What drives poor functioning in the at-risk mental state? A systematic review

Schizophrenia Research xxx (2014) xxx–xxx

SCHRES-06045; No of Pages 11

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Schizophrenia Research

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Review

What drives poor functioning in the at-risk mental state?A systematic review

Jack Cotter a,⁎, Richard J. Drake a, Sandra Bucci b, Joseph Firth a, Dawn Edge a,b, Alison R. Yung a,c

a Institute of Brain, Behaviour and Mental Health, University of Manchester, United Kingdomb School of Psychological Sciences, University of Manchester, United Kingdomc Orygen Youth Health Research Centre, University of Melbourne, Australia

⁎ Corresponding author at: Institute of Brain, Behaviouof Manchester, Room 3.306, Jean McFarlane Building, OxfoUnited Kingdom. Tel.: +44 161 275 5970; fax: +44 161 3

E-mail addresses: [email protected] (J. [email protected] (R.J. Drake), [email protected] (J. Firth), dawn.ed(D. Edge), [email protected] (A.R. Yung).

http://dx.doi.org/10.1016/j.schres.2014.09.0120920-9964/© 2014 Elsevier B.V. All rights reserved.

Please cite this article as: Cotter, J., et al., Whhttp://dx.doi.org/10.1016/j.schres.2014.09.01

a b s t r a c t
a r t i c l e i n f o
Article history:
Received 26 June 2014Received in revised form 18 August 2014Accepted 4 September 2014Available online xxxx
Keywords:At-risk mental stateUltra-high riskClinical high riskPsychosisFunctioningSystematic review

Background: Transition to psychotic disorder has been the traditional outcome of interest for research in the at-riskmental state (ARMS). However, there is growing recognition that individuals with ARMS may function poorlyregardless of whether they develop psychosis. We aimed to review the literature to determine whether there arespecific factors associated with, or predictive of, functional impairment in the ARMS population.Method: An electronic database search of MEDLINE, PsycINFO and Embase from inception until May 2014 was con-ducted using keyword search terms synonymouswith the at-riskmental state and functioning. Eligible studieswereoriginal peer-reviewed English language research articles with populations that met validated at-risk diagnosticcriteria and examined the cross-sectional or longitudinal association between any variable and a measure of func-tioning.Results: Seventy-two eligible studies were identified. Negative symptoms and neurocognitive impairment wereassociated with poor functioning in cross-sectional studies. Negative and disorganised symptoms, neurocognitivedeficits and poor functioning at baselinewere predictive of poor functional outcome in longitudinal studies. Positive
symptoms were unrelated to functioning in both cross-sectional and longitudinal studies. Functional disability waspersistent and resistant to current treatments.Conclusions:Negative anddisorganised symptoms and cognitive deficits pre-date frankpsychotic symptoms and arerisk factors for poor functioning. This is consistent with a subgroup of ARMS individuals potentially havingneurodevelopmental schizophrenia. Treatments aimed at improving functioning must be considered a priority onpar with preventing transition to psychosis in the development of future interventions in the ARMS group.
© 2014 Elsevier B.V. All rights reserved.

1. Introduction

Criteria have been developed to identify individuals vulnerable to de-veloping a psychotic disorder (Yung et al., 1996, 1998;Miller et al., 2002).These have been referred to as the prodromal, ultra-high risk (UHR),clinical high-risk (CHR) and at-risk mental state (ARMS) criteria (Fusar-Poli et al., 2013). In brief, the standard at-risk criteria are the presence ofsubthreshold psychotic symptoms and/or full threshold psychoticsymptoms that resolved spontaneously and/or a trait risk factor for psy-chotic disorder (such as positive family history) combined with signifi-cant deterioration in mental state. The UHR criteria have been widely

r and Mental Health, Universityrd Road, Manchester M13 9PL,06 7945.ter),[email protected] (S. Bucci),[email protected]

at drives poor functioning in2

used and are associated with a high risk of developing psychotic disor-der. A recent meta-analysis found that rates of onset of psychosis are22% in 1 year, 29% in 2 years and 36% after 3 years (Fusar-Poli et al.,2012).

In addition to the development of psychosis (Yung et al., 2003;Masonet al., 2004; Thompson et al., 2011; Cornblatt et al., 2012), there hasrecently been a growing interest in poor functioning as an outcome of in-terest in itself (Yung et al., 2010; Barbato et al., 2013; Fulford et al., 2013;Kim et al., 2013; Lin et al., 2013) and in identifying factors predictive oflong-term functional disability (Fusar-Poli et al., 2009; Lin et al., 2011;Carrión et al., 2013; Meyer et al., in press). For a large proportion ofARMS patients functioning remains impaired, regardless of transition tofull-threshold psychosis or symptomatic remission (Addington et al.,2011a; Schlosser et al., 2012; Carrión et al., 2013; de Wit et al., 2014). Itis important to establishwhether particular aspects of illness consistentlyunderlie functional disability in order to improve our understanding ofthis patient group. Therefore, the aim of this reviewwas to systematicallyappraise the literature to identify variables associated with, or predictiveof, functional impairment in the ARMS population.

the at-risk mental state? A systematic review, Schizophr. Res. (2014),

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2. Method

This review was conducted in line with the PRISMA guidelines forreporting systematic reviews (Moher et al., 2009).

2.1. Eligibility criteria

Eligible studies were original research articles published in peer-reviewed journals, with populations that met the diagnostic criteriafor being ‘at-risk’, ‘ultra-high risk’ or at ‘clinical-high risk’ (or similarlydefined) of psychosis based on a clinically validated instrument. Studieswere included that examined the cross-sectional relationship betweenany variable and a measure of functioning, or reported the longitudinalrelationship between baseline variables and subsequent functional out-come. For the purposes of this review, functioning was defined as mea-sures relating to the frequency of, quality of, or satisfaction with social,academic or occupational activity. Intervention studies that examinedfunctioning pre- and post-intervention were eligible.

Studies that included only subjects at genetic risk who had not metthe formal diagnostic criteria for being at ultra-high risk (or similarlydefined) of psychosis, case studies and non-English language articleswere excluded.

2.2. Search strategy

On the 1st of May 2014 an electronic database search of OvidMEDLINE, PsycINFO and Embase using the following keywords was con-ducted: “at risk mental state” or “ultra high risk”, “UHR”, “clinical highrisk”, “CHR”, “prodrom*” and “psychos*” or “psychot*”, “schizo*” and“social function*” or “role function*”, “global function*”, “psychosocialfunction*”, “functional outcome”, “academic function*”, “communityfunction*”, “occupational function*”, “school function*”, “work func-tion*”. Reference lists of retrieved articles were also reviewed by handfor additional relevant publications not identified in the initial electron-ic search.

2.3. Study selection and data extraction

Two reviewers (J.C. and J.F.) independently screened articles foreligibility. Any disagreements were resolved through discussion. Forall eligible studies, a standardised tool was developed to record:(1) study characteristics (study design, year of publication, countrywhere the work was performed); (2) sample demographics (samplesize, gender composition, mean age); (3) the at-risk screening instru-ment used to assess eligibility; (4) functioning data (measure(s) used,mean sample scores); (5) variables examined for their associationwith functioning; and (6) summary of study findings. For interventionstudies, we also recorded: (7) intervention and comparator arms; and(8) treatment duration.

3. Results

The study selection and exclusion process are summarised in Fig. 1.Our initial database search retrieved 384 unique citations after the re-moval of duplicates. Of these, 271 were excluded at the title–abstractstage and a further 55 following full-paper screening. Full text articleswere excluded due to the use of ineligible populations (n = 9), studiesnot examining the relationship between functioning and any other var-iable (n = 44) or not being original research studies (n = 2). Fourteenadditional papers were identified from reviewing reference lists of arti-cles. Seventy-two papers met the full inclusion criteria, and fell broadlyinto the categories of observational (Table 1) and intervention studies(Table 2). These were conducted in North America (n = 35), Europe(n = 20), Australia (n = 10) and South Korea (n = 7). There were 12different measures of functioning used by studies within this review,which are briefly summarised in Supplementary Table 1. These included

Please cite this article as: Cotter, J., et al., What drives poor functioning inhttp://dx.doi.org/10.1016/j.schres.2014.09.012

‘global’ measures such as the Global Assessment of Functioning (GAF;Hall, 1995) and Social and Occupational Functioning Assessment Scale(SOFAS; Goldman et al., 1992), which provide a single score indicativeof overall impairment. Functioning was also examined using separatemeasures of social and role (occupational/educational) functioning,such as the Global Functioning: Social (GFS; Auther et al., 2006) andRole (GFR; Niendam et al., 2006a) scales.

3.1. ARMS subgroup

One study found that patients meeting the genetic risk and deterio-ration subgroup criteria had significantly better global functioning thanthose presenting with attenuated psychotic symptoms in the year priorto entering the study. However, due to rapid deterioration, functioningin these groups did not differ at study inception (Miller et al., 2003). Thisis consistent with research reporting no significant differences in globalfunctioning between ARMS diagnostic sub-groups (Lemos-Giráldezet al., 2009).

3.2. Symptoms

Positive psychotic symptoms are sub-threshold and often transient inARMS patients. These were associated neither with functioning in cross-sectional studies, nor with long-term functional outcome (Niendamet al., 2006b; Shim et al., 2008a; Carrión et al., 2011; Corcoran et al.,2011; Eslami et al., 2011; Lin et al., 2011; Barbato et al., 2013; Carriónet al., 2013; Kim et al., 2013; Walder et al., 2013; Meyer et al., in press).

Cross-sectional evidence indicated that negative symptoms (Niendamet al., 2006b; Cornblatt et al., 2007; Svirskis et al., 2007; Willhite et al.,2008; Velthorst et al., 2010; Raballo et al., 2011; Valmaggia et al., 2013;Walder et al., 2013; Meyer et al., in press) and disorganised and generalsymptoms (Cornblatt et al., 2007; Comparelli et al., 2010; Velthorstet al., 2010; Corcoran et al., 2011; Fulford et al., 2013; Kim et al., 2013;Walder et al., 2013; Meyer et al., in press) were consistently associatedwith a broad range of global, social and role functioning measures.When each of these symptom clusters was entered into regression analy-ses, only negative symptoms remained significantly associated with poorfunctioning (Corcoran et al., 2011; Fulford et al., 2013; Kim et al., 2013;Meyer et al., in press). However, longitudinal evidence indicated thatboth negative (Lin et al., 2011; Schlosser et al., 2012; Meyer et al., inpress) and disorganised symptoms at baseline (Bearden et al., 2011;Eslami et al., 2011; Carrión et al., 2013; Ziermans et al., 2014) were alsoamongst the strongest independent predictors of long-term functionaloutcome.

A keymethodological limitation of this area is that negative symptomitems in the Structured Interview for Prodromal Syndromes (SIPS; Milleret al., 2002) overlapwithmeasures of functioning. This is one of themaininstruments used to characterise ARMS patients, particularly in NorthAmerican studies. Meyer et al. (in press) reported that removal of twoSIPS negative items from the functional assessment resulted in a substan-tial drop in the magnitude of association between negative symptomsand social and role functioning both at baseline and at follow-up(Meyer et al., in press). This also greatly increased the strength of associ-ation between neurocognition and disorganised symptoms and function-ing in the cross-sectional and longitudinal analyses. Future studies shouldtake this potential confounding of items into account when performinganalyses.

3.3. Duration of symptoms

Global functioning did not significantly differ between patients withlong (N1 year) and short (b1 year) durations of untreated attenuatedpsychotic symptoms (Chung et al., 2010). However, a longer durationof prodromal symptoms was associated with increased impairment onthe ‘Interpersonal behaviour’ and ‘Prosocial activities’ subscales of theSocial Functioning Scale (Shim et al., 2008a). A longer duration of



Screen

ing

Iden

�fica�o

nInclud

edEligibility

Records iden�fied throughdatabase searching

(n = 714)

Addi�onal records iden�fiedthrough other sources

(n = 14)

Records a�er duplicates removed(n = 398)

Records screened(n = 398)

Records excluded(n = 271)

Full-text ar�cles assessedfor eligibility

(n = 127)

Full - text ar�cles excluded(n = 55)

Wrong popula�on (n = 9)Associa�ons not inves�gated (n = 44)

Review paper (n = 2)

Studies included in review(n = 72)

Fig. 1. PRISMA flow diagram.

3J. Cotter et al. / Schizophrenia Research xxx (2014) xxx–xxx

untreated attenuated psychotic symptoms at baseline was also signifi-cantly predictive of poorer functional improvement over the subsequent12 months, independent of sex, age and the severity of symptoms(Fusar-Poli et al., 2009).

3.4. Anxiety

Comorbid anxiety disorders affect approximately 15% of ARMSpatients at presentation to services (Fusar-Poli et al., 2014). In additionto clinically diagnosable disorders, this population also report highlevels of anxiety symptoms (Niendam et al., 2009a; Chudleigh et al.,2011). In the largest cross-sectional study to date, self-reported anxietysymptoms were found to be modestly correlated with global function-ing (measured with the GAF) and a single-item measure of role func-tioning, but not with more detailed measures including the GlobalFunctioning: Social and Role scales (Fulford et al., 2013). These associa-tions were no longer significant after controlling for negative symp-toms. Smaller studies also reported no association between socialfunctioning and either clinician-rated anxiety symptoms (Shim et al.,2008a) or self-reported social phobia (Chudleigh et al., 2011). Similarly,anxiety symptoms at baseline did not significantly differ between thoseclassified into good and poor long-term social and role functioning out-come groups (Carrión et al., 2013).

Two studies have also examined the relationship between obsessive–compulsive (OC) symptoms and functional disability. The severity of OCsymptoms and degree of functional impairment were not correlated ineither sample (Niendam et al., 2009a; Hur et al., 2012). However, seem-ingly conflicting results were found when patients in these studies weredichotomised into high and low OC symptom groups. Niendam et al.


(2009b) reported no significant differences between the two groups inglobal, social or role functioning or on any measures of clinical symptomseverity. In contrast, Hur et al. (2012) reported that patients in the highOC symptom group exhibited poorer global functioning. However,patients in the high OC group also exhibited significantly higher levelsof negative and disorganised symptoms, making it unclear whetherlower GAF scores were due to more marked functional impairment ormore severe negative and disorganised symptoms in this group.

3.5. Low mood

Around 40% of ARMS patients present with comorbid depressivedisorder (Fusar-Poli et al., 2014). However, it is difficult to interpretthe direction of causality of cross-sectional evidence in this domain. Itis plausible that poor functioning may in part be driving low mood.The level of social dysfunction is reportedly comparable in ARMSpatients with and without a lifetime diagnosis of major depressivedisorder (Corcoran et al., 2011). However, several studies convergedto show that self-reported and interviewer-rated depressive symptomswere correlated with various measures of social and global functioning,but where subsequent regression analyses were performed, depressivesymptoms did not explain variance in functioning over and above neg-ative symptoms (Niendamet al. 2006b; Chudleigh et al., 2011; Corcoranet al. 2011; Kim et al., 2013). However, the largest cross-sectional studyin this area reported that interviewer-rated depressive symptoms weresignificantly associated with lower global and social functioning inde-pendently of negative symptoms (Fulford et al. 2013). Across thesestudies, low mood was not associated with various measures of rolefunctioning (Chudleigh et al., 2011; Fulford et al., 2013; Kim et al.,



Table 1Observational studies.

Reference + country N (male/female) At-risk screeninginstrument

Key variable(s) examined forassociation with functioning

Functioningmeasure(s)

Design

Addington et al. (2013)— Canada, USA 360 (210/150) SIPS Childhood trauma GFS, GFR Cross-sectionalAmminger et al. (2012) — Austria 81 (27/54) PANSS Erythrocyte membrane phospholipid

compositionGAF Cross-sectional

Auther et al. (2012) — USA 101 (66/35) SIPS Lifetime cannabis use and abuse GFS, GFR Cross-sectional +longitudinal

Barbato et al. (2013) — Canada, USA 137 (81/56) SIPS Neurocognition, social cognition SFS Cross-sectionalBearden et al. (2011) — USA 54 (38/16) SIPS Formal thought disorder GFS, GFR LongitudinalCarrión et al. (2011) — USA 127 (85/42) SIPS Neurocognition GFS, GFR Cross-sectionalCarrión et al. (2013) — USA 92 (58/34) SIPS Symptoms, neurocognition GFS, GFR LongitudinalChudleigh et al. (2011) — Australia 20 (11/9) CAARMS Symptoms, depression, social anxiety SFS, SOFAS,

WHODAS-IICross-sectional

Chung et al. (2010) — South Korea 38 (31/7) CAARMS Duration of untreated at risk symptoms GAF Cross-sectionalCorcoran et al. (2008) — USA 32 (26/6) SIPS Substance use GAF Cross-sectional +

longitudinalCorcoran et al. (2011) — USA 56 (43/13) SIPS Symptoms, depression, ethnicity SAS-SR Cross-sectionalCornblatt et al. (2007) — USA 121 (79/42) SIPS Symptoms GAF, GFS, GFR Cross-sectional +

longitudinalComparelli et al. (2010) — Italy 26 (N/R) CAARMS Symptoms GAF Cross-sectionalEslami et al. (2011) — USA 22 (12/10) SIPS Neurocognition SAS-SR LongitudinalFulford et al. (2013) — USA 98 (58/40) SIPS Symptoms, depression, anxiety GAF, GFS,

GFR, SCOSCross-sectional

Fusar-Poli et al. (2009) — Italy 49 (32/17) ERIraos Symptoms, duration of untreated at risksymptoms

GAF Longitudinal

Fusar-Poli et al. (2011) — UK 15 (8/7) CAARMS Brain activity (fMRI) during a workingmemory task

GAF Longitudinal

Goghari et al. (2014) — UK 96 (76/20) CAARMS Spatial working memory, IQ GAF Cross-sectionalHur et al. (2012)— South Korea 65 (40/25) CAARMS/SIPS Obsessive–compulsive symptoms GAF Cross-sectionalJahshan et al. (2012) — USA 26 (17/9) SIPS Information processing (EEG) GAF Cross-sectionalJalbrzikowski et al. (2013) — USA 58 (39/19) SIPS Reciprocal social behaviour GFS, GFR Cross-sectional +

longitudinalJang et al. (2011) — South Korea 57 (37/20) CAARMS Symptoms, antipsychotic use SFS Cross-sectional +

longitudinalKarlsgodt et al. (2009) — USA 36 (27/9) SIPS White matter integrity GAF, GFS, GFR LongitudinalKim et al. (2013) — South Korea 60 (35/25) SIPS Symptoms, depression, coping style,

resilience, sex, antipsychotic useQLS Cross-sectional

Lavoie et al. (2014) — Australia 126 (73/51) CAARMS Structural brain abnormalities SOFAS Cross-sectionalLemos-Giráldez et al. (2009)— Spain 61 (40/21) SIPS Sex, ARMS diagnostic subgroup GAF Cross-sectional +

longitudinalLin et al. (2011) — Australia 230 (99/131) CAARMS Symptoms, neurocognition, depression GAF, SOFAS, QLS LongitudinalMachielsen et al. (2010)— Netherlands 59 (52/7) SIPS Lifetime cannabis abuse disorder GAF Cross-sectionalMeyer et al. (in press) — USA 167 (107/60) SIPS Symptoms, neurocognition GFS, GFR Cross-sectional +

longitudinalMittal et al. (2011) — USA 40 (26/14) SIPS Dyskinesia GFS, GFR Cross-sectional +

longitudinalNiendam et al. (2006b) — USA 45 (29/16) SIPS Symptoms, neurocognition, depression SAS, SCOS Cross-sectionalNiendam et al. (2007a) — USA 31 (18/13) SIPS Executive function GFS, GFR Cross-sectionalNiendam et al. (2007b) — USA 35 (21/14) SIPS Symptoms, neurocognition GFS, GFR,

SAS, SCOSLongitudinal

Niendam et al. (2009a) — USA 64 (39/25) SIPS Obsessive–compulsive symptoms GFS, GFR Cross-sectionalO'Brien et al. (2006) — USA 26 (14/12) SIPS Family interaction SCOS Cross-sectional +

longitudinalO'Brien et al. (2008) — USA 40 (26/14) SIPS Family interaction SCOS LongitudinalO'Brien et al. (2009) — USA 33 (20/13) SIPS Family interaction SCOS LongitudinalPerez et al. (2012) — USA 98 (58/40) SIPS Information processing GAF, GFS, GFR Cross-sectional +

longitudinalRaballo et al. (2011) — Australia 223 (95/128) CAARMS Symptoms GAF Cross-sectionalRuhrmann et al. (2008) — Germany 157 (94/63) ERIraos Symptoms, depression, sex MSQoL Cross-sectionalSabb et al. (2010) — USA 40 (28/12) SIPS Brain activity (fMRI) during a language

processing taskSAS Cross-sectional +

longitudinalSchlosser et al. (2012) — USA 84 (52/32) SIPS Symptoms, anxiety, antipsychotic and

antidepressant useGFS, GFR Longitudinal

Shim et al. (2008a) — South Korea 32 (19/13) CAARMS Symptoms, duration of untreated at risksymptoms, depression, anxiety,obsessive–compulsive symptoms

GAF, SFS Cross-sectional

Smieskova et al. (2012) — Switzerland 31 (22/9) BSIP Insular grey matter volume GAF Cross-sectionalSong et al. (2013) — South Korea 50 (30/20) SIPS Personality dimensions GFS, GFR Cross-sectionalStanford et al. (2011) — USA 63 (50/13) SIPS Social cognition GAF, SAS-SR Cross-sectionalSvirskis et al. (2007) — Finland 39 (N/R) SIPS Symptoms GAF, QLS Cross-sectionalThompson et al. (2013) — Australia 30 (14/16) CAARMS Attributional style SOFAS, GFS,

GFRCross-sectional

Valmaggia et al. (2013)— Australia, UK 318 (149/169) CAARMS Symptoms GAF Cross-sectionalvan Tricht et al. (2010) — Netherlands 61 (42/19) SIPS Information processing (EEG) PAS Cross-sectionalVelthorst et al. (2010) — Finland,Germany, Netherlands, UK

239 (131/108) SIPS/BSABS Symptoms WHODAS-II Cross-sectional


Please cite this article as: Cotter, J., et al., What drives poor functioning in the at-risk mental state? A systematic review, Schizophr. Res. (2014),http://dx.doi.org/10.1016/j.schres.2014.09.012


Table 1 (continued)


Key variable(s) examined forassociation with functioning


Design

Velthorst et al. (2012) — Netherlands 201 (99/102) CAARMS Ethnicity SOFAS Cross-sectionalWalder et al. (2013)— USA 276 (163/113) SIPS Symptoms, sex GFS, GFR, PAS Cross-sectionalWillhite et al. (2008) — USA 68 (49/19) SIPS Symptoms, sex GAF Cross-sectionalZiermans et al. (2014) — Netherlands 43 (27/16) SIPS/BSABS Symptoms, neurocognition GAF Longitudinal

Abbreviations: BSABS: Bonn Scale for the Assessment of Basic Symptoms; BSIP: Basel Screening Instrument for Psychosis; CAARMS: Comprehensive Assessment of At-Risk Mental States;ERIraos: Early Recognition Inventory; GAF: Global Assessment of Functioning; GFR: Global Functioning: Role Scale; GFS: Global Functioning: Social Scale;MSQoL:Modular System for Qualityof Life; N/R: not reported; PANSS: Positive and Negative Syndrome Scale; PAS: Premorbid Adjustment Scale; QLS: Heinrichs–Carpenter Quality of Life Scale; SAS: UCLA Social AttainmentSurvey; SAS-SR: Social Adjustment Scale — Self Report; SCOS: Strauss–Carpenter Outcome Scale; SFS: Social Functioning Scale; SIPS: Structured Interview for Prodromal Syndromes;SOFAS: Social and Occupational Functioning Assessment Scale; WHODAS-II: World Health Organization Disability Assessment Schedule.


2013), suggesting that depression affects social activity more than itaffects engagement inwork or education. This is consistentwith evidencethat depression is the strongest independent predictor of ‘psychosocialquality of life’ (i.e. subjective satisfaction with one's social situation) inthe ARMS group (Ruhrmann et al., 2008). Depressive symptoms did notsignificantly differ at baseline between those with ‘good’ and ‘poor’long-term functional outcome defined using either global (Lin et al.,2011) or separate social and role functioning measures (Carrión et al.,2013).

3.6. Substance use and disorders

Evidence for a relationship between substance use and poor function-ing remains inconclusive. Cross-sectional research indicated that globalfunctioning did not significantly differ between ARMS patients with orwithout a diagnosed lifetime cannabis use disorder (Machielsen et al.,2010). Groups classified as having good or poor functional outcome at3–5 year follow-up were also found to have comparable rates of DSM-IV substance-related disorders at baseline (Carrión et al., 2013). However,global functioning has been reported to decline during periods of recentcannabis and cocaine use (Corcoran et al., 2008). Whereas social, butnot role functioning, was reportedly better both at baseline and at3 year follow-up in lifetime cannabis users compared to non-users(Auther et al., 2012).

3.7. Dyskinesia

Spontaneousmovement abnormalities were significantly associatedwith impaired role functioning at baseline and were predictive of de-cline in social functioning over a 1-year follow-up in 40 clinical-highrisk patients, independently of medication use (Mittal et al., 2011).

3.8. Neurocognitive assessment

IQ was unrelated to functional disability (Cornblatt et al., 2007;Corcoran et al., 2011; Lin et al., 2011; Carrión et al., 2013; Goghari et al.,2014). However, deficits in composite neurocognitive performance(Barbato et al., 2013) and discrete neurocognitive domains including pro-cessing speed (Carrión et al., 2011; Meyer et al., in press), verbal learningand memory (Niendam et al., 2006b; Lin et al., 2011; Meyer et al., inpress), reasoning and problem solving (Niendam et al., 2006b; Meyeret al., in press), spatial working memory (Goghari et al., 2014), informa-tion processing (Perez et al., 2012) and executive function (Niendamet al., 2007a; Meyer et al., in press) have all been significantly correlatedwith increased functional impairment in cross-sectional studies. Regres-sion analyses indicate that verbal learning and memory (Niendam et al.,2006b) and composite neurocognitive performance (Meyer et al., inpress) account for unique variance in social and role functioning indepen-dently of negative symptoms.

Impaired neurocognitive performance at baseline was also predictiveof poor long-term social and occupational outcome, independently ofclinical symptom severity (Eslami et al., 2011; Lin et al., 2011; Carriónet al., 2013;Meyer et al., in press). However, the three largest longitudinal


studies to date reported slightly differing results with regard to whichvariables were most strongly predictive of functional outcome. Lin et al.(2011) dichotomised 230 UHR patients into good and poor outcomegroups based on a cluster analysis using a combination of SOFAS(Goldman et al., 1992) and Quality of Life Scale (QLS; Heinrichs et al.,1984) scores at follow-up, two to thirteen years after initial presentationto services. Impaired verbalmemory at baselinewas the strongest predic-tor of poor functional outcome. In the first of two studies comprised ofpartially overlapping subsamples of the North American Prodrome Longi-tudinal Study, impaired verbal memory at baseline was also predictive ofpoor role outcome (Carrión et al., 2013), whereas reduced processingspeed significantly predicted poor social outcome. Thesewere both signif-icant after adjusting for clinical symptoms and functioning in eachdomain at baseline. In contrast, Meyer et al. (in press) reported that com-posite neurocognitive score was no longer predictive of long-term socialfunctioning after accounting for negative symptoms. However, compositeneurocognition accounted for unique variance above and beyond nega-tive symptoms in role functioning at follow-up. Negative symptomspartially mediated the relationship between neurocognition and socialand role functioning both at baseline and at follow-up. However, as men-tioned previously, removal of overlapping SIPS negative items resulted ina substantial increase in the strength of association between cognitionand functional outcome such that it became a significant predictor(Meyer et al., in press).

Two small studies reported that neurocognitive performance at base-linewas not predictive of subsequent functional outcome (Niendamet al.,2007b; Ziermans et al., 2014). However, significant improvement in socialfunctioningwas associatedwith improved processing speed, visual learn-ing and memory (Niendam et al., 2007b).

3.9. Neuroimaging

Cross-sectional evidence indicates that bilateral insular grey mattervolume positively correlated with global functioning (Smieskova et al.,2012); however, structural abnormalities of the orbitofrontal cortexdid not (Lavoie et al., 2014). Electroencephalography studies have alsoreported mixed evidence regarding information processing abnormali-ties and functioning (van Tricht et al., 2010; Jahshan et al., 2012).Lower white matter integrity in temporal regions at baseline has beenreported to significantly predict decline in both social and role functioningover a subsequent 15-month follow-up (Karlsgodt et al., 2009). Anteriorcingulate cortex (ACC) and left inferior frontal gyrus overactivationduring a language processing task were also associated with poorerlong-term social functioning (Sabb et al., 2010). A 1-year longitudinalfMRI study reported that improved global functioning correlated with in-creased activation in the right ACC during aworkingmemory task (Fusar-Poli et al., 2011). This signified a normalising of brain function, as patientsdemonstrated a significant under-activation in this region at baseline.

3.10. Social cognition

In the largest cross-sectional study conducted in this area to date,emotion recognition and Theory of Mind performance were correlated



Table 2Intervention studies.

Primary analysis publications


Design Intervention Comparator(s) Treatment duration(weeks)


Addington et al. (2011b) — Canada 51 (36/15) SIPS RCT CBT Supportive therapy 26 GAF, SFSAmminger et al. (2010) — Austria 81 (27/54) PANSS RCT Long-chain omega-3 PUFA Placebo 12 GAFHauser et al. (2009) — Germany 16 (12/4) SIPS/PANSS/BSABS Non-RCT Psychoeducation None 7 GAFMcGlashan et al. (2006) — Canada, USA 60 (39/21) SIPS RCT Olanzapine Placebo 52 GAFMcGorry et al. (2002) — Australia 59 (34/25) BPRS/CASH RCT CBT + risperidone Needs-based supportive psychotherapy 26 GAFMcGorry et al. (2013) — Australia 193 (76/117) CAARMS RCT CBT + risperidone CBT + placebo, supportive therapy + placebo, TAU 52 GAFMorrison et al. (2004) — UK 58 (40/18) PANSS RCT CBT TAU 26 GAFMorrison et al. (2012) — UK 288 (180/108) CAARMS RCT CBT TAU 26 GAFO'Brien et al. (2007) — USA 16 (8/8) SIPS Non-RCT Psychoeducational multi-family group therapy None 39 GAF, SCOSRuhrmann et al. (2007) — Germany 124 (70/54) ERIraos RCT Needs-focused intervention + amisulpride Needs-focused intervention 12 GAFShim et al. (2008b) — South Korea 27 (16/11) CAARMS Non-RCT Antipsychotic medication (various) None 35 GAF, SFSvan der Gaag et al. (2012) — Netherlands 201 (99/102) CAARMS RCT CBT TAU 26 SOFAS

Interim/secondary analysis publications

Reference + country Primary publication Analysis type N (male/female) Treatment duration (weeks) Functioning measure(s)

Marshall et al. (2012) — Canada Addington et al. (2011b) — Canada Secondary 48 (33/15) 26 GAF, SFSMiller et al. (2003) — Canada, USA McGlashan et al. (2006) — USA/Canada Interim 60 (39/21) 0 GAFPhillips et al. (2007) — Australia McGorry et al. (2002) — Australia Secondary 41 (N/R) 26 GAFWoods et al. (2003) — Canada, USA McGlashan et al. (2006) — USA/Canada Interim 60 (39/21) 8 GAFYung et al. (2011) — Australia McGorry et al. (2013) — Australia Interim 193 (76/117) 26 GAF

Abbreviations: BPRS: Brief Psychiatric Rating Scale; BSABS: Bonn Scale for the Assessment of Basic Symptoms; CAARMS: Comprehensive Assessment of At-Risk Mental States; CASH: Comprehensive Assessment of Symptoms and History; CBT: Cog-nitive Behavioural Therapy; ERIraos: Early Recognition Inventory; GAF: Global Assessment of Functioning; N/R: not reported; PANSS: Positive and Negative Syndrome Scale; PUFA: polyunsaturated fatty acid; RCT: randomised controlled trial; SCOS:Strauss–Carpenter Outcome Scale; SFS: Social Functioning Scale; SIPS: Structured Interview for Prodromal Syndromes; SOFAS: Social and Occupational Functioning Assessment Scale; TAU: treatment as usual.

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with social functioning (Barbato et al., 2013). Structural equationmodelling indicated a significant association between social cognitionand social functioning that was not mediated by neurocognition(Barbato et al., 2013). Similarly, parent-reported social responsivenesswas correlated with functioning at baseline and predicted social func-tioning at 7-month follow-up (Jalbrzikowski et al., 2013). In contrast, asmaller study reported no associations between functioning and perfor-mance on four Theory of Mind tasks (Stanford et al., 2011). DespiteARMS patients exhibiting a more externalised attributional style com-pared to healthy controls, this was also unrelated to social or occupa-tional functioning (Thompson et al., 2013).

3.11. Family environment

Family support was predictive of better functioning (O'Brien et al.,2006, 2007, 2008, 2009). Caregiver warmth at baseline interview wassignificantly associated with patients' improvement in functioningover 3 and 4 months (O'Brien et al., 2006, 2008). ARMS adolescents'conversational problem solving abilities, along with the degree of con-structive communication displayed with their primary caregiver alsopositively correlated with functioning at 6-month follow-up (O'Brienet al., 2009).

3.12. Trauma

The only study in this area reported role functioning to be weakly butsignificantly correlatedwithpsychological, physical and total bullying andoverall trauma in childhood in a cross-sectional study (Addington et al.,2013). Social functioning however only correlatedwith physical bullying.Neither was directly associated with neglect or abuse in childhood.

3.13. Personality characteristics

Adaptive coping and resiliencewere associatedwith better function-ing, over and above negative symptoms (Kim et al., 2013). Better socialfunctioning significantly correlated with higher cooperativeness but notself-directedness or self-transcendence. Role functioning was unrelatedto any temperament or character dimensions (Song et al., 2013).

3.14. Sex

Various cross-sectional and longitudinal studies have reported nosignificant sex differences in functioning (Miller et al., 2003; Cornblattet al., 2007; Lemos-Giráldez et al., 2009; Kim et al., 2013). However, thelargest study to date reported significantly poorer social and role func-tioning in males (Walder et al., 2013). Males also report experiencingless positive social support (Willhite et al., 2008) and poorer subjectivesatisfaction with relationships (Ruhrmann et al., 2008).

3.15. Ethnicity

Social functioning has been reported to be significantly poorer inethnic minority (non-Caucasian) patients (Corcoran et al., 2011). Amuch larger study that distinguished ethnicity through nationality(Dutch or non-Dutch) also reported a trend difference in functioning,with Dutch nationals exhibiting marginally better functioning afteradjusting for potential confounders (Velthorst et al., 2012). However,when examined longitudinally, ethnicity was reported to be unrelatedto functional outcome within this population (Carrión et al., 2013).

3.16. Interventions

3.16.1. Antipsychotic medicationObservational studies suggest that antipsychotic medication use is

unrelated to social or occupational functioning (Niendam et al., 2007b;Jang et al., 2011), subjective satisfaction with social relationships (Kim


et al., 2013) or long-term functional recovery (Schlosser et al., 2012;Carrión et al., 2013). Despite no differences in cognitive impairment orpositive symptoms, patients in one study who were taking antipsychoticmedication exhibited significantly poorer functioning (Niendam et al.,2006b). However, this could be due to increased symptom severityprior to the assessment that warranted the use of medication. In contrast,a small, uncontrolled, open-label study found that ARMS patients' pre-scribed antipsychoticmedication experienced significant, butmodest im-provement in functioning, though this remained markedly impairedcompared to the general population (Shim et al., 2008b). An open-labelstudy examining a needs-focused intervention delivered with or withoutamisulpride also reported significantly better global functioning after 12-weeks of treatment in those who received amisulpride (Ruhrmann et al.,2007). Unlike other trials, this study also reported a significant improve-ment in negative symptoms. However, a randomised, double-blind,placebo-controlled study of olanzapine reported no beneficial effects onfunctioning over placebo, despite significant improvement in positivesymptoms (Woods et al., 2003; McGlashan et al., 2006).

3.16.2. Psychosocial interventionsRandomised controlled trials assessing the effectiveness of cognitive

behavioural therapy (CBT) in ARMS have reported no significant benefitson functioning, despite improvements in positive symptoms and reduc-tions in transition rates (Morrison et al., 2004; Addington et al., 2011b;Marshall et al., 2012; Morrison et al., 2012; van der Gaag et al., 2012).CBT combined with low doses of risperidone was also ineffective at im-proving functional outcome (McGorry et al., 2002; Phillips et al., 2007;Yung et al., 2011; McGorry et al., 2013). Small single-arm feasibility stud-ies examining the effectiveness of psychoeducation have producedmixedresults. A 9-monthmulti-family group treatment reported significant im-provement in global and role functioning, in conjunction with improvedpositive and general symptoms (O'Brien et al., 2007). However, mostparticipants (81%) were also receivingmedication, and all were receivingadditional psychological therapies. In contrast, Hauser et al. (2009) re-ported no significant differences in global functioning following sevenpsychoeducation treatment sessions.

3.16.3. Omega-3 fatty acidsA 12-week randomised, double-blind, placebo-controlled trial

reported significantly better global functioning after 1 year in thoserandomised to receive an omega-3 polyunsaturated fatty acid nutritionalsupplement compared to those receiving placebo (Amminger et al.,2010). Improvement in functioning correlated with a change in omega-6 to omega-3 ratio from baseline to the end of treatment. Significantimprovements in positive, negative and general symptoms were also ob-served. This was the only study that reported improvements in function-ing comparable to levels observed in healthy individuals, though baselinefunctioning in these patients was also considerably higher than in mostother ARMS intervention studies. Measures taken at baseline indicatedthat lower levels of erythrocyte nervonic acid correlated with poorerglobal functioning as well as worse negative and disorganised symptoms(Amminger et al., 2012). However, docosahexaenoic and arachidonic acidlevels were unrelated to functioning.

4. Discussion

4.1. Summary of results

This is the first systematic review on factors associated with func-tional impairment in the ARMS population. Across the broad range ofmeasures, negative symptoms, disorganisation and neurocognitivedeficits were consistently associated with poor functioning. Functionaldisability was unrelated to positive psychotic symptoms. Cross-sectionaland longitudinal studies were largely consistent, although longitudinalstudies emphasised a greater role of disorganised symptoms in predictingfunctional outcome. Functioning at baseline was predictive of long-term




course only when social and role measures were examined separately:global measures were not associated with outcome (Eslami et al., 2011;Lin et al., 2011; Carrión et al., 2013;Meyer et al., in press). Childhood trau-ma and social cognition were associated with functional impairment incross-sectional studies, though the relationship between these variablesand long-term functional outcome has yet to be established. A supportivefamily environment and high personal resilience may also help minimisefunctional impairment. Intervention studies strengthened the evidencethat dysfunction occurs independently of positive symptoms.

4.2. ARMS aetiology

At-risk patients are not a homogeneous group. Only aminority devel-op a frank psychotic disorder (Fusar-Poli et al., 2012; Nelson et al., 2013),suggesting that attenuated psychotic symptoms may arise frommultipleaetiologies. ARMS patients commonly present with comorbid axis I disor-ders (Rietdijk et al., 2013; de Wit et al., 2014; Fusar-Poli et al., 2014)which can be associated with ‘incidental psychotic-like experiences’(Yung et al., 2009). This may partially explain the inconsistent relation-ships between functional disability and both mood disorder and sub-stance use, which are each known to be associated with psychoticexperiences. The finding of better functioning in ARMS patients with ahistory of cannabis abuse compared to those with no history (Autheret al., 2012) in particular suggests that substance-induced attenuatedpsy-chotic symptoms may have a different underlying cause from symptomsthat arise in the absence of substance use trigger.

The core findings of this review however were consistent, suggestingthatmost individualsmeeting the ARMS criteria share some fundamentalunderlying pathology, consistent with the neurodevelopmental hypothe-sis of schizophrenia (Murray and Lewis, 1987; Weinberger, 1987; Fatemiand Folsom, 2009). Negative and disorganised symptoms and cognitivedeficits pre-date frank psychotic symptoms and impair functioning froman early age. Positive symptoms manifest later in the illness course,when functional disability has already become entrenched. Findings donot appear to be confounded due to more severe clinical symptoms inthose who subsequently transitioned to psychosis, though further evi-dence is required to determinewhether this is true for neurocognitive im-pairment (Carrión et al., 2013). This review is consistent with previousreports that negative symptoms and neurocognition are strong determi-nants of functional outcome in schizophrenia, while early evidence sug-gests that social cognition may similarly be associated (Ventura et al.,2009; Fett et al., 2011; Hunter and Barry, 2012).

4.3. Clinical implications

These results emphasise the importance of early identification andintervention in this patient group who, even in the absence of frank-psychotic symptoms, display cognitive impairment, marked social dys-function and a range of non-psychotic symptoms and comorbid disorders.Functioning has been evaluated as one of a number of secondary out-comes in treatment studies to date. Despite reductions in symptomseverity and transition rates (Stafford et al., 2013; Hutton and Taylor,2014), current routine clinical interventions are ineffective at improv-ing functioning (van der Gaag et al., 2013). This may be because factorsthat place an individual at risk for poor functioning are different fromthose that increase the risk of transition to full-threshold psychosis. Asfunctional impairment persists regardless of transition (Addingtonet al., 2011a; Schlosser et al., 2012; Carrión et al., 2013) or symptomaticremission (deWit et al., 2014), there is a clear need for the developmentof treatments that can both prevent transition and ameliorate functionaldisability (Fowler et al., 2010). Incorporation of cognitive and social cog-nitive remediation programmesmay be beneficial, given the encouragingpreliminary results observed in schizophrenia (Wykes et al., 2011; Sackset al., 2013; Statucka and Walder, 2013). International multisite trials ofomega-3 polyunsaturated fatty acid are also currently underway to repli-cate the benefits to both transition and functioning previously reported


(Nelson et al., 2008). Based on the results of this review, efforts to reducenegative symptoms may be particularly beneficial for functioning. Thereis currently lack of interventions specifically targeting this range of symp-toms in the at-risk population.

4.4. Limitations

Functioning is a critical component in understanding the full burdenof a disorder, but is often poorly defined and overlooked (Brissos et al.,2011; Lin et al., 2013). All of the interventions and many of the observa-tional studies included in this reviewused globalmeasures of functioning,such as the GAF (Hall, 1995) and SOFAS (Goldman et al., 1992), whichprovide crude assessment of overall impairment, but lack sensitivity tovariation or associations within distinct functioning subdomains. TheGAF is further limited by its conflation of symptoms and functioning, soit is difficult to distinguish whether low GAF scores are truly driven bypoor functioning or due to severe clinical symptoms. The SOFAS looks toovercome this issue by only examining functioning; however, there isgrowing evidence that social and role functioning may be more stronglyassociated with different aspects of illness and should be examineddiscretely (Cornblatt et al., 2007; Carrión et al., 2013; Fulford et al.,2013). Many of the functioning measures used by studies were also orig-inally developed for use in established psychotic disorders, and containitems not applicable to this population. Future studies should thereforeexamine social and role functioning as separate domains, usingmeasuressensitive to dysfunction in the ARMS population that incorporate age andphase of illness, such as the GFS and GFR scales (Auther et al., 2006;Niendam et al., 2006a) and theMultidimensional Adolescent FunctioningScale (Wardenaar et al., 2013).

A strength of this review is the broad-scoping eligibility criteria,providing a comprehensive overview of the literature. Previous reviewshave examined the role of comorbid mood disorders and neurocognitivedeficits in relation to functioning (Niendam et al., 2009b; Fusar-Poli et al.,2014), but did not consider factors such as intensity and duration ofpsychotic and non-psychotic symptoms, demographics and family envi-ronment. However, the inclusion of such a large number of publicationsdid not permit more in-depth critical appraisal of individual studies. Thesubsequent variation in the design of included studies also made it diffi-cult to assess methodological quality using a common and meaningfulmetric. Finally, the majority of this review comprises evidence obtainedfrom cross-sectional studies due to the disproportionately greaternumber of such publications. Longitudinal studies have begun to emergein this area and provide more informative evidence.

4.5. Conclusions

Negative and disorganised symptoms andneurocognitive impairmentare key drivers of functional impairment in ARMS cohorts. These factorsare also thought to underlie functional disability in schizophrenia. Thissuggests similarity in underlying pathology, despite only a minority ofpatients subsequently developing a frank psychotic disorder. That posi-tive symptomatology does not appear to be amajor determinant of func-tioning is supported by the lack of efficacy shown by current clinicalinterventions, which have instead focused on reducing positive symptomseverity and preventing transition to psychosis. There is a need for thedevelopment of novel therapieswith an emphasis on improving function-ing. Research is also needed to establish the long-term relationshipbetween factors such as social cognition and childhood traumawith func-tional outcome in the ARMS population.

Role of funding sourceJ.C. is supported by a University of Manchester PhD studentship.

ContributorsA.Y., J.C. and R.D. contributed to the conception of the review. J.C. designed and per-

formed the literature search. J.C. and J.F. screened articles for eligibility and extracteddata from eligible studies. J.C. wrote the first draft of the manuscript. A.Y., R.D., S.B., J.F.




and D.E. critically revised the manuscript. All authors contributed to and approved thefinal manuscript.

Conflict of interestNone.

AcknowledgementThe authors would like to thank Agata Golawska for assistance during the article

screening stage.

Appendix A. Supplementary data

Supplementary data to this article can be found online at http://dx.doi.org/10.1016/j.schres.2014.09.012.

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What drives poor functioning in the at-risk mental state? A systematic review

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