European Psychiatry 29 (2014) 449455

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Original article

Impact of primary negative symptoms on functional outcomes

in schizophrenia
G. Fervaha a,*,b, G. Foussias a,b,c, O. Agid a,b,c, G. Remington a,b,c
a
Schizophrenia Division, Centre for Addiction and Mental Health, 250, College Street, M5T 1R8 Toronto, Ontario, Canada
b
Institute of Medical Science, University of Toronto, Toronto, Canada
c
Department of Psychiatry, University of Toronto, Toronto, Canada

A R T I C L E I N F O A B S T R A C T

Article history: Objective: Negative symptoms are known to undermine functional outcomes in people with
Received 7 November 2013 schizophrenia; however, most studies have not accounted for whether these symptoms were primary
Received in revised form 3 January 2014 or secondary to other psychopathological factors. The present study examined the impact of primary
Accepted 26 January 2014
negative symptoms on functional outcomes in patients with schizophrenia.
Available online 14 March 2014
Method: The sample included 1427 patients with schizophrenia who completed the baseline visit in the
CATIE study. Symptoms were assessed with the Positive and Negative Syndrome Scale and Calgary
Keywords:
Depression Scale, extrapyramidal side effects with the Simpson-Angus scale, and functional status with
Schizophrenia
Functional outcome
the Heinrichs-Carpenter Quality of Life Scale.
Negative symptoms Results: Negative symptoms were signicantly and inversely related to each domain of functioning
Primary symptoms examined. These relationships remained after statistically controlling for the inuence of potential
Avolition-Apathy sources of secondary negative symptoms. In addition, the relationships between negative symptoms and
Psychosocial functioning specic domains of functioning remained in patients who had mild/absent positive, depressive, anxiety
and extrapyramidal symptoms. Negative symptoms were associated with functional outcomes even in
antipsychotic-free patients.
Conclusions: Primary negative symptoms signicantly contribute to the functional impairment seen in
people with schizophrenia. A better understanding of the etiology and pathobiology of these symptoms
is required to guide the search for effective therapeutics that promote functional recovery.
2014 Elsevier Masson SAS. All rights reserved.

1. Introduction prominent presentation of confounding variables (e.g., suspicious-

The negative symptoms of schizophrenia are a prevalent
feature of the disorder [8], and have long been recognized as
being intimately linked with poor functional outcomes [4,15,53].
Negative symptoms include symptoms of blunted affect, alogia,
anhedonia, asociality and avolition/apathy [38]. Severity of these
symptoms however may be inuenced by factors not intrinsically
linked to the disease process such as drug-related akinesia [56],
depression and suspiciousness [11,24], to name a few (Fig. 1). That
said, the inuence of negative symptoms not ascribed to such
secondary sources on functional outcomes is less clear.
There are in general two manners in which primary (i.e.,
idiopathic) negative symptoms can be examined. The rst is to
restrict patient selection by excluding those individuals with
* Corresponding author. Tel.: +416 535 8501x34818; fax: +416 979 4292.
E-mail address: gagan.fervaha@utoronto.ca (G. Fervaha).
ness). To this end, therapeutic intervention can be used to determine
whether a negative symptom is extrinsic to the disease process (e.g.
use of anticholinergics for antipsychotic-induced akinesia) [11].
While some studies have parsed out a group of patients with
idiopathic and enduring negative symptoms (i.e., decit syndrome)
[12], and found these patients have worse functioning than those
without such symptoms [10,19,26,32,37,51,61], most studies
examining negative symptoms dimensionally across patients with
schizophrenia have not controlled for potential sources of secondary
negative symptoms. The second method to examine primary
negative symptoms is through statistical covariation analyses. This
method aims to examine the relationship between negative
symptom severity and some outcome variable while statistically
partially out the variance accounted for by other potentially
confounding variables (e.g., depression) [48].
Negative symptoms have been consistently linked to poor
functioning in numerous studies across a broad range of patients
with schizophrenia including both rst-episode and chronic

0924-9338/$ see front matter 2014 Elsevier Masson SAS. All rights reserved.
http://dx.doi.org/10.1016/j.eurpsy.2014.01.007
450 G. Fervaha et al. / European Psychiatry 29 (2014) 449455
Fig. 1. Illustration of potential sources of secondary non-idiopathic negative symptoms. This list is not meant to be exhaustive, rather it is intended to simply highlight the
many variables that can potentially inuence negative symptom assessment. It should also be noted that although primary and secondary negative symptoms are viewed as
distinct, they are in fact not mutually exclusive.
samples [9,1618,20,21,25,30,33,39,45,47,52,54,57]; however,
most of these investigations have not specically examined the
impact of primary negative symptoms on functional status. There
are nonetheless some exceptions. A few studies have statistically
controlled for select sources of potential secondary negative
symptoms such as positive and/or depressive symptoms
[16,17,21,39,47,52,54], while others have excluded patients with
moderate-severe depression or extrapyramidal symptoms [20,25].
These prior studies although suggestive that primary negative
symptoms impact functioning have only controlled for, either
statistically or through study design, one or more potentially
confounding sources of negative symptoms; these studies have not
concurrently controlled for a range of factors known to related to
secondary negative symptoms including psychosis, depression,
anxiety and extrapyramidal symptoms.
The present study sought to examine the relationship between
primary negative symptoms and functional outcomes in a broad
range of patients with schizophrenia. Based on previous work, we
hypothesized that negative symptoms would have a signicant
impact on functional outcome, whereby greater negative symptom
severity is associated with poorer functional status. We further
hypothesized that this signicant relationship between negative
symptoms and functioning will be maintained after statistically
and experimentally controlling for potential sources of secondary
negative symptoms such as psychosis, depression, anxiety and/or
extrapyramidal symptoms. Lastly, we hypothesized that primary
negative symptoms would have an impact on each facet of
community functioning examined, including social, vocational and
recreational functioning.
2. Method
2.1. Study design and participants
Data were drawn from the baseline visit of the Clinical
Antipsychotic Trial of Intervention Effectiveness (CATIE) schizo-
phrenia study. Details of the study design and rationale [62], as
well as primary ndings [42], have been presented elsewhere. The
primary purpose of the CATIE study was to compare the
effectiveness of atypical and conventional antipsychotic medica-
tions through a randomized controlled trial conducted between
January 2001 and December 2004 at 57 sites in the United States
(16 university clinics, 10 state mental health agencies, 7 Veterans
Affairs medical centers, 6 private nonprot agencies, 4 private-
practice sites, and 14 mixed-system sites). One thousand four
hundred and ninety-three patients were initially randomized to
receive olanzapine (7.530 mg/day), perphenazine (832 mg/day),
quetiapine (200800 mg/day), risperidone (1.56 mg/day), or
ziprasidone (40160 mg/day) under double-blind conditions and
were followed up to 18 months or until treatment was
discontinued for any reason [62]. Data reported in the present
study are from the pre-randomization baseline visit before
initiation of any experimental treatment.
The study inclusion criteria have been reported previously [62].
Briey, participants were eligible if they were between the ages of 18
and 65 years and had a diagnosis of schizophrenia conrmed using
the Structured Clinical Interview for DSM-IV Axis I Disorders [22].
Participants were excluded from the study if they had a diagnosis of
schizoaffective disorder, mental retardation, or other cognitive
disorders; had only one episode of schizophrenia; were pregnant or
breast-feeding; or had a serious and unstable medical condition.
The study was approved by the institutional ethics review
board at each site, and written informed consent was obtained
from the patients or their legal guardians.
2.2. Outcome measures
2.2.1. Functioning and subjective experience
The principal measure of interest in the present study was the
Heinrichs-Carpenter Quality of Life Scale (QLS) [29]. The QLS is a
rater-administered semi-structured interview instrument, which
assesses functional status. The scale consists of 21 items rated on a
0 to 6 scale (higher scores reect better functioning) and is
comprised of four subscales: interpersonal relations, instrumental
role functioning, intrapsychic foundations, and use of common
objects and activities. The QLS is one of the most widely used
instruments in schizophrenia research to assess real-world
functional status [41], and is related to achievement of objective
functional milestones (e.g. employment, independent living, etc.)
[28]. As the intrapsychic foundations subdomain of the QLS has
been cited to have conceptual overlap with certain negative
symptoms, it was not included in the present analyses. Also, in an
effort to preserve scale psychometric properties as originally
dened [29], we did not create a modied QLS total score
(excluding intrapsychic foundations); rather, the remaining 3
domains of functioning were examined individually.
The Drug Attitude Inventory (DAI) [31] was employed to assess
patients subjective experience and attitude toward medication.
The DAI employed consists of 10 items with a binary yes/no
response format, with scores ranging from 10 to 10 (high scores
 G. Fervaha et al. / European Psychiatry 29 (2014) 449455
indicating a more positive subjective experience/attitude toward
medication). This scale, through its subjective experience compo-
nent, encompasses experiences of dysphoria.
2.2.2. Symptoms/psychopathology
Psychopathology was assessed using derived factor scores from
the Positive and Negative Syndrome Scale (PANSS) [34,44]. The
PANSS is a 30 item clinician-rated instrument which assesses
positive, negative and general psychiatric symptoms, which are
rated on a 1 to 7 scale (high scores reecting greater symptom
severity). Negative symptoms were evaluated using the negative
symptom factor score [44], which includes the following items:
blunted affect, emotional withdrawal, poor rapport, apathetic
social withdrawal, lack of ow, motor retardation and active social
avoidance. Severity of anxiety was assessed using a single item
from the general psychopathology subscale, and a score of 4 or
above on this item indicated a moderate-severe level of anxiety.
This single item has been shown to be signicantly related to more
comprehensive multidimensional measures of anxiety [43].
Depressive symptoms were assessed with the Calgary Depres-
sion Scale for Schizophrenia (CDSS) [1], a measure specically
designed to assess depressive symptoms in schizophrenia separate
from negative symptoms [3,14]. The CDSS consists of 9 items rated
on a 0 to 3 scale (higher scores reecting more severe depression).
Individuals with a score greater than 6 on this instrument were
identied as meeting CDSS criteria for a major depressive episode
(i.e. having moderate-severe depression) [2].
2.2.3. Medication-related side effects
Extrapyramidal symptoms were evaluated using the abbre-
viated Simpson-Angus Rating Scale (SAS) [60,64], which contains 6
items rated on a scale from 0 to 4 (higher scores denoting more
severe side effects). The specic items include: gait, arm dropping,
shoulder shaking, elbow rigidity, wrist rigidity, and tremor.
Patients scoring greater than one (i.e., mild severity) on any item
on the SAS were identied has having signicant extrapyramidal
side effects.
2.3. Statistical analyses
First, Pearsons product-moment correlations were computed
to examine the zero-order relationship between negative
symptoms and each domain of functioning including interper-
sonal relations (social), instrumental role functioning (voca-
tional), and use of common objects and activities (recreational).
Next, the potential inuence of various clinical variables on
negative symptom severity was examined using correlation
analysis.
The impact of primary negative symptoms on functional
outcome was examined using two separate analytic methods.
The rst method involved statistically controlling for potential
sources of secondary negative symptoms. The impact of primary
negative symptoms on functioning was evaluated using stepwise
hierarchical multiple regression modeling, where sources of
possible secondary negative symptoms were entered into the
model rst as a single block, and negative symptoms were entered
second. Another set of models were computed where sources of
secondary negative symptoms were entered second, negative
symptoms third, and various sociodemographic and additional
clinical variables were entered rst. This latter model was
computed to explore whether other factors that may inuence
negative symptoms such as sex, subjective experience/attitude
toward medication, and years of antipsychotic exposure have an
impact on functioning, and further whether negative symptoms
continue to impact functioning even once these variables are
statistically accounted for.
451
The second method involved controlling for secondary negative
symptoms through experimental study design. In this analysis,
patients with schizophrenia who were experiencing moderate-
severe psychosis, depression, anxiety or extrapyramidal symptoms
were excluded. The impact of negative symptoms on functioning
was then evaluated using linear regression modeling. This analysis
was repeated including only those patients who reported not
taking any antipsychotic medication for at least the preceding two
weeks.
A 2-sided P value of less than 0.05 was considered statistically
signicant. Statistical analyses were carried out using SPSS version
20 (IBM Corporation, Armonk, NY).
3. Results
3.1. Patient characteristics
Baseline demographic and clinical characteristics of the sample
are presented in Table 1. The study sample includes 1427
individuals with schizophrenia for whom symptom severity, side
effect burden and functioning data were available.
3.2. Negative symptoms and functioning
Negative symptoms were in fact signicantly correlated with
each domain of functioning, including interpersonal relations
(r = 0.42, P < 0.001), instrumental role functioning (r = 0.24,
P < 0.001), and use of common objects and activities (r = 0.30,
P < 0.001); for all domains assessed, greater negative symptom
burden was associated with poorer functioning.
3.3. Secondary inuences on negative symptom burden
Negative symptom severity was signicantly associated with
various clinical variables including psychosis (r = 0.26, P < 0.001),
depression (r = 0.18, P < 0.001), anxiety (r = 0.12, P < 0.001) and
extrapyramidal symptom severity (r = 0.15, P < 0.001); specically
greater severity of these other clinical symptoms was related to
greater negative symptoms severity scores.
3.4. Primary negative symptoms statistical control
Negative symptoms were signicantly and inversely related to
functioning even after potential sources of secondary negative
symptoms were statistically accounted for (Table 2). The impact of
these primary negative symptoms remained for each area of
functioning assessed, including social, vocational and recreational.
Notably, the potential sources of secondary negative symptoms
were also signicantly associated with functioning, especially
positive and depressive symptoms (Table 2); specically, greater
positive and depressive symptom severity was related to worse
functioning in all domains assessed.
Next, we included a more exhaustive list of sociodemographic
and clinical variables, such as age, sex, presence of a substance use
disorder and obesity/waist circumference, into the stepwise
hierarchical regression model as the rst step, with all of these
variables being entered into the rst block. Even after statistically
(over-)controlling for these potential confounding variables,
negative symptoms still held a signicant and inverse relationship
with each facet of functioning evaluated (Table 3).
3.5. Primary negative symptoms experimental control
After excluding patients who were experiencing moderate-
severe psychosis, depression, anxiety and/or extrapyramidal
452 G. Fervaha et al. / European Psychiatry 29 (2014) 449455

Table 1
Sociodemographic and clinical characteristics for the study sample (n = 1427).

Variable Mean (SD) or % Range (minmax)

Age (years) 40.6 (11.1) 1867

Sex (males) 74.2
Race (white) 61.3
Employment status (unemployed) 84.1
Crisis stabilization in past 3 months (true) 27.3
Patients education (years) 12.1 (2.2) 121
Illness duration (years since rst prescribed antipsychotic medication) 14.4 (10.7) 056
PANSS (total score) 75.5 (17.5) 31140
PANSS positive factor score 21.9 (6.7) 845
PANSS negative factor score 19.3 (6.7) 740
PANSS disorganization factor score 16.8 (5.3) 737
PANSS excitement factor score 7.1 (2.9) 421
PANSS anxiety/depression factor score 10.4 (3.8) 422
PANSS anxiety item 2.9 (1.3) 17
CDSS (total score) 4.6 (4.4) 022
QLS (total score) 2.7 (1.1) 0.35.9
QLS interpersonal relations subscale score 2.5 (1.3) 0.06.0
QLS instrumental role subscale score 1.8 (1.6) 0.06.0
QLS intrapsychic foundations subscale score 3.1 (1.2) 0.06.0
QLS common objects subscale score 3.4 (1.2) 0.56.0
EPS score (average score) 0.2 (0.3) 02.7
Moderate-severe psychosis 76.9
Moderate-severe depression 33.6
Moderate-severe anxiety 27.7
Moderate-severe EPS 12.6

PANSS: Positive and Negative Syndrome Scale; CDSS: Calgary Depression Scale for Schizophrenia; QLS: Quality of Life Scale; EPS: extrapyramidal symptoms; SD: standard
deviation; Min: minimum value; Max: maximum value.

symptoms, 215 patients remained. Among these individuals,
negative symptoms were signicantly and inversely related to each
facet of functioning assessed, including interpersonal relations
(R2 = 0.12, F1,213 = 27.55, P < 0.001; b = 0.34, P < 0.001), instru-
mental role functioning (R2 = 0.10, F1,213 = 22.73, P < 0.001;
b = 0.31, P < 0.001), and use of common objects and activities
(R2 = 0.10, F1,213 = 2300, P < 0.001; b = 0.31, P < 0.001).
As antipsychotic medication itself may produce secondary
negative symptoms [6,59], we re-examined the above analyses
including only patients who reported being antipsychotic-free for
at least the preceding two weeks. Fifty-six patients who
were experiencing mild psychosis, depression, anxiety and/or
extrapyramidal symptoms and were not taking antipsychotic
medication were included in this analysis. Even for these patients,
negative symptoms were signicantly and inversely related to
each facet of functioning evaluated, including interpersonal
relations (R2 = 0.05, F1,55 = 2.98, P < 0.001; b = 0.23, P = 0.09),
instrumental role functioning (R2 = 0.10, F1,55 = 6.11, P < 0.001;
b = 0.32, P = 0.02), and use of common objects and activities
(R2 = 0.25, F1,55 = 17.87, P < 0.001; b = 0.50, P < 0.001), albeit the
relationship between negative symptoms and social functioning in
this population trended toward signicance. The pattern of results
was also similar for patients receiving antipsychotic medication
(data not shown).

Table 2
Stepwise multiple regression models with different facets of functioning as the dependant variable.

Model Step Variable added b t P R2 change

a
1 QLS interpersonal relations
1 PANSS positive 0.13 5.14 < 0.001 0.082
CDSS 0.10 3.83 < 0.001
PANSS anxiety 0.03 0.95 0.34
EPS 0.04 1.61 0.11
2 PANSS negative 0.36 14.45 < 0.001 0.117

2 QLS instrumental roleb

1 PANSS positive 0.13 7.80 < 0.001 0.046
CDSS 0.06 2.20 0.04
PANSS anxiety 0.02 0.56 0.57
EPS 0.03 1.28 0.20
2 PANSS negative 0.19 7.05 < 0.001 0.032
c
3 QLS common objects and activities
1 PANSS positive 0.09 3.22 < 0.001 0.045
CDSS 0.06 2.18 0.03
PANSS anxiety 0.13 4.49 < 0.001
EPS 0.07 2.81 0.005
2 PANSS negative 0.27 10.33 < 0.001 0.067

QLS: Quality of Life Scale; PANSS: Positive and Negative Syndrome Scale; CDSS: Calgary Depression Scale for Schizophrenia; EPS: extrapyramidal symptoms.
a
R2 = 0.202, F5,1421 = 71.88, P < 0.001.
b
R2 = 0.079, F5,1421 = 24.25, P < 0.001.
c
R2 = 0.112, F5,1421 = 35.75, P < 0.001.
 G. Fervaha et al. / European Psychiatry 29 (2014) 449455 453

Table 3
Stepwise multiple regression models with different facets of functioning as the dependant variable with additional sociodemographic/clinical predictors.

Model Step Variable added b t P R2 change

a
1 QLS interpersonal relations
1 Age 0.16 4.80 < 0.001 0.054
Sex 0.08 2.96 0.003
Ethnicity 0.04 1.59 0.11
Duration of illness 0.04 1.11 0.27
SUD 0.002 0.08 0.94
Recent exacerbation 0.04 1.47 0.14
Waist circumference 0.06 2.52 0.01
DAI 0.10 3.74 < 0.001
2 PANSS positive 0.10 3.63 < 0.001 0.065
CDSS 0.11 4.12 < 0.001
PANSS anxiety 0.02 0.68 0.50
EPS 0.01 0.40 0.69
3 PANSS negative 0.36 13.92 < 0.001 0.112

2 QLS instrumental roleb

1 Age 0.04 1.17 0.24 0.049
Sex 0.10 3.66 < 0.001
Ethnicity 0.03 1.05 0.30
Duration of illness 0.12 3.35 0.001
SUD 0.08 3.04 0.002
Recent exacerbation 0.05 1.76 0.08
Waist circumference 0.02 0.92 0.36
DAI 0.06 2.06 0.04
2 PANSS positive 0.11 3.68 < 0.001 0.038
CDSS 0.07 2.46 0.01
PANSS anxiety 0.001 0.32 0.97
EPS 0.004 0.14 0.89
3 PANSS negative 0.22 7.87 < 0.001 0.041
c
3 QLS common objects and activities
1 Age 0.05 1.54 0.13 0.072
Sex 0.05 1.89 0.06
Ethnicity 0.10 3.77 < 0.001
Duration of illness 0.09 2.46 0.01
SUD 0.10 3.98 < 0.001
Recent exacerbation 0.09 3.35 0.001
Waist circumference 0.08 2.94 0.003
DAI 0.09 3.28 0.001
2 PANSS positive 0.03 1.04 0.30 0.031
CDSS 0.06 2.01 0.04
PANSS anxiety 0.11 3.69 < 0.001
EPS 0.08 3.08 0.002
3 PANSS negative 0.28 10.32 < 0.001 0.067

QLS: Quality of Life Scale; PANSS: Positive and Negative Syndrome Scale; CDSS: Calgary Depression Scale for Schizophrenia; EPS: extrapyramidal symptoms; SUD: substance
use disorder or alcohol use disorder; DAI: drug attitude inventory. Duration of illness or disease chronicity is indexed by years of antipsychotic exposure.
a
R2 = 0.231, F13,1326 = 30.66, P < 0.001.
b
R2 = 0.127, F13,1326 = 14.90, P < 0.001.
c
R2 = 0.170, F13,1326 = 20.88, P < 0.001.

4. Discussion functioning. That is, it is possible that greater severity of primary

Negative symptoms were found to be a signicant contributor
to the functional impairment seen in patients with schizophrenia.
While many studies have noted this relationship [9,16
18,20,21,25,30,33,39,45,47,52,54,57], the present study extends
these ndings and conrms that primary idiopathic negative
symptoms serve as an impediment to functional recovery. The
present study has many strengths, one of which was the inclusion
of a large sample of patients, which allowed for the employment of
different strategies, both statistical and experimental, to control
for several variables that might potentially overlap with the
negative symptom construct.
In an effort to control for secondary non-idiopathic negative
symptoms we employed two methods [5,46]. First, we statistically
controlled for these symptoms by only examining the variance in
negative symptoms once that covariance with other variables (e.g.
depression) had been parsed. It should be noted that this method
underestimates the variance ascribed to primary negative symp-
toms [35], and thus underestimates the relationship with
negative symptoms is associated with higher ratings of say
extrapyramidal symptoms [13,50], or even that these latter
symptoms are etiologically linked with negative symptoms.
Another manner in which primary negative symptoms can be
examined is to restrict examination to patients who not severely
affected by secondary factors such as depression and suspicious-
ness. However, here too it is difcult to exclude all potential
sources of non-idiopathic negative symptoms [55]. It should also
be noted that the primary versus secondary distinction could be
made through clinical judgment; however, such clinical inferences
may be unreliable [23]. Nonetheless, use of standardized instru-
ments such as the Schedule for the Decit Syndrome [36], that
highlight various putative sources of secondary negative symp-
toms and examines history/course of symptoms, increase the
validity of the primary versus secondary symptom distinction.
Distinguishing between primary and secondary negative
symptoms is indeed an important clinical issue, as the underlying
pathophysiology and therefore potential treatments differ for each
of these. Primary negative symptom psychopathology has been
454 G. Fervaha et al. / European Psychiatry 29 (2014) 449455
linked to fronto-parietal neural dysfunction [27,40,58,63];
whereas secondary negative symptoms will have more diffuse
underlying mechanisms, depending on the source. It therefore
follows that treatment strategies will differ for primary versus
secondary negative symptoms [11,49].
It is noteworthy that negative symptoms explained a large
portion of variance in functional status, even after the variance
ascribed to clinical variables such as psychosis, depression, anxiety
and extrapyramidal symptoms has been statistically accounted for
(Table 2). In fact, for social and recreational functioning, the
variance accounted for by negative symptoms alone was greater
than that accounted for by the other four clinical variables.
Moreover, examination of the standardized regression coefcients
(i.e., beta weights) in the multiple regression model (Tables 2 and
3), suggests that negative symptoms had the greatest relative
effect on each facet of functioning evaluated. This nding is
consistent with previous work demonstrating that negative
symptoms continue to have explanatory power in predicting
functional outcome, even after a host of other variables have been
accounted for [16,17,21,39,47,52,54], and highlights the central
role of negative symptoms in the prediction of functional outcome
[20,25].
One additional strength of the present study that should be
mentioned was the examination of multiple domains of function-
ing. Primary negative symptoms demonstrated a signicant and
deleterious impact on social, vocational and recreational function-
ing, highlighting the pervasive adverse effects of these symptoms
in terms of real-world community functioning. The present study
therefore extends previous ndings, which have typically exam-
ined the impact of negative symptoms on a single domain or
composite measure of functional status.
In evaluating the present study on the impact of idiopathic
negative symptoms on functional outcome, some limitations
warrant mention. First, patients were entering into a treatment
trial; therefore, the ndings may not be generalizable to patients
stabilized on their medications. Second, in the analyses statistically
controlling for secondary factors, the factors included were not
exhaustive and it is thus possible that some of the variance
ascribed to primary negative symptoms is in fact due to non-
idiopathic inuences (e.g. environmental deprivation; Fig. 1) [55].
Third, although negative symptoms demonstrated a signicant
relationship with functional status and explained the largest
amount of variance relative to the other factors examined, the
overall amount of variance explained, although not trivial, was far
from comprehensive. This may, at least in part, be due to
measurement variance as a result of including many raters from
different sites. Alternatively, it may be due to the inclusion of a
heterogeneous sample of patients with minimal inclusion criteria
(i.e., inclusion of patients with acute exacerbation, co-morbid
illnesses, substance use, etc.) [62]. To this end, previous studies in
more homogenous samples of stable outpatients with schizo-
phrenia have found that negative symptoms explain a larger
portion of the variance in functioning scores [20,25,39]. Another
limitation includes the use of the PANSS to evaluate negative
symptoms. Although the PANSS is one of the most widely used
rating scales to evaluate schizophrenia psychopathology, it
includes only a limited number of items assessing negative
symptoms [38].
As the negative symptoms of schizophrenia are increasingly
being embraced as multidimensional [7], with certain facets (e.g.,
amotivation/apathy) demonstrating greater impact on functional
outcomes [17,20,25], it will be an important area of research to
discern potential secondary sources of negative symptoms that
differentially affect one domain of negative symptoms over
another. Furthermore, it will also be important to examine
whether specic primary negative symptoms (e.g., blunted affect)
inuence functional outcomes after other possible variables have
been controlled for. Some studies have for example demonstrated
that amotivation/apathy adversely affects functioning even after
factors such as psychosis and/or depression have been statistically
accounted for [16,17,21,39]; however, the potential inuence of
additional well-known variables that can affect negative symp-
toms (e.g., akinesia) were not concurrently accounted for, leaving
open the possibility that the negative symptoms evaluated were, at
least in part, not idiopathic.
The results of the present study afrm that negative symptoms
undermine functioning in patients with schizophrenia, and this
adverse inuence is seen even after other confounders have been
taken into account. That said, treatments aimed at primary
negative symptoms should promote functional recovery. Investi-
gations into the underlying pathobiology of negative symptoms
should take into account the potential for these symptoms to
covary with other clinical factors.
Disclosure of interest
Mr. Fervaha has received research support from an Ontario
Graduate Scholarship and a Canadian Institute of Health Research
(CIHR) Vanier Canada Graduate Scholarship. Dr. Foussias has
received research support from a CIHR Clinician-Scientist Training
Award, an APA-AstraZeneca Young Minds in Psychiatry Award, and
a NARSAD Young Investigator Award; has been involved in
research sponsored by Medicure Inc., and Neurocrine Bioscience;
served on advisory boards for Roche; and has received speaker fees
from Roche, Lundbeck, and Novartis. Dr. Agid has received research
support from Pzer Inc. and Janssen-Ortho; consultant fees from
Janssen-Ortho, Eli Lilly Inc. US, Eli Lilly Canada, Sepreacor,
Sunovion and Lundbeck; and speakers fees from Janssen-Ortho,
Eli Lilly Inc. US, Eli Lilly Canada, Novartis, Sepracor and Sunovion.
Dr. Remington has received research support from the Schizo-
phrenia Society of Ontario, CIHR, Research Hospital Fund Canada
Foundation for Innovation, Canadian Diabetes Association, Novar-
tis Canada, Medicure Inc., and Neurocrine Bioscience; as a co-
investigator he has received research support from the Canadian
Psychiatric Research Foundation and Pzer Inc.; consultant fees
from Laboratorios Farmaceuticos ROVI, Synchroneuron, Novartis,
and Roche; and speakers fees from Novartis.
Acknowledgements
Data used in the preparation of this article were obtained from
the limited access datasets (Version 1) distributed from the NIH-
supported Clinical Antipsychotic Trials of Intervention Effective-
ness in Schizophrenia (CATIE-Sz). This is a multisite, clinical trial
of persons with schizophrenia comparing the effectiveness of
randomly assigned medication treatment. The study was sup-
ported by NIMH Contract #N01MH90001 to the University of
North Carolina at Chapel Hill. The ClinicalTrials.gov identier is
NCT00014001. This manuscript reects the views of the authors
and may not reect the opinions or views of the CATIE-Sz Study
Investigators or the NIH.
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