APA Summary

Mechanisms of functional improvement in a 2-year trial of cognitive enhancement therapy for early schizophrenia

S. M. Eack1,2*, M. F. Pogue-Geile3, D. P. Greenwald2, S. S. Hogarty2 and M. S. Keshavan2,4

1 School of Social Work, University of Pittsburgh, Pittsburgh, PA, USA 2 Western Psychiatric Institute and Clinic, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA 3 Department of Psychology, University of Pittsburgh, Pittsburgh, PA, USA 4 Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA

Background. Cognitive rehabilitation has emerged as an effective treatment for addressing cognitive impairments

and functional disability in schizophrenia; however, the degree to which changes in various social and non-social

cognitive processes translate into improved functioning during treatment remains unclear. This research sought to

identify the neurocognitive and social-cognitive mechanisms of functional improvement during a 2-year trial of

cognitive enhancement therapy (CET) for early-course schizophrenia.

Method. Patients in the early course of schizophrenia were randomly assigned to CET (n=31) or an enriched supportive therapy control (n=27) and treated for up to 2 years. A comprehensive neurocognitive assessment battery and the Mayer–Salovey–Caruso Emotional Intelligence Test (MSCEIT) were completed annually, along with measures

of functioning. Mediator analyses using mixed-effects growth models were conducted to examine the effects of

neurocognitive and social-cognitive improvement on functional change.

Results. Improvements over 2 years in neurocognition and the emotion management branch of the MSCEIT were

found to be significantly related to improved functional outcome in early-course schizophrenia patients. Neuro-

cognitive improvement, primarily in executive functioning, and social-cognitive change in emotion management also

mediated the robust effects of CET on functioning.

Conclusions. Improvements in neurocognition and social cognition that result from cognitive rehabilitation are both

significant mediators of functional improvement in early-course schizophrenia. Cognitive rehabilitation programs for

schizophrenia may need to target deficits in both social and non-social cognition to achieve an optimal functional

response.

Received 1 April 2010; Revised 29 June 2010; Accepted 29 July 2010; First published online 22 September 2010

Key words : Cognitive rehabilitation, cognitive remediation, psychosocial treatment, social cognition.

Introduction

Schizophrenia is a chronic mental disorder that is

characterized by significant impairments in cognition

and functioning. Marked deficits have been observed

in social and non-social cognitive domains (Penn

et al. 1997; Heinrichs & Zakzanis, 1998), which cross-

sectional and longitudinal studies have found to be

significant and consistent predictors of functional

outcome (Green et al. 2000; Couture et al. 2006). Such

findings have fueled arguments for the treatment

of cognitive impairments in schizophrenia as a key

mechanism for improving functioning in the disorder

(Hogarty & Flesher, 1992; Green & Nuechterlein,

1999).

While the pharmacological treatment of cognitive

impairments in schizophrenia has produced limited

improvements (Keefe et al. 2007; Sergi et al. 2007),

a number of psychosocial cognitive rehabilitation

approaches have emerged as effective methods for

addressing cognitive deficits in the disorder (McGurk

et al. 2007). One integrated approach to the remedi-

ation of social and non-social cognitive impairments in

schizophrenia that has been shown to be particularly

effective at improving cognition and functioning in

the disorder is cognitive enhancement therapy (CET;

Hogarty & Greenwald, 2006). In the initial CET study

* Address for correspondence: S. M. Eack, Ph.D., University of

Pittsburgh School of Social Work, 2117 Cathedral of Learning,

Pittsburgh, PA 15260, USA.

(Email: [email protected])

Psychological Medicine (2011), 41, 1253–1261. f Cambridge University Press 2010 doi:10.1017/S0033291710001765

ORIGINAL ARTICLE

with chronically ill patients, we demonstrated that

CET resulted in marked improvements in processing

speed, neurocognition and social cognition, as well

as social adjustment (Hogarty et al. 2004). A 1-year

follow-up study also showed that these improvements

could be maintained after the completion of treatment

(Hogarty et al. 2006). Recently, we tested the effects

of CET as an early intervention approach with 58

early-course schizophrenia out-patients, and again

found substantial improvements in neurocognition

(d=0.46) and social cognition (d=1.55), but not pro- cessing speed, which was relatively preserved among

early-course patients. In addition, large (d=1.53) and broad functional improvements were observed in

vocational functioning, activities of daily living and

other domains of social adjustment (Eack et al. 2009,

in press).

The effects of CET and other cognitive rehabilitation

approaches on functional outcome strongly support

the treatment of cognition as a critical mechanism for

functional improvement in schizophrenia. Unfortu-

nately, few studies have explicitly tested the degree to

which improvements in cognition contribute to func-

tional improvement. In the initial CET study with

chronically ill patients, we found that improvements

in processing speed served as a significant partial

mediator of CET effects on social adjustment (Hogarty

et al. 2006). Wykes et al. (2007) studied cognitive re-

mediation therapy among early-onset patients and

found that improvements in executive functioning,

working memory and planning were related to im-

proved social behavior; however, previous studies of

that intervention with chronic patients did not de-

monstrate a link between changes in neurocognitive

domains and functioning (Reeder et al. 2004, 2006).

To date, no studies have examined the effect of both

improved neurocognition and social cognition on

functional outcome during cognitive rehabilitation in

schizophrenia.

Having recently found substantial functional ben-

efits of CET in early schizophrenia during a 2-year

randomized trial (Eack et al. 2009), we now examine

the degree to which social-cognitive and neurocog-

nitive enhancement during this trial served as active

mechanisms of functional improvement in these early-

course patients. It was hypothesized that both im-

proved neurocognition and social cognition would

contribute to improvements in functioning, and

mediate the differential effects of CET on functional

outcome. Unlike our initial CET study (Hogarty et al.

2006), the mediational effects of improved processing

speed were not investigated, as this sample of early-

course patients demonstrated relatively preserved

performance in processing speed that did not change

with treatment (Eack et al. 2009).

Method

Participants

Participants consisted of 58 early-course out-patients

with schizophrenia (n=38) or schizo-affective dis- order (n=20), as assessed by the Structured Clinical Interview for DSM-IV (First et al. 2002), treated in a

2-year trial of CET. The early course of schizophrenia

was defined for this research as no greater than 8 years

since the first emergence of psychotic symptoma-

tology. Eligible participants included individuals with

schizophrenia, schizo-affective, or schizophreniform

disorder stabilized on antipsychotic medications who

experienced their first psychotic symptom within the

past 8 years, were not abusing substances for at least

2 months prior to study enrollment, had an intelli-

gence quotient (IQ) o80, and exhibited significant social and cognitive disability on the Cognitive Style

and Social Cognition Eligibility Interview (Hogarty

et al. 2004). The Cognitive Style and Social Cognition

Eligibility Interview is a structured interview measure

that was used to ensure that enrolled patients experi-

enced significant cognitive and functional disability

warranting treatment. Demographic and clinical

characteristics of CET and enriched supportive therapy

(EST) patients are presented in Table 1.

Treatments

Participants were treated with either CET or an EST

control, both of which have been described in detail

elsewhere (Hogarty et al. 2004; Eack et al. 2009).

Briefly, CET is a comprehensive cognitive rehabili-

tation intervention designed to address the social

and non-social cognitive deficits that limit functional

recovery from schizophrenia. Patients treated with

CET complete approximately 60 h of computer-based

training in attention, memory, and problem-solving

and 45 small-group social-cognitive therapy sessions

designed to enhance perspective-taking, social context

appraisal, foresightfulness, and getting the ‘gist’ out

of social situations. EST is an illness management

and education approach based on personal therapy

(Hogarty, 2002), which provides patients with psy-

choeducation about schizophrenia and teaches ap-

plied coping strategies to reduce stress. EST is tailored

to the patient’s level of recovery, and begins with

weekly 30–60 min individual therapy sessions. As

patients progress through the treatment, increasingly

complex coping strategies are taught and applied, and

therapy sessions are provided on a biweekly basis.

All participants were maintained on antipsychotic

medications approved by the US Food and Drug

Administration for the treatment of schizophrenia

or schizo-affective disorder.

1254 S. M. Eack et al.

Measures

Neurocognition

A comprehensive battery of paper-and-pencil and

computerized neuropsychological tests representing

the domains of verbal and working memory, executive

functioning, language ability, psychomotor speed and

neurological soft signs was used to assess the neuro-

cognitive mechanisms of CET effects on functional

outcome. These domains assessed reflect the promi-

nent areas of cognitive impairment in schizophrenia,

and are largely consistent with those outlined by

the Measurement and Treatment Research to Improve

Cognition in Schizophrenia (MATRICS) committee

(Green et al. 2004). Items from tests of these domains

were combined into an overall composite measure of

neurocognitive function, and included immediate and

delayed recall items from stories A and B of the

Revised Wechsler Memory Scale (Wechsler, 1987); List

A total recall, short-term free recall, and long-term

free recall from the California Verbal Learning Test

(Delis et al. 1987); digit span, digit symbol, picture

arrangement, and vocabulary items from the Revised

Wechsler Adult Intelligence Scale (Wechsler, 1981);

Trails B time to completion (Reitan & Waltson,

1985); perseverative and non-perseverative errors,

categories completed, and percentage of conceptual

responses from the Wisconsin Card Sorting Test

(Heaton et al. 1993); total move score and ratio of

initiation to execution (planning) time from the Tower

of London (W. C. Culbertson and E. A. Zillmer, Tower

of London-DX Manual, unpublished results); and

cognitive-perceptual and repetition-motor subscales

from the Neurological Evaluation Scale (Buchanan &

Table 1. Demographic and clinical characteristics of patients treated with CET or EST

Variable CET (n=31) EST (n=27) pa

Demographics

Age, years 25.88 (6.46) 25.97 (6.26) 0.955

Male 0.617

n 20 20

% 65 74

Caucasian 0.662

n 21 19

% 68 70

Attended college 0.713

n 9 10

% 29 37

Not employed 0.772

n 8 7

% 26 26

Schizophrenia 0.916

n 21 17

% 68 63

Time since first psychotic symptom,

years

3.07 (2.34) 3.32 (2.16) 0.675

IQ 97.74 (7.66) 98.52 (9.74) 0.736

Symptoms

BPRS total 39.77 (9.21) 40.70 (10.64) 0.723

Wing Negative Symptoms Scale 18.35 (4.14) 18.15 (3.63) 0.842

Raskin Depression Scale 6.77 (2.77) 6.33 (1.98) 0.494

Covi Anxiety Scale 5.84 (2.08) 6.11 (2.22) 0.632

Medications

CPZ dose at baseline, mg 381.18 (271.99) 460.68 (335.05) 0.323

CPZ dose at year 1, mg 402.33 (332.93) 529.38 (374.13) 0.215

CPZ dose at year 2, mg 473.58 (384.43) 548.71 (402.05) 0.520

CET, Cognitive enhancement therapy; EST, enriched supportive therapy;

IQ, intelligence quotient; BPRS, Brief Psychiatric Rating Scale; CPZ, chlorpromazine.

Values are given as mean (standard deviation). a x2 Test or independent t test, two-tailed, for significant differences between CET

and EST participants.

Mechanisms of CET effects 1255

Heinrichs, 1989). Items were scaled to a common

metric and then averaged to form an overall neuro-

cognitive composite. The reliability of this composite

was good (Cronbach’s a=0.87).

Social cognition

Social cognition was assessed using the MATRICS-

recommended Mayer–Salovey–Caruso Emotional

Intelligence Test (MSCEIT; Mayer et al. 2003). The

MSCEIT is a performance-based measure of emotional

intelligence that requires participants to solve

emotionally laden problems regarding the perception,

facilitation, understanding and management of

emotion. In keeping with the developers’ adminis-

tration guidelines, patients completed the MSCEIT as

a computerized, self-administered test in this research.

The instrument consisting of 141 items across eight

distinct tasks forms the emotion perception, facili-

tation, understanding, and management branches

of Salovey & Mayer’s (1990) proposed four-branch

model of emotional intelligence. Although the

MATRICS committee only recommended the use of

the emotion management branch of the MSCEIT, all

four branches were used in this research. We have

previously shown the MSCEIT to be a reliable measure

of social cognition that is unique from both neuro-

cognitive function and symptomatology (Eack et al.

2010), and the MATRICS initiative has demonstrated

the test–retest reliability of the emotion management

branch of the instrument to be adequate (Nuechterlein

et al. 2008). Behavioral ratings of social cognition pre-

viously reported on were not considered for mediator

analyses, due to their completion by the same raters

who assessed functional outcome and were not blind

to treatment assignment.

Functional outcome

Functional outcome was assessed largely using field

standards of social adjustment and functioning in

schizophrenia. Measures included the Social Ad-

justment Scale-II (Schooler et al. 1979), Global Assess-

ment Scale (Endicott et al. 1976), Major Role Inventory

(Hogarty et al. 1974) and Performance Potential In-

ventory (Department of Health and Human Services,

1986; Hogarty et al. 2004). These measures have been

described in greater detail in previous reports (Eack

et al. 2009), and together they cover the broad domains

of social, vocational, family, sexual, independent liv-

ing, and leisure functioning. An overall composite in-

dex of functional outcome was used to avoid excessive

inference testing among the large number of items

gleaned from these instruments. This composite was

calculated by scaling individual functional outcome

items to a common metric and then averaging them

to form the functional outcome composite, which

displayed good internal consistency (Cronbach’s a= 0.87).

Procedures

Participants were recruited from out-patient services

at Western Psychiatric Institute and Clinic in

Pittsburgh, and nearby community clinics. Patients

who met eligibility requirements were randomly as-

signed to CET or EST and treated for 2 years in their

respective treatment condition. Cognitive and func-

tional assessments were performed prior to treatment

and then annually at 12 and 24 months using the

aforementioned measures by study clinicians or

trained neuropsychologists, who were not blind to

treatment assignment. However, assessors adminis-

tering the performance-based neurocognitive and

MSCEIT tests were blind to clinical assessments of

functional outcome. There were no significant differ-

ences between treatment groups with regard to

demographic and symptom characteristics at baseline,

attrition, or medication characteristics (Eack et al.

2009). Of the 58 patients randomized and treated,

49 and 46 completed 1 and 2 years of treatment, re-

spectively. All participants provided written informed

consent prior to participation, and the study was

reviewed annually by the University of Pittsburgh

Institutional Review Board.

Data analysis

Mechanisms of functional improvement during CET

were analysed using path analysis based on the me-

diator-analytic framework for clinical trials outlined

by Kraemer et al. (2002). This framework is based on

seminal work by Baron & Kenny (1986), where a series

of linear models are used to evaluate the impact of

treatment assignment or choice (CET v. EST) on an

outcome (improved functional outcome) through an

intermediate treatment response or putative mediator

(improved cognition). In a clinical trial, treatment as-

signment or choice has k levels corresponding to the

number of treatment groups in the trial (in this case,

two levels, CET or EST). In order to demonstrate that

improved cognition is a mediator between treatment

assignment and improved functional outcome, several

conditions must be met.

First, treatment assignment must be associated with

outcome response, that is, assignment to CET v. EST

must have a direct impact on changes in functional

outcome (criterion A). This condition is otherwise

known as a main effect of treatment on outcome, and

establishes that the type of treatment provided

(e.g. CET v. EST) is associated with different changes

in outcome (e.g. individuals in CET improve more on

1256 S. M. Eack et al.

functional outcome than those in EST). Second, treat-

ment assignment must be associated with response to

an intermediate outcome or mediator, that is, assign-

ment to CET v. EST must have a direct impact on

changes in cognition (criterion B). This condition es-

tablishes that the type of treatment provided is also

associated with a differential response on the putative

mediator (e.g. individuals in CET improve more on

cognition than those in EST). Third, changes in the

mediator must be associated with changes in the out-

come, or changes in cognition must have a direct im-

pact on changes in functional outcome (criterion C).

This condition demonstrates the interrelationship be-

tween improvement on the mediator and improved

outcome. Linear models used to assess this relation-

ship across treatment groups first adjust for treatment

assignment to remove the possibility of an illusory

association between the mediator and outcome, simply

because of their shared relationship with treatment

assignment (which is given from criteria A and B).

Finally, the direct effect of treatment assignment on

changes in outcome must be reduced, after accounting

for the association between changes in the mediator

and changes in the outcome. That is, the relationship

between assignment to CET v. EST and changes in

functional outcome will be reduced (i.e. partially ex-

plained by the mediator) or eliminated (i.e. entirely

explained by the mediator) after adjusting for the as-

sociation between changes in cognition and changes in

functional outcome (criterion D). When criterion D is

met, the direct effect of treatment assignment on

changes in outcome is reduced because the total effect

of treatment is partitioned into its direct and indirect

(through the mediator) components.

Within the context of this research, these principles

of mediation were applied to examine whether treat-

ment assignment to CET (v. EST) resulted in improved

functional outcome, and whether this differential

functional improvement was mediated by the ben-

eficial effect of treatment assignment to CET on neuro-

cognition and social cognition. To accomplish this, a

series of path analyses employing linear mixed-effects

growth models was used to show that, consistent with

previous reports from this trial (Eack et al. 2007, 2009),

treatment assignment to CET resulted in greater im-

provement in functional outcome (criterion A) and the

putative mediators, neurocognition and social cog-

nition (criterion B), compared with EST. Next, mixed-

effects models examined the association between

changes in neurocognition and social cognition, and

changes in functional outcome (criterion C), by pre-

dicting functional outcome from the neurocognition

composite and MSCEIT branch scores over the

course of the study (i.e. time-varying covariates) after

adjusting for treatment assignment (Singer & Willet,

2003). Finally, the adjusted direct effect of CET on

functional outcome after controlling for cognitive

change was obtained from these models, as well as

the indirect effect of treatment assignment to CET

on functional outcome through improved cognition

(criterion D).

It is important to note that both treatment groups

(CET and EST) are included in all of these models, as

CET-specific effects or the true effect of CET on both

cognition and functional outcome can only be esti-

mated in contrast to a control condition. This is one of

the core principles of experimental designs and ran-

domized clinical trials (Campbell & Stanley, 1963),

where improvement within the CET group alone

could be a function of many different factors other

than the specific elements of the treatment (e.g. re-

peated testing effects, the provision of skilled clin-

icians, the use of supportive therapy). The use of a

randomized control condition is designed to control

for these factors, and EST in particular is designed to

control for the non-specific effects of supportive treat-

ment. As such, only improvements in CET that exceed

those of patients treated with EST can be considered

true, CET-specific treatment effects, and it is these

CET-specific effects that are the subject of mediator

analyses. In fact, because of this property of rando-

mized controlled trials, the examination of mediators

in the context of clinical trials is particularly advan-

tageous, as the source of differential change in both

the outcome and mediator is known and inferences

regarding causality are considerably strengthened

(Kraemer et al. 2002).

All mixed-effects models employed intent-to-treat

analyses with all 58 patients who received any

exposure to their respective treatment condition.

Missing data were handled using the expectation-

maximization approach (Dempster et al. 1977). In

addition, all models adjusted for the potential con-

founding effects of age, gender, illness duration and

IQ at baseline, as well as current medication dose.

Only confounders that demonstrated a significant

effect on outcome change were retained to conserve

power. Model coefficients are presented using z-scale

transformations to ease interpretation and coefficient

comparisons. The size and significance of mediation

effects was estimated using the MacKinnon et al. (2002)

asymptotic z’ test of indirect effects.

Results

Mediating effects of neurocognitive and

social-cognitive improvement on functional change

Neurocognitive and social-cognitive correlates and

mediators of functional improvement among

Mechanisms of CET effects 1257

early-course patients participating in a 2-year trial of

CET are presented in Table 2. Neurocognitive com-

posite improvement was significantly related to im-

provements in functional outcome, with patients who

experienced larger neurocognitive gains during the

course of the trial also experiencing a greater func-

tional response. With regard to social cognition, of the

four branches of the MSCEIT that were examined, only

the emotion management branch demonstrated a sig-

nificant longitudinal relationship with functional

change. Fig. 1 presents the results of path models ex-

amining the mediating effect of overall neurocognitive

and emotion management improvement on functional

outcome. As shown in Fig. 1a, CET exerted a signi-

ficant effect on the neurocognitive composite, which in

turn was directly related to improved function. This

cascade of neurocognitive change proved to signi-

ficantly mediate the robust direct effects of CET on

functional outcome (z’=1.55, n=58, p=0.040). A similar pattern of results was observed for the MSCEIT

emotion management branch, where CET had its lar-

gest effects, which again was related to functional

improvement and significantly mediated the effects

of CET on functioning (zk=1.58, n=58, p=0.037, see Fig. 1b). When examining the relative impact of neuro-

cognitive and social-cognitive improvement on func-

tional outcome concurrently, improved emotion

management continued to demonstrate a significant

direct effect on functional improvement [B=0.14, de- grees of freedom (df)=86, p=0.045], whereas the effect of neurocognitive change on functioning was only mar-

ginal, but of similar magnitude (B=0.14, df=86, p= 0.055). Interestingly, overall changes inneurocognition

were not associated with improvements in the

MSCEIT managing emotions subscale (B=0.07, df=87, p=0.459), although improved neurocognition was significantly associated with improvements in the

MSCEIT understanding emotions subscale (B=0.22, df=87, p=0.009). Together, these findings indicate largely independent improvements in both neurocog-

nition and social cognition, particularly emotion man-

agement, as mechanisms of functional change during

CET in early-course schizophrenia.

Table 2. Associations between changes in neurocognition and social cognition and improved functional outcome (n=58)a

Variable

DFunctional outcome

Direct effectb Mediator effectc

B S.E. t df p zk

DNeurocognition composite 0.15 0.07 2.14 89 0.035 1.55*

DSocial cognition (MSCEIT)

DPerceiving emotions x0.07 0.07 x1.08 87 0.281 x0.99 DFacilitating emotions x0.05 0.06 x0.77 87 0.443 x0.63 DUnderstanding emotions x0.00 0.07 x0.02 87 0.983 x0.02 DManaging emotions 0.15 0.07 2.11 87 0.037 1.58*

S.E., Standard error; df, degrees of freedom; MSCEIT, Mayer–Salovey–Caruso Emotional Intelligence Test. a Results are based on mixed-effects growth models with a single cognition variable as the primary covariate, adjusting for

age, gender, intelligence quotient, illness duration, medication dose, and treatment assignment. b Direct effects represent direct relationships between changes in cognition and changes in functional outcome. c Mediator effects represent the intervening effect of changes in cognition on cognitive enhancement therapy effects on

functional outcome.

* p<0.05.

∆Neuro- cognition

0.23* 0.15*

0.52**/0.47**

(a)

(b)

0.28* 0.15*

0.52**/0.47**

∆Managing emotions

∆Functional outcome

∆Functional outcome

CET (1=Yes; 0=No)

CET (1=Yes; 0=No)

Fig. 1. Neurocognitive (a) and social-cognitive (b) mediators

of the effects of cognitive enhancement therapy (CET) on

functional outcome in early-course schizophrenia (n=58). Regression weights on the right of the slash (/) represent

direct effects of CET on functional outcome after adjusting for

the mediator (* p<0.05, ** p<0.01).

1258 S. M. Eack et al.

Mediating effects of improvement in individual

neurocognitive tasks on functional change

Having found evidence for improvements in overall

neurocognitive ability as a significant mediator of CET

effects on functioning at the composite level, we pro-

ceeded to conduct a series of exploratory analyses to

examine the degree to which individual neurocog-

nitive tests contributed to this effect. Results revealed

that improved delayed recall on the Wechsler Memory

Scale (B=0.13, df=82, p=0.029) and long-term free recall on the California Verbal Learning Test (B=0.12, df=87, p=0.036) were significantly related to greater functional improvement, and reduced time to complete

Trails B (B=x0.16, df=87, p=0.010) and perseverative (B=x0.12, df=88, p=0.017) and non-perseverative (B=x0.10, df=87, p=0.033) errors on the Wisconsin Card Sorting Test were also associated with greater

functional gains. Despite several direct relationships

between changes in verbal memory, executive func-

tion domains, and improved functional outcome, de-

creases in Trails B time to completion proved to be the

only significant neurocognitive mediator of CET ef-

fects on functioning (z’=1.62, n=58, p=0.036). Such results suggest the importance of verbal memory and

executive functioning improvement to functional out-

come in early-course schizophrenia, and point to im-

proved executive performance as a key neurocognitive

mediator of CET effects on functioning.

Discussion

Cognition has emerged as a key target of schizo-

phrenia treatment, and a variety of psychosocial cog-

nitive rehabilitation programs have been developed

and shown to be effective at improving both cognition

and functional outcome in the disorder (McGurk et al.

2007). Unfortunately, the mechanisms of functional

improvement that accrue from these interventions re-

main largely unknown, and thus the degree to which

targeting cognition results in meaningful gains in

functioning is not clear. We conducted a first investi-

gation of the neurocognitive and social-cognitive

mechanisms of functional improvement during a

2-year trial of CET for patients in the early course of

schizophrenia. Overall, improvements in neurocog-

nitive composite scores were significantly associated

with improved functioning, which partially mediated

the effect of CET on functional outcome. Of the four

branches of the MSCEIT that were examined, only

the MATRICS-recommended emotion management

branch proved to be a significant mediator of CET

effects on functioning. Exploratory analyses of indi-

vidual neurocognitive tests also revealed significant

relationships between verbal memory, executive

function, and functional improvement, with decreased

Trails B time to completion exerting a significant

mediating effect on functioning. Such findings signify

both neurocognitive and social-cognitive improve-

ment, particularly in the domains of executive per-

formance and emotion management, as mechanisms

of functional improvement during cognitive rehabili-

tation in early schizophrenia.

The results of this investigation support previous

cross-sectional and naturalistic longitudinal studies

documenting the importance of both neurocognition

and social cognition to functional outcome in schizo-

phrenia (Sergi et al. 2006; Brekke et al. 2007, 2009).

Consistent with previous studies (Green et al. 2000),

verbal memory improvements were the most reliable

neurocognitive predictors of functional change in this

research, and may represent an important neurocog-

nitive precursor for benefiting most from treatment

strategies used in CET, such as active thinking, giving

feedback, responding to coaching, and abstracting the

social gist. Improvements in social cognition also

proved to be important contributors to functional

outcome and mediated CET effects on functioning.

Unfortunately, despite growing evidence on the im-

portance of social cognition to functional outcome

(Couture et al. 2006), the majority of cognitive rehabili-

tation approaches do not address social-cognitive

impairments.

Although the results of this research begin to pro-

vide some evidence of a mediational relationship

between changes in neurocognition, social cognition,

and functional outcome within the context of a clinical

trial, it is important to remember that not all mediators

are causal mechanisms (Kraemer et al. 2002). In ad-

dition, correlational analyses of change cannot dis-

ambiguate the direction of mediational relationships,

and it is possible that a bidirectional relationship exists

between improved cognition and functioning. The

clear identification of causality and directionality with

regard to a mediator requires a priori studies designed

to manipulate the presence or absence of a putative

mechanism. This research lays the foundation for such

studies, by identifying a need for controlled trials that

examine the functional effects of treating neurocog-

nition and social cognition either alone or jointly.

Further, both social-cognitive and neurocognitive im-

provements were only partial mediators of functional

improvement, which indicates the presence of other

active mechanisms of functional change. These may

include such factors as increased socialization or

decreased anxiety and negative symptoms.

In addition, although a modest number of inference

tests were conducted when examining associations

between cognitive and functional change, corrections

for multiple inference testing were not conducted and

Mechanisms of CET effects 1259

these results would not have survived type I error

corrections. As such, care will need to be taken when

interpreting these findings until confirmation from

future studies. Finally, it is also important to note that

the measurement of social cognition in this study was

restricted to the MSCEIT, and that future studies will

need to expand to broader measures of social cog-

nition. It should be noted, however, that these findings

do support the recommendations of the MATRICS

committee to use the emotion management branch

of the instrument, which we have previously observed

to be the most sensitive to social-cognitive treatment

effects (Eack et al. 2007).

In summary, this first study of the effects of im-

proved neurocognition and social cognition on func-

tional outcome during a randomized trial of cognitive

rehabilitation for early schizophrenia found that im-

provements in neurocognitive and social-cognitive

domains both served as significant mediators of

functional improvement. These results suggest that

functional recovery from the illness might best be

promoted through the early application of cognitive

rehabilitation programs that target both social and

non-social cognition.

Acknowledgements

This work was supported by grant no. KL2 RR024154

from the National Center for Research Resources

(NCRR), a component of the National Institutes of

Health (NIH) and NIH Roadmap for Medical Research,

and its contents are solely the responsibility of the au-

thors and do not necessarily represent the official view

of NCRR or NIH. Information on NCRR is available at

http://www.ncrr.nih.gov/. Information on Re-engin-

eering the Clinical Research Enterprise can be obtained

from http://nihroadmap.nih.gov/clinicalresearch/

overview-translational.asp. In addition, this work was

supported by NIH grants MH-79537 (S.M.E.) and MH-

60902 (M.S.K.). We thank the late Gerard E. Hogarty for

his leadership and direction as co-principal investi-

gator of this study, and Susan Cooley, Anne Louise

DiBarry, Konasale Prasad, Haranath Parepally, Debra

Montrose, Diana Dworakowski, Mary Carter and Sara

Fleet for their help in various aspects of the study.

Declaration of Interest

None.

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