Original article 303
Duloxetine as adjunctive treatment to clozapine in patients
with schizophrenia: a randomized, placebo-controlled trial
Umberto Mico’a, Antonio Brunoa, Gianluca Pandolfoa, Vincenzo Maria Romeoa,
Domenico Mallamacea, Concetta D’Arrigob, Edoardo Spinab,c,
Rocco A. Zoccalia and Maria Rosaria A. Muscatelloa
Antidepressant drugs have often been used as an
augmentation strategy for those patients who have
demonstrated a suboptimal response to clozapine. The
present 16-week double-blind, randomized, placebo-
controlled trial study aimed to explore the efficacy and
c
tolerability of duloxetine add-on pharmacotherapy on
clinical symptomatology and executive cognitive
functioning in a sample of patients with treatment-resistant
schizophrenia receiving clozapine. After clinical and
neurocognitive assessments, the patients were randomly
allocated to receive, in a double-blind design, at a dose of
60 mg per day of duloxetine or a placebo. A final sample
of 33 patients completed the study. The results obtained
indicate that duloxetine added to stable clozapine
treatment showed a beneficial effect on the negative and
general psychopathological symptomatology in a sample
of treatment-resistant schizophrenic patients. With regard
to executive cognitive functions, duloxetine augmentation
Introduction
Antipsychotic drugs are considered the cornerstone of
treatment for schizophrenia (Lieberman et al., 2005); the
primary intervention for the stabilization of acute
episodes and the prevention of psychotic relapses and
recurrences in patients with schizophrenia. Clozapine, an
atypical antipsychotic agent with a low potential for
extrapiramidal adverse events (AEs) and a beneficial
effect on treatment compliance and suicide mortality
(Hennen and Baldessarini, 2005; Tiihonen et al., 2009a),
is the treatment of choice for nonresponder schizophrenic
patients (Kane et al., 1988; Wahlbeck et al., 1999). Yet,
approximately 30–60% of clozapine-treated patients
achieve only poor or partial response or are unable to
tolerate several adverse effects associated to clozapine
treatment or high-therapeutic dosages (Chakos et al.,
2001; Tuunainen et al., 2002). The development of
treatment strategies to effectively treat residual symp-
toms remains a therapeutic challenge. In clinical practice,
adjunctive pharmacotherapy is one of the most common
treatment strategies for those patients whose response
to clozapine is considered suboptimal (Sernyak and
Rosenheck, 2004; Remington et al., 2005), and it may
relief residual psychotic symptoms or address specific
target symptoms (e.g., aggression, cognition) that are
unresponsive to clozapine monotherapy (Buckley et al., 2001).
0268-1315
c 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
of clozapine had no significant effects. The findings provide
evidence that duloxetine augmentation of clozapine
treatment is safe and well tolerated and may be of benefit
for patients who are partially responsive to clozapine
monotherapy. Int Clin Psychopharmacol 26:303–310
2011 Wolters Kluwer Health | Lippincott Williams & Wilkins.
International Clinical Psychopharmacology 2011, 26:303–310
Keywords: augmentation, clozapine, duloxetine, schizophrenia
a
Department of Neurosciences, Section of Psychiatry, Psychiatric and
Anaesthesiological Sciences, bDepartment of Clinical and Experimental Medicine
and Pharmacology, Section of Pharmacology and cIstituto di Ricovero e Cura a
Carattere Scientifico (IRCCS), Centro Neurolesi ‘Bonino-Pulejo’, Messina, Italy
Correspondence to Dr Maria Rosaria A. Muscatello, Department
of Neurosciences, Psychiatric and Anesthesiological Sciences, Policlinico
Universitario Via Consolare Valeria, Messina 98125 Italy
Tel: +090 22212092; fax: +090 695136;
e-mail: mmuscatello@unime.it
Received 4 April 2011 Accepted 8 August 2011
Clinical guidelines (NICE Guidelines, 2002) suggest a
second antipsychotic in addition to clozapine in partially
responder patients with schizophrenia (Glick et al., 2004; Jo-
siassen et al., 2005; Genç et al., 2007; Zink et al.,
2009; Muscatello et al., 2011); nevertheless, no particular
combination strategy has been shown to be superior to the
others (Cipriani et al., 2010), and the potential advantages
of antipsychotic polypharmacy need to be weighted against
an increased risk of metabolic adverse effects (Correll et al.,
2007). Pharmacotherapies adjunctive to clozapine treat-
ment have also included mood stabilizers or anticonvul-
sants, such as valproate (Centorrino et al., 1994),
lamotrigine (Kremer et al., 2004; Zoccali et al., 2007; Tiiho-
nen et al., 2009b), and topiramate (Tiihonen et al.,
2005; Afshar et al., 2008; Muscatello et al., 2010), whereas
clozapine augmentation by carbamazepine should be
avoided as this combination has been implicated in fatal
agranulocytosis (Gerson et al., 1994).
Antidepressant drugs have often been used as an augmen-
tation strategy to enhance clozapine efficacy based on the
therapeutic rationale of addressing negative and resistant
symptoms (Evins and Goff, 1996). Conceptual proximity
and partial overlap between negative and depressive
symptoms (social withdrawal, apathy, anhedonia, and motor
retardation) have made antidepressants a natural and
DOI: 10.1097/YIC.0b013e32834bbc0d
 304 International Clinical Psychopharmacology 2011, Vol 26 No 6
common choice for the treatment of negative symptoms. As
tricyclic antidepressants added to clozapine showed little
benefit and an increased risk of toxicity (Chong and
Remington, 2000), the evidence from literature is more in
favor of augmentation with selective serotonin-reuptake
inhibitor (SSRI) and more recent compounds, such as the
noradrenergic and specific serotonergic antidepressants
(Buchanan et al., 1996; Zullino et al., 2002; Silver et al.,
2003; Zoccali et al., 2004; Berk et al., 2009). A recent meta-
analysis of 22 randomized controlled trials aimed to analyze
the efficacy of add-on antidepressants to clozapine and
other antipsychotics evidenced that antidepressants were
more effective than placebo in treating the negative
symptoms of schizophrenia (Singh et al., 2010).
After the second generation of antidepressants, including
the SSRIs and bupropion, and other dual-action com-
pounds, the selective serotonin–noradrenaline reuptake
inhibitors (SNRIs) emerged as a new class of dual-action
antidepressants. Duloxetine [LY248686; (+)-N-methyl-
3-(1-naphthalenyloxy)-2 thiophenepropanamine] is an
SNRI and inhibits the reuptake of serotonin and
noradrenaline, although it is a 3-fold to 4-fold more
potent inhibitor of serotonin (Bymaster et al., 2001).
Within the SNRI class, when compared with venlafaxine,
duloxetine shows a more balanced affinity, but is still
more selective for the 5-HT transporter (Stahl et al.,
2005). In addition, duloxetine has little or no affinity for
muscarinic, histamine-1, and b1-adrenergic receptors,
which may result in a side-effect profile similar to that
observed for SSRIs. Duloxetine has proven to be effective
in the treatment of depression (Nemeroff et al., 2002), in
major depressive disorder (MDD) with and without
melancholic features (Mallinckrodt et al., 2005), and in
patients with dysthymia and double depression (Koran
et al., 2007). In addition, duloxetine at a dose range of
40–60 mg per day has been proven to be anxiolytic and
analgesic (Bech et al., 2006; Lunn et al., 2009). In a
6-week, open-label, observational clinical trial (Englisch
et al., 2008), 20 patients with recurrent MD episodes in
the course of psychotic disorders (paranoid schizophrenia,
disorganized schizophrenia, schizoaffective disorder, and
brief psychotic disorder) received duloxetine at flexible
doses (mean dose at endpoint, 83.3 ± 26.3 mg/day) added
to stable antipsychotic treatment (clozapine, ziprasidone,
risperidone, amisulpride, and others). Results indicated
that duloxetine treatment significantly improved depres-
sive symptoms, as evidenced by mean changes on Calgary
Depression Rating Scale for Schizophrenia (CDSS) and
Hamilton Depression Scale total scores. Moreover,
psychotic negative symptoms improved considerably, as
assessed by mean change on Positive and Negative
Syndrome Scale (PANSS)-negative subscale score at the
end of the trial. The authors thus suggested the potential
efficacy of duloxetine augmentation of antipsychotic
drugs for the treatment of depressive episodes in the
course of psychotic disorders.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
The neurocognitive performance of patients with schizo-
phrenia, mainly in the cognitive subdomains of executive
functions, memory, and attention, was found to closely
correlate with several key outcome domains, representing
a limiting factor for treatment success and rehabilitation
(Green, 1996; Kirkpatrick et al., 2006). Cognitive impair-
ment should be considered as important as other clinical
symptoms of schizophrenia, and the improvement of
neurocognitive deficits is a key factor in the treatment of
the illness. However, recent clinical trials indicated only
modest cognitive benefits of second-generation relative
to first-generation antipsychotics (Hill et al., 2010). The
selectivity for the reuptake of serotonin (5-HT) and
noradrenaline makes duloxetine potentially interesting in
the treatment of cognitive impairment because imbal-
ance or deficiency in 5-HT and/or noradrenaline systems
has been found to contribute to cognitive deficits
(Reneman et al., 2001; Ressler and Nemeroff, 2001).
Concerning cognitive functioning, duloxetine treatment
for 8 weeks resulted in a significant improvement
compared with placebo on measures of cognitive func-
tions in a sample of elderly patients with MDD (Raskin
et al., 2007). Most of the improvement was observed in
verbal learning and memory domains, whereas measures
of executive functioning and focused attention showed
no duloxetine–placebo difference.
To the best of our knowledge, no double-blind, placebo-
controlled trials have been performed to examine the
clinical effect of adjunctive duloxetine to clozapine when
clozapine treatment has failed to induce a satisfactory
therapeutic response in treatment-resistant schizophrenia.
On the basis of the evidence from the literature, this
study was aimed to explore the efficacy of duloxetine
add-on pharmacotherapy on clinical symptomatology and
executive cognitive functioning in a sample of patients
with treatment-resistant schizophrenia demonstrating
an incomplete response to clozapine.
Methods
Patients
The study was carried out at the Psychiatry Unit of the
University Hospital of Messina, Italy. Forty outpatients,
24 men and 16 women, aged 23–48 years, who met the
Diagnostic and Statistical Manual and Mental Disorder-
IV criteria for schizophrenia and demonstrated persistent
positive and negative symptoms despite an adequate trial
of clozapine, were included in this study. Patients scoring
25 or more on the brief psychiatric rating scale (Overall
and Gorham, 1962) at both the screening and baseline
evaluation were classified as partial responders or non-
responders (Munro et al., 2004). The patients’ age, sex, and
clozapine mean dose are shown in Table 1. The duloxetine
and placebo groups were compared for the different
variables. All patients had been on clozapine monotherapy
at the highest tolerable range (450–650 mg/day), for at
least 1 year; the dose had been stable for at least 1 month

before the study and was left unchanged throughout the
study. The patients did not receive any antidepressant or
anticonvulsant drugs for a period of 2 months before the
study. The criteria for exclusion were primary or secondary
diagnosis of bipolar disorder, either manic or mixed
episode, as defined by Diagnostic and Statistical Manual
and Mental Disorder-IV Text Revision; active suicide
intent, or a suicide attempt in the preceding 6 months;
significant concurrent medical illnesses, organic brain
disease, dementia, or a traumatic brain injury; history of
substance and alcohol dependence (excluding nicotine),
mental retardation, and pregnant or lactating women were
excluded. Women of childbearing potential were required
to have a negative pregnancy test at the screening, and to
practice a medically acceptable method of contraception.
All the patients provided written informed consent after a
full explanation of the protocol design, which had been
approved by the local ethics committee. The patients were
recruited from January 2009, and the follow-up was
completed by December 2009.
Study design
This study was a 16-week double-blind, randomized,
placebo-controlled trial of adjunctive duloxetine to
clozapine treatment in schizophrenia. After baseline
evaluation, patients were randomly assigned to receive
adjunctive treatment with either duloxetine or placebo
(once daily) under double-blind conditions, using a
randomization automated system on a 1 : 1 basis. The
randomization list was held securely throughout the
study, and released only after study completion. Both
duloxetine and placebo were dispensed in identical-
appearing capsules.
The dose of duloxetine was 60 mg per day, which is the
maximum dose recommended by the Food and Drug
Administration for duloxetine in the treatment of major
depression (Cymbalta United States product information
sheet), was established at T0 and maintained until the
end of the trial at week 16. It has been evidenced that
duloxetine at a dose of 60 mg per day should be the dose
necessary for sufficient binding-site occupancy (Bech
et al., 2006; Takano et al., 2006), During the study, no
additional medications were allowed.
Table 1 Demographic and clinical characteristics of the clozapine
groups (duloxetine vs. placebo)
Duloxetine Placebo
Patients entered (completers) 20 (17) 20 (16)
Sex (male/female) 13/7 11/9
Age (years), mean ± standard deviation 35.9 ± 7.1 34 ± 6.8
Duration of illness (years), 6.8 ± 3.1 6.1 ± 3.2
mean ± standard deviation
Clozapine dose (mg/day), 503.3 ± 66.7 533.3 ± 67.2 0.174b
mean ± standard deviation
a
Fisher’s exact test.
b
Mann–Whitney U-test.
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Duloxetine add-on in schizophrenia Mico’ et al. 305
The following rating scales were used: the Brief
Psychiatric Rating Scale (BPRS) (Overall and Gorham,
1962), the PANSS (Kay et al., 1987), and the CDSS
(Addington et al., 1993), administered at baseline (week
0), and weeks 16.
Neurocognitive functioning was assessed with the
Wisconsin card-sorting test (WCST; Heaton et al.,
1993), the verbal fluency task (controlled oral word
association test, Spreen and Benton, 1977), and the
stroop color-word test (Trenerry et al., 1989). WCST is a
commonly used measure of concept formation and
flexibility of abstract thought in schizophrenia, although
it is useful to assess executive functioning. Measures of
performance included the number of completed cate-
gories and the number of preservative errors. The tests
were selected for the inclusion of functions frequently
attributed to the frontal lobes and widely used in the
study of cognition in schizophrenia.
All assessments tools were administered by experienced
clinicians and trained raters who were well versed with
the use of the rating scales; however, inter-rater reliability
for these assessments was not established by formal
training. Each patient had the same person administering
psychopathological and cognitive tests, and conducting
clinical interviews.
Patients attended seven visits: initial screening (week 1),
randomization (week 0) and five further visits at weeks 2,
4, 8, 12, and 16. Data for clinical and neurocognitive
assessments were collected at weeks 0 and 16; the design
of interest intervals has been chosen with the aim of
reducing possible sources of bias that may affect a
person’s performance on executive and cognitive tasks,
such as procedural learning or practice effects. Practice
effects are defined as increase in a patient’s test score
from one administration to the next; common causes of
practice-induced score gains are recall effects, procedural
learning, reduced anxiety in or growing familiarity with
the testing environment (Goldberg et al., 2007; Bartels
et al., 2010). With regard to the different cognitive
domains, executive functions showed highest score
increases over time as a result of a higher repetition rate
or the use of less alternate forms (Bartels et al., 2010).
At each visit, safety assessments included recording of
AEs, physical examination, vital signs measurements
(systolic and diastolic blood pressure, pulse rate, and
P body weight), electrocardiograph, and monitoring of
value extrapyramidal symptoms (by neurological examination
— and nonstructured interview). A routine set of laboratory
0.748a tests was performed at baseline and at the end of
0.187b
0.436b the study.
Statistical analysis
Data obtained from the study underwent check and
quality control and, subsequently, to descriptive and
 306 International Clinical Psychopharmacology 2011, Vol 26 No 6
inferential statistical analysis. Owing to the small sample
size and data not normally distributed, the analyses were
carried out by nonparametric tests. An intention-to-treat
analysis with last observation carried forward was
performed. Continuous data were expressed as mean ±
standard deviation: comparison between the groups at
baseline and at end of weeks was performed using the
Mann–Whitney U-test for two independent samples; the
within-group differences in efficacy ratings between
baseline and final test were analyzed by the Wilcoxon
rank-sum test. To measure the magnitude of a treatment
effect, effect size was provided by using Cohen’s d
statistic, which gives a measure of the standardized
differences in the mean values of change in scores
between medication. With regard to noncontinuous data,
the comparison between the two groups was made by
using the Fisher’s exact test.
Taking into account that multiple correlations increase
the risk of type 1 errors, a Bonferroni correction was
applied, and a significance of P value of less than 0.005
was chosen. The statistical analysis was performed with
Statistical Package for the Social Sciences (SPSS) 11.5
software (SPSS Inc., 2002).
Results
Treatment groups were well matched at baseline (Table 1);
baseline measures of psychopathology confirmed the
presence of residual psychopathology. According to BPRS
total score, patients might be considered as ‘mildly ill’
(Leucht et al., 2005), and this is congruent with the
presence of residual symptoms due to a partial response to
clozapine. Thirty-three patients completed the study
(82.5% completion rate). Discontinuation rates were 15%
for duloxetine and 20% for placebo. Three discontinuations
in the duloxetine group were all attributed to treatment-
emergent AEs (headache, sleepiness, and nausea). Among a
total of four dropouts in the placebo group, three were due
to noncompliance with the visits and one withdrew due to a
subjectively assessed lack of efficacy.
Tables 2 and 3 show the baseline and final scores of
the different efficacy measures for the duloxetine and the
placebo groups. Concerning clinical symptoms, at the
baseline visit (day 0), there were no significant differences
between duloxetine and control groups on PANSS, BPRS,
and CDSS scores. Taking a score of seven on the CDSS as a
cut-off value for depressive symptoms (Addington et al.,
1990), the number of patients who rated positive for
depressive symptoms before adjunctive treatment with
duloxetine was negligible. At endpoint (week 16), significant
differences between groups emerged at PANSS domains
‘negative’ (U = 44.000, P r 0.004), ‘psychopatology’ (U =
38.000, P r 0.001), and total scores (U = 37.500, P r 0.001).
With regard to cognitive performances, no significant
differences between clozapine and control groups were
found during the study.
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In active groups, within-group comparison revealed that
duloxetine augmentation of clozapine significantly re-
duced PANSS domains ‘negative’, ‘psychopatology’, as
well as total score, depressive (CDSS), and overall clinical
symptomathology (BPRS), as evidenced by score changes
at the end of the trial; conversely, positive symptoms did
not significantly improve over the time of treatment.
With regard to cognitive functioning, as measured by
Stroop test, verbal fluency, and WCST, duloxetine
augmentation of clozapine had no significant effects.
Table 4 shows the differences in both symptom
improvement and the magnitude of treatment effect
between duloxetine and placebo groups. Duloxetine,
compared with placebo, was significantly associated with
a greater reduction in PANSS-negative (P < 0.0001),
PANNS-psychopatology (P < 0.0001), and total score
(P < 0.0001), BPRS total score (P < 0.0001), and CDSS
total score (P < 0.0001); conversely, no significant
differences between duloxetine and placebo groups were
found in mean scores change on PANSS-positive, Stroop
test, verbal fluency, and WCST.
The combination duloxetine–clozapine was generally well
tolerated. The most common side effects were gastro-
intestinal symptoms (four patients, 23.5%), headache
(four patients, 23.5%), and one patient (5.8%) reported
a blurred vision. These AEs were generally mild and
disappeared or decreased in intensity with continuation
of treatment. No clinically significant changes in blood
pressure, heart rate, respiratory rate, temperature, and in
biochemical and hematological parameters were recorded,
and no acute extrapyramidal effects, seizures, or cardiac
events occurred. Three of 16 patients experienced
at least one AE while receiving placebo; these included
constipation (n = 1), insomnia (n = 1), and nausea
(n = 1).
Discussion
The results obtained from this double-blind, place-
bo-controlled trial, indicate that duloxetine added to
stable clozapine treatment showed a beneficial effect
mainly on the negative and general psychopathological
symptomatology in a sample of treatment-resistant
schizophrenic patients partially responsive to clozapine
monotherapy. Duloxetine was significantly more effica-
cious than placebo in reducing negative and psycho-
pathology symptoms as measured by change on the
PANSS total score and negative and psychopathology
subscale scores. The improvement in the overall psycho-
pathological state is highlighted by changes in BPRS
scores during duloxetine treatment. A reduction of
affective symptomatology, as expressed by the reduction
of CDSS total scores, was also observed. Conversely, in
placebo-treated patients no significant changes in the
overall clinical state or in negative and positive symptoms
were observed.
 Duloxetine add-on in schizophrenia Mico’ et al. 307

Table 2 Clinical changes in clozapine patients receiving duloxetine versus placebo at baseline and week 16 (last observation carried
forward)
Duloxetine (N = 20) Placebo (N = 20) Mann–Whitney U-test

Baseline Week 16 Baseline Week 16 Difference Difference

Mean (SD) Mean (SD) Mean (SD) Mean (SD) at baseline at week 16

PANSS
Positive 10.6 (2.9) 9.7 (2.5) 9.9 (2.1) 9.7 (1.5) 104.000 0.744 103.000 0.713
Negativea 19.4 (1.4) 15.1 (3.9) 19.1 (1.8) 19.7 (2.5) 103.500 0.713 44.000 0.004
General psychopathologyb 36.2 (9.8) 25.5 (9.1) 35 (9.1) 36.5 (8.6) 99.500 0.595 38.000 0.001
Total scorec 66.2 (12.7) 50.3 (14.2) 65.2 (12.5) 66.1 (10.5) 100.000 0.624 37.500 0.001
BPRS total scored 36.3 (8.6) 27.9 (7.3) 34.4 (7.3) 34.2 (6.7) 104.500 0.744 50.000 0.009
CDSS total scoree 5.9 (2.1) 2.7 (2.6) 4.7 (1.9) 4.5 (1.7) 70.000 0.081 61.500 0.033

BPRS, Brief Psychiatric Rating Scale; CDSS, Calgary Depression Rating Scale for Schizophrenia; PANSS, Positive and Negative Syndrome Scale; SD, standard
deviation.
a
Wilcoxon rank-sum test: Z = – 3.090/P = 0.002.
b
Z = – 3.109/P = 0.002.
c
Z = – 3.072/P = 0.002.
d
Z = – 3.072/P = 0.002.
e
Z = – 3.090/P = 0.002.

Table 3 Cognitive functions at baseline (t0) and at week 16 in clozapine patients receiving duloxetine versus placebo (last observation
carried forward)
Duloxetine (N = 20) Placebo (N = 20) Mann–Whitney U-test

Baseline Week 16 Baseline Week 16 Difference Difference

Mean (SD) Mean (SD) Mean (SD) Mean (SD) at baseline at week 16

Stroop test 53.1 (23.7) 51.6 (27.6) 55.3 (19.2) 55.1 (16.5) 109.500 0.902 111.500 0.967
Phonemic fluency 19.7 (10.8) 20.2 (12.5) 22.1 (8.0) 22.5 (7.4) 70.000 0.081 78.500 0.161
Semantic fluency 31.3 (7.2) 32.3 (6.8) 30.7 (6.1) 30.3 (5.7) 107.500 0.838 97.000 0.539
WCST
Perseverative errors 39.7 (18.5) 36.6 (13.5) 37.5 (15.8) 36.8 (14.1) 93.000 0.436 110.000 0.935
Categories 1.7 (1.4) 1.8 (1.4) 1.8 (1) 1.9 (0.9) 102.000 0.683 100.000 0.624

WCST, Wisconsin card-sorting test.

Table 4 Significance of change during the study period and effect in patients with psychotic disorders and recurrent MDD
sizes for efficacy measures (Englisch et al., 2008). As no other published studies
Duloxetine Placebo evaluated the effect of duloxetine in patients with
Change Change
schizophrenia, our results might be compared with the
Efficacy measures Mean (SD) Mean (SD) P valuea Cohen’s d effects of venlafaxine, a selective dual-reuptake inhibitor
PANSS
of serotonin and noradrenaline sharing with duloxetine a
Positive – 0.8 (1.9) – 0.2 (0.9) 0.148 0.4 similar pharmacological profile. Venlafaxine at the mean
Negative – 4.4 (3.1) 0.7 (1.9) < 0.0001 1.9 dose of 146 mg per day added to clozapine in a 6-week
General – 10.4 (11.7) 0.3 (2.6) < 0.0001 1.2
psychopathology
open trial (Mazeh et al., 2004) was proven to be effective
Total score – 15.9 (14.9) 0.8 (3.9) < 0.0001 1.5 in improving depressive and negative symptoms and
BPRS total score – 8.3 (6.7) – 0.2 (2.1) < 0.0001 1.6 general psychopathology scores in a sample of 19
CDSS total score – 3.2 (3.1) 0.1 (1.1) < 0.0001 1.4
Stroop test – 1.5 (11.5) – 0.2 (4.6) 0.870 0.1 depressed patients with schizophrenia.
Phonemic fluency 0.5 (5.1) 0.4 (2.4) 1.000 0.0
Semantic fluency 1.1 (3.1) – 0.3 (2.9) 0.148 0.4 In this study, an addition of duloxetine to clozapine was
WCST generally well tolerated, apart from mild and transient
Perseverative – 3.1 (8.8) – 0.7 (3.0) 0.967 0.3
errors
side effects, such as gastrointestinal symptoms and
Categories 0.1 (2.3) 0.1 (0.5) 0.539 0.0 headache, and none of the patients dropped out due to
AEs. Furthermore, psychotic positive symptoms remained
BPRS, Brief Psychiatric Rating Scale; CDSS, Calgary Depression Rating Scale
for Schizophrenia; PANSS, Positive and Negative Syndrome Scale; SD, standard stable and none of the patients experienced a switch to
deviation; WCST, Wisconsin card-sorting test.
a
mania or a psychotic exacerbation.
Mann–Whitney U-test.
As many antidepressants and antipsychotics share com-
The reduction of depressive and negative symptoms, and mon metabolic pathways and influence the activity of
of global psychopathology, as measured by PANSS- various drug-metabolizing enzymes, the possibility of
psychopathology subscale during duloxetine add-on pharmacokinetic interactions between these drugs must
treatment has been documented in a previous open trial be taken into account. Adjunctive treatment of anti-
aimed to evaluate the antidepressive effect of duloxetine depressant to an ongoing antipsychotic therapy can raise

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
 308 International Clinical Psychopharmacology 2011, Vol 26 No 6
blood levels of antipsychotic drugs, as demonstrated for
fluvoxamine (Hiemke et al., 1994), fluoxetine and
paroxetine (Spina et al., 1998; Spina et al., 2000), and
venlafaxine (Repo-Tiihonen et al., 2005). Duloxetine is
both a substrate and a moderately potent inhibitor of
CYP2D6, whereas it has been reported to have no
significant inhibitory effect on the activity of CYP1A2,
CYP2C9, CYP2C19, and CYP3A4 in vitro (Skinner et al.,
2003). Although serum concentrations of clozapine were
not measured in this study, duloxetine at a dose of 60 mg
per day had little or no effect on the pharmacokinetics of
clozapine and olanzapine, whereas it caused a modest,
but statistically significant increase in the plasma
concentrations of risperidone active fraction, as demon-
strated by a drug monitoring trial conducted on a sample
of 22 outpatients with schizophrenia or schizoaffective
disorder (Santoro et al., 2010). Conversely, Englisch et al.
(2008) found that duloxetine (mean dose, 83.3 ± 26.3 mg/
day) and clozapine (11 patients, mean dose, 350.0 ±
127.0 mg/day) was associated with increased side effects
attributable to the raise in clozapine and desmethylclo-
zapine serum levels that required small adaptations of
clozapine dosage. This effect of the pharmacokinetic
interactions, maybe due to the relatively high dosage of
duloxetine, has important clinical implications, as the rise
in clozapine blood levels can cause marked side effects
and an increase of toxicity (Spina and de Leon, 2007).
Moreover, it can be considered a potentially confusing
element, as the improvement in clinical symptomatology
reported after duloxetine add-on therapy may result from
an increase of clozapine plasma concentrations. The lack
of significant kinetic interactions between duloxetine
(60 mg) and clozapine leads us to suppose that the
therapeutic effect shown by duloxetine on the clinical
symptomatology of treatment-resistant schizophrenic
patients may result from a pharmacodynamic mechanism
involving the receptor profiles of the two drugs, with
duloxetine additively complementing the clozapine
receptor profile and hence exerting a synergistic action
on the multiple receptor subtypes and on the neuro-
transmitter systems involved in the pathophysiology of
schizophrenic symptoms. However, the underlying me-
chanisms are yet unidentified. Given that noradrenergic
underactivity has been assumed to be associated with
negative symptoms (Yamamoto and Hornykiewicz, 2004),
it can be hypothesized that the noradrenergic action of
duloxetine may have had a role in reducing negative
symptoms.
Our study highlighted that the improvement in negative
symptoms and in overall psychopathology was not
associated with a concomitant improvement in cognitive
functions, which contrary to expectations, did not
significantly change in duloxetine-treated patients. Nor-
adrenergic reuptake inhibition in the prefrontal cortex
should enhance both dopamine and noradrenaline levels,
as both neurotransmitters, in this area, depend on the
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
noradrenaline transporter for reuptake (Moron et al.,
2002); thus, it has been suggested that compounds with
mechanisms of action of the noradrenergic type should
exert their positive effect on executive functions (Stahl
et al., 2003). In a sample of patients with MDD,
duloxetine was reported effective in improving verbal
learning and memory, with no effects on executive
functioning and focused attention (Raskin et al., 2007).
A recent open trial showed that both escitalopram
(10 mg/day) and duloxetine (60 mg/day) improved verbal
and visual working memory, sustained attention, inhibi-
tion of automated responses, set shifting, and planning in
73 depressed patients; however, the cognitive functions
of depressed patients did not improve enough to reach
the levels of performance of the controls (Herrera-
Guzmán et al., 2010). The possibility that the improve-
ment in cognitive dysfunctions was independent from the
effect on depressive symptomatology could not be ruled
out, as cognitive symptoms in depressed patients are
usually fluctuating over time and only attentional deficits
were found in remitted patients with MDD (Weiland-
Fielder et al., 2004), thus suggesting a certain degree of
association between cognitive impairment and clinical
symptoms. In schizophrenia, cognitive symptoms are
thought to constitute an independent core feature of
schizophrenia with a peculiar patophysiology, and their
treatment still remains a challenge, underscoring the
pressing need for further research efforts in this area.
This study shows certain limitations, due to the small
sample size; furthermore, no formal assessment of side
effects and EPS was used, as they were monitored at each
visit by clinical interview and neurological examination.
Nevertheless, this is, to our knowledge, the first double-
blind, placebo-controlled trial to explore the use of
duloxetine as an add-on therapy in schizophrenia. Our
findings provide evidence that duloxetine augmentation
of clozapine treatment is well tolerated and may be of
benefit for patients who are partially responsive to
clozapine monotherapy, supporting the need of further
double-blind, placebo-controlled trials in larger samples
of patients to evaluate the therapeutic potential of
duloxetine augmentation of clozapine and other
antipsychotic drugs.
Acknowledgements
Conflicts of interest
There are no conflicts of interest.
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