CM E

Management of
Negative Symptoms in Schizophrenia
CM E EDUCATIONAL OBJECTIVES

1. Describe negative symptoms in

patients with schizophrenia.
2. Discuss evidence-based approach-
es to manage negative symptoms.
3. Review clinical trials focusing on the
treatment of negative symptoms.

Jeffrey T. Rado, MD, is Assistant Profes-

sor of Psychiatry and Internal Medicine,
Rush University Medical Center.
Address correspondence to: Jeffrey T.
Rado, MD, 2150 West Harrison, Chicago,
IL 60612; fax: 312-942-7284; or email: jef-
frey_rado@rush.edu.

© iStockphoto.com/Richard Johnson
Dr. Rado has disclosed the following
relevant financial relationships: Eli Lilly;
Otsuka; and Neuronetics: and Eli Lilly:
Speakers’ bureau.
doi: 10.3928/00485713-20110425-05

S
chizophrenia involves positive and
negative symptom domains. Nega-
tive symptoms often remain despite
available treatments and persist in a large
number of patients. Furthermore, they are
associated with considerable functional
impairment and increased morbidity. No
specific treatments are approved by the
Food and Drug Administration (FDA) for
management of negative symptoms. This
article reviews the current state of research
regarding the treatment of negative symp-
toms, including novel pharmacologic and
neuromodulatory therapies.
DEFINITION OF NEGATIVE
SYMPTOMS
The broad definition of negative
symptoms includes primary and sec-
ondary types. Primary symptoms are
a manifestation of schizophrenia,
whereas secondary symptoms may be
due to preoccupation with delusions or
hallucinations, comorbid depression or
medication adverse effects (eg, extra-
pyramidal symptoms or sedation).1
Based on a recent consensus state-
ment, negative symptoms are defined
as asociality, blunted affect, avoli-
tion, alogia and anhedonia.2 Asocial
patients exhibit reduced interpersonal
interactions. Blunted affect may mani-
fest as lack of voice modulation, poor
eye contact, or scarcity of communi-
cative gestures and facial expression.
Avolition is reduced motivation and
may exhibit as poor self-care. Patients
with alogia demonstrate reduced ver-
bal output. Finally, anhedonia (ie, the
inability to experience pleasure) is
evidenced by scarcity of recreational
and leisure activities and reduced in-
terest in sexual activities.

Jeffrey T. Rado, MD

PSYCHIATRIC ANNALS 41:5 | MAY 2011 PsychiatricAnnalsOnline.com | 265

4105Rado.indd 265 5/9/2011 3:08:56 PM


Recent Randomized Placebo-controlled Trials of
Adjunctive Treatment of Negative Symptoms21,26,27,45,46
N = 60, DSM-IV-TR
4 weeks
schizophrenia
N = 40, DSM-IV-TR
8 weeks
schizophrenia
N = 39, DSM-IV-TR
schizophrenia or
6 weeks
schizoaffective
disorder
N = 40, DSM-IV-TR
8 weeks
schizophrenia
N = 21, DSM-IV-TR
8 weeks
schizophrenia
Adapted from Cho et al, Kane et al, Akhondzadeh et al, Abbasi et al, and Joffe et al.
SIGNIFICANCE OF NEGATIVE
SYMPTOMS
Negative symptoms occur at a rate
of 50% to 90% in first-episode patients
with schizophrenia. Antipsychotic treat-
ment typically reduces this rate to 35% to
70%.3,4 The deficit syndrome, which re-
fers to patients with predominant negative
symptoms, is also associated with more
severe cognitive disorganization.5
Negative symptoms usually predict
poorer psychosocial and vocational func-
tioning. A study of 101 first episode pa-
tients with schizophrenia found that those
with predominant and persistent negative
symptoms demonstrated more impaired in-
sight into their illness compared with those
without predominant negative symptoms.6
Impaired insight is associated with reduced
adherence to antipsychotic medications and
increased risk of relapse. In a prospective
study of 77 patients with schizophrenia,
Tsai et al found that high levels of negative
symptoms led to significantly poorer social
266 | PsychiatricAnnalsOnline.com
4105Rado.indd 266
CM E
TABLE.
Armodafinil
50 mg, 100 mg, or Adjunctive to oral risperidone, olanzapine,
200 mg daily or paliperidone (stable dose ≥ 4 weeks)
Sildenafil
75 mg daily Adjunctive to oral risperidone (6 mg/day)
Mirtazapine
Adjunctive to haloperidol, trifluoperazine,
fluphenazine, levomepromazine, chlorpro-
30 mg daily
tixine, zuclopentixol, flupentixol, periciazine,
sulpiride, or a combination of these
30 mg daily Adjunctive to oral risperidone (6 mg/day)
15 mg daily for 2 weeks Adjunctive to oral risperidone (dose not
then 30 mg daily reported)
functioning, higher levels of anxiety and
lower appraisal of competence.7
In a study of older patients (n = 78)
with schizophrenia, interpersonal skills
were adversely affected by the presence of
negative symptoms.8 In addition, impair-
ment in relationships, recreational activi-
ties and work performance were related to
increased severity of negative symptoms
in 99 first-episode patients with schizo-
phrenia.9
NEUROBIOLOGY OF NEGATIVE
SYMPTOMS
The pathophysiological basis of nega-
tive symptoms is unknown. In magnetic
resonance imaging (MRI) studies, nega-
tive symptoms were associated with re-
duced brain size and reduced left temporal
lobe and medial frontal cortex grey matter
volume. For example, reduced gray matter
volume was found in the bilateral superior
temporal gyri and anterior amygdala/hip-
pocampal complex in 16 patients with
-3.4 + 2.07 on the PANSS negative
subscale score for the 200 mg dose
vs. placebo (effect size = 1.69 (CI =
0.78-2.6), no P value reported)
-12.20 + 3.44 on the PANSS negative
subscale score active group vs. -6.26
+ 4.41 in placebo (P < .001)
-3.60 + 2.58 on the PANSS negative
subscale score for mirtazapine vs.
-0.89+1.73 for placebo (P < .001)46
-13.45+4.04 on the PANSS negative
subscale score vs. -7.65 + 2.90 for
placebo (P < .001)45
-10.97 on the SANS for mirtazapine
vs -4.45 for placebo (P < .01)
schizophrenia and predominant negative
symptoms compared with controls.10
In addition, brain MRIs from 27 pa-
tients with schizophrenia and a predomi-
nance of negative symptoms demonstrat-
ed reduced gray matter volume in the left
superior temporal gyrus and insular cor-
tex, left medial temporal lobe, and the an-
terior cingulate and medial frontal gyri.11
Further, patients suffering from negative
symptoms also demonstrate reduced blood
flow to the right prefrontal area, temporal
lobe, and cerebellum on positron emission
tomography (PET) brain scans.12
In summary, an association between
negative symptoms and frontal cortical
hypoactivity is supported by neuroimag-
ing studies.
PHARMACOLOGIC APPROACHES TO
NEGATIVE SYMPTOMS
History
New drug development in schizophre-
nia historically focused on improvement in
PSYCHIATRIC ANNALS 41:5 | MAY 2011
5/9/2011 3:09:03 PM

positive symptoms. Negative symptoms,
however, often remain despite improve-
ment in positive symptoms. Reflecting
the fact that no intervention demonstrates
consistent clinical benefit, no agent has
an FDA-approved indication for negative
symptoms. In this context, a recent Nation-
al Institute of Mental Health (NIMH) con-
sensus statement declared that “persistent
and clinically significant negative symp-
toms are an unmet therapeutic need.”2
A key challenge to detecting the effect
of antipsychotic agents on negative symp-
toms is the question of “pseudospecific-
ity.”2 Clinical drug trials in schizophrenia
typically involve patients with an acute
exacerbation of positive symptoms. This
can make reduction in negative symptoms
more difficult to detect. Improvement of
negative symptoms in these individuals
may occur as a result of improvement in
dysphoria and positive symptoms, both
of which can worsen negative symptoms.
As a result, it is unclear whether the med-
ication is truly exerting a direct effect on
negative symptoms.
The Use of Antipsychotics
First-generation antipsychotics (FGAs)
are associated with an increased risk of
extrapyramidal symptoms (EPS), which
may induce secondary negative symptoms.
Further, they have not been effective for
primary negative symptoms.
Clinical trials of second-generation
antipsychotics (SGAs) describe vary-
ing degrees of improvement in negative
symptoms. In one review, a small to mod-
erate effect size of 0.39 (-0.45 to -0.33, P
< .0001) was observed in a meta-analy-
sis of 36 randomized controlled trials of
SGAs for negative symptoms involving
7,323 patients.13 Because most of the
studies recruited patients with predomi-
nant positive symptoms (ie, hallucina-
tions, delusions), as previously discussed,
this makes it more difficult to detect an
improvement in negative symptoms.
Another meta-analysis compared the
efficacy of SGAs with that of FGAs. It
PSYCHIATRIC ANNALS 41:5 | MAY 2011
4105Rado.indd 267
CM E
included 150 double blind studies involv-
ing 21,533 participants and compared nine
different SGAs to various FGAs.14 Four
SGAs (ie, amisulpride, clozapine, olanzap-
ine, and risperidone) were more efficacious
than FGAs for the treatment of negative
symptoms. Other agents (ie, aripiprazole,
quetiapine, sertindole, ziprasidone, and
zotepine) did not demonstrate increased
efficacy over FGAs. In support of this ob-
servation, olanzapine and risperidone were
moderately superior to FGAs for negative
symptoms in another meta-analysis of reg-
istration studies.15
Whether one specific agent among the
SGAs is superior for negative symptoms
is also unclear. For instance, in phase 2 of
the Clinical Antipsychotic Trials of Inter-
vention Effectiveness (CATIE) Study, 99
patients who discontinued their phase 1 as-
signment because of lack of efficacy were
randomly assigned to either open-label clo-
zapine or olanzapine, risperidone, or que-
tiapine under double blind conditions. The
effect of clozapine on negative symptoms
relative to these other agents was modest
and not statistically significant.16 Further-
more, a meta-analysis of 78 head-to-head
comparisons of SGAs found no significant
differences among these agents for nega-
tive symptoms, with the exception of the
superiority of quetiapine over clozapine in
two small studies from China.17
Combination Therapy
To maximize efficacy for negative
symptoms, antidepressants were studied
in combination with antipsychotics, with
mixed results. A recent Cochrane review of
five short-term studies totaling 190 patients
concluded that larger and longer-term stud-
ies of combination therapy are needed.18 A
meta-analysis of add-on antidepressants
for negative symptoms in schizophrenia
included 23 randomized, controlled trials
lasting 4 to 12 weeks and involved 809 pa-
tients.19 A moderate effect size (-0.48) in fa-
vor of antidepressants was found. None of
these studies found citalopram, mianserin,
reboxetine, or sertraline effective. The most
significant benefit occurred with fluoxetine,
trazodone, and ritanserin (a 5-HT2 antago-
nist). Controversy remains, however, as
to whether the observed improvement in
negative symptoms is primarily due to a
reduction in depressive symptoms.
Several additional antidepressant stud-
ies were published since these meta-analy-
ses were reported. Escitalopram added to
antipsychotic therapy for 10 weeks in 40
patients with schizophrenia did not sig-
nificantly reduce negative symptoms.20 By
contrast, 8 weeks of adjunctive mirtazap-
ine in 21 stable patients with schizophrenia
demonstrated a significant reduction (P <
.05) in mean baseline to endpoint SANS
scores (-10.97) compared with placebo (-
4.45) (see Table, page 266).21 Significant
improvement was also found in two addi-
tional studies adding mirtazapine to risperi-
done or to FGAs.
A fourth study investigating mirtazap-
ine add-on to SGAs, however, did not find
a benefit.22 Because combination therapy
may increase the risk of adverse effects,
drug-drug interactions and health care
costs, further evaluation is warranted be-
fore recommending this strategy.
Efficacy of Non-amphetamine
Stimulants
The efficacy of modafinil for negative
symptoms was examined in a series of
studies. Investigators failed to find a signifi-
cant improvement in negative symptoms in
two 8-week, randomized double blind tri-
als of adjunctive modafanil.23,24 Similarly,
an 8-week, randomized study of modafinil
added to clozapine did not show benefit for
negative symptoms.25
A double blind, placebo-controlled
trial of 60 patients with stable schizo-
phrenia studied armodafinil, a long-act-
ing isomer of modafinil (see Table, page
266).26 Patients on stable antipsychotic
doses were randomized in a 1:1:1:1 ratio
to armodafinil (50 mg, 100 mg, or 200
mg) or placebo for 4 weeks. Patients in
the 200-mg dose group experienced a
significant reduction in the mean PANSS
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5/9/2011 3:09:04 PM

Negative Symptom Subscale score (effect
size = 169). Patients also experienced re-
ductions in their SANS scores, although
statistical significance was not reported.
Other Agents
A double blind, randomized, study
compared risperidone plus sildenafil to ris-
peridone plus placebo in 40 patients with
schizophrenia. PANSS Negative Symptom
Subscale scores significantly improved in
those taking adjunctive sildenafil versus
placebo (P = .02) (see Table, page 266).27
Studies of adjunctive memantine produced
mixed results with one positive (n = 22) and
one negative trial (n = 135). Proof of con-
cept studies investigating NMDA receptor
antagonists (cycloserine, sarcosine, and d-
serine), omega fatty acids and minocylcine
as adjunctive therapy demonstrated prom-
ising but preliminary results.22 In contrast,
studies with raloxifene, lamotrigine, val-
proate, galantamine, buspirone, reboxetine,
and atomoxetine all failed to demonstrate a
benefit for negative symptoms.22
NEUROMODULATORY APPROACHES
TO NEGATIVE SYMPTOMS
Electroconvulsive Therapy
Although most trials of electroconvul-
sive therapy (ECT) in schizophrenia did
not measure negative symptoms, a few
small studies did formally assess these
symptoms and found a benefit for ECT.
For example, a significant improvement in
SANS scores occurred in 15 patients with
schizophrenia on stable antipsychotics
following an open-label add-on course of
eight to 20 ECT sessions (P < .05).28
Other studies, however, did not find a
benefit. For example, 253 patients with
treatment-resistant schizophrenia given a
combination of ECT and flupenthixol did
not experience an improvement in nega-
tive symptoms.29 Matheson et al recently
analyzed five systematic reviews with
meta-analyses of ECT studies in schizo-
phrenia conducted since 2000.30 Al-
though a “medium size” benefit for over-
all clinical improvement in schizophrenia
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4105Rado.indd 268
CM E
was found, the authors did not make any
conclusions about ECT’s specific benefit
for negative symptoms.
Transcranial Magnetic Stimulation
Transcranial magnetic stimulation
(TMS) delivers intense, intermittent mag-
netic pulses produced by an electrical
Patients also experienced
reductions in their SANS
scores, although statistical
significance was not reported.
charge into a ferromagnetic coil.31 The use
of TMS for negative symptoms was first
reported by Cohen et al.32 Six inpatients
with schizophrenia on stable antipsychotic
doses underwent treatments 5 days per
week for 2 weeks at 80% MT and a dosage
of 20, 2-second, 20 Hz stimulations with a
58-second intertrain interval (ITI) applied
to the prefrontal cortex (side not defined).
PANSS Negative Symptom Subscale
scores significantly decreased (P < .02).
A second study administered daily
TMS treatments at 100% MT over the
left dorsolateral prefrontal cortex (DLP-
FC) (20, 3.5-second, 10 Hz stimulations
with a 10-second ITI) to 10 patients with
negative symptoms associated with their
schizophrenia.33 SANS scores decreased
from a mean baseline of 49.0 (± 10.7) to
44.7 (± 11.8) post-treatment (P < .001).
In a third study, 4 weeks of daily TMS
(24, 5-second, 15 Hz stimulations with a
25-second ITI) was administered over the
left DLPFC to four patients with schizo-
phrenia. PANSS Negative Symptom Sub-
scale scores decreased from a mean of
29.25 at baseline to 19.5 following treat-
ment (P value not reported).34
A final open-label trial administered 2
weeks of daily TMS (20, 2-second stimula-
tions with a 58-second ITI) to 27 patients
with schizophrenia at either 3 Hz, 20 Hz,
or a stimulation set individually at each
patient’s EEG-derived alpha frequency. A
patient’s alpha-wave frequency refers to
any rhythmic activity detected between 8
to 12 Hz on EEG. The greatest reduction
in PANSS Negative Symptom Subscale
scores (29.6%) occurred in the patients re-
ceiving the alpha frequency stimulus versus
the other two groups (< 9%) (P = .007).35
TMS was administered over the left
DLPFC in seven, published sham-con-
trolled studies.36-42 In the first study, TMS
(20, 5-second, 10 Hz stimulations with a
30-second ITI) was given at 100% MT for
10 daily sessions in a randomized, double
blind study. Twenty-two hospitalized pa-
tients with schizophrenia on stable psycho-
tropic regimens who received active TMS
experienced no significant improvement in
the PANSS Negative Symptom Subscale
score versus the sham group.37
Identical TMS treatment parameters
(except 110% MT) and duration were em-
ployed in a similar study of 20 inpatients
with schizophrenia or schizoaffective dis-
order on stable antispychotics.37 Here,
significantly greater improvement on the
PANSS Negative Symptom Subscale score
was reported for the active versus sham
group (no P value reported). However,
Novak et al did not find a significant effect
with 10 daily sessions of higher frequency
(ie, 20 Hz) TMS (40, 2.5-second stimula-
tions with 30-second ITI, at 90% MT) in
16 patients with schizophrenia.38
Seventeen patients with schizophrenia
were randomly assigned in a double blind
study by Mogg et al to either 10 daily ac-
PSYCHIATRIC ANNALS 41:5 | MAY 2011
5/9/2011 3:09:05 PM

tive TMS (20, 10-second, 10 Hz stimula-
tions at 110% MT, with 50-second ITI) or
sham treatments.39 The investigators did
not find a significant difference between
active or sham groups. By contrast, Pri-
kryl et al (2007) employed a greater num-
ber of treatments and found a significant
effect for TMS on negative symptoms in
22 patients with schizophrenia.40 Patients
were randomly assigned to active (15, 10-
second stimulations, at 110% MT, with
30-second ITI) or sham TMS for 15 con-
secutive daily treatments. Active TMS led
to a 29% reduction in the PANSS Nega-
tive Symptom Subscale score and a 50%
reduction in the SANS score.
Another study randomly assigned 10
patients with schizophrenia to 10 days
of active TMS (10, 4.9-second, stimula-
tions at 110% MT, with a 30-second ITI)
or a sham procedure.41 Greater improve-
ment in the PANSS Negative Symptom
Subscale score occurred in the active
versus sham TMS group (P = .008). A
unique aspect of this study is that the
authors included depression assessments
(Calgary Depression Scale Schizophre-
nia [CDSS]) at baseline and follow-up
to evaluate whether improvement in
mood might confound improvements in
negative symptoms. Changes in negative
symptoms scores did not correlate with
changes in the CDSS score.
Schneider compared 20 active daily
TMS treatments (20, 5-second stimula-
tions, at 110% MT, with 15-second ITI,
at 1 Hz or 10 Hz) with sham TMS in 51
patients with schizophrenia.42 The 10 Hz
treatment group experienced significantly
greater improvement on the SANS score
(percentage improvement not reported)
compared with the 1 Hz and sham groups
(P = .031). No significant changes were
noted on the Hamilton Depression Rating
Scale (HAM-D), providing evidence that
the observed changes were not attributable
to improvements in depression.
TMS for negative symptoms of
schizophrenia was also evaluated in two
meta-analyses. The first, by Freitas and
PSYCHIATRIC ANNALS 41:5 | MAY 2011
4105Rado.indd 269
CM E
colleagues, evaluated only those trials
employing more than one session of
high frequency stimulation over the left
DLPFC (ie, eight studies involving 107
patients), as this has been the most ex-
tensively used approach to specifically
address negative symptoms.43 When
analyzing only the active arms of these
studies, the authors found an effect size
of 0.58 (using a random effects model)
and 0.49 (using a mixed effect model).
The authors concluded that high fre-
quency TMS over the left DLPFC led
to a “modest to moderate” reduction
in negative symptoms. When they only
considered sham-controlled data, how-
ever, the pooled weighted effect size was
0.27 with no significant improvement in
patients receiving active compared with
sham stimulation. Of note, two positive
trials were excluded from this analysis
because of inadequate data.
A subsequent meta-analysis did in-
clude these two trials plus two previously
unpublished trials.44 In total, the authors
analyzed nine randomized, controlled
trials involving 213 patients. The mean
effect size was 0.63 (96% CI, 0.11-1.15)
for studies employing high frequency (>
10 Hz) TMS, leading the authors to con-
clude that TMS for negative symptoms
warrants further study.
CONCLUSION
Negative symptoms are chronic and
persistent in patients with schizophrenia,
causing impairment in psychosocial and
vocational functioning. Currently avail-
able treatments do not provide adequate
relief of these symptoms. Although im-
provement in some patients was observed
with studies of SGAs, antidepressants,
and therapeutic neuromodulation, larger,
and better designed trials are needed.
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