impact of primary negative symptoms on functional outcomes in schizophrenia

European Psychiatry xxx (2014) xxx–xxx

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EURPSY-3127; No. of Pages 7

Original article

Impact of primary negative symptoms on functional outcomesin 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, Canadab Institute of Medical Science, University of Toronto, Toronto, Canadac Department of Psychiatry, University of Toronto, Toronto, Canada

A R T I C L E I N F O

Article history:

Received 7 November 2013

Received in revised form 3 January 2014

Accepted 26 January 2014

Available online xxx

Keywords:

Schizophrenia

Functional outcome

Negative symptoms

Primary symptoms

Avolition-Apathy

Psychosocial functioning

A B S T R A C T

Objective: Negative symptoms are known to undermine functional outcomes in people with

schizophrenia; however, most studies have not accounted for whether these symptoms were primary

or secondary to other psychopathological factors. The present study examined the impact of primary

negative symptoms on functional outcomes in patients with schizophrenia.

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

Depression Scale, extrapyramidal side effects with the Simpson-Angus scale, and functional status with

the Heinrichs-Carpenter Quality of Life Scale.

Results: Negative symptoms were significantly and inversely related to each domain of functioning

examined. These relationships remained after statistically controlling for the influence of potential

sources of secondary negative symptoms. In addition, the relationships between negative symptoms and

specific 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 significantly 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.

Available online at

ScienceDirectwww.sciencedirect.com

1. Introduction

The negative symptoms of schizophrenia are a prevalentfeature of the disorder [8], and have long been recognized asbeing 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 thesesymptoms however may be influenced by factors not intrinsicallylinked to the disease process such as drug-related akinesia [56],depression and suspiciousness [11,24], to name a few (Fig. 1). Thatsaid, the influence of negative symptoms not ascribed to suchsecondary 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 first is torestrict patient selection by excluding those individuals with

* Corresponding author. Tel.: +416 535 8501x34818; fax: +416 979 4292.

E-mail address: [email protected] (G. Fervaha).

Please cite this article in press as: Fervaha G, et al. Impact of primarEuropean Psychiatry (2014), http://dx.doi.org/10.1016/j.eurpsy.2014

0924-9338/$ – see front matter � 2014 Elsevier Masson SAS. All rights reserved.

http://dx.doi.org/10.1016/j.eurpsy.2014.01.007

prominent presentation of confounding variables (e.g., suspicious-ness). To this end, therapeutic intervention can be used to determinewhether 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 withidiopathic and enduring negative symptoms (i.e., deficit syndrome)[12], and found these patients have worse functioning than thosewithout such symptoms [10,19,26,32,37,51,61], most studiesexamining negative symptoms dimensionally across patients withschizophrenia have not controlled for potential sources of secondarynegative symptoms. The second method to examine primarynegative symptoms is through statistical covariation analyses. Thismethod aims to examine the relationship between negativesymptom severity and some outcome variable while statisticallypartially out the variance accounted for by other potentiallyconfounding variables (e.g., depression) [48].

Negative symptoms have been consistently linked to poorfunctioning in numerous studies across a broad range of patientswith schizophrenia including both first-episode and chronic

y negative symptoms on functional outcomes in schizophrenia..01.007


mailto:[email protected]


http://www.sciencedirect.com/science/journal/09249338


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 influence 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.

G. Fervaha et al. / European Psychiatry xxx (2014) xxx–xxx2

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samples [9,16–18,20,21,25,30,33,39,45,47,52,54,57]; however,most of these investigations have not specifically examined theimpact of primary negative symptoms on functional status. Thereare nonetheless some exceptions. A few studies have statisticallycontrolled for select sources of potential secondary negativesymptoms such as positive and/or depressive symptoms[16,17,21,39,47,52,54], while others have excluded patients withmoderate-severe depression or extrapyramidal symptoms [20,25].These prior studies although suggestive that primary negativesymptoms impact functioning have only controlled for, eitherstatistically or through study design, one or more potentiallyconfounding sources of negative symptoms; these studies have notconcurrently controlled for a range of factors known to related tosecondary negative symptoms including psychosis, depression,anxiety and extrapyramidal symptoms.

The present study sought to examine the relationship betweenprimary negative symptoms and functional outcomes in a broadrange of patients with schizophrenia. Based on previous work, wehypothesized that negative symptoms would have a significantimpact on functional outcome, whereby greater negative symptomseverity is associated with poorer functional status. We furtherhypothesized that this significant relationship between negativesymptoms and functioning will be maintained after statisticallyand experimentally controlling for potential sources of secondarynegative symptoms such as psychosis, depression, anxiety and/orextrapyramidal symptoms. Lastly, we hypothesized that primarynegative symptoms would have an impact on each facet ofcommunity functioning examined, including social, vocational andrecreational functioning.

2. Method

2.1. Study design and participants

Data were drawn from the baseline visit of the ClinicalAntipsychotic Trial of Intervention Effectiveness (CATIE) schizo-phrenia study. Details of the study design and rationale [62], aswell as primary findings [42], have been presented elsewhere. Theprimary purpose of the CATIE study was to compare theeffectiveness of atypical and conventional antipsychotic medica-tions through a randomized controlled trial conducted betweenJanuary 2001 and December 2004 at 57 sites in the United States(16 university clinics, 10 state mental health agencies, 7 VeteransAffairs medical centers, 6 private nonprofit agencies, 4 private-practice sites, and 14 mixed-system sites). One thousand four


hundred and ninety-three patients were initially randomized toreceive olanzapine (7.5–30 mg/day), perphenazine (8–32 mg/day),quetiapine (200–800 mg/day), risperidone (1.5–6 mg/day), orziprasidone (40–160 mg/day) under double-blind conditions andwere followed up to 18 months or until treatment wasdiscontinued for any reason [62]. Data reported in the presentstudy are from the pre-randomization baseline visit beforeinitiation of any experimental treatment.

The study inclusion criteria have been reported previously [62].Briefly, participants were eligible if they were between the ages of 18and 65 years and had a diagnosis of schizophrenia confirmed usingthe Structured Clinical Interview for DSM-IV Axis I Disorders [22].Participants were excluded from the study if they had a diagnosis ofschizoaffective disorder, mental retardation, or other cognitivedisorders; had only one episode of schizophrenia; were pregnant orbreast-feeding; or had a serious and unstable medical condition.

The study was approved by the institutional ethics reviewboard at each site, and written informed consent was obtainedfrom 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 theHeinrichs-Carpenter Quality of Life Scale (QLS) [29]. The QLS is arater-administered semi-structured interview instrument, whichassesses functional status. The scale consists of 21 items rated on a0 to 6 scale (higher scores reflect better functioning) and iscomprised of four subscales: interpersonal relations, instrumentalrole functioning, intrapsychic foundations, and use of commonobjects and activities. The QLS is one of the most widely usedinstruments in schizophrenia research to assess real-worldfunctional status [41], and is related to achievement of objectivefunctional milestones (e.g. employment, independent living, etc.)[28]. As the intrapsychic foundations subdomain of the QLS hasbeen cited to have conceptual overlap with certain negativesymptoms, it was not included in the present analyses. Also, in aneffort to preserve scale psychometric properties as originallydefined [29], we did not create a modified QLS total score(excluding intrapsychic foundations); rather, the remaining 3domains of functioning were examined individually.

The Drug Attitude Inventory (DAI) [31] was employed to assesspatients’ subjective experience and attitude toward medication.The DAI employed consists of 10 items with a binary yes/noresponse format, with scores ranging from �10 to 10 (high scores



G. Fervaha et al. / European Psychiatry xxx (2014) xxx–xxx 3

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indicating a more positive subjective experience/attitude towardmedication). This scale, through its subjective experience compo-nent, encompasses experiences of dysphoria.

2.2.2. Symptoms/psychopathology

Psychopathology was assessed using derived factor scores fromthe Positive and Negative Syndrome Scale (PANSS) [34,44]. ThePANSS is a 30 item clinician-rated instrument which assessespositive, negative and general psychiatric symptoms, which arerated on a 1 to 7 scale (high scores reflecting greater symptomseverity). Negative symptoms were evaluated using the negativesymptom factor score [44], which includes the following items:blunted affect, emotional withdrawal, poor rapport, apatheticsocial withdrawal, lack of flow, motor retardation and active socialavoidance. Severity of anxiety was assessed using a single itemfrom the general psychopathology subscale, and a score of 4 orabove on this item indicated a moderate-severe level of anxiety.This single item has been shown to be significantly related to morecomprehensive multidimensional measures of anxiety [43].

Depressive symptoms were assessed with the Calgary Depres-sion Scale for Schizophrenia (CDSS) [1], a measure specificallydesigned to assess depressive symptoms in schizophrenia separatefrom negative symptoms [3,14]. The CDSS consists of 9 items ratedon a 0 to 3 scale (higher scores reflecting more severe depression).Individuals with a score greater than 6 on this instrument wereidentified 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 6items rated on a scale from 0 to 4 (higher scores denoting moresevere side effects). The specific items include: gait, arm dropping,shoulder shaking, elbow rigidity, wrist rigidity, and tremor.Patients scoring greater than one (i.e., mild severity) on any itemon the SAS were identified has having significant extrapyramidalside effects.

2.3. Statistical analyses

First, Pearson’s product-moment correlations were computedto examine the zero-order relationship between negativesymptoms 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 influence of various clinical variables onnegative symptom severity was examined using correlationanalysis.

The impact of primary negative symptoms on functionaloutcome was examined using two separate analytic methods.The first method involved statistically controlling for potentialsources of secondary negative symptoms. The impact of primarynegative symptoms on functioning was evaluated using stepwisehierarchical multiple regression modeling, where sources ofpossible secondary negative symptoms were entered into themodel first as a single block, and negative symptoms were enteredsecond. Another set of models were computed where sources ofsecondary negative symptoms were entered second, negativesymptoms third, and various sociodemographic and additionalclinical variables were entered first. This latter model wascomputed to explore whether other factors that may influencenegative symptoms such as sex, subjective experience/attitudetoward medication, and years of antipsychotic exposure have animpact on functioning, and further whether negative symptomscontinue to impact functioning even once these variables arestatistically accounted for.


The second method involved controlling for secondary negativesymptoms through experimental study design. In this analysis,patients with schizophrenia who were experiencing moderate-severe psychosis, depression, anxiety or extrapyramidal symptomswere excluded. The impact of negative symptoms on functioningwas then evaluated using linear regression modeling. This analysiswas repeated including only those patients who reported nottaking any antipsychotic medication for at least the preceding twoweeks.

A 2-sided P value of less than 0.05 was considered statisticallysignificant. Statistical analyses were carried out using SPSS version20 (IBM Corporation, Armonk, NY).

3. Results

3.1. Patient characteristics

Baseline demographic and clinical characteristics of the sampleare presented in Table 1. The study sample includes 1427individuals with schizophrenia for whom symptom severity, sideeffect burden and functioning data were available.

3.2. Negative symptoms and functioning

Negative symptoms were in fact significantly correlated witheach 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 symptomburden was associated with poorer functioning.

3.3. Secondary influences on negative symptom burden

Negative symptom severity was significantly associated withvarious clinical variables including psychosis (r = 0.26, P < 0.001),depression (r = 0.18, P < 0.001), anxiety (r = 0.12, P < 0.001) andextrapyramidal symptom severity (r = 0.15, P < 0.001); specificallygreater severity of these other clinical symptoms was related togreater negative symptoms severity scores.

3.4. Primary negative symptoms – statistical control

Negative symptoms were significantly and inversely related tofunctioning even after potential sources of secondary negativesymptoms were statistically accounted for (Table 2). The impact ofthese primary negative symptoms remained for each area offunctioning assessed, including social, vocational and recreational.Notably, the potential sources of secondary negative symptomswere also significantly associated with functioning, especiallypositive and depressive symptoms (Table 2); specifically, greaterpositive and depressive symptom severity was related to worsefunctioning in all domains assessed.

Next, we included a more exhaustive list of sociodemographicand clinical variables, such as age, sex, presence of a substance usedisorder and obesity/waist circumference, into the stepwisehierarchical regression model as the first step, with all of thesevariables being entered into the first block. Even after statistically(over-)controlling for these potential confounding variables,negative symptoms still held a significant and inverse relationshipwith 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



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

Variable Mean (SD) or % Range (min–max)

Age (years) 40.6 (11.1) 18–67

Sex (males) 74.2 –

Race (white) 61.3 –

Employment status (unemployed) 84.1 –

Crisis stabilization in past 3 months (true) 27.3 –

Patient’s education (years) 12.1 (2.2) 1–21

Illness duration (years since first prescribed antipsychotic medication) 14.4 (10.7) 0–56

PANSS (total score) 75.5 (17.5) 31–140

PANSS – positive factor score 21.9 (6.7) 8–45

PANSS – negative factor score 19.3 (6.7) 7–40

PANSS – disorganization factor score 16.8 (5.3) 7–37

PANSS – excitement factor score 7.1 (2.9) 4–21

PANSS – anxiety/depression factor score 10.4 (3.8) 4–22

PANSS – anxiety item 2.9 (1.3) 1–7

CDSS (total score) 4.6 (4.4) 0–22

QLS (total score) 2.7 (1.1) 0.3–5.9

QLS – interpersonal relations subscale score 2.5 (1.3) 0.0–6.0

QLS – instrumental role subscale score 1.8 (1.6) 0.0–6.0

QLS – intrapsychic foundations subscale score 3.1 (1.2) 0.0–6.0

QLS – common objects subscale score 3.4 (1.2) 0.5–6.0

EPS score (average score) 0.2 (0.3) 0–2.7

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.


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symptoms, 215 patients remained. Among these individuals,negative symptoms were significantly and inversely related to eachfacet 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 secondarynegative symptoms [6,59], we re-examined the above analysesincluding only patients who reported being antipsychotic-free forat least the preceding two weeks. Fifty-six patients whowere experiencing mild psychosis, depression, anxiety and/or

Table 2Stepwise multiple regression models with different facets of functioning as the depend

Model Step Variable added

1 QLS – interpersonal relationsa

1 PANSS – positive

CDSS

PANSS – anxiety

EPS

2 PANSS – negative

2 QLS – instrumental roleb


CDSS

PANSS – anxiety

EPS


3 QLS – common objects and activitiesc


CDSS

PANSS – anxiety

EPS


QLS: Quality of Life Scale; PANSS: Positive and Negative Syndrome Scale; CDSS: Calgara 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.


extrapyramidal symptoms and were not taking antipsychoticmedication were included in this analysis. Even for these patients,negative symptoms were significantly and inversely related toeach facet of functioning evaluated, including interpersonalrelations (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 therelationship between negative symptoms and social functioning inthis population trended toward significance. The pattern of resultswas also similar for patients receiving antipsychotic medication(data not shown).

ant variable.

b t P R2 change

�0.13 �5.14 < 0.001 0.082

�0.10 �3.83 < 0.001

0.03 0.95 0.34

�0.04 �1.61 0.11

�0.36 �14.45 < 0.001 0.117

�0.13 �7.80 < 0.001 0.046

�0.06 �2.20 0.04

0.02 0.56 0.57

�0.03 �1.28 0.20

�0.19 �7.05 < 0.001 0.032

�0.09 �3.22 < 0.001 0.045

�0.06 �2.18 0.03

0.13 4.49 < 0.001

�0.07 �2.81 0.005

�0.27 �10.33 < 0.001 0.067

y Depression Scale for Schizophrenia; EPS: extrapyramidal symptoms.



Table 3Stepwise 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

1 QLS – interpersonal relationsa

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


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

3 QLS – common objects and activitiesc

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


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.


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4. Discussion

Negative symptoms were found to be a significant contributorto 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 extendsthese findings and confirms that primary idiopathic negativesymptoms serve as an impediment to functional recovery. Thepresent study has many strengths, one of which was the inclusionof a large sample of patients, which allowed for the employment ofdifferent strategies, both statistical and experimental, to controlfor several variables that might potentially overlap with thenegative symptom construct.

In an effort to control for secondary non-idiopathic negativesymptoms we employed two methods [5,46]. First, we statisticallycontrolled for these symptoms by only examining the variance innegative symptoms once that covariance with other variables (e.g.depression) had been parsed. It should be noted that this methodunderestimates the variance ascribed to primary negative symp-toms [35], and thus underestimates the relationship with


functioning. That is, it is possible that greater severity of primarynegative symptoms is associated with higher ratings of sayextrapyramidal symptoms [13,50], or even that these lattersymptoms are etiologically linked with negative symptoms.Another manner in which primary negative symptoms can beexamined is to restrict examination to patients who not severelyaffected by secondary factors such as depression and suspicious-ness. However, here too it is difficult to exclude all potentialsources of non-idiopathic negative symptoms [55]. It should alsobe noted that the primary versus secondary distinction could bemade through clinical judgment; however, such clinical inferencesmay be unreliable [23]. Nonetheless, use of standardized instru-ments such as the Schedule for the Deficit Syndrome [36], thathighlight various putative sources of secondary negative symp-toms and examines history/course of symptoms, increase thevalidity of the primary versus secondary symptom distinction.

Distinguishing between primary and secondary negativesymptoms is indeed an important clinical issue, as the underlyingpathophysiology and therefore potential treatments differ for eachof these. Primary negative symptom psychopathology has been




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linked to fronto-parietal neural dysfunction [27,40,58,63];whereas secondary negative symptoms will have more diffuseunderlying mechanisms, depending on the source. It thereforefollows that treatment strategies will differ for primary versussecondary negative symptoms [11,49].

It is noteworthy that negative symptoms explained a largeportion of variance in functional status, even after the varianceascribed to clinical variables such as psychosis, depression, anxietyand extrapyramidal symptoms has been statistically accounted for(Table 2). In fact, for social and recreational functioning, thevariance accounted for by negative symptoms alone was greaterthan that accounted for by the other four clinical variables.Moreover, examination of the standardized regression coefficients(i.e., beta weights) in the multiple regression model (Tables 2 and3), suggests that negative symptoms had the greatest relativeeffect on each facet of functioning evaluated. This finding isconsistent with previous work demonstrating that negativesymptoms continue to have explanatory power in predictingfunctional outcome, even after a host of other variables have beenaccounted for [16,17,21,39,47,52,54], and highlights the centralrole of negative symptoms in the prediction of functional outcome[20,25].

One additional strength of the present study that should bementioned was the examination of multiple domains of function-ing. Primary negative symptoms demonstrated a significant anddeleterious impact on social, vocational and recreational function-ing, highlighting the pervasive adverse effects of these symptomsin terms of real-world community functioning. The present studytherefore extends previous findings, which have typically exam-ined the impact of negative symptoms on a single domain orcomposite measure of functional status.

In evaluating the present study on the impact of idiopathicnegative symptoms on functional outcome, some limitationswarrant mention. First, patients were entering into a treatmenttrial; therefore, the findings may not be generalizable to patientsstabilized on their medications. Second, in the analyses statisticallycontrolling for secondary factors, the factors included were notexhaustive and it is thus possible that some of the varianceascribed to primary negative symptoms is in fact due to non-idiopathic influences (e.g. environmental deprivation; Fig. 1) [55].Third, although negative symptoms demonstrated a significantrelationship with functional status and explained the largestamount of variance relative to the other factors examined, theoverall amount of variance explained, although not trivial, was farfrom comprehensive. This may, at least in part, be due tomeasurement variance as a result of including many raters fromdifferent sites. Alternatively, it may be due to the inclusion of aheterogeneous sample of patients with minimal inclusion criteria(i.e., inclusion of patients with acute exacerbation, co-morbidillnesses, substance use, etc.) [62]. To this end, previous studies inmore homogenous samples of stable outpatients with schizo-phrenia have found that negative symptoms explain a largerportion of the variance in functioning scores [20,25,39]. Anotherlimitation includes the use of the PANSS to evaluate negativesymptoms. Although the PANSS is one of the most widely usedrating scales to evaluate schizophrenia psychopathology, itincludes only a limited number of items assessing negativesymptoms [38].

As the negative symptoms of schizophrenia are increasinglybeing embraced as multidimensional [7], with certain facets (e.g.,amotivation/apathy) demonstrating greater impact on functionaloutcomes [17,20,25], it will be an important area of research todiscern potential secondary sources of negative symptoms thatdifferentially affect one domain of negative symptoms overanother. Furthermore, it will also be important to examinewhether specific primary negative symptoms (e.g., blunted affect)


influence functional outcomes after other possible variables havebeen controlled for. Some studies have for example demonstratedthat amotivation/apathy adversely affects functioning even afterfactors such as psychosis and/or depression have been statisticallyaccounted for [16,17,21,39]; however, the potential influence ofadditional well-known variables that can affect negative symp-toms (e.g., akinesia) were not concurrently accounted for, leavingopen the possibility that the negative symptoms evaluated were, atleast in part, not idiopathic.

The results of the present study affirm that negative symptomsundermine functioning in patients with schizophrenia, and thisadverse influence is seen even after other confounders have beentaken into account. That said, treatments aimed at primarynegative symptoms should promote functional recovery. Investi-gations into the underlying pathobiology of negative symptomsshould take into account the potential for these symptoms tocovary with other clinical factors.

Disclosure of interest

Mr. Fervaha has received research support from an OntarioGraduate Scholarship and a Canadian Institute of Health Research(CIHR) Vanier Canada Graduate Scholarship. Dr. Foussias hasreceived research support from a CIHR Clinician-Scientist TrainingAward, an APA-AstraZeneca Young Minds in Psychiatry Award, anda NARSAD Young Investigator Award; has been involved inresearch sponsored by Medicure Inc., and Neurocrine Bioscience;served on advisory boards for Roche; and has received speaker feesfrom Roche, Lundbeck, and Novartis. Dr. Agid has received researchsupport from Pfizer Inc. and Janssen-Ortho; consultant fees fromJanssen-Ortho, Eli Lilly Inc. US, Eli Lilly Canada, Sepreacor,Sunovion and Lundbeck; and speaker’s 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 – CanadaFoundation for Innovation, Canadian Diabetes Association, Novar-tis Canada, Medicure Inc., and Neurocrine Bioscience; as a co-investigator he has received research support from the CanadianPsychiatric Research Foundation and Pfizer Inc.; consultant feesfrom Laboratorios Farmaceuticos ROVI, Synchroneuron, Novartis,and Roche; and speaker’s fees from Novartis.

Acknowledgements

Data used in the preparation of this article were obtained fromthe 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 trialof persons with schizophrenia comparing the effectiveness ofrandomly assigned medication treatment. The study was sup-ported by NIMH Contract #N01MH90001 to the University ofNorth Carolina at Chapel Hill. The ClinicalTrials.gov identifier isNCT00014001. This manuscript reflects the views of the authorsand may not reflect the opinions or views of the CATIE-Sz StudyInvestigators or the NIH.

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impact of primary negative symptoms on functional outcomes in schizophrenia

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