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

Schizophrenia Research 159 (2014) 267–277

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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 b c

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

a r t i c l e

i n f o

Article history: Received 26 June 2014 Received in revised form 18 August 2014 Accepted 4 September 2014 Available online 24 September 2014 Keywords: At-risk mental state Ultra-high risk Clinical high risk Psychosis Functioning Systematic review

a b s t r a c t Background: Transition to psychotic disorder has been the traditional outcome of interest for research in the at-risk mental state (ARMS). However, there is growing recognition that individuals with ARMS may function poorly regardless of whether they develop psychosis. We aimed to review the literature to determine whether there are specific 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 conducted using keyword search terms synonymous with the at-risk mental state and functioning. Eligible studies were original peer-reviewed English language research articles with populations that met validated at-risk diagnostic criteria and examined the cross-sectional or longitudinal association between any variable and a measure of functioning. Results: Seventy-two eligible studies were identified. Negative symptoms and neurocognitive impairment were associated with poor functioning in cross-sectional studies. Negative and disorganised symptoms, neurocognitive deficits and poor functioning at baseline were predictive of poor functional outcome in longitudinal studies. Positive symptoms were unrelated to functioning in both cross-sectional and longitudinal studies. Functional disability was persistent and resistant to current treatments. Conclusions: Negative and disorganised symptoms and cognitive deficits pre-date frank psychotic symptoms and are risk factors for poor functioning. This is consistent with a subgroup of ARMS individuals potentially having neurodevelopmental schizophrenia. Treatments aimed at improving functioning must be considered a priority on par 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 developing 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 (FusarPoli et al., 2013). In brief, the standard at-risk criteria are the presence of subthreshold psychotic symptoms and/or full threshold psychotic symptoms that resolved spontaneously and/or a trait risk factor for psychotic disorder (such as positive family history) combined with significant deterioration in mental state. The UHR criteria have been widely

⁎ Corresponding author at: Institute of Brain, Behaviour and Mental Health, University of Manchester, Room 3.306, Jean McFarlane Building, Oxford Road, Manchester M13 9PL, United Kingdom. Tel.: +44 161 275 5970; fax: +44 161 306 7945. E-mail addresses: [email protected] (J. Cotter), [email protected] (R.J. Drake), [email protected] (S. Bucci), joseph.fi[email protected] (J. Firth), [email protected] (D. Edge), [email protected] (A.R. Yung).

http://dx.doi.org/10.1016/j.schres.2014.09.012 0920-9964/© 2014 Elsevier B.V. All rights reserved.

used and are associated with a high risk of developing psychotic disorder. A recent meta-analysis found that rates of onset of psychosis are 22% 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; Mason et al., 2004; Thompson et al., 2011; Cornblatt et al., 2012), there has recently been a growing interest in poor functioning as an outcome of interest 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 of long-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 of ARMS patients functioning remains impaired, regardless of transition to full-threshold psychosis or symptomatic remission (Addington et al., 2011a; Schlosser et al., 2012; Carrión et al., 2013; de Wit et al., 2014). It is important to establish whether particular aspects of illness consistently underlie functional disability in order to improve our understanding of this patient group. Therefore, the aim of this review was to systematically appraise the literature to identify variables associated with, or predictive of, functional impairment in the ARMS population.

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2. Method This review was conducted in line with the PRISMA guidelines for reporting systematic reviews (Moher et al., 2009). 2.1. Eligibility criteria Eligible studies were original research articles published in peerreviewed journals, with populations that met the diagnostic criteria for being ‘at-risk’, ‘ultra-high risk’ or at ‘clinical-high risk’ (or similarly defined) of psychosis based on a clinically validated instrument. Studies were included that examined the cross-sectional relationship between any variable and a measure of functioning, or reported the longitudinal relationship between baseline variables and subsequent functional outcome. For the purposes of this review, functioning was defined as measures relating to the frequency of, quality of, or satisfaction with social, academic or occupational activity. Intervention studies that examined functioning pre- and post-intervention were eligible. Studies that included only subjects at genetic risk who had not met the formal diagnostic criteria for being at ultra-high risk (or similarly defined) of psychosis, case studies and non-English language articles were excluded. 2.2. Search strategy On the 1st of May 2014 an electronic database search of Ovid MEDLINE, PsycINFO and Embase using the following keywords was conducted: “at risk mental state” or “ultra high risk”, “UHR”, “clinical high risk”, “CHR”, “prodrom*” and “psychos*” or “psychot*”, “schizo*” and “social function*” or “role function*”, “global function*”, “psychosocial function*”, “functional outcome”, “academic function*”, “community function*”, “occupational function*”, “school function*”, “work function*”. Reference lists of retrieved articles were also reviewed by hand for additional relevant publications not identified in the initial electronic search. 2.3. Study selection and data extraction Two reviewers (J.C. and J.F.) independently screened articles for eligibility. Any disagreements were resolved through discussion. For all eligible studies, a standardised tool was developed to record: (1) study characteristics (study design, year of publication, country where the work was performed); (2) sample demographics (sample size, gender composition, mean age); (3) the at-risk screening instrument used to assess eligibility; (4) functioning data (measure(s) used, mean sample scores); (5) variables examined for their association with functioning; and (6) summary of study findings. For intervention studies, 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 removal of duplicates. Of these, 271 were excluded at the title–abstract stage and a further 55 following full-paper screening. Full text articles were excluded due to the use of ineligible populations (n = 9), studies not examining the relationship between functioning and any other variable (n = 44) or not being original research studies (n = 2). Fourteen additional papers were identified from reviewing reference lists of articles. Seventy-two papers met the full inclusion criteria, and fell broadly into 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 12 different measures of functioning used by studies within this review, which are briefly summarised in Supplementary Table 1. These included

‘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 indicative of overall impairment. Functioning was also examined using separate measures of social and role (occupational/educational) functioning, such as the Global Functioning: Social (GFS; Auther et al., 2006) and Role (GFR; Niendam et al., 2006a) scales. 3.1. ARMS subgroup One study found that patients meeting the genetic risk and deterioration subgroup criteria had significantly better global functioning than those presenting with attenuated psychotic symptoms in the year prior to entering the study. However, due to rapid deterioration, functioning in these groups did not differ at study inception (Miller et al., 2003). This is consistent with research reporting no significant differences in global functioning between ARMS diagnostic sub-groups (Lemos-Giráldez et al., 2009). 3.2. Symptoms Positive psychotic symptoms are sub-threshold and often transient in ARMS patients. These were associated neither with functioning in crosssectional studies, nor with long-term functional outcome (Niendam et 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; Carrión et al., 2013; Kim et al., 2013; Walder et al., 2013; Meyer et al., in press). Cross-sectional evidence indicated that negative symptoms (Niendam et 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 general symptoms (Cornblatt et al., 2007; Comparelli et al., 2010; Velthorst et 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 associated with a broad range of global, social and role functioning measures. When each of these symptom clusters was entered into regression analyses, only negative symptoms remained significantly associated with poor functioning (Corcoran et al., 2011; Fulford et al., 2013; Kim et al., 2013; Meyer et al., in press). However, longitudinal evidence indicated that both negative (Lin et al., 2011; Schlosser et al., 2012; Meyer et al., in press) and disorganised symptoms at baseline (Bearden et al., 2011; Eslami et al., 2011; Carrión et al., 2013; Ziermans et al., 2014) were also amongst the strongest independent predictors of long-term functional outcome. A key methodological limitation of this area is that negative symptom items in the Structured Interview for Prodromal Syndromes (SIPS; Miller et al., 2002) overlap with measures of functioning. This is one of the main instruments used to characterise ARMS patients, particularly in North American studies. Meyer et al. (in press) reported that removal of two SIPS negative items from the functional assessment resulted in a substantial drop in the magnitude of association between negative symptoms and social and role functioning both at baseline and at follow-up (Meyer et al., in press). This also greatly increased the strength of association between neurocognition and disorganised symptoms and functioning in the cross-sectional and longitudinal analyses. Future studies should take this potential confounding of items into account when performing analyses. 3.3. Duration of symptoms Global functioning did not significantly differ between patients with long (N1 year) and short (b1 year) durations of untreated attenuated psychotic symptoms (Chung et al., 2010). However, a longer duration of prodromal symptoms was associated with increased impairment on the ‘Interpersonal behaviour’ and ‘Prosocial activities’ subscales of the Social Functioning Scale (Shim et al., 2008a). A longer duration of

Idenficaon

J. Cotter et al. / Schizophrenia Research 159 (2014) 267–277

Records idenfied through database searching (n = 714)

269

Addional records idenfied through other sources (n = 14)

Eligibility

Records screened (n = 398)

Full-text arcles assessed for eligibility (n = 127)

Included

Screening

Records aer duplicates removed (n = 398)

Studies included in review (n = 72)

Records excluded (n = 271)

Full - text arcles excluded (n = 55) Wrong populaon (n = 9) Associaons not invesgated (n = 44) Review paper (n = 2)

Fig. 1. PRISMA flow diagram.

untreated attenuated psychotic symptoms at baseline was also significantly predictive of poorer functional improvement over the subsequent 12 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 ARMS patients at presentation to services (Fusar-Poli et al., 2014). In addition to clinically diagnosable disorders, this population also report high levels of anxiety symptoms (Niendam et al., 2009a; Chudleigh et al., 2011). In the largest cross-sectional study to date, self-reported anxiety symptoms were found to be modestly correlated with global functioning (measured with the GAF) and a single-item measure of role functioning, but not with more detailed measures including the Global Functioning: Social and Role scales (Fulford et al., 2013). These associations were no longer significant after controlling for negative symptoms. Smaller studies also reported no association between social functioning 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 those classified into good and poor long-term social and role functioning outcome groups (Carrión et al., 2013). Two studies have also examined the relationship between obsessive– compulsive (OC) symptoms and functional disability. The severity of OC symptoms and degree of functional impairment were not correlated in either sample (Niendam et al., 2009a; Hur et al., 2012). However, seemingly conflicting results were found when patients in these studies were dichotomised into high and low OC symptom groups. Niendam et al.

(2009b) reported no significant differences between the two groups in global, social or role functioning or on any measures of clinical symptom severity. In contrast, Hur et al. (2012) reported that patients in the high OC symptom group exhibited poorer global functioning. However, patients in the high OC group also exhibited significantly higher levels of negative and disorganised symptoms, making it unclear whether lower GAF scores were due to more marked functional impairment or more severe negative and disorganised symptoms in this group. 3.5. Low mood Around 40% of ARMS patients present with comorbid depressive disorder (Fusar-Poli et al., 2014). However, it is difficult to interpret the direction of causality of cross-sectional evidence in this domain. It is plausible that poor functioning may in part be driving low mood. The level of social dysfunction is reportedly comparable in ARMS patients with and without a lifetime diagnosis of major depressive disorder (Corcoran et al., 2011). However, several studies converged to show that self-reported and interviewer-rated depressive symptoms were correlated with various measures of social and global functioning, but where subsequent regression analyses were performed, depressive symptoms did not explain variance in functioning over and above negative symptoms (Niendam et al. 2006b; Chudleigh et al., 2011; Corcoran et al. 2011; Kim et al., 2013). However, the largest cross-sectional study in this area reported that interviewer-rated depressive symptoms were significantly associated with lower global and social functioning independently of negative symptoms (Fulford et al. 2013). Across these studies, low mood was not associated with various measures of role functioning (Chudleigh et al., 2011; Fulford et al., 2013; Kim et al.,

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Table 1 Observational studies. Reference + country

N (male/female)

At-risk screening instrument

Key variable(s) examined for association with functioning

Functioning measure(s)

Design

Addington et al. (2013) — Canada, USA Amminger et al. (2012) — Austria

360 (210/150) 81 (27/54)

SIPS PANSS

GFS, GFR GAF

Cross-sectional Cross-sectional

Auther et al. (2012) — USA

101 (66/35)

SIPS

Childhood trauma Erythrocyte membrane phospholipid composition Lifetime cannabis use and abuse

GFS, GFR

Barbato et al. (2013) — Canada, USA Bearden et al. (2011) — USA Carrión et al. (2011) — USA Carrión et al. (2013) — USA Chudleigh et al. (2011) — Australia

137 (81/56) 54 (38/16) 127 (85/42) 92 (58/34) 20 (11/9)

SIPS SIPS SIPS SIPS CAARMS

Neurocognition, social cognition Formal thought disorder Neurocognition Symptoms, neurocognition Symptoms, depression, social anxiety

38 (31/7) 32 (26/6)

CAARMS SIPS

Duration of untreated at risk symptoms Substance use

SFS GFS, GFR GFS, GFR GFS, GFR SFS, SOFAS, WHODAS-II GAF GAF

Cross-sectional + longitudinal Cross-sectional Longitudinal Cross-sectional Longitudinal Cross-sectional

SIPS SIPS

Symptoms, depression, ethnicity Symptoms

SAS-SR GAF, GFS, GFR GAF SAS-SR GAF, GFS, GFR, SCOS GAF

Chung et al. (2010) — South Korea Corcoran et al. (2008) — USA Corcoran et al. (2011) — USA Cornblatt et al. (2007) — USA

56 (43/13) 121 (79/42)

Comparelli et al. (2010) — Italy Eslami et al. (2011) — USA Fulford et al. (2013) — USA

26 (N/R) 22 (12/10) 98 (58/40)

CAARMS SIPS SIPS

Symptoms Neurocognition Symptoms, depression, anxiety

Fusar-Poli et al. (2009) — Italy

49 (32/17)

ERIraos

Fusar-Poli et al. (2011) — UK

15 (8/7)

CAARMS

Goghari et al. (2014) — UK Hur et al. (2012) — South Korea Jahshan et al. (2012) — USA Jalbrzikowski et al. (2013) — USA

96 (76/20) 65 (40/25) 26 (17/9) 58 (39/19)

CAARMS CAARMS/SIPS SIPS SIPS

Symptoms, duration of untreated at risk symptoms Brain activity (fMRI) during a working memory task Spatial working memory, IQ Obsessive–compulsive symptoms Information processing (EEG) Reciprocal social behaviour

Jang et al. (2011) — South Korea

57 (37/20)

CAARMS

Symptoms, antipsychotic use

SFS

Karlsgodt et al. (2009) — USA Kim et al. (2013) — South Korea

36 (27/9) 60 (35/25)

SIPS SIPS

GAF, GFS, GFR QLS

Longitudinal

GAF GAF GAF GFS, GFR

Cross-sectional Cross-sectional Cross-sectional Cross-sectional + longitudinal Cross-sectional + longitudinal Longitudinal Cross-sectional

Lavoie et al. (2014) — Australia Lemos-Giráldez et al. (2009) — Spain

126 (73/51) 61 (40/21)

CAARMS SIPS

Lin et al. (2011) — Australia Machielsen et al. (2010) — Netherlands Meyer et al. (in press) — USA

230 (99/131) 59 (52/7) 167 (107/60)

CAARMS SIPS SIPS

Symptoms, neurocognition, depression Lifetime cannabis abuse disorder Symptoms, neurocognition

GAF, SOFAS, QLS GAF GFS, GFR

SOFAS GAF

Mittal et al. (2011) — USA

40 (26/14)

SIPS

Dyskinesia

GFS, GFR

Niendam et al. (2006b) — USA Niendam et al. (2007a) — USA Niendam et al. (2007b) — USA

45 (29/16) 31 (18/13) 35 (21/14)

SIPS SIPS SIPS

Symptoms, neurocognition, depression Executive function Symptoms, neurocognition

Niendam et al. (2009a) — USA O'Brien et al. (2006) — USA

64 (39/25) 26 (14/12)

SIPS SIPS

Obsessive–compulsive symptoms Family interaction

SAS, SCOS GFS, GFR GFS, GFR, SAS, SCOS GFS, GFR SCOS

O'Brien et al. (2008) — USA O'Brien et al. (2009) — USA Perez et al. (2012) — USA

40 (26/14) 33 (20/13) 98 (58/40)

SIPS SIPS SIPS

Family interaction Family interaction Information processing

SCOS SCOS GAF, GFS, GFR

CAARMS ERIraos SIPS

GAF MSQoL SAS

223 (95/128) 157 (94/63) 40 (28/12)

Schlosser et al. (2012) — USA

84 (52/32)

SIPS

Shim et al. (2008a) — South Korea

32 (19/13)

CAARMS

Smieskova et al. (2012) — Switzerland Song et al. (2013) — South Korea Stanford et al. (2011) — USA Svirskis et al. (2007) — Finland Thompson et al. (2013) — Australia

31 (22/9) 50 (30/20) 63 (50/13) 39 (N/R) 30 (14/16)

BSIP SIPS SIPS SIPS CAARMS

Symptoms Symptoms, depression, sex Brain activity (fMRI) during a language processing task Symptoms, anxiety, antipsychotic and antidepressant use Symptoms, duration of untreated at risk symptoms, depression, anxiety, obsessive–compulsive symptoms Insular grey matter volume Personality dimensions Social cognition Symptoms Attributional style

Valmaggia et al. (2013) — Australia, UK van Tricht et al. (2010) — Netherlands Velthorst et al. (2010) — Finland, Germany, Netherlands, UK

318 (149/169) 61 (42/19) 239 (131/108)

CAARMS SIPS SIPS/BSABS

Symptoms Information processing (EEG) Symptoms

Longitudinal

GAF

White matter integrity Symptoms, depression, coping style, resilience, sex, antipsychotic use Structural brain abnormalities Sex, ARMS diagnostic subgroup

Raballo et al. (2011) — Australia Ruhrmann et al. (2008) — Germany Sabb et al. (2010) — USA

Cross-sectional Cross-sectional + longitudinal Cross-sectional Cross-sectional + longitudinal Cross-sectional Longitudinal Cross-sectional

Cross-sectional Cross-sectional + longitudinal Longitudinal Cross-sectional Cross-sectional + longitudinal Cross-sectional + longitudinal Cross-sectional Cross-sectional Longitudinal

GFS, GFR

Cross-sectional Cross-sectional + longitudinal Longitudinal Longitudinal Cross-sectional + longitudinal Cross-sectional Cross-sectional Cross-sectional + longitudinal Longitudinal

GAF, SFS

Cross-sectional

GAF GFS, GFR GAF, SAS-SR GAF, QLS SOFAS, GFS, GFR GAF PAS WHODAS-II

Cross-sectional Cross-sectional Cross-sectional Cross-sectional Cross-sectional Cross-sectional Cross-sectional Cross-sectional

J. Cotter et al. / Schizophrenia Research 159 (2014) 267–277

271

Table 1 (continued) Reference + country

N (male/female)

At-risk screening instrument

Key variable(s) examined for association with functioning

Functioning measure(s)

Design

Velthorst et al. (2012) — Netherlands Walder et al. (2013) — USA Willhite et al. (2008) — USA Ziermans et al. (2014) — Netherlands

201 (99/102) 276 (163/113) 68 (49/19) 43 (27/16)

CAARMS SIPS SIPS SIPS/BSABS

Ethnicity Symptoms, sex Symptoms, sex Symptoms, neurocognition

SOFAS GFS, GFR, PAS GAF GAF

Cross-sectional Cross-sectional Cross-sectional 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 Quality of 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 Attainment Survey; 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 it affects engagement in work or education. This is consistent with evidence that depression is the strongest independent predictor of ‘psychosocial quality of life’ (i.e. subjective satisfaction with one's social situation) in the ARMS group (Ruhrmann et al., 2008). Depressive symptoms did not significantly 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 functioning remains inconclusive. Cross-sectional research indicated that global functioning did not significantly differ between ARMS patients with or without a diagnosed lifetime cannabis use disorder (Machielsen et al., 2010). Groups classified as having good or poor functional outcome at 3–5 year follow-up were also found to have comparable rates of DSMIV substance-related disorders at baseline (Carrión et al., 2013). However, global functioning has been reported to decline during periods of recent cannabis and cocaine use (Corcoran et al., 2008). Whereas social, but not role functioning, was reportedly better both at baseline and at 3 year follow-up in lifetime cannabis users compared to non-users (Auther et al., 2012). 3.7. Dyskinesia Spontaneous movement abnormalities were significantly associated with impaired role functioning at baseline and were predictive of decline in social functioning over a 1-year follow-up in 40 clinical-high risk 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 processing speed (Carrión et al., 2011; Meyer et al., in press), verbal learning and memory (Niendam et al., 2006b; Lin et al., 2011; Meyer et al., in press), reasoning and problem solving (Niendam et al., 2006b; Meyer et al., in press), spatial working memory (Goghari et al., 2014), information processing (Perez et al., 2012) and executive function (Niendam et al., 2007a; Meyer et al., in press) have all been significantly correlated with increased functional impairment in cross-sectional studies. Regression analyses indicate that verbal learning and memory (Niendam et al., 2006b) and composite neurocognitive performance (Meyer et al., in press) account for unique variance in social and role functioning independently of negative symptoms. Impaired neurocognitive performance at baseline was also predictive of poor long-term social and occupational outcome, independently of clinical symptom severity (Eslami et al., 2011; Lin et al., 2011; Carrión et al., 2013; Meyer et al., in press). However, the three largest longitudinal

studies to date reported slightly differing results with regard to which variables were most strongly predictive of functional outcome. Lin et al. (2011) dichotomised 230 UHR patients into good and poor outcome groups 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 presentation to services. Impaired verbal memory at baseline was the strongest predictor of poor functional outcome. In the first of two studies comprised of partially overlapping subsamples of the North American Prodrome Longitudinal Study, impaired verbal memory at baseline was also predictive of poor role outcome (Carrión et al., 2013), whereas reduced processing speed significantly predicted poor social outcome. These were both significant after adjusting for clinical symptoms and functioning in each domain at baseline. In contrast, Meyer et al. (in press) reported that composite neurocognitive score was no longer predictive of long-term social functioning after accounting for negative symptoms. However, composite neurocognition accounted for unique variance above and beyond negative symptoms in role functioning at follow-up. Negative symptoms partially mediated the relationship between neurocognition and social and role functioning both at baseline and at follow-up. However, as mentioned previously, removal of overlapping SIPS negative items resulted in a substantial increase in the strength of association between cognition and functional outcome such that it became a significant predictor (Meyer et al., in press). Two small studies reported that neurocognitive performance at baseline was not predictive of subsequent functional outcome (Niendam et al., 2007b; Ziermans et al., 2014). However, significant improvement in social functioning was associated with improved processing speed, visual learning and memory (Niendam et al., 2007b). 3.9. Neuroimaging Cross-sectional evidence indicates that bilateral insular grey matter volume positively correlated with global functioning (Smieskova et al., 2012); however, structural abnormalities of the orbitofrontal cortex did not (Lavoie et al., 2014). Electroencephalography studies have also reported mixed evidence regarding information processing abnormalities and functioning (van Tricht et al., 2010; Jahshan et al., 2012). Lower white matter integrity in temporal regions at baseline has been reported to significantly predict decline in both social and role functioning over a subsequent 15-month follow-up (Karlsgodt et al., 2009). Anterior cingulate cortex (ACC) and left inferior frontal gyrus overactivation during a language processing task were also associated with poorer long-term social functioning (Sabb et al., 2010). A 1-year longitudinal fMRI study reported that improved global functioning correlated with increased activation in the right ACC during a working memory task (FusarPoli et al., 2011). This signified a normalising of brain function, as patients demonstrated 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

272

Table 2 Intervention studies. Primary analysis publications N (male/female)

At-risk screening instrument

Design

Intervention

Comparator(s)

Treatment duration (weeks)

Functioning measure(s)

Addington et al. (2011b) — Canada Amminger et al. (2010) — Austria Hauser et al. (2009) — Germany McGlashan et al. (2006) — Canada, USA McGorry et al. (2002) — Australia McGorry et al. (2013) — Australia Morrison et al. (2004) — UK Morrison et al. (2012) — UK O'Brien et al. (2007) — USA Ruhrmann et al. (2007) — Germany Shim et al. (2008b) — South Korea van der Gaag et al. (2012) — Netherlands

51 (36/15) 81 (27/54) 16 (12/4) 60 (39/21) 59 (34/25) 193 (76/117) 58 (40/18) 288 (180/108) 16 (8/8) 124 (70/54) 27 (16/11) 201 (99/102)

SIPS PANSS SIPS/PANSS/BSABS SIPS BPRS/CASH CAARMS PANSS CAARMS SIPS ERIraos CAARMS CAARMS

RCT RCT Non-RCT RCT RCT RCT RCT RCT Non-RCT RCT Non-RCT RCT

CBT Long-chain omega-3 PUFA Psychoeducation Olanzapine CBT + risperidone CBT + risperidone CBT CBT Psychoeducational multi-family group therapy Needs-focused intervention + amisulpride Antipsychotic medication (various) CBT

Supportive therapy Placebo None Placebo Needs-based supportive psychotherapy CBT + placebo, supportive therapy + placebo, TAU TAU TAU None Needs-focused intervention None TAU

26 12 7 52 26 52 26 26 39 12 35 26

GAF, SFS GAF GAF GAF GAF GAF GAF GAF GAF, SCOS GAF GAF, SFS 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 Miller et al. (2003) — Canada, USA Phillips et al. (2007) — Australia Woods et al. (2003) — Canada, USA Yung et al. (2011) — Australia

Addington et al. (2011b) — Canada McGlashan et al. (2006) — USA/Canada McGorry et al. (2002) — Australia McGlashan et al. (2006) — USA/Canada McGorry et al. (2013) — Australia

Secondary Interim Secondary Interim Interim

48 (33/15) 60 (39/21) 41 (N/R) 60 (39/21) 193 (76/117)

26 0 26 8 26

GAF, SFS GAF GAF GAF 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: Cognitive 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 equation modelling indicated a significant association between social cognition and social functioning that was not mediated by neurocognition (Barbato et al., 2013). Similarly, parent-reported social responsiveness was correlated with functioning at baseline and predicted social functioning at 7-month follow-up (Jalbrzikowski et al., 2013). In contrast, a smaller study reported no associations between functioning and performance on four Theory of Mind tasks (Stanford et al., 2011). Despite ARMS patients exhibiting a more externalised attributional style compared to healthy controls, this was also unrelated to social or occupational 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 was significantly associated with patients' improvement in functioning over 3 and 4 months (O'Brien et al., 2006, 2008). ARMS adolescents' conversational problem solving abilities, along with the degree of constructive communication displayed with their primary caregiver also positively correlated with functioning at 6-month follow-up (O'Brien et al., 2009). 3.12. Trauma The only study in this area reported role functioning to be weakly but significantly correlated with psychological, physical and total bullying and overall trauma in childhood in a cross-sectional study (Addington et al., 2013). Social functioning however only correlated with physical bullying. Neither was directly associated with neglect or abuse in childhood. 3.13. Personality characteristics Adaptive coping and resilience were associated with better functioning, over and above negative symptoms (Kim et al., 2013). Better social functioning significantly correlated with higher cooperativeness but not self-directedness or self-transcendence. Role functioning was unrelated to any temperament or character dimensions (Song et al., 2013). 3.14. Sex Various cross-sectional and longitudinal studies have reported no significant sex differences in functioning (Miller et al., 2003; Cornblatt et al., 2007; Lemos-Giráldez et al., 2009; Kim et al., 2013). However, the largest study to date reported significantly poorer social and role functioning in males (Walder et al., 2013). Males also report experiencing less positive social support (Willhite et al., 2008) and poorer subjective satisfaction with relationships (Ruhrmann et al., 2008). 3.15. Ethnicity Social functioning has been reported to be significantly poorer in ethnic minority (non-Caucasian) patients (Corcoran et al., 2011). A much 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 after adjusting for potential confounders (Velthorst et al., 2012). However, when examined longitudinally, ethnicity was reported to be unrelated to functional outcome within this population (Carrión et al., 2013). 3.16. Interventions 3.16.1. Antipsychotic medication Observational 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

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et al., 2013) or long-term functional recovery (Schlosser et al., 2012; Carrión et al., 2013). Despite no differences in cognitive impairment or positive symptoms, patients in one study who were taking antipsychotic medication exhibited significantly poorer functioning (Niendam et al., 2006b). However, this could be due to increased symptom severity prior to the assessment that warranted the use of medication. In contrast, a small, uncontrolled, open-label study found that ARMS patients' prescribed antipsychotic medication experienced significant, but modest improvement in functioning, though this remained markedly impaired compared to the general population (Shim et al., 2008b). An open-label study examining a needs-focused intervention delivered with or without amisulpride also reported significantly better global functioning after 12weeks of treatment in those who received amisulpride (Ruhrmann et al., 2007). Unlike other trials, this study also reported a significant improvement in negative symptoms. However, a randomised, double-blind, placebo-controlled study of olanzapine reported no beneficial effects on functioning over placebo, despite significant improvement in positive symptoms (Woods et al., 2003; McGlashan et al., 2006). 3.16.2. Psychosocial interventions Randomised controlled trials assessing the effectiveness of cognitive behavioural therapy (CBT) in ARMS have reported no significant benefits on functioning, despite improvements in positive symptoms and reductions 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 improving functional outcome (McGorry et al., 2002; Phillips et al., 2007; Yung et al., 2011; McGorry et al., 2013). Small single-arm feasibility studies examining the effectiveness of psychoeducation have produced mixed results. A 9-month multi-family group treatment reported significant improvement in global and role functioning, in conjunction with improved positive and general symptoms (O'Brien et al., 2007). However, most participants (81%) were also receiving medication, and all were receiving additional psychological therapies. In contrast, Hauser et al. (2009) reported no significant differences in global functioning following seven psychoeducation treatment sessions. 3.16.3. Omega-3 fatty acids A 12-week randomised, double-blind, placebo-controlled trial reported significantly better global functioning after 1 year in those randomised to receive an omega-3 polyunsaturated fatty acid nutritional supplement compared to those receiving placebo (Amminger et al., 2010). Improvement in functioning correlated with a change in omega6 to omega-3 ratio from baseline to the end of treatment. Significant improvements in positive, negative and general symptoms were also observed. This was the only study that reported improvements in functioning comparable to levels observed in healthy individuals, though baseline functioning in these patients was also considerably higher than in most other ARMS intervention studies. Measures taken at baseline indicated that lower levels of erythrocyte nervonic acid correlated with poorer global functioning as well as worse negative and disorganised symptoms (Amminger et al., 2012). However, docosahexaenoic and arachidonic acid levels were unrelated to functioning. 4. Discussion 4.1. Summary of results This is the first systematic review on factors associated with functional impairment in the ARMS population. Across the broad range of measures, negative symptoms, disorganisation and neurocognitive deficits were consistently associated with poor functioning. Functional disability was unrelated to positive psychotic symptoms. Cross-sectional and longitudinal studies were largely consistent, although longitudinal studies emphasised a greater role of disorganised symptoms in predicting functional outcome. Functioning at baseline was predictive of long-term

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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 trauma and social cognition were associated with functional impairment in cross-sectional studies, though the relationship between these variables and long-term functional outcome has yet to be established. A supportive family environment and high personal resilience may also help minimise functional impairment. Intervention studies strengthened the evidence that dysfunction occurs independently of positive symptoms. 4.2. ARMS aetiology At-risk patients are not a homogeneous group. Only a minority develop a frank psychotic disorder (Fusar-Poli et al., 2012; Nelson et al., 2013), suggesting that attenuated psychotic symptoms may arise from multiple aetiologies. ARMS patients commonly present with comorbid axis I disorders (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 relationships between functional disability and both mood disorder and substance use, which are each known to be associated with psychotic experiences. The finding of better functioning in ARMS patients with a history of cannabis abuse compared to those with no history (Auther et al., 2012) in particular suggests that substance-induced attenuated psychotic symptoms may have a different underlying cause from symptoms that arise in the absence of substance use trigger. The core findings of this review however were consistent, suggesting that most individuals meeting the ARMS criteria share some fundamental underlying pathology, consistent with the neurodevelopmental hypothesis of schizophrenia (Murray and Lewis, 1987; Weinberger, 1987; Fatemi and Folsom, 2009). Negative and disorganised symptoms and cognitive deficits pre-date frank psychotic symptoms and impair functioning from an early age. Positive symptoms manifest later in the illness course, when functional disability has already become entrenched. Findings do not appear to be confounded due to more severe clinical symptoms in those who subsequently transitioned to psychosis, though further evidence is required to determine whether this is true for neurocognitive impairment (Carrión et al., 2013). This review is consistent with previous reports that negative symptoms and neurocognition are strong determinants of functional outcome in schizophrenia, while early evidence suggests that social cognition may similarly be associated (Ventura et al., 2009; Fett et al., 2011; Hunter and Barry, 2012).

(Nelson et al., 2008). Based on the results of this review, efforts to reduce negative symptoms may be particularly beneficial for functioning. There is currently lack of interventions specifically targeting this range of symptoms in the at-risk population. 4.4. Limitations Functioning is a critical component in understanding the full burden of 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 observational studies included in this review used global measures of functioning, such as the GAF (Hall, 1995) and SOFAS (Goldman et al., 1992), which provide crude assessment of overall impairment, but lack sensitivity to variation or associations within distinct functioning subdomains. The GAF is further limited by its conflation of symptoms and functioning, so it is difficult to distinguish whether low GAF scores are truly driven by poor functioning or due to severe clinical symptoms. The SOFAS looks to overcome this issue by only examining functioning; however, there is growing evidence that social and role functioning may be more strongly associated with different aspects of illness and should be examined discretely (Cornblatt et al., 2007; Carrión et al., 2013; Fulford et al., 2013). Many of the functioning measures used by studies were also originally developed for use in established psychotic disorders, and contain items not applicable to this population. Future studies should therefore examine social and role functioning as separate domains, using measures sensitive to dysfunction in the ARMS population that incorporate age and phase of illness, such as the GFS and GFR scales (Auther et al., 2006; Niendam et al., 2006a) and the Multidimensional Adolescent Functioning Scale (Wardenaar et al., 2013). A strength of this review is the broad-scoping eligibility criteria, providing a comprehensive overview of the literature. Previous reviews have examined the role of comorbid mood disorders and neurocognitive deficits in relation to functioning (Niendam et al., 2009b; Fusar-Poli et al., 2014), but did not consider factors such as intensity and duration of psychotic and non-psychotic symptoms, demographics and family environment. However, the inclusion of such a large number of publications did not permit more in-depth critical appraisal of individual studies. The subsequent variation in the design of included studies also made it difficult to assess methodological quality using a common and meaningful metric. Finally, the majority of this review comprises evidence obtained from cross-sectional studies due to the disproportionately greater number of such publications. Longitudinal studies have begun to emerge in this area and provide more informative evidence.

4.3. Clinical implications 4.5. Conclusions These results emphasise the importance of early identification and intervention in this patient group who, even in the absence of frankpsychotic symptoms, display cognitive impairment, marked social dysfunction and a range of non-psychotic symptoms and comorbid disorders. Functioning has been evaluated as one of a number of secondary outcomes in treatment studies to date. Despite reductions in symptom severity and transition rates (Stafford et al., 2013; Hutton and Taylor, 2014), current routine clinical interventions are ineffective at improving functioning (van der Gaag et al., 2013). This may be because factors that place an individual at risk for poor functioning are different from those that increase the risk of transition to full-threshold psychosis. As functional impairment persists regardless of transition (Addington et al., 2011a; Schlosser et al., 2012; Carrión et al., 2013) or symptomatic remission (de Wit et al., 2014), there is a clear need for the development of treatments that can both prevent transition and ameliorate functional disability (Fowler et al., 2010). Incorporation of cognitive and social cognitive remediation programmes may be beneficial, given the encouraging preliminary results observed in schizophrenia (Wykes et al., 2011; Sacks et al., 2013; Statucka and Walder, 2013). International multisite trials of omega-3 polyunsaturated fatty acid are also currently underway to replicate the benefits to both transition and functioning previously reported

Negative and disorganised symptoms and neurocognitive impairment are key drivers of functional impairment in ARMS cohorts. These factors are also thought to underlie functional disability in schizophrenia. This suggests similarity in underlying pathology, despite only a minority of patients subsequently developing a frank psychotic disorder. That positive symptomatology does not appear to be a major determinant of functioning is supported by the lack of efficacy shown by current clinical interventions, which have instead focused on reducing positive symptom severity and preventing transition to psychosis. There is a need for the development of novel therapies with an emphasis on improving functioning. Research is also needed to establish the long-term relationship between factors such as social cognition and childhood trauma with functional outcome in the ARMS population. Role of funding source J.C. is supported by a University of Manchester PhD studentship. Contributors A.Y., J.C. and R.D. contributed to the conception of the review. J.C. designed and performed the literature search. J.C. and J.F. screened articles for eligibility and extracted data from eligible studies. J.C. wrote the first draft of the manuscript. A.Y., R.D., S.B., J.F.

J. Cotter et al. / Schizophrenia Research 159 (2014) 267–277 and D.E. critically revised the manuscript. All authors contributed to and approved the final manuscript. Conflict of interest None.

Acknowledgement The authors would like to thank Agata Golawska for assistance during the article screening stage.

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