17427843, 2020, 3, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/bcpt.13384 by Cochrane Chile, Wiley Online Library on [05/03/2023].

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Received: 25 October 2019 
|
  Revised: 26 December 2019 
|
  Accepted: 27 December 2019

DOI: 10.1111/bcpt.13384

MINIREVIEW

Polypharmacy in schizophrenia

Lone Baandrup1,2

1
Centre for Neuropsychiatric Schizophrenia
Research (CNSR), Mental Health Centre
Glostrup, Glostrup, Denmark
2
Mental Health Centre Copenhagen,
Hellerup, Denmark
Correspondence
Lone Baandrup, Mental Health Centre
Copenhagen, Gentofte Hospitalsvej 15, 4,
DK-2900 Hellerup, Denmark.
Email: lone.baandrup@regionh.dk
Abstract
Schizophrenia is a severe mental disorder characterized by a heterogeneous symp-
tom profile which comprises a clinical platform for widespread use of polypharmacy
even though antipsychotic monotherapy is the recommended treatment regimen.
This narrative review provides a summary of the current gap between evidence
and practice for use of antipsychotic combination therapy in patients with schizo-
phrenia. Antipsychotic polypharmacy is frequently prescribed instead of following
international consensus of clozapine monotherapy in treatment-resistant patients.
Antipsychotic-benzodiazepine combination therapy clearly has a role in the treat-
ment of acute agitation whereas there is no evidence to support an effect on core
schizophrenia symptoms when chronically prescribed. Antidepressants are typically
added to antipsychotic treatment in case of persistent negative symptoms. Available
evidence suggests that antidepressants may improve negative symptom control in
schizophrenia. Combining an antipsychotic with an antiepileptic is not supported by
any firm evidence, but individual mood stabilizers have come out positively in single
trials. Generally, the evidence base for polypharmacy in schizophrenia maintenance
treatment is sparse but may be warranted in certain clinical situations. Therapeutic
benefits and side effects should be carefully monitored and considered to ensure
a beneficial risk-benefit ratio if prescribing polypharmacy for specific clinical
indications.

KEYWORDS
antidepressants, antiepileptics, antipsychotics, benzodiazepines, combination treatment

1  |   BACKGROU N D executive functioning, attention and information processing.1

Schizophrenia is a severe and often chronic mental disorder
which most often manifests in adolescence or early adulthood
resulting in marked loss of functioning and reduced quality of
life.1 Treatment of schizophrenia is a challenging task due to a
heterogenous and variable symptom profile which can be clas-
sified into several symptom domains. The psychotic symptom
domain covers symptoms like hallucinations, delusions, dis-
ordered speech and behaviour; the negative symptom domain
covers symptoms like lack of energy, apathy, isolation, self-ne-
glect and anhedonia, whereas the cognitive symptom domain
includes impairment across different cognitive tasks including
This wide variation in symptomatology and the frequently com-
plex clinical picture potentially pave the way for clinical situa-
tions where polypharmacy might seem a straightforward choice
for clinicians striving to efficiently ameliorate the symptoms
of their patients. Antipsychotics are the basic drug of choice
for treating the psychotic symptoms of schizophrenia, but cli-
nicians might find it rational to combine with an antidepressant
for negative symptoms, benzodiazepines for comorbid anxiety
or distress, or perhaps a mood stabilizer in patients suffering
from incapacitating mood instability. In addition, some clini-
cians find it rational to combine several antipsychotic drugs
when aiming for a superior effect and hoping to reduce side

Basic Clin Pharmacol Toxicol. 2020;126:183–192. wileyonlinelibrary.com/journal/bcpt |

© 2020 Nordic Association for the Publication of BCPT     183
(former Nordic Pharmacological Society)
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184      BAANDRUP

effects. However, most of these clinician-argued reasons for efficacy, and treatment choice is therefore mainly based on
antipsychotic combination treatment lack a clear rationale and side effect profile.4 The only exception is clozapine with firm
documentation for therapeutic benefit.2 evidence of superior efficacy in patients with schizophrenia
In the light of the discrepancies outlined above, this re- not having responded to ≥2 previous antipsychotic agents (ie
view provides a summary of the current gap between ev- treatment resistance).4 Clozapine is a third-line compound as
idence and practice for use of antipsychotic combination a consequence of the risk of severe side effects, including a
therapy in patients with schizophrenia. This narrative re- need to follow standardized blood monitoring due to a 0.9%
view is based on literature collected from sequential lit- risk of agranulocytosis.5 It is a substantial problem in schizo-
erature searches in PubMed from inception to December phrenia treatment that marked delays are often observed be-
2019, reference lists in existing reviews and papers, and fore clozapine is introduced to treatment-resistant patients.
conference presentations on the main topic of antipsychotic Observational data point to a mean delay of almost 50 months6
combination treatment. Thus, this review was not done before treatment-resistant patients are offered clozapine de-
using standard search criteria and methods for a systematic spite well-established evidence of its superior efficacy in this
review. Notably, several decisions were made during the patient group.7,8 Instead, patients are often treated with vari-
process regarding which data were reviewed and presented. ous forms of non-evidence-based antipsychotic polypharmacy
An effort was done to preferentially include studies from and high-dose regimens.6,9 Studies show that the barriers re-
secondary mental health services in order to ensure com- stricting clozapine prescribing reside with the clinicians rather
parability between included study populations. The review than with the patients.9,10
focuses on secondary (and where not available, primary) Antipsychotic monotherapy is the evidence-based and
literature investigating the outcome of antipsychotic com- recommended treatment regimen for both acute symptom
bination treatment. exacerbation4 and for maintenance treatment to prevent fu-
ture symptom relapse.11,12 There is no evidence to support
monotherapy with pharmaceutical compounds other than
2  |   IN TRO D U C T ION TO T H E antipsychotics. A simplified version of a treatment guide-
PH A R M ACO LOGICA L T R E AT MENT line for use of antipsychotics in schizophrenia is shown
O F S CH IZ O P H R E N IA in Figure 2. This figure illustrates the sequential use of
monotherapy with different antipsychotic compounds in-
Antipsychotics are the cornerstone of the pharmacological cluding monotherapy with clozapine before proceeding
treatment of schizophrenia and exert their therapeutic effect to polypharmacy.13-15 If prescribing polypharmacy, this
mainly through antagonism of striatal dopamine D2 recep- should preferentially be a clozapine combination due to
tors.3 The D2 binding affinity of antipsychotic medication
is, however, not restricted to the hyperactive part of the stria-
tum. Consequently, the D2 blockade during treatment with
antipsychotic agents also involves other parts of the stria-
tum including the motor part (causing extrapyramidal side
effects), cortical and thalamic D2 receptors together with the
tuberoinfundibular system (causing hyperprolactinaemia).
See Figure 1 for an overview of the dopaminergic pathways
in the brain.
The increasing number of different antipsychotic drugs
vary in affinity for a range of other (than D2) receptors in
the brain, including other dopamine receptor subtypes and
receptors for norepinephrine, serotonin, histamine and ace-
tylcholine which has direct relevance for their side effect
profile.3
Table 1 gives an overview of a selected set of both first- and
second-generation antipsychotics and their receptor profiles
depicted as the strength of their binding affinities. Generally,
antipsychotics block the listed receptors; however, a smaller
group of newer antipsychotics instead exert their action via
dopamine D2 partial agonism (aripiprazole, brexpiprazole and
cariprazine). In general, the currently available antipsychot-
ics are believed to show equivalence regarding antipsychotic F I G U R E 1   The dopaminergic pathways in the brain
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BAANDRUP      185

T A B L E 1   Receptor binding profiles for a selected set of first- and second-generation antipsychotics

Antipsychotic D2 Partial D2 Partial D3 5-HT-2A α1 M1 H1

Amisulpride +++     − − − −
Aripiprazole   +++ + ++ ++ − +
Brexpiprazole   +++ + +++ ++ − +
Cariprazine   +++ +++ ++ + − +
Clozapine +     ++ +++ +++ +++
Haloperidol +++     ++ ++ − +
Lurasidone +++     +++ ++ − −
Olanzapine ++     +++ ++ ++ +++
Paliperidone +++     ++++ +++ − ++
Perphenazine +++     +++ ++ − +++
a a
Quetiapine +     ++ +++ ++ +++a
Risperidone +++     ++++ +++ − ++
Sertindole +++     ++++ +++ − +
Ziprasidone +++     ++++ ++ − ++
Zuclopenthixol +++     ++ ++ − +
Abbreviations: 5-HT-2A, serotonin 2A receptor; D2, dopamine D2 receptor; D3, dopamine D3 receptor; H1, histamine type 1 receptor; M1, muscarinic acetylcholine
type 1 receptor; α1, alpha-1 adrenergic receptor.
a
The binding affinity is mainly due to the metabolite norquetiapine.

the superior efficacy of clozapine in treatment-resistant pa-
tients (further discussed below).
3  |   A N T IP SYCHOT IC
PO LY P H A R M AC Y
Antipsychotic polypharmacy, that is concomitant treat-
ment with two or more different antipsychotic compounds,
is the combination regimen that has attracted most atten-
tion in the literature. The frequency of antipsychotic poly-
pharmacy prescribing varies geographically with higher
incidences in Asia and Europe than in North America.16
Changes in prescribing practice also vary geographically
with the prevalence of antipsychotic polypharmacy in-
creasing insignificantly in North America from the 1980s
(12.7%) to the 2000s (17.0%), decreasing significantly
from 1980 (55.5%) to 2000 (19.2%) in Asia and varying
non-significantly in Europe.16
Clinical indications for antipsychotic polypharmacy typ-
ically include insufficient treatment response to monother-
apy, intolerable side effects, and patients that are trapped
on polypharmacy during a process of cross-titration from
one antipsychotic to another.17 Predictors of long-term

Trial of a single SGA

Trial of a single SGA or FGA (not previously tried)

Clozapine

F I G U R E 2   Simplified version of Clozapine + FGA, SGA or ECT

treatment algorithm for schizophrenia
adapted from the Texas Medication
Algorithm Project (TMAP). Texas Trial of a single FGA or SGA (not previously tried)

Department of State Health Services, 2008.

ECT, electroconvulsive therapy; FGA, Combination therapy, for example SGA+FGA, SGA+ SGA, FGA or SGA + ECT, FGA or
first-generation antipsychotic; SGA, second- SGA + other agent
generation antipsychotic (eg mood stabilizer)
 |
186      BAANDRUP
antipsychotic polypharmacy have been shown to include
the following: symptom severity (psychotic symptoms),
previous treatments (clozapine and long-acting injectable
antipsychotic agents), service use (more contact with out-
patient services), social factors and socio-demographic sta-
tus (younger age).18 Clinical disadvantages that have been
shown to be closely associated with antipsychotic poly-
pharmacy include increased burden of side effects, wors-
ened adherence due to treatment complexity, higher total
dosages, difficulties assessing response to an individual an-
tipsychotic when ≥2 compounds are given concomitantly,
increased risk of drug-drug interaction and medication er-
rors.19-21 Antipsychotic polypharmacy has not been found
to be associated with increased risk of death when com-
pared with antipsychotic monotherapy in patients with
schizophrenia as judged from large register-based obser-
vational data.22,23 When specifically looking at long-term
antipsychotic polypharmacy compared with monotherapy,
a UK study using anonymized electronic health records
reported a weak association with all-cause mortality.24
However, in the fully adjusted model, which used standard
propensity scores to reduce the effect of confounding by
indication, the estimates were no longer statistically signif-
icant.24 In line with this, another large UK study, this time
drawing data from primary care medication records found
that relative to monotherapy, antipsychotic polypharmacy
was not associated with mortality.25 Likewise, a popula-
tion-based nested case-control study from China concluded
that antipsychotic polypharmacy did not contribute to the
excess mortality observed in patients with schizophrenia
compared with the background population.26
Theoretically, it is difficult to find a rationale for com-
bining antipsychotics because of their similar mechanism of
action, that is via dopamine D2 receptor antagonism. Thus,
there is no reason to expect an increased antipsychotic effi-
cacy when combining two antipsychotics above what is ob-
tained when increasing the dosage of one single antipsychotic.
Several reviews of clinical trials investigating different com-
binations of antipsychotic compounds were published from
2007 to 2009 all convincingly concluding the same: antipsy-
chotic polypharmacy is not superior to monotherapy except
in the group of partially clozapine responsive patients where
an additional antipsychotic effect may be obtained by add-
ing another antipsychotic.27-30 However, the effect size was
small to moderate at best. The meta-analyses published after
2009 have generally not been able to replicate the positive
findings for augmenting clozapine treatment with an addi-
tional antipsychotic compound,31-34 but results are mixed.35
The most recent meta-analysis indicates a potential therapeu-
tic effect on negative symptoms only when augmenting with
aripiprazole (a partial dopamine D2 agonist) compared with
antipsychotic monotherapy (standardized mean difference
[SMD] −0.41; 95% confidence interval [CI] −0.79 to −0.03;
17427843, 2020, 3, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/bcpt.13384 by Cochrane Chile, Wiley Online Library on [05/03/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
N = 532).36 If choosing to combine two antipsychotic com-
pounds with the aim of obtaining supplementary efficacy, the
rational choice will be to combine two compounds with dif-
ferent receptor profiles (cf. Table 1), as for example clozapine
and aripiprazole.
The evidence summarized above is derived from random-
ized controlled trials which are sometimes criticized for low
external generalizability due to the restrictive features of a
clinical trial. Real-life evidence can sometimes better be de-
rived from pragmatic observational designs. Recent observa-
tional and non-controlled data indicate that specifically the
clozapine-aripiprazole combination might be associated with
reduced risk of relapse in patients with schizophrenia com-
pared with clozapine monotherapy.37 In this register-based
cohort study of more than 62 000 patients with schizophrenia
from the Finnish registers, the authors reported a hazard ratio
(HR) for hospitalization of 0.86 (95% CI 0.79-0.94) for the
clozapine-aripiprazole combination therapy compared with
clozapine monotherapy. Since augmenting antipsychotics are
usually not added to clozapine until monotherapy has been
found to be inadequate, these observational data are not in
direct conflict with the evidence based on controlled data
as summarized above. Furthermore, these data support cur-
rent clinical treatment guidelines that opt the possibility to
augment with another antipsychotic when clozapine mono-
therapy is not sufficiently effective or when dose titration is
limited by side effects (cf. Figure 2). Non-clozapine combi-
nations are only recommended as the very last treatment op-
tion when clozapine monotherapy and, if indicated, clozapine
combination treatment have proven ineffective, because of
the lack of evidence supporting non-clozapine antipsychotic
combinations.38 As a minimal requirement, treatment guide-
lines recommend systematically monitoring for side effects
and careful documentation of these as well as of any thera-
peutic effect to be sure to maintain a favourable risk-benefit
ratio.38
For acute phase schizophrenia, a recent naturalistic
study39 demonstrated that adding another antipsychotic in
patients who had not responded to two previous antipsychot-
ics was associated with significant global symptom improve-
ment. However, this study did not control for total dose, and
thus, the improvement with antipsychotic polypharmacy in
non-responders to monotherapy may also be partly explained
by increased total antipsychotic dosage.
For patients who have been treated with antipsychotic
polypharmacy continuously, a few clinical trials have
been performed investigating the clinical course of illness
when patients are switched from antipsychotic polyphar-
macy (two concomitant antipsychotics) to antipsychotic
monotherapy. Essock et al40 randomized 127 schizophre-
nia patients to continued antipsychotic polypharmacy or
switch to monotherapy, but this study did not adjust for
reduced dose in the monotherapy group, and therefore,

BAANDRUP
a bias in favour of antipsychotic polypharmacy was in-
herent. They reported that more than half of the patients
were able to tolerate conversion to monotherapy. Most of
the non-converters returned to their previous polytherapy
regimen. Constantine et al41 randomized 104 outpatients
to continued polypharmacy or switch to monotherapy and
found that switch patients had greater increases in symp-
tom score than stay patients after 6-12 months' follow-up.
Furthermore, they found a higher discontinuation rate in
the switch (42%) vs the stay group (13%). Borlido et al42
performed a smaller randomized trial (N = 35) reporting no
change in total symptom scores for the antipsychotic poly-
pharmacy vs monotherapy group after 12 weeks and a suc-
cess rate of almost 80% who could be safely transitioned
to antipsychotic monotherapy. Matsui et al43 gathered data
from a total of six trials (only two of them double-blind)
investigating switch from antipsychotic polypharmacy to
monotherapy and found in a meta-analysis a difference in
all-cause discontinuation in favour of staying on antipsy-
chotic polypharmacy. However, this was not reflected in
differences between groups regarding relapse, efficacy, or
side effects.43 A UK non-randomized intervention study
has documented that a quality improvement programme
F I G U R E 3   Mechanism of action of benzodiazepines. The GABA-A receptor is composed of five transmembrane glycoprotein subunits
arranged around the central chloride channel. Each subunit consists of four domains. Benzodiazepines bind to a specific site and thereby increase
the affinity of the GABA-A receptor for GABA. This then increases the likelihood that the receptor will open for chloride ions (light blue), which
decreases the excitability of the neuron. Figure reprinted from Soyka49
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     187
can induce change in the prescribing culture and reduce
rates of antipsychotic polypharmacy from 57% to 16% in
psychiatric inpatients.44 Thus, based on the currently avail-
able data, it must be considered rational and safe to initi-
ate a gradual switch from antipsychotic polypharmacy to
monotherapy in patients where specific reasons do not cau-
tion against this. The clinical history of the patient and the
anticipated risks associated with a possible relapse should
be considered when deciding if, how and when a switch
from antipsychotic polypharmacy to antipsychotic mono-
therapy should be initiated.
Antipsychotic polypharmacy has also been investigated
from a health economic point of view. Clinical follow-up
studies point to the fact that, in general, patients treated with
antipsychotic polypharmacy when dismissed from the hospi-
tal are more likely to be readmitted compared with patients
prescribed antipsychotic monotherapy, also when adjusting
for confounding by indication.45,46 This seems to be in con-
trast to evidence from larger register-derived data sets which
describe either no association of antipsychotic polypharmacy
with risk of hospital admission25 or perhaps a protective ef-
fect regarding risk of rehospitalization.37 In general, antipsy-
chotic polypharmacy has been found to be associated with
 |
188      BAANDRUP
higher total costs of treatment including longer duration of
inpatient stay.46,47
4  |   A N TIP SYCH OT IC -
BE N ZO D IA Z E P IN E CO MB INAT I ON
TR EAT M EN T
In clinical practice, benzodiazepines exert their effect by
acting as allosteric modulators on the gamma-aminobu-
tyric acid (GABA)-A receptors and thus potentiating the
GABAergic system. The structure of the GABA-A receptor
and benzodiazepine binding site is illustrated in Figure 3.
Benzodiazepines are efficient drugs for agitation, anx-
iety and insomnia, and they are a necessary part of symp-
tom control in the acute phase of symptom exacerbation or
severe psychotic relapse in patients with schizophrenia.48
However, benzodiazepine treatment is often prolonged
after the acute phase which is problematic due to an un-
favourable side effect profile including cognitive impair-
ment (impaired concentration, memory and attention),
risk of falls (especially in the elderly) and development of
tolerance and dependence.49 Furthermore, several larger
observational studies have documented an increased risk
of death with antipsychotic-benzodiazepine combina-
tion treatment in patients with schizophrenia.22,23,50 This
includes both increased mortality from suicide, which
is most probably a result of confounding by indication,
but it also includes increased risk of death from natural
causes which is not readily explainable as confounding
by indication and should raise a red flag as to a potential
problem with the safety of the high-frequent use of this
combination treatment. Another worrying side effect that
has been suspected with long-term benzodiazepine use is
an increased risk of developing dementia.51 It has been
difficult to convincingly establish a cause-effect relation-
ship, but the association has been confirmed when trying
to control for protopathic bias, that is reverse causation
bias.52
In clinical practice, healthcare professionals are some-
times reluctant to discontinue chronic treatment with ben-
zodiazepines in patients with schizophrenia, because they
anticipate that this might induce insomnia, clinical instabil-
ity, increased risk of relapse and need of rehospitalization.53
However, clinical trial data point to the fact that patients
with schizophrenia, who have been long-term treated with
an antipsychotic-benzodiazepine combination, can be suc-
cessfully tapered off their treatment with benzodiazepines
without measurable worsening of withdrawal symptoms,54
sleep continuity variables, subjective sleep quality55 or cir-
cadian rest-activity cycles.56 Benzodiazepines are known
to suppress the amount of deep sleep (also known as slow-
wave sleep) which is especially problematic in schizophrenia
17427843, 2020, 3, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/bcpt.13384 by Cochrane Chile, Wiley Online Library on [05/03/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
since most patients already suffer from severe sleep distur-
bances including reduced or a total lack of slow-wave sleep.57
Clinical trial data indicate that this disturbance in sleep ar-
chitecture is at least partly reversible upon benzodiazepine
discontinuation.55
Add-on medications to facilitate benzodiazepine dis-
continuation have been extensively investigated. In a recent
Cochrane Review58 covering the topic, the following re-
sults were emphasized: several different pharmacological
interventions had been investigated but mostly in under-
powered studies of low scientific quality. Most results were
based on single small-sized randomized trials with a high
risk of type II error. Consequently, the results could not be
translated into any meaningful clinical recommendation,
except that treatment with additional medication during
benzodiazepine taper cannot generally be recommended.
The circadian stabilizing pituitary gland hormone, mel-
atonin, might be used as augmenting agent for patients
with schizophrenia during benzodiazepine discontinuation
if comorbid sleep disturbances are present since add-on
melatonin improves subjective sleep disturbances in these
cases.55
5  |  ANTIPSYCHOTIC-
ANTIDEPRESSANT COM BINATI ON
TREATM ENT
Persistent negative symptoms despite adequate control of
psychotic symptoms are seen in a substantial number of
patients with schizophrenia, exceeding the estimated prev-
alence of primary enduring negative symptoms (the deficit
syndrome) of 15%-20%.59 Where psychotic (also known
as positive) symptoms reflect a distortion in perception or
thought, negative symptoms reflect an absence or reduc-
tion of normal functions related to motivation or interest
(eg avolition, anhedonia and asociality) or to expressive
functions (eg blunted affect and alogia).60 Negative symp-
toms are challenging to investigate in clinical trials due
to difficulties in distinguishing between primary nega-
tive symptoms and negative symptoms secondary to psy-
chotic symptoms, depression or antipsychotic side effects.
Persistent negative symptoms limit the possibility of re-
covery and are associated with poorer social and occupa-
tional functioning and reduced likelihood of independent
living. Due to the clinical similarities and difficulties dis-
tinguishing between negative symptoms and depression,
antidepressants seem (from a clinical point of view) to
be a rational choice for treatment of persistent negative
symptoms that do not respond to antipsychotic treatment.
Antidepressants are a diverse group of agents, but a com-
mon trait is inhibition of neurotransmitter reuptake, spe-
cifically acting on the serotonergic and the noradrenergic

BAANDRUP
F I G U R E 4   The origin and projections
of the noradrenergic system (above) and the
serotonergic system (below)
systems.61 Figure 4 shows the origin and projections of the
noradrenergic and serotonergic systems.
Recent meta-analyses indicate that there is some evi-
dence of a small to moderate effect of combining an anti-
depressant with antipsychotic treatment for total symptom
score improvement.32,36 Selective serotonin reuptake in-
hibitors (SSRIs) and mirtazapine (a noradrenergic, specific
serotonergic agent) are the compounds that have been most
often investigated. As regards effect specifically on neg-
ative symptoms, the latest meta-regression found a small
therapeutic effect of SSRIs (SMD −0.26; 95% CI −0.50
to −0.02; N = 922) and a larger effect of serotonergic and
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     189
noradrenergic reuptake inhibitors (SNRIs) (SMD −1.40;
95% CI −2.44 to −0.36; N = 40), but no effect of mirtazap-
ine.36 Limitations of the current studies include small sample
size, short trial duration and failure to control for change in
secondary negative symptoms. Observational register-based
data have pointed to the fact that antipsychotic-antidepres-
sant combination treatment seems to be associated with a
markedly lower risk of suicide compared with antipsychotic
monotherapy among patients with schizophrenia (HR 0.15;
95% CI 0.03-0.77).23 Likewise, all-cause mortality has been
found to be decreased in patients with schizophrenia treated
with antidepressants compared with no exposure (HR 0.85,
 |
190      BAANDRUP
95% CI 0.73-0.98).50 These results add to the overall view of
a potentially beneficial effect of combining an antipsychotic
with an antidepressant in patients with schizophrenia and de-
pressive/negative symptoms.
6  |   A N TIP SYCH OT IC -
AN TIE P ILE P T IC COMB INAT ION
TR EAT M EN T
Augmenting antipsychotic treatment with an antiepileptic (or
mood stabilizer) stems from clinical practice where this has
been considered an option in a subgroup of patients with the
aim of reducing aggression or stabilizing mood outside the
licensed indication of bipolar disorder. Regarding the lat-
ter use, especially patients diagnosed with schizoaffective
disorder are in the clinical target group for combined treat-
ment with an antipsychotic and a mood stabilizer although
there is no firm evidence base to support this clinical prac-
tice.36 Theoretically, antiepileptic drugs may reduce ag-
gression by reducing neuronal hyper-excitability associated
with aggression, but the current evidence is not convinc-
ing.62 The clinical practice of combining an antipsychotic
with an antiepileptic in patients with schizophrenia has been
the subject of several smaller clinical trials with the latest
meta-regression results36 indicating that lamotrigine might
be associated with a therapeutic effect regarding total psy-
chopathology score (SMD −0.73; 95% CI −1.26 to −0.20;
N = 98) as well as psychotic (SMD −0.69; 95% CI −1.20 to
−0.18; N = 67) and negative symptom score (SMD −0.96;
95% CI −1.40 to −0.52; N  =  98), whereas carbamazepine
had no effect. When specifically addressing clozapine com-
bination treatment, a systematic review and meta-analysis
reported that lamotrigine was superior to placebo augmenta-
tion in both total psychopathology score (SMD 0.57; 95% CI
0.25-0.89; N = 161), psychotic symptoms (SMD 0.34; 95%
CI 0.02-0.65) and negative symptoms (SMD 0.43; 95% CI
0.11-0.75).63 Lithium seemed to exert a therapeutic effect on
total symptom score (SMD −0.63; 95% CI −0.94 to −0.32;
N = 254), but no effect on psychotic or negative symptoms
in isolation.64 However, positive results were associated with
considerable uncertainty because the positive effect sizes
were inversely correlated with the frequently low quality of
the meta-analysed trials.36
An effectiveness study based on US national Medicaid
data65 found that initiating use of a mood stabilizer in pa-
tients with schizophrenia on stable treatment with a single
antipsychotic was associated with an increased risk of all-
cause mortality (HR 1.31; 95% CI 1.04-1.66). The authors
used propensity scores to control for confounding by indi-
cation, but they acknowledged that residual confounding by
unmeasured variables might still partially have explained the
results. An increased risk of suicidal ideation and suicide
17427843, 2020, 3, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/bcpt.13384 by Cochrane Chile, Wiley Online Library on [05/03/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
behaviour in patients treated with antiepileptic drugs was
announced by the US Food and Drug Administration (FDA)
in 2008 and an expert consensus statement from 2013 ad-
dressed this point.66 This report concluded that results from
retrospective and case-control studies were contradictory
and that some antiepileptic drugs were associated with psy-
chotropic adverse events (depression, psychosis, irritability)
that might lead to suicidal ideation and behaviour, but that
the actual suicide risk was judged as very low. The report
mentioned that FDA's warning indicated an increased risk
of suicide with all antiepileptic drugs, even though statis-
tical significance was only found for topiramate and lam-
otrigine out of the eleven antiepileptics that were studied.
It was noted that two other antiepileptics, valproic acid and
carbamazepine, were associated with a small protective ef-
fect against suicidality and that the inclusion of three addi-
tional studies resulted in the loss of statistical significance
for the increased suicide risk with lamotrigine.66 Overall,
the results are mixed and increased risk of death with use
of antiepileptics in patients with schizophrenia represents a
concern that cannot be completely ruled out based on the
current data.
7  |  CONCLUSIONS
In the acute phase treatment of schizophrenia, certain antip-
sychotic combination regimens (with benzodiazepines or an-
other antipsychotic) might be necessary to ensure adequate
symptom control. For schizophrenia maintenance treatment,
the evidence base does not, in general, provide support for
antipsychotic combination treatment. However, specific
combinations might be justified from a rational and clinical
data supported point of view in selected situations. If antipsy-
chotic combination treatment is prescribed in specific clini-
cal situations, therapeutic benefits and side effects should be
carefully monitored and considered to continuously ensure a
favourable risk-benefit ratio.
CONFLICT OF INTEREST
The author has no conflicts of interest to declare.
ORCID
Lone Baandrup  https://orcid.org/0000-0003-1662-2720
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How to cite this article: Baandrup L. Polypharmacy in
schizophrenia. Basic Clin Pharmacol Toxicol.
2020;126:183–192. https​://doi.org/10.1111/bcpt.13384​