Age-Specific Prevalence and Incidence of Dementia Diagnoses Among Older US Adults With Schizophrenia

Key Points

Question  What are the age-specific incidence and prevalence of dementia among older US adults with schizophrenia?

Findings  In this cohort study of 8 011 773 individuals in a national Medicare database from 2007 to 2017, at 66 years of age, 27.9% of individuals with schizophrenia also had a dementia diagnosis compared with 1.3% of individuals without a serious mental illness. The prevalence of dementia diagnoses among people with schizophrenia at 66 years of age was similar to the prevalence at 88 years of age for the group without serious mental illness.

Meaning  The findings suggest that further study is needed about the processes and impairments that lead to dementia diagnoses in patients with schizophrenia as well as prevention and treatment strategies.

Importance  People with schizophrenia are at high risk of receiving a diagnosis of dementia. Understanding the magnitude and timing of this increased risk has important implications for practice and policy.

Objective  To estimate the age-specific incidence and prevalence of dementia diagnoses among older US adults with schizophrenia and in a comparison group without serious mental illness (SMI).

Design, Setting, and Participants  This retrospective cohort study used a 50% random national sample of Medicare beneficiaries 66 years or older with fee-for-service plans and Part D prescription drug coverage from January 1, 2007, to December 31, 2017. The cohort with schizophrenia included adults with at least 12 months of continuous enrollment in fee-for-service Medicare and Part D and at least 2 outpatient claims or at least 1 inpatient claim for schizophrenia during the qualifying years. The comparison group included adults with at least 12 months of continuous enrollment in fee-for-service Medicare and Part D and without a diagnosis of schizophrenia, bipolar disorder, or recurrent major depressive disorder during the qualifying year. Data were analyzed from January 1 to July 31, 2020.

Main Outcomes and Measures  Dementia was defined using the Centers for Medicare & Medicaid Services Chronic Conditions Warehouse diagnosis codes for Alzheimer disease and related disorders or senile dementia. Incident diagnoses were defined by at least 12 consecutive eligible months without a qualifying code before meeting dementia criteria.

Results  The study population of 8 011 773 adults 66 years or older (63.4% women; mean [SD] age, 74.0 [8.2] years) included 74 170 individuals with a diagnosis of schizophrenia (56.6% women) and 7 937 603 without an SMI diagnosis (63.5% women) who contributed 336 814 and 55 499 543 person-years of follow-up, respectively. At 66 years of age, the prevalence of diagnosed dementia was 27.9% (17 640 of 63 287) among individuals with schizophrenia compared with 1.3% (31 295 of 2 389 512) in the group without SMI. By 80 years of age, the prevalence of dementia diagnoses was 70.2% (2011 of 2866) in the group with schizophrenia and 11.3% (242 094 of 2 134 602) in the group without SMI. The annual incidence of dementia diagnoses per 1000 person-years at 66 years of age was 52.5 (95% CI, 50.1-54.9) among individuals with schizophrenia and 4.5 (95% CI, 4.4-4.6) among individuals without SMI and increased to 216.2 (95% CI, 179.9-252.6) and 32.3 (95% CI, 32.0-32.6), respectively, by 80 years of age.

Conclusions and Relevance  In this cohort study, compared with older adults without SMI, those with schizophrenia had increased risk of receiving a diagnosis of dementia across a wide age range, possibly because of cognitive and functional deterioration related to schizophrenia or factors contributing to other types of dementia. High rates of dementia among adults with schizophrenia have implications for the course of illness, treatment, and service use.

Schizophrenia is characterized by psychotic symptoms such as hallucinations and delusions, cognitive impairment, and functional deficits. The disorder typically begins in early adulthood and is associated with premature mortality and often with substantial disability.^1,2 Dementia is defined by impaired cognition and function. Owing to its effects on behavior and the ability to function independently, dementia markedly affects individuals, families, the health care system, and social welfare programs.^3,4 Accumulating evidence from outside the US suggests that people with schizophrenia have a higher than expected risk of dementia.^5-9 In the US, a prevalence study of 18 740 Medicare beneficiaries reported that 21% of older adults with schizophrenia (n = 208) were diagnosed with dementia, which translated into an increased odds of approximately 5.8 after controlling for age, sex, race, and educational level.¹⁰

The causes and neuropathological basis of dementia among people with schizophrenia are not well understood. For example, in a postmortem study of 100 consecutive brains of middle-aged and older adult patients with schizophrenia,¹¹ 72% had moderate or severe cognitive impairment but only 9% met neuropathological criteria for Alzheimer disease (AD). In the largest epidemiologic study on this topic to date, which involved 20 683 individuals with schizophrenia in Denmark,⁶ a 2-fold excess risk of dementia diagnoses among patients with schizophrenia was not meaningfully diminished after controlling for medical comorbidities, such as diabetes, coronary artery disease, or cerebrovascular diseases, which are risk factors for dementia. Thus, the excess risk of developing dementia among patients with schizophrenia may not be due to an increased risk of AD neuropathology¹¹ or to high prevalence of metabolic problems that are known risk factors for dementia.^12,13 Instead, individuals with schizophrenia are hypothesized to have decreased cognitive reserve that, combined with the cognitive decline of aging, puts them at increased risk of crossing a clinical threshold to warrant a dementia diagnosis.¹⁴

A recent meta-analysis of 6 studies on rates of dementia among people with schizophrenia,¹⁵ all of which were from outside the US, noted a paucity of relevant US research. A better understanding of the incidence and prevalence of dementia among adults with schizophrenia in the US may inform efforts to improve prevention, treatment, and service delivery. For this study, 11 years of US Medicare data were used to examine the age-specific incidence and prevalence of dementia diagnoses among people 66 years or older who had received a diagnosis of schizophrenia and in a comparison group of older adults without serious mental illness (SMI).

This cohort study used data from national Medicare Parts A, B, and D claims from January 1, 2007, to December 31, 2017. Because of Centers for Medicare & Medicaid Services regulations on the size of research data sets, a random sample of approximately 50% of all Part D–enrolled beneficiaries with fee-for-service coverage were included. These beneficiaries had complete claims data on Medicare-covered health services and prescription medications. The institutional review boards of the New York State Psychiatric Institute, New York; Columbia University Department of Psychiatry, New York, New York; and Rutgers University, New Brunswick, New Jersey, approved the study and deemed that informed consent was not required for use of retrospective data. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.

The cohort with schizophrenia for the prevalence analysis included all individuals 66 years or older with at least 12 months of continuous enrollment in fee-for-service Medicare and Part D and at least 2 outpatient claims or at least 1 inpatient claim for schizophrenia during the qualifying period. The comparison group included all individuals 66 years or older with at least 12 months of continuous enrollment in fee-for-service Medicare and Part D and without a diagnosis of schizophrenia, bipolar disorder, or recurrent major depressive disorder during the qualifying year. Individuals with bipolar disorder or recurrent major depressive disorder were excluded from the comparison condition to reduce the possibility of diagnostic overlap with schizophrenia. Because of the 1-year qualifying period and because Medicare eligibility typically begins at 65 years of age, only individuals 66 years or older met the eligibility criteria. For the analyses of incident dementia diagnoses, individuals with any claims with dementia diagnoses or prescription claims for a cholinesterase inhibitor or memantine hydrochloride in the 12-month baseline period were excluded. Race/ethnicity is assigned by self-report in Medicare claims and was included in the study because of previous research showing differences in the prevalence and incidence of dementia among racial/ethnic groups.²

Two outpatient codes or 1 inpatient code in any position in the diagnosis list were required to meet the diagnostic criteria for schizophrenia, dementia, and other SMI.¹⁶ When individuals met the criteria for schizophrenia, they were considered to retain the condition at all future ages of observation. Dementia was defined using the diagnostic codes used by Centers for Medicare & Medicaid Services Chronic Conditions Warehouse algorithm for AD and related disorders or senile dementia.¹⁷ eTable 1 in the Supplement gives the codes from the International Classification of Diseases, Ninth Revision and International Statistical Classification of Diseases and Related Health Problems, Tenth Revision that were used to define these conditions. Compared with in-person cognitive impairment assessments among older members of the general population, a claims-based definition using this list of diagnostic codes has shown a sensitivity of 85.5%, a specificity of 85.9%, and a κ of 0.70 for the diagnosis of dementia.¹⁸ For dementia, 2 outpatient diagnoses had to have been received within a 365-day period. The type of dementia was determined according to diagnostic codes given in the first year, starting with the initial dementia diagnosis, and were categorized as AD, vascular dementia, or unspecified/other. For the incident case analyses, the second observed qualifying code defined the date of diagnosis. For sensitivity analysis, we used a narrower definition of dementia that excluded potentially reversible causes of dementia (eTable 2 in the Supplement gives the narrower list of codes). The broader Centers for Medicare & Medicaid Services Chronic Conditions Warehouse list of diagnoses codes was used in the primary analysis because of its authoritative source and prior validation work.¹⁸

Data were analyzed from January 1 to July 31, 2020. The prevalence and incidence of diagnosed dementia were calculated for each year of age for the overall sample and separately by sex. Follow-up for the prevalence analyses began after the 1-year qualifying period was completed and ended with death, end of data availability, or loss of eligibility, whichever came first. For the incidence calculations, follow-up ended with death, diagnosis of dementia, end of data availability, or loss of eligibility, whichever came first. Prevalence rates were also calculated by race/ethnicity and for AD and vascular dementia diagnoses. Stratification by age, sex, and race/ethnicity directly controlled for differences in the demographic distributions between people with schizophrenia and those without SMI. Because individuals diagnosed with dementia were also considered to retain the condition at all future ages, prevalent dementia cases for each year of age included incident cases and all previously identified cases. We provide 95% CIs in the text for selected outcomes to show the significance of findings in these population-based analyses.

To empirically evaluate 1 aspect of the validity of a dementia diagnosis, which is a known risk factor for mortality,¹⁹ mortality rates for a given age were compared between the cohorts with schizophrenia alone and with co-occurring dementia and schizophrenia. To examine the possibility that for individuals with schizophrenia, dementia was diagnosed to facilitate admission to nursing homes, rates of nursing home admission within 30 and 90 days of new dementia diagnoses were calculated for the cohort with schizophrenia and the cohort without SMI.

Among the study population of 8 011 773 adults 66 years or older (63.4% women and 36.6% men; mean [SD] age, 74.0 [8.2] years), the group with schizophrenia included 74 170 individuals who met the claims-based diagnostic criteria for schizophrenia. The comparison group included 7 937 603 individuals without SMI. Table 1 provides the sex and race/ethnicity of the 2 groups. The group with schizophrenia included a higher percentage of men (43.4% vs 36.5%) and Black individuals (20.5% vs 7.8%) and a lower percentage of women (56.6% vs 63.5%) and non-Hispanic White individuals (68.6% vs 81.4%).

At 66 years of age, the prevalence of dementia diagnoses was 27.9% (17 640 of 63 287) in the group with schizophrenia compared with 1.3% (31 295 of 2 389 512) in the group without SMI (21.5 times higher). By 80 years of age, the prevalence of dementia diagnoses was 70.2% (2011 of 2866) in the group with schizophrenia and 11.3% (242 094 of 2 134 602) in the group without SMI (6.2 times higher) (Table 2 and eFigure 1 in the Supplement). With use of the narrower definition, at 66 years of age, the prevalence of dementia diagnoses was 23.2% (14 660 of 63 287) in the group with schizophrenia compared with 1.0% (24 885 of 2 389 512) in the group without SMI (23.2 times higher). By 80 years of age, with the narrower definition of dementia diagnoses, the prevalence was 61.7% (1768 of 2866) in the group with schizophrenia and 9.6% (204 275 of 2 134 602) in the group without SMI (6.4 times higher) (eTable 3 in the Supplement).

Figure 1 shows the prevalence of dementia diagnoses in the 3 largest racial/ethnic study groups. At 66 years of age, the prevalence of dementia diagnoses among non-Hispanic White individuals was 27.6% (12 021 of 43 483); among Black individuals, 28.8% (3808 of 13 217); and among Hispanic individuals, 28.6% (1290 of 4508). At 80 years of age, the prevalence was 69.3% (1305 of 1883) among non-Hispanic white individuals, 74.6% (405 of 543) among Black individuals, and 67.7% (243 of 359) among Hispanic individuals (Figure 1 and eTable 4 in the Supplement).

Among 46 048 adult Medicare beneficiaries 66 years or older who had schizophrenia but not preexisting dementia, the annual incidence of dementia diagnoses per 1000 person-years increased from 52.5 (95% CI, 50.1-54.9) for adults aged 66 years to 216.2 (95% CI, 179.9-252.6) for adults aged 80 years. Among 7 300 048 adults without SMI and preexisting dementia, the corresponding increase per 1000 person-years was from 4.5 (95% CI, 4.4-4.6) for adults aged 66 years to 32.3 (95% CI, 32.0-32.6) for adults aged 80 years (Figure 2 and Table 3).

Using the narrower set of dementia diagnoses, the annual incidence of dementia diagnoses per 1000 person-years increased from 46.6 (95% CI, 44.4-48.8) for adults aged 66 years to 180.3 (95% CI, 150.5-210.1) for adults aged 80 years. Among 7 390 157 adults without SMI and preexisting dementia, the corresponding increase was from 3.6 (95% CI, 3.5-3.7) for adults aged 66 years to 28.1 (95% CI, 27.8-28.4) for adults aged 80 years (eTable 5 in the Supplement).

At 66 years of age, 5.0% (3147 of 63 287) of individuals with schizophrenia had a diagnosis of vascular dementia compared with 0.2% (4476 of 2 389 512) in the non-SMI comparison group. By 80 years of age, the prevalence of vascular dementia diagnoses was 15.6% (446 of 2866) in the group with schizophrenia and 1.5% (32 141 of 2 134 602) in the group without SMI. The prevalence of AD diagnoses at 66 years of age was 8.2% (5179 of 63 287) in the group with schizophrenia and 0.4% (8677 of 2 389 512) in the group without SMI. By 80 years of age, the prevalence of AD diagnoses was 37.2% (1065 of 2866) in the group with schizophrenia and 5.1% (108 836 of 2 134 602) in the comparison group (eTables 6 and 7 in the Supplement).

In the group with schizophrenia, 29.4% (2948 of 10 014) first received a dementia diagnosis while in a nursing home compared with 16.5% (184 872 of 1 119 632) in the group without SMI. Among people who were not in a nursing home at the time of their first diagnosis of dementia, 25.2% in the group with schizophrenia (1779 of 7066) and in the group without SMI (235 817 of 934 760) were admitted to a nursing home within 30 days of dementia diagnosis. Within 90 days of dementia diagnosis, this rate increased to 30.8% (2178 of 7066) in the group with schizophrenia and 28.7% (268 708 of 934 760) in the group without SMI (eTable 8 in the Supplement).

At 66 years of age, the mortality rate per 1000 person-years was 125.2 (95% CI, 119.0-131.5) for persons with schizophrenia and dementia diagnoses compared with 60.8 (95% CI, 58.2-63.5) for persons with schizophrenia without a dementia diagnosis. At 80 years of age, the corresponding mortality rates were 199.7 (95% CI, 177.4-222.1) and 172.7 (95% CI, 139.7-205.7) (eTable 9 and eFigure 2 in the Supplement).

In the group without SMI, the annual mortality rate at 66 years of age per 1000 person-years was 138.4 (95% CI, 133.5-143.2) for persons with dementia diagnoses and 17.8 (95% CI, 17.6-18.0) for persons without a dementia diagnosis. At 80 years of age, the corresponding mortality rates were 181.9 (95% CI, 179.9-183.9) and 45.9 (95% CI, 45.6-46.2) (eTable 9 and eFigure 2 in the Supplement).

This retrospective longitudinal cohort study found a markedly elevated rate of dementia diagnoses among US Medicare beneficiaries 66 years or older who had schizophrenia compared with beneficiaries who did not have an SMI diagnosis. Age-specific analyses revealed that people with schizophrenia compared with those without SMI received dementia diagnoses at younger ages. Notably, the prevalence of diagnosed dementia among people with schizophrenia at 66 years of age was similar to the prevalence of diagnosed dementia at 88 years of age for the group without SMI. Increased incidence of dementia diagnoses in the group with schizophrenia showed the greatest increase at younger ages but was apparent across the older adult life span. Elevated rates of dementia diagnoses among older adults with schizophrenia were present in men, women, and all racial/ethnic groups. In the population with schizophrenia, which is known to be associated with a high risk of premature death,² dementia diagnoses were associated with an additional increased risk of mortality, especially among those who were younger.

The elevated risk of dementia diagnoses among people with schizophrenia found in the present study is consistent with results from other countries^5-9 and 1 earlier US report.¹⁰ Compared with the findings from a study of the long-term risk of dementia in persons with schizophrenia in Denmark,⁶ the rates of dementia diagnoses in the US were higher. One possible contributor to this difference is the substantially higher rates of dementia in the general population in the US compared with Denmark.²⁰ Prior work in the US¹⁰ included all Medicare recipients 65 years or older and found an adjusted odds ratio of 5.8 for a diagnosis of dementia among individuals diagnosed with schizophrenia. This overall odds ratio is consistent with the results of the present study, but the prior investigation did not examine age-specific prevalence. Because dementia was diagnosed at younger ages in the group with schizophrenia than in the group without SMI, the magnitude of the increased incidence and prevalence was larger among people in their late 60s than among older people.

The causes of increased rates of dementia among people with schizophrenia are not fully understood. Factors associated with dementia, such as cardiovascular disease, hyperlipidemia, smoking, and substance use disorders, are especially common among individuals with schizophrenia.^12,13 Prior research, however, suggests that the risk of dementia among people with schizophrenia is largely independent of substance use disorders or comorbid medical conditions, although lower adherence to treatments prescribed for hypertension, diabetes, and vascular disease may contribute to the risk.⁶ Decreased cognitive reserve associated with schizophrenia and the cumulative effect of behavioral and metabolic factors associated with dementia that are common in individuals with schizophrenia may accelerate the rate at which individuals in this group cross a cognitive functioning threshold warranting a clinical dementia diagnosis.

Individuals with schizophrenia commonly take several psychotropic medications during the course of their lifetime. Whether and how these affect the onset and course of dementia need further investigation. For example, benzodiazepines, which are commonly prescribed to people with schizophrenia,²¹ are associated with worsened cognition and may be associated with increased risk of dementia in the general population.^22-24 For individuals with schizophrenia, antipsychotics are associated with improved clinical outcomes²⁵ and lower mortality rates,²⁶ but effects on other and longer-term outcomes are less clear.²⁷ Antipsychotics are labeled with a cautionary warning for use in individuals with dementia because of an increased risk of death. Investigations of the effects of antipsychotic treatment on mortality and other key clinical outcomes among older adults with schizophrenia and dementia are urgently needed.

The current population-based analyses did not attempt to control for comorbidities that might contribute to the differences in risk of incident dementia diagnosis. Instead, results were stratified by sex and race/ethnicity to assess outcomes in demographic groups. This approach aligned with our primary goal of defining the real-world clinical burden of dementia diagnoses in individuals with schizophrenia.

The high proportion of older adults with schizophrenia who had dementia diagnoses in Medicare claims may have been attributable in part to factors that are not neuropathological. For example, life events such as the death of a spouse or other caregivers that necessitate skilled nursing care or other assistance may be associated with a lower threshold for clinical dementia diagnoses. In these situations, dementia diagnoses may facilitate nursing home admissions because of the stringent federal eligibility criteria for placing adults with schizophrenia or other mental illnesses in long-term nursing facilities.²⁸ However, the present analyses did not reveal a large excess of nursing home admissions within 30 or 90 days of the first dementia diagnosis in the group with schizophrenia.

As expected, dementia diagnoses were associated with higher mortality rates, although this association among people with schizophrenia was smaller than in the comparison population without SMI. One reason for this attenuation may be that, among people with schizophrenia, the mortality rate due to other causes was high and any additional effects of dementia were therefore modest. As suggested by postmortem research,¹¹ dementia diagnosed in people with schizophrenia may be less severe or neuroanatomically different from dementia diagnosed in the general population and may reflect progression of or accelerated aging associated with schizophrenia.²⁹

Cognitive and functional decline that surpasses the threshold for a dementia diagnosis in individuals with schizophrenia brings serious clinical challenges, including proper assessment and management. For example, the US Food and Drug Administration’s black box warning of increased risk of death when antipsychotics are used by people with dementia³⁰ directly contradicts recommendations for first-line treatment of schizophrenia. In the absence of evidence-based guidance on pharmacologic treatment strategies, an innovative approach is a cognitive health toolkit that provides materials for assessment and service planning.³¹ Additional research is needed to determine evidence-based pharmacotherapies for individuals with schizophrenia who develop dementia.

Much remains to be learned about the onset, course, and management of schizophrenia in patients with comorbid dementia. It is not known why some adults but not others with schizophrenia undergo progressive cognitive decline decades before the usual onset of dementia in the general population.³² Identification of modifiable risk factors, possibly including anticholinergic medications,³³ inadequately treated psychosis, and comorbid medical conditions such as hypertension and diabetes, may help focus prevention efforts. Further investigation is also needed of the clinical assessment of dementia in patients with schizophrenia, particularly broad neuropsychological assessment that covers the characteristic cognitive deficits of both schizophrenia and dementia and the evaluation of different medication classes for treatment and the course of illness in people with schizophrenia and dementia. Given the large number of affected individuals, high priority should be given to research in these areas that will aid in the development of clinical practice guidelines for the prevention, assessment, and management of dementia in adults with schizophrenia.

A limitation of large-scale, claims-based research of neuropsychiatric conditions is that the research relies on clinical diagnoses that cannot be confirmed by clinical interview or pathologic results. The validity of claims-based diagnoses of dementia used in these analyses has been demonstrated in the general population, and age-specific prevalence estimates of diagnosed dementia from the cohort without SMI closely tracked population estimates from prior investigations using Medicare data¹⁰ and from other sources.³⁴ However, this algorithm has not been validated for patients with schizophrenia.

Because cognitive impairment is a core component of schizophrenia, deciding when an individual’s cognitive functioning warrants a dementia diagnosis is a clinical challenge that has been the subject of considerable research and commentary.³⁵ Factors contributing to diagnostic challenges include preexisting cognitive impairment and difficulties conducting comprehensive neuropsychological testing in individuals with schizophrenia.

Analyses using Medicare claims may reveal increased rates of dementia diagnoses compared with actual rates of confirmed dementia. The list of diagnosis codes included in the validated dementia algorithm in the primary analyses included some potentially reversible causes of cognitive impairment. Clinically it is important to identify and address these causes. However, use of a narrower set of dementia diagnoses in sensitivity analyses revealed reduced dementia diagnoses rates of only about 20%, with proportionate reductions in the group with schizophrenia and the group without SMI; the prevalence of dementia diagnoses among individuals with schizophrenia remained more than 20 times higher than that in the group without SMI at 66 years of age.

In this cohort study, the prevalence and incidence of dementia diagnoses was markedly elevated among older adults with schizophrenia compared with individuals without an SMI. Approximately 28% of the group with schizophrenia had received a diagnosis of dementia before 66 years of age, indicating early-onset dementia. The implications of this high rate of comorbidity are substantial for families and for the service system, which must provide high levels of care for individuals with a combination of disabling conditions and uncertain treatment pathways.

Accepted for Publication: January 11, 2021.

Published Online: March 10, 2021. doi:10.1001/jamapsychiatry.2021.0042

Corresponding Author: T. Scott Stroup, MD, MPH, Department of Psychiatry, Columbia University Vagelos College of Physicians and Surgeons, 1051 Riverside Dr, Room 6715, New York, NY 10032 (Scott.Stroup@nyspi.columbia.edu).

Author Contributions: Drs Huang and Gerhard had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Stroup, Olfson, Wall, Gerhard.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Stroup.

Critical revision of the manuscript for important intellectual content: Olfson, Huang, Wall, Goldberg, Devanand, Gerhard.

Statistical analysis: Huang, Wall, Goldberg.

Obtained funding: Stroup, Olfson.

Administrative, technical, or material support: Stroup, Devanand, Gerhard.

Supervision: Devanand, Gerhard.

Conflict of Interest Disclosures: Dr Stroup reported receiving grants from the National Institute of Mental Health (NIMH) during the conduct of the study and personal fees for continuing medical education activity from Intra-Cellular Therapies Inc outside the submitted work. Dr Olfson reported receiving grants from the NIMH during the conduct of the study. Dr Huang reported receiving grants from the NIMH during the conduct of the study. Dr Wall reported receiving grants from the NIMH during the conduct of the study. Dr Devanand reported receiving grants from the National Institute on Aging (NIA) and NIMH during the conduct of the study and personal fees for serving as scientific advisor from Acadia Pharmaceutical Inc, Eisai Co, Ltd, Genentech, Inc, and Sunovion Pharmaceutical Inc and for serving on a data safety monitoring board from GreenValley Inc outside the submitted work. Dr Gerhard reported receiving grants from the NIA and NIMH during the conduct of the study; grants and personal fees from Bristol Myers Squibb outside the submitted work; and personal fees from Eisai Co, Ltd, Merck & Co, Pfizer, Inc, Eli Lilly and Company, and IntraCellular Therapies Inc outside the submitted work. No other disclosures were reported.

Funding/Support: This study was supported by grant 3P50MH115843-02S1 from the NIMH (Dr Stroup).

Role of the Funder/Sponsor: The NIMH had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.