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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-


ness). To this end, therapeutic intervention can be used to determine
The negative symptoms of schizophrenia are a prevalent whether a negative symptom is extrinsic to the disease process (e.g.
feature of the disorder [8], and have long been recognized as use of anticholinergics for antipsychotic-induced akinesia) [11].
being intimately linked with poor functional outcomes [4,15,53]. While some studies have parsed out a group of patients with
Negative symptoms include symptoms of blunted affect, alogia, idiopathic and enduring negative symptoms (i.e., decit syndrome)
anhedonia, asociality and avolition/apathy [38]. Severity of these [12], and found these patients have worse functioning than those
symptoms however may be inuenced by factors not intrinsically without such symptoms [10,19,26,32,37,51,61], most studies
linked to the disease process such as drug-related akinesia [56], examining negative symptoms dimensionally across patients with
depression and suspiciousness [11,24], to name a few (Fig. 1). That schizophrenia have not controlled for potential sources of secondary
said, the inuence of negative symptoms not ascribed to such negative symptoms. The second method to examine primary
secondary sources on functional outcomes is less clear. negative symptoms is through statistical covariation analyses. This
There are in general two manners in which primary (i.e., method aims to examine the relationship between negative
idiopathic) negative symptoms can be examined. The rst is to symptom severity and some outcome variable while statistically
restrict patient selection by excluding those individuals with 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
* Corresponding author. Tel.: +416 535 8501x34818; fax: +416 979 4292.
E-mail address: gagan.fervaha@utoronto.ca (G. Fervaha). 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, hundred and ninety-three patients were initially randomized to
most of these investigations have not specically examined the receive olanzapine (7.530 mg/day), perphenazine (832 mg/day),
impact of primary negative symptoms on functional status. There quetiapine (200800 mg/day), risperidone (1.56 mg/day), or
are nonetheless some exceptions. A few studies have statistically ziprasidone (40160 mg/day) under double-blind conditions and
controlled for select sources of potential secondary negative were followed up to 18 months or until treatment was
symptoms such as positive and/or depressive symptoms discontinued for any reason [62]. Data reported in the present
[16,17,21,39,47,52,54], while others have excluded patients with study are from the pre-randomization baseline visit before
moderate-severe depression or extrapyramidal symptoms [20,25]. initiation of any experimental treatment.
These prior studies although suggestive that primary negative The study inclusion criteria have been reported previously [62].
symptoms impact functioning have only controlled for, either Briey, participants were eligible if they were between the ages of 18
statistically or through study design, one or more potentially and 65 years and had a diagnosis of schizophrenia conrmed using
confounding sources of negative symptoms; these studies have not the Structured Clinical Interview for DSM-IV Axis I Disorders [22].
concurrently controlled for a range of factors known to related to Participants were excluded from the study if they had a diagnosis of
secondary negative symptoms including psychosis, depression, schizoaffective disorder, mental retardation, or other cognitive
anxiety and extrapyramidal symptoms. disorders; had only one episode of schizophrenia; were pregnant or
The present study sought to examine the relationship between breast-feeding; or had a serious and unstable medical condition.
primary negative symptoms and functional outcomes in a broad The study was approved by the institutional ethics review
range of patients with schizophrenia. Based on previous work, we board at each site, and written informed consent was obtained
hypothesized that negative symptoms would have a signicant from the patients or their legal guardians.
impact on functional outcome, whereby greater negative symptom
severity is associated with poorer functional status. We further 2.2. Outcome measures
hypothesized that this signicant relationship between negative
symptoms and functioning will be maintained after statistically 2.2.1. Functioning and subjective experience
and experimentally controlling for potential sources of secondary The principal measure of interest in the present study was the
negative symptoms such as psychosis, depression, anxiety and/or Heinrichs-Carpenter Quality of Life Scale (QLS) [29]. The QLS is a
extrapyramidal symptoms. Lastly, we hypothesized that primary rater-administered semi-structured interview instrument, which
negative symptoms would have an impact on each facet of assesses functional status. The scale consists of 21 items rated on a
community functioning examined, including social, vocational and 0 to 6 scale (higher scores reect better functioning) and is
recreational functioning. comprised of four subscales: interpersonal relations, instrumental
role functioning, intrapsychic foundations, and use of common
2. Method objects and activities. The QLS is one of the most widely used
instruments in schizophrenia research to assess real-world
2.1. Study design and participants functional status [41], and is related to achievement of objective
functional milestones (e.g. employment, independent living, etc.)
Data were drawn from the baseline visit of the Clinical [28]. As the intrapsychic foundations subdomain of the QLS has
Antipsychotic Trial of Intervention Effectiveness (CATIE) schizo- been cited to have conceptual overlap with certain negative
phrenia study. Details of the study design and rationale [62], as symptoms, it was not included in the present analyses. Also, in an
well as primary ndings [42], have been presented elsewhere. The effort to preserve scale psychometric properties as originally
primary purpose of the CATIE study was to compare the dened [29], we did not create a modied QLS total score
effectiveness of atypical and conventional antipsychotic medica- (excluding intrapsychic foundations); rather, the remaining 3
tions through a randomized controlled trial conducted between domains of functioning were examined individually.
January 2001 and December 2004 at 57 sites in the United States The Drug Attitude Inventory (DAI) [31] was employed to assess
(16 university clinics, 10 state mental health agencies, 7 Veterans patients subjective experience and attitude toward medication.
Affairs medical centers, 6 private nonprot agencies, 4 private- The DAI employed consists of 10 items with a binary yes/no
practice sites, and 14 mixed-system sites). One thousand four response format, with scores ranging from 10 to 10 (high scores
G. Fervaha et al. / European Psychiatry 29 (2014) 449455 451

indicating a more positive subjective experience/attitude toward The second method involved controlling for secondary negative
medication). This scale, through its subjective experience compo- symptoms through experimental study design. In this analysis,
nent, encompasses experiences of dysphoria. patients with schizophrenia who were experiencing moderate-
severe psychosis, depression, anxiety or extrapyramidal symptoms
2.2.2. Symptoms/psychopathology were excluded. The impact of negative symptoms on functioning
Psychopathology was assessed using derived factor scores from was then evaluated using linear regression modeling. This analysis
the Positive and Negative Syndrome Scale (PANSS) [34,44]. The was repeated including only those patients who reported not
PANSS is a 30 item clinician-rated instrument which assesses taking any antipsychotic medication for at least the preceding two
positive, negative and general psychiatric symptoms, which are weeks.
rated on a 1 to 7 scale (high scores reecting greater symptom A 2-sided P value of less than 0.05 was considered statistically
severity). Negative symptoms were evaluated using the negative signicant. Statistical analyses were carried out using SPSS version
symptom factor score [44], which includes the following items: 20 (IBM Corporation, Armonk, NY).
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 3. Results
from the general psychopathology subscale, and a score of 4 or
above on this item indicated a moderate-severe level of anxiety. 3.1. Patient characteristics
This single item has been shown to be signicantly related to more
comprehensive multidimensional measures of anxiety [43]. Baseline demographic and clinical characteristics of the sample
Depressive symptoms were assessed with the Calgary Depres- are presented in Table 1. The study sample includes 1427
sion Scale for Schizophrenia (CDSS) [1], a measure specically individuals with schizophrenia for whom symptom severity, side
designed to assess depressive symptoms in schizophrenia separate effect burden and functioning data were available.
from negative symptoms [3,14]. The CDSS consists of 9 items rated
on a 0 to 3 scale (higher scores reecting more severe depression). 3.2. Negative symptoms and functioning
Individuals with a score greater than 6 on this instrument were
identied as meeting CDSS criteria for a major depressive episode Negative symptoms were in fact signicantly correlated with
(i.e. having moderate-severe depression) [2]. each domain of functioning, including interpersonal relations
(r = 0.42, P < 0.001), instrumental role functioning (r = 0.24,
2.2.3. Medication-related side effects P < 0.001), and use of common objects and activities (r = 0.30,
Extrapyramidal symptoms were evaluated using the abbre- P < 0.001); for all domains assessed, greater negative symptom
viated Simpson-Angus Rating Scale (SAS) [60,64], which contains 6 burden was associated with poorer functioning.
items rated on a scale from 0 to 4 (higher scores denoting more
severe side effects). The specic items include: gait, arm dropping, 3.3. Secondary inuences on negative symptom burden
shoulder shaking, elbow rigidity, wrist rigidity, and tremor.
Patients scoring greater than one (i.e., mild severity) on any item Negative symptom severity was signicantly associated with
on the SAS were identied has having signicant extrapyramidal various clinical variables including psychosis (r = 0.26, P < 0.001),
side effects. 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
2.3. Statistical analyses greater severity of these other clinical symptoms was related to
greater negative symptoms severity scores.
First, Pearsons product-moment correlations were computed
to examine the zero-order relationship between negative 3.4. Primary negative symptoms statistical control
symptoms and each domain of functioning including interper-
sonal relations (social), instrumental role functioning (voca- Negative symptoms were signicantly and inversely related to
tional), and use of common objects and activities (recreational). functioning even after potential sources of secondary negative
Next, the potential inuence of various clinical variables on symptoms were statistically accounted for (Table 2). The impact of
negative symptom severity was examined using correlation these primary negative symptoms remained for each area of
analysis. functioning assessed, including social, vocational and recreational.
The impact of primary negative symptoms on functional Notably, the potential sources of secondary negative symptoms
outcome was examined using two separate analytic methods. were also signicantly associated with functioning, especially
The rst method involved statistically controlling for potential positive and depressive symptoms (Table 2); specically, greater
sources of secondary negative symptoms. The impact of primary positive and depressive symptom severity was related to worse
negative symptoms on functioning was evaluated using stepwise functioning in all domains assessed.
hierarchical multiple regression modeling, where sources of Next, we included a more exhaustive list of sociodemographic
possible secondary negative symptoms were entered into the and clinical variables, such as age, sex, presence of a substance use
model rst as a single block, and negative symptoms were entered disorder and obesity/waist circumference, into the stepwise
second. Another set of models were computed where sources of hierarchical regression model as the rst step, with all of these
secondary negative symptoms were entered second, negative variables being entered into the rst block. Even after statistically
symptoms third, and various sociodemographic and additional (over-)controlling for these potential confounding variables,
clinical variables were entered rst. This latter model was negative symptoms still held a signicant and inverse relationship
computed to explore whether other factors that may inuence with each facet of functioning evaluated (Table 3).
negative symptoms such as sex, subjective experience/attitude
toward medication, and years of antipsychotic exposure have an 3.5. Primary negative symptoms experimental control
impact on functioning, and further whether negative symptoms
continue to impact functioning even once these variables are After excluding patients who were experiencing moderate-
statistically accounted for. 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, extrapyramidal symptoms and were not taking antipsychotic
negative symptoms were signicantly and inversely related to each medication were included in this analysis. Even for these patients,
facet of functioning assessed, including interpersonal relations negative symptoms were signicantly and inversely related to
(R2 = 0.12, F1,213 = 27.55, P < 0.001; b = 0.34, P < 0.001), instru- each facet of functioning evaluated, including interpersonal
mental role functioning (R2 = 0.10, F1,213 = 22.73, P < 0.001; relations (R2 = 0.05, F1,55 = 2.98, P < 0.001; b = 0.23, P = 0.09),
b = 0.31, P < 0.001), and use of common objects and activities instrumental role functioning (R2 = 0.10, F1,55 = 6.11, P < 0.001;
(R2 = 0.10, F1,213 = 2300, P < 0.001; b = 0.31, P < 0.001). b = 0.32, P = 0.02), and use of common objects and activities
As antipsychotic medication itself may produce secondary (R2 = 0.25, F1,55 = 17.87, P < 0.001; b = 0.50, P < 0.001), albeit the
negative symptoms [6,59], we re-examined the above analyses relationship between negative symptoms and social functioning in
including only patients who reported being antipsychotic-free for this population trended toward signicance. The pattern of results
at least the preceding two weeks. Fifty-six patients who was also similar for patients receiving antipsychotic medication
were experiencing mild psychosis, depression, anxiety and/or (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 is associated with higher ratings of say
Negative symptoms were found to be a signicant contributor extrapyramidal symptoms [13,50], or even that these latter
to the functional impairment seen in patients with schizophrenia. symptoms are etiologically linked with negative symptoms.
While many studies have noted this relationship [9,16 Another manner in which primary negative symptoms can be
18,20,21,25,30,33,39,45,47,52,54,57], the present study extends examined is to restrict examination to patients who not severely
these ndings and conrms that primary idiopathic negative affected by secondary factors such as depression and suspicious-
symptoms serve as an impediment to functional recovery. The ness. However, here too it is difcult to exclude all potential
present study has many strengths, one of which was the inclusion sources of non-idiopathic negative symptoms [55]. It should also
of a large sample of patients, which allowed for the employment of be noted that the primary versus secondary distinction could be
different strategies, both statistical and experimental, to control made through clinical judgment; however, such clinical inferences
for several variables that might potentially overlap with the may be unreliable [23]. Nonetheless, use of standardized instru-
negative symptom construct. ments such as the Schedule for the Decit Syndrome [36], that
In an effort to control for secondary non-idiopathic negative highlight various putative sources of secondary negative symp-
symptoms we employed two methods [5,46]. First, we statistically toms and examines history/course of symptoms, increase the
controlled for these symptoms by only examining the variance in validity of the primary versus secondary symptom distinction.
negative symptoms once that covariance with other variables (e.g. Distinguishing between primary and secondary negative
depression) had been parsed. It should be noted that this method symptoms is indeed an important clinical issue, as the underlying
underestimates the variance ascribed to primary negative symp- pathophysiology and therefore potential treatments differ for each
toms [35], and thus underestimates the relationship with 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]; inuence functional outcomes after other possible variables have
whereas secondary negative symptoms will have more diffuse been controlled for. Some studies have for example demonstrated
underlying mechanisms, depending on the source. It therefore that amotivation/apathy adversely affects functioning even after
follows that treatment strategies will differ for primary versus factors such as psychosis and/or depression have been statistically
secondary negative symptoms [11,49]. accounted for [16,17,21,39]; however, the potential inuence of
It is noteworthy that negative symptoms explained a large additional well-known variables that can affect negative symp-
portion of variance in functional status, even after the variance toms (e.g., akinesia) were not concurrently accounted for, leaving
ascribed to clinical variables such as psychosis, depression, anxiety open the possibility that the negative symptoms evaluated were, at
and extrapyramidal symptoms has been statistically accounted for least in part, not idiopathic.
(Table 2). In fact, for social and recreational functioning, the The results of the present study afrm that negative symptoms
variance accounted for by negative symptoms alone was greater undermine functioning in patients with schizophrenia, and this
than that accounted for by the other four clinical variables. adverse inuence is seen even after other confounders have been
Moreover, examination of the standardized regression coefcients taken into account. That said, treatments aimed at primary
(i.e., beta weights) in the multiple regression model (Tables 2 and negative symptoms should promote functional recovery. Investi-
3), suggests that negative symptoms had the greatest relative gations into the underlying pathobiology of negative symptoms
effect on each facet of functioning evaluated. This nding is should take into account the potential for these symptoms to
consistent with previous work demonstrating that negative covary with other clinical factors.
symptoms continue to have explanatory power in predicting
functional outcome, even after a host of other variables have been Disclosure of interest
accounted for [16,17,21,39,47,52,54], and highlights the central
role of negative symptoms in the prediction of functional outcome Mr. Fervaha has received research support from an Ontario
[20,25]. Graduate Scholarship and a Canadian Institute of Health Research
One additional strength of the present study that should be (CIHR) Vanier Canada Graduate Scholarship. Dr. Foussias has
mentioned was the examination of multiple domains of function- received research support from a CIHR Clinician-Scientist Training
ing. Primary negative symptoms demonstrated a signicant and Award, an APA-AstraZeneca Young Minds in Psychiatry Award, and
deleterious impact on social, vocational and recreational function- a NARSAD Young Investigator Award; has been involved in
ing, highlighting the pervasive adverse effects of these symptoms research sponsored by Medicure Inc., and Neurocrine Bioscience;
in terms of real-world community functioning. The present study served on advisory boards for Roche; and has received speaker fees
therefore extends previous ndings, which have typically exam- from Roche, Lundbeck, and Novartis. Dr. Agid has received research
ined the impact of negative symptoms on a single domain or support from Pzer Inc. and Janssen-Ortho; consultant fees from
composite measure of functional status. Janssen-Ortho, Eli Lilly Inc. US, Eli Lilly Canada, Sepreacor,
In evaluating the present study on the impact of idiopathic Sunovion and Lundbeck; and speakers fees from Janssen-Ortho,
negative symptoms on functional outcome, some limitations Eli Lilly Inc. US, Eli Lilly Canada, Novartis, Sepracor and Sunovion.
warrant mention. First, patients were entering into a treatment Dr. Remington has received research support from the Schizo-
trial; therefore, the ndings may not be generalizable to patients phrenia Society of Ontario, CIHR, Research Hospital Fund Canada
stabilized on their medications. Second, in the analyses statistically Foundation for Innovation, Canadian Diabetes Association, Novar-
controlling for secondary factors, the factors included were not tis Canada, Medicure Inc., and Neurocrine Bioscience; as a co-
exhaustive and it is thus possible that some of the variance investigator he has received research support from the Canadian
ascribed to primary negative symptoms is in fact due to non- Psychiatric Research Foundation and Pzer Inc.; consultant fees
idiopathic inuences (e.g. environmental deprivation; Fig. 1) [55]. from Laboratorios Farmaceuticos ROVI, Synchroneuron, Novartis,
Third, although negative symptoms demonstrated a signicant and Roche; and speakers fees from Novartis.
relationship with functional status and explained the largest
amount of variance relative to the other factors examined, the Acknowledgements
overall amount of variance explained, although not trivial, was far
from comprehensive. This may, at least in part, be due to Data used in the preparation of this article were obtained from
measurement variance as a result of including many raters from the limited access datasets (Version 1) distributed from the NIH-
different sites. Alternatively, it may be due to the inclusion of a supported Clinical Antipsychotic Trials of Intervention Effective-
heterogeneous sample of patients with minimal inclusion criteria ness in Schizophrenia (CATIE-Sz). This is a multisite, clinical trial
(i.e., inclusion of patients with acute exacerbation, co-morbid of persons with schizophrenia comparing the effectiveness of
illnesses, substance use, etc.) [62]. To this end, previous studies in randomly assigned medication treatment. The study was sup-
more homogenous samples of stable outpatients with schizo- ported by NIMH Contract #N01MH90001 to the University of
phrenia have found that negative symptoms explain a larger North Carolina at Chapel Hill. The ClinicalTrials.gov identier is
portion of the variance in functioning scores [20,25,39]. Another NCT00014001. This manuscript reects the views of the authors
limitation includes the use of the PANSS to evaluate negative and may not reect the opinions or views of the CATIE-Sz Study
symptoms. Although the PANSS is one of the most widely used Investigators or the NIH.
rating scales to evaluate schizophrenia psychopathology, it
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