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Evaluation of the Cost-effectiveness of Services for Schizophrenia in the UK Across the Entire Care Pathway in a Single Whole-Disease Model

Evaluation of the Cost-effectiveness of Services for Schizophrenia in the UK Across the Entire... Key Points Question Which interventions are cost- IMPORTANCE The existing economic models for schizophrenia often have 3 limitations; namely, effective for the prevention and they do not cover nonpharmacologic interventions, they report inconsistent conclusions for treatment of schizophrenia? antipsychotics, and they have poor methodologic quality. Findings In this decision analytical model using a simulated cohort of OBJECTIVES To develop a whole-disease model for schizophrenia and use it to inform resource 200 000 individuals, the following allocation decisions across the entire care pathway for schizophrenia in the UK. interventions were found to be cost-effective: practice as usual plus DESIGN, SETTING, AND PARTICIPANTS This decision analytical model used a whole-disease model cognitive behavioral therapy for to simulate the entire disease and treatment pathway among a simulated cohort of 200 000 individuals at clinical high risk of individuals at clinical high risk of psychoses or with a diagnosis of psychosis or schizophrenia being psychosis; a mix of hospital admission treated in primary, secondary, and tertiary care in the UK. Data were collected March 2016 to and crisis resolution and home December 2018 and analyzed December 2018 to April 2019. treatment team for individuals with acute psychosis; receipt of amisulpride, EXPOSURES The whole-disease model used discrete event simulation; its structure and input data risperidone, or olanzapine combined were informed by published literature and expert opinion. Analyses were conducted from the with family intervention for individuals perspective of the National Health Service and Personal Social Services over a lifetime horizon. Key with first-episode psychosis; and receipt interventions assessed included cognitive behavioral therapy, antipsychotic medication, family of clozapine for individuals with intervention, inpatient care, and crisis resolution and home treatment team. treatment-resistant schizophrenia. MAIN OUTCOMES AND MEASURES Life-time costs and quality-adjusted life-years. Meaning The results of this study suggest that cost savings and/or RESULTS In the simulated cohort of 200 000 individuals (mean [SD] age, 23.5 [5.1] years; 120 800 additional quality-adjusted life years [60.4%] men), 66 400 (33.2%) were not at risk of psychosis, 69 800 (34.9%) were at clinical high may be gained by replacing current risk of psychosis, and 63 800 (31.9%) had psychosis. The results of the whole-disease model suggest interventions with more cost-effective the following interventions are likely to be cost-effective at a willingness-to-pay threshold of interventions. £20 000 ($25 552) per quality-adjusted life-year: practice as usual plus cognitive behavioral therapy for individuals at clinical high risk of psychosis (probability vs practice as usual alone, 0.96); a mix of Supplemental content hospital admission and crisis resolution and home treatment team for individuals with acute psychosis (probability vs hospital admission alone, 0.99); amisulpride (probability vs all other Author affiliations and article information are listed at the end of this article. antipsychotics, 0.39), risperidone (probability vs all other antipsychotics, 0.30), or olanzapine (probability vs all other antipsychotics, 0.17) combined with family intervention for individuals with first-episode psychosis (probability vs family intervention or medication alone, 0.58); and clozapine for individuals with treatment-resistant schizophrenia (probability vs other medications, 0.81). CONCLUSIONS AND RELEVANCE The results of this study suggest that the current schizophrenia service configuration is not optimal. Cost savings and/or additional quality-adjusted life-years may be gained by replacing current interventions with more cost-effective interventions. JAMA Network Open. 2020;3(5):e205888. doi:10.1001/jamanetworkopen.2020.5888 Open Access. This is an open access article distributed under the terms of the CC-BY License. JAMA Network Open. 2020;3(5):e205888. doi:10.1001/jamanetworkopen.2020.5888 (Reprinted) May 27, 2020 1/12 JAMA Network Open | Psychiatry Cost-effectiveness of Services for Schizophrenia Across the Entire Care Pathway in a Whole-Disease Model Introduction Economic models have increasingly been used to inform decision-making regarding health care, as they provide an explicit way of synthesizing all available data to simulate the likely costs and consequences of using alternative interventions under scenarios that cannot be directly observed in the real world. A 2020 systematic review found several limitations of existing economic models for schizophrenia. Most existing models (83%) focused on antipsychotic medications, while there was a lack of models for nonpharmacologic interventions, such as cognitive behavioral therapy (CBT), family intervention, and crisis resolution and home treatment team (CRHT). Second, no antipsychotic medication was shown to be clearly cost-effective compared with the others because of inconsistent or even contradictory conclusions reported by different studies. Third, the quality of existing models was considered low. This systematic review highlighted issues relating to inconsistent assumptions and uses of evidence, which negatively affect the quality of existing economic studies in schizophrenia. Greater consistency could be achieved through the development of generic models that have been agreed on by key stakeholders. A whole-disease model (WDM) represents a type of generic model that is unique in that it can be used to inform multiple resource allocation decisions across the entire care pathway. Whole-disease models are large-scale models that involve simulating whole disease and treatment pathways, thereby allowing for the economic evaluation of options for the prevention, early identification, diagnosis, treatment, and follow-up of a given disease using a single consistent model. This type of system-level modeling approach has been successfully applied to a number of disease areas, including cancer, metabolic diseases, and cardiovascular diseases. However, such an approach has not been applied to any mental health disorders. The aim of this study was to develop a WDM for schizophrenia services and use it to assess the cost-effectiveness of a range of interventions in the UK. Methods This study was reported according to the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) reporting guideline for reporting health economic evaluations. Per the Common Rule, ethical approval and informed patient consent were not required given that this is a modeling study with no direct patient contact or influence on patient care directly related to this work. The methods for developing the schizophrenia WDM were mainly informed by the methodologic framework set out by Tappenden et al. To help with the development and validation of the WDM, a group of 13 multidisciplinary stakeholders was convened though snowball sampling. The background of the 13 stakeholders included health care professionals practicing in the National Health Service (9 [69.2%]), academic researchers with expertise in mental health economic evaluation (12 [92.3%]), commissioners of mental health services (5 [38.5%]), and service users (2 [15.4%]). Population The target population for the model was individuals referred to secondary care mental health services in the UK because of psychotic symptoms, with a mean (SD) age of 23.5 (5.1) years and a sex ratio of 1.5:1 (men to women). Of those referred, 33.2% were not at risk of psychosis, 34.9% were at clinical high risk of psychosis (CHR-P), and 31.9% were individuals with psychosis. Those not at risk of psychosis were included because they also use resources associated with schizophrenia services (eg, specialist assessments). Decision Problems The decision problems to be addressed by the WDM were identified from the scope of the schizophrenia clinical guidelines developed by the National Institute for Health and Care Excellence JAMA Network Open. 2020;3(5):e205888. doi:10.1001/jamanetworkopen.2020.5888 (Reprinted) May 27, 2020 2/12 JAMA Network Open | Psychiatry Cost-effectiveness of Services for Schizophrenia Across the Entire Care Pathway in a Whole-Disease Model 7,8 (NICE). A total of 5 topics were identified (Table 1), which span most of the breadth of the Table 1. Decision Problems Addressed Using schizophrenia pathway, ranging from the use of CBT for individuals at CHR-P to antipsychotic the Schizophrenia Whole-Disease Model medication for individuals with treatment-resistant schizophrenia (TRS). Interventions and Topic comparators Interventions for Practice as usual Outcomes and Cost Perspective patients at CHR-P Practice as usual plus 16 In accordance with the NICE Reference Case for economic evaluations, outcomes were valued in sessions of CBT Interventions for Hospital admission alone terms of quality-adjusted life-years (QALYs), which are the product of health-related quality of life individuals with Mix of hospital admission and quantity of life lived (ie, survival). Costs included those relevant to the National Health Service acute psychosis and CRHT and Personal Social Services. Costs were reported in 2016 to 2017 UK pounds. Both costs and QALYs First-line oral Amisulpride antipsychotic were discounted at an annual rate of 3.5%. Aripiprazole medication for FEP Haloperidol Statistical Analysis Olanzapine Placebo Model Design and Implementation Quetiapine For each intervention under assessment, the consequences of treatment were grouped into the Risperidone following 4 categories: clinical benefits (eg, preventing relapse), clinical harms (eg, adverse effects), Family intervention Antipsychotic medication costs (eg, cost of providing the intervention and treating its adverse effects), and cost savings (eg, for FEP alone reduced cost of treating relapse). Not all consequences of interventions were included; common Family intervention alone reasons for exclusion were that the treatment was not expected to affect patient outcomes and Antipsychotic medication plus 20 sessions of family there was a lack of evidence. For example, clinical harms were only modeled for antipsychotic intervention First-line oral Clozapine medications, not for psychosocial interventions because of a lack of adverse event data for antipsychotic Haloperidol nonpharmacologic interventions. The key consequences of all interventions included in the medication for TRS Olanzapine schizophrenia WDM are summarized in eAppendix 1 in the Supplement. Quetiapine A WDM with a lifetime horizon was implemented using discrete event simulation in SIMUL8 Risperidone 2019 software (Simul8 Corp). Discrete event simulation is an individual-level modeling approach in Abbreviations: CHR-P, clinical high risk of which the clinical course of individual patients through the system is determined according to their psychosis; CRHT, crisis resolution and home characteristics, previous events, and chance. The probability of events may be based on patient treatment team; CBT, cognitive behavioral history (eg, number of previous relapses) within the model and demographic characteristics (eg, age therapy; FEP, first-episode psychosis; TRS, and sex). The implemented WDM covers 16 components (Figure), grouped into the following 4 treatment-resistant schizophrenia. modules: module A, initial assessment pathway; module B, CHR pathway; module C, psychosis pathway; and module D, out-of-scope and death pathway. The overall model logic is described in detail in eAppendix 2 in the Supplement. A list of key assumptions and simplifications of the model is presented in eAppendix 3 in the Supplement. Under the traditional piecewise framework for economic evaluation, the assessment of each decision problem listed in Table 1 would only involve running 1 part of the entire WDM (eg, assessment of topic 1 would only involve running the CHR pathway). However, because the underlying rationale of using a WDM approach is that all interventions are interrelated (ie, changes made to 1 intervention might affect the others), the entire WDM was run repeatedly for each decision problems listed in Table 1. Input Data In general, health economic models require 4 types of evidence, as follows: clinical evidence (baseline event risks, treatment effects and adverse events); health-related quality of life estimates (preference-based utility values); health care resource use; and costs. Model parameters were informed by numerous evidence sources, including systematic reviews and meta-analyses, clinical trials, clinical audits, observational studies, resource use surveys, costing studies, health valuation studies, and expert opinion. Evidence was mainly obtained from the meta-analyses conducted by the 7,8 NICE schizophrenia Guideline Development Groups, supplemented with new evidence identified from rapid reviews of the literature conducted by the authors. A lack of evidence was identified for many parameters, including the long-term clinical effectiveness and adverse effects of interventions (eg, CBT, family intervention, and antipsychotic medications) and up-to-date costs of managing patients with schizophrenia in remission. When no relevant data were identified, expert opinion was JAMA Network Open. 2020;3(5):e205888. doi:10.1001/jamanetworkopen.2020.5888 (Reprinted) May 27, 2020 3/12 JAMA Network Open | Psychiatry Cost-effectiveness of Services for Schizophrenia Across the Entire Care Pathway in a Whole-Disease Model used to inform the required model parameters, with alternative plausible values tested in sensitivity analyses. A summary of the key model parameters is reported in Table 2; a complete list of all model parameters, including data sources, is reported in eAppendix 4 in the Supplement. Model Checking Extensive model verification and validation activities were undertaken, including white-box tests (scrutinizing the programming code) and black-box tests (testing the behavior of the model), checking results with stakeholders and comparing results with published literature. The details of white-box and black-box tests conducted are reported in eAppendix 5 in the Supplement. The overall model behavior was checked by 1 of us (P.T.). In addition, 7 members of a service user advisory group affiliated with the Maudsley Biomedical Research Centre, London, commented on the model structure and key assumptions. Model Evaluation Methods In accordance with the lower end of the cost-effectiveness threshold range used by NICE, interventions with an incremental cost-effectiveness ratio lower than £20 000 ($25 552) per QALY were considered cost-effective. The incremental cost-effectiveness ratio was defined as the difference in the expected cost of 2 interventions, divided by the difference in the expected effects of the 2 interventions. Extensive sensitivity analyses were undertaken to test the robustness of the results of the base case analyses to different sets of assumptions and using different input data, including 1-way and multiway sensitivity analysis to assess the consequences of uncertainty regarding the value of a single or multiple parameter(s); structural sensitivity analysis to assess the consequences of uncertainty regarding the structural assumptions of the model (eg, whether CBT can prevent psychosis or just delay the transition to psychosis); and probabilistic sensitivity analyses that examine the consequences of joint uncertainty of multiple parameters simultaneously. Figure. Model Structure Module A: Module B: CHR pathway Module C: Psychosis Specialist pathway assessment pathway 1. Model entry Receive Acute FEP 4. CHR wait for 10. Manage 5. CHR on CBT CBT CBT acute psychosis CHR FEP 2. Assessment Receive monitoring only 6. CHR under 8. CHR recover 12. Nonacute monitoring Stable FEP 15. Diagnosis Accept AP psychosis on AP receive treatment 11. FEP wait for Do not receive CBT treatment or monitoring 7. CHR not under 9. CHR convert Not at risk monitoring Accept FI only 13. Psychosis on FI Stable FEP; do not receive treatment 14. Psychosis stop treatment 3. Out of scope Die Die 16. Death Module D: out of scope and death pathway Abbreviations: AP, antipsychotic medication; CBT, cognitive behavioral therapy; CHR, clinical high risk of psychosis; FEP, first-episode psychosis; and FI, family intervention. JAMA Network Open. 2020;3(5):e205888. doi:10.1001/jamanetworkopen.2020.5888 (Reprinted) May 27, 2020 4/12 JAMA Network Open | Psychiatry Cost-effectiveness of Services for Schizophrenia Across the Entire Care Pathway in a Whole-Disease Model Table 2. Summary of Key Parameters Used in the Schizophrenia Whole-Disease Model Parameter Baseline value Distribution Epidemiologic data, % Age, mean, y 23.52 Normal (SE, 2.85) Men 60.40 Beta (α = 665.61; β = 436.39) Starting disease status Not at risk of psychosis 33.21 Dirichlet (n = 276, N = 831) At CHR-P 34.90 Dirichlet (n = 290; N = 831) FEP 31.89 Dirichlet (n = 265; N = 831) Service provision data, % CBT Provision 41.01 Beta (α = 1011; β = 1454) Take up 51.00 Beta (α = 510; β = 490) Family intervention Provision 30.98 Beta (α = 589; β = 1312) Take up 38.49 Beta (α = 224; β = 358) Antipsychotic Provision 100.00 Assumed fixed Take up for patients with FEP 97.38 Beta (α = 484; β = 13) Delay in initiation of clozapine, y 3.98 Gamma (α = 137.25; β = 0.023) Clinical effectiveness data: nonpharmacologic interventions, RR Transition to psychosis for CBT vs practice as usual 0.41 Log normal (ln[SE], 0.29) Relapse for family intervention vs standard care 0.63 Log normal (ln[SE], 0.16) or other control Clinical effectiveness data: antipsychotic medication for individuals with FEP, OR Annual probability of all-cause discontinuation 0.82 Beta (α = 4949.54; β = 1079.87) for patients on placebo Amisulpride vs placebo 0.18 Log normal (ln[SE], 0.49) Aripiprazole vs placebo 0.24 Log normal (ln[SE], 0.51) Haloperidol vs placebo 0.21 Log normal (ln[SE], 0.34) Olanzapine vs placebo 0.11 Log normal (ln[SE], 0.31) Quetiapine vs placebo 0.21 Log normal (ln[SE], 0.32) Risperidone vs placebo 0.15 Log normal (ln[SE], 0.40) Haloperidol LAI vs placebo 0.15 Log normal (ln[SE], 0.45) Paliperidone LAI vs placebo 0.19 Log normal (ln[SE], 0.53) Clinical effectiveness data: antipsychotics for individuals with TRS, OR Annual probability of discontinuing clozapine because 0.02 Beta (α = 4.98; β = 310.02) of inefficacy Haloperidol vs clozapine 5.56 Log normal (ln[SE], 0.35) Olanzapine vs clozapine 1.37 Log normal (ln[SE], 0.34) Quetiapine vs clozapine 4.35 Log normal (ln[SE], 0.69) Risperidone vs clozapine 2.27 Log normal (ln[SE], 0.40) Health-related quality of life data Individuals At CHR-P 0.71 Beta (α = 100.22; β = 40.78) With psychosis in remission 0.80 Normal (SE, 0.04) With psychosis in relapse 0.67 Normal (SE, 0.06) Disutility Weight gain 0.03 Normal (SE, 0.01) EPS 0.07 Normal (SE, 0.01) Diabetes 0.09 Normal (SE, 0.05) (continued) JAMA Network Open. 2020;3(5):e205888. doi:10.1001/jamanetworkopen.2020.5888 (Reprinted) May 27, 2020 5/12 JAMA Network Open | Psychiatry Cost-effectiveness of Services for Schizophrenia Across the Entire Care Pathway in a Whole-Disease Model Table 2. Summary of Key Parameters Used in the Schizophrenia Whole-Disease Model (continued) Parameter Baseline value Distribution Cost data, £ CBT Cost per session 97.00 Gamma (α = 44.44; β = 2.18) Sessions, No. 16 Assumed fixed Family intervention Cost per session 112.00 Gamma (α = 44.44; β = 2.52) Sessions, No. 20 Assumed fixed Oral antipsychotic, per d Amisulpride 0.47 Gamma (α = 22.68; β = 0.02) Aripiprazole 4.08 Gamma (α = 23.80; β = 0.17) Haloperidol 0.37 Gamma (α = 30.86; β = 0.01) Olanzapine 0.13 Gamma (α = 13.72; β = 0.01) Quetiapine 1.24 Gamma (α = 6.25; β = 0.20) Risperidone 0.36 Gamma (α = 5.41; β = 0.07) Clozapine 1.56 Gamma (α = 156.25; β = 0.01) LAI antipsychotic Haloperidol, 28 d 6.56 Gamma (α = 13.72; β = 0.48) Paliperidone, 30 d 334.45 Gamma (α = 82.64; β = 4.05) Attendance at clozapine clinic 16.40 Gamma (α = 44.44; β = 0.37) Managing patients with nonrelapsed schizophrenia, per y 14 983.45 Gamma (α = 2.04; β = 7341.89) Assessing an acute episode of psychosis 507.00 Gamma (α = 348.55; β = 1.45) CRHT team, per contact 197.45 Gamma (α = 44.44; β = 4.44) Contacts with CRHT team, mean, No. 16.3 Gamma (α = 78.32; β = 0.21) Abbreviations: CBT, cognitive behavioral therapy; Hospital bed-day 379.00 Gamma (α = 44.44; β = 8.52) CHR-P, clinical high risk of psychosis; CRHT, crisis Bed-days during 1 relapse, mean, No. 138.90 Weibull (α = 0.65; β = 0.61) resolution and home treatment team; EPS, Cost of adverse events extrapyramidal symptoms; FEP, first-episode Weight gain psychosis; LAI, long-acting injectable; ln, natural log; OR, odds ratio; RR, relative risk; TRS, treatment- Year 1 97.20 Gamma (α = 44.44; β = 2.19) resistant schizophrenia. Year 2 onwards 309.68 Gamma (α = 3.77; β = 6755.56) A complete list of all parameters used in the model Acute EPS, per episode 51.95 Gamma (α = 44.44; β = 1.17) and their data sources are reported in eAppendix 3 in Diabetes, per y 1336.31 Gamma (α = 124 044.44; β = 0.01) the Supplement. Neutropenia, per episode 469.48 Gamma (α = 92 802.96; β = 0.01) To convert to US dollars, multiply by 1.2776. Following published guidance, a cohort of 200 000 patients was adopted for deterministic analyses and 1000 samples were used for probabilistic sensitivity analysis. The stability of results was tested to different numbers of patients and probabilistic sensitivity analysis runs. No prespecified level of statistical significance was set. Results The base case and probabilistic sensitivity analysis results are presented in Table 3 and summarized in this section. The simulated cohort had a mean (SD) age of 23.5 (5.1) years, with 120 800 (60.4%) men, 66 400 (33.2%) not at risk of psychosis, 69 800 (34.9%) at CHR-P, and 63 800 (31.9%) with psychosis. Interventions for Patients at CHR-P The base case analysis suggests that practice as usual plus CBT dominates practice as usual alone. The cost savings of CBT are substantial (£1243 [$1588] per person), likely because the evidence used to inform the WDM suggests that CBT can delay the transition from CHR-P to psychosis, and the JAMA Network Open. 2020;3(5):e205888. doi:10.1001/jamanetworkopen.2020.5888 (Reprinted) May 27, 2020 6/12 JAMA Network Open | Psychiatry Cost-effectiveness of Services for Schizophrenia Across the Entire Care Pathway in a Whole-Disease Model treatment cost for individuals with psychosis or schizophrenia is much higher than the treatment cost −5 for individuals at CHR-P. On the other hand, the QALY gains of CBT are marginal (5.19 × 10 per person), likely because evidence used in the WDM suggests that the utility for individuals at CHR-P is similar to individuals with psychosis. Assuming a willingness-to-pay (WTP) threshold of £20 000 ($25 552) per QALY gained, the probability that practice as usual plus CBT is cost-effective compared to practice as usual alone was estimated to be 0.96. Interventions for Individuals With Acute Psychosis The base case analysis suggests that a mix of CRHT and hospital admission produces the same QALY gains and additional cost savings (£3655 [$4670] per person) than hospital admission alone. This is because the evidence used to inform the WDM suggests equivalent effectiveness between hospital admission and CRHT, and the cost of hospital admission is much higher than the cost of CRHT services. Assuming a WTP threshold of £20 000 ($25 552) per QALY gained, the probability that a mix of CRHT and hospital admission is cost-effective compared with hospital admission alone was estimated to be 0.99. Table 3. Deterministic and Probabilistic Results of Cost-effectiveness Analysis Deterministic results PSA results, per QALY Discounted mean Incremental b b b b Intervention Cost per person, £ QALYs per person Cost, £ QALY ICER WTP, £20 000 WTP, £30 000 Interventions for patients at CHR-P PAU plus CBT 167 452 19.1904 −1243 0.0000 Dominating 0.95 0.95 PAU alone 168 695 19.1904 NA NA Dominated 0.05 0.05 Interventions for individuals with acute psychosis Mix of hospital admission 168 078 19.1904 −3655 0.000 Dominating 1.00 1.00 and CRHT Hospital admission alone 171 733 19.1904 NA NA Dominated 0.00 0.00 First-line oral antipsychotic medication for FEP Quetiapine 168 539 19.2005 1670 0.0071 235 211 0.06 0.06 Haloperidol 168 538 19.1981 NA NA Extendedly dominated 0.06 0.06 Aripiprazole 171 340 19.1977 NA NA Dominated 0.01 0.02 Risperidone 166 869 19.1934 1056 0.0112 94 286 0.30 0.30 Placebo 174 128 19.1931 NA NA Dominated 0.00 0.00 Amisulpride 165 813 19.1822 NA NA NA 0.39 0.39 Olanzapine 167 455 19.1794 NA NA Dominated 0.17 0.17 Family intervention for FEP Antipsychotic medication plus 167 905 19.2033 NA NA Dominating 0.58 0.62 family intervention Family intervention alone 175 065 19.1987 NA NA Dominated 0.09 0.10 Antipsychotic medication alone 168 261 19.1849 NA NA Dominated 0.33 0.28 First-line oral antipsychotic medication for TRS Clozapine 162 215 19.1977 NA NA Dominating 0.81 0.81 Olanzapine 165 444 19.1925 NA NA Dominated 0.16 0.16 Risperidone 169 324 19.1889 NA NA Dominated 0.03 0.03 Haloperidol 170 008 19.1883 NA NA Dominated 0.00 0.01 Quetiapine 172 043 19.1867 NA NA Dominated 0.00 0.00 Abbreviations: CBT, cognitive behavioral therapy; CHR-P, clinical high risk of psychosis; Probability for the intervention to be most cost-effective within each topic. CRHT, crisis resolution and home treatment team; FEP, first-episode psychosis; ICER, b To convert to US dollars, multiply by 1.2776. incremental cost-effectiveness ratio; NA, not applicable; PAU, practice as usual; PSA, probabilistic sensitivity analysis; QALY, quality-adjusted life-year; TRS, treatment- resistant schizophrenia; WTP, willingness to pay. JAMA Network Open. 2020;3(5):e205888. doi:10.1001/jamanetworkopen.2020.5888 (Reprinted) May 27, 2020 7/12 JAMA Network Open | Psychiatry Cost-effectiveness of Services for Schizophrenia Across the Entire Care Pathway in a Whole-Disease Model First-Line Oral Antipsychotic Medication for Individuals With FEP The base case analysis suggests that, of the 7 interventions assessed, amisulpride was the most cost- effective option, followed by risperidone and olanzapine. This is because the evidence used to inform the WDM suggests that these antipsychotic medications are associated with the lowest probability of all-cause drug discontinuation. Assuming a WTP threshold of £20 000 ($25 552) per QALY gained, amisulpride is most likely to be cost-effective (0.39), followed by risperidone (0.30) and olanzapine (0.17). The probability of any antipsychotic medication being the most cost-effective option was less than 0.05. Family Intervention for Individuals With FEP The base case analysis suggests that antipsychotic medication plus family intervention dominates both antipsychotic alone and family intervention alone. This is because the evidence used to inform the WDM suggests that family intervention can prevent relapse of psychosis, and the cost of treating relapse is much higher than the cost of family intervention. Assuming a WTP threshold of £20 000 ($25 552) per QALY gained, the probability that antipsychotic medication plus family intervention is the most cost-effective option compared with medication or family intervention alone was estimated to be 0.58. First-Line Oral Antipsychotic Medications for Individuals With TRS The base case analysis suggests that clozapine dominates all other antipsychotic medications. This is because the evidence used in the WDM suggests that, of the 5 antipsychotics assessed for individuals with TRS, clozapine was associated with the lowest all-cause discontinuation rate (including discontinuation due to inefficacy, intolerability, and nonadherence) and was less likely to cause acute extrapyramidal symptoms. Assuming a WTP threshold of £20 000 ($25 552) per QALY gained, the probability that clozapine is the most cost-effective option compared with other medications was estimated to be 0.81. Summary of Base Case Results Assuming a WTP pay threshold of £20 000 ($25 552) per QALY, the most cost-effective interventions were practice as usual plus 16 sessions of CBT for individuals with CHR-P. A mix of CRHT and hospital admission was most cost-effective for individuals with acute psychosis; amisulpride, risperidone, or olanzapine combined with 20 sessions of family intervention was most cost-effective for individuals with FEP; and clozapine was most cost-effective for individuals with TRS. Sensitivity Analyses The results of the sensitivity analyses are summarized in eAppendix 6 in the Supplement. They suggest that the conclusions for interventions for patients at CHR-P, for individuals with acute psychosis, and for first-line oral antipsychotic medication for those with FEP and TRS were robust to all types of sensitivity analyses conducted. The conclusion for family intervention for individuals with FEP was robust to all types of sensitivity analyses except the following: changes in the choice of first-line antipsychotic; effectiveness of family intervention in preventing relapse; and number of family intervention sessions provided. Antipsychotic medication alone was the most cost-effective intervention when amisulpride was used as the first-line antipsychotic medications for individuals with FEP; when the relative risk of family intervention in preventing relapse was increased from 0.63 to 0.83; or when a brief (ie, number of sessions and effectiveness halved) version of family intervention was assumed. JAMA Network Open. 2020;3(5):e205888. doi:10.1001/jamanetworkopen.2020.5888 (Reprinted) May 27, 2020 8/12 JAMA Network Open | Psychiatry Cost-effectiveness of Services for Schizophrenia Across the Entire Care Pathway in a Whole-Disease Model Discussion Comparing Results With Published Literature Comparison of our results with published literature by individual topic is detailed in eAppendix 7 in the Supplement and summarized in this section. Our findings regarding interventions for patients at CHR-P and with acute psychosis and for first-line oral antipsychotic medication for individuals with 12-19 FEP and with TRS are consistent with published literature. For first-line oral antipsychotic medication for individuals with FEP, both the schizophrenia WDM and the model developed by the NICE schizophrenia Guideline Development Group found that no antipsychotic medication can be considered clearly more cost-effective than the other options. However, the schizophrenia WDM found amisulpride to be the most cost-effective option, while the NICE model suggests amisulpride was the least cost-effective option. This is likely because of differences in the input data used. The systematic review conducted by the NICE schizophrenia Guideline Development Group in 2008 found amisulpride to be associated with the second highest probability of relapse (second only to 20,21 haloperidol), while the latest systematic reviews, which included additional trials, showed amisulpride to be associated with among the lowest probabilities of all-cause discontinuation and relapse rate. Implications for Clinical Practice The results of our analyses suggest that adoption of the following interventions could result in cost savings compared with the current service: practice as usual plus 16 sessions of CBT for individuals at CHR-P; a mix of hospital admission and CRHT for individuals with acute psychosis; antipsychotic medication (amisulpride, risperidone, or olanzapine) combined with 20 sessions of family intervention for individuals with FEP; and clozapine for individuals with TRS. Adoption of clozapine for individuals with TRS also resulted in additional QALYs. The results suggest that a brief family intervention (ie, 10 sessions) would not be cost-effective for individuals with FEP. Strengths and Limitations There are 3 key strengths of this study. First, it fills the evidence gap by presenting the first model- based economic analysis of the following interventions: CBT for individuals with CHR-P, CRHT for individuals with acute psychosis, family intervention for individuals with FEP, and clozapine and other atypical antipsychotics for individuals with TRS. There has been an increased interest in investment in brief family intervention because of resource constraints. However, our study showed that while a 20-session family intervention was cost-effective for individuals with FEP, a 10-session family intervention was not. This finding might change the current practice of providing family interventions. Second, this study provides an up-to-date assessment of antipsychotic medication for 20,21 individuals with FEP based on the results of the latest network meta-analyses and modeled the cost and health consequences of 5 adverse effects of antipsychotics, including extrapyramidal symptoms, weight gain, glucose intolerance, diabetes, and neutropenia. Our analysis found amisulpride to be among the most cost-effective antipsychotics because of its therapeutic superiority in preventing relapse. Considering the current market share of amisulpride in the UK (ie, 1.39%), our findings may change the current clinical practice of prescribing antipsychotics. Third, all results presented within this study were based on a well-documented WDM, which is populated with input data carefully selected from high-quality literature. Extensive validation activities were undertaken to ensure the quality of the schizophrenia WDM. To our knowledge, this is the first WDM developed for the economic evaluation of a mental health disorder. This study also has limitations. There are 2 major limitations of the schizophrenia WDM developed within this study. First, owing to resource constraints, input data for the WDM were 7,8 obtained from published systematic reviews reported in the NICE schizophrenia guidelines, supplemented with new evidence identified from rapid reviews, rather than by undertaking our own de novo systematic reviews. As such, it is possible that newer high-quality evidence has not been JAMA Network Open. 2020;3(5):e205888. doi:10.1001/jamanetworkopen.2020.5888 (Reprinted) May 27, 2020 9/12 JAMA Network Open | Psychiatry Cost-effectiveness of Services for Schizophrenia Across the Entire Care Pathway in a Whole-Disease Model included in the model. Second, as with any health economic model, the credibility of the schizophrenia WDM and its results are largely dependent on the quantity and quality of the evidence used to inform it. While searching for input data for the WDM, a lack of evidence was identified for many parameters, such as long-term clinical effectiveness and adverse effects of interventions (eg, CBT, family intervention, and antipsychotics) and up-to-date costs of managing patients with schizophrenia in remission. Even when evidence was available, it often had certain limitations, such as variation in criteria for relapse, relatively short follow-up periods, unclear masking, incomplete outcome data, and selective reporting. However, the model was designed to be adapted and reused, and thus, results can be updated as new or better-quality evidence is identified. Conclusions The results of this study suggested that the following interventions are likely to be cost-effective: CBT for individuals at CHR-P; a mix of hospital admission and CRHT for individuals with acute psychosis; amisulpride, risperidone, or olanzapine combined with family intervention for individuals with FEP; and clozapine for individuals with TRS. Cost savings and additional quality-adjusted life- years may be gained by replacing current interventions with more cost-effective interventions. ARTICLE INFORMATION Accepted for Publication: March 21, 2020. Published: May 27, 2020. doi:10.1001/jamanetworkopen.2020.5888 Open Access: This is an open access article distributed under the terms of the CC-BY License.©2020JinHetal. JAMA Network Open. Corresponding Author: Huajie Jin, PhD, King’s Health Economics, Institute of Psychiatry, Psychology, and Neuroscience at King’s College London, Box 024, The David Goldberg Centre, De Crespigny Park, Denmark Hill, London SE5 8AF, United Kingdom (huajie.jin@kcl.ac.uk). Author Affiliations: King’s Health Economics, Institute of Psychiatry, Psychology, and Neuroscience, King’s College London, London, United Kingdom (Jin, Byford); Health Economics and Decision Science, University of Sheffield School of Health and Related Research, Sheffield, United Kingdom (Tappenden); Department of Psychosis Studies, Institute of Psychiatry, Psychology, and Neuroscience, King’s College London, London, United Kingdom (MacCabe); Loughborough University School of Business and Economics, Loughborough, United Kingdom (Robinson). Author Contributions: Dr Jin had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Concept and design: All authors. Acquisition, analysis, or interpretation of data: All authors. Drafting of the manuscript: Jin, Tappenden. Critical revision of the manuscript for important intellectual content: All authors. Statistical analysis: Jin, Tappenden, Robinson. Obtained funding: MacCabe. Administrative, technical, or material support: All authors. Supervision: Tappenden, MacCabe, Robinson, Byford. Conflict of Interest Disclosures: Dr MacCabe reported receiving grants from the Medical Research Council during the conduct of the study and grants and nonfinancial support from Lundbeck outside the submitted work. No other disclosures were reported. Additional Contributions: The authors thank those stakeholders who kindly volunteered their time to input into the model and who remain anonymous. Paul McCrone, PhD (Faculty of Education, Health and Human Sciences, University of Greenwich), provided valued advice on the development and validation of the whole-disease model. None of these individuals were compensated for their time. JAMA Network Open. 2020;3(5):e205888. doi:10.1001/jamanetworkopen.2020.5888 (Reprinted) May 27, 2020 10/12 JAMA Network Open | Psychiatry Cost-effectiveness of Services for Schizophrenia Across the Entire Care Pathway in a Whole-Disease Model REFERENCE 1. National Institute for Health and Care Excellence. Guide to the Methods of Technology Appraisal. National Institute for Health and Care Excellence; 2013. 2. Jin H, Tappenden P, Robinson S, et al. A systematic review of economic models across the entire schizophrenia pathway. Pharmacoeconomics. 2020. doi:10.1007/s40273-020-00895-6 3. Tappenden P, Chilcott J, Brennan A, Squires H, Stevenson M. Whole disease modeling to inform resource allocation decisions in cancer: a methodological framework. Value Health. 2012;15(8):1127-1136. doi:10.1016/j.jval. 2012.07.008 4. Jin H. Using Whole Disease Modelling to Inform Resource Allocation Decisions in Schizophrenia Services. Thesis. King’s College London; 2019. 5. Husereau D, Drummond M, Petrou S, et al. Consolidated Health Economic Evaluation Reporting Standards (CHEERS) statement. Pharmacoeconomics. 2013;31(5):361-367. doi:10.1007/s40273-013-0032-y 6. Fusar-Poli P, Byrne M, Badger S, Valmaggia LR, McGuire PK. Outreach and support in south London (OASIS), 2001-2011: ten years of early diagnosis and treatment for young individuals at high clinical risk for psychosis. Eur Psychiatry. 2013;28(5):315-326. doi:10.1016/j.eurpsy.2012.08.002 7. National Institute of Health and Care Excellence. Psychosis and schizophrenia in adults: prevention and management. Updated March 1, 2014. Accessed April 29, 2020. https://www.nice.org.uk/guidance/cg178 8. National Institute of Health and Care Excellence. Psychosis and schizophrenia in children and young people: recognition and management. Updated October 26, 2016. Accessed April 29, 2020. https://www.nice.org.uk/ guidance/cg155 9. Pidd M. Computer Simulation in Management Science. 5th ed. John Wiley and Sons, Inc; 2006. 10. Davis S, Stevenson M, Tappenden P, Wailoo AJ. NICE DSU Technical Support Document 15: cost-effectiveness modelling using patient-level simulation. Published April 2014. Accessed September 9, 2018. http://nicedsu.org. uk/wp-content/uploads/2016/03/TSD15_Patient-level_simulation.pdf 11. Murphy SM, Irving CB, Adams CE, Waqar M. Crisis intervention for people with severe mental illnesses. Cochrane Database Syst Rev. 2015;(12):CD001087. doi:10.1002/14651858.CD001087.pub5 12. Ising HK, Lokkerbol J, Rietdijk J, et al. Four-year cost-effectiveness of cognitive behavior therapy for preventing first-episode psychosis: the Dutch Early Detection Intervention Evaluation (EDIE-NL) Trial. Schizophr Bull. 2017;43 (2):365-374. 13. McCrone P, Johnson S, Nolan F, et al. Economic evaluation of a crisis resolution service: a randomised controlled trial. Epidemiol Psichiatr Soc. 2009;18(1):54-58. doi:10.1017/S1121189X00001469 14. Gutierrez-Recacha P, Chisholm D, Haro JM, Salvador-Carulla L, Ayuso-Mateos JL. Cost-effectiveness of different clinical interventions for reducing the burden of schizophrenia in Spain. Acta Psychiatr Scand Suppl. 2006;432(432):29-38. doi:10.1111/j.1600-0447.2006.00917.x 15. Phanthunane P, Vos T, Whiteford H, Bertram M. Cost-effectiveness of pharmacological and psychosocial interventions for schizophrenia. Cost Eff Resour Alloc. 2011;9(6):6. doi:10.1186/1478-7547-9-6 16. Anh NQ, Linh BN, Ha NT, Phanthunane P, Huong NT. Schizophrenia interventions in Vietnam: primary results from a cost-effectiveness study. Glob Public Health. 2015;10(Supppl 1):S21-S39. doi:10.1080/17441692.2014. 17. Davies LM, Drummond MF. Assessment of costs and benefits of drug therapy for treatment-resistant schizophrenia in the United Kingdom. Br J Psychiatry. 1993;162:38-42. doi:10.1192/bjp.162.1.38 18. Glennie J. Pharmacoeconomic evaluations of clozapine in treatment-resistant schizophrenia and risperidone in chronic schizophrenia. Updated January 1, 1997. Accessed April 29, 2020. https://www.cadth.ca/ pharmacoeconomic-evaluations-clozapine-treatment-resistant-schizophrenia-and-risperidone-chronic-0 19. Oh PI, Iskedjian M, Addis A, Lanctôt K, Einarson TR. Pharmacoeconomic evaluation of clozapine in treatment- resistant schizophrenia: a cost-utility analysis. Can J Clin Pharmacol. 2001;8(4):199-206. 20. Zhao YJ, Lin L, Teng M, et al. Long-term antipsychotic treatment in schizophrenia: systematic review and network meta-analysis of randomised controlled trials. BJPsych Open. 2016;2(1):59-66. doi:10.1192/bjpo.bp.115. 21. Leucht S, Cipriani A, Spineli L, et al. Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis. Lancet. 2013;382(9896):951-962. doi:10.1016/S0140-6736 (13)60733-3 22. Okpokoro U, Adams CE, Sampson S. Family intervention (brief) for schizophrenia. Cochrane Database Syst Rev. 2014(3):CD009802. doi:10.1002/14651858.CD009802.pub2 JAMA Network Open. 2020;3(5):e205888. doi:10.1001/jamanetworkopen.2020.5888 (Reprinted) May 27, 2020 11/12 JAMA Network Open | Psychiatry Cost-effectiveness of Services for Schizophrenia Across the Entire Care Pathway in a Whole-Disease Model 23. NHS Digital. Prescription Cost Analysis: England, 2016. Published March 30, 2017. Accessed March 3, 2016. https://digital.nhs.uk/data-and-information/publications/statistical/prescription-cost-analysis/ prescription-cost-analysis-england-2016 SUPPLEMENT. eAppendix 1. Key Consequences of Interventions Considered in the Model eAppendix 2. Description of the Design-Oriented Model eAppendix 3. List of Assumptions and Simplifications of the Model eAppendix 4. Summary of Key Input Data eAppendix 5. White-Box and Black-Box Tests Conducted eAppendix 6. Results of Sensitivity Analysis eAppendix 7. Comparing Results With Published Literature eReferences. JAMA Network Open. 2020;3(5):e205888. doi:10.1001/jamanetworkopen.2020.5888 (Reprinted) May 27, 2020 12/12 Z P Z P P Z P Z P Z P Z P Z P Z P P P Z P Z P Z P Z P Z P Z P Z P Z P Z P Z P Z P Z P Z P Z P Z P Z P Z P Z Z P Z P P Z P P Z Z P P P P P P P P P Z P Z P Z P Z P Z P Z Z P Z P Z P P S Z P Z P http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png JAMA Network Open American Medical Association

Evaluation of the Cost-effectiveness of Services for Schizophrenia in the UK Across the Entire Care Pathway in a Single Whole-Disease Model

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Copyright 2020 Jin H et al. JAMA Network Open.
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Abstract

Key Points Question Which interventions are cost- IMPORTANCE The existing economic models for schizophrenia often have 3 limitations; namely, effective for the prevention and they do not cover nonpharmacologic interventions, they report inconsistent conclusions for treatment of schizophrenia? antipsychotics, and they have poor methodologic quality. Findings In this decision analytical model using a simulated cohort of OBJECTIVES To develop a whole-disease model for schizophrenia and use it to inform resource 200 000 individuals, the following allocation decisions across the entire care pathway for schizophrenia in the UK. interventions were found to be cost-effective: practice as usual plus DESIGN, SETTING, AND PARTICIPANTS This decision analytical model used a whole-disease model cognitive behavioral therapy for to simulate the entire disease and treatment pathway among a simulated cohort of 200 000 individuals at clinical high risk of individuals at clinical high risk of psychoses or with a diagnosis of psychosis or schizophrenia being psychosis; a mix of hospital admission treated in primary, secondary, and tertiary care in the UK. Data were collected March 2016 to and crisis resolution and home December 2018 and analyzed December 2018 to April 2019. treatment team for individuals with acute psychosis; receipt of amisulpride, EXPOSURES The whole-disease model used discrete event simulation; its structure and input data risperidone, or olanzapine combined were informed by published literature and expert opinion. Analyses were conducted from the with family intervention for individuals perspective of the National Health Service and Personal Social Services over a lifetime horizon. Key with first-episode psychosis; and receipt interventions assessed included cognitive behavioral therapy, antipsychotic medication, family of clozapine for individuals with intervention, inpatient care, and crisis resolution and home treatment team. treatment-resistant schizophrenia. MAIN OUTCOMES AND MEASURES Life-time costs and quality-adjusted life-years. Meaning The results of this study suggest that cost savings and/or RESULTS In the simulated cohort of 200 000 individuals (mean [SD] age, 23.5 [5.1] years; 120 800 additional quality-adjusted life years [60.4%] men), 66 400 (33.2%) were not at risk of psychosis, 69 800 (34.9%) were at clinical high may be gained by replacing current risk of psychosis, and 63 800 (31.9%) had psychosis. The results of the whole-disease model suggest interventions with more cost-effective the following interventions are likely to be cost-effective at a willingness-to-pay threshold of interventions. £20 000 ($25 552) per quality-adjusted life-year: practice as usual plus cognitive behavioral therapy for individuals at clinical high risk of psychosis (probability vs practice as usual alone, 0.96); a mix of Supplemental content hospital admission and crisis resolution and home treatment team for individuals with acute psychosis (probability vs hospital admission alone, 0.99); amisulpride (probability vs all other Author affiliations and article information are listed at the end of this article. antipsychotics, 0.39), risperidone (probability vs all other antipsychotics, 0.30), or olanzapine (probability vs all other antipsychotics, 0.17) combined with family intervention for individuals with first-episode psychosis (probability vs family intervention or medication alone, 0.58); and clozapine for individuals with treatment-resistant schizophrenia (probability vs other medications, 0.81). CONCLUSIONS AND RELEVANCE The results of this study suggest that the current schizophrenia service configuration is not optimal. Cost savings and/or additional quality-adjusted life-years may be gained by replacing current interventions with more cost-effective interventions. JAMA Network Open. 2020;3(5):e205888. doi:10.1001/jamanetworkopen.2020.5888 Open Access. This is an open access article distributed under the terms of the CC-BY License. JAMA Network Open. 2020;3(5):e205888. doi:10.1001/jamanetworkopen.2020.5888 (Reprinted) May 27, 2020 1/12 JAMA Network Open | Psychiatry Cost-effectiveness of Services for Schizophrenia Across the Entire Care Pathway in a Whole-Disease Model Introduction Economic models have increasingly been used to inform decision-making regarding health care, as they provide an explicit way of synthesizing all available data to simulate the likely costs and consequences of using alternative interventions under scenarios that cannot be directly observed in the real world. A 2020 systematic review found several limitations of existing economic models for schizophrenia. Most existing models (83%) focused on antipsychotic medications, while there was a lack of models for nonpharmacologic interventions, such as cognitive behavioral therapy (CBT), family intervention, and crisis resolution and home treatment team (CRHT). Second, no antipsychotic medication was shown to be clearly cost-effective compared with the others because of inconsistent or even contradictory conclusions reported by different studies. Third, the quality of existing models was considered low. This systematic review highlighted issues relating to inconsistent assumptions and uses of evidence, which negatively affect the quality of existing economic studies in schizophrenia. Greater consistency could be achieved through the development of generic models that have been agreed on by key stakeholders. A whole-disease model (WDM) represents a type of generic model that is unique in that it can be used to inform multiple resource allocation decisions across the entire care pathway. Whole-disease models are large-scale models that involve simulating whole disease and treatment pathways, thereby allowing for the economic evaluation of options for the prevention, early identification, diagnosis, treatment, and follow-up of a given disease using a single consistent model. This type of system-level modeling approach has been successfully applied to a number of disease areas, including cancer, metabolic diseases, and cardiovascular diseases. However, such an approach has not been applied to any mental health disorders. The aim of this study was to develop a WDM for schizophrenia services and use it to assess the cost-effectiveness of a range of interventions in the UK. Methods This study was reported according to the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) reporting guideline for reporting health economic evaluations. Per the Common Rule, ethical approval and informed patient consent were not required given that this is a modeling study with no direct patient contact or influence on patient care directly related to this work. The methods for developing the schizophrenia WDM were mainly informed by the methodologic framework set out by Tappenden et al. To help with the development and validation of the WDM, a group of 13 multidisciplinary stakeholders was convened though snowball sampling. The background of the 13 stakeholders included health care professionals practicing in the National Health Service (9 [69.2%]), academic researchers with expertise in mental health economic evaluation (12 [92.3%]), commissioners of mental health services (5 [38.5%]), and service users (2 [15.4%]). Population The target population for the model was individuals referred to secondary care mental health services in the UK because of psychotic symptoms, with a mean (SD) age of 23.5 (5.1) years and a sex ratio of 1.5:1 (men to women). Of those referred, 33.2% were not at risk of psychosis, 34.9% were at clinical high risk of psychosis (CHR-P), and 31.9% were individuals with psychosis. Those not at risk of psychosis were included because they also use resources associated with schizophrenia services (eg, specialist assessments). Decision Problems The decision problems to be addressed by the WDM were identified from the scope of the schizophrenia clinical guidelines developed by the National Institute for Health and Care Excellence JAMA Network Open. 2020;3(5):e205888. doi:10.1001/jamanetworkopen.2020.5888 (Reprinted) May 27, 2020 2/12 JAMA Network Open | Psychiatry Cost-effectiveness of Services for Schizophrenia Across the Entire Care Pathway in a Whole-Disease Model 7,8 (NICE). A total of 5 topics were identified (Table 1), which span most of the breadth of the Table 1. Decision Problems Addressed Using schizophrenia pathway, ranging from the use of CBT for individuals at CHR-P to antipsychotic the Schizophrenia Whole-Disease Model medication for individuals with treatment-resistant schizophrenia (TRS). Interventions and Topic comparators Interventions for Practice as usual Outcomes and Cost Perspective patients at CHR-P Practice as usual plus 16 In accordance with the NICE Reference Case for economic evaluations, outcomes were valued in sessions of CBT Interventions for Hospital admission alone terms of quality-adjusted life-years (QALYs), which are the product of health-related quality of life individuals with Mix of hospital admission and quantity of life lived (ie, survival). Costs included those relevant to the National Health Service acute psychosis and CRHT and Personal Social Services. Costs were reported in 2016 to 2017 UK pounds. Both costs and QALYs First-line oral Amisulpride antipsychotic were discounted at an annual rate of 3.5%. Aripiprazole medication for FEP Haloperidol Statistical Analysis Olanzapine Placebo Model Design and Implementation Quetiapine For each intervention under assessment, the consequences of treatment were grouped into the Risperidone following 4 categories: clinical benefits (eg, preventing relapse), clinical harms (eg, adverse effects), Family intervention Antipsychotic medication costs (eg, cost of providing the intervention and treating its adverse effects), and cost savings (eg, for FEP alone reduced cost of treating relapse). Not all consequences of interventions were included; common Family intervention alone reasons for exclusion were that the treatment was not expected to affect patient outcomes and Antipsychotic medication plus 20 sessions of family there was a lack of evidence. For example, clinical harms were only modeled for antipsychotic intervention First-line oral Clozapine medications, not for psychosocial interventions because of a lack of adverse event data for antipsychotic Haloperidol nonpharmacologic interventions. The key consequences of all interventions included in the medication for TRS Olanzapine schizophrenia WDM are summarized in eAppendix 1 in the Supplement. Quetiapine A WDM with a lifetime horizon was implemented using discrete event simulation in SIMUL8 Risperidone 2019 software (Simul8 Corp). Discrete event simulation is an individual-level modeling approach in Abbreviations: CHR-P, clinical high risk of which the clinical course of individual patients through the system is determined according to their psychosis; CRHT, crisis resolution and home characteristics, previous events, and chance. The probability of events may be based on patient treatment team; CBT, cognitive behavioral history (eg, number of previous relapses) within the model and demographic characteristics (eg, age therapy; FEP, first-episode psychosis; TRS, and sex). The implemented WDM covers 16 components (Figure), grouped into the following 4 treatment-resistant schizophrenia. modules: module A, initial assessment pathway; module B, CHR pathway; module C, psychosis pathway; and module D, out-of-scope and death pathway. The overall model logic is described in detail in eAppendix 2 in the Supplement. A list of key assumptions and simplifications of the model is presented in eAppendix 3 in the Supplement. Under the traditional piecewise framework for economic evaluation, the assessment of each decision problem listed in Table 1 would only involve running 1 part of the entire WDM (eg, assessment of topic 1 would only involve running the CHR pathway). However, because the underlying rationale of using a WDM approach is that all interventions are interrelated (ie, changes made to 1 intervention might affect the others), the entire WDM was run repeatedly for each decision problems listed in Table 1. Input Data In general, health economic models require 4 types of evidence, as follows: clinical evidence (baseline event risks, treatment effects and adverse events); health-related quality of life estimates (preference-based utility values); health care resource use; and costs. Model parameters were informed by numerous evidence sources, including systematic reviews and meta-analyses, clinical trials, clinical audits, observational studies, resource use surveys, costing studies, health valuation studies, and expert opinion. Evidence was mainly obtained from the meta-analyses conducted by the 7,8 NICE schizophrenia Guideline Development Groups, supplemented with new evidence identified from rapid reviews of the literature conducted by the authors. A lack of evidence was identified for many parameters, including the long-term clinical effectiveness and adverse effects of interventions (eg, CBT, family intervention, and antipsychotic medications) and up-to-date costs of managing patients with schizophrenia in remission. When no relevant data were identified, expert opinion was JAMA Network Open. 2020;3(5):e205888. doi:10.1001/jamanetworkopen.2020.5888 (Reprinted) May 27, 2020 3/12 JAMA Network Open | Psychiatry Cost-effectiveness of Services for Schizophrenia Across the Entire Care Pathway in a Whole-Disease Model used to inform the required model parameters, with alternative plausible values tested in sensitivity analyses. A summary of the key model parameters is reported in Table 2; a complete list of all model parameters, including data sources, is reported in eAppendix 4 in the Supplement. Model Checking Extensive model verification and validation activities were undertaken, including white-box tests (scrutinizing the programming code) and black-box tests (testing the behavior of the model), checking results with stakeholders and comparing results with published literature. The details of white-box and black-box tests conducted are reported in eAppendix 5 in the Supplement. The overall model behavior was checked by 1 of us (P.T.). In addition, 7 members of a service user advisory group affiliated with the Maudsley Biomedical Research Centre, London, commented on the model structure and key assumptions. Model Evaluation Methods In accordance with the lower end of the cost-effectiveness threshold range used by NICE, interventions with an incremental cost-effectiveness ratio lower than £20 000 ($25 552) per QALY were considered cost-effective. The incremental cost-effectiveness ratio was defined as the difference in the expected cost of 2 interventions, divided by the difference in the expected effects of the 2 interventions. Extensive sensitivity analyses were undertaken to test the robustness of the results of the base case analyses to different sets of assumptions and using different input data, including 1-way and multiway sensitivity analysis to assess the consequences of uncertainty regarding the value of a single or multiple parameter(s); structural sensitivity analysis to assess the consequences of uncertainty regarding the structural assumptions of the model (eg, whether CBT can prevent psychosis or just delay the transition to psychosis); and probabilistic sensitivity analyses that examine the consequences of joint uncertainty of multiple parameters simultaneously. Figure. Model Structure Module A: Module B: CHR pathway Module C: Psychosis Specialist pathway assessment pathway 1. Model entry Receive Acute FEP 4. CHR wait for 10. Manage 5. CHR on CBT CBT CBT acute psychosis CHR FEP 2. Assessment Receive monitoring only 6. CHR under 8. CHR recover 12. Nonacute monitoring Stable FEP 15. Diagnosis Accept AP psychosis on AP receive treatment 11. FEP wait for Do not receive CBT treatment or monitoring 7. CHR not under 9. CHR convert Not at risk monitoring Accept FI only 13. Psychosis on FI Stable FEP; do not receive treatment 14. Psychosis stop treatment 3. Out of scope Die Die 16. Death Module D: out of scope and death pathway Abbreviations: AP, antipsychotic medication; CBT, cognitive behavioral therapy; CHR, clinical high risk of psychosis; FEP, first-episode psychosis; and FI, family intervention. JAMA Network Open. 2020;3(5):e205888. doi:10.1001/jamanetworkopen.2020.5888 (Reprinted) May 27, 2020 4/12 JAMA Network Open | Psychiatry Cost-effectiveness of Services for Schizophrenia Across the Entire Care Pathway in a Whole-Disease Model Table 2. Summary of Key Parameters Used in the Schizophrenia Whole-Disease Model Parameter Baseline value Distribution Epidemiologic data, % Age, mean, y 23.52 Normal (SE, 2.85) Men 60.40 Beta (α = 665.61; β = 436.39) Starting disease status Not at risk of psychosis 33.21 Dirichlet (n = 276, N = 831) At CHR-P 34.90 Dirichlet (n = 290; N = 831) FEP 31.89 Dirichlet (n = 265; N = 831) Service provision data, % CBT Provision 41.01 Beta (α = 1011; β = 1454) Take up 51.00 Beta (α = 510; β = 490) Family intervention Provision 30.98 Beta (α = 589; β = 1312) Take up 38.49 Beta (α = 224; β = 358) Antipsychotic Provision 100.00 Assumed fixed Take up for patients with FEP 97.38 Beta (α = 484; β = 13) Delay in initiation of clozapine, y 3.98 Gamma (α = 137.25; β = 0.023) Clinical effectiveness data: nonpharmacologic interventions, RR Transition to psychosis for CBT vs practice as usual 0.41 Log normal (ln[SE], 0.29) Relapse for family intervention vs standard care 0.63 Log normal (ln[SE], 0.16) or other control Clinical effectiveness data: antipsychotic medication for individuals with FEP, OR Annual probability of all-cause discontinuation 0.82 Beta (α = 4949.54; β = 1079.87) for patients on placebo Amisulpride vs placebo 0.18 Log normal (ln[SE], 0.49) Aripiprazole vs placebo 0.24 Log normal (ln[SE], 0.51) Haloperidol vs placebo 0.21 Log normal (ln[SE], 0.34) Olanzapine vs placebo 0.11 Log normal (ln[SE], 0.31) Quetiapine vs placebo 0.21 Log normal (ln[SE], 0.32) Risperidone vs placebo 0.15 Log normal (ln[SE], 0.40) Haloperidol LAI vs placebo 0.15 Log normal (ln[SE], 0.45) Paliperidone LAI vs placebo 0.19 Log normal (ln[SE], 0.53) Clinical effectiveness data: antipsychotics for individuals with TRS, OR Annual probability of discontinuing clozapine because 0.02 Beta (α = 4.98; β = 310.02) of inefficacy Haloperidol vs clozapine 5.56 Log normal (ln[SE], 0.35) Olanzapine vs clozapine 1.37 Log normal (ln[SE], 0.34) Quetiapine vs clozapine 4.35 Log normal (ln[SE], 0.69) Risperidone vs clozapine 2.27 Log normal (ln[SE], 0.40) Health-related quality of life data Individuals At CHR-P 0.71 Beta (α = 100.22; β = 40.78) With psychosis in remission 0.80 Normal (SE, 0.04) With psychosis in relapse 0.67 Normal (SE, 0.06) Disutility Weight gain 0.03 Normal (SE, 0.01) EPS 0.07 Normal (SE, 0.01) Diabetes 0.09 Normal (SE, 0.05) (continued) JAMA Network Open. 2020;3(5):e205888. doi:10.1001/jamanetworkopen.2020.5888 (Reprinted) May 27, 2020 5/12 JAMA Network Open | Psychiatry Cost-effectiveness of Services for Schizophrenia Across the Entire Care Pathway in a Whole-Disease Model Table 2. Summary of Key Parameters Used in the Schizophrenia Whole-Disease Model (continued) Parameter Baseline value Distribution Cost data, £ CBT Cost per session 97.00 Gamma (α = 44.44; β = 2.18) Sessions, No. 16 Assumed fixed Family intervention Cost per session 112.00 Gamma (α = 44.44; β = 2.52) Sessions, No. 20 Assumed fixed Oral antipsychotic, per d Amisulpride 0.47 Gamma (α = 22.68; β = 0.02) Aripiprazole 4.08 Gamma (α = 23.80; β = 0.17) Haloperidol 0.37 Gamma (α = 30.86; β = 0.01) Olanzapine 0.13 Gamma (α = 13.72; β = 0.01) Quetiapine 1.24 Gamma (α = 6.25; β = 0.20) Risperidone 0.36 Gamma (α = 5.41; β = 0.07) Clozapine 1.56 Gamma (α = 156.25; β = 0.01) LAI antipsychotic Haloperidol, 28 d 6.56 Gamma (α = 13.72; β = 0.48) Paliperidone, 30 d 334.45 Gamma (α = 82.64; β = 4.05) Attendance at clozapine clinic 16.40 Gamma (α = 44.44; β = 0.37) Managing patients with nonrelapsed schizophrenia, per y 14 983.45 Gamma (α = 2.04; β = 7341.89) Assessing an acute episode of psychosis 507.00 Gamma (α = 348.55; β = 1.45) CRHT team, per contact 197.45 Gamma (α = 44.44; β = 4.44) Contacts with CRHT team, mean, No. 16.3 Gamma (α = 78.32; β = 0.21) Abbreviations: CBT, cognitive behavioral therapy; Hospital bed-day 379.00 Gamma (α = 44.44; β = 8.52) CHR-P, clinical high risk of psychosis; CRHT, crisis Bed-days during 1 relapse, mean, No. 138.90 Weibull (α = 0.65; β = 0.61) resolution and home treatment team; EPS, Cost of adverse events extrapyramidal symptoms; FEP, first-episode Weight gain psychosis; LAI, long-acting injectable; ln, natural log; OR, odds ratio; RR, relative risk; TRS, treatment- Year 1 97.20 Gamma (α = 44.44; β = 2.19) resistant schizophrenia. Year 2 onwards 309.68 Gamma (α = 3.77; β = 6755.56) A complete list of all parameters used in the model Acute EPS, per episode 51.95 Gamma (α = 44.44; β = 1.17) and their data sources are reported in eAppendix 3 in Diabetes, per y 1336.31 Gamma (α = 124 044.44; β = 0.01) the Supplement. Neutropenia, per episode 469.48 Gamma (α = 92 802.96; β = 0.01) To convert to US dollars, multiply by 1.2776. Following published guidance, a cohort of 200 000 patients was adopted for deterministic analyses and 1000 samples were used for probabilistic sensitivity analysis. The stability of results was tested to different numbers of patients and probabilistic sensitivity analysis runs. No prespecified level of statistical significance was set. Results The base case and probabilistic sensitivity analysis results are presented in Table 3 and summarized in this section. The simulated cohort had a mean (SD) age of 23.5 (5.1) years, with 120 800 (60.4%) men, 66 400 (33.2%) not at risk of psychosis, 69 800 (34.9%) at CHR-P, and 63 800 (31.9%) with psychosis. Interventions for Patients at CHR-P The base case analysis suggests that practice as usual plus CBT dominates practice as usual alone. The cost savings of CBT are substantial (£1243 [$1588] per person), likely because the evidence used to inform the WDM suggests that CBT can delay the transition from CHR-P to psychosis, and the JAMA Network Open. 2020;3(5):e205888. doi:10.1001/jamanetworkopen.2020.5888 (Reprinted) May 27, 2020 6/12 JAMA Network Open | Psychiatry Cost-effectiveness of Services for Schizophrenia Across the Entire Care Pathway in a Whole-Disease Model treatment cost for individuals with psychosis or schizophrenia is much higher than the treatment cost −5 for individuals at CHR-P. On the other hand, the QALY gains of CBT are marginal (5.19 × 10 per person), likely because evidence used in the WDM suggests that the utility for individuals at CHR-P is similar to individuals with psychosis. Assuming a willingness-to-pay (WTP) threshold of £20 000 ($25 552) per QALY gained, the probability that practice as usual plus CBT is cost-effective compared to practice as usual alone was estimated to be 0.96. Interventions for Individuals With Acute Psychosis The base case analysis suggests that a mix of CRHT and hospital admission produces the same QALY gains and additional cost savings (£3655 [$4670] per person) than hospital admission alone. This is because the evidence used to inform the WDM suggests equivalent effectiveness between hospital admission and CRHT, and the cost of hospital admission is much higher than the cost of CRHT services. Assuming a WTP threshold of £20 000 ($25 552) per QALY gained, the probability that a mix of CRHT and hospital admission is cost-effective compared with hospital admission alone was estimated to be 0.99. Table 3. Deterministic and Probabilistic Results of Cost-effectiveness Analysis Deterministic results PSA results, per QALY Discounted mean Incremental b b b b Intervention Cost per person, £ QALYs per person Cost, £ QALY ICER WTP, £20 000 WTP, £30 000 Interventions for patients at CHR-P PAU plus CBT 167 452 19.1904 −1243 0.0000 Dominating 0.95 0.95 PAU alone 168 695 19.1904 NA NA Dominated 0.05 0.05 Interventions for individuals with acute psychosis Mix of hospital admission 168 078 19.1904 −3655 0.000 Dominating 1.00 1.00 and CRHT Hospital admission alone 171 733 19.1904 NA NA Dominated 0.00 0.00 First-line oral antipsychotic medication for FEP Quetiapine 168 539 19.2005 1670 0.0071 235 211 0.06 0.06 Haloperidol 168 538 19.1981 NA NA Extendedly dominated 0.06 0.06 Aripiprazole 171 340 19.1977 NA NA Dominated 0.01 0.02 Risperidone 166 869 19.1934 1056 0.0112 94 286 0.30 0.30 Placebo 174 128 19.1931 NA NA Dominated 0.00 0.00 Amisulpride 165 813 19.1822 NA NA NA 0.39 0.39 Olanzapine 167 455 19.1794 NA NA Dominated 0.17 0.17 Family intervention for FEP Antipsychotic medication plus 167 905 19.2033 NA NA Dominating 0.58 0.62 family intervention Family intervention alone 175 065 19.1987 NA NA Dominated 0.09 0.10 Antipsychotic medication alone 168 261 19.1849 NA NA Dominated 0.33 0.28 First-line oral antipsychotic medication for TRS Clozapine 162 215 19.1977 NA NA Dominating 0.81 0.81 Olanzapine 165 444 19.1925 NA NA Dominated 0.16 0.16 Risperidone 169 324 19.1889 NA NA Dominated 0.03 0.03 Haloperidol 170 008 19.1883 NA NA Dominated 0.00 0.01 Quetiapine 172 043 19.1867 NA NA Dominated 0.00 0.00 Abbreviations: CBT, cognitive behavioral therapy; CHR-P, clinical high risk of psychosis; Probability for the intervention to be most cost-effective within each topic. CRHT, crisis resolution and home treatment team; FEP, first-episode psychosis; ICER, b To convert to US dollars, multiply by 1.2776. incremental cost-effectiveness ratio; NA, not applicable; PAU, practice as usual; PSA, probabilistic sensitivity analysis; QALY, quality-adjusted life-year; TRS, treatment- resistant schizophrenia; WTP, willingness to pay. JAMA Network Open. 2020;3(5):e205888. doi:10.1001/jamanetworkopen.2020.5888 (Reprinted) May 27, 2020 7/12 JAMA Network Open | Psychiatry Cost-effectiveness of Services for Schizophrenia Across the Entire Care Pathway in a Whole-Disease Model First-Line Oral Antipsychotic Medication for Individuals With FEP The base case analysis suggests that, of the 7 interventions assessed, amisulpride was the most cost- effective option, followed by risperidone and olanzapine. This is because the evidence used to inform the WDM suggests that these antipsychotic medications are associated with the lowest probability of all-cause drug discontinuation. Assuming a WTP threshold of £20 000 ($25 552) per QALY gained, amisulpride is most likely to be cost-effective (0.39), followed by risperidone (0.30) and olanzapine (0.17). The probability of any antipsychotic medication being the most cost-effective option was less than 0.05. Family Intervention for Individuals With FEP The base case analysis suggests that antipsychotic medication plus family intervention dominates both antipsychotic alone and family intervention alone. This is because the evidence used to inform the WDM suggests that family intervention can prevent relapse of psychosis, and the cost of treating relapse is much higher than the cost of family intervention. Assuming a WTP threshold of £20 000 ($25 552) per QALY gained, the probability that antipsychotic medication plus family intervention is the most cost-effective option compared with medication or family intervention alone was estimated to be 0.58. First-Line Oral Antipsychotic Medications for Individuals With TRS The base case analysis suggests that clozapine dominates all other antipsychotic medications. This is because the evidence used in the WDM suggests that, of the 5 antipsychotics assessed for individuals with TRS, clozapine was associated with the lowest all-cause discontinuation rate (including discontinuation due to inefficacy, intolerability, and nonadherence) and was less likely to cause acute extrapyramidal symptoms. Assuming a WTP threshold of £20 000 ($25 552) per QALY gained, the probability that clozapine is the most cost-effective option compared with other medications was estimated to be 0.81. Summary of Base Case Results Assuming a WTP pay threshold of £20 000 ($25 552) per QALY, the most cost-effective interventions were practice as usual plus 16 sessions of CBT for individuals with CHR-P. A mix of CRHT and hospital admission was most cost-effective for individuals with acute psychosis; amisulpride, risperidone, or olanzapine combined with 20 sessions of family intervention was most cost-effective for individuals with FEP; and clozapine was most cost-effective for individuals with TRS. Sensitivity Analyses The results of the sensitivity analyses are summarized in eAppendix 6 in the Supplement. They suggest that the conclusions for interventions for patients at CHR-P, for individuals with acute psychosis, and for first-line oral antipsychotic medication for those with FEP and TRS were robust to all types of sensitivity analyses conducted. The conclusion for family intervention for individuals with FEP was robust to all types of sensitivity analyses except the following: changes in the choice of first-line antipsychotic; effectiveness of family intervention in preventing relapse; and number of family intervention sessions provided. Antipsychotic medication alone was the most cost-effective intervention when amisulpride was used as the first-line antipsychotic medications for individuals with FEP; when the relative risk of family intervention in preventing relapse was increased from 0.63 to 0.83; or when a brief (ie, number of sessions and effectiveness halved) version of family intervention was assumed. JAMA Network Open. 2020;3(5):e205888. doi:10.1001/jamanetworkopen.2020.5888 (Reprinted) May 27, 2020 8/12 JAMA Network Open | Psychiatry Cost-effectiveness of Services for Schizophrenia Across the Entire Care Pathway in a Whole-Disease Model Discussion Comparing Results With Published Literature Comparison of our results with published literature by individual topic is detailed in eAppendix 7 in the Supplement and summarized in this section. Our findings regarding interventions for patients at CHR-P and with acute psychosis and for first-line oral antipsychotic medication for individuals with 12-19 FEP and with TRS are consistent with published literature. For first-line oral antipsychotic medication for individuals with FEP, both the schizophrenia WDM and the model developed by the NICE schizophrenia Guideline Development Group found that no antipsychotic medication can be considered clearly more cost-effective than the other options. However, the schizophrenia WDM found amisulpride to be the most cost-effective option, while the NICE model suggests amisulpride was the least cost-effective option. This is likely because of differences in the input data used. The systematic review conducted by the NICE schizophrenia Guideline Development Group in 2008 found amisulpride to be associated with the second highest probability of relapse (second only to 20,21 haloperidol), while the latest systematic reviews, which included additional trials, showed amisulpride to be associated with among the lowest probabilities of all-cause discontinuation and relapse rate. Implications for Clinical Practice The results of our analyses suggest that adoption of the following interventions could result in cost savings compared with the current service: practice as usual plus 16 sessions of CBT for individuals at CHR-P; a mix of hospital admission and CRHT for individuals with acute psychosis; antipsychotic medication (amisulpride, risperidone, or olanzapine) combined with 20 sessions of family intervention for individuals with FEP; and clozapine for individuals with TRS. Adoption of clozapine for individuals with TRS also resulted in additional QALYs. The results suggest that a brief family intervention (ie, 10 sessions) would not be cost-effective for individuals with FEP. Strengths and Limitations There are 3 key strengths of this study. First, it fills the evidence gap by presenting the first model- based economic analysis of the following interventions: CBT for individuals with CHR-P, CRHT for individuals with acute psychosis, family intervention for individuals with FEP, and clozapine and other atypical antipsychotics for individuals with TRS. There has been an increased interest in investment in brief family intervention because of resource constraints. However, our study showed that while a 20-session family intervention was cost-effective for individuals with FEP, a 10-session family intervention was not. This finding might change the current practice of providing family interventions. Second, this study provides an up-to-date assessment of antipsychotic medication for 20,21 individuals with FEP based on the results of the latest network meta-analyses and modeled the cost and health consequences of 5 adverse effects of antipsychotics, including extrapyramidal symptoms, weight gain, glucose intolerance, diabetes, and neutropenia. Our analysis found amisulpride to be among the most cost-effective antipsychotics because of its therapeutic superiority in preventing relapse. Considering the current market share of amisulpride in the UK (ie, 1.39%), our findings may change the current clinical practice of prescribing antipsychotics. Third, all results presented within this study were based on a well-documented WDM, which is populated with input data carefully selected from high-quality literature. Extensive validation activities were undertaken to ensure the quality of the schizophrenia WDM. To our knowledge, this is the first WDM developed for the economic evaluation of a mental health disorder. This study also has limitations. There are 2 major limitations of the schizophrenia WDM developed within this study. First, owing to resource constraints, input data for the WDM were 7,8 obtained from published systematic reviews reported in the NICE schizophrenia guidelines, supplemented with new evidence identified from rapid reviews, rather than by undertaking our own de novo systematic reviews. As such, it is possible that newer high-quality evidence has not been JAMA Network Open. 2020;3(5):e205888. doi:10.1001/jamanetworkopen.2020.5888 (Reprinted) May 27, 2020 9/12 JAMA Network Open | Psychiatry Cost-effectiveness of Services for Schizophrenia Across the Entire Care Pathway in a Whole-Disease Model included in the model. Second, as with any health economic model, the credibility of the schizophrenia WDM and its results are largely dependent on the quantity and quality of the evidence used to inform it. While searching for input data for the WDM, a lack of evidence was identified for many parameters, such as long-term clinical effectiveness and adverse effects of interventions (eg, CBT, family intervention, and antipsychotics) and up-to-date costs of managing patients with schizophrenia in remission. Even when evidence was available, it often had certain limitations, such as variation in criteria for relapse, relatively short follow-up periods, unclear masking, incomplete outcome data, and selective reporting. However, the model was designed to be adapted and reused, and thus, results can be updated as new or better-quality evidence is identified. Conclusions The results of this study suggested that the following interventions are likely to be cost-effective: CBT for individuals at CHR-P; a mix of hospital admission and CRHT for individuals with acute psychosis; amisulpride, risperidone, or olanzapine combined with family intervention for individuals with FEP; and clozapine for individuals with TRS. Cost savings and additional quality-adjusted life- years may be gained by replacing current interventions with more cost-effective interventions. ARTICLE INFORMATION Accepted for Publication: March 21, 2020. Published: May 27, 2020. doi:10.1001/jamanetworkopen.2020.5888 Open Access: This is an open access article distributed under the terms of the CC-BY License.©2020JinHetal. JAMA Network Open. Corresponding Author: Huajie Jin, PhD, King’s Health Economics, Institute of Psychiatry, Psychology, and Neuroscience at King’s College London, Box 024, The David Goldberg Centre, De Crespigny Park, Denmark Hill, London SE5 8AF, United Kingdom (huajie.jin@kcl.ac.uk). Author Affiliations: King’s Health Economics, Institute of Psychiatry, Psychology, and Neuroscience, King’s College London, London, United Kingdom (Jin, Byford); Health Economics and Decision Science, University of Sheffield School of Health and Related Research, Sheffield, United Kingdom (Tappenden); Department of Psychosis Studies, Institute of Psychiatry, Psychology, and Neuroscience, King’s College London, London, United Kingdom (MacCabe); Loughborough University School of Business and Economics, Loughborough, United Kingdom (Robinson). Author Contributions: Dr Jin had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Concept and design: All authors. Acquisition, analysis, or interpretation of data: All authors. Drafting of the manuscript: Jin, Tappenden. Critical revision of the manuscript for important intellectual content: All authors. Statistical analysis: Jin, Tappenden, Robinson. Obtained funding: MacCabe. Administrative, technical, or material support: All authors. Supervision: Tappenden, MacCabe, Robinson, Byford. Conflict of Interest Disclosures: Dr MacCabe reported receiving grants from the Medical Research Council during the conduct of the study and grants and nonfinancial support from Lundbeck outside the submitted work. No other disclosures were reported. Additional Contributions: The authors thank those stakeholders who kindly volunteered their time to input into the model and who remain anonymous. Paul McCrone, PhD (Faculty of Education, Health and Human Sciences, University of Greenwich), provided valued advice on the development and validation of the whole-disease model. None of these individuals were compensated for their time. JAMA Network Open. 2020;3(5):e205888. doi:10.1001/jamanetworkopen.2020.5888 (Reprinted) May 27, 2020 10/12 JAMA Network Open | Psychiatry Cost-effectiveness of Services for Schizophrenia Across the Entire Care Pathway in a Whole-Disease Model REFERENCE 1. National Institute for Health and Care Excellence. Guide to the Methods of Technology Appraisal. National Institute for Health and Care Excellence; 2013. 2. Jin H, Tappenden P, Robinson S, et al. A systematic review of economic models across the entire schizophrenia pathway. Pharmacoeconomics. 2020. doi:10.1007/s40273-020-00895-6 3. Tappenden P, Chilcott J, Brennan A, Squires H, Stevenson M. Whole disease modeling to inform resource allocation decisions in cancer: a methodological framework. Value Health. 2012;15(8):1127-1136. doi:10.1016/j.jval. 2012.07.008 4. Jin H. Using Whole Disease Modelling to Inform Resource Allocation Decisions in Schizophrenia Services. Thesis. 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Family intervention (brief) for schizophrenia. Cochrane Database Syst Rev. 2014(3):CD009802. doi:10.1002/14651858.CD009802.pub2 JAMA Network Open. 2020;3(5):e205888. doi:10.1001/jamanetworkopen.2020.5888 (Reprinted) May 27, 2020 11/12 JAMA Network Open | Psychiatry Cost-effectiveness of Services for Schizophrenia Across the Entire Care Pathway in a Whole-Disease Model 23. NHS Digital. Prescription Cost Analysis: England, 2016. Published March 30, 2017. Accessed March 3, 2016. https://digital.nhs.uk/data-and-information/publications/statistical/prescription-cost-analysis/ prescription-cost-analysis-england-2016 SUPPLEMENT. eAppendix 1. Key Consequences of Interventions Considered in the Model eAppendix 2. Description of the Design-Oriented Model eAppendix 3. List of Assumptions and Simplifications of the Model eAppendix 4. Summary of Key Input Data eAppendix 5. White-Box and Black-Box Tests Conducted eAppendix 6. Results of Sensitivity Analysis eAppendix 7. Comparing Results With Published Literature eReferences. JAMA Network Open. 2020;3(5):e205888. doi:10.1001/jamanetworkopen.2020.5888 (Reprinted) May 27, 2020 12/12 Z P Z P P Z P Z P Z P Z P Z P Z P P P Z P Z P Z P Z P Z P Z P Z P Z P Z P Z P Z P Z P Z P Z P Z P Z P Z P Z Z P Z P P Z P P Z Z P P P P P P P P P Z P Z P Z P Z P Z P Z Z P Z P Z P P S Z P Z P

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