Research

JAMA Psychiatry | Original Investigation

Evaluation of Brain-Body Health in Individuals

With Common Neuropsychiatric Disorders
Ye Ella Tian, MBBS, PhD; Maria A. Di Biase, PhD; Philip E. Mosley, MD, PhD; Michelle K. Lupton, PhD; Ying Xia, PhD;
Jurgen Fripp, PhD; Michael Breakspear, MD, PhD; Vanessa Cropley, PhD; Andrew Zalesky, PhD

Multimedia
IMPORTANCE Physical health and chronic medical comorbidities are underestimated, Supplemental content
inadequately treated, and often overlooked in psychiatry. A multiorgan, systemwide
characterization of brain and body health in neuropsychiatric disorders may enable
systematic evaluation of brain-body health status in patients and potentially identify
new therapeutic targets.

OBJECTIVE To evaluate the health status of the brain and 7 body systems across common
neuropsychiatric disorders.

DESIGN, SETTING, AND PARTICIPANTS Brain imaging phenotypes, physiological measures,

and blood- and urine-based markers were harmonized across multiple population-based
neuroimaging biobanks in the US, UK, and Australia, including UK Biobank; Australian
Schizophrenia Research Bank; Australian Imaging, Biomarkers, and Lifestyle Flagship Study
of Ageing; Alzheimer’s Disease Neuroimaging Initiative; Prospective Imaging Study of Ageing;
Human Connectome Project–Young Adult; and Human Connectome Project–Aging.
Cross-sectional data acquired between March 2006 and December 2020 were used
to study organ health. Data were analyzed from October 18, 2021, to July 21, 2022.
Adults aged 18 to 95 years with a lifetime diagnosis of 1 or more common neuropsychiatric
disorders, including schizophrenia, bipolar disorder, depression, generalized anxiety disorder,
and a healthy comparison group were included.

MAIN OUTCOMES AND MEASURES Deviations from normative reference ranges for composite
health scores indexing the health and function of the brain and 7 body systems. Secondary
outcomes included accuracy of classifying diagnoses (disease vs control) and differentiating
between diagnoses (disease vs disease), measured using the area under the receiver
operating characteristic curve (AUC).

RESULTS There were 85 748 participants with preselected neuropsychiatric disorders

(36 324 male) and 87 420 healthy control individuals (40 560 male) included in this study.
Body health, especially scores indexing metabolic, hepatic, and immune health, deviated
from normative reference ranges for all 4 neuropsychiatric disorders studied. Poor body
health was a more pronounced illness manifestation compared to brain changes in
schizophrenia (AUC for body = 0.81 [95% CI, 0.79-0.82]; AUC for brain = 0.79 [95% CI,
0.79-0.79]), bipolar disorder (AUC for body = 0.67 [95% CI, 0.67-0.68]; AUC for brain = 0.58
[95% CI, 0.57-0.58]), depression (AUC for body = 0.67 [95% CI, 0.67-0.68]; AUC for
brain = 0.58 [95% CI, 0.58-0.58]), and anxiety (AUC for body = 0.63 [95% CI,
0.63-0.63]; AUC for brain = 0.57 [95% CI, 0.57-0.58]). However, brain health enabled more
accurate differentiation between distinct neuropsychiatric diagnoses than body health
(schizophrenia-other: mean AUC for body = 0.70 [95% CI, 0.70-0.71] and mean AUC
for brain = 0.79 [95% CI, 0.79-0.80]; bipolar disorder-other: mean AUC for body = 0.60
[95% CI, 0.59-0.60] and mean AUC for brain = 0.65 [95% CI, 0.65-0.65]; depression-other:
mean AUC for body = 0.61 [95% CI, 0.60-0.63] and mean AUC for brain = 0.65 [95% CI, Author Affiliations: Author
0.65-0.66]; anxiety-other: mean AUC for body = 0.63 [95% CI, 0.62-0.63] and mean AUC affiliations are listed at the end of this
article.
for brain = 0.66 [95% CI, 0.65-0.66).
Corresponding Author: Ye Ella Tian,
CONCLUSIONS AND RELEVANCE In this cross-sectional study, neuropsychiatric disorders MBBS, PhD, Department of
shared a substantial and largely overlapping imprint of poor body health. Routinely Psychiatry, Melbourne
Neuropsychiatry Centre, Melbourne
monitoring body health and integrated physical and mental health care may help reduce Medical School, the University of
the adverse effect of physical comorbidity in people with mental illness. Melbourne, Level 3, Alan Gilbert
Building, 161 Barry St, Carlton,
JAMA Psychiatry. 2023;80(6):567-576. doi:10.1001/jamapsychiatry.2023.0791 Melbourne, Victoria, 3053, Australia
Published online April 26, 2023. (ye.tian2@unimelb.edu.au).

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 Research Original Investigation Evaluation of Brain-Body Health in Individuals With Common Neuropsychiatric Disorders
M
ental illness is associated with higher rates of chronic
physical illness, including coronary heart disease,
obesity, and diabetes,1,2 compared to the general
population. This contributes substantially to the global health
and economic burden due to increased morbidity, disability,
and mortality.3,4 Yet in psychiatric care and services, physical
health has been neglected and inadequately managed for
decades.1
Despite increased awareness of physical health in
psychiatry,5,6 recognizing and treating chronic physical illness
remains a challenge. Poor physical health in patients is likely
underestimated due to existing disparities in health care for
people with mental illness, such as lack of access to adequate
primary care,7 diagnostic overshadowing,8,9 and difficulties
with acknowledging10 and reporting medical problems for
some patients.11,12 Further work is thus needed to understand
associations between mental and physical comorbidities, which
may facilitate holistic and integrated care in psychiatry.
Most meta-research has focused on cardiovascular and
metabolic comorbidities in psychiatry, as summarized in a re-
view by Firth and colleagues.5 While infectious13 and immune-
related comorbidities14,15 have also been investigated, the
chronic illness burden of common diseases affecting other body
systems is scarcely explored.6,16 The association between brain
and body health as well as the associated disease risk and physi-
cal multimorbidity across body systems hence remain poorly
characterized.
We systematically investigated brain and body health in
common neuropsychiatric conditions (ie, schizophrenia, bi-
polar disorder, depression, and generalized anxiety disor-
der). Using brain images, physiological measures, and blood-
and urine-based markers acquired in more than 100 000
individuals, we established composite organ health scores
for 2 brain and 7 body systems. We computed age- and sex-
specific normative reference ranges for each organ’s health
score based on healthy comparison individuals and quanti-
fied the extent to which individuals with the above condi-
tions deviated from the established normative ranges. This
enabled us to develop multiorgan health profiles for each neu-
ropsychiatric condition and estimate the relative effect of
these profiles in each individual’s body systems and physical
health. We suggest that the management of serious neuropsy-
chiatric disorders should acknowledge the importance of
physical health and target restoration of both brain and body
function.
Methods
Participants
This study integrated brain imaging data (structural and
diffusion-weighted magnetic resonance imaging [MRI]) with
physical and physiological data (where available) acquired
from individuals participating in the following consortia
studies from March 2006 to December 2020: UK Biobank; Aus-
tralian Schizophrenia Research Bank; Australian Imaging, Bio-
markers and Lifestyle Flagship Study of Ageing; the Alzhei-
mer Disease Neuroimaging Initiative; the Prospective Imaging
568 JAMA Psychiatry June 2023 Volume 80, Number 6 (Reprinted)
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Key Points
Question Do specific organ systems manifest poor health in
individuals with common neuropsychiatric disorders?
Findings This multicenter population-based cohort study
including 85 748 adults with neuropsychiatric disorders and
87 420 healthy control individuals found that poor body health,
particularly of the metabolic, hepatic, and immune systems, was a
more marked manifestation of mental illness than brain changes.
However, neuroimaging phenotypes enabled differentiation
between distinct neuropsychiatric diagnoses.
Meaning Management of serious neuropsychiatric disorders
should acknowledge the importance of poor physical health and
target restoration of both brain and body function.
Study of Ageing; the Human Connectome Project–Young Adult;
and the Human Connectome Project–Aging. All data are cross-
sectional. T1-weighted MRI brain images were available for
22 005 individuals aged 18 to 95 years collectively sourced from
the 7 consortia, and diffusion-weighted MRI brain images were
available for 20 283 individuals (mean [SD]; range age, (60.6
[11.5]; 18-95 years) from all cohorts except the Australian
Imaging, Biomarkers and Lifestyle Study of Ageing. Physical
and physiological assessments were sourced from 175 944 in-
dividuals (mean [SD]; range age, 54.8 [8.1]; 37-74 years) par-
ticipating in UK Biobank.
Ethical approval was obtained as follows: for UK Bio-
bank, from the North West Multi-centre Research Ethics
Committee; the Australian Schizophrenia Research Bank, Mel-
bourne Health Human Research Committee (Project ID:
2010.250); the Australian Imaging, Biomarkers and Lifestyle
Flagship Study of Ageing, the institutional ethics committees
of Austin Health, St Vincent’s Health, Hollywood Private Hos-
pital and Edith Cowan University; the Alzheimer’s Disease Neu-
roimaging Initiative, according to the ethical standards of the
institutional and/or national research committee of each site
and with the 1964 Helsinki declaration and its later amend-
ments or comparable ethical standards; Prospective Imaging
Study of Ageing, from the Human Research Ethics Commit-
tees of QIMR Berghofer Medical Research Institute and the Uni-
versity of Queensland; Human Connectome Project, the
Washington University–University of Minnesota Human Con-
nectome Project consortium. Details pertaining to each co-
hort are described in eMethods in Supplement 1. Written in-
formed consent was obtained from all participants. The study
followed the Strengthening the Reporting of Observational
Studies in Epidemiology (STROBE) reporting guideline.
Brain and Body Phenotypes
Regionally specific brain phenotypes derived from T1-
weighted MRI, including cortical thickness and cortical and
subcortical gray matter (GM) volume were selected to profile
brain GM health (eTable 1 in Supplement 1). Brain white mat-
ter (WM) health was profiled using tract-specific measures of
WM microstructure, including fractional anisotropy and mean
diffusivity (eTable 2 in Supplement 1). Data were harmonized
using ComBat17,18 to control for site and scanner variation.
jamapsychiatry.com
 Evaluation of Brain-Body Health in Individuals With Common Neuropsychiatric Disorders Original Investigation Research

Details of imaging processing, quality control, and pheno-
type extraction are described in eMethods in Supplement 1.
Physical assessments and blood and urine sample assays
were available for UK Biobank participants. Assessment de-
tails and procedures for processing biological samples are
described elsewhere.19 Physical and physiological measures
known to inform the function and health of 7 body systems
were selected and grouped into pulmonary, musculoskeletal,
kidney, metabolic, hepatic, cardiovascular, and immune
systems (eFigure 1A and eTable 3 in Supplement 1). Data cu-
ration and the handling of missing data are described in
eMethods in Supplement 1.
Normative Modeling
Following previous work,20 generalized additive models for
location, scale, and shape were used to establish sex-specific
normative reference ranges (mean and centiles) across the
adult life span for each brain and body phenotype (eFig-
ure 1B in Supplement 1), based on individuals without any
neuropsychiatric illness or other serious medical conditions
(eMethods in Supplement 1). The normative reference ranges
were then used to estimate standardized phenotypic devia-
tion scores (z scores) for individuals with a neuropsychiatric
disorder (schizophrenia, bipolar disorder, depression, or
generalized anxiety disorder). 21,22 A deviation score was
estimated separately for each brain and body phenotype
(age and sex specific), quantifying the number of standard
deviations an individual deviated from the reference
median. Deviation scores for healthy individuals were esti-
mated using 10-fold cross-validation (eMethods in Supple-
ment 1).
Estimating Organ System–Specific Health Scores
A principled approach was developed to summarize pheno-
typic deviation scores at an organ system level to enable sys-
tematic mapping of multisystem health profiles. Phenotypes
were grouped based on relevance to the health and function
of 2 brain systems (GM and WM) (eTables 1 and 2 in Supple-
ment 1) and 7 body systems (pulmonary, musculoskeletal,
kidney, metabolic, hepatic, cardiovascular, and immune)
(eTable 3 in Supplement 1). Deviations from the established
normative ranges for all phenotypes relevant to a particular
system were subsequently combined to yield a single organ-
specific health score (OHS) for each system and individual,
excluding those with comorbid psychiatric conditions.
Health scores were calibrated such that OHS = 0 indicates
the median of healthy, normal organ function and OHS < 0
suggests a potential deterioration of organ health, control-
ling for age and sex.
For example, to estimate phenotype weights for the meta-
bolic health score, the patient group comprised individuals di-
agnosed with chronic metabolic diseases, including diabetes
and disorders of lipoprotein metabolism (eMethods and
eTable 4 in Supplement 1). In this way, phenotypes differen-
tiating chronic metabolic diseases were weighted highly
when computing the composite metabolic health score and
analogously for the other organ systems (eFigure 1C in Supple-
ment 1). The phenotype weights were then used to compute
organ health scores for individuals with 1 or more neuropsy-
chiatric disorders (eMethods and eTables 5-9 in Supple-
ment 1).
Ten-fold cross-validation was performed to ensure that
organ health scores were not computed for the same indi-
viduals who were used to estimate phenotype weights. A
composite body health score was also computed using all
body phenotypes. Differences in organ health scores
between disorder groups and the healthy comparison group
were tested using analysis of covariance, adjusting for age
and sex. The false discovery rate (FDR) was using the
Benjamini-Hochberg procedure across 4 disorder
groups × 10 organ systems = 40 tests. Cross-validated logis-
tic regression models were trained to classify an individual’s
diagnostic status based on phenotypic deviation scores
(eFigure 1D and eMethods in Supplement 1).
Results
There were 85 748 participants with preselected neuropsychi-
atric disorders (36 324 male) and 87 420 healthy control
individuals (40 560 male) included in this study. The Table pro-
vides demographic and clinical characteristics.

Table. Demographic Characteristics Stratified by Diagnosis

Brain phenotypes
T1-weighted MRI Diffusion MRI Body phenotypes
No. of Age, mean No. of Age, mean No. of Age, mean
Study groupa individuals (SD), y Male, No. (%) individuals (SD), y Male, No. (%) individualsb (SD), y Male, No. (%)
Healthy control 10 889 59.0 (13.5) 5096 (46.8) 10 005 58.6 (13.5) 4673 (46.7) 84 308 53.2 (7.9) 39 255 (46.4)
Schizophrenia 390 43.8 (13.7) 136 (34.9) 383 43.3 (13.5) 135 (35.2) 2100 55.8 (8.4) 1184 (56.4)
Bipolar disorder 600 62.5 (7.5) 289 (48.2) 546 62.5 (7.5) 253 (46.3) 5853 55.0 (8.0) 2696 (46.1)
Depression 9902 63.0 (7.4) 3435 (34.7) 9256 63.1 (7.5) 3188 (34.4) 81 631 55.8 (7.9) 27 923 (34.2)
Generalized 2063 62.2 (7.3) 733 (35.5) 1920 62.3 (7.4) 689 (35.9) 11 456 54.3 (7.6) 3841 (33.5)
anxiety disorder
Dementia 370 72.5 (8.1) 184 (49.7) 206 71.7 (8.3) 125 (60.7) 6506 64.7 (5.0) 3470 (53.3)
Abbreviation: MRI, magnetic resonance imaging. Supplement 1).
a b
Clinical groups are defined based on lifetime diagnosis (eMethods in Individuals with at least 1 body phenotype available were included.

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 Research Original Investigation Evaluation of Brain-Body Health in Individuals With Common Neuropsychiatric Disorders

Figure 1. Brain and Body Health Scores in Neuropsychiatric Disorders Stratified by Organ System

A Cardiovascular B Pulmonary C Musculoskeletal D Immune

Schizophrenia Schizophrenia Schizophrenia Schizophrenia

–0.05 –0.5 –0.4 –0.7
Healthy Healthy Healthy Healthy
comparison –0.03 comparison –0.3 comparison –0.2 comparison –0.4
–0.05 0 –0.05 –0.5 0 -0.5 –0.4 0 –0.4 –0.7 0 –0.7
–0.03 –0.03 –0.3 -0.3 –0.2 -0.2 –0.4 –0.4
0 0 Bipolar 0 0 Bipolar 0 0 Bipolar 0 0 Bipolar
disorder disorder disorder disorder
0 0 0 0 0 0 0 0
–0.03 –0.03 -0.3 -0.3 –0.2 –0.2 –0.4 –0.4
–0.05 –0.05 -0.5 -0.5 –0.4 –0.4 –0.7 –0.7
Generalized Depression Generalized Depression Generalized Depression Generalized Depression
anxiety disorder anxiety disorder anxiety disorder anxiety disorder

E Hepatic F Kidney G Metabolic H Body

Schizophrenia Schizophrenia Schizophrenia Schizophrenia

–0.9 –0.5 –1.3 –1.8
Healthy Healthy Healthy Healthy
–0.5 –0.2 –0.7 –0.9
comparison comparison comparison comparison
0 0 0 0
–0.9 –0.9 –0.5 –0.5 –1.3 –1.3 –1.8 -0.9 –1.8
–0.5 –0.2 –0.2 –0.7 –0.9
0 0 –0.5 Bipolar 0 0 Bipolar 0 0 –0.7 Bipolar 0 0 Bipolar
disorder disorder disorder disorder
0 0 0 0 0 0 0 0
–0.2 –0.2 –0.7 –0.9 –0.9
–0.5 –0.5 –0.7
–0.9 –0.9 –0.5 –0.5 –1.3 –1.3 –1.8 –1.8
Generalized Depression Generalized Depression Generalized Depression Generalized Depression
anxiety disorder anxiety disorder anxiety disorder anxiety disorder

I Brain gray matter J Brain white matter

Schizophrenia Schizophrenia
–0.5 –0.2
Healthy Healthy
-0.2 -0.1
comparison comparison
–0.5 0 –0.5 –0.2 0 –0.2
–0.2 –0.2 –0.1 –0.1
0 0 Bipolar 0 0 Bipolar
0 0 disorder 0 0 disorder
–0.2 –0.2 –0.1 –0.1

–0.5 –0.5 –0.2 –0.2

Generalized Depression Generalized Depression

anxiety disorder anxiety disorder

Organ and system health scores were computed for each organ system (2 brain and 7 body) and for each individual. A score of 0 indicates healthy, normal organ
function (ie, median score across healthy comparison individuals), and scores below 0 suggest deterioration of organ health, controlling for age and sex. Radial axes
show the mean of estimated organ and system health scores across individuals within each neuropsychiatric disorder and healthy comparison individuals. An overall
body health score was estimated using all body phenotypes. Distributions of estimated organ and system health scores across individuals in each group are shown in
eFigure 6 in Supplement 1.

Normative Models −0.80 [1.49]), and generalized anxiety disorder (mean [SD]
Normative reference ranges across the adult life span were OHS, −0.53 [1.35]) compared to healthy individuals. Consis-
established for 203 imaging, blood, urine, and physiological tent across the 4 disorders, poor organ health was most evi-
markers. Phenotypic variation was best modeled by the dent for the metabolic system (mean OHS range: −1.24 to
Box-Cox t distribution compared to the other 20 distribution −0.45), hepatic system (mean OHS range: −0.85 to −0.21), im-
families evaluated (eFigure 2 in Supplement 1). Both linear mune system (mean OHS range: −0.65 to −0.19), and kidney
and nonlinear patterns of age-related trajectories were system (mean OHS range: −0.37 to −0.12) (Figure 2).
captured across different phenotypes (eFigure 3 in Supple- Of the disorders studied, brain health was poorest in in-
ment 1). dividuals with schizophrenia (mean [SD] GM/WM OHS, −0.37
[0.63]/−0.12 [0.67]). In contrast, bipolar disorder (mean [SD]
Multisystem Health Profiles in Neuropsychiatric Disorders GM/WM OHS, −0.11 [0.62]/−0.16 [0.52]), depression (mean [SD]
We found that all organ-specific health scores were on aver- GM/WM OHS, −0.14 [0.77]/−0.15 [0.65]), and generalized anxi-
age significantly lower in individuals with neuropsychiatric ety disorder (mean [SD] GM/WM OHS, −0.10 [0.53]/−0.10
disorders compared to age- and sex-matched healthy peers [0.45]) groups showed only marginally poorer brain health rela-
(Figures 1 and 2; eFigures 4-6 in Supplement 1). Specifically, tive to healthy control individuals. The effect sizes observed
body health scores were markedly lower for individuals with in brain health scores were consistent with subtle structural
schizophrenia (mean [SD] OHS, −1.65 [1.80]), bipolar disor- brain changes observed in individuals with bipolar disorder,
der (mean [SD] OHS, −0.81 [1.48]), depression (mean [SD] OHS, depression, or anxiety,23-26 while effect sizes for schizophre-

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 Evaluation of Brain-Body Health in Individuals With Common Neuropsychiatric Disorders Original Investigation Research

Figure 2. Brain and Body Health Scores in Neuropsychiatric Disorders Stratified by Diagnosis Group

A Schizophrenia B Bipolar disorder

Cardiovascular Cardiovascular
–1.8 –0.9
Body Brain white matter Body Brain gray matter
–1.8 –1.8 –0.9 –0.9
–0.9 –0.5
-0.9 –0.9 –0.5
–0.5
Metabolic Musculoskeletal Metabolic 0 Brain white matter
–1.8 0 –1.8 –0.9 –0.5 –0.9
0 0 0 0
–0.9 –0.9 –0.5
0 0 0 0

0 0 0 0
–0.9 –0.9 –0.5 –0.5
Hepatic 0 0 Hepatic 0 0
–1.8 0 –1.8 –0.9 0 –0.9
Brain gray matter Musculoskeletal
–0.9 –0.5 –0.5
–0.9
–0.9 –0.5
–1.8 –1.8 –0.9 –0.9
Immune Renal Immune Pulmonary
–1.8 –0.9
Pulmonary Renal

C Depression D Generalized anxiety disorder

Cardiovascular Cardiovascular
–0.9 –0.6
Body Brain gray matter Body Pulmonary
–0.9 –0.9 –0.6 –0.6

–0.4 –0.3
–0.4 –0.4 –0.3 –0.3
Metabolic Brain white matter Metabolic Brain white matter
–0.9 0 –0.9 –0.6 0 –0.6
–0.4 0 0 –0.3 0 0
–0.4 –0.3
0 0 0 0

0 0 0 0
–0.4 –0.4 –0.3 –0.3
Hepatic 0 0 Hepatic 0 0
–0.9 –0.9 –0.6 –0.6
0 0
Pulmonary Brain gray matter
–0.4 –0.4 –0.3 –0.3
–0.4 –0.3
–0.9 –0.9 –0.6 –0.6
Immune Musculoskeletal Immune Renal
–0.9 –0.6
Renal Musculoskeletal

Radial plots show the mean estimated organ health scores within each neuropsychiatric disorder. Organ systems in each plot were organized counterclockwise
according to the mean health score from the smallest to the largest value.

nia were relatively small to moderate.27,28 Body health was
on average poorer than brain health in these patients, which
may be partly explained by physical comorbidities (eFigure 7
in Supplement 1).
Diagnostic Classification Using Brain and Body Phenotypes
Despite the neural basis of the included disorders, we found
that body phenotypes provided the most accurate diagnostic
classification for schizophrenia (area under the receiver op-
erating characteristic curve [AUC], 0.81; 95% CI, 0.79-0.82),
bipolar disorder (AUC, 0.67; 95% CI, 0.67-0.68), depression
(AUC, 0.67; 95% CI, 0.67-0.67), and generalized anxiety dis-
order (AUC = 0.63; 95% CI, 0.63-0.63) compared to both brain
phenotypes (AUC for schizophrenia = 0.79 [95% CI, 0.79-
0.79], bipolar disorder = 0.58 [95% CI, 0.57-0.58], depres-
sion = 0.58 [95% CI, 0.58-0.58], and anxiety = 0.57 [95% CI,
0.57-0.58]) and individual body systems (Figure 3A). When ex-
amining whether deviations of brain or body phenotypes would
most accurately differentiate 2 neuropsychiatric diagnoses
(transdiagnostic), we found that brain phenotypes substan-
tially outperformed body phenotypes (schizophrenia-other:
mean AUC for body = 0.70 [95% CI, 0.70-0.71] and mean AUC
for brain = 0.79 [95% CI, 0.79-0.79]; bipolar disorder-other:
mean AUC for body = 0.60 [95% CI, 0.59-0.60] and mean AUC
for brain = 0.65 [95% CI, 0.65-0.65]; depression-other: mean
AUC for body = 0.61 [95% CI, 0.60-0.63] and mean AUC for
brain = 0.65 [95% CI, 0.65-0.66]; anxiety-other: mean AUC
for body = 0.63 [95% CI, 0.62-0.63] and mean AUC for
brain = 0.66 [95% CI, 0.65-0.66]) (Figure 3B).
Supplementary Analyses
Supplementary analyses were undertaken to contrast the above
findings with organ health scores evaluated in a neurodegen-
erative condition (dementia). Similar to the above findings,
we found that dementia manifested markedly poor body health
(mean [SD] OHS, −1.61 [1.73]). Most people (6269/6506 [96.4%])
had not experienced dementia onset at the time of body
function assessment. However, brain health was substan-
tially poorer in individuals with dementia (mean [SD] GM/
WM OHS, −0.59 [0.56]/−0.20 [0.60]) compared to the 4

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 572
Figure 3. Accuracy of Diagnostic and Transdiagnostic Disease Classification

A Diagnostic classification

Schizophrenia Body
Cardiovascular
Bipolar disorder Pulmonary
Musculoskeletal
Depression Immune
Kidney
Generalized anxiety disorder Hepatic
Research Original Investigation

Metabolic
0.50 0.55 0.60 0.65 0.70 0.75 0.80 0.85 Brain gray matter
Brain white matter
AUC

B Transdiagnostic classification

Schizophrenia

Bipolar disorder

Depression

JAMA Psychiatry June 2023 Volume 80, Number 6 (Reprinted)

Generalized anxiety disorder

0.50 0.55 0.60 0.65 0.70 0.75 0.80 0.85

AUC

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A, A logistic regression model was trained to classify an individual’s diagnostic status, including specific diseases and healthy control. Classification models were established for each organ system, using organ-specific phenotypic
deviation scores. Each row represents 1 target disease group, and icons are positioned to indicate the classification accuracy, as quantified by the area under the receiver operating characteristic curve (AUC). B, A logistic regression model
was trained to classify an individual’s diagnostic status between disease pairs. Each row represents 1 target disease group, and icons are positioned to the average accuracy in differentiating each disease group from all the other groups.

© 2023 American Medical Association. All rights reserved.

jamapsychiatry.com
Evaluation of Brain-Body Health in Individuals With Common Neuropsychiatric Disorders
 Evaluation of Brain-Body Health in Individuals With Common Neuropsychiatric Disorders
neuropsychiatric disorders studied (eFigures 4-6 in Supple-
ment 1). Unlike these 4 neuropsychiatric disorders, we found
that brain phenotypes outperformed all body systems for de-
mentia classification (GM AUC, 0.91; 95% CI, 0.91-0.91 and WM
AUC, 0.83; 95% CI, 0.83-0.84), although body phenotypes con-
tinued to provide modest diagnostic utility (AUC, 0.73;
95% CI, 0.72-0.73) (eFigure 8A in Supplement 1). This sug-
gests that neurodegeneration was a more prominent manifes-
tation of dementia compared to poor physical health. We also
found that dementia was characterized by a distinct profile of
brain deviations, enabling accurate differentiation from the
other 4 diagnostic groups (mean GM AUC, 0.89; 95% CI, 0.89-
0.89 and mean WM AUC, 0.81; 95% CI, 0.81-0.82) (eFigure 8B
in Supplement 1). Pairwise transdiagnostic classification ac-
curacies are shown in eFigure 9A and B in Supplement 1.
High-ranked brain GM and WM phenotypes transdiagnosti-
cally associated with dementia are shown in eFigure 9C and
D and eFigure 10 in Supplement 1.
Discussion
In this cross-sectional study, by establishing normative mod-
els of brain and body function over the adult life span using
population-based cohorts, we mapped multisystem health
profiles for 4 common neuropsychiatric disorders. We showed
that individuals diagnosed with these neuropsychiatric dis-
orders were not only characterized by deviations from nor-
mative reference ranges for brain phenotypes but also pre-
sented considerably poorer physical health across multiple
body systems compared to their healthy peers. Poor physical
health was a more pronounced manifestation of neuropsychi-
atric illness than brain health. However, brain phenotypes
enabled more accurate differentiation between pairs of neu-
ropsychiatric diagnoses.
Despite profound deviations from established normative
reference ranges for multiple body systems (eg, metabolic, he-
patic, immune, and kidney), chronic physical comorbidities
were often not diagnosed (eFigure 7 in Supplement 1), even
years after body function assessment. Disparities in these
physical health outcomes may reflect the lack of physical
examination,7,29 preventive screening, intervention,30,31 and
access to standard health care systems common among people
with mental illness.5
Across the 4 neuropsychiatric disorder groups, the meta-
bolic, hepatic, and immune systems consistently showed poor
health scores. Poor metabolic health is consistent with the com-
monly reported increased risk of developing metabolic dis-
eases, including diabetes,32-34 metabolic syndrome,35,36 and
obesity,37 in people with mental illness and may be partly at-
tributable to adverse effects of antipsychotics38 and chronic
stress.39,40 Chronic psychological stress is associated with men-
tal illness and leads to dysregulation of the hypothalamic-
pituitar y-adrenal axis and endoc rine and metabolic
systems.41-43 Hence, our findings of poor metabolic health in
neuropsychiatric illness could be due to chronic stress exac-
erbating a genetic disposition for these conditions through
dysregulation of metabolic and endocrine pathways. Poor
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Original Investigation Research
hepatic health may be associated with excessive alcohol
consumption,44 higher rates of hepatitis B and hepatitis C
i n f e c t i o n , 1 3 , 4 5 a n d p s yc h o t r o p i c d r u g - i n d u c e d
hepatotoxicity46,47 in people with mental illness. In contrast,
poor immune health could be a driver or consequence of the
reciprocally increased risk between immune-inflammatory re-
sponse and psychiatric disorders.14,48,49 Although to a lesser
extent, significantly poorer kidney health was also observed
in these patients, which may in part relate to the adverse ef-
fects of mood stabilizers, especially lithium,50,51 while poor pul-
monary and musculoskeletal health may be associated with
smoking,52 disease-related sedentary behaviors, physical
inactivity,53 and social withdrawal.54
Poor body health may also be associated with premature
aging in midlife. Biological brain age deviates from chrono-
logical age in a number of brain disorders.55,56 This suggests a
process of accelerated brain aging and may explain why some
individuals manifest increased risk of age-related disease.
To test these hypotheses, longitudinal studies are needed to
determine the interplay between brain and body health
throughout the course of psychiatric illness.
Whereas body phenotypes were generally more accurate
than the brain in diagnostic classification, classification mod-
els for brain phenotypes outperformed all body systems in
differentiating distinct diagnoses. Our models are not in-
tended for disease classification under clinical settings, but
rather provide an alternative and quantitative mapping of
how brain and body systems may be differentially affected in
neuropsychiatric conditions. Our results suggest that patterns
of abnormal deviations in brain GM and WM were relatively
distinct between different neuropsychiatric disorders. This dis-
tinction was strongest for schizophrenia compared to anxi-
ety, depression, and bipolar disorder, where the latter 3 could
not be accurately differentiated. This may be partly ex-
plained by the higher comorbidity rates among the 3 disor-
ders compared to schizophrenia in the UK Biobank cohort
(eMethods in Supplement 1), diagnostic instability,57,58 and
shared neurobiology and neural-behavior mechanisms59-62
across the 3 disorders.
In supplementary analyses, to provide a point of refer-
ence, we compared our findings of poor body health to a com-
mon neurodegenerative condition (ie, dementia). We found
that dementia manifested the poorest brain and body health
of all the disorders studied (eFigure 4 in Supplement 1). Al-
though dementia is often associated with progressive GM
loss,63,64 the most extreme deviations from normative ranges
were observed in the metabolic and hepatic systems (eFig-
ure 5 in Supplement 1), consistent with the 4 neuropsychiat-
ric conditions. The combination of insulin resistance and he-
patic dysfunction in dementia has been hypothesized to lead
to inadequate clearance from the brain of amyloid and toxic
metabolites produced by the liver, which cross the blood-
brain barrier,65 leading to brain inflammation and pathology.
Of note, body phenotypes were assessed when participants
were relatively young (Table) and had not experienced de-
mentia onset or diagnosis (prodromal, 6269/6506 [96.4%]) at
the time of body function assessment. Our results suggest that
physical health may have deteriorated in these individuals,
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 Research Original Investigation Evaluation of Brain-Body Health in Individuals With Common Neuropsychiatric Disorders

possibly contributing to the risk of developing dementia later
in life.66,67 Prospective studies are needed to track organ health
throughout the life span and identify when body and brain sys-
tems first deviate from the normative reference ranges estab-
lished here. Future work is also needed to test whether our or-
gan health scores, especially the metabolic and hepatic health
scores, can predict dementia onset and enable early identifi-
cation of individuals at risk of dementia.
Our findings provide biological evidence supporting the
adoption of established preventive public health principles
and strategies commonly used in the general population for
physical illness (eg, Diabetes Prevention Program68) in psy-
chiatry care to complement disease-specific psychotropic
medication and psychological treatments. This may be a cost-
effective way to reduce disease burden and mortality across
neuropsychiatric conditions.5
The physical health of people with mental illness needs
to be routinely assessed and adequately managed to reduce
morbidity and mortality and improve patient well-being.1,31 The
organ-specific health scores developed in our study enabled
a systematic and holistic evaluation of brain-body health
status in people with common neuropsychiatric disorders. Fur-
ther work is needed to determine whether our organ health
scores enable prediction of physical comorbidity in advance
of disease onset and identification of individuals at risk of de-
veloping physical illness. This in turn could drive new preven-
tive strategies.
Limitations
This study has limitations. Body phenotypes were only avail-
able in 1 cohort (UK Biobank), and participants in this cohort
had a narrower age range (37 to 74 years) than in other co-
horts (18 to 95 years). This limited a comprehensive charac-
terization of age-related changes in body systems across the
adult life span. Brain health scores were restricted to MRI-
derived phenotypes. Inclusion of neuroimaging phenotypes
such as magnetic resonance spectroscopy of cerebral
metabolites69,70 would complement the MRI-derived pheno-
types used here and further characterize brain health in a way
that that might be more sensitive to early brain dysfunction.
Nevertheless, MRI scans and other physiological markers com-
prising our organ health scores are already widely accessible
in clinical and primary care settings, facilitating direct, cost-
effective, and feasible clinical implementation. Further, a
within-individual comparison of brain and body health de-
viations was not feasible, because not all brain and body
phenotypes were available for all individuals. It is also impor-
tant to acknowledge biases inherent to the cohorts studied. UK
Biobank predominantly comprises individuals of White Brit-
ish ancestry, and further work is needed to test our models in
individuals of various races and ethnicities. Individuals
with serious illness may have been unable or less likely to
participate in certain assessments, yielding sampling biases in
disease cohorts and underestimation of illness severity and
comorbidities.71
Conclusions
In this study, marked deviations from normative reference
ranges for brain and body health were evident across mul-
tiple organ systems in people with neuropsychiatric disor-
ders in this study. The metabolic, hepatic, and immune sys-
tems showed the poorest health and function for the disorders
studied. Despite the unequivocal neural basis of common neu-
ropsychiatric disorders, the findings of this study suggest that
poor body health and function may be important illness mani-
festations that require ongoing treatment in patients. Rou-
tinely monitoring body health and integrated physical and
mental health care in psychiatric practice may provide cost-
effective targets for reducing the adverse effect of physical
comorbidity in people with mental illness.

ARTICLE INFORMATION
Accepted for Publication: February 15, 2023.
Published Online: April 26, 2023.
doi:10.1001/jamapsychiatry.2023.0791
Author Affiliations: Department of Psychiatry,
Melbourne Neuropsychiatry Centre, Melbourne
Medical School, the University of Melbourne,
Melbourne, Victoria, Australia (Tian, Di Biase,
Cropley, Zalesky); Clinical Brain Networks Group,
Queensland Institute of Medical Research
Berghofer Medical Institute, Brisbane, Queensland,
Australia (Mosley); Queensland Brain Institute,
Brisbane, Queensland, Australia (Mosley);
Australian e-Health Research Centre,
Commonwealth Scientific and Industrial Research
Organisation Health and Biosecurity, Brisbane,
Queensland, Australia (Mosley, Xia, Fripp);
Queensland Institute of Medical Research
Berghofer Medical Research Institute, Brisbane,
Queensland, Australia (Lupton); Discipline of
Psychiatry, College of Health, Medicine and
Wellbeing, the University of Newcastle, Newcastle,
New South Wales, Australia (Breakspear); School of
Psychological Sciences, College of Engineering,
Science and Environment, the University of
Newcastle, Newcastle, New South Wales, Australia
(Breakspear); Department of Biomedical
Engineering, Faculty of Engineering and
Information Technology, the University of
Melbourne, Melbourne, Victoria, Australia
(Zalesky).
Author Contributions: Dr Tian had full access to all
the data in the study and takes responsibility for the
integrity of the data and the accuracy of the data
analyses.
Concept and design: Tian, Zalesky.
Acquisition, analysis, or interpretation of data:
All authors.
Drafting of the manuscript: Tian, Zalesky.
Critical revision of the manuscript for important
intellectual content: All authors.
Statistical analysis: Tian, Zalesky.
Obtained funding: Tian, Zalesky.
Administrative, technical, or material support: Tian,
Mosley, Lupton, Breakspear, Zalesky.
Supervision: Cropley, Zalesky.
Conflict of Interest Disclosures: Dr Zalesky
reported grants from National Health and Medical
Research Council Senior Research Fellowship
during the conduct of the study. No other
disclosures were reported.
Funding/Support: Dr Tian was supported by the
Mary Lugton Postdoctoral Fellowship. Dr Zalesky
was supported by the Senior Rebecca L. Cooper
Fellowship. Dr Cropley was supported by National
Health and Medical Research Council grant
APP1177370. Dr Breakspear was supported by
National Health and Medical Research Council grant
APP2008612. Some of the data collection and
sharing for this project was funded by the
Alzheimer’s Disease Neuroimaging Initiative (ADNI)
(National Institutes of Health Grant U01
AG024904) and Department of Defense ADNI
(Department of Defense award number
W81XWH-12-2-0012).
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.

574 JAMA Psychiatry June 2023 Volume 80, Number 6 (Reprinted) jamapsychiatry.com

© 2023 American Medical Association. All rights reserved.

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 Evaluation of Brain-Body Health in Individuals With Common Neuropsychiatric Disorders
Additional Contributions: Some of the data used
in the preparation of this article were obtained from
the Australian Imaging Biomarkers and Lifestyle
Flagship Study of Ageing (AIBL), funded by the
Commonwealth Scientific and Industrial Research
Organisation, which was made available at the
Alzheimer’s Disease Neuroimaging Initiative (ADNI)
database (https://adni.loni.usc.edu/). The AIBL
researchers contributed data but did not
participate in analysis or writing of this report. AIBL
researchers are listed at: https://aibl.csiro.au/. Some
of the data used in preparation of this article were
obtained from the ADNI database (https://adni.loni.
usc.edu/). As such, the investigators within the
ADNI contributed to the design and
implementation of ADNI or provided data but did
not participate in analysis or writing of this report.
A complete list of ADNI investigators can be found
at: http://adni.loni.usc.edu/wp-content/uploads/
how_to_apply/ADNI_Acknowledgement_List.pdf.
We thank the chief investigators of the Australian
Schizophrenia Research Bank: Vaughan Carr, Ulrich
Schall, Rodney Scott, Assen Jablensky, Bryan
Wowry, Patricia Michie, Stanley Catts, Frans
Henskens, Christos Pantelis, Carmel Loughland.
The Australian Schizophrenia Research Bank chief
investigators did not participate in analysis or
writing of this report. Some of the data were
curated and analyzed using the Linkage
Infrastructure, Equipment and Facilities—General
Purpose Graphics Processing Unit facility hosted at
the University of Melbourne, Parkville, Victoria,
Australia. This facility was established with the
assistance of LIEF grant LE170100200.
Additional Information: We acknowledge UK
Biobank, a major biomedical database, the Human
Connectome Project, and the National Institute of
Mental Health data archive. Alzheimer’s Disease
Neuroimaging Initiative is funded by the National
Institute on Aging, the National Institute of
Biomedical Imaging and Bioengineering, AbbVie,
Alzheimer’s Association, Alzheimer’s Drug
Discovery Foundation, Araclon Biotech, BioClinica,
Biogen, Bristol Myers Squibb, CereSpir, Cogstate,
Eisai, Elan Pharmaceuticals, Eli Lilly, EuroImmun, F.
Hoffmann-La Roche and its affiliated company
Genentech, Fujirebio, GE Healthcare, IXICO,
Janssen Alzheimer Immunotherapy Research &
Development, Johnson & Johnson Pharmaceutical
Research & Development, Lumosity, Lundbeck,
Merck, Meso Scale Diagnostics, NeuroRx Research,
Neurotrack Technologies, Novartis Pharmaceuticals
Corporation, Pfizer, Piramal Imaging, Servier,
Takeda Pharmaceutical Company, and Transition
Therapeutics. The Canadian Institutes of Health
Research provides funds to support Alzheimer’s
Disease Neuroimaging Initiative clinical sites in
Canada. Private sector contributions are facilitated
by the Foundation for the National Institutes of
Health. The grantee organization is the Northern
California Institute for Research and Education, and
the study is coordinated by the Alzheimer’s
Therapeutic Research Institute at the University of
Southern California, Los Angeles. Alzheimer’s
Disease Neuroimaging Initiative data are
disseminated by the Laboratory for Neuro Imaging
at the University of Southern California, Los
Angeles. Some of the data used in preparation of
this article were obtained from the Prospective
Imaging Study of Ageing: Genes, Brain and
Behaviour database, funded by the National Health
and Medical Research Council (APP1095227) of the
Australian Government. Some of the data used in
jamapsychiatry.com
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the preparation of this article were obtained from
the Australian Schizophrenia Research Bank.
The Australian Schizophrenia Research Bank is
supported by the National Health and Medical
Research Council of Australia, the Pratt Foundation,
Ramsay Health Care, the Viertel Charitable
Foundation and the Schizophrenia Research
Institute.
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