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JAMA Netw Open
JAMA Netw Open
JAMA Network Open
2574-3805
American Medical Association

39254976
10.1001/jamanetworkopen.2024.32401
zoi240973
Research
Original Investigation
Online Only
Psychiatry
Risk Factors for Natural Cause Mortality in Schizophrenia
Risk Factors for Natural Cause Mortality in Schizophrenia
Risk Factors for Natural Cause Mortality in Schizophrenia
Dickerson Faith PhD 1
Khan Sabahat MD 1
Origoni Andrea BA 1
Rowe Kelly BA 1
Katsafanas Emily BS 1
Harvin Alexander BS 1
Yang Shuojia MS 2
Yolken Robert MD 2
1 Stanley Research Program, Sheppard Pratt, Baltimore, Maryland
2 Department of Pediatrics, Johns Hopkins School of Medicine, Baltimore, Maryland
Article Information

Accepted for Publication: July 15, 2024.

Published: September 10, 2024. doi:10.1001/jamanetworkopen.2024.32401

Open Access: This is an open access article distributed under the terms of the CC-BY-NC-ND License. © 2024 Dickerson F et al. JAMA Network Open.

Corresponding Author: Faith Dickerson, PhD, Sheppard Pratt, 6501 N Charles St, Baltimore, MD 21204 (fdickerson@sheppardpratt.org).
Author Contributions: Dr Dickerson 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: Dickerson, Khan, Katsafanas, Yolken.

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

Drafting of the manuscript: Dickerson, Yang, Yolken.

Critical review of the manuscript for important intellectual content: All authors.

Statistical analysis: Yolken.

Obtained funding: Dickerson.

Administrative, technical, or material support: Dickerson, Khan, Origoni, Katsafanas, Harvin, Yang.

Supervision: Dickerson, Khan, Katsafanas.

Conflict of Interest Disclosures: Dr Yolken reported being a board member of the Stanley Medical Research Institute during the conduct of the study. No other disclosures were reported.

Funding/Support: This work was supported by grants 90028420 (Dr Yolken) and 07-1690 (Dr Dickerson) from the Stanley Medical Research Institute and by a grant from Boehringer Ingelheim (Dr Dickerson).

Role of the Funder/Sponsor: The funders 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.

Data Sharing Statement: See Supplement 2.

10 9 2024
9 2024
10 9 2024
7 9 e243240116 3 2024
15 7 2024
Copyright 2024 Dickerson F et al. JAMA Network Open.
https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article distributed under the terms of the CC-BY-NC-ND License.
jamanetwopen-e2432401.pdf

Key Points

Question

Is cognitive functioning associated with the risk of natural cause mortality in schizophrenia?

Findings

In this cohort study of 844 individuals with schizophrenia, lower cognitive functioning was significantly associated with the risk of natural cause mortality. Other associated factors included tobacco smoking, obesity, divorced or separated marital status, and cardiopulmonary and autoimmune disorders.

Meaning

These findings suggest that efforts should be directed to improving cognitive functioning in persons with schizophrenia who have additional risk factors for mortality.

This cohort study examines whether lower cognitive function is a risk factor for natural cause mortality among individuals with schizophrenia.

Importance

Schizophrenia is associated with premature mortality from mostly natural causes. Decreased cognitive functioning has been identified as a determinant of mortality in the general population. However, there have been few prospective studies of this issue in persons with schizophrenia.

Objective

To examine whether lower cognitive functioning is a risk factor for natural cause mortality in schizophrenia.

Design, Setting, and Participants

This prospective cohort study included persons with schizophrenia or schizoaffective disorder enrolled between February 1, 1999, and December 31, 2022, at a nonprofit psychiatric system in Baltimore, Maryland. Participants were evaluated using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and other clinical measures.

Exposure

Natural cause mortality.

Main Outcomes and Measures

Associations of cognitive function, obesity, tobacco smoking, and medical conditions with natural cause mortality were evaluated using Cox proportional hazards regression models.

Results

Of the 844 participants enrolled (mean [SD] age, 39.6 [12.1] years; 533 male [63.2%]), 158 (18.7%) died of natural causes during a median follow-up of 14.4 years (range, 7.0 days to 23.9 years). The most significant factor associated with mortality was lower cognitive functioning as measured by the RBANS (Cox coefficient, −0.04; 95% CI, −0.05 to −0.03; z = −5.72; adjusted P < .001). Additional factors independently associated with mortality included the diagnosis of an autoimmune disorder (hazard ratio [HR], 2.86; 95% CI, 1.83-4.47; z = 4.62; adjusted P < .001), tobacco smoking (HR, 2.26; 95% CI, 1.55-3.30; z = 4.23; adjusted P < .001), diagnosis of chronic obstructive pulmonary disease (HR, 3.31; 95% CI, 1.69-6.49; z = 3.48; adjusted P = .006), body mass index as a continuous variable (HR, 1.06; 95% CI, 1.02-1.09; z = 3.30; adjusted P = .01), diagnosis of a cardiac rhythm disorder (HR, 2.56; 95% CI, 1.40-4.69; z = 3.06; adjusted P = .02), and being divorced or separated (HR, 1.80; 95% CI, 1.22-2.65; z = 2.97; adjusted P = .02). An RBANS score below the 50th percentile displayed a joint association with being a smoker, having an elevated body mass index, and having a diagnosis of an autoimmune or a cardiac rhythm disorder.

Conclusions and Relevance

In this prospective cohort study, lower cognitive functioning was a risk factor for natural cause mortality in schizophrenia. Efforts should be directed at methods to improve cognitive functioning, particularly among individuals with additional risk factors.
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pmcIntroduction

Persons with schizophrenia die, on average, more than 10 years younger than those in the overall population.1,2,3 Most of this excess mortality is due to natural causes of death, such as cardiovascular disease, cancer, and respiratory disease.2 Despite advances in medical treatment and longer survival for most populations, the mortality gap between persons with schizophrenia and those in the general population appears to be increasing.4

Persons with schizophrenia have an increased prevalence of modifiable risk factors for mortality that contribute to this mortality excess.5,6 These factors include obesity, tobacco smoking, and substance use. The presence of comorbid medical conditions, such as cardiac, respiratory, endocrine, and autoimmune disorders, also increases mortality risk among persons with schizophrenia as these conditions are found disproportionately in this population.7,8 The association of psychiatric medications with natural cause mortality in schizophrenia has also been studied, showing that second-generation antipsychotics in particular have a protective influence3 and that benzodiazepines increase risk.9 These studies, however, did not take into account other risk factors, such as tobacco smoking and obesity.

Reduced cognitive functioning has been established as a core feature of schizophrenia10 but has been the focus of only limited investigation as a contributor to premature mortality in this population. Several studies have found that reduced cognitive functioning is associated with increased mortality for persons with a number of different medical conditions11,12 as well as in the overall population.13,14,15 Prospective cohort studies using cognitive measures may reveal more accurately the association between reduced cognitive functioning and subsequent natural cause mortality among persons with schizophrenia.

The Sheppard Pratt Stanley cohort was established in 1999 and has enrolled individuals with schizophrenia since that time. In this study, we examined the association between cognitive functioning and other potential risk factors at the time of enrollment with subsequent natural cause mortality. We hypothesized that lower cognitive functioning is a risk factor for natural cause mortality and would display joint associations with other risk factors prevalent in this population, such as tobacco smoking and co-occurring illnesses.

Methods

Participants were recruited at Sheppard Pratt, a nonprofit psychiatric health system in Maryland, and enrolled between February 1, 1999, and December 31, 2022. This cohort study was approved by the institutional review boards of Sheppard Pratt and the Johns Hopkins School of Medicine, and participants provided written informed consent. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.16

The inclusion criteria were a diagnosis of schizophrenia or schizoaffective disorder based on the Structured Clinical Interview for DSM-IV Axis 1 Disorders,17 age 18 to 65 years, and English language proficiency. Exclusion criteria were history of intravenous substance abuse or intellectual disability; HIV infection or serious medical disorder that would impair cognitive functioning; and a primary diagnosis of alcohol or substance use disorder per Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) criteria.18

Participants were interviewed and medical charts reviewed; information was obtained about demographics (age, sex, self-identified race and ethnicity [Asian, Black, Hispanic, White, and other], education, marital status, and diagnosis [schizophrenia vs schizoaffective disorder]); co-occurring medical conditions from a review of systems; current tobacco smoking, including the number of packs of cigarettes smoked per day; history of substance abuse or dependence apart from nicotine or caffeine; and current medications. Race and ethnicity were included as racial disparities in mortality outcomes are well established in the US.19,20 Psychiatric symptoms were assessed using the Positive and Negative Syndrome Scale.21 Body mass index (BMI) was calculated from measured weight in kilograms divided by height in meters squared.

Cognitive functioning was assessed using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS),22 which comprises 12 subtests to calculate 5 index scores and a total score. Test indexes are immediate memory (list learning and story memory tasks); visuospatial and constructional (figure copy and line orientation tasks); language (picture naming and semantic fluency tasks); attention (digit span and coding tasks); and delayed memory (list recall, story recall, figure recall, and list recognition tasks). Each index score is expressed as a partially age-adjusted standard score based on 10-year intervals. The index scores are combined to yield an RBANS total score of 40 to 60, with higher scores indicating better overall cognitive functioning.

At baseline, a blood sample was drawn to measure antibodies to infectious agents and markers of inflammation as previously described.23,24 The list of variables analyzed and number of imputed values are provided in eMethods 1 in Supplement 1.

Mortality Status at Follow-Up

The US National Death Index25,26 provided the date and cause of death for deceased participants through December 31, 2022. The duration of observation was calculated for each participant as the time between the baseline study visit and December 31, 2022, or the date of death. A total 39 individuals who died from unnatural causes, such as suicide or accidents, were excluded from the principal analyses but were included in sensitivity analyses in which they were examined as competing risks.

Statistical Analysis

Standardized mortality ratios were calculated using data for all deaths from the 2020 US Social Security Period Life Table data, calculated by sex and by age decade at time of death. Total years of potential life lost were estimated by subtracting each participant’s age at death from 75 (the life expectancy of the general population) and summing these differences for the entire sample as previously described.24,27

The association of 106 baseline cognitive, demographic, serologic, and clinical variables (eMethods 1 in Supplement 1) with mortality were evaluated with the least absolute shrinkage and selection operator (LASSO) method using Cox proportional hazards regression models and selection by cross validation. Factors selected by LASSO (defined by coefficients with absolute values ≥0.05) were subsequently entered into a single Cox proportional hazards regression model and displayed as Kaplan-Meier plots to identify the risk factors that were independently associated with increased hazards of natural cause mortality. Other than the cognitive measures described above, the variables were not standardized. Further details of the statistical methods are provided in eMethods 2 in Supplement 1.

All statistical analyses were performed using Stata, version 18 (StataCorp LLC). A 2-sided P < .05 was considered significant.

Results

Study Sample

The study cohort consisted of 844 participants (mean [SD] age, 39.6 [12.1] years; 311 female [36.8%] and 533 male [63.2%]; and 339 Black [40.2%], 476 White [56.4%], and 29 other [3.4%] race) (Table 1). Participants were followed up for a median observation period of 14.4 years (range, 7.0 days to 23.9 years); the total number of person-years of observation was 12 314. The mean (SD) BMI among participants alive at follow-up or who were dead of natural causes was 30.4 (6.4) and 31.4 (5.9), respectively. A total of 109 participants (12.9%) were divorced or separated. A flowchart of participants is shown in eFigure 1 in Supplement 1.

Table 1. Characteristics of Participants at Baseline and by Natural Cause Mortality

Characteristic	No. of participants (%)	
Total sample (N = 844)	Alive at follow-up (n = 686)	Dead from natural causes (n = 158)	
Demographic variables				
Age at enrollment, mean (SD), ya	39.6 (12.1)	37.7 (11.9)	48.1 (18.6)	
Sexb				
Female	311 (36.8)	241 (35.1)	70 (44.3)	
Male	533 (63.2)	445 (64.9)	88 (55.7)	
Race and ethnicity				
Blacka	339 (40.2)	303 (44.2)	36 (22.8)	
Whitea	476 (56.4)	357 (52.0)	119 (75.3)	
Otherc	29 (3.4)	26 (3.8)	3 (1.9)	
Education, mean (SD), y	12.4 (2.3)	12.5 (2.4)	12.3 (2.4)	
Maternal educationb	12.7 (2.7)	12.7 (2.7)	12.3 (2.6)	
Divorced or separateda	109 (12.9)	69 (10.1)	40 (25.3)	
Diagnosis of schizophrenia vs schizoaffective disorder	451 (53.4)	364 (53.1)	87 (55.1)	
Clinical variables				
PANSS score, mean (SD)d				
Total	75.1 (14.2)	75.4 (14.4)	73.2 (13.4)	
Positive	19.1 (5.3)	19.2 (5.3)	18.8 (5.0)	
Negative	20.1 (4.9)	20.2 (5.0)	19.6 (4.8)	
General	35.8 (7.8)	36.0 (7.8)	34.8 (7.4)	
Tobacco smoker, cigarette packs/da	509 (60.3)	388 (56.5)	121 (76.6)	
0	335 (39.7)	298 (43.4)	37 (23.4)	
>0 to ≤0.5	198 (23.5)	165 (24.1)	33 (20.9)	
>0.5 to ≤1.0	204 (24.2)	157 (22.9)	47 (29.8)	
>1	107 (12.7)	66 (9.6)	41 (26.0)	
Recent substance misusee,f	106 (12.6)	96 (14.0)	10 (6.3)	
BMI, mean (SD)	30.6 (6.3)	30.4 (6.4)	31.4 (5.9)	
Psychotropic medications				
Atypical antipsychotic	703 (83.3)	571 (83.2)	132 (83.5)	
Olanzapine	205 (24.3)	158 (23.0)	47 (29.8)	
Risperidone	228 (27.0)	189 (27.6)	39 (24.7)	
Clozapinee	166 (19.7)	122 (17.8)	44 (27.9)	
Ziprasidone	45 (5.3)	40 (5.8)	5 (3.2)	
Quetiapine	111 (13.2)	95 (13.9)	16 (10.1)	
Aripiprazole	64 (7.6)	57 (8.3)	7 (4.4)	
Antidepressantb	341 (40.4)	264 (38.5)	77 (48.7)	
Bupropion	41 (4.9)	31 (4.5)	10 (6.3)	
Fluoxetinee	49 (5.8)	32 (4.7)	17 (10.8)	
Sertraline	62 (7.4)	49 (7.1)	13 (8.2)	
Trazodone	96 (11.4)	85 (12.4)	11 (7.0)	
Escitalopram	25 (3.0)	23 (3.4)	2 (1.3)	
Tricyclic	20 (2.4)	13 (1.9)	7 (4.4)	
Anticonvulsantb	281 (33.3)	215 (31.3)	66 (41.8)	
Valproate	179 (21.2)	139 (20.3)	40 (25.3)	
Gabapentina	32 (3.8)	19 (2.8)	13 (8.2)	
Carbamazepine	34 (4.0)	24 (3.5)	10 (6.3)	
Lamotrigine	24 (2.8)	22 (3.2)	2 (1.3)	
Topiramate	16 (1.9)	14 (2.0)	2 (1.3)	
Lithium	104 (12.3)	87 (12.7)	17 (10.8)	
Anticholinergic	285 (33.8)	233 (34.0)	52 (32.9)	
Benzodiazepineb	209 (24.8)	158 (23.0)	51 (32.3)	
Comorbid medical conditions				
Musculoskeletala	116 (13.7)	80 (11.7)	36 (22.8)	
Endocrine				
Type 2 diabetesb	112 (13.3)	82 (12.0)	30 (19.0)	
Type 1 diabetese	16 (1.9)	9 (1.3)	7 (4.4)	
Hypothyroid	92 (10.9)	64 (9.3)	28 (17.7)	
Genitourinary	86 (10.2)	65 (9.5)	21 (13.3)	
Respiratory				
COPDa	22 (2.6)	9 (1.3)	13 (8.2)	
Emphysema	7 (0.8)	4 (0.6)	3 (1.9)	
Sleep apnea	21 (2.5)	17 (2.5)	4 (2.5)	
Chronic cough	33 (3.9)	26 (3.8)	7 (4.4)	
Other	127 (15.1)	109 (15.9)	18 (11.4)	
Neoplastic	21 (2.5)	14 (2.0)	7 (4.4)	
Cardiovascular				
Hypertensione	232 (27.4)	173 (25.2)	59 (37.3)	
Hyperlipidemia	215 (25.5)	166 (24.2)	49 (31.0)	
Structuralb	38 (4.5)	26 (3.8)	12 (7.6)	
Arrhythmiae	31 (3.7)	19 (2.8)	12 (7.6)	
Murmur	52 (6.2)	40 (5.8)	12 (7.6)	
Othere	48 (5.7)	32 (4.7)	16 (10.1)	
Gastrointestinal	302 (35.8)	242 (35.3)	60 (38.0)	
Hematologic	58 (6.9)	46 (6.7)	12 (7.6)	
Autoimmunea	45 (5.3)	26 (3.8)	19 (12.0)	
Lupus	2 (<1.0)	1 (<1.0)	1 (<1.0)	
Rheumatoid arthritis	10 (1.2)	6 (0.9)	4 (2.5)	
Psoriasis	12 (1.4)	7 (1.0)	5 (3.2)	
Multiple sclerosis	1 (<1.0)	0	1 (<1.0)	
Crohn disease	3 (<1.0)	3 (0.4)	0	
Type 1 diabetes	16 (1.9)	9 (1.3)	7 (4.4)	
Other	1 (<1.0)	0	1 (<1.0)	
Hepatic				
Hepatitis	27 (3.2)	20 (2.9)	7 (4.4)	
Enzyme elevation	19 (2.3)	17 (2.5)	2 (1.3)	
Neurologic				
Strokeb	8 (1.0)	4 (0.6)	4 (2.5)	
Head injury	102 (12)	81 (11.8)	21 (13.3)	
Seizure disorder	58 (6.9)	37 (5.4)	21 (13.3)	
Migraine	70 (8.3)	58 (8.5)	12 (7.6)	
ADHDe	32 (3.8)	32 (4.7)	0	
Tardive dyskinesia	35 (4.2)	26 (3.8)	9 (5.7)	
Other	41 (4.9)	38 (5.5)	3 (1.9)	
Dermatologic	93 (11.0)	80 (11.7)	13 (8.2)	
Abbreviations: ADHD, attention-deficit/hyperactivity disorder; BMI, body mass index (calculated as weight in kilograms divided by height in meters squared); COPD, chronic ostructive pulmonary disease; PANSS, Positive and Negative Syndrome Scale.

a P ≤ .001.

b P ≤ .05.

c Includes self-reported Asian, Hispanic, or other.

d The range for the positive and negative scales is 7 to 49, and the range for the general psychopathology scale is 16 to 112. Total is the sum of these scales, with higher scores indicating more severe symptoms.

e P ≤ .01.

f Substance misuse in past 3 months.

Causes of Death and Comparison With Mortality Rates in the General Population

A total of 158 participants died from natural causes during the study period. Causes of death based on the death certificates were due to the following types of disorders: cardiovascular or circulatory (69 [43.7%]), neoplastic (33 [20.9%]), respiratory (20 [12.7%]), neurologic (5 [3.2%]), gastrointestinal (6 [3.8%]), endocrine or metabolic (10 [6.3%]), infectious (3 [1.9%]), or genitourinary (5 [3.2%]) disorders or other natural causes (7 [4.4%]). The mean (SD) age at death was 60.5 (9.6) years. As shown in eTable 1 in Supplement 1, except for males aged 40 to 50 years, participants with schizophrenia had increased standardized mortality rates compared with the overall population for each sex and age decade. The mean (SD) years of potential life lost vs the overall population was 14.7 (9.3). Detailed mortality data by each year of life (ages 25-82 years for female participants and 24-80 years for male participants) is shown in eTable 2 in Supplement 1.

Associations With Mortality

As shown in Table 2, having a lower level of cognitive functioning, as measured by RBANS total score, had the strongest association with natural cause mortality as determined by the z value (Cox coefficient, −0.04; 95% CI, −0.05 to −0.03; z = −5.72; adjusted P < .001). As shown in Figure 1, the hazard of mortality was associated with the degree of cognitive impairment, particularly in the lowest 2 quartiles, with hazard ratios (HRs) of 2.04 (95% CI, 1.30-3.20; P < .001) and 2.23 (95% CI, 1.43-3.50; P < .001), respectively, vs the highest quartile. Body mass index, analyzed as a continuous variable, was also independently associated with natural cause mortality (HR, 1.06; 95% CI, 1.02-1.09; z score = 3.30; adjusted P = .01). As shown in eFigure 2 in Supplement 1, the highest mortality was among participants with BMIs in the highest quartile (BMI ≥33.8) vs lowest quartile (HR, 1.79; 95% CI, 1.10-2.89; P = .02), while the other quartiles showed no association with natural cause mortality.

Table 2. Factors Identified by LASSO and Subsequent Cox Proportional Hazards Regression Analysesa

Measureb	LASSO coefficient	HR (95% CI)	Cox coefficient (95% CI)	z Score	P value	Adjusted P valuec	
RBANS total score	−0.31	0.96 (0.95 to 0.98)	−0.04 (−0.05 to −0.03)	−5.72	<.001	<.001	
Autoimmune disorder	−0.17	2.86 (1.83 to 4.47)	1.05 (0.61 to 1.50)	4.62	<.001	<.001	
Tobacco smoking	−0.24	2.26 (1.55 to 3.30)	0.82 (0.44 to 1.19)	4.23	<.001	<.001	
COPD	−0.16	3.31 (1.69 to 6.49)	1.20 (0.52 to 1.87)	3.48	<.001	.006	
Body mass index	0.21	1.06 (1.02 to 1.09)	0.05 (0.02 to 0.09)	3.30	<.001	.01	
Cardiac rhythm disorder	−0.11	2.56 (1.40 to 4.69)	0.94 (0.34 to 1.55)	3.06	.003	.02	
Divorced or separated	−0.10	1.80 (1.22 to 2.65)	0.59 (0.20 to 0.97)	2.97	.003	.02	
Measles IgG	−0.12	0.62 (0.42 to 0.91)	−0.48 (−0.88 to −0.09)	−2.42	.02	NS	
Cytomegalovirus IgG	−0.10	0.84 (0.73 to 0.98)	−0.17 (−0.32 to −0.02)	−2.26	.02	NS	
Gabapentin	−0.08	1.60 (0.85 to 3.01)	0.47 (−0.16 to 1.10)	1.46	NS	NS	
Varicella zoster virus IgG	−0.10	0.81 (0.57 to 1.14)	−0.22 (−0.57 to 0.13)	−1.22	NSd	NS	
Age of onset	−0.05	0.99 (0.97 to 1.01)	−0.01 (−0.03 to 0.01)	−1.19	NS	NS	
Year of study entry	−0.08	0.98 (0.94 to 1.02)	−0.02 (−0.07 to 0.02)	−1.08	NS	NS	
Fluoxetine	−0.08	1.36 (0.72 to 2.54)	0.31 (−0.32 to 0.93)	0.95	NS	NS	
Abbreviations: COPD, chronic obstructive pulmonary disease; HR, hazard ratio; LASSO, least absolute shrinkage and selection operator; NS, not significant; RBANS, Repeatable Battery for the Assessment of Neuropsychological Status.

a The model is consistent with the proportional hazards assumptions as determined by the calculation of Schoenfeld residuals (χ2 = 19.38; df = 16; P = .25).

b Factors were identified by LASSO and subsequently incorporated into a single Cox proportional hazards regression model.

c Adjusted P values were determined by false discovery analyses.

d P ≥ .10.

Figure 1. Association Between Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Quartile Scores and Natural Cause Mortality

The RBANS total score by quartiles (with Q4 the highest and Q1 the lowest cognitive functioning) is associated with natural cause mortality (Q1 vs Q4: hazard ratio, 2.04; 95% CI, 1.30-3.20; P < .001; Q2 vs Q4: hazard ratio, 2.23; 95% CI, 1.43-3.50; P < .001).

Additional factors independently associated with natural cause mortality included tobacco smoking (HR, 2.26; 95% CI, 1.55-3.30; z = 4.23; adjusted P < .001); diagnosis of an autoimmune disorder (HR, 2.86; 95% CI, 1.83-4.47; z = 4.62; adjusted P < .001), chronic obstructive pulmonary disease (COPD) (HR 3.31; 95% CI, 1.69-6.49; z = 3.48; adjusted P = .006), or a cardiac rhythm disorder (HR, 2.56; 95% CI, 1.40-4.69; z = 3.06; adjusted P = .02) (Figure 2) and being divorced or separated (HR, 1.80; 95% CI, 1.22-2.65; z = 2.97; adjusted P = .02) (eFigure 3 in Supplement 1). In terms of tobacco smoking, there was a quantitative association between exposure and mortality, with the highest hazard found in participants who reported smoking more than 1 pack of cigarettes per day vs nonsmokers (HR, 2.97; 95% CI, 1.84-4.80; P < .001) (eFigure 4 in Supplement 1).

Figure 2. Association Between Binary Variables and Natural Cause Mortality

We also determined the joint associations of lower cognitive functioning, defined as less than the 50th percentile of the RBANS total score, and other factors independently associated with increased natural cause mortality. Significant joint associations were noted between lower cognitive functioning and BMI, tobacco smoking, diagnosis of an autoimmune disorder, and diagnosis of a cardiac rhythm disorder (Figure 3). A significant joint effect was not noted between lower cognitive functioning and divorced or separated marital status or COPD.

Figure 3. Joint Effects of Low Levels of Cognitive Functioning and Other Factors Associated With Natural Cause Mortality

Survival associated with the joint effect of low Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) total score, defined as less than or equal to or greater than the 50th percentile. In all cases, the hazard for low RBANS total score and the presence of the indicated risk factor was significantly lower than each of the other 3 categories (Wald test P < .05).

We also examined the association between specific cognitive domains and natural cause mortality. As shown in eTable 3 in Supplement 1, while all of the RBANS indexes were significantly associated with increased mortality, the strongest association was with lower scores on the language index (Cox coefficient, −0.02; 95% CI, −0.03 to −0.01; z = −3.45; P = .001). This score is based on performance on tasks of word fluency and picture naming and tapping aspects of expressive and receptive language skills. Semantic fluency is also seen as a measure of higher-order executive functioning.

We performed sensitivity analyses to document the robustness of the association between RBANS total score and natural cause mortality. We examined the potential confounding effects of imputed data by omitting the imputed values for BMI, the only risk factor in the final model that had imputed values. The association between BMI and natural cause mortality remained significant in these analyses (Cox coefficient, 0.07; 95% CI, 0.03-0.10; z = 3.78; P < .001). We also tested the proportional hazards assumption that the HR does not vary over time by calculating the Schoenfeld residuals. As shown in Table 2, this analysis indicated that the assumptions of the model were not violated. We also examined the association of including the 39 individuals who died of unnatural causes as competing risks in Cox proportional hazards regression models. These analyses resulted in HR values essentially unchanged from models where these individuals were excluded (eTable 4 in Supplement 1).

Discussion

The role of cognitive functioning as a risk factor for mortality in schizophrenia has not been widely studied, possibly because such studies require prospective individual cognitive testing and long-term follow-up. Our findings are consistent with studies in the general population that have found reduced cognitive functioning as a mortality risk.13,14,15 Several studies were in older populations,28 although some were in populations with a similar age distribution as our cohort. For example, a large community-based study in England found that adults younger than 65 years without identified cognitive problems but in the lowest quartile of cognitive functioning had an increased mortality hazard; the analysis was adjusted for social class, education, physical activity, and alcohol use but not tobacco smoking.13

The one previous set of studies of cognition and mortality in schizophrenia also found an association between reduced cognitive functioning and increased mortality; the ages of persons in that cohort and the duration of follow-up were similar to those in the current study.29,30 However, important factors associated with mortality, including tobacco smoking, obesity, and medical conditions, were not included in the analyses.

There are several possible explanations for the association between cognitive functioning and mortality. Worse cognitive functioning may indirectly contribute to survival by reducing persons’ abilities to identify somatic illness symptoms, seek medical treatment, and comply with treatment regimens, as has been suggested as an explanation for worse cancer outcomes of persons with schizophrenia than those in the general population.31,32 Reduced language abilities may impair interactions with medical professionals and contribute to reduced quality of medical care received overall by persons with schizophrenia.33 Problems with delayed memory may reduce health literacy and negatively affect recall of and follow-through with recommended medical treatments.13,34 Our finding of a significant joint association of lower cognitive functioning and persistent somatic illnesses, such as COPD, as well as autoimmune and cardiac rhythm disorders is consistent with this possibility.

An important implication of these findings is that cognitive functioning is an important measurement in individuals with schizophrenia.30 Another implication is that compensation may need to be made for cognitive deficits in this population in terms of explanation and instructions accompanying medical interventions. It may be helpful for medical professionals to tailor their communications in order to optimize the patients’ understanding of medical illnesses and recommended treatments. In addition, it is possible that improvement in cognitive functioning itself may lead indirectly to reduced mortality in this population; however, there currently are no approved medications for cognitive enhancement in schizophrenia. Cognitive remediation, a psychosocial intervention, may be effective in improving cognitive functioning but is not widely available.35

We also found an association between the presence of an autoimmune disorder at enrollment and natural cause mortality. The participants had a range of autoimmune disorders, including systemic lupus, type 1 diabetes, and rheumatoid arthritis. While an increased rate of autoimmune disorders has been described in schizophrenia, these disorders have not been previously studied as contributors to natural cause mortality. However, our findings are consistent with studies of mortality due to autoimmune disorders in other populations.36

Our finding about the significance of tobacco smoking and the amount of daily tobacco use as risk factors is consistent with previous reports on mortality in schizophrenia.27,37,38 While rates of tobacco smoking have declined in persons with schizophrenia, the prevalence is still more than 3 times that in US adults overall.39 In the current study, smoking was independently associated with mortality and also had a joint association with cognitive score. All evidence suggests that the cessation of tobacco smoking in persons with schizophrenia would make the single largest contribution to reducing premature mortality in this population.24

Another variable that emerged as significant in this study was elevated BMI. While the mean BMI was in the obesity range (>30) for participants who were either alive or dead at follow-up, consistent with other studies in schizophrenia,40,41 even additional degrees of obesity added to the mortality risk. The association between elevated BMI and mortality in the general population is well established.42 The results of a recent study of BMI as an independent mortality risk in schizophrenia showed that obesity and morbid obesity were associated with mortality in younger and middle-aged persons with schizophrenia,43 similar to the age of participants in our sample.

We also found that natural cause mortality was associated with cardiac rhythm disorders and COPD, consistent with the association between these disorders and mortality in several other populations.44 Another factor that emerged as significantly associated with mortality was divorced or separated marital status, which has been associated with mortality in population-based studies45,46 but has not been a focus in schizophrenia. While only 12.9% of our sample were previously married, the variable exerted a significant influence. The mechanisms underlying the association may include social isolation and loneliness.47

Strengths and Limitations

Strengths of the study include the thorough in-person clinical assessment performed at baseline, the relatively large sample size for a prospective investigation, the detailed information about causes of death, and the length of the follow-up period. In addition, the study is novel in the inclusion of a standard cognitive evaluation as well as comorbid conditions and serologic markers in the analysis.

Our study also has several limitations. First, we did not have data about participants’ interim history, including emergent medical conditions and medical care received during the follow-up period. Studies have suggested that persons with schizophrenia may be less likely to receive evidence-based treatment for some medical conditions, which may also contribute to mortality outcomes.48 Second, while smoking at baseline was associated with mortality in our model, we do not know who in the sample subsequently quit smoking. Third, we assessed cognition using a brief cognitive battery that did not include an assessment of working memory or a thorough assessment of executive functioning. Fourth, although the participants appeared to be representative of persons with schizophrenia in our treatment settings, we cannot be sure that these findings are generalizable to the full population of persons with schizophrenia. Fifth, our sample size was not adequate to determine whether cognitive functioning or other variables were associated with specific causes of death. Further analysis of the cohort with an increased number of person-years of observation may result in increased statistical power for the detection of less common associations with natural cause mortality. Finally, while we used the LASSO method to examine the contributions of a large number of covariates, other methods, such as additional machine learning tools and factor analyses, might lead to additional associations and the testing of causative hypotheses. These and developing machine learning methods should be applied in future studies in larger patient populations. In addition, while our sample size was relatively large (covering 12 314 person-years), it is possible that some covariates were not identified due to a limited sample size but might be identified in a larger sample or longer follow-up period. Of particular interest would be covariates that were identified in the LASSO analysis but were not significant in the subsequent Cox models, such as antibodies to viral agents, specific medications, and substance use disorders.

Conclusions

In this cohort study, reduced cognitive functioning was associated with increased mortality in individuals with schizophrenia, particularly in those with additional risk factors. Effective methods to improve cognitive functioning may result in a substantial reduction in mortality in this population.

Supplement 1. eMethods 1. List of Variables Entered Into the LASSO Analysis

eMethods 2. Detailed Description of Statistical Analyses

eReferences.

eTable 1. Standardized Mortality Ratios

eTable 2. Detailed Mortality Tables by Sex and Year of Age

eTable 3. Association of RBANS Index Scores and Natural Cause Mortality

eTable 4. Competing-Risk Analysis of the Association Between Determinants and Natural Cause Mortality

eFigure 1. CONSORT Diagram

eFigure 2. Association Between BMI Quartiles and Natural Cause Mortality

eFigure 3. Association Between Divorced or Separated Status and Natural Cause Mortality

eFigure 4. Association Between Cigarette Packs per Day (PPD) and Natural Cause Mortality

Supplement 2. Data Sharing Statement
==== Refs
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