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Contents lists available at ScienceDirect

Asian Journal of Psychiatry

journal homepage: www.elsevier.com/locate/ajp

Review

Antipsychotic treatment of schizophrenia: An update

Dawn Bruijnzeel, Uma Suryadevara, Rajiv Tandon *
Department of Psychiatry, University of Florida College of Medicine, 1149 Newell Drive, L4-100, Gainesville, FL 32611, USA

A R T I C L E I N F O A B S T R A C T

Article history: The primary objectives in the treatment of schizophrenia are to reduce the frequency and severity of
Received 7 August 2014 psychotic exacerbation, ameliorate a broad range of symptoms, and improve functional capacity and
Accepted 10 August 2014 quality of life. Treatment includes pharmacotherapy and a range of psychosocial interventions.
Available online xxx
Antipsychotics are the cornerstone of pharmacological treatment for schizophrenia. The sixty-five
antipsychotics available in the world are classified into two major groups: first-generation
Keywords: (conventional) agents (FGAs) and second-generation (atypical) agents (SGAs). Whereas clozapine is
Schizophrenia
found to be more efficacious than other agents among otherwise treatment-refractory schizophrenia
Treatment
Antipsychotic
patients, other differences in efficacy between antipsychotic agents are minor. There are, however,
Review pronounced differences in adverse effect profiles among the 65 antipsychotic medications. Although the
Effectiveness 14 SGAs differ ‘‘on average’’ from the 51 FGAs in terms of being associated with a lower risk of EPS and
Guideline greater risk of metabolic side-effects, substantial variation within the two classes with regard to both
risks and other relevant clinical properties undermines the categorical distinction between SGAs and
FGAs. Choice of antipsychotic medication should be based on prior treatment response, individual
preference, medical history and individual patient vulnerabilities. An individualized treatment approach
with ongoing risk–benefit monitoring and collaborative decision-making is outlined. Even as rapid
neuroscience advances promise revolutionary improvements in the future, a thoughtful and disciplined
approach can provide enhanced outcomes for all schizophrenia patients today.
ß 2014 Published by Elsevier B.V.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
2. Antipsychotic agents: pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
3. Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
4. Safety and tolerability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
4.1. Impact on overall outcome. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
5. Optimizing individual outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
5.1. Treatments for Schizophrenia other than Antipsychotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
5.1.1. Pharmacological Treatments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
5.1.2. Psychosocial treatments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
5.2. Unmet needs and future directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
6. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000

1. Introduction

Schizophrenia is a chronic remitting and relapsing psychotic

disorder with significant impairments in social and vocational
functioning, multiple psychiatric and medical comorbidities, and
* Corresponding author. Tel.: +1 352 294 0400; fax: +1 352 379 2627. increased mortality (Tandon et al., 2008a, 2009). There are
E-mail address: tandon@ufl.edu (R. Tandon). multiple illness dimensions that are variably responsive to

http://dx.doi.org/10.1016/j.ajp.2014.08.002
1876-2018/ß 2014 Published by Elsevier B.V.

Please cite this article in press as: Bruijnzeel, D., et al., Antipsychotic treatment of schizophrenia: An update. Asian J. Psychiatry (2014),
http://dx.doi.org/10.1016/j.ajp.2014.08.002
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currently available treatments which include medications, psy-
chological therapies, and social supports (Tandon et al., 2008b,
2013a,b). Since the introduction of chlorpromazine, the first
antipsychotic, into clinical practice 60 years ago, antipsychotic
medications have become the cornerstone in the pharmacotherapy
of schizophrenia. This article provides a broad overview of
available antipsychotics and guidance regarding their utilization
in the treatment of schizophrenia.
2. Antipsychotic agents: pharmacology
There are 65 antipsychotic medications utilized across the
world and 15–40 of these agents are available in any country. They
are classified into groups of first- and second-generation
antipsychotics (FGAs and SGAs, respectively), with the one
pharmacological property shared by all currently available
antipsychotic agents being their ability to block the dopamine
D-2 receptor (Creese et al., 1976; Johnstone et al., 1978; Kapur and
Remington, 2001). Aripiprazole, the only antipsychotic which is
not a D-2 antagonist, is a partial agonist with low intrinsic activity
at the D-2 receptor and therefore behaves as an antagonist in the
mesolimbic dopamine system. Even with reference to dopamine
D-2 antagonism (or partial agonism in the case of aripiprazole),
antipsychotic medications differ in their binding affinity to the
receptor. Antipsychotic medications have a range of other
pharmacological properties with significant differences among
available agents which, in turn, substantially explains differences
in their side-effect profiles. Antipsychotic agents also differ with
reference to a range of pharmacokinetic attributes and while all 65
are available in an oral formulation, 13 are available as short-
acting injectable preparations and 11 as long-acting injectable
preparations.
3. Efficacy
Schizophrenia is characterized by positive symptoms, disorga-
nization, negative symptoms, cognitive deficits, mood and motor
symptoms, with the types and severity of symptoms differing
among patients and over the course of the illness (Heckers et al.,
2010; Tandon and Carpenter, 2012; Tandon and Maj, 2008; Tapp
et al., 2001). Both FGAs and SGAs are effective in reducing positive
and disorganization symptoms, but are only minimally effective
for negative and cognitive symptoms which contribute signifi-
cantly to the disability associated with schizophrenia. Antipsy-
chotics have been consistently found to be superior to placebo in
reducing risk of relapse in schizophrenia (Gilbert et al., 1995;
Leucht et al., 2012), with no consistent differences amongst the
different antipsychotic agents in this regard. While virtually all
FGAs were introduced into clinical practice between 1952 and
1976, clozapine was the only SGA developed during that time.
Since 1990, thirteen additional SGAs were introduced into clinical
practice which were all initially believed to be more efficacious and
tolerable than FGAs. However, results of large-scale studies, such
as the Clinical Antipsychotic Trials of Intervention Effectiveness
(CATIE) study, which compared one FGA (perphenazine) and four
SGAs (olanzapine, quetiapine, risperidone, and ziprasidone),
indicated that the SGAs may be no more effective than the FGAs
and also may not be associated with better cognitive or social
outcomes (Keefe et al., 2007; Lieberman et al., 2005; Swartz et al.,
2007). The European First Episode Schizophrenia Trial, which
compared open-label treatment with haloperidol, amisulpride,
olanzapine, quetiapine, or ziprasidone in first-episode schizophre-
nia, also suggested the absence of significant benefits for SGAs over
FGAs (Davidson et al., 2009; Kahn et al., 2008).
A meta-analysis of haloperidol-controlled trials indicated that
only some SGAs (notably clozapine, olanzapine, amisulpride, and
Please cite this article in press as: Bruijnzeel, D., et al., Antipsychotic treatment of schizophrenia: An update. Asian J. Psychiatry (2014),
http://dx.doi.org/10.1016/j.ajp.2014.08.002
risperidone) were more efficacious than haloperidol (Leucht et al.,
2009a). Although this observation can be partly explained by
differences in the haloperidol dose used in the different trials
(Geddes et al., 2000; Hugenholtz et al., 2006; Tandon and
Nasrallah, 2006), the modest differential efficacy cannot be
dismissed as a mere methodological artifact (Leucht et al.,
2013). In contrast, no major differences in efficacy among various
antipsychotics have been observed in meta-analyses of placebo-
controlled studies, with haloperidol found to have efficacy similar
to the SGAs (Tandon and Jibson, 2005; Leucht et al., 2009b). Though
limited, comparisons of SGAs with low- and mid-potency FGAs and
comparisons among the FGAs suggest no consistent differences in
efficacy, except for clozapine’s superiority in treatment-refractory
schizophrenia (Kane et al., 1988). Finally, direct comparisons
between various SGAs reveal inconsistent differences in efficacy,
except for an advantage for clozapine in treatment-refractory
schizophrenia (McEvoy et al., 2006; Leucht et al., 2009c; Lewis
et al., 2006). Comparative studies in the early stages of
schizophrenia have also found no significant differences in efficacy
among antipsychotics (Derks et al., 2010; Salimi et al., 2009).
All available antipsychotics have robust efficacy for positive
symptoms and disorganization, with no consistent differences
found in efficacy for these domains. Response over the first 2–4
weeks of antipsychotic therapy is highly predictive of long-term
response (Kinon et al., 2010). The maximum effect, however, may
not be achieved for several months, and trajectories of response
vary considerably across patients. Responsiveness to antipsy-
chotics also varies as a function of stage of illness, with first-
episode patients responding faster and at a higher rate than those
at later stages of the illness (Emsley et al., 2006). Antipsychotics
are less consistently effective in reducing negative symptoms
and much of their effect on negative symptoms may be
associated with reduction in positive symptoms. While anti-
psychotics ameliorate negative symptoms linked with positive
symptoms, they can worsen negative symptoms associated with
EPS (Tandon et al., 2000). Antipsychotic agents have no
demonstrable efficacy against primary enduring (‘‘deficit’’)
negative symptoms. Similarly, antipsychotics can ameliorate
depressive symptoms in conjunction with producing improve-
ment in positive symptoms, but can also cause ‘‘neuroleptic
dysphoria’’ associated with EPS (Voruganti and Awad, 2004).
Although antipsychotics can improve attention in patients with
schizophrenia, findings concerning their effects on other cogni-
tive impairments are inconsistent and may include worsening of
cognition. No consistent differences have been found among
antipsychotics in effects on neurocognitive dysfunction, with net
impact determined by the agent’s beneficial effects on attention
versus deleterious effects due to EPS and anticholinergic activity
of the antipsychotic and of anticholinergic agents used to treat
EPS (Hill et al., 2010; Tandon et al., 2010). Consequently, the net
effect of an antipsychotic on negative symptoms is generally
determined by the extent to which it reduces negative symptoms
associated with positive symptoms and triggers negative
symptoms related to EPS; the same applies for antipsychotic
effects on the domains of depression and cognition. Antipsy-
chotic medications substantially decrease likelihood of relapse in
schizophrenia, without any consistent differences among agents
(Leucht et al., 2012). Since medication nonadherence is common
in schizophrenia, long-acting injectable antipsychotics may have
an advantage over oral treatment in reducing relapse rates
(Nasrallah, 2007).
4. Safety and tolerability
Antipsychotic medications cause a range of neurological,
metabolic, cardiovascular, gastrointestinal, hematological,
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genitourinary, musculoskeletal, endocrine, and other side-
effects. In contrast to their broadly similar efficacy, antipsychotics
differ markedly in their adverse-effect profiles. Compared with the
FGAs, the SGAs have generally been believed to have a lower risk of
EPS but a higher risk of metabolic adverse effects. However, due to
differences in pharmacological profiles within the FGA and SGA
classes, there is substantial variation within both classes in their
propensity to cause EPS and metabolic adverse effects (Tandon and
Halbreich, 2003; Weiden, 2007). Thus, no categorical distinction can
be made between so-called FGAs and SGAs even with regard to these
risks (Smith et al., 2008; Tandon, 2011). Antipsychotic medications
also differ in their propensity to cause other side effects, such as
sedation, hypotension, cardiac arrhythmias, prolactin elevation and
related sexual dysfunction, and anticholinergic effects, with substan-
tial variation within both the FGAs and the SGAs for each of these
effects, without any definitive categorical separation between the
two classes (Bonham and Abbott, 2008; Fischer-Barnicol et al., 2008).
The side-effects with different agents also depend on the patients
with schizophrenia, who vary in their vulnerability to develop
various adverse effects. The likelihood that a patient will develop
a particular side effect thus depends on the agent selected, how
that agent is used (e.g., dose, titration method, the other agents
used in combination with the antipsychotics), and the patient’s
vulnerability.
4.1. Impact on overall outcome
Untreated schizophrenia is associated with increased mortality,
poor vocational and social functioning, and impairments in
subjective and objective measures of quality of life. Although
antipsychotic treatment ameliorates a range of symptom domains
and reduces likelihood of relapse in patients with schizophrenia,
the extent to which such treatment improves lifespan and
psychosocial function in patients with schizophrenia is less clear
(Wunderink et al., 2013).
5. Optimizing individual outcomes
Given the significant variability in drug pharmacokinetics and
treatment response in individual patients, it should be emphasized
that broadly equivalent efficacy across patient groups does not
translate into equal efficacy in individual patients. It is not
currently possible to predict which antipsychotic may be optimal
for a given patient. There is no single best agent or best dose for all
patients, although dose ranges for optimal effectiveness do appear
to exist. Decisions about antipsychotic therapy therefore often
entail a trial and error process involving careful monitoring of
response and adverse effects, an ongoing risk–benefit assessment,
and judicious switching if necessary (Table 1). To achieve optimal
therapy for schizophrenia, clinicians must balance efficacy, risks
and benefits of treatments in a way that is customized for the
needs and vulnerabilities of the individual patient. The meticu-
lous application of this approach can reduce the significant gap
between what we know about best practices and the therapy
that is actually provided for patients with schizophrenia (Bollini
et al., 2008; Buchanan et al., 2010; Marder et al., 2004; Nasrallah
et al., 2005; Remington et al., 2010; Tandon et al., 2006a,b;
Torres-Gonzalez et al., 2014).
5.1. Treatments for Schizophrenia other than Antipsychotics
5.1.1. Pharmacological Treatments
In view of the limitations of antipsychotic medications in the
pharmacotherapy of various symptom domains of schizophrenia,
combinations of antipsychotics and adjunctive treatment with
other psychotherapeutic agents are frequently utilized in its
Please cite this article in press as: Bruijnzeel, D., et al., Antipsychotic treatment of schizophrenia: An update. Asian J. Psychiatry (2014),
http://dx.doi.org/10.1016/j.ajp.2014.08.002
3
Table 1
Steps to achieve optimum outcomes with currently available antipsychotics.
1.Considerations in selecting the best antipsychotic for a particular patient
 Equivalent efficacy across agents
 Individual variability in response
 No good predictor of individual response to different agents
 Different agents have different side effects
 Different patients have different vulnerabilities and preferences
2.Proper antipsychotic trial sequence
 Begin with systematic 6–10 week trial of one antipsychotic with optimal
dosing
 If inadequate response, follow with systematic trial of monotherapy
with one or more other antipsychotics at adequate dose and duration
 If inadequate response, follow with a trial of clozapine or a long-acting
antipsychotic
 Follow with a trial of clozapine, if not tried before
 Only then consider other strategies (e.g., antipsychotic polypharmacy)
3.Good practice guidelines for ongoing antipsychotic treatment
 Measurement-based individualized care
 Repeated assessment of efficacy using reliably defined treatment
targets (facilitated by use of standard rating scales)
 Careful assessment of adverse effects
 Care consistent with health monitoring protocols
 Standard protocols customized to individual vulnerabilities/needs and
specific agent
 Ongoing collaboration with patient in decision-making
treatment. Antidepressant agents are useful in treating depressive
and anxiety symptoms that persist after reduction of positive
symptoms with antipsychotic treatment (Tapp et al., 2001;
Tandon et al., 2010). Evidence for the effectiveness of other
pharmacological approaches in the treatment of schizophrenia is
currently weak.
5.1.2. Psychosocial treatments
Although this overview focuses on pharmacological treatment
of schizophrenia, it should be noted that a range of psychological
and social treatments should constitute an essential part of the
treatment of schizophrenia. Research on psychosocial approaches
to treatment of schizophrenia has yielded incremental evidence of
efficacy of cognitive-behavior therapy (CBT), social skills training
(SST), family psychoeducation, assertive community treatment
(ACT), and supported employment. These interventions are
therefore recommended for clinical application (Kreyenbuhl
et al., 2010).
5.2. Unmet needs and future directions
Although antipsychotic treatment of schizophrenia has pro-
gressed only modestly since the introduction of chlorpromazine
sixty years ago (despite the development of 64 additional
antipsychotic agents), three advances in our understanding of
the neurobiology and clinical expression of schizophrenia generate
optimism about the likelihood of important breakthroughs in the
near future. First, the delineation of distinct psychopathological
dimensions has led to a broadening of therapeutic targets beyond
psychotic symptoms to include key clinical dimensions such as
cognitive deficits and negative symptoms (Barch et al., 2013;
Heckers et al., 2013; Tandon, 2012; Table 2). Second, the discovery
of pathophysiological mechanisms of disease causation will help
deconstruct schizophrenia, offering novel targets for drug discov-
ery, and providing better predictive markers of individual response
and adverse effects (Keshavan et al., 2008; Schizophrenia Working
Group, 2014). Third, the introduction of the new diagnostic
category of ‘‘attenuated psychosis syndrome’’ in DSM-5 as a
condition for further study (Tsuang et al., 2013) facilitates our
ability toward early intervention of schizophrenia in the prodrome
of the illness.
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Table 2
Strategies to address unmet needs in treatment of schizophrenia.
Need
1. Schizophrenia has multiple psychopathological
dimensions with varying pathophysiological
underpinnings
2. Many pathologies appear relevant in schizophrenia
other than ‘‘dopaminergic excess’’
3. Schizophrenia has distinct stages of illness with
distinct pathological underpinnings and clinical
expression.
4. There are significant variations in how different
individuals respond to the same treatment in
terms of both efficacy and side-effects
6. Summary
Schizophrenia is characterized by positive, negative, cognitive,
disorganization, motor, and mood symptoms. Antipsychotics are
the mainstay of the pharmacological treatment of schizophrenia.
Findings related to the efficacy for positive symptoms and
disorganization suggest no consistent differences among available
antipsychotics, with the exception of clozapine’s superior efficacy
for treatment-resistant schizophrenia. Efficacy for negative,
depressive, and cognitive symptoms appears to be determined
by (1) the extent to which reduction in positive symptoms brings
about improvement in these other domains and (2) the extent to
which extrapyramidal side effects (EPS) and anticholinergic effects
(of the antipsychotic and of agents used to treat EPS) exacerbate
them. Thus, the ability of antipsychotics to produce a potent
antipsychotic effect without EPS and need for concomitant
anticholinergic therapy yields multiple therapeutic benefits. In
contrast to their broadly similar efficacy, antipsychotics differ
markedly in their propensity to cause various adverse effects.
Choice of antipsychotic medication should be based on individual
preference, prior treatment response and side-effects experienced,
medical history and risk factors, and adherence history, with side-
effect profile being the major determinant of antipsychotic choice.
Even as ongoing research bears the promise of revolutionary
advances in the quality of lives of persons with schizophrenia in
the future, optimizing current treatment can yield meaningful
improvements today.
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