Acta Psychiatr Scand 2002: 106: 323–330 Copyright ª Blackwell Munksgaard 2002

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SCANDINAVICA
ISSN 0001-690X

Review article
Antipsychotic combination therapy in
schizophrenia. A review of efficacy and risks
of current combinations
Freudenreich O, Goff DC. Antipsychotic combination therapy in O. Freudenreich1, D. C. Goff2
schizophrenia. A review of efficacy and risks of current combinations. 1
Psychiatrist, MGH Schizophrenia Program,
Acta Psychiatr Scand 2002: 106: 323–330. ª Blackwell Munksgaard 2002 Massachusetts General Hospital, Department of
Psychiatry, Clinical Instructor in Psychiatry, Harvard
Objective: To review the literature on efficacy and risks of combining Medical School and 2Director, MGH Schizophrenia
antipsychotics (atypical with atypical or conventional) and suggest a Program, Massachusetts General Hospital, Department
rationale and strategies for future clinical trials. of Psychiatry, Associate Professor of Psychiatry, Harvard
Medical School, Boston, MA, USA
Method: A computerized Medline search supplemented by an
examination of cross-references and reviews was performed.
Results: Empirical evidence for the efficacy of combining
antipsychotics is too limited to draw firm conclusions. The practice of
augmenting clozapine with more Ôtightly boundÕ D2 receptor
antagonists as exemplified by risperidone augmentation of clozapine
has some empirical and theoretical support. The risks of augmentation
strategies have not been studied systematically. No study has examined
the economic impact of combination treatment.
Conclusion: Further trials of antipsychotic combination therapies are Key words: antipsychotic agents; schizophrenia;
needed before this currently unsupported practice can be treatment outcome; drug therapy combination
recommended. Rationales for combination treatment include a Oliver Freudenreich, MGH Schizophrenia Program,
broadening of the range of receptor activity or an increase in D2 Freedom Trail Clinic, 25 Staniford Street, 2nd Floor,
receptor occupancy with certain atypical agents. Trial methodology Boston, MA 02114, USA
needs to take into account subject characteristics, duration of E-mail: ofreud@massmed.org
treatment, optimization of monotherapy comparators, and
appropriate outcome measures. Accepted for publication June 20, 2002

that clozapine was combined with other antipsy-

Introduction
Should antipsychotic medications be combined to
optimize the treatment of patients with schizo-
phrenia? The answer is yes, if clinical practice in
many European countries and the US is taken as
evidence for the utility of this approach. According
to recent surveys of prescribing patterns in the US,
about 15% of out-patients with schizophrenia
receive two or more antipsychotics [Sources:
Wang et al. (1) and IMS Health – The National
Disease and Therapeutic Index (NDTI) for year
2000] and the rate of combination treatment
approaches 50% among in-patients [Source:
Ereshefsky (2)]. Quetiapine is most frequently
prescribed in combination (42%), followed by
risperidone (18%), olanzapine (17%) and cloza-
pine (14%). A survey of 32 Danish hospitals found
chotics in 35% of cases (3).
It can be argued that, compared with high-
potency conventional antipsychotics, most second
generation antipsychotics constitute inherent com-
bination therapy because of their Ôbroad-spectrumÕ
receptor blockade, with clozapine, the most effec-
tive antipsychotic, possessing one of the most
diverse receptor-binding profiles (4). However,
there is a paucity of evidence to guide treatment
in patients who fail monotherapy with clozapine.
While augmentation of clozapine with other anti-
psychotics has been supported in some preliminary
studies and can be rationalized, based on some
theoretical considerations, the database supporting
this strategy is quite inadequate. Evidence in
support of other possible combinations of antipsy-
chotics is even more lacking. The widespread

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Freudenreich and Goff

practice of combining antipsychotics in the relative
absence of supporting evidence and contrary to
guidelines recommending monotherapy has been
called psychiatry’s Ôdirty little secretÕ (5).
We will review the existing empirical evidence
for combining antipsychotic medications for the
treatment of schizophrenia as well as the potential
risks of currently employed combination strategies.
The focus will be on combinations of atypical
antipsychotics with other atypical or conventional
antipsychotics. We will then delineate possible
theoretical rationales for combination therapy
and discuss methodological issues that complicate
clinical trials designed to evaluate antipsychotic
combination therapy.
Review of antipsychotic combinations: efficacy and risks
Methods
The English literature was searched using Medline
and by perusing key articles and book chapters for
trials combining antipsychotic medications in
schizophrenia. Studies were identified according
to whether they employed a randomized controlled
trial (RCT) design, open prospective treatment
(OPT), or a retrospective chart review (RCR). One
major source of information was a recently pub-
lished review of clozapine augmentation by Chong
and Remington (6). Only studies allowing some
estimate of treatment response based on rating
scales of psychopathology were included. We will
review these studies in some detail, supplemented
by single case reports when applicable to highlight
risks of combination therapy.
Results
Studies employing an RCT, OPT, or RCR design
were identified for the following antipsychotic
combinations: clozapine-chlorpromazine (RCT),
clozapine-sulpiride (RCT), clozapine-risperidone
(three OPTs), clozapine-pimozide (RCR), cloza-
pine-loxapine (OPT), olanzapine-sulpiride (OPT),
and olanzapine-risperidone (OPT) (Table 1).
Following up their own initial positive case
series, Shiloh et al. (7) added the selective D2
antagonist, sulpiride (600 mg ⁄ day) to clozapine in

Table 1. Efficacy studies of combination antipsychotics in schizophrenia (atypical agent combined with atypical or typical agent)

Antipsychotic combination Study type n Scales, dose, efficacy Side-effects

Clozapine plus sulpiride (7) RCT 28 Scales: BPRS, SANS, SAPS Worsened sialorrhea
Sulpiride dose: 600 mg ⁄ day (n ¼ 1)
50% improved >20% BPRS Worsened TD (n ¼ 1)
50% showed no improvement Increased prolactin
Clozapine plus chlorpromazine (8) RCT 57 Scale: BPRS Not reported
CPZ dose: not reported
Combination treatment similar
to clozapine monotherapy
Clozapine plus risperidone (9) OPT 12 Scale: BPRS Akathisia (n ¼ 4)
Risperidone dose: 3.8 mg ⁄ day Hypersalivation (n ¼ 5)
10 ⁄ 12 showed >20% improvement
BPRS (mean decrease 11.9 points)
Clozapine plus risperidone (10) OPT 12 Scale: BPRS Orthostatic
Risperidone dose: 5.3 mg ⁄ day Hypotension (n ¼ 1)
No improvement by >20% BPRS
Clozapine plus risperidone (11) OPT 13 Scale: PANSS Worsening
Risperidone dose: 3.0 mg ⁄ day (mean) Compulsion (n ¼ 1)
7 ⁄ 13 showed >20% improvement in
PANSS scores
Clozapine plus pimozide (14) RCR 7 Scale: BPRS Not reported
Pimozide dose: 4 mg ⁄ day
Mean 24 point BPRS decrease
Clozapine plus loxapine (16) OPT 7 Scale: BPRS Not reported
Loxapine dose range 25–200 mg ⁄ day
Range of BPRS improvement 19–38 points
Olanzapine plus sulpiride (17) OPT 6 Scale: BPRS Not reported
Sulpiride dose: 60–600 mg ⁄ day
Mean improvement BPRS 42%
Olanzapine plus risperidone (18) OPT 5 Scale: BPRS No side-effects noted
Olanzapine dose: 10–15 mg ⁄ day
Risperidone dose: 1–5 mg ⁄ day
Mean decrease of BPRS 30%

RCT – randomized controlled trial; OPT – open prospective treatment; RCR – retrospective chart review.

324

a double-blind, placebo-controlled, 10-week trial
in 28 schizophrenia patients who had partially
responded to clozapine monotherapy. Ratings of
general psychopathology (BPRS total score), neg-
ative symptoms (SANS total score) and psychotic
symptoms (SAPS total score) were significantly
improved with combination therapy compared
with the monotherapy group. A reduction in
BPRS total score of 20% or greater occurred in
50% of patients in the combination therapy group
compared with 8% of patients receiving mono-
therapy; the mean reductions in BPRS total scores
were 8.7 and 2.3 for sulpiride and placebo, respec-
tively. However, half of patients showed no
improvement (BPRS change <5%) with combina-
tion therapy. No extrapyramidal side-effects were
noted, although one patient had an increase in
sialorrhea and another patient’s tardive dyskinesia
worsened with addition of sulpiride. Serum prolac-
tin concentrations were significantly elevated in the
sulpiride group as well.
In a preliminary report, Potter et al. (8) summa-
rized results from a randomized, double-blind,
flexible-dose, 8-week trial comparing clozapine,
chlorpromazine, and the combination of the two
drugs in 57 schizophrenia in-patients at a mental
health center in Shanghai. Combination treatment
did not significantly reduce symptoms as measured
by the BPRS compared with clozapine monother-
apy, whereas the group receiving monotherapy
with chlorpromazine exhibited significantly higher
levels of withdrawal, conceptual disorganization,
unusual thoughts and hostility compared with the
two groups receiving clozapine. Side-effects were
not reported.
Three open trials combining clozapine and
risperidone have been published. Henderson and
Goff (9) reported a 20% or greater decline in total
BPRS scores in 10 of 12 out-patients 4 weeks after
risperidone (mean dose 3.8 mg ⁄ day) was openly
added to clozapine (mean dose 479 mg ⁄ day).
BPRS total scores decreased an average of 11.9
points, from 42.2 to 30.3. Mean serum clozapine
concentrations were non-significantly increased by
2% after addition of risperidone in seven patients
for whom serum levels were obtained. No changes
in heart rate or blood pressure were recorded,
although four patients complained of mild
akathisia, and hypersalivation recurred in five
patients. This positive experience contrasts with
deGroot et al.’s report (10) of an open 4-week trial
in which risperidone (mean dose 5.3 mg ⁄ day) was
added to clozapine in 12 hospitalized patients. One
patient dropped out because of orthostatic hypo-
tension. None of the remaining 11 patients
improved by more than 20% on their PANSS
Antipsychotic combination therapy in schizophrenia
total score. Clozapine serum concentrations were
not significantly affected by addition of risperi-
done. Taylor et al. (11) reported a 20% or greater
reduction in total PANSS total scores in 7 of 13
inpatients following open augmentation of cloza-
pine with risperidone (mean dose 3.0 mg). One
subject’s compulsive rubbing of her head wors-
ened. Two small open case series describe an
additional five patients in whom clozapine was
successfully augmented by addition of risperidone
(12, 13). In two cases, the BPRS total scores
declined by 9 and 10 points, whereas the PANSS
total score declined by 20–30%, in the three
additional patients.
Several additional case series have described
therapeutic benefit associated with the addition of
a conventional antipsychotic to an atypical agent.
Friedman et al. (14) reviewed charts from seven
patients in whom pimozide (mean dose of
4 mg ⁄ day, range 2–8 mg ⁄ day) was openly added
to clozapine (425 mg ⁄ day, range 325–600 mg ⁄ day).
Mean BPRS scores decreased by 24 points from 51
to 27. Clozapine blood levels were not reported.
Takhar (15) added pimozide 3 mg ⁄ day to olanza-
pine in a single case and reported a reduction in the
BPRS total score from 56 to 38. Mowerman and
Siris (16) prospectively added open-label loxapine
(25–200 mg ⁄ day) to clozapine in seven patients for
a period of 18–50 months. Improvements in BPRS
total scores ranged from 19 to 38 points. In the two
patients with the best improvement, the change was
noticeable within a few weeks. In an open trial of
sulpiride (60–600 mg ⁄ day) augmentation of ola-
nzapine (20–40 mg ⁄ day) in six treatment-resistant
patients, Raskin et al. (17) reported a mean 42%
decline in BPRS total scores after 2–6 weeks. Three
patients (50%) exhibited marked improvement. No
adverse events were described. Finally, in another
open trial reported by Lerner et al. (18), five
patients received the combination risperidone plus
olanzapine when switched from either risperidone
to the combination or from olanzapine to the
combination. Total BPRS score decreased by 30%
with no side-effects noted.
Thus, a total of 147 patients were studied in all
of the reviewed trials, with 85 in controlled trials.
Almost all studies meeting minimal design criteria
(RCT, OPT, RCR; rating scale of psycho-
pathology) augmented the antipsychotic agent
clozapine. Antipsychotics used for augmentation
were chlorpromazine, sulpiride, risperidone,
pimozide, and loxapine. Only two double-blind,
randomized trials have been reported; a positive
trial examining the sulpiride ⁄ clozapine combina-
tion and a preliminary report of a negative trial
in which chlorpromazine and clozapine were
325
Freudenreich and Goff
combined. The combination of risperidone and
clozapine has been reported most commonly,
although no adequately controlled trial has been
reported to support its use. There is a suggestion that
when effective, about half of the patients clearly
respond to augmentation, and that improvement is
seen within a few weeks. However, not all trials
supported the efficacy of combination treatment.
Risks of combination therapy
The risks of polypharmacy have not been system-
atically studied in prospective trials. A large RCR
in a German clinic identified 416 patients who
received clozapine at a mean dose of 213 mg ⁄ day
combined with a conventional antipsychotic (19).
Combination treatment was associated with more
electroencephalogram alterations, delirious states,
and hypersalivation; the comparison group, how-
ever, received a substantially lower clozapine dose
(165 mg ⁄ day), which could account for side-effects
attributed to combination treatment. To examine
the effects of risperidone augmentation of cloza-
pine on prolactin levels, Henderson et al. (20)
matched 20 out-patients treated with the combina-
tion of clozapine and risperidone with 20 patients
on clozapine only. Mean prolactin levels were
8.42 ng ⁄ ml for clozapine alone compared with
35.76 ng ⁄ ml on the combination. Side-effects
related to elevated prolactin levels were not
assessed. Several cases have also been reported of
side-effects associated with the combination of
risperidone and clozapine, including atrial ectopia
(21), worsening of obsessive-compulsive symptoms
(22), and agranulocytosis (23).
One major theoretical concern that has not been
addressed is the possible loss of atypicality and
increased risk of extrapyramidal symptoms and
tardive dyskinesia when combining D2 –blocking
agents to atypical agents. Longer-term trials involv-
ing large numbers of subjects will be necessary to
determine whether addition of high-potency D2
blockers increases the risk for tardive dyskinesia. In
the Shilah trial of sulpiride augmentation of cloza-
pine (7), one patient experienced worsening tardive
dyskinesia. One case report describes new Parkin-
sonian symptoms when a patient received olanza-
pine added onto haloperidol (24).
The potential of additive side-effects from over-
lapping receptor profiles would also include anti-
cholinergic toxicity from addition of low potency
conventional antipsychotics (e.g. thioridizine or
chlorpromazine) to clozapine. Other potential
additive effects include orthostatic hypotension
and cardiac conduction delay. Addition of thio-
ridazine to ziprasidone is of particular concern
326
given the potential of each agent to delay cardiac
conduction. A case of priapism was attributed in
part to combining olanzapine and risperidone (25).
The other category of adverse effects involves
pharmacokinetic interactions. Drug–drug interac-
tions have not been established between antipsy-
chotic combinations, but this issue has not been
well studied. Whereas two small prospective trials
found no interaction between risperidone and
clozapine, two cases have been reported in which
clozapine blood concentrations doubled after
addition of risperidone (26, 27). Additional con-
trolled studies are needed to examine this and other
possible combinations.
Obviously, an adverse consequence of combina-
tion treatment is the economic cost of this strategy
if employed long-term. No studies are available
that examine the economic risks. Another area of
risk that has been neglected is the effect of
combination treatment on sudden death and mor-
tality. One prospective 10-year study of 88 patients
by Waddington et al. (28) found reduced survival
in the study cohort if more than one antipsychotic
was given (relative risk 2.46).
Discussion
In the absence of compelling empirical evidence, a
rationale for future clinical trials combining anti-
psychotics can be based on three theoretical
considerations.
Hypothesis one
Combining antipsychotics may lead to optimal
dopamine D2 receptor occupancy in a subgroup of
refractory or partially responsive patients who
require higher levels of D2 occupancy. This ratio-
nale is consistent with our finding that most reports
of enhanced efficacy with combination treatment
involved addition of high-potency D2 blockers to
clozapine, and with quetiapine’s ranking in recent
surveys as the agent most frequently involved in
combination treatment. Studies with conventional
agents have suggested that maximal efficacy occurs
with D2 occupancy of 70% or greater, although
some patients fail to respond to conventional
antipsychotics despite achieving adequate levels of
D2 occupancy (29). The mechanism responsible for
the superior efficacy of clozapine compared with
selective D2 blockers remains uncertain; however,
clozapine’s efficacy is achieved at D2 occupancy
levels below 60% (30). D2 receptor occupancy is a
dynamic process determined, in part, by the drug’s
dissociation constant and the relative concentra-
tions of drug and receptors. Kapur and Seeman (31)

have drawn attention to clozapine’s dissociation
constant for D2 receptor binding which, along with
quetiapine, is more than 500-fold greater than the
dissociation constant for haloperidol. They argue
that Ôloose bindingÕ of atypical agents may explain
relatively low levels of sustained D2 occupancy and
the relative absence of extrapyramidal symptoms
(EPS) and hyperprolactinemia, since agents with
high dissociation constants are readily displaced by
endogenous release of dopamine (32). Augmenta-
tion of clozapine with a more Ôtightly boundÕ drug,
such as haloperidol or risperidone, would be
expected to increase D2 receptor occupancy. In a
preliminary trial, Kapur et al. (33) demonstrated
that addition of haloperidol to clozapine in five
patients increased D2 occupancy and elevated
serum prolactin concentrations. The expected in-
crease in ratings of EPS did not achieve statistical
significance in this small sample. Whether increased
D2 occupancy resulting from this approach will
enhance therapeutic response to clozapine remains
to be established. Whereas clozapine and quetia-
pine are too loosely bound to achieve sustained D2
occupancy above 70%, olanzapine, which has an
intermediate dissociation constant, can produce
these levels of D2 occupancy at daily doses of
approximately 30–40 mg (34). A recent controlled
trial found a trend towards enhanced efficacy in
treatment-resistant patients when the average dose
of olanzapine was increased from 19.6 to 30.4 mg
per day (35). Whereas optimizing D2 occupancy of
clozapine and quetiapine would, in theory, require
coadministration of a higher-affinity D2 blocker,
this goal could be achieved with olanzapine by
relatively high-dose monotherapy.
Hypothesis two
Another rationale for combination therapy is the
goal of attaining a diverse range of receptor
activities, rather than merely optimizing D2 occu-
pancy. This rationale is also implicit in Hypothesis
1, as optimization of D2 occupancy with an
atypical agent only makes sense if the atypical
agent contributes a therapeutic effect mediated by
mechanisms other than D2 receptor blockade.
Perhaps the strongest argument for this hypothesis
comes from the example of clozapine, which
consistently demonstrates superior efficacy of
uncertain mechanism compared with conventional
agents. Adrenergic, glutamatergic and serotonergic
receptors have been identified as possible contrib-
utors to clozapine’s superior efficacy for psychotic
symptoms, negative symptoms, and prophylaxis
against relapse (36–38). The atypical agents differ
from most conventional agents in their relative
Antipsychotic combination therapy in schizophrenia
affinity for serotonin 5HT2a receptors in relation
to D2 affinity (39), but differ among themselves in
activity at other serotonin receptor subtypes, as
well as activity at muscarinic and adrenergic
receptors (40). Clozapine, quetiapine and olanza-
pine may also differ from risperidone and conven-
tional agents in the attenuation of behavioral
responses to glutamatergic NMDA antagonists
(37). Because clozapine acts at most, if not all,
receptors that have been implicated as medi-
ating non-dopaminergic therapeutic mechanisms,
efficacy would seem least likely to be enhanced by
adding other drugs to clozapine (except for
enhancement of D2 occupancy). In contrast, com-
binations of most other atypical agents would
produce more diverse receptor activity of uncertain
clinical benefit.
Hypothesis three
The combination of antipsychotic agents may
allow clinicians to minimize side-effects associated
with higher doses of a single drug while maintain-
ing efficacy by the use of lower doses of two drugs
which differ in side-effect profiles. This approach
may be valid for the control of dose-related side-
effects that are specific to certain drugs. Examples
would include lowered seizure threshold, drooling,
and sedation achieved by lowering the dose of
clozapine while adding a second antipsychotic.
Although neither weight gain nor impairment of
glucose metabolism have been shown to be dose-
related with clozapine (41), Reinstein et al. (42)
reported improvements in both adverse effects
following the addition of quetiapine and reduction
of the clozapine dose in 65 patients. This approach
will require better delineation of the relationships
between serum concentrations of specific drugs and
dose-limiting side-effects, as well as careful assess-
ment of potential pharmacokinetic interactions.
Methodological considerations. Any future trial of
antipsychotic combination treatment should be
sufficiently powered both to reliably detect thera-
peutic effects of as-yet uncertain magnitude, as well
as to minimize the risk of type I error resulting
from the selective reporting of small positive trials
(43). Stern et al. (44) reviewed the sample size and
number of outcome variables for double-blind,
placebo-controlled, conventional antipsychotic
augmentation drug trials. In their sample of 13
published trials, they found a mean of 34.5 subjects
and 25 outcome measures per trial. The likelihood
of finding a positive result by chance in each
study was calculated to be 63%. They concluded
that augmentation trials need 40–100 subjects,
327
Freudenreich and Goff
depending upon variability of outcome measures
and effect size. Outcome measures should be
identified a priori and strictly limited in number.
One approach in lieu of increasing sample size is
the randomized trial design in individual patients
[for details see (45, 46)].
Further, in future trials, closer attention should
be paid to meaningful outcome measures and
patient selection. As it is unlikely that a magic
bullet is going to be found to address all domains
of known psychopathology and deficits, the aug-
mentation approach probably has to be symptom-
focused. The most important question to pose is
what constitutes clinically meaningful improve-
ment. A risk-benefit analysis might conclude that
small gains in certain symptoms (like 20% im-
provement on a total psychopathology scale) might
not be worthwhile given the risks and expense of
combining antipsychotic agents. Death as a poten-
tial outcome of polypharmacy deserves more
attention.
It seems inadvisable to use convenience samples
that are inhomogeneous with regard to subtype,
prior medication responsiveness and stage of
illness. The issue of staging has received little
attention in psychiatry (47). Patients in an early,
acute stage of illness might respond very differently
to interventions than patients who have entered a
chronic stage after the 5-year period of decline
described by Manfred Bleuler (48). Baseline sever-
ity, which generally reflects the degree of respon-
siveness to monotherapy, may also influence results
of trials, as seen in the disparate results between
risperidone augmentation of clozapine in Hender-
son’s (9) out-patient sample (producing a positive
response in patients presumably more responsive
to monotherapy at baseline) and deGroot’s (10)
negative experience in in-patients. However,
Taylor’s in-patient cohort did respond to the
augmentation strategy (11). More work is needed
to define treatment resistance and partial remis-
sion, including standardized definitions of ade-
quate treatment trials with atypical monotherapy
prior to combination trials (49, 50). Progress in
defining subtypes based on medication response is
needed, although some approaches are promising
(51). Until definitions are adopted, it will be
important to carefully characterize patient samples
according to clinical subtype, stage, medication
responsiveness and baseline symptom severity.
Finally, the ideal trial would address a logical
fallacy of the typical add-on combination or
augmentation trial that is often not mentioned: if
antipsychotic B is added to antipsychotic A and the
patient improves, it is assumed that antipsychotic
A is augmented by antipsychotic B. However, this is
328
not the only possible explanation. It is also
conceivable that antipsychotic B alone would be
more effective for the patient in question. Only
trials comparing optimal monotherapy with A and
B as well as their combination will fully clarify the
value of the combination. At the least, the study
design should include a method for optimizing
monotherapy treatment prior to initiation of the
randomized trial of combination treatment. Even
with this precaution, it may be necessary for one
comparator cell to include an increase in dose of
monotherapy, in addition to a placebo control
group, to assure that any clinical benefit results
from combination treatment rather than more
aggressive dosing.
Conclusion
Antipsychotic combination treatment clearly
requires further studies before clinical recommen-
dations can be made. It is intriguing that the
likelihood of augmentation of an atypical agent
roughly correlates inversely with the degree of
ÔtightnessÕ of D2 binding, with quetiapine being the
most augmented drug in clinical practice in USA.
A focus on optimization of D2 occupancy in
combination with clozapine may be a particularly
promising area for clinical trials. Beyond efficacy,
antipsychotic combinations will have to show in
future trials that they are not only safe but also
cost-effective. It can be argued that resources are
better spent on psychosocial programs that focus
on improving functional outcomes until efficacy of
combination antipsychotic treatment is adequately
established to justify the considerable cost.
In the interim, until further trials are conducted,
a thoughtful approach to the individual patient
recognizes the limitations of our knowledge about
combining antipsychotics, and includes close mon-
itoring of a time-limited trial, which should be
attempted only after optimal monotherapy has
been provided. Sequential monotherapy trials
should be performed before resorting to augmen-
tation trials in refractory patients. It will be
important for clinical research to catch up with
clinical practice in this aspect of the management
of refractory patients.
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