Balancing Therapeutic Safety and Efficacy to Improve Clinical and Economic Outcomes in Schizophrenia: A Managed Care Perspective

Published Online: June 28, 2014
Junqing Liu, PhD, MSW
Schizophrenia is a serious mental disorder associated with high morbidity and mortality, reduced life expectancy, and increased economic burden. Antipsychotic agents used for the management of schizophrenia are often associated with undesirable adverse effects, such as weight gain and metabolic abnormalities, contributing to elevated risk of cardiovascular disease, diabetes, and mortality. Contributors to the growing economic burden of schizophrenia include direct (eg, medical care and hospitalization) and indirect costs (eg, lost productivity and mortality). Strategies to reduce these expenditures include the use of generic medications, improving treatment adherence, avoidance of switching antipsychotic therapies, reducing disease relapses, and appropriate management of cardiometabolic disease. Arguably, while pharmacy benefit and managed care strategies (eg, prior authorization, prescription caps, copayments and patient cost-sharing strategies, tiered formulary pricing, and gap coverage) are designed and implemented to reduce healthcare costs, they may have the unintended result of creating barriers to treatment access and thereby contribute to further adverse patient outcomes. Managed care professionals should be cognizant of the drivers of cost and the need for cardiometabolic monitoring to individualize care for patients with schizophrenia. Further, comprehensive disease management plans should be developed that include the monitoring of disease progression and treatment adherence, while factoring in medication and healthcare administration costs.

Am J Manag Care. 2014;20:S174-S183
The Burden of Disease in Schizophrenia

Despite the ongoing medical research into schizophrenia and the increasing amount of literature that is published every decade, the mental disorder continues to be incompletely understood. The annual incidence of schizophrenia ranges from 8 to 40 cases per 100,000 individuals, or 1 in 10,000 adults, with a relatively similar rate across all continents. In urban areas, the documented incidence of the mental disorder appears to be higher than in non-urban areas, with an overall lifetime risk of developing schizophrenia of approximately 0.7%.1,2 Although the cardinal features of positive (ie, impaired reality) and negative (ie, loss of range of affect, impulse, desire, volition, and striving) symptoms are central to schizophrenia, it has become further recognized that the psychotic phase of schizophrenia is preceded by a premorbid phase (ie, cognitive, motor, or social deficits) and a prodromal phase (ie, attenuated positive symptoms and/or functional decline).3 After the psychotic phase of excessive (ie, florid) positive symptoms, the patient enters a stable phase in which negative symptoms occur, with continuing cognitive, social, and functional decline. Following each psychotic episode, there are variable degrees of recovery to the patient’s baseline state of well-being. Consequently, disease control in the early stage of treatment is essential.3 In addition, schizophrenia is linked to at least a 1.9-fold increased rate of mortality, relative to healthy individuals, which is not entirely explained by disease-specific factors, such as an expected increased rate of suicide.4 One study published in 2008 demonstrated that when comparing their survival with the general population, patients with schizophrenia or schizoaffective disorder 30 years after initial diagnosis had a significantly higher mortality rate. Median survival following diagnosis was 35.9 years for people with schizophrenia and 39.3 years for patients with schizoaffective disorder. The leading causes of death among those patients were cardiovascular disease (CVD) (29%), neoplastic disease (19%), and pulmonary disease (17%).5

CVD is very prevalent among patients with schizophrenia. Compared with non-schizophrenia controls in a population-based study, patients with schizophrenia demonstrated higher rates of CVD (27% vs 17%, odds ratio [OR] 1.76; 95% CI 1.72-1.81)and diabetes (males aged 30 to 39 years, adjusted OR 1.57; 95% CI 1.3-1.91; females age 30 to 39 years, adjusted OR 1.72; 95% CI 1.44-2.04), and were more likely to be of older age and lower socioeconomic status.6 The increased risk of CVD associated with schizophrenia is further linked to a reduction in average life expectancy, relative to non-schizophrenic patients, of approximately 20% from 76 years (72 years in men, 80 years in women) to 61 years (57 years in men, 65 years in women). Two-thirds of patients with schizophrenia versus only half of patients without schizophrenia will eventually die of coronary heart disease (CHD).7 An examination of the predicted risk of CHD from the large-scale Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study, compared with National Health and Nutrition Examination Survey III data, demonstrated a higher 10-year CHD risk in males (9.4% vs 7%; P = .0001) and females (6.3% vs 4.2%; P = .0001), higher smoking rates (68% vs 35%; P <.001), rates of diabetes (13% vs 3%; P <.001), and hypertension (27% vs 17%; P <.001), and lower high-density lipoprotein (HDL) cholesterol levels (43.7 vs 49.3 mg/dL; P <.001).8,9

Evidence has linked weight gain to the observed impaired glucose tolerance, higher rates of diabetes and hypertension, and increased mortality.10 One study from 2001 estimated that a mean weight gain of 2.5 kg per person would result in 366 additional diabetics and 1833 hypertensive patients per 100,000 people over 10 years, and similarly, a weight gain of 12.5 kg per person would result in an additional 2505 diabetic and 9169 hypertensive patients per 100,000 people. Further, the study linked a 2.5-kg and 12.5-kg weight gain per person to an additional 30 and 751 deaths per 100,000 people over 10 years, respectively.10 It is well documented that many of the antipsychotic medications typically used to treat schizophrenia are associated with the adverse effect of weight gain.11-13 To put the impact of medication-induced weight gain into perspective, Fontaine et al found that while clozapine would prevent 492 potential suicide deaths per 100,000 patients with schizophrenia, the weight gain associated with the use of clozapine would also result in 416 additional deaths over the same time period.10 Despite the clear link between these medications and weight gain, hypertension, and diabetes, it should be noted that patients with schizophrenia have also been reported to have impaired glucose tolerance prior to treatment with antipsychotic medications, suggesting a potential genetic linkage or susceptibility.14,15 All of these factors together highlight the significant burden of disease that is associated with the nonpsychiatric consequences of schizophrenia.

The Cost of Schizophrenia Treatment

Schizophrenia is a complex psychiatric disease that is very challenging to manage appropriately, and treatments are often associated with a high risk of nonpsychiatric morbidity and mortality, including CVD and diabetes. To achieve the delicate balance between efficacy and safety, it is important to examine the cost factors associated with the disease.

The direct and indirect costs associated with schizophrenia are summarized in Table 1.16-18 Direct medical costs include the expenses associated with treatment, such as psychotherapy, medication, and hospitalization, and the cost of managing complications, such as CVD and diabetes. Direct nonmedical costs include society’s cost of managing patients with schizophrenia in the community. CVD is the leading cause of death in the United States and accounts for 17% of all healthcare expenditures in the country. Between 2010 and 2030, the total direct cost (in 2008 dollars) resulting from CVD is projected to triple, from $273 billion to $818 billion. During that time, the indirect cost of CVD is also estimated to increase by 61%, from $172 billion to $276 billion.19 The estimated cost of diabetes in the United States was $245 billion in 2012, including $176 billion resulting from direct medical costs and $69 billion from indirect costs, a 47% increase from 2007.20 The overall economic burden of schizophrenia in 2002 was estimated to be $62.7 billion, with $22.7 billion in direct healthcare costs, $7.6 billion in direct non-healthcare costs, and $32.4 billion in indirect costs.16

Indirect costs associated with schizophrenia include the loss of productivity and the loss of life. While lost productivity has been shown to have the highest overall impact on the cost of schizophrenia, the direct healthcare expenditures associated with drug therapy, hospitalization, physician/psychiatric treatment, and long-term/ day care are also major drivers of the economic burden tied to schizophrenia.16-18 Relapse of psychotic symptoms and hospital admissions and readmissions are also important, potentially preventable drivers of cost in schizophrenia. According to a study published in 2013, patients with a relapse within the past 6 months increased the cost of care 4-fold relative to patients without a relapse.21 Adherence to antipsychotic medication therapy is a critical component of preventing relapse in patients with schizophrenia, because monthly relapse occurs in approximately 3.5% of patients who are maintained on neuroleptics versus 11% for patients who have discontinued their antipsychotic medication.22 Treatment nonadherence is estimated to occur in 7.6% of patients per month in the community setting, and approximately 40% of hospital readmissions for patients with schizophrenia are attributed to nonadherence, with 60% owing to the loss of neuroleptic efficacy.22 A study on factors associated with high schizophrenia-related costs published in 2013 demonstrated that patients with poor perceived health status were more likely to be in the high-cost treatment group, whereas patients who were older or who had a spouse were less likely to be in that high-cost group.23 Further, in comparison with older patients, younger patients, African Americans, patients with private insurance, or patients in the northeastern United States had higher relative schizophrenia-related direct medical costs, providing intriguing insight into potential drivers of cost for this complicated disease.23

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