International Journal of Neuropsychopharmacology (2014), 17, 10831093.

f CINP 2012 R E V IE W
doi:10.1017/S1461145712000399

Critical review of antipsychotic polypharmacy

in the treatment of schizophrenia

W. Wolfgang Fleischhacker1* and Hiroyuki Uchida2,3*

1
Department of Psychiatry and Psychotherapy, Medical University Innsbruck, Innsbruck, Austria
2
Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, Japan
3
Centre for Addiction and Mental Health, Geriatric Mental Health Program, Toronto, Canada

Abstract
Antipsychotic polypharmacy remains prevalent ; it has probably increased for the treatment of schizo-
phrenia in real-world clinical settings. The current evidence suggests some clinical benets of anti-
psychotic polypharmacy, such as better symptom control with clozapine plus another antipsychotic, and a
reversal of metabolic side-eects with a concomitant use of aripiprazole. On the other hand, the in-
terpretation of ndings in the literature should be made conservatively in light of the paucity of good
studies and potentially serious side-eects. Also, although the available data are still limited, two smaller-
scale clinical trials provide preliminary evidence that converting antipsychotic polypharmacy to mono-
therapy could be a valid and reasonable treatment option. Several studies have explored strategies to
change physicians antipsychotic polypharmacy prescribing behaviours. These have revealed that, while
the impact of purely educational interventions may be limited, more aggressive procedures such as
directly notifying physicians by letters or phone calls can be more eective in reducing antipsychotic
polypharmacy. In conclusion, antipsychotic polypharmacy can work for some clinically dicult con-
ditions ; however, it should be the exception rather than the rule and may be avoidable in many patients.
More importantly, the paucity of the data clearly emphasizes the need for further investigations on not
only advantages and disadvantages of antipsychotic polypharmacy, but also regarding eective inter-
ventions in already prescribed polypharmacy regimens.
Received 30 December 2011 ; Reviewed 30 January 2012 ; Revised 17 February 2012 ; Accepted 22 March 2012 ;
First published online 2 May 2012
Key words : Add-on treatment, adjunctive treatment, antipsychotic, combination, polypharmacy,
schizophrenia.

Introduction recommends antipsychotic monotherapy for the

rst three stages [stage 1, a second-generation anti-
Basically all available schizophrenia treatment guide-
psychotic (SGA) ; stage 2, a SGA not tried in stage 1
lines recommend antipsychotic monotherapy and
or 2 rst-generation antipsychotic (FGA) ; stage 3,
suggest the use of two or more antipsychotics only as
clozapine] and only proposes the use of antipsychotic
a last resort (Addington et al. 2005 ; Argo et al. 2008 ;
polypharmacy at stage 4 (clozapine plus SGA, FGA
Buchanan et al. 2010 ; Falkai et al. 2005 ; National
or electroconvulsive therapy) and thereafter (Argo
Collaborating Centre for Mental Health, 2010 ; Royal
et al. 2008). Moreover, the World Federation of
Australian and New Zealand College of Psychiatrists,
Societies of Biological Psychiatry Guidelines empha-
2005). For example, the NICE guideline states not to
size antipsychotic monotherapy except for treatment-
initiate antipsychotic combinations, except for short
resistant cases for which the combination of clozapine
periods when changing medications (National
with risperidone or sulpiride may reect the best
Collaborating Centre for Mental Health, 2010).
treatment options (Falkai et al. 2005). Such rec-
Similarly, the Texas Medication Algorithm Project
ommendations in favour of antipsychotic mono-
therapy are unequivocal irrespective of geographical
Address for correspondence : Dr W. Wolfgang Fleischhacker, regions ; in fact, the Japanese guidelines also advocate
Anichstrae 35, 6020 Innsbruck, Austria.
the use of a single antipsychotic drug for the treatment
Tel. : +43 512 504 23669 Fax : +43 512 504 25267
Email : wolfgang.eischhacker@i-med.ac.at of schizophrenia (Japanese Society of Psychiatry and
* Both authors contributed equally to this work. Neurology, 2008).
1084 W. W. Fleischhacker and H. Uchida
Despite all of these recommendations, antipsychotic
polypharmacy is common in real-world clinical set-
tings with prevalence rates varying widely (470 %),
depending on the setting and the patient population
(Ito et al. 2005 ; Koen et al. 2008 ; Paton et al. 2003 ;
Procyshyn et al. 2010 ; Santone et al. 2011 ; Stahl &
Grady, 2006 ; Tsutsumi et al. 2011 ; Xiang et al. 2007).
Furthermore, the use of antipsychotic polypharmacy
seems to be increasing in some countries. Gilmer et al.
(2007) analysed the data from Medicaid beneciaries
with schizophrenia (n=15 962) in San Diego County
and found the proportion of patients receiving second-
generation antipsychotic polypharmacy to have in-
creased from 3.3 % in 1999 to 13.7 % in 2004. This
trend was also observed in a nationwide cohort study
of all newly diagnosed patients with schizophrenia
in Denmark (n=13 600) between 1996 and 2005 ; the
percentage of patients treated with antipsychotic
polypharmacy except for cross-tapering situations
increased from 16.7 to 37.1 % over a 10-yr period
(Nielsen et al. 2010). On the other hand, a longitudinal
chart review of a 12 yr observation period found a
considerable decrease of combination treatments in
Austria (Edlinger et al. 2005).
In the present review, advantages and dis-
advantages of antipsychotic polypharmacy are sum-
marized. In addition, the reasons why physicians
utilize antipsychotic polypharmacy are discussed.
Finally, we describe potentially successful inter-
ventions for reducing antipsychotic polypharmacy.
As there is no clear consensus on the denition of
polypharmacy , combination treatment or adjunc- several clinical trials have demonstrated ecacy of
tive treatment , we have classied polypharmacy as
follows : antipsychotic polypharmacy (i.e. a concur-
rent use of more than one antipsychotic drug) and
psychotropic polypharmacy (i.e. the combination of
an agent from a dierent class of psychotropic drugs
with an antipsychotic) for the purpose of this review.
In this manuscript, we focus on antipsychotic poly-
pharmacy.
Potential advantages of antipsychotic polypharmacy
Polypharmacy with clozapine
Even though antipsychotic polypharmacy is fre-
quently employed for the treatment of schizophrenia,
controlled data are limited. Clozapine is the anti-
psychotic for which by far the most combination
studies exist. Following a number of case reports and
case series, the rst placebo controlled, randomized
clinical trial (RCT) was performed by Shiloh et al.
(1997), who reported a favourable eect of a clozapine/
sulpiride combination in patients who had not
responded to clozapine monotherapy. The most fre-
quent combination studied is clozapine and risper-
idone. A number of small, open trials published in the
last century were followed by double blind RCTs,
which were inconclusive. While Freudenreich et al.
(2007) and Josiassen et al. (2005) found advantages
when adding risperidone to clozapine over a placebo
control group in double blind RCTs (n=40 and n=24,
respectively), these positive results could not be con-
rmed by another RCT (n=30) by Anil Yagcioglu et al.
(2005) and Akdede et al. (2006). In the largest sample
evaluated so far, Honer et al. (2006) compared the e-
cacy of clozapine combined with risperidone to cloza-
pine plus placebo in 68 patients with schizophrenia
who had previously failed to respond to clozapine
monotherapy in an 8 wk double blind RCT. No sig-
nicant dierence between groups was found for
symptomatic benet : six of 34 (17.6 %) patients receiv-
ing additional risperidone and nine of 34 (26.5 %)
patients receiving add-on placebo responded to treat-
ment. The mean dierence in the change of the Positive
and Negative Syndrome Scale (PANSS) total score be-
tween groups amounted to only 0.1 [95 % condence
interval (CI) x7.3 to 7.0].
Zink et al. (2009) added either ziprasidone (n=12)
or risperidone (n=12) to clozapine in an RCT of
treatment-resistant schizophrenia patients and found
improvements on both combinations. These ndings
are dicult to interpret given the lack of a mono-
therapy control group.
A Cochrane review concluded that, although
clozapine plus another antipsychotic drug, it was not
possible to show whether any particular combination
strategy was superior to the others (Cipriani et al.
2009). However, the discrepancy between results may
be attributable to dierent study designs, especially
regarding study duration. Paton et al. (2007) meta-
analysed the data from four RCTs (166 patients) ; the
two studies with a duration of o10 wk favoured
antipsychotic polypharmacy with clozapine in terms
of response dened as a o20 % reduction in the
PANSS or Brief Psychiatric Rating Scale [response
rates : 42 % vs. 9 % ; relative risk (RR) 4.41, 95 % CI
1.3814.07, p=0.01], whereas the two studies of
<10 wk duration did not (26 % vs. 27 % ; RR 0.59, 95 %
CI 0.271.30). More recently, Correll et al. (2009) con-
ducted a meta-analysis of 19 studies (1229 patients),
including 28 monotherapy and 19 co-treatment arms,
and compared therapeutic and adverse eects be-
tween antipsychotic polypharmacy and monotherapy
in schizophrenia. The antipsychotic used the most was
clozapine (11 studies, 542 patients). Antipsychotic
 Antipsychotic polypharmacy 1085

Table 1. Eects of aripiprazole on side-eects induced by ongoing antipsychotic drugs

Baseline Prolactin Metabolic

Author (yr) n Duration AP Add-on AP level parameters EPS

Shim et al. (2007) 56 8 wk HPD APZ Decreased n.a. n.s.

PLB
Chang et al. (2008) 62 8 wk CLZ APZ Decreased TG n.s.
PLB
Henderson et al. (2009) 16 10 wk OLZ APZ n.a. BW n.s.
PLB TG
VLDL
Kane et al. (2009) 323 16 wk RIS APZ RIS group : n.s. n.s.
QTP PLB decreased
Fleischhacker et al. (2010) 207 16 wk CLZ APZ n.a. BW n.s.
PLB TC
LDL
Chen et al. (2010) 24 8 wk RIS APZ RIS group : n.s. n.s.
ASP decreased
SLP
Yasui-Furukori et al. (2010) 16 816 wk RIS APZ Decreased n.a. n.a.

AP, Antipsychotic ; EPS, extrapyramidal side-eects ; HPD, haloperidol ; APZ, aripiprazole ; PLB, placebo ; CLZ, clozapine ;
OLZ, olanzapine ; RIS, risperidone ; QTP, quetiapine ; ASP, amisulpiride ; SLP, sulpiride ; TG, triglyceride ; BW, body weight ;
VLDL, very low density lipoprotein ; TC, total cholesterol ; LDL, low density lipoprotein ; n.a., not available ; n.s., not signicant.

polypharmacy was found to be superior to mono-
therapy with regard to all-cause discontinuation (RR
0.65, 95 % CI 0.540.78, p<0.00001). However, in light
of the small number of trials included and the con-
siderable inhomogeneity concerning study method-
ology, as well as a lack of sucient adverse event data
and dosage information, this nding needs to be in-
terpreted with much caution. Especially, the unavail-
ability of adverse event data is of concern considering
the necessity of long-term antipsychotic treatment
for schizophrenia (Uchida et al. 2011). Furthermore, a
majority of the data come from one specic region
(China), which limits the generalizability of the data.
Moreover, this is a mix of trials in which patients were
started on combination treatments and studies in
which the second drug was added later. In view of
these limitations, the authors modestly concluded
that antipsychotic polypharmacy may be superior to
monotherapy in certain clinical situations although
the database was subject to possible publication
bias and too heterogeneous to justify clinical rec-
ommendations. Finally, in a large, prospective, long-
term observational study of schizophrenia treatment
(the Schizophrenia Outpatient Health Outcomes
Study sponsored by Eli Lilly), treatment with more
than one antipsychotic drug was associated with a
lower likelihood of recovery at month 36 compared to
olanzapine [odds ratio (OR) 0.564, 95 % CI 0.3630.876,
p=0.0108 ; Novick et al. 2009), although details on the
combination of antipsychotic drugs were not reported
(Haro et al. 2003). Moreover, antipsychotic poly-
pharmacy was not directly compared to monotherapy
with any other antipsychotic.
Thus, although the ndings are not always consist-
ent, clozapine augmented with another antipsychotic
drug may be benecial for symptom control.
A number of pharmacological considerations, al-
though speculative, have been put forward to explain
some of the positive clinical eects of combining
clozapine with other antipsychotics. For example,
clozapines low dopamine D2 blockade could be aug-
mented by adding an antipsychotic, especially in the
case of strong and specic D2 blockers such as the
benzamides. Superior ecacy may also be explained
by the fact that combining two antipsychotics leads to
a higher overall dose of chlorpromazine equivalents
(Procyshyn et al. 2010 ; Suzuki et al. 2004). Finally, en-
hanced ecacy could be the result of pharmacokinetic
interactions leading to higher plasma levels of the re-
spective antipsychotic drugs.
Non-clozapine polypharmacy
Due to its unique mechanism of action, aripiprazole
may reverse metabolic side-eects caused by ongoing
antipsychotic treatment. As shown in Table 1,
1086 W. W. Fleischhacker and H. Uchida
prolactin elevation and metabolic side-eects have
been shown to be fully or partially ameliorated (Chang
et al. 2008 ; Chen et al. 2010 ; Fleischhacker et al.
2010 ; Henderson et al. 2009 ; Kane et al. 2009 ; Shim
et al. 2007 ; Yasui-Furukori et al. 2010). For example, a
16-wk double-blind, randomized placebo-controlled
trial with an open-label extension phase of 12 wk
examined the eects of adjunctive use of aripiprazole
(515 mg/d) in out-patients with schizophrenia
who were receiving clozapine and had experienced a
weight gain of o2.5 kg (Fleischhacker et al. 2010).
A signicant dierence in weight loss was reported
for add-on aripiprazole vs. placebo. Concomitant use
of aripiprazole also resulted in signicantly greater
reductions in total and low-density lipoprotein (LDL)
cholesterol. These results demonstrated that combin-
ing aripiprazole and clozapine resulted in signicant
weight, body mass index (BMI) and fasting cholesterol
benets for patients treated with clozapine. However,
there were no dierences regarding treatment out-
comes between groups as measured by the PANSS.
Kane et al. (2009) found no signicant reduction in
body weight, total cholesterol or LDL in another
double-blind RCT of adjunctive aripiprazole in pa-
tients with schizophrenia or schizoaective disorder
treated with quetiapine or risperidone (aripiprazole,
n=126 ; placebo, n=118), although the combination
resulted in a decrease of serum prolactin levels in the
risperidone group. A recent RCT that examined eects
of switching from olanzapine, quetiapine or risper-
idone to aripiprazole demonstrated that the anti-
psychotic switch was associated with reductions in
weight and serum triglyceride levels, compared to
staying on the same antipsychotics (Stroup et al. 2011).
All evidence taken together conrms the favourable
metabolic prole of aripiprazole but provides no
rationale for a clozapine/aripiprazole combination
from an ecacy perspective.
Low potency antipsychotic drugs such as quetia-
pine seem to be utilized in addition to other anti-
psychotics in order to obtain sedative eects to
counteract agitation, excitement and insomnia.
Across-sectional study revealed that 64 % of quetia-
pine-treated in-patients with mixed diagnoses re-
ceived the drug as a pro re nata (prn) dose in an acute-
care psychiatric hospital in the US (Philip et al. 2008).
The most common reason for ordering prn quetiapine
was agitation (75 %), followed by insomnia (9 %) and
agitation/anxiety (8 %). Another prescription survey
in the US of Medicaid recipients with a diagnosis
of schizophrenia demonstrated that quetiapine was
more likely associated with antipsychotic poly-
pharmacy (Ganguly et al. 2004). Of a total of 31 435
patients with schizophrenia, the prevalence of long-
term (i.e. lasting >2 months) antipsychotic poly-
pharmacy was 23 % ; low-potency antipsychotic
drugs such as quetiapine and chlorpromazine were
strongly associated with long-term antipsychotic
polypharmacy.
In conclusion, the available research suggests
that there appear to be some clinical benets of
antipsychotic polypharmacy in clinically dicult
conditions. However, these ndings need to be inter-
preted with much caution in light of the paucity of
controlled data and the potential of side-eects, as
described below.
Potential disadvantages of antipsychotic
polypharmacy
First, antipsychotic polypharmacy has been reported
to be associated with excessively high total anti-
psychotic dosages (Procyshyn et al. 2010 ; Suzuki et al.
2004), which in turn are expected to increase the risk of
dose-related adverse events, including extrapyramidal
motor side-eects as well as cognitive impairment
(Jeste et al. 1995 ; Lemmens et al. 1999 ; Sakurai et al.
2012). A prescription survey that included 435 out-
patients with mixed diagnoses in Canada between
2005 and 2006 found that the prescribed daily dose :
dened daily dose (the international unit of drug
utilization that has been approved by WHO) ratio for
patients who were receiving antipsychotic poly-
pharmacy was signicantly greater than that for those
receiving antipsychotic monotherapy (1.940.12 vs.
0.940.04, p<0.005 ; Procyshyn et al. 2010). Similar
ndings were also observed in a retrospective case-
control study of multiple vs. single antipsychotic
treatment in 140 psychiatric in-patients with mixed
diagnoses (Centorrino et al. 2004). They revealed
that, while the median initial doses were nearly
identical at admission for both the polypharmacy and
monotherapy groups (200 mg/d vs. 201 mg/d chlor-
promazine equivalents), the median total nal anti-
psychotic dose at discharge was 78 % higher for those
receiving antipsychotic polypharmacy vs. mono-
therapy (475 mg/d vs. 267 mg/d chlorpromazine
equivalents). These ndings underscore that anti-
psychotic polypharmacy results in increases of total
doses of antipsychotics. Therefore, in theory, the use of
multiple antipsychotic drugs is expected to lead to a
dose-dependent increase of antipsychotic side-eects
(Jeste et al. 1995 ; Lemmens et al. 1999 ; Sakurai et al.
2012).
Second, the accumulated evidence on substrates,
inducers and inhibitors in the cytochrome P450 system

clearly indicates that the use of two or more
drugs can lead to relevant drug interactions. For ex-
ample, CYP3A4 and CYP2D6 are involved in the
metabolism of frequently used antipsychotic drugs
(Urichuk et al. 2008). Drug interactions can result in
unexpected increases in peripheral drug concen-
trations, which could result in a greater incidence
and/or severity of side-eects. Similarly, such drug
interactions can also result in decreases of drug con-
centrations, with insucient treatment as a possible
consequence.
Third, in light of medication cost, antipsychotic
polypharmacy, especially with SGAs, is of serious
concern in terms of cost-eectiveness. Stahl & Grady
(2006) examined the cost of prescribed antipsychotic
drugs for 4795 out-patients who received anti-
psychotic polypharmacy, using the data from
California Medicaid fee-for-service pharmacy claims.
Polypharmacy cost up to three times more per patient
than monotherapy ; the mean amount paid per patient
for a 75-d period for patients who had received
monotherapy was $2382 and that for patients who had
received antipsychotic polypharmacy was as high as
$7536. High cost associated with antipsychotic poly-
pharmacy has also been conrmed by reports from
other clinical settings (Baandrup et al. 2011 ; Zhu et al.
2008) ; this seems a consistent trend irrespective of
geographic region.
Fourth, antipsychotic polypharmacy may be as-
sociated with an increased risk of death, although
ndings are inconsistent. For example, a 10-yr pro-
spective study that included a cohort of 88 in-patients
with schizophrenia in Ireland demonstrated that 39
of the 88 patients died ; the maximum number of
antipsychotics given concurrently for each individual
predicted reduced survival (RR 2.46, 95 % CI
1.105.47, p=0.03 ; Waddington et al. 1998). A
population-based study of a cohort of 7217 Finns
demonstrated similar ndings (Joukamaa et al. 2006).
During a 17-yr follow-up, 39 of 99 people with
schizophrenia died ; after adjustment for age, gender,
somatic diseases and other potential risk factors for
premature death, the increased RR of natural death
was 2.50 (95 % CI 1.464.30) per one antipsychotic
agent added to the regimen. Antipsychotic poly-
pharmacy is often associated with greater amounts of
total antipsychotic dose (Procyshyn et al. 2010 ; Suzuki
et al. 2004). An association between a greater degree
of exposure to antipsychotic drugs and a higher risk
for sudden cardiac death has been reported for
both typical and atypical antipsychotic drugs (Ray
et al. 2009). Combined, these ndings suggest that
excessive antipsychotic dosing due to polypharmacy
Antipsychotic polypharmacy 1087
could result in the increased risk of cardiac sudden
death, which may explain the observed association
between antipsychotic polypharmacy and increased
death rates. On the other hand, a large population-
based, nested casecontrol study has not conrmed
the increased risk of death in patients treated with
antipsychotic polypharmacy (Baandrup et al. 2010b).
From a population of 27 633 patients with schizo-
phrenia or non-aective psychoses in Denmark, 193
who died of natural causes within a 2-yr period and
1937 age- and gender-matched controls were ident-
ied. Risk of natural death did not increase with
the number of concurrently used antipsychotic
drugs in comparison to antipsychotic monotherapy
(no antipsychotics : OR 1.48, 95 % CI 0.892.46 ; 2
antipsychotics : OR 0.91, 95 % CI 0.611.36 ; o3 anti-
psychotics : OR 1.16, 95 % CI 0.682.00). Hence,
although the possibility for increased mortality due
to antipsychotic polypharmacy is still inconclusive,
physicians need to be aware of this potentially
serious risk.
Finally, complicated regimens of antipsychotic
polypharmacy may discourage patients from taking
pills as prescribed. Although a relationship between
adherence and polypharmacy has not been in-
vestigated in schizophrenia, previous reports in other
chronic illnesses such as diabetes and hypertension
have demonstrated that the use of multiple medi-
cations often lowers patients adherence to medi-
cations, resulting in poorer outcomes (Benner et al.
2009 ; van Bruggen et al. 2009). Benner et al. (2009)
evaluated the association between prescription bur-
den and medication adherence in 5759 patients who
were started on antihypertensive and lipid-lowering
therapy in the US. Among patients treated with none,
one and two medications in the year prior to starting
therapy, 41, 35 and 30 % respectively of patients
were adherent. Furthermore, among patients with
o10 medications, only 20 % were adherent. This re-
lationship also seems true for patients with diabetes ;
an inverse relationship was observed between the
number of drugs and patients medication adherence
in 1283 patients in the Netherlands (van Bruggen
et al. 2009). If this relationship also holds true for
schizophrenia, the negative impact of using multiple
antipsychotics on adherence behaviour would be ob-
vious.
In summary, antipsychotic polypharmacy can cause
a variety of problems in terms of safety, acceptability,
cost and outcomes. Although some ndings are
inconsistent, physicians should take note of these
potential adverse eects when considering poly-
pharmacy.
1088 W. W. Fleischhacker and H. Uchida
Why do physicians prescribe polypharmacy?
Surveys have identied a variety of reasons for the
use of antipsychotic polypharmacy (Correll et al. 2011 ;
Ito et al. 2005 ; Sernyak & Rosenheck, 2004). Sernyak &
Rosenheck (2004) interviewed the treating psy-
chiatrists of 66 patients with schizophrenia who re-
ceived multiple antipsychotic drugs at two Veterans
Administration medical centres in the US. The most
common reason for the use of antipsychotic poly-
pharmacy was reducing positive symptoms (61 %),
followed by reducing negative symptoms (20 %), de-
creasing total amount of medication (9 %) and reduc-
ing extrapyramidal symptoms (5 %). In addition,
psychiatric symptoms were thought to have been
refractory to adequate duration and dosage of
antipsychotic monotherapy in 65 % of patients.
Interestingly, although antipsychotic polypharmacy
was intended to be transitional during a process of
antipsychotic switch in 39 % of patients, the switch
had been successfully completed in only 46 % of these
patients after 612 months. On the other hand, not
only psychiatrists but also nurses may be involved
in the decision-making process. Ito et al. (2005) exam-
ined the factors associated with antipsychotic poly-
pharmacy and excessive dosing in 96 patients with
schizophrenia in 19 acute psychiatric units in Japan
and elucidated nurses requests and psychiatrists
characteristics and perceptions of prescribing practice
and algorithms. Logistic regression analysis revealed
that the use of multiple antipsychotic drugs and ex-
cessive dosing were inuenced by the psychiatrists
scepticism towards the use of algorithms ( I doubt the
validity and evidence of an algorithm ) and nurses
requests for more drugs (I would like to ask a psy-
chiatrist to increase the current dosage or add another
drug ). A survey of prescriber attitudes towards anti-
psychotic polypharmacy by Correll et al. (2011) pro-
vided additional information on the rationale and
concerns around this practice. Forty-four psychiatrists
who participated in this survey reported using anti-
psychotic polypharmacy in 17.0 % of antipsychotic-
treated patients. They rated when they felt prescribing
multiple antipsychotic drugs was justied (0=0 % to
10=100 %), and how concerned they were (0=none to
10=extreme) on a 10-point scale. The reason given the
largest degree of justication was cross-titration
(9.21.4, meanS.D.), followed by a failed clozapine
trial (8.22.2), randomized, controlled clinical trial
evidence (8.02.0), and clozapine intolerance
(7.72.6). Prescribers felt moderately (5.01.9) con-
cerned about antipsychotic polypharmacy, mostly due
to chronic side-eects (7.62.0), lack of evidence
Table 2. Characteristics associated with antipsychotic
polypharmacy
Demographics and employment status
Male
Young
Single
Unemployment
Symptomatology
Severe psychopathology
Residual psychotic symptoms
Poor cognitive function
Poor insight into illness
Presence of psychiatric co-morbidity
Treatment settings and conditions
Psychiatric hospital
In-patients
Involuntary admission
More frequent admissions
Use of depot
Biancosino et al. (2005), Chakos et al. (2006), Grech & Taylor
(2012), Morrato et al. (2007), Santone et al. (2011), Sim et al.
(2004), Xiang et al. (2007).
(7.12.2), non-adherence risk (6.72.3), mortality risk
(6.73.2), increased cost (4.92.5) and higher total
antipsychotic dose (4.22.9).
Thus, these surveys indicate that psychiatrists claim
to utilize antipsychotic polypharmacy as a last resort,
mainly to try to manage dicult to treat patients with
schizophrenia. Indeed, the use of antipsychotic poly-
pharmacy has been reported to be associated with
dicult clinical situations, including severe psycho-
pathology, residual psychotic symptoms, poor insight
into illness and involuntary admission (Table 2 ;
Biancosino et al. 2005 ; Chakos et al. 2006 ; Grech &
Taylor, 2012 ; Morrato et al. 2007 ; Santone et al. 2011 ;
Sim et al. 2004 ; Xiang et al. 2007). However, is anti-
psychotic polypharmacy really used as a last resort?
The answer may be no in many cases. According to a
recent systematic review of longitudinal antipsychotic
prescriptions in out-patients with schizophrenia in
Tokyo, 34.1 % of 208 patients who started on mono-
therapy gave up monotherapy with the initial anti-
psychotic in favour of an antipsychotic switch (27.4 %)
and/or polypharmacy (17.8 %) within 2 yr (Tsutsumi
et al. 2011). The main reason for switching was in-
eectiveness ; interestingly, this happened despite the
fact that the monotherapy dose was below the re-
commended dosage range in 47.4 % of the patients
who were switched. Moreover, in a subgroup of 100
patients who were antipsychotic-free, polypharmacy
was initiated after a median of one antipsychotic had

been tried for a median of 84 d. These ndings raise
the concern that psychiatrists may start polypharmacy
without exploring the entire dose range of more than
one dierent antipsychotic.
Switching from polypharmacy to
monotherapy clinical trials
While the evidence on how antipsychotic poly-
pharmacy is utilized in clinical practice has accumu-
lated, data on how to deal with patients with
schizophrenia who are being treated with multiple
antipsychotic medications are still scarce. Suzuki et al.
(2004) conducted a pragmatic open-label trial to con-
vert antipsychotic polypharmacy to monotherapy in
47 patients with chronic schizophrenia in a cross-
tapered fashion. Twenty-four patients (54.5 %) re-
mained stable, 10 patients (22.7 %) improved and 10
(22.7 %) worsened. Overall, social functioning, evalu-
ated by the Global Assessment of Functioning and
the Clinical Global Impression, remained unchanged.
The 10 deteriorated patients improved again shortly
after the reintroduction of their original treatment
regimens. Essock et al. (2011) have reported a 6-month
RCT, within which 127 out-patients with schizo-
phrenia who were receiving two antipsychotics were
either switched to monotherapy by discontinuing one
antipsychotic or stayed on polypharmacy. Time to all-
cause treatment discontinuation was shorter in the
monotherapy group. Furthermore, treatment discon-
tinuation was signicantly more frequent in the
monotherapy group than in the polypharmacy group
(31.0 % vs. 14.3 %). However, looking at it from a dif-
ferent angle, two-thirds of the patients assigned to the
monotherapy group were successfully switched to
monotherapy. In addition, no signicant dierence
was observed between the two groups with regard to
psychiatric symptom change or incidence of hospital-
ization. Furthermore, BMI decreased signicantly
in the monotherapy group, compared to the poly-
pharmacy group.
Although the data are still limited, in light of the
feasibility of switching patients from polypharmacy to
monotherapy, as well as potential benets associated
with the switch, the next challenge will be in predict-
ing who should be maintained on polypharmacy and
who can be switched to monotherapy.
Although further investigations are clearly war-
ranted, the current available evidence suggests that
converting antipsychotic polypharmacy to mono-
therapy could be a useful and reasonable treatment
option in schizophrenia. Moreover, even though there
is a certain risk of clinical worsening following a
Antipsychotic polypharmacy 1089
switch to monotherapy, clinicians always have the
option to reinstate polypharmacy.
Interventions to modify physicians prescribing
habits regarding polypharmacy
Interventions to change physicians prescribing
habits constitute another strategy to reduce anti-
psychotic polypharmacy. Factors involved in pre-
scribing patterns are complex. Availability and
dissemination of treatment guidelines and rec-
ommendations have not always produced the desired
change in physicians prescribing behaviours (Chen
et al. 2000 ; Leslie & Rosenheck, 2004 ; Paton et al.
2008 ; Sernyak et al. 2003). Baandrup et al. (2010a)
found that multifaceted educational interventions
failed to decrease antipsychotic co-prescribing in
schizophrenia in Denmark. The intervention was
aimed at psychiatric healthcare providers and con-
sisted of 1 d of didactic lectures, six 3-h educational
outreach visits and an electronic automatic reminder
during drug prescribing. However, no signicant
dierence in the prevalence of antipsychotic poly-
pharmacy was observed between the intervention
and control groups. In the UK, an audit of anti-
psychotic prescriptions followed by feedback of
benchmarked data and delivery of bespoke change
interventions did not reduce the prevalence of high-
dose therapy and antipsychotic polypharmacy (base-
line 43 % ; re-audit 39 %) either (Paton et al. 2008). On
the other hand, Thompson et al. (2008) demonstrated
a decrease in antipsychotic polypharmacy prescribing
with a somewhat more aggressive intervention in the
UK. In this controlled study with a 5-month follow-
up, the intervention included a 30-min structured
personal visit to consultant psychiatrists, dissem-
ination of a workbook for doctors and nurses and
reminder stickers on charts for patients who were
receiving multiple antipsychotic drugs. Ward phar-
macists applied removable reminder stickers to
medication charts when patients were given poly-
pharmacy and the stickers remained as long as two
or more antipsychotic drugs were used. At the 5-
month follow-up, the prevalence of antipsychotic
polypharmacy had modestly decreased in the inter-
vention group (from 47.8 to 40.4 %). In an earlier
study, Laska et al. (1980) had demonstrated that
educating clinicians to reduce the use of multiple
antipsychotics in the treatment of schizophrenia had
only a modest impact in a state psychiatric centre in
the US. Subsequently, a computerized drug review
system was implemented, which notied clinicians of
medication orders deviating from clinical guidelines,
1090 W. W. Fleischhacker and H. Uchida
which resulted in a drastic 10-fold decrease in the
rate of antipsychotic polypharmacy prescribing.
Hazra et al. also examined the impact of active
prescription monitoring and direct feedback from
pharmacists on antipsychotic polypharmacy in a
psychiatric hospital in Canada (Hazra et al. 2011).
As a result, a three-fold decrease in the prevalence
rates of polypharmacy was observed after 2 yr and
co-prescriptions of three antipsychotics were eec-
tively eliminated. These ndings suggest that active
monitoring of prescribing patterns, in conjunction
with targeted educational interventions, can have a
signicant impact on prescribing practices.
In summary, while educational interventions that
are passive have only accounted for small eects, a
more active form of intervention such as directly no-
tifying physicians by letters or phone calls can de-
crease the use of antipsychotic polypharmacy, even if
it may be perceived as fostering a big-brother -like
atmosphere (Laska et al. 1980).
Conclusions
Because of the limited evidence on antipsychotic
polypharmacy, especially with regard to its potential
ecacy, it is not possible to draw rm and denitive
conclusions on this mode of therapy. Ecacy ad-
vantages of clozapine plus another antipsychotic and a
reversal of metabolic side-eects with the concomitant
use of aripiprazole may apply in clinically dicult
situations. On the other hand, side-eects associated
with antipsychotic polypharmacy as well as increased
treatment cost have consistently been reported.
Moreover, clinical trials have shown that poly-
pharmacy could be converted to monotherapy in a
majority of cases although the available data are still
limited. Furthermore, antipsychotic polypharmacy can
be reduced through changes in physicians prescribing
habits with appropriate interventions. We therefore
tentatively conclude that antipsychotic polypharmacy
may work for some dicult to treat patients. However,
it should be the exception rather than the rule and
judicious safety/tolerability monitoring is essential.
The necessity of maintaining patients on such a treat-
ment regimen needs to be regularly re-evaluated. Since
the topics that are covered in this review are extensive
and the quality of the available reports is very variable,
we have conducted a synthetic review. Due to the
nature of such a review, the articles cited may reect a
certain selection bias of the authors, although we have
strived for balance. Given the paucity of available data,
further studies on this clinically highly relevant issue
are warranted.
Acknowledgement
The authors thank Dr Takefumi Suzuki for his in-
sightful comments.
Statement of Interest
Dr Fleischhacker has received research grants from
Alkermes, Janssen Cilag, Eli Lilly, BMS/Otsuka and
Pzer. He has received honoraria for educational
programmes from Janssen, Pzer and AstraZeneca,
speaking fees from AstraZeneca, Pzer, Janssen Cilag,
Roche, Lundbeck, BMS/Otsuka and advisory board
honoraria from BMS/Otsuka, Wyeth, Janssen Cilag
Neurosearch, Amgen, Lundbeck, Endo, United
Biosource, Targacept, MedAvante and AstraZeneca.
Dr Uchida has received grants from Pzer, speakers
honoraria from Otsuka Pharmaceutical, Eli Lilly,
Novartis Pharma, Shionogi, and Janssen Pharma
within the past 2 yr.
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