Economic considerations of cognition and functional outcomes in patients with schizophrenia: A systematic literature review

Schizophrenia Research: Cognition 1 (2014) e27–e33

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Schizophrenia Research: Cognition journal homepage: http://www.schizrescognition.com/

Economic considerations of cognition and functional outcomes in patients with schizophrenia: A systematic literature review Nicolas Furiak a, Amy Duhig b,⁎, Julie Myers a, Amber Pitts a, Steven Hass b, Robert Klein a a b

Medical Decision Modeling Inc., Indianapolis, IN, USA AbbVie Inc., North Chicago, IL, USA

a r t i c l e

i n f o

Article history: Received 26 July 2013 Received in revised form 30 October 2013 Accepted 5 November 2013 Available online 18 February 2014 Keywords: Cognition Schizophrenia Economic UPSA Residential

a b s t r a c t Background: The primary focus of research in schizophrenia has been on the positive symptoms, with findings that clearly establish their economic burden. More recently, research has expanded to focus on another core symptom of schizophrenia, namely cognitive impairments. While this work has established the adverse impact of cognitive impairments associated with schizophrenia (CIAS) on functional outcomes, their relationship to the economic impact of schizophrenia has not been systematically evaluated. Objective: The aim of this research was to perform a systematic literature review identifying evidence that evaluates: 1) the economic impact of CIAS and its treatments, including health-state utilities, and 2) the economic evidence associated with improvements in the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery and the University of California Performance Skills Assessment (UPSA). Method: A systematic search of articles published from January 1999–April 2013 was conducted. Studies reporting direct costs, indirect costs, and quality of life impacts of CIAS and costs of CIAS interventions were reviewed. Results: Forty-three studies met inclusion criteria. Twenty-four focused on indirect costs (work-related outcomes) associated with cognitive impairments and 14 studies included residential status outcomes. Four studies concentrated on the direct cost of cognitive remediation therapy. Three studies reported quality of life outcomes, but none used health-state utilities. Eight studies focused on the UPSA and its relationship to community outcomes. Only two studies were cost-effectiveness analyses. Conclusions: Despite the growing scientific literature relating CIAS to adverse outcomes, the translation of outcomes into economic outcomes is seldom reported. Should novel pharmacotherapies and/or psychosocial treatments require reimbursement from health authorities and/or other payers, many gaps warrant attention in order to demonstrate the economic value of these therapies. © 2014 Elsevier Inc. All rights reserved.

1. Introduction The current approaches to pharmacological treatment of patients with schizophrenia are based upon stabilization of psychotic symptoms through the use of antipsychotic therapies. The ability of first- and second-generation antipsychotics to stabilize patients and to reduce the incidence of costly relapse is well-documented. (Leucht et al., 2012) Moreover, the literature is replete with studies evaluating differential effectiveness and cost-effectiveness within the array of treatments administered to patients with schizophrenia for treatment of psychotic symptoms. (Ascher-Svanum et al., 2009; Edwards et al., 2005; Furiak et al., 2009; Heeg et al., 2005) However, two other core symptoms of schizophrenia also merit economic analysis, cognitive impairment and negative symptoms, because these symptoms may also ⁎ Corresponding author at: 1 N. Waukegan Rd., N. Chicago, IL 60064. Tel.: + 847 938 8575; fax: +847 937 1992. E-mail address: [email protected] (A. Duhig). 2215-0013/$ – see front matter © 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.scog.2013.11.001

represent manifestations significantly associated with the cost of the illness. The focus of this paper is the body of literature documenting the economics of cognitive impairment associated with schizophrenia (CIAS) and its treatments. Nearly every patient with schizophrenia experiences a cognitive decrement from the premorbid state. (Keefe, 2008; Keefe et al., 2005; Manschreck and Boshes, 2007) Even patients with neuropsychological test scores similar to healthy controls have comparatively lower mean functional performance scores. (Keefe et al., 2005; Kremen et al., 2000) There is an extensive literature documenting the aspects of function (e.g., social functioning, residential, occupational functioning, and quality of life) associated with CIAS. Studies of patients with other psychiatric disorders have documented differences in costs and economic burden in patients who do, versus who do not, have cognitive impairments (e.g., Mackin et al., 2011). Research in patients with schizophrenia has shown that those with higher functional and cognition scores predictably achieve significant employment and residential milestones, such as independent living

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status and employment status. (Harvey et al., 2009) The question of whether improving cognition results in economic benefits remains and has yet to be examined systematically, largely because of the lack of currently available effective treatments. There is evidence supporting the clinical benefits of cognitive remediation therapy (CRT), in both conventional and computerized formats. (Patel et al., 2010; Wykes et al., 2007) However, these benefits were realized only when added to another form of psychiatric rehabilitation (e.g., supported employment, strategy training) versus adding CRT to usual care. (McGurk et al., 2007; Wykes et al., 2011) Cognitive remediation methods are still developing, and there remains uncertainty over which techniques should be employed and whether the outcomes are beneficial in terms of sustained effects on cognition or improved functioning. (National Institute for Health and Clinical Excellence, 2009) Due to variability in methodological rigor of the studies and the observed effectiveness of cognitive remediation, further research is required. In addition to psychosocial treatments, pharmacotherapies have also been identified as potentially viable options for improving cognition. In recognition of the need to facilitate the study and registration of pharmacologic agents for the treatment of CIAS, the US National Institute of Mental Health (NIMH) developed an initiative called “Measurement and Treatment Research to Improve Cognition in Schizophrenia” (MATRICS). In partnership with the US Food and Drug Administration (FDA), industry, and academia, NIMH developed and published a consensus statement regarding how pharmacologic agents for the treatment of CIAS may be assessed (http://www. matrics.ucla.edu/matrics-recommendations.shtml). The MATRICS task force developed the MATRICS Consensus Cognitive Battery (MCCB) and selected it, along with a performance-based measure: the University of California Performance Skills Assessment (UPSA), as co-primary trial outcomes for evaluation of new therapies. Demonstrating benefit according to these measures is the first step in establishing the efficacy of novel pharmacotherapies to treat CIAS. In addition to meeting efficacy hurdles, new therapies for CIAS will have to meet an array of economic expectations and demonstrate value for money in order for them to be reimbursed and made available to patients in need of treatment. The pursuit of economic evidence in parallel with efficacy assessments is critical due to decreases in the availability of health care funds. Understanding the current state of economic evidence regarding CIAS and its treatments is a prerequisite for establishing a foundation of knowledge from which to build future research. The aim of this study was to perform a systematic literature review to identify evidence evaluating: 1) the economic impact of CIAS and its treatments, including their impact on health-state utilities, and 2) the economic evidence associated with improvements in the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery and the University of California Performance Skills Assessment (UPSA). 2. Methods Systematic searches of English language articles published from January 1999 through April 2013 were conducted in multiple databases: PubMed, EMBASE, MEDLINE In-Process & other Non-Indexed Citations, EconLit, PsycINFO, and Clinicaltrials.gov. Abstracts from scientific conferences were also searched including: Schizophrenia International Research Society (SIRS), International Congress on Schizophrenia Research (ICOSR); American College of Neuropsychopharmacology (ACNP); European College of Neuropsychopharmacology (ECNP), Mt. Sinai Conference on Cognition in Schizophrenia, the European Conference on Schizophrenia Research, American Psychological Association, and the International Society of Pharmacoeconomics Research (ISPOR). Articles before 1999 were excluded because, before that time, there was limited

evidence regarding cognitive impairments, their functional consequences or appropriate interventions to address them. (Green, 1996; Bellack et al., 1999). The literature search terms were developed to capture studies providing pharmacoeconomic information on direct and indirect costs, quality of life assessments associated with CIAS, as well as costs of CIAS treatments. Direct costs are defined as those incurred for medical treatment, such as visits with a physician, emergency room costs, hospitalization costs, community mental health costs, etc. Indirect costs are those associated with lost productivity/work due to patient disability, lost productivity/work by caregivers, societal costs (e.g., incarceration), etc. Literature regarding quality of life was included because of the importance of these measures in the calculation of the quality adjusted life year (QALY), which is widely used as the denominator of cost-effectiveness ratios in economic analyses. For several countries, this metric is a critical component of evaluations that determine reimbursement for new pharmaceutical therapies. The literature included in this review was specific to that dealing with economic, societal, residential and occupational outcomes of patients with schizophrenia. The structure of the final search strategy for PubMed, including search terms and limits, is shown in Table 1 with references from search #6 being saved for review. This strategy was adapted for searches in the additional databases listed above. References from these searches were then reviewed using the inclusion and exclusion criteria detailed in Table 2. Included studies were required to contain at least one reference to direct costs, indirect costs, costs associated with cognitive therapies or quality of life measurement. Reference lists of included studies were also reviewed for additional potentially relevant studies. Included studies were assessed for similarities with respect to study design, treatment examined (if any), and outcomes evaluated. Results of studies with similar outcomes/treatments were compared. Included studies were also assessed chronologically to determine how research in this area has evolved over time.

3. Results Table 3 displays the characteristics of the 43 included studies. Twenty-four of these studies focused on work-related effects of cognitive deficits, such as wages earned, hours worked, employment status, and patient level predictors (PLPs) of employment (column 7 of Table 3). Four studies concentrated on cost-related outcomes of CRT. There were three studies reporting quality of life (QoL) outcomes, but none of these assessed QoL using health-state utilities. Nine of the included studies focused on the ability of UPSA to identify patients most likely to achieve improved functional milestones. Of the 43 studies, nine were randomized-controlled trials (RCTs), 32 had an Table 1 PubMed search strategy (also customized for Embase, Medline In-Process, The Cochrane Library, and clinicaltrials.gov). Search #

Term

1

(schizophrenia[MeSH]) AND (“cognitive deficit syndrome” OR cognition OR cognitive OR “cognitive impairment” OR neurocognition OR neurocognitive) #1 limited to: editorial, letter, comment, case report #1 NOT #2 #3 limited to: animals #3 NOT #4 #5 AND (economic OR cost-effectiveness OR cost⁎ OR burden OR productivity OR value OR societal OR financial OR resource OR absenteeism OR disability OR employment OR vocational OR occupational OR expenditure OR “quality-adjusted life years” OR residential)

2 3 4 5 6

⁎ truncated term.

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observational design (i.e., retrospective cohort or cross-sectional) and two were cost-effectiveness analyses (CEA).

rehabilitation center in a large city with potentially better employment opportunities and access to successful work rehabilitation. Krishnadas et al. also failed to find a significant correlation between cognitive function and disability in a sample of schizophrenia patients from India. (Krishnadas et al., 2007) A large portion (75%) of patients in this study remained employed despite cognitive deficits. This pattern of results was similar to those of other studies from India, indicating potential socio-cultural factors. (Thara, 2004). Trials investigating the impact of interventions targeting cognition (e.g., CRT, neurocognitive enhancement therapy) alone or in conjunction with other psychosocial interventions (e.g., supported employment) have found robust improvements in employment outcomes with treatment. Improvement in employment outcomes such as number of hours and/or weeks worked (Bell et al., 2008, 2005 McGurk et al., 2009, 2007, 2005; Wexler and Bell, 2005) and higher wage earnings (Bell et al., 2005; Eack et al., 2011; McGurk et al., 2009, 2007) are strongly supported in this literature. Support has also been found for the impact of these interventions on the ability to maintain employment or achieve a higher rate of competitivewage employment (Bell et al., 2005, 2008; Eack et al., 2011; McGurk et al., 2005), successful job placement (Vauth et al., 2005), and satisfaction with employment status. (Eack et al., 2011).

3.1. Employment outcomes

3.2. Residential outcomes

An early study of the impact of CIAS on employment outcomes was conducted by McGurk and colleagues, focusing on associations between neurocognitive functioning and employment status (i.e., full-time, part-time, unemployed) (2000). Univariate analyses indicated that level of cognitive functioning was the most important difference between the three employment groups, with the full-time employed group performing better than the other groups on every cognitive domain assessed. Differences were also found, depending on the cognitive domain evaluated, between the fulltime and part-time groups and the part-time and unemployed groups. In subsequent research, McGurk and colleagues evaluated predictors of work outcomes (e.g., sustained employment) in a supported employment setting over a two-year period. (McGurk et al., 2003) Results indicated that higher levels of cognition, varying by type of cognition assessed, were associated with higher wages earned and hours worked. They then examined this cohort over an additional two-year period, for a total of four years of observation. (McGurk and Mueser, 2006) Analyses suggested that cognitive functioning was even more predictive of wages earned and hours worked during the latter two years of the study than in the first two years. Furthermore, patients with lower levels of cognition required more hours of job support and a higher number of employment specialist contacts. Other researchers have also found associations between cognitive deficits and work and employment outcomes. These studies generally found significant associations between cognitive functioning and current and past employment. (Gould et al., 2013; Jaeger et al., 2006; Rosenheck et al., 2006; Verdoux et al., 2010) Additionally, cognitive impairment was linked to cooperativeness, work habits, work quality, social skills and personal presentation as measured by the Work Behavior Inventory. (Bell and Bryson, 2001) Furthermore, cognitive functioning was found to be predictive of endpoints such as vocational functioning, obtaining competitive employment and capability to work, as well as poorer work performance (Bowie et al., 2010; Evans et al., 2004; Giugiario et al., 2012; Hoffmann et al., 2003; Lysaker et al., 2002; Mausbach et al., 2011). Not all studies have supported the connection between CIAS and employment outcomes. Srinivasan and Tirupati (2005) found cognitive deficits were not significantly related to work status or performance. This study examined a relatively small number of patients (n=88) and was performed on patients from a specialized

Several studies found cognitive functioning to be predictive of residential status. (Leung et al., 2008; Mausbach et al., 2007, 2008; Twamley et al., 2002) Cognitive impairment was found to be associated with poorer performance of activities of daily living and ability to live independently. (Gupta et al., 2003; Harvey et al., 2009; Jaeger et al., 2006; Mausbach et al., 2010, 2011 Self-assessment of functional ability was associated with both residential independence and financial responsibility. (Gould et al., 2013).

Table 2 Inclusion and exclusion criteria. Inclusion criteria • Publication in which the area of interest is cognition in schizophrenia • Studies providing information on the following topics: ○ Direct costs ○ Indirect costs ○ Costs associated with cognitive therapies Exclusion criteria • Non-English – articles where only the abstract is in English (but the publication was not) • Opinion-based – articles including, but not limited to, editorials, comments, non-systematic reviews, and letters • Disease state – studies that do not focus on cognition in schizophrenia • Case study – articles describing case studies and/or case reports • Withdrawn – studies that were published and subsequently withdrawn • In vitro/animal studies – studies conducted in vitro or in animals (e.g., rats, pigs, mice, etc.) rather than in humans • Not an outcome of interest – trials that did not report economic outcomes • Outside of time parameters – articles that were published prior to the inclusion years

3.3. Quality of life We were not able to identify any studies that discussed qualityadjusted life years in studies of CIAS. While not specifically a focus of this research, other measures of quality of life were noted in the literature accessed for this study. Conflicting results were noted, with self-reported QoL (World Health Organization Quality of Life-BREF) being unrelated to cognitive functioning. (Hofer et al., 2005) However, a significant correlation was reported between cognitive impairment and poorer QoL as measured by the disease-specific Quality of Life Scale, an interview-based assessment. (Lipkovich et al., 2009; Savilla et al., 2008). 3.4. Studies examining cost of care Those studies that included an assessment of direct costs were conducted in the UK. Patel et al. found a significant relationship between higher cognition scores (better) and lower total costs (85% of which were direct costs) from a UK societal perspective. (Patel et al., 2006) In a study of direct costs associated with CRT intervention, Wykes et al. (2003) found increased day care costs associated with CRT, but inferred that increased use of day care may provide important benefits such as improved social function and QoL. These authors subsequently conducted a CEA of CRT showing reduced cost and improved outcomes at the end of treatment, but a small increase in cost at follow-up despite a durable benefit of improved memory. (Wykes et al., 2007) This observation was confirmed in a subsequent 2010 analysis comparing the cost-effectiveness of CRT plus usual care to usual care alone at both short-term (14 weeks) and medium-term (40 weeks) treatment periods. (Patel et al., 2010) Neither total health/social care nor societal costs were different between the two treatment groups at either time period. The mean cost difference

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Table 3 Summary of included studies. Study

Duration

N

Study Design

Study Aim/Objective

Economic Outcomes Assessed

1 2

(Dickerson et al., 1999) (McGurk and Meltzer, 2000)

N/A N/A

72 30

Cross-sectional Cross-sectional

Residential status Employment

3

(Bell and Bryson, 2001)

26 weeks 33

Single-arm trial

4

(Roder et al., 2001)

73

5

(Auslander et al., 2001)

12 months N/A

Prospective cohort Cross-sectional

6

(Lysaker et al., 2002)

7 weeks

121

7

(Twamley et al., 2002)

N/A

111

Prospective cohort Cross-sectional

8

(McGurk et al., 2003)

2 years

30

Single-arm trial

9

(Hoffmann et al., 2003)

N/A

53

Cross-sectional

To identify factors that predict degree of residential independence To evaluate the relationship between neurocognitive functioning and occupational status in schizophrenia patients with stable work status (full-time, part-time, unemployed) To evaluate the contribution of cognitive impairment on rate of work rehabilitation To test the efficacy of 3 skills training programs in the residential, vocational, and recreational domains To compare living status with standardized measures of psychopathology, cognition and health-related quality of wellbeing, and determine predictors of living status To evaluate whether measures of insight predict performance in a work rehabilitation program To examine the relationship between the UPSA and cognitive functioning and living status To examine the relationship of cognitive functioning and clinical symptoms with competitive employment outcomes for patients in a supported employment program To test outcome predictors of functioning in patients enrolled in a vocational rehabilitation program To test the durability of the effects of CRT vs. intensive occupational therapy (control) 6 months after therapies were withdrawn. Data on use of services and costs of therapy were also collected To examine the effect of symptom severity and cognitive impairment on living status To examine the relationship of cognitive functioning and clinical symptoms with vocational outcomes and identify predictors To assess the relationship of cognitive deficits and treatment outcomes in terms of QoL, needs, and psychosocial functioning To evaluate the effects of CAST + vocational rehabilitation vs. TSSN + Vocational rehabilitation vs. Vocational rehabilitation alone To evaluate productivity outcomes after 6 and 12 months of work therapy vs. NET + work therapy To examine the relationship between work functioning and cognition, clinical and demographic variables, and social functioning To examine the effectiveness of cognitive training + supported employment vs. supported employment for improving competitive employment outcomes To review past work demonstrating that cognitive remediation treatment with work therapy or supported employment has lasting improvements in cognition and work functioning To evaluate factors associated with participation in competitive employment, participation in other employment activities, and earnings of those employed To examine the associations between cognition and costs in patients with schizophrenia To evaluate the long-term association of cognitive impairment and work outcomes To determine association of cognitive profile with functional outcomes To evaluate long-term employment and hospitalization outcomes of supported employment vs. supported employment + cognitive training To evaluate the effectiveness of CRT vs. treatment as usual

251

10 (Wykes et al., 2003)

6 months 33

RCT

11 (Gupta et al., 2003)

N/A

Cross-sectional

12 (Evans et al., 2004)

4 months 112

13 (Hofer et al., 2005)

N/A

60

Prospective cohort Cross-sectional

14 (Vauth et al., 2005)

1 year

138

RCT

15 (Bell et al., 2005)

1 year

145

RCT

16 (Srinivasan and Tirupati, 2005) 17 (McGurk et al., 2005)

N/A

88

Cross-sectional

1 year

44

RCT

18 (Wexler and Bell, 2005)

N/A

19 (Rosenheck et al., 2006)

N/A

20 (Patel et al., 2006)

6 months 85

21 (McGurk and Mueser, 2006) 22 (Jaeger et al., 2006)

4 years

30 250

23 (McGurk et al., 2007)

18 months 3 years

24 (Wykes et al., 2007)

40 weeks 85

RCT

25 (Niekawa et al., 2007)

N/A

47

26 (Krishnadas et al., 2007)

N/A

50

Controlled observational study Cross-sectional

27 (Mausbach et al., 2007)

N/A

434

Cross-sectional

28 (Mausbach et al., 2008)

N/A

434

Cross-sectional

29 (Savilla et al., 2008)

N/A

57

Cross-sectional

30 (Bell et al., 2008)

2 years

72

RCT

31 (Leung et al., 2008)

N/A

238

Cross-sectional

85

Literature review

1438 Undetermined

44

Retrospective cohort Single-arm trial Prospective cohort RCT

To examine financial competence in patients with schizophrenia and the relationship between financial competence and cognitive function To compare neurocognitive functioning between patients with schizophrenia and normal controls, and to determine a relationship between cognition and functional disability To identify subscales for the UPSA-Brief and establish its initial concurrent validity by demonstrating its relationship with other measures of functioning To examine the sensitivity and specificity of the UPSA for prediction of independent living status To investigate the relationship between cognitive function, symptoms, and QoL To determine the effect of NET vs. NET + supported employment on functional outcomes

Employment Residential status and employment Residential status

Employment, PLPs Residential status Employment, PLPs

Employment, PLPs Direct costs

Residential status Employment, PLPs PLPs, QoL Employment Employment Employment Employment

Employment

Employment

Direct and indirect costs Employment, PLPs Residential status and employment Employment

Direct and indirect costs, CEA (memory improvement/cost) Financial competence

Employment performance Residential status

Residential status QoL Employment Residential status and employment

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Table 3 (continued) Study

Duration

N

34

Study Design

32 (McGurk et al., 2009)

2 years

RCT

33 (Lipkovich et al., 2009)

24 weeks 414

34 (Harvey et al., 2009)

N/A

390

Retrospective data analysis Cross-sectional

35 (Patel et al., 2010)

40 wks

85

RCT

36 (Verdoux et al., 2010)

2 years

108

37 (Mausbach et al., 2010)

N/A

205

Prospective cohort Cross-sectional

38 (Bowie et al., 2010) 39 (Eack et al., 2011)

N/A 2 years

291 58

Cross-sectional RCT

40 (Mausbach et al., 2011)

N/A

367

Cross-sectional

41 (Giugiario et al., 2012)

N/A

253

Cross-sectional

42 (Gould et al., 2013)

N/A

195

Cross-sectional

43 (McClure et al., 2013)

N/A

139

Cross-sectional

Study Aim/Objective To examine whether neuropsychological and cross-sectional symptomatic status differentially predict elements of functional outcome To evaluate the effects of CRT + vocational rehabilitation vs. vocational rehabilitation on cognitive functioning and work outcomes To evaluate the relationship among cognition, psychopathology, and psychosocial functioning To examined the similarity of performance-based assessments of everyday functioning, real-world disability, and achievement of milestones To examine the costs and cost-effectiveness of usual care vs. usual care + CRT To explore whether self-perceived cognitive deficits predict occupational outcomes To examine the usefulness of the UPSA-B for prediction of ‘real-world’ functioning To examine predictors of functional deficits To examine the effects of cognitive enhancement therapy vs. enriched supportive therapy (control) on employment outcomes To examine the sensitivity and specificity of the UPSA to predict residential and employment status To examine the relationship among insight, psychopathology, cognitive function, and competitive employment To explore self-assessment accuracy and real-world functioning To evaluate functional capacity and real-world functioning in patients with SPD

Economic Outcomes Assessed

Employment QoL Residential status

Direct and indirect costs, CEA (memory improvement/cost) Employment Residential status Employment, predictors Employment Residential status and employment Employment Residential status and employment Residential status and employment

Abbreviations: CAST = Computer assisted cognitive strategy training, CEA = cost-effectiveness analysis, CRT = cognitive remediation therapy, NET = neurocognitive enhancement therapy, QoL = quality of life, PLP = Patient-Level Predictors, RCT = randomized controlled trial, SPD = schizotypal personality disorder, TSSN = Training of self-management skills for negative symptoms.

was lower at the 40 week assessment than at the 14 week assessment, suggesting cost-savings due to CRT are realized in the shortterm, but not sustained. The authors hypothesized that this was due to increased use of community/outpatient services. 3.5. Longitudinal trends Table 3 lists the studies included in this analysis in chronological order. In general, older studies focused on employment outcomes and their predictors, but not the costs associated with them. After 2005, there was an increased focus on evaluating employment outcomes in response to cognitive remediation therapies in randomized trial settings and follow-up studies of increased duration (1–4 years). One cost-effectiveness analysis from trial data was found from 2010, quantifying cost-effectiveness as the additional cost of a 1% gain in the number of patients improving working memory. Although another study evaluated the relationship between quality of life and cognitive function, none reported cost-effectiveness ratios as cost/quality adjusted life year gained. Only one study reported changes in resource use given cognitive interventions compared to usual treatment, nine studies included versions of UPSA, but none of the studies assessed cognition using the MCCB. Studies evaluating functional capacity in patients with schizophrenia (Table 3, rows 27–43) suggest that increased functional capacity is correlated with greater achievement of functional milestones in employment and independent residential status. 4. Discussion The objective of this research was to perform a systematic literature review to assess economic evaluations of the impact of CIAS and its treatments. The search strategy yielded 43 studies published between January 1999 and April 2013. Three of the studies used costs as a key component of their analyses, with a fourth reporting

the added cost of CRT. Three of the selected studies attempted to evaluate quality of life, but none collected utility measurements from either the perspective of the patient or society. Instead of the cost/ QALY metric typically used in cost-effectiveness studies, two studies that reported cost-effectiveness ratios reported an alternative measure: Incremental cost for each 1% gain in the proportion of the population demonstrating an improvement in overall cognition. Although some studies included measures that are part of the MATRICS battery, none used these measures to evaluate the benefits of psychosocial cognitive interventions. Instead, the studies used a vast array of methodologies, endpoints, and timeframes, making it difficult to draw definitive conclusions regarding the economic benefits of addressing cognitive impairments via interventions. In recent years, the field of pharmacoeconomics has grown in parallel with the increasing demands by reimbursement authorities. New therapies are expected to provide value for money and avoid substantial burden to formulary or national health budgets. Government agencies such as the National Institute for Health and Care Excellence (NICE) in the United Kingdom, the Canadian Agency for Drugs and Technologies in Health (CADTH), Scottish Medicines Consortium (SMC), and Institut für Qualität in Germany have committed to cost, effectiveness, and costeffectiveness measures in evaluating new therapies. Each evaluates new drugs in accordance with their healthcare budgets and societal norms. In some cases, these agencies specify thresholds at which they consider a new drug acceptable for reimbursement. These thresholds are expressed as the incremental cost of an added therapy (versus current standards of care) divided by the incremental gain in QALYs. In the US, cost of care and other measures of benefit, rather than cost/ QALY are considered in reimbursement decisions made by managed care organization. Current data on the direct costs associated with CIAS is limited and is insufficient to support economic modeling that would address the needs of reimbursement authorities. An additional data gap identified through this research is proper utility measurement for CIAS. Historically, utility

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data collected during research of positive symptoms in patients with schizophrenia have been collected from the patient perspective and/or the perspective of persons not afflicted with the disease (sometimes referred to the “societal perspective” or the “layman’). In general, these studies have shown that patients with schizophrenia evaluate the utility of their health state higher than those in the societal realm, likely due to patient-level factors such as a lack of awareness of their disease as it relates to societal norms. Additionally, they may lack the cognitive ability to understand the severity of schizophrenia in general. Briggs et al. (2008) collected direct utility measures from patients and laypersons and showed that patients rated the same health state descriptions higher than laypersons. Their descriptions of health states had much in common with those found in an earlier study by Lenert et al. (Lenert et al., 2004) who estimated societal utilities of similar magnitude. Therefore, it may be critical to gather utility data from both perspectives to accommodate differences across cultures. Another factor in the approval of new pharmacological or psychosocial treatments, especially for national European formularies, may be assessments of cost savings to society in indirect costs through improvements in the lost productivity of patient and their caregivers. Cost/QALY calculations may include a separate category with these costs if properly documented, but in general, the direct cost offsets of new therapies and cost/QALY estimates take precedence. Evidence regarding the relationship of indirect cost to CIAS is perhaps the most robust component of the literature at this time. Perhaps most important for the development of new pharmacotherapies is advancing the level of evidence supporting the relationship of the FDA endorsed MCCB and UPSA clinical trial endpoints to direct costs, indirect costs and utilities. The MATRICS endorsed outcome measures (MCCB, UPSA) are currently in use in late stage clinical trials of new pharmacotherapies, so it is somewhat expected that incremental economic gains associated with these metrics are not yet available. Until these linkages are made, it will be difficult to make economic arguments via modeling in order to gain reimbursement for CIAS interventions. Future study of pharmacotherapies and psychotherapies to treat CIAS could fill the gaps identified by the results of this study if the design of trials were to include key economic elements. Investigators anticipating the challenges of demonstrating value for money for new pharmacotherapies and psychosocial interventions need to systematically collect resource use, direct and indirect cost, and employment-related data. The availability of these data would greatly enhance the base of knowledge on CIAS interventions and the economic impact they may have. Equally important is the collection of quality of life data (particularly utilities) in anticipation of satisfying cost/QALY thresholds common in formulary environments outside the US. Role of Funding Source The design, study conduct analysis, and financial support of the research were funded by AbbVie. Contributors There are no other contributors other than the authors and those who are described in the Acknowledgements. Conflict of interest AbbVie participated in the interpretation of data, review, and approval of the manuscript. AD and SH are employees of AbbVie and may own AbbVie stocks or options. JM, RK and AP are employees at Medical Decision Modeling Inc. and have no conflicts of interest to report. NF was employed by Medical Decision Modeling Inc. at the time of manuscript preparation and has no conflicts of interest to report.

Acknowledgments The authors would like to acknowledge the contribution of Dr. Susan McGurk who reviewed and provided helpful comments on a draft of this manuscript and Dr. Phil Harvey who assisted with the conceptualization of the paper, the search strategy and provided input on a draft of the manuscript. We would also like to thank Mark Day, who provided editing and proofreading assistance, and Yasir Malik who helped with manuscript formatting.

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