an SGA who could only receive oral
medication. 84 of 227 participants in CUtLASS 1 were
receiving a depot antipsychotic at baseline; the vast
majority of these individuals was switched to oral agents
(FGA or SGA) and did poorly. Only twelve subjects were
initially randomized to receive a depot antipsychotic but
this number had tripled to 35 by the end of the one-year
study. These findings of CUtLASS support the importance
of treatment adherence and the potential utility of longacting injectable antipsychotic agents in the treatment of
schizophrenia (Kane, 2006a; Tiihonen et al., 2006;

R. Tandon et al. / Schizophrenia Research 100 (2008) 2038

Nasrallah, 2007). A re-assessment of the role of the eleven

currently-available long-acting injectable antipsychotic
preparations around the world is warranted.
7.3. Clozapine versus other SGAs
In band 2 of CUtLASS (Lewis et al., 2006b), 136
patients exhibiting a poor response to 2 antipsychotic
agents were randomized to receive either clozapine or a
non-clozapine SGA and their quality of life compared
over one year. Clozapine was found to be significantly
superior to non-clozapine SGAs with reference to symptoms (p = 0.01) and exhibited a trend towards superiority
with regard to quality of life (p = 0.08) in this group of
patients. In fact, among patients with treatmentrefractory schizophrenia, clozapine still has the largest
body of evidence supporting its greater efficacy (Kane
et al., 1988; Chakos et al., 2001; Tuunainen et al., 2002);
its potential for agranulocytosis and other major adverse
effects has generally limited its use to patients with
otherwise treatment-refractory schizophrenia. Results
from the efficacy arm of phase-2 in CATIE (McEvoy
et al., 2006) also support the greater efficacy of clozapine in poorly responsive schizophrenia patients. In
contrast to the compelling data supporting its superiority
over FGAs and other SGAs in treatment-refractory
patients and those with high suicidality (Meltzer et al.,
2003), there is no such evidence of clozapine's greater
effectiveness in first-episode (Lieberman et al., 2003) or
other patient populations.
7.4. Comparisons of non-clozapine second-generation
antipsychotics to each other
The other ten SGAs (amisulpride, aripiprazole, olanzapine, paliperidone, perospirone, quetiapine, risperidone, sertindole, ziprasidone and zotepine) are generally
considered first-line antipsychotic agents (World Psychiatric Associations, 2002; Kane et al., 2003; Miller
et al., 2004; American Psychiatric Association, 2004;
Falkai et al., 2005). Utilizing the direct head-to-head
RCT approach, how do non-clozapine SGAs compare in
efficacy? There have been twenty-six published randomized, controlled clinical trials of reasonable size (N 100
patients) comparing two or more non-clozapine SGAs in
patients with schizophrenia and schizoaffective disorder
(Lieberman et al., 2005; Tran et al., 1997; Peuskens
et al., 1999; Mullen et al., 2001; Conley and Mahmoud,
2001; Sechter et al., 2002; Martin et al., 2002; Jeste
et al., 2003; Potkin et al., 2003; Addington et al., 2004;
McQuade et al., 2004; Mortimer et al., 2004; Simpson
et al., 2004; Breier et al., 2005; Potkin et al., 2006;

27

Azorin et al., 2006; Zhong et al., 2006; Kinon et al.,

2006a,b; Lecrubier et al., 2006; Chrzanowski et al.,
2006; Olie et al., 2006; Davidson et al., 2007; McEvoy
et al., 2007; Volavka et al., 2002; McCue et al., 2006).
Twenty-three of these studies were sponsored by the
manufacturer of one of the SGAs (Tran et al., 1997;
Peuskens et al., 1999; Mullen et al., 2001; Conley and
Mahmoud, 2001; Sechter et al., 2002; Martin et al., 2002;
Jeste et al., 2003; Potkin et al., 2003; Addington et al.,
2004; McQuade et al., 2004; Mortimer et al., 2004;
Simpson et al., 2004; Breier et al., 2005; Potkin et al.,
2006; Azorin et al., 2006; Zhong et al., 2006; Kinon et al.,
2006a,b; Lecrubier et al., 2006; Chrzanowski et al., 2006;
Olie et al., 2006; Davidson et al., 2007; McEvoy et al.,
2007). Although the technical quality of pharmaceuticalsponsored studies is generally good (Lexchin et al., 2003),
they are more likely to obtain outcomes favorable to the
product of the sponsor (Melander et al., 2003; Perlis et al.,
2005; Lexchin et al., 2003; Montgomery et al., 2004).
Such favorable outcomes may result from design biases
(eg., using favorable doses of the sponsor's compound
and comparator) or asking the right questions (eg.,
focusing on outcomes favorable to the sponsor's
product) (Heres et al., 2006; Williamson et al., 2005).
Despite such biases, these pharmaceutical-sponsored
RCTs comparing non-clozapine SGAs have not found
consistent differences in efficacy among the agents
compared (Tandon and Fleischhacker, 2005). Discrepancies between points of emphasis in the abstract and actual
findings of individual studies, however, can frequently
contribute to reader perceptions of differential efficacy
(Safer, 2002).
In the first not fully industry-supported RCT comparing these agents (Volavka et al., 2002), Volavka and
colleagues noted that clozapine, olanzapine and risperidone, but not haloperidol, yielded significant reductions
in PANSS total scores in schizophrenia patients with a
history of a suboptimal treatment response; only clozapine
and olanzapine were found to be superior to haloperidol.
The authors commented that therapeutic effects in their
trial were modest and their clinical relevance was limited.
The authors additionally noted that a major limitation of
their study was a cohort effect that potentially biased
comparisons in favor of olanzapine. The study further
supports clozapine's greater efficacy in otherwise treatment-refractory patients with schizophrenia.
In a more recent industry-independent clinical trial
(McCue et al., 2006), 327 newly hospitalized patients were
randomized to a minimum 3-week open-label treatment
with aripiprazole, haloperidol, olanzapine, quetiapine,
risperidone, or ziprasidone and changes in symptoms and
times to discharge were compared. Although there were no

28

R. Tandon et al. / Schizophrenia Research 100 (2008) 2038

significant differences among the six groups in terms of

change in symptomatology, those receiving haloperidol,
olanzapine, or risperidone were significantly more likely to
exhibit sufficient improvement to be discharged than those
receiving aripiprazole, quetiapine, or ziprasidone. Findings
of the study have limited generalizability and are difficult
to interpret in view of a variety of methodological shortcomings, including differences across groups with regard
to speed of titration to their effective dose, unreliable endpoint (discharge-ability as assessed by the treating
clinician), and short trial duration (3 weeks).
8. CATIE
Phase-1 and phase-2 results from the U.S.A. government-funded Clinical Antipsychotic Trials of Intervention
Effectiveness (CATIE) in schizophrenia have been
published (Lieberman et al., 2005; McEvoy et al., 2006;
Stroup et al., 2006a). In terms of duration (18 months) and
numbers of patients (1,460), CATIE is the most
comprehensive RCT ever conducted in chronic schizophrenia. In the first phase of this three-phase trial, 1,460
patients with chronic schizophrenia were randomized to
receive perphenazine (an FGA) or risperidone, olanzapine,
quetiapine, or ziprasidone (four SGAs) (Table 2). At study
entry, patients were relatively stable with moderate illness
severity on average (CGI-S = 4; PANSS total = 75.7; (Guy,
1976; Leucht et al., 2005)) and three-quarters of them were
receiving an antipsychotic. Patients were randomized to
receive perphenazine, risperidone, olanzapine, quetiapine,
or ziprasidone (Stroup et al., 2003). Phase-1 study
completion rate was 26 percent across the 18-month
study- 36% for olanzapine, 26% for risperidone, 25% for
perphenazine, 21% for ziprasidone, and 18% for quetiapine. Patients were likely to stay on olanzapine significantly longer than on the other four agents; there were no
significant differences between the other four agents in
this regard. More recently, the authors reported the
presence of broad neurocognitive deficits in a vast
majority of CATIE participants at baseline (Keefe et al.,
2006) with modest improvement during the course of
treatment without any significant differences among
patients receiving the five agents (Keefe et al., 2007).
While small improvements in psychosocial functioning
were observed among study patients over the 18-month
study, there were no differences across the five treatment
arms (Swartz et al., 2007). There were no differences in
quality of life measures between patients in the five
treatment arms (Rosenheck et al., 2006). Finally, perphenazine was described by the authors to be the most
cost-effective agent because it was less costly but no less
effective than the other agents (Rosenheck et al., 2006).

The 1,052 patients who prematurely discontinued

phase-1 treatment on an initially-assigned SGA were
eligible to participate in phase-2 of the study. Of note, they
could choose to enter either the clozapine (efficacy
pathway) or the ziprasidone (tolerability pathway) arms of
the study regardless of their reason for discontinuing
phase-1. Ninety-nine subjects chose to participate in the
clozapine-other SGA comparator study (McEvoy et al.,
2006); 444 chose to participate in the ziprasidone-other
SGA comparator study (Stroup et al., 2006a); and 509
chose to exit the study. In the clozapine pathway, individuals were assigned to receive either clozapine or
another SGA which they had not received in phase-1. In
the ziprasidone pathway, individuals were assigned to
receive ziprasidone or another SGA which they had
not received in phase-1. Treatment effectiveness in this
phase was again primarily measured by the duration that
patients remained on their originally assigned antipsychotic medication. In phase-2, clozapine was found to be
more effective than other SGAs among patients who
participated in the efficacy arm (McEvoy et al., 2006)
whereas risperidone and olanzapine were noted to be
more effective than quetiapine and ziprasidone among
patients who chose to participate in the tolerability arm
(Stroup et al., 2006a).
Results of this landmark study warrant close scrutiny
because of its importance and a range of methodological
considerations (Table 2, Moller, 2005; Tandon, 2006a;
Kane, 2006b; Tandon, 2006b; Meltzer and Bobo, 2006;
Casey, 2006; Kasper and Winkler, 2006; Freedman et al.,
2006; Janicak, 2006; Essock et al., 2006; Rosenheck et al.,
2007a). The FGA-SGA comparison is compromised by
the assignment of the 231 patients with tardive dyskinesia
to treatment with SGAs but not the FGA perphenazine.
While this may have been clinically desirable because
SGAs are associated with a lower risk of tardive dyskinesia
than FGAs (Correll et al., 2004; Kane, 2006c; Tarsy and
Baldessarini, 2006), patients with tardive dyskinesia are
known to suffer from a more severe and less treatmentresponsive form of the illness along with a much higher
propensity for EPS (Tenback et al., 2006). Consequently,
investigators conducted comparisons between perphenazine and the SGAs after excluding patients with tardive
dyskinesia. In conjunction with the inclusion-exclusion
criteria of the study, this ensured a study sample at
relatively low risk for EPS (Tandon, 2006a; Kane, 2006b;
Tandon, 2006b; Meltzer and Bobo, 2006) and therefore a
reduced assay sensitivity to detect differences in EPS
(Tandon and Constantine, 2006; Rosenheck et al., 2007b).
This reduced assay sensitivity is confirmed by the fact that
while CATIE documented more frequent treatment
discontinuation because of EPS among perphenazine-

R. Tandon et al. / Schizophrenia Research 100 (2008) 2038

treated patients, it did not detect any differences in various

EPS ratings between patients treated with perphenazine or
SGAs. Since SGA-FGA differences in spectrum of efficacy
are principally driven by the lower liability of SGAs to
cause EPS, CATIE's finding of no differences in EPS
between perphenazine and the study SGAs might explain
why it also found no differences in overall effectiveness,
cognition, negative symptoms, and tardive dyskinesia
(Tandon and Constantine, 2006; Fig. 1). Since findings of
any study apply to populations similar to the one examined,
CATIE's findings of no FGA-SGA difference in any
measure of efficacy would specifically apply to patients
with schizophrenia at low risk for EPS.
The comparison between the different agents was significantly biased by differences in switching rates across
the five agents in the context of the risk of switching
antipsychotics among relatively stable, moderately ill
schizophrenia patients (on average) as in CATIE. In
phase-1 of the study, a significant association between
antipsychotic switching rates and 18-month all-cause
discontinuation was noted; when these switching effects
were controlled for, no significant differences in effectiveness among the five agents remained (Essock et al.,
2006). The comparison between different SGAs may
have been further compromised by the suboptimal dosing
of quetiapine and ziprasidone (and possibly risperidone)
relative to olanzapine (Kane et al., 2003).
These methodological issues (Tandon, 2006a; Kane,
2006b; Tandon, 2006b; Meltzer and Bobo, 2006; Casey,
2006; Kasper and Winkler, 2006; Freedman et al., 2006;
Janicak, 2006; Essock et al., 2006; Rosenheck et al., 2007a;

29

Tandon and Constantine, 2006; Rosenheck et al., 2007b)

do not invalidate the many important lessons from this
landmark study, but instead suggest the need to understand
its findings in the context of its study design and integrate
its results with those of other relevant studies.
8.1. What do CATIE and CUtLASS tell us
Both CATIE and CUtLASS were large, industryindependent, randomized, controlled clinical trials which
provide us with substantial information about antipsychotic treatment of schizophrenia. Their findings are best
understood in the context of their study populations and
designs and suggest the following conclusions:
(i) SGAs are not uniformly or consistently more
effective than FGAs;
(ii) if differences in EPS and anticholinergic use
between FGAs and SGAs can be eliminated, then
differences in effectiveness between them can be
substantially diminished or even removed;
(iii) antipsychotic effectiveness in schizophrenia is
still unsatisfactory; completion rate on initiallyassigned antipsychotic treatment arm at 18 months
in CATIE was 26%;
(iv) different challenges exist in balancing efficacy
and tolerability with different agents;
(v) the process of switching antipsychotics can be
risky (Essock et al., 2006; Davis et al., 2006);
(vi) given enormous individual variability in drug
handling, responsivity, and susceptibility to and

Fig. 1. How can first- and second-generation antipsychotics be more effective?

30

R. Tandon et al. / Schizophrenia Research 100 (2008) 2038

tolerance of different adverse effects, no single

approach works for all patients; and
(vii) clozapine is still the gold standard in the treatment
of otherwise unresponsive schizophrenia.

ditional requisite studies to better understand and

discriminate between them, disseminate maximally
current and accurate information about these agents to
all who use them, and articulate practice standards that
promote appropriate use of these medications.

9. Optimizing antipsychotic therapy in schizophrenia

Despite significant advances in our understanding of
the nature of the disease, schizophrenia remains one of
the most challenging medical conditions of our times. It
is characterized by high morbidity and mortality, and
available treatments for schizophrenia are incompletely
and variably effective and associated with a range of
adverse effects. Despite these impediments, however,
the individualized provision of a comprehensive array of
treatment, rehabilitative and social support services can
effectively promote recovery of persons with schizophrenia (Fig. 2, (Tandon et al., 2006)).
While existing antipsychotic treatments for schizophrenia are not completely satisfactory, they can
substantially reduce disease burden and make a meaningful difference in the life of each individual patient.
Towards this end, critical evaluation of the sizable body
of available information about antipsychotics and its
individualized application are essential along with efforts to resolve important unanswered clinical questions.
In this regard, we need to characterize antipsychotic
agents using all the available information, conduct ad-

10. Evaluating the evidence and the science of

antipsychotic therapy
FGAs and SGAs both constitute very heterogeneous
classes of antipsychotic medications. The principal distinction between SGAs and FGAs is the ability of
the former to provide an equivalent antipsychotic effect
with a lower liability to cause EPS, although there is
substantial variation within each class in this regard.
Clinical trial data collectively indicate that SGAs may
demonstrate a broader spectrum of efficacy than FGAs
(equivalent efficacy in positive symptoms and variably
greater efficacy in negative, mood, and cognitive symptoms), substantially related to their lower propensity to
cause motor side-effects. Whereas neither the modestly
greater efficacy of SGAs over FGAs nor its significant
explanation by the reduced propensity of SGAs versus
FGAs to cause EPS is fully established, they are consistent with the preponderance of data. Recent findings
further reinforce the importance of achieving an antipsychotic effect without EPS. Clozapine is more effective than other antipsychotic agents in treatment-

Fig. 2. Recovery means optimizing individual outcomes.

R. Tandon et al. / Schizophrenia Research 100 (2008) 2038

refractory schizophrenia patients (specifically those with

antipsychotic-refractory positive symptoms), ameliorating symptoms in about one-third of such patients; reduced
EPS liability does not explain this greater efficacy.
Indirect comparisons of efficacy across studies and
direct comparisons in the relatively few randomized,
controlled head-to-head studies between other SGAs
suggest that they are essentially similar with regards to
overall efficacy and efficacy in treating positive and
negative symptoms; if differences exist, these are small.
The occasional observation of the superior efficacy of
some SGAs may be explained by the fact that optimal
dose ranges for olanzapine, risperidone, and amisulpride
are somewhat better defined than those for quetiapine,
ziprasidone, and aripiprazole. Additionally, the need for
multiple-daily dosing and administration with food may
complicate the real-life optimal dosing of ziprasidone.
In view of the significant individual variability in drug
pharmacokinetics and treatment responsivity, it should
also be emphasized that equivalent overall efficacy across
patient groups does not translate into equal efficacy in each
individual patient. There is no best agent or a best dose of
any agent for all patients. It is not currently possible to
prospectively predict which antipsychotic medication
might be optimal for a given patient. Decisions about
antipsychotic therapy consequently entail a trial and error
process with careful monitoring of clinical response and
adverse effects and an ongoing risk-benefit assessment.
Substantial differences in the adverse effect profiles
of these medications are very well documented and
different individuals are differentially tolerant of different adverse effects. Generally, SGAs have a lower
propensity to induce EPS than FGAs although there are
differences among both groups of agents with regard to
the ease and consistency with which an adequate antipsychotic effect can be achieved without EPS (Tandon
and Jibson, 2002; Weiden, 2007). Metabolic side-effects
which increase the risk of ischemic heart disease (weight
gain, dyslipidemia, diabetes mellitus) have recently received particular attention (Newcomer, 2005; Franciosi
et al., 2005). In view of their likely contribution to the
increased mortality of persons with schizophrenia, they
warrant close attention. Although SGAs are generally
associated with metabolic adverse effects to a greater
extent than FGAs, there are variations among both
SGAs and FGAs with regard to their liability to cause
these side-effects. CATIE, for example, found olanzapine to cause more weight gain and related metabolic
side-effects than perphenazine, risperidone and quetiapine to cause equivalent weight gain to perphenazine,
while ziprasidone caused fewer metabolic problems
than perphenazine. Other adverse effects differ among

31

FGAs and SGAs as well (Tandon et al., 2006); the

impact of these adverse effects on both the safety and
tolerability of these agents differs across individuals. A
minimum protocol for monitoring adverse effects
should be implemented and this needs to be customized
to the patient's specific vulnerabilities/needs and the
agent selected (Marder et al., 2004; Constantine et al.,
2006, Table 3).
If bothersome or hazardous adverse effects develop,
informed treatment adjustments should be made collaboratively by the physician-patient team (Seale et al., 2006).
Switching antipsychotics because of inadequate efficacy or
poor tolerability has been found to be useful (Weiden et al.,
2003; Tandon et al., 2006), but the risks of discontinuing a
partially effective treatment need to be weighed against the
benefits of switching to a possibly more effective one
(Tandon, 2006a; Davis et al., 2006; Edlinger et al., 2005);
both the risks and benefits were evident in CATIE and to a
more limited extent in CUtLASS.
Antipsychotic treatment has a significant impact on
the long-term course of schizophrenic illness and can
significantly facilitate recovery (Fig. 2). Early intervention has much promise in reducing the substantial decline in function that frequently accompanies the onset
of schizophrenic illness, but effects of early antipsychotic treatment and differences between agents are inadequately characterized. Extrapolating effectiveness
findings from trials conducted in chronically ill subjects
as in CATIE and CUtLASS to first-episode patients
warrant great caution. While previous studies suggest benefits of SGAs over FGAs in this population
(Schooler, 2007), results of the recently completed
European First-Episode Schizophrenia Trial (EUFEST,
Fleischhacker et al., 2005) are awaited with great interest. In later stages of schizophrenia, high rates of
treatment nonadherence result in incomplete remissions
and frequent relapses; a variety of pharmacological,
psychosocial, and disease-management strategies can be
utilized to improve treatment adherence and promote
recovery (Kane, 2006a; Tandon et al., 2006).
11. The individual with schizophrenia, the physician
providing antipsychotic treatment, and the
treatment system
It is the responsibility of every individual patient, his
or her doctor, and the clinic in which the patient is
receiving treatment to ensure that the best possible
treatment is being provided to enable the best possible
outcome to be achieved (Anthony, 1993; Tandon et al.,
2006; Tunner and Salzer, 2006; Committee on Crossing
the Quality Chasm, 2005).

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R. Tandon et al. / Schizophrenia Research 100 (2008) 2038

Table 3
Minimum Health Monitoring Recommendations (adapted from Mount Sinai Conference (Marder et al., 2004) and State of Florida (Constantine et al.,
2006) Guidelines)
Baseline
History
Weight (BMI)
Waist circumference
Blood pressure
Fasting Gluc & Hb A1c
Fasting lipid profile
Sexual Function
EPS and TD
Ocular evaluation

X
X
X
X
X
X
X
X
X

4 Weeks

8 Weeks

12 Weeks

Quarterly

X
X
X
X
X
X
X

Annually
X

X
X

X
X
X
X
X
X
X

The frequency of monitoring may need to be increased if the patient has additional vulnerability to that adverse effect or the agent utilized is more
likely to cause it. Other monitoring based on agent and patient.
Agent-specific monitoring (eg., WBC monitoring with clozapine).

Collaboratively, the person with schizophrenia and

their doctor need to evaluate antipsychotic treatment
options, weigh issues of efficacy and safety/tolerability
in the context of available information and the patient's
preferences, and choose a suitable treatment. Treatment
targets should be explicitly defined, the impact of treatment on the individual carefully monitored, and adjustments in treatment made based on response. Data related
to reliable measures of symptomatology, side-effects,
risk factors for metabolic and other diseases, appropriate
laboratory tests, measurement of mild EPS, and other
relevant individualized risk-benefit data should be
obtained in a timely manner, included in the medical
records and utilized to assist decision-making. Fiscal
implications should be considered in conjunction with
the various clinical considerations.
The treatment system needs to ensure that adequate
resources are available to clinicians and patients to optimize individual recovery. A full range of treatment
options along with a culture of recovery and accountability are crucial. Necessary information should be
provided to the patient and suitable tools provided to the
treating psychiatrist to promote best-possible collaborative treatment. The system can promote the appropriate
use of evidence-based treatments by clearly enunciating
principles of good practice, requiring outcome measurement, monitoring actual practice, and providing feedback to clinicians about their practice (Table 4).
The psychiatrist should provide disciplined and targeted pharmacological treatment whose impact (both
beneficial and adverse effects along with their functional
implications) is reliably measured. The advisability of any
pharmacological treatment is determined by balancing the
expected benefits against the potential risks of that
treatment, considering the costs of the treatment. Pharmacological treatment decisions made by the psychiatrist in

conjunction with the individual receiving treatment for

schizophrenia include initial choice of antipsychotic,
dosing strategy of chosen agent, determination of specific
treatment target and assessment of response, and choosing
between available options (e.g., allowing more time,
changing the dose, adding another medication, switching
antipsychotics) in the event of an unsatisfactory response.
The approach of formulating explicit rules for
sequential decision-making should be complemented by
efforts to carefully scrutinize pharmacological practices
outside the norm. The norm is generally defined by a
combination of clinical trial evidence and expert
consensus; outlier analysis is the tool employed to
identify pharmacological practices outside these normative parameters (Constantine et al., 2006). A proximate
objective of antipsychotic treatment of schizophrenia is to
achieve a maximum reduction of positive symptoms
while avoiding EPS or using anticholinergic medications.
Although it is possible to achieve this goal with suitablydosed FGA treatment in a fair number of individuals,
SGA treatment may provide a better likelihood of more
predictably accomplishing this objective (Fig. 1). If the

Table 4
Strategies to encourage evidence-based antipsychotic therapy (adapted
from Constantine et al., 2006)
Promulgate clear guidelines for use.
Articulate principles of use [Defined objectives]
Indicate how to use [Dosing, trial duration, sequence]
Specify protocols and tools for monitoring [Efficacy, physical health]
Provide point-of-care aids to treating physician.
Information about prescription refills, etc.
Track actual prescribing practices and use a hierarchy of interventions
to guide them.
Monitor practice and provide feedback.
Targeted interventions for unusual practices.

R. Tandon et al. / Schizophrenia Research 100 (2008) 2038

initially selected treatment does not accomplish this goal,

appropriate treatment adjustments need to be made. Other
key objectives include optimizing reduction of other
symptom domains while minimizing adverse effects
considering individual patient vulnerabilities and preferences. Since cardiovascular disease is the principal
contributor to the doubling of age-standardized mortality
among persons with schizophrenia, metabolic and other
risk factors for ischemic heart disease warrant particular
attention (Newcomer, 2005; Franciosi et al., 2005).
12. Government and the pharmaceutical industry
For maximization of the public good with regards to the
treatment of schizophrenia, the 9th leading cause of
medical disability in the world, governments bear the
responsibility for promoting the best possible treatment of
this devastating illness. Towards the goal of optimal
pharmacotherapy, governments oversee the drug registration process, ensure broad public access to necessary
treatments, review drug labeling, and promote dissemination of good quality information about treatments.
Although governments around the world are beginning
to recognize the enormous individual and public costs of
schizophrenia, they lag in efforts at reducing the stigma
(Schomerus et al., 2006) and addressing other barriers to
optimal recovery. Although existing treatments for
schizophrenia are not completely satisfactory, they are
fairly effective and can enable affected individuals to lead
more productive and satisfying lives. SGAs, by virtue of
their equivalent efficacy for positive symptoms with a
lower propensity to cause EPS than FGAs, are generally
preferred antipsychotic agents for many patients but their
moderately greater value needs to be considered in the
context of the cost differential (Patel et al., 2007). Current
pharmaco-economic studies in this regard are, however, of
limited value at this time (Hansen et al., 2006; Polsky et al.,
2006). Just as relative prescribing costs of antipsychotic
agents differ substantially across countries, mental health
delivery systems vary as well. Given the substantial
individual variation in antipsychotic response, it is useful
to have a broad range of antipsychotic treatment options
available in all settings. Each system should ensure
effective and efficient utilization of all treatment and
rehabilitative options to maximally promote individual
recovery among the largest number of people receiving
mental health services in the context of its resource
constraints. Reimbursement strategies should also encourage psychosocial and disease management best practices
that can substantially improve outcomes in schizophrenia.
Stronger initiatives to promote development of more
effective treatments are necessary. Through mandates and

33

incentives, government also needs to ensure the timely

conduction of high quality clinical trials that address
important questions of clinical practice. As vital questions
remain unanswered, increased funding for relevant
clinical trials is essential (Stroup et al., 2006b; Honer
et al., 2007). A more effective pharmaco-epidemiological
surveillance system needs to be developed in countries
across the world and mechanisms to efficiently share data
should be strengthened. Robust efforts to promote bestpossible treatment need to be made and better incentives
to study critical clinical questions provided. Additionally,
government should monitor dissemination of accurate
information about available treatments.
Pharmaceutical companies should be commended for
accepting mandatory registration of all their clinical trials;
they should now consistently comply with this registration
process (Zarin et al., 2005; Kane et al., 2007). Comprehensive data from all clinical trials should be made
available in a timely manner. The industry should be
encouraged to develop more effective treatments for
schizophrenia. The high costs and high risks associated
with drug development (particularly for a broadly
characterized entity such as schizophrenia) are disincentives to the development of truly innovative treatments for
schizophrenia- but that is what is clearly needed! Existing
treatments also can be better utilized and pharmaceutical
companies need to be encouraged and/or required to more
fully characterize their products and describe strategies for
their optimal use. For example, it has been clear that
original dosing strategies recommended for virtually all
SGAs were suboptimal- risperidone being overdosed and
olanzapine, quetiapine, and ziprasidone being underdosed. Yet the manufacturers of these products have not
conducted comprehensive studies to better elucidate
proper dosing or initiated serious efforts to get their
product labels suitably changed. Similarly, no RCTs
comparing effectiveness of long-acting risperidone microspheres to long-acting injectable FGAs have been
initiated despite the importance of this topic. Information
relevant to many areas of antipsychotic practice in schizophrenia is inadequate; high-quality trials addressing
questions of clinical import need to be conducted in a
timely manner.
13. In conclusion
Different antipsychotic agents pose different challenges in terms of balancing efficacy and safetytolerability and there is considerable individual variability
in antipsychotic response and vulnerability to different
adverse effects. Antipsychotic treatment needs to be
individually tailored to promote optimal recovery and this

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R. Tandon et al. / Schizophrenia Research 100 (2008) 2038

requires careful monitoring and ongoing joint decisionmaking by the clinician-patient team about choice of
antipsychotic agent, dosing, continuation/switching, and
augmentation. Although existing antipsychotic treatments
for schizophrenia are not completely satisfactory, they can
meaningfully reduce the devastating effects of the illness.
Even as we try to develop better treatments, we need to
better characterize and compare existing treatments. A
balanced understanding of our extensive data repository
on treatments for schizophrenia is essential and effective
mechanisms for fair dissemination of this information are
necessary. A meticulous application of this understanding
can reduce the significant gap between what we know and
how we provide antipsychotic pharmacotherapy for
persons with schizophrenia. Collectively, we can do
much to better utilize existing treatments to optimize
individual outcomes and reduce the considerable morbidity and mortality associated with the illness.
Role of the funding source
The analysis was independently conducted and the manuscript
independently prepared by the members of the WPA Section of
Pharmacopsychiatry. There was no external funding or support for the
development of this statement.
Contributors
Rajiv Tandon, M.D.,1 Hans-Juergen Moeller, M.D., Ph.D.,2 R.H.
Belmaker, M.D.,3 Wagner, F. Gattaz, M.D., Ph.D.,4 Juan J. Lopez-Ibor,
Jr., M.D., Ph.D.,5 Ahmed Okasha, M.D., Ph.D.,6 Bruce Singh, M.B.B.
S., Ph.D.,7 Dan J. Stein, M.D., Ph.D.8 Jean-Pierre Olie, M.D., Ph.D.,9
and Wolfang Fleischhacker, M.D.,10 for the Section of Pharmacopsychiatry, World Psychiatry Association
1. Chief of Psychiatry, State of Florida Program of Mental Health,
Tallahassee, Florida, USA.
2. Professor and Chair, Psychiatry Department, University of
Munich, Munich, Germany.
3. Professor and Chair, Department of Psychiatry, Ben Gurion
University of the Negev, Beersheva, Israel.
4. Professor and Chair, Institute of Psychiatry, University of Sao
Paulo, Sao Paulo, Brazil.
5. Professor and Chair, Institute of Psychiatry, Complutense
University, Madrid, Spain.
6. Professor and Chair, Institute of Psychiatry, Ain Shams
University, Cairo, Egypt.
7. Cato Professor and Chair, Department of Psychiatry, University
of Melbourne, Melbourne, Australia.
8. Professor and Chair, Department of Psychiatry, University of
Cape Town, Cape Town, South Africa.
9. Professor and Chair, Department of Psychiatry, CentreHospitale Saint-Anne, Paris, France.
10. Professor of Psychiatry and Vice-Chair, Department of
Psychiatry, University of Innsbruck, Innsbruck, Austria.
Conflict of interest
Disclosure statement
This statement was independently developed by the Section of
Pharmacopsychiatry (Chair: Hans-Juergen Moeller) of the World
Psychiatric Association. While fully endorsed by the Section, the

statement does not purport to be an official document of the

Association. Whereas the 41 members of the Section have varying
degrees of potential conflicts of interest, relevant disclosure of the ten
authors is provided herein. Drs. Belmaker, Lopez-Ibor, Okasha, and
Tandon report no current conflicts relevant to this article. Within the
previous five years, however, Dr. Tandon has been a consultant for and
received speakership honoraria supported by AstraZeneca, Bristol
Myers-Squibb, Eli Lilly, Janssen, and Pfizer. The content of the article
is not part of the purview of Dr. Tandon's current employment by the
State of Florida which bears no responsibility its contents. Dr Moeller is
a consultant for and on the speakership bureaus of AstraZeneca,
Bristol-Myers Squibb, Eisai, Eli Lilly, GlaxoSmithKline, Janssen,
Lundbeck, Organon, Pfizer, Sanofi-Aventis, Sepracor, and Wyeth.
Dr. Gattaz has received research support and speakership honoraria
from AstraZeneca, Bristol Myers-Squibb, Eli Lilly, and Janssen-Cilag.
Dr. Olie is a consultant for Eli Lilly, Janssen, Pierre Fabre, Servier, and
Sanofi-Aventis. Dr Singh is a consultant for and has received research
support from AstraZeneca, Bristol-Myers Squibb, Eli Lilly, and
Janssen-Cilag. Dr. Stein has received research grants and/or speakership honoraria from AstraZeneca, Eli Lilly, GlaxoSmithKline, Johnson
and Johnson, Lundbeck, Orion, Pfizer, Pharmacia, Roche, Servier,
Solvay, Sumitomo, Tikvah, and Wyeth. Dr. Fleischhacker has received
research grants from, is a consultant for and on the speakership bureaus
of AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Janssen Cilag, Otsuka,
Pfizer, and Wyeth.
Acknowledgement
Members of the WPA Section on Pharmacopsychiatry:
A. Carlo Altamura, David S. Baldwin, David Baron, Michael
Bauer, R.H. Belmaker, Pierre Blier, Patrice Boyer, William E. Bunney,
Graham Burrows, Wolfang Fleischhacker, Daniel Flores, Wagner F.
Gattaz, Guy Goodwin, Gerardo Heinze, Ian Hindmarch, Hans Hippius,
Cyril Hoschl, Siegfried Kasper, Per Kragh-Sorensen, Juan J. LopezIbor, Ulrik Malt, Bruno Millet, Sung Kil Min, Hans-Juergen Moeller
(Chair), Jaime Monti, Bruno Muller-Oerlinghausen, Franz MullerSpahn, David J. Nutt, Ahmed Okasha, Jean Pierre Olie, Eugene S.
Paykel, Giorgio Racagni, Perry Renshaw, Raben Rosenberg, Bernd
Saletu, Bruce Singh, Dan J. Stein, Rajiv Tandon, Marcio Versiani,
Eduard Vieta, and Joseph Zohar.

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