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REVIEW

Review and analysis of hospitalization costs associated with antipsychotic nonadherence in the treatment of schizophrenia in the United StatesShawn X. Sun a, Gordon G. Liu b, Dale B. Christensen c and Alex Z. Fu d

a Health Outcomes Department, Walgreens Health Services, Deerfield, IL, USA

b Department of Health Economics and Management, Peking University Guanghua School of Management, Beijing, China

c School of Pharmacy, University of North Carolina, Chapel Hill, NC, USAd Department of Quantitative Health Sciences, Cleveland Clinic, Cleveland,

OH, USA

Address for correspondence: Alex Z. Fu, PhD, Department of Quantitative Health Sciences, Cleveland Clinic, 9500 Euclid Avenue/Wb‑4, Cleveland, OH 44195, USA. Tel.: +1 216 445 7745; Fax: +1 216 445 2781; fuz@ccf.org

Key words: Antipsychotics – Economic – Hospitalization cost – Nonadherence – Schizophrenia

0300-7995

doi:10.1185/030079907X226050

All rights reserved: reproduction in whole or part not permitted

CuRRenT MeDICAL ReSeARCH AnD OPInIOn®

VOL. 23, NO. 10, 2007, 2305–2312

© 2007 LIBRAPHARM LIMITeD

Paper 4018 2305

Objective: To review the literature addressing the economic outcomes of nonadherence in the treatment of schizophrenia, and to utilize the review results to provide an update on the economic impact of hospitalizations among schizophrenia patients related to antipsychotic nonadherence.

Methods: A structured search of EMBASE, Ovid MEDLINE, PubMed and PsycINFO for years 1995–2007 was conducted to identify published English-language articles addressing the economic impact of antipsychotic nonadherence in schizophrenia. The following key words were used in the search: compliance, noncompliance, adherence, nonadherence, relapse, economic, cost, and schizophrenia. A bibliographic search of retrieved articles was performed to identify additional studies. For a study to be included, the date of publication had to be from 1/1/1995 to 6/1/2007, and the impact of nonadherence had to be measured in terms of direct healthcare costs or inpatient days. Subsequently, an estimate of incremental hospitalization costs related to antipsychotic non adherence was extrapolated at the US national level based on the reviewed studies (nonadherence rate and hospitalization rate) and the National Inpatient Sample of Healthcare Cost and Utilization Project (average daily hospitalization costs).

Results: Seven studies were identified and reviewed based on the study design, measurement of medication nonadherence, study setting, and cost outcome results. Despite the varied adherence measures across studies, all articles reviewed showed that antipsychotic nonadherence was related to an increase in hospitalization rate, hospital days or hospital costs. We also estimated that the national rehospitalization costs related to antipsychotic nonadherence was $1479 million, ranging from $1392 million to $1826 million in the US in 2005.

Limitations: The estimate of rehospitalization costs was restricted to schizophrenia patients from the Medicaid program. Additionally, the studies we reviewed did not capture the newer antipsychotic drugs (ziprasidone, aripiprazole and paliperidone). Thus, the nonadherence rates or rehospitalization rates might have changed after these new drugs came to the market, which could limit our cost estimation.

Conclusions: Poor adherence to antipsychotic medications was consistently associated with higher risk of relapse and rehospitalization and higher hospitalization costs. To reduce the cost of hospitalizations among schizophrenia patients, it seems clear that efforts to increase medication adherence should be undertaken.

A B S T R A C T

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2306 Hospitalization costs of antipsychotic nonadherence © 2007 LIBRAPHARM LTD – Curr Med Res Opin 2007; 23(10)

Introduction

Schizophrenia is a chronic mental disorder that severely affects patients’ multi-functional well-being and quality of life. Although schizophrenia has a prevalence rate of only 1% in the US, it is the most costly mental health disorder and one of the most costly chronic illnesses1. In 2002, the overall cost of schizophrenia in the United States was nearly $63 billion2. A significant proportion of direct costs is attributable to hospital izations for both the first episode and relapses, ranging from 15 to 58%3,4. More importantly, relapses are often associated with poor adherence to medication therapies5–7. For example, a meta-analysis of clinical trials with an average follow-up of 9.7 months found a relapse rate of 53% among patients whose medications were discon tinued, compared with 16% among those who continued antipsychotic drug treatment8.

Adherence to medication is well-recognized as essential to ensuring the maximum effectiveness of the medical treatment in general9,10, and the psychiatric therapy in particular11,12. However, approximately half of the patients with chronic diseases fail to adhere to the prescribed medications13. Nonadherence often leads to an increase in morbidity, mortality, and resource utilization14,15. It is estimated that approximately 125 000 deaths are attributable to nonadherence each year, and over $100 billion costs per year are due to nonadherence with medications as a result of hospital admissions, emergency room visits and repeated doctor visits in the United States13.

For schizophrenia patients, poor adherence to anti-psychotic medications has been found to be associated with greater symptom levels12, higher risk of relapse6,16 and re-hospitalization and emergency room visits17–29, sustained functional impairment and poor community adjustment30,31. For example, compared with patients who did not have gaps in medication therapy, patients who had a gap of more than 30 days were four times more likely to be hospitalized32. Although adherence to medication regimens is crucial to preventing relapse and rehospitalization, approximately half of the schizo-phrenia patients were reported to have experienced some difficulties adhering to medication therapies11. Maxim izing adherence is a great challenge for clinicians, researchers, and policy-makers to continue seeking a more effective and sustained therapy for schizophrenia patients in a cost-effective manner.

While it is well-documented that medication adherence results in a reduced use of other healthcare services, especially hospital care9,19,33–36, the literature offers little empirical evidence of the extent to which adherence to antipsychotics leads to significant cost savings among schizophrenic patients. Reducing the need for hospitalization is one of the most important

goals in the management of schizophrenia. Enhancing patient compliance can prevent or delay relapse, reduce hospital ization, and improve patient’s quality of life, which potentially leads to an overall reduction in the cost of care. To the best of our knowledge, no published studies available have reviewed the impact of antipsychotic nonadherence on hospitalization costs in the treatment of schizophrenia. In addition, the available estimate in the literature is over a decade old6 and may not reflect the current medical practice. Thus, it will be desirable to provide updated information. We also believe a review and analysis on this topic is important at this time due to the recent implementation of the Medicare Part D program. Since most schizophrenia patients were enrolled in the Medicaid program before 2006, many of them would be enrolled in the Medicare Part D after January 2006. The outcome in terms of medication adherence and hospitalization costs will be a more important research topic for the Medicare budget.

The purpose of this article is to review the literature addressing the economic impact of hospitalizations related to antipsychotic nonadherence in the treatment of schizophrenia. We also seek to extend the review results to provide an update on the incremental hospital-ization costs related to antipsychotic nonadherence.

MethodsLiterature search

A structured search of EMBASE, MEDLINE, Ovid MEDLINE, PubMed, and PsycINFO databases was conducted to identify published English-language articles on the economic impact of medication nonadherence in schizophrenia. A combination of the following search terms was used: compliance, noncompliance, adherence, nonadherence, relapse, economic, cost, and schizo phrenia. We also performed a bibliographic search of retrieved articles to identify additional studies. The databases and references were searched for relevant articles published between January 1, 1995 and June 1, 2007.

Literature synthesis

A total of 825 articles were identified by applying the above searching keywords. Each article was examined using the following inclusion and exclusion criteria: (1) based on schizophrenia population in the United States, (2) assessed antipsychotic nonadherence, (3) estimated hospitalization events and/or costs associated with antipsychotic nonadherence, (4) excluded review articles, though retrieved review articles were used in bibliographic search. We limited our review to

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© 2007 LIBRAPHARM LTD – Curr Med Res Opin 2007; 23(10) Hospitalization costs of antipsychotic nonadherence Sun et al. 2307

published studies relating to re-hospitalization costs, and excluded others7,11,37,38, because hospitalization cost is one of the greatest components of direct treatment costs. Seven studies met our selection criteria and were included in this review. For each article, we extracted data on the following items: study design, study period, study setting, nonadherence measure and cut-off level, and results.

Cost extrapolation

We extracted the data regarding the nonadherence rate, hospitalization rate, and antipsychotic-related inpatient treatment costs from the identified studies. In order to estimate the hospitalization costs in more recent years, we also extracted the average daily hospital costs from National Inpatient Sample of Healthcare Cost and Utilization Project (HCUP-NIS), which is developed and maintained by the Agency for Healthcare Research and Quality (AHRQ)39. We then estimated the rehospital ization costs from medication nonadherence using the following equation based on the available inputs from the corresponding studies:

Y = N × P × Rn × (R

hn × C

hn – R

ha × C

ha) × C

1/C

0 (1)

where Y is the total rehospitalization costs, N represents the number of US population in 2005, P is the prevalence rate of schizophrenia, R

n is the nonadherence

rate, Rhn

and Rha represent the hospitalization rate for

nonadherent and adherent patients respectively, Chn

and C

ha represent the average hospitalization costs for

nonadherent and adherent patients, C1 and C

0 are the

average daily hospital costs in 2005 and the study year of the corresponding studies, which were extrapolated from the most recent HCUP-NIS 2005 data. Table 2 lists the values of each component and explanation of the calculation.

ResultsLiterature review

A total of seven studies met our selection criteria (Table 1). Of these, two used logistic and ordinary least-square linear regression analyses25,40, while the remainder used survival model6, decision analytic model41, negative binomial model42, state transition model43 or two-part model44, respectively. Table 1 summarized the main features and results of these articles.

In a survival analysis conducted by Weiden and Olfson6, the monthly nonadherence rate was estimated at 7.6% after discharge from inpatient hospitals based on review of published literature, and the monthly

relapse rates were estimated to be 3.5% for patients adhered to antipsychotics and 11% for those who discontinued their medications. The inpatient cost for the index hospital izations of a cohort was estimated at $2.3 billion (1993 dollars) based on 1986 national expenditures data for inpatient mental health care. These estimates were entered into a survival model to obtain the real world estimate of relapse rate for this cohort, which was further used to estimate the hospital costs due to nonadherence. The total hospital costs attributable to nonadherence for antipsychotics were estimated as $705 million within 2 years of discharge, with $370 million in the first year and $335 million in the second year. It should be pointed out that in this study, the authors did not specify how adherence was measured and how the cut-off level for adherence versus nonadherence was determined.

Using decision analytic models under a variety of assumptions for probability of adherence and relapse rates and rehospitalization costs, Glazer and Ereshefsky41 compared the potential economic outcomes associated with alternative antipsychotic treatments in schizo-phrenia. They derived the probability of medication adherence, relapse and rehospitalization based on published data and authors’ clinical experience. The probability of medication adherence during one year was estimated at 80% for depot, 50% for traditional oral neuroleptic, and 65% for atypical antipsychotics. The probability of rehospitalization was estimated at 10% for adherent patients and 55% for nonadherent patients. The calculated annual total direct treatment cost per patient was $7162 for atypical antipsychotics compared to $5752 for traditional oral neuroleptic and $4595 for depot agent.

In a retrospective study based on drug and hospital claims data in 1989 and 1990 from the Wisconsin Medicaid program, Svarstad et al.40 directly quantified the economic costs associated with rehospitalization from nonadherence using regression analysis. In this study, adherence measure was determined based on the regularity of medication use. A refill gap of 3 months or more for oral medication (6 months or more for depot) was defined as irregular use. This study found that 82 patients (19%) used medication irregularly in a cohort of 424 patients with schizophrenia. Irregular users were found to have significantly higher hospitalization rates than regular users (33 vs. 19%). Irregular schizophrenia patients had nearly twice as many hospital costs ($3421 vs. 1799) as regular ones.

Valenstein et al.25 used medication possession ratio (MPR) and refill gap as adherence measures in a retro-spective study based on a large sample of patients from national Veterans Affairs (VA) hospitals. MPR was calculated by dividing the number of days’ medication supply a patient received by the number of days’ supply

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2308 Hospitalization costs of antipsychotic nonadherence © 2007 LIBRAPHARM LTD – Curr Med Res Opin 2007; 23(10)

the patient needed to receive for continuous medication treatment during the study period. Refill gaps were determined based on the number of continuous months that a patient did not have a refill of the antipsychotic medication during the study year. Patients with MPR less than 0.8 (poor adherence) were 2.4 times more likely to be admitted to hospital than those with good adherence (0.8 ≤ MPR ≤ 1.1). The rate of admission for patients with poor adherence was significantly higher

than adherent patients (23 vs. 10%). For patients who were admitted, the study found that those with poor adherence spent 9 more days in the hospitals than adherent ones, using linear regression analysis.

Harman et al.42 used a negative binomial model to examine the impact of interruption in Medicaid coverage on the use of inpatient services for schizophrenia patients enrolled in the Utah Medicaid program from December 1990 through December

Table 1. Studies on the economic impact of medication nonadherence in the treatment of schizophrenia

Reference Design Setting Study period

Nonadherence measure and cut-off level

Results

Weiden and Olfson 19956

Survival analysis

US national sample

1993 Average of published non-adherence rates

The national hospital costs from neuroleptic nonadherence is about $370 million in the first year and $335 million in the second year

Glazer and Ereshefsky 199641

Decision analytic model

N/A N/A Published literature The probability of medication adherence during one year was estimated at 80% for depot, 50% for traditional oral neuroleptic, and 65% for atypical antipsychotics. The annual total direct treatment cost per patient was estimated at $7162 for atypical antipsy-chotics compared to $5752 for traditional oral neuroleptic and $4595 for depot agent

Svarstad et al. 200140

Logistic and linear regression model

Wisconsin Medicaid patients

1989–1990 Irregular use (a refill gap of 3 months or more for oral medication and 6 months or more for depot)

19% schizophrenia patients used medication irregularly. Irregular users had higher hospitalization rate (33 vs. 19%), more hospital days (13.9 vs. 3.6 days), and higher hospital costs ($3421 vs. 1799)

Valenstein et al. 200225

Logistic and linear regression model

National VA patients

Oct 1998–Sept 1999

Medication possession ratio (MPR): poor adherence (MPR< 0.8), good adherence (MPR = 0.80–1.10), and excess fills (MPR >1.10)

Approximately 39% of patients receiving one antipsychotic drug or two different anti-psychotics had poor adherence. 17% of those patients receiving one antipsychotic medication were admitted. Patients with poor adherence were 2.4 times more likely to be admitted to hospitals. Once admitted, patients with poor adherence had more hospital days than those with good adherence (33 vs. 24 days)

Harman et al. 200342

Negative binomial model

Utah Medicaid patients

Dec 1990–Dec 1994

Interruption in Medicaid: 2 or more continuous months without coverage, followed by renewed coverage

About 20% Medicaid beneficiaries had interruptions. Patients with an interruption experienced more hospitalizations (1.36 vs 0.73 admissions) and had more hospital days than those with no interruption (21.9 vs. 13.6 days)

Mortimer et al. 200343

State transition model

US and UK N/A Based on expert opinion and from analysis of literature

Olanzapine and risperidone patients had higher nonadherence and relapse rates, and higher annual direct costs ($530 higher for olanzapine, $485 higher for risperidone) than patients with quetiapine

Gilmer et al. 200444

Two part model

California Medicaid patients

Dec 1998– 2000

Cumulative possession ratios: nonadherent (0.00–0.49), partially adherent (0.50–0.79), adherent (0.80–1.10), and excess fills (>1.10)

Adherent patients were found to have lower rates of hospitalization (14%) than those who were nonadherent (35%), partially adherent (24%), or had excess fills (25%). Adherent patients had significantly lower annual hospital costs than those who were nonadherent ($1025 vs. 3413)

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© 2007 LIBRAPHARM LTD – Curr Med Res Opin 2007; 23(10) Hospitalization costs of antipsychotic nonadherence Sun et al. 2309

1994. An interruption was identified if a patient had two or more continuous months without Medicaid coverage, followed by renewed coverage. During the 4-year study period, 367 out of a total 1915 schizophrenia patients were identified as having experienced interruptions. Patients with an interruption were found to have more hospitalizations (1.36 vs. 0.73 admissions, p < 0.001) and more hospital days (21.9 vs. 13.6 days, p < 0.001) than those with no interruptions. Due to the lack of data on the use of medications and services during the interruption periods that were not paid for by Medicaid, it was not clear if the gaps in Medicaid coverage corresponded with gaps in compliance. It was possible that patients might have obtained medications in some other ways, such as getting samples from a medical clinic.

Mortimer et al.43 performed a state transition model analysis based on the assumption that differences in side-effect profiles among antipsychotics lead to different adherence rates, which lead to differences in relapse rates and treatment costs. Probability values for entry into the model were obtained from analysis of relevant published literature and from a survey of a panel of leading experts on schizophrenia. The modeling results indicated that the difference between quetiapine and ziprasidone was small and statistically insignificant in nonadherence and relapse rates and treatment costs, but olanzapine and risperidone had less favorable side-effect profiles, higher nonadherence and relapse rates, and were associated with higher incremental costs ($530 per-patient per year higher for olanzapine, $485 per-patient per year higher for risperidone) than patients with quetiapine.

Using claims data from schizophrenia patients enrolled in California Medi-Cal during years 1998 and 2000, Gilmer et al.44 evaluated the relationship between adherence to antipsychotic medication and healthcare expenditures. Adherence was measured by the cumulative possession ratio, which was calculated by dividing the number of days medications were available for consumption by the number of days subjects were eligible for Medi-Cal. Cumulative possession ratios (CPR) were categorized as nonadherent (0.00–0.49), partially adherent (0.50–0.79), adherent (0.80–1.10), and excess medication fillers (>1.10). Adherent patients were found to have lower rates of hospitalization (14%) than those who were nonadherent (35%), partially adherent (24%), or had excess fills (25%). Adherent patients had significantly lower annual hospital costs than those who were nonadherent ($1025 vs. 3413).

Summary of reviewed studies

The studies measured (non) adherence mostly in different ways, the time period of observation of

adherence differed, and the cut-off levels for adherence versus nonadherence varied. However, the two studies by Gilmer et al. and Valenstein et al. used similar adherence measures and the same cut-off levels for adherence versus nonadherence. They found that adherences in the range of 0–0.49 were associated with higher rates of psychiatric hospitalization (27–35%) than adherences in the range of 0.5–0.79 and 0.8–1.1 (hospitalization rates 17–24% and 10–14%, respectively).

Cost extrapolation

Table 2 lists the specific inputs, including nonadherence rate, rehospitalization rate, annual hospitalization costs associated with the use of antipsychotic drugs, and the daily hospital costs. The daily hospital costs were extrapolated from HCUP 2005 data. The detailed calculation is shown in Table 2. Based on the study results by Gilmer et al.44 as a base-case, it was estimated that the hospitalization costs due to antipsychotic non-adherence in 2005 were $1479 million.

We conducted sensitivity analysis using data from Svarstad et al.40 (Table 2) and Valenstein et al.25 studies. The hospitalization costs from medication nonadherence in 2005 were estimated at $1392 million and $1826 million, respectively.

Discussion

While study designs and adherence measures varied across the studies we reviewed, all seven articles found that poor adherence with antipsychotic medication were associated with increased risk of relapse and inpatient hospitalization. Based on the review results, we have provided an update on the national hospitalization costs due to antipsychotic nonadherence in the treatment of schizophrenia.

We used the study results by Gilmer et al.44 to estimate the incremental rehospitalization costs in the United States as a base-case because their study applied well recognized nonadherence measurements and also provided nonadherence rates, cut-off levels, rehospitaliz ation rates, and hospital costs. From the remaining studies we reviewed, two compared relapse rates and rehospitalization costs associated with specific anti psychotic drugs41,43. However, they lacked data on the economic impact of nonadherence. The Weiden and Olfson study6 was based on 1986 National Institute of Mental Health Client/Patient Sample Survey data which is too old for estimating recent hospitalization costs. The study by Harman et al.42 used interruption in Medicaid coverage, which is not the best indicators of nonadherence. The remaining

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2310 Hospitalization costs of antipsychotic nonadherence © 2007 LIBRAPHARM LTD – Curr Med Res Opin 2007; 23(10)

two studies either directly estimated the hospital costs or assessed the incremental hospital days from nonadherence. However, the study by Valenstein et al.25 used VA patient data, which might not be a good representation of the national schizophrenia population. The study by Svarstad et al.40 used a refill gap of 3 months as a nonadherence measure, which is not ideal. Nevertheless, these two studies were used in the sensitivity analysis to compare with the results using findings from Gilmer et al.44.

It appears that the estimated rehospitalization cost based on the Svarstad et al. study ($1392 million) are slightly lower than that from the Gilmer et al. study ($1479 million). It is possible that the Svarstad et al. study which used a nonadherence measure based on a refill gap of 3 months or more for oral medication (6 months or more for depot) may have excluded more nonadherent patients compared with the Gilmer et al. study, which used CPR < 0.8 as a definition for nonadherence. Therefore, it is likely that the estimation based on study results from Svarstad et al. under estimated the economic impact of nonadherence nationally.

The estimated rehospitalization costs based on the Valenstein et al. study are higher than those in the other two studies. One of the reasons contributing to this may be that the Valenstein et al. study used VA patients whose average length of hospital stay is significantly longer than that of non-VA patients. Therefore, the estimation based on VA schizophrenia

populations may overestimate the hospital-related cost of nonadherence. In addition, the Valenstein et al. study did not include depot medications, which have been shown to have a higher adherence rate than oral antipsychotics41. It is likely that both the nonadherence rate and the hospital ization costs would have been lower if depot medications had been included.

We estimated national hospitalization costs from antipsychotic nonadherence in 2005 based on the most recent HCUP data by the time of our study. However, such results might be limited if the adherence and rehospitalization rates with antipsychotics and the prevalence rate of schizophrenia changed significantly in recent years. The studies we reviewed did not include the newer atypical antipsychotics including ziprasidone, aripiprazole and paliperidone, which came to the US market between 2001 and 2007. We were unable to examine whether the nonadherence rates or rehospital ization rates changed after these new drugs came to the market. However, we believe that it is unlikely non adherence rates or rehospitalization rates will change when we have included other second-generation anti psychotics (clozapine, risperidone, olanzapine, and quetiapine) in our reviewed studies. According to the National Institute of Mental Health funded Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Study45, which is the largest, longest, and most comprehensive independent trial ever carried out to examine existing medication therapies for schizophrenia, these new antipsychotic

Table 2 Estimation of the rehospitalization costs due to antipsychotic nonadherence

Variables Gilmer et al.44 Svarstad et al.40

Nonadherence measure and cut-off level 0 ≤ MPR ≤ 0.49 0.5 ≤ MPR ≤ 0.79

Refill gap ≥ 3 months

US population in 2005 (N) 296.4 million 296.4 million 296.4 million

Prevalence rate of schizophrenia (P) 0.01 0.01 0.01

Nonadherence rate (Rn 0.24 0.16 0.19

Hospitalization rate for nonadherent patients (Rhn) 0.35 0.24 0.33

Annual hospitalization costs for nonadherent patients (Chn) $3413 $2689 $3421

Hospitalization rate for adherent patients (Rha) 0.14 0.14 0.19

Annual hospitalization costs for adherent patients (Cha) $1025 $1025 $1799

Hospital costs per day in 2005 (C1) $1658 $1658 $1658

Hospital costs per day in the study year of the corresponding studies (C0)

$1096

$1096

$528

Subtotal ($ million) $1122 $357 $1392

Total costs ($ million) $1479 $1392

The rehospitalization costs (Y) were estimated using the following equation: Y = (N × P × Rn × Rhn × Chn – N × P × Rn × Rha × Cha) × C1/C0

N × P: the number of schizophrenia patients N × P × Rn: the number of nonadherent schizophrenia patients N × P × Rn × Rhn: the number of hospitalized nonadherent schizophrenia patients N × P × Rn × Rhn × Chn: total hospital costs for nonadherent schizophrenia patients N × P × Rn × Rha × Cha: total hospital costs for nonadherent schizophrenia patients if they had been adherent (N × P × Rn × Rhn × Chn – N × P × Rn × Rha × Cha): incremental total hospital costs due to nonadherence (N × P × Rn × Rhn × Chn – N × P × Rn × Rha × Cha) × C1/C0: incremental total hospital costs due to nonadherence in 2005 The equation can also be rewritten as: Y = N × P × Rn × (Rhn × Chn – Rha × Cha) × C1/C0

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drugs were found to be equally as effective and as well tolerated as the older ones. This finding was also supported by other recent studies showing that the new atypical antipsychotic ziprasidone did not do better than other atypical agents in terms of discontinuation rate46,47. Thus, no evidence so far showed that the new antipsychotic drugs developed in recent years had different nonadherence and rehospitalization rates from the older ones.

An additional limitation in estimating the rehospital-ization costs is that our study was restricted to schizophrenia patients mostly from the Medicaid programs, which might not be representative of the US national population. Nonetheless, additional sensitivity analyses using data from other populations were conducted and the results were found to be similar. Therefore, the cost estimates we calculated are deemed to be reasonable.

Of the seven studies reviewed, we found that only two studies25,44 used similar adherence measures and cut-off levels. Because most studies used different adherence measurements, comparison is not easy. Future studies are warranted to standardize adherence measures and cut-off levels, which would help develop real-time alert to detect nonadherence and facilitate timely interventions for better schizophrenia treatment.

Conclusions

There is a consensus in the literature on medication adherence in schizophrenia that poor adherence leads to poor outcomes both in terms of health and costs. From our review, we identified that poor adherence with antipsychotic medication was consistently associated with increased risk of relapse and inpatient hospital-ization. We also found that the incremental annual rehospitalization costs associated with nonadherence of antipsychotics are sizable, with $1479 million in the US in 2005. Therefore, in order to maximize the effect of pharmacologic treatment and reduce the relapse and the cost of hospitalizations among schizophrenia patients, efforts should be undertaken to search for more effective treatment with better adherence outcome. Targeting nonadherent patients specifically would be cost-effective to both improve patient health outcomes and save healthcare costs in schizophrenia treatment.

Acknowledgments

Declaration of interest: No funds were received for this study, and no editorial assistance was received in the preparation of this manuscript.

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CrossRef links are available in the online published version of this paper:http://www.cmrojournal.com

Paper CMRO-4018_3, Accepted for publication: 16 July 2007Published Online: 13 August 2007doi:10.1185/030079907X226050

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