M E TAB OLI S M CL I NI CAL AN D EX PE R IM EN TA L 6 4 ( 2 0 15 ) S 1 1 – S1 5

Available online at www.sciencedirect.com

Metabolism
www.metabolismjournal.com

Biomarkers of psychiatric diseases: Current status

and future prospects

Madhu Kalia a,⁎, Jorge Costa e Silva b

a
Thomas Jefferson University, Philadelphia, PA 19107
b
Brazilian Brain Institute, 22461-210 Rio de Janeiro, Brazil

A R T I C LE I N FO AB S T R A C T

Keywords: Abnormal behavior and disturbed cognition, often assumed to represent psychiatric illness,
Depression may actually result from some form of occult organic brain disease that can be detected
Schizophrenia by means of one or more biomarkers. This truth was discovered more than a century ago by
Bipolar disorder Aloysius Alzheimer, a German psychiatrist and neuropathologist. As a psychiatrist, he
Suicidality described the behavioral manifestations of “senile dementia” in a 51-year-old female; as a
neuropathologist, he was the first to recognize the significance of the senile plaques and
neurofibrillary tangles found in her brain after her death at age 55 years. It was Alzheimer who
made the connection between these “biomarkers” and the symptoms of the increasingly
prevalent disease that now bears his name. In recent years, the search for psychiatry-relevant
biomarkers of major depression, schizophrenia, bipolar disease, and other important
psychiatric/neuropsychiatric disorders has intensified. Biomarkers in psychiatry and
neuropsychiatry have the potential of clarifying the etiology of an ambiguous clinical
presentation—making it possible, for example, to detect underlying differences between
psychological maladies that have confusingly similar symptoms. In addition, attempts are
now being made to classify mental disorders on the basis of biomarkers. Biomarkers may also
disclose the presence of a previously unsuspected physical explanation for behavior(s)
originally presumed to be “psychiatric” in origin. Although clinically usable biomarkers in the
diagnosis and treatment of mental illness await validation, candidate genomic biomarkers
and protein profiling of candidate biomarkers in psychiatry are rapidly gaining ground as areas
of interest, with considerable future potential. This review considers biomarker-related issues
germane to psychiatry and neuropsychiatry in the context of new data that can be used to
tailor therapies to the individual psychiatric patient.
© 2015 Elsevier Inc. All rights reserved.

1. Biomarker-related issues pertinent
to psychiatry
Over 100 years ago, Aloysius Alzheimer observed plaques and
neurofibrillary tangles in the brains of two demented patients
post-mortem. One of them, Auguste Deter exhibited bizarre
behavioral symptoms at the early age of 51 years, together
with a marked loss of short-term memory. She died in 1906 at
age 55 and, in a lecture later that year, Alzheimer presented her
“psychiatric” picture—described as “presenile dementia”—
in juxtaposition with the neuropathologic findings. This
syndrome, first reported 108 years ago and now alarmingly
prevalent, has been widely known as Alzheimer's disease
since 1911 [1–3].

⁎ Corresponding author at: Thomas Jefferson University, Suite 520, 1020 Walnut Street, Philadelphia, PA 19107. Tel.: + 1 215 920 5134.
E-mail addresses: madhu.kalia@jefferson.edu, mkalia@msn.com (M. Kalia).

http://dx.doi.org/10.1016/j.metabol.2014.10.026
0026-0495/© 2015 Elsevier Inc. All rights reserved.
S12 M E TAB OLI S M CL I NI CAL AN D EX PE RI M EN TA L 6 4 ( 2 0 15 ) S 1 1 – S1 5
In recent years, increasing efforts have been made to classify
mental disorders on the basis of objective biological markers
(biomarkers), and to include this exercise in the standard
diagnostic process [4–6]. Biomarkers have been defined as:
Measurable characteristics that reflect biological function or dysfunc-
tion, response to a therapeutic measure, or indication of the natural
progression of disease (Biomarkers Definitions Working Group
2001) [7]. Biomarkers in the field of psychiatry have the
potential of being particularly significant because they could
clarify the etiology of psychiatric problems, confirm the
diagnosis of disorders with similar symptoms, and predict the
course of the disorder and determine how to treat [8]. This is
important because, in psychiatry, the close association between
symptoms and pathology is tenuous and varied and “…the
majority of psychiatric symptoms are best regarded as features,
which can arise in a multitude of settings and which reflect a
variety of underlying causes.… Consequently, in the absence of
any definitive neurobiological underpinning for neuropsychi-
atric diseases, psychiatric classification remains dependent on
eliciting signs and symptoms of mental illness. This is the
central problem from which many other difficulties in psychi-
atry arise” [9].
At present, diagnosis of psychiatric disorders relies pri-
marily on a personal psychiatric interview and evaluation
based on international guidelines (ICD-10, World Health
Organization 2014) [10], and the recently updated classifica-
tion system of mental disorders (DSM-5) [11,12]. The updated
DSM-5 of diagnostic criteria and classification guidelines
was published on May 19, 2013 after a 14-year revision
process that included consultation with expert workgroups
(clinicians and researchers). DSM-5 was designed as a
“diagnostic tool” that considers different disorders as distinct
entities. However, the boundaries between disorders have not
been strictly defined in these guidelines, which makes it
difficult to distinguish among fundamentally different disor-
ders with similar symptoms [10].
Since the traditional differentiation of psychiatric pheno-
types has been almost entirely based on clinical symptoms,
without taking biological differences into account, patient
subgroups are difficult to discriminate [13]. The NIMH has
attempted to correct this deficiency of the DSM-5 by launching
an alternative framework based on pathophysiology, especially
as disclosed by genomics and neuroscience. The NIMH has
introduced its Domain Criteria (RDoC) project, in which each of
five “domains” reflects a brain system whose functioning is
impaired to different degrees in different psychiatric condi-
tions [10,14]. Such an approach is intended to improve
therapeutic intervention that could reduce the relapse rates of
psychiatry patients. For this reason, a major research goal in
psychiatry is to develop and use biomarkers to identify “at risk”
individuals and to objectively diagnose and/or determine the
severity of mental illness [15]. It is hoped that RDoC domain
criteria will facilitate reliable and valid diagnoses, identify new
targets for treatment development, detect subgroups for treat-
ment selection, and provide a better match between research
findings and clinical decision making [14].
Expanded knowledge of molecular signatures, including
protein expression levels, could enhance our understanding of
the molecular pathways that underlie the clinical manifesta-
tion and disease course of mental disorders [16]. As evidence of
this recent interest in putative potential biomarkers in psychi-
atry, there have been over 302 articles published on this topic –
which includes gene expression levels (Ovid MEDLINE: key
words psychiatry and biomarkers), with 103 articles published
between 2012 and 2014, as compared to 24 published between
2002 and 2004.
In this review we will discuss recent concepts related to
biomarkers in psychiatry, provide an update on how bio-
markers are currently being used in the practice of psychiatry
and in clinical trials in psychiatry, and examine future trends.
The focus will be on published data on biomarkers that can be
used in tailoring therapies to the individual psychiatric patient.
However, it should be pointed out that, despite numerous
recent advances in neuroscience and genetic research, the
diagnosis of major classes of psychiatric disorders has not yet
been correlated with clinically usable (or validated) biomarkers
[15], nor are there many genetic and other biomarkers available
that can reliably guide the diagnosis of psychiatric disorders
[10]. Nevertheless, candidate genomic biomarkers and protein
profiling of serum candidate biomarkers in psychiatry consti-
tute an area of growing interest and can be expected to have
considerable future potential [17–21].
2. Mood disorders
2.1. Major depressive disorder (MDD)
Recent biomarker research in psychiatry has involved use of
multimodal approaches, such as neuroimaging, genetics, prote-
omics, metabolomics, to explore potential predictor and medi-
ator biomarkers of the rapidly acting antidepressants ketamine
and scopolamine. The goal, as described by Niciu, et al. [22] is “…
to improve pathophysiological understanding, personalize
treatment selection, and expand our armamentarium of novel
therapeutics.” Treatment of depression (antidepressant medi-
cation and electroconvulsive therapy) has been shown to
influence oxidative stress and inflammatory markers [23]. In
most of these studies the relationship between variations
in levels of biomarkers and changes in depressive symptoms
has not been studied thoroughly enough to permit conclusions
about the usefulness of biomarkers as indicators of the effective-
ness of treatment of depression [23].
Although assessment of pre-treatment biomarkers has the
potential to enhance clinical decision making in psychiatry, the
usefulness of candidate biomarkers in evaluation of treatment
efficacy needs to be more firmly established. A number of studies
have attempted to measure treatment progress over time by
means of treatment-response biomarkers. Validation of these
treatment-response biomarkers and the careful monitoring of
their changes can be expected to provide useful information
about treatment efficacy in the future [23]. Examples of depres-
sion-related biomarkers follow:
(a) C-reactive protein (CRP). The potential of biomarkers to
predict the onset of depression: In a prospective study,
increased CRP levels were associated with an increased
risk for hospitalization with depression [24]. Higher CRP
levels have also been identified as an independent risk
factor for de novo depression in women [23,25], and a
 M E TAB OLI S M CL I NI CAL AN D EX PE R IM EN TA L 6 4 ( 2 0 15 ) S 1 1 – S1 5
CRP level higher than 3 mg/L was associated with a
four-fold increase in the likelihood of recurrent depression
in men [26]. A meta-analysis of longitudinal studies has
shown that elevated CRP levels were associated with an
increased risk of depressive symptoms [27]. In addition to
increased CRP levels, high kynurenic acid levels have also
been found to be positively associated with an increased
risk of development of depression [28].
(b) Cytokines: Significantly higher concentrations of cyto-
kines such as tumor necrosis factor-α (TNF-α) [23] and
interleukin-6 (IL-6) [29] have been identified in patients
with major depression. In a meta-analysis of peripheral
biomarkers in community and clinical populations,
elevated IL-1 and IL-6 have been positively associated
with depression [30].
(c) Neopterin: Levels of plasma neopterin are increased in
depressed patients [31–35] — particularly in patients
suffering from melancholia [33,36].
(d) Malondialdehyde (MDA): MDA levels are increased in
depressed patients [31] and a similar relationship has
been found in depressed patients suffering from chronic
heart failure [37].
(e) Isoprostanes: Levels of isoprostanes are elevated in
patients suffering from depression, as demonstrated by
higher urinary concentrations of 8-iso-PGF2α [38,39] and
of a β-oxidant metabolite of 8-iso-PGF2α.
(f) Epigenetics and depression: Altered DNA methylation
patterns of genes have been associated with depression,
with epigenetic modifications of the brain-derived neuro-
trophic factor-6 (BDNF-6) exon being found in adolescent
offspring of mothers who smoked during pregnancy
[40,41]. Methylation changes affecting the glucocorticoid
receptor [42–44] and serotonin transporters [45] have been
reported in children (not in adults) following exposure of
mothers to prenatal stressors such as smoking, maternal
depression, partner violence and war [40,45].
(g) Serum S100B, a new biomarker for mood disorders:
Histopathological post-mortem studies on brains of
patients with mood disorders consistently show reduc-
tions in astrocyte density in several brain regions
[46,47]. These reductions have been shown to be
reversed by antidepressive treatment [48]. The glial
marker protein S100B has been shown to reflect glial
involvement in the pathogenesis of mood disorders,
particularly MDD [47] and findings strongly support the
concept that S100B is a reliable and sensitive biomarker
for mood disorders.
2.1.1. Bipolar disorder (BD)
The need for biomarkers is especially great in BD because this
psychiatric condition may be characterized by diverse pre-
sentations in mood polarity combined with very high rates
of co-morbidity [49]. A recent meta-analysis has shown that
brain-derived neurotrophic factor (BDNF) is decreased and
pro-inflammatory markers (PIMs) are increased in BD. There
is also preliminary evidence that these biomarkers change
over time and respond to treatment [49]. Further studies are
needed to determine whether BDNF and PIMs are useful in
evaluating the treatment and prevention of BD-associated
cognitive dysfunction.
S13
3. Schizophrenia (SZ)
Biomarkers of SZ have been classified as “state related,”
which are detected during the acute phases of the disease
(psychotic episodes), and “trait related,” which are present
throughout the course of the disease. A biomarker is said to
qualify as an “endophenotype” if it is heritable, trait-related,
and associated with an illness that occurs in the population
(such as SZ). However, it seems to make more sense to think
of endophenotypes, not as “biomarkers” but as intermediate
phenotypes in specific individuals who are at increased genetic
risk of developing an illness like SZ and who, unaffected by the
disease at the time, nevertheless possesses one or more of its
biomarkers. In families with a schizophrenic member, there is
an increased prevalence of endophenotypic traits of SZ among
nonaffected family members.
The most prominent molecular endophenotypes and bio-
markers of schizophrenia are [i] central nervous system
neurotransmitters – dopamine (DA) and GABA – and [ii] neural
signal transduction pathways [50]. Biomarkers facilitate an early
diagnosis of schizophrenia. Identification of endophenotypes
is a useful way of estimating genetic risk among apparently
unaffected family members [50].
Increasingly sophisticated study of biomarkers and
endophenotypes of schizophrenia – a puzzling biological
disorder – should help investigators improve understanding
of the interaction between the genetic, environmental and
epigenetic factors that underlie SZ's clinical manifestations.
The role of interleukin-2 in different groups of symptoms
and cognitive performance in schizophrenic patients was
recently investigated [51]. This study showed that SZ patients
had significantly lower levels of IL-2 than healthy controls,
leading to the conclusion that IL-2 might be involved in the
mechanisms related to the cognitive deterioration and bizarre
symptomatology that often characterize schizophrenia.
4. Suicidality
Suicide is a leading cause of death in psychiatric patients.
Biomarkers that could predict and track suicidal states will
have immediate practical applications with desirable societal
implications [52]. The ability of gene expression biomarkers
found in the circulating blood to predict mood state [53] and
symptoms of psychosis have been investigated [54]. Putative
biomarkers related to suicidality have been validated in four
male cohorts of suicides [55]. After correction for multiple
comparisons, four biomarkers differentiated future and past
hospitalizations with suicidality in the prospective cohorts of
individuals with either bipolar disease or psychosis. SAT1
(spermidine/spermine N1-acetyltransferase 1) was identified
as the top biomarker comporting with alterations of the
polyamine system in the brains of suicides [52].
4.1. Conclusions and future directions
One of modern psychiatry's high-priority research goals is
to develop biomarkers that can identify “at risk” individuals
and diagnose and/or estimate severity of mental illness [15].
S14 M E TAB OLI S M CL I NI CAL AN D EX PE RI M EN TA L 6 4 ( 2 0 15 ) S 1 1 – S1 5
While the hope of psychiatrists and neuroscientists is to
discover an easy and accurate way to detect and diagnose
mental disease, there are several concerns about the potential
use of psychiatric biomarkers [56] (Singh and Rose): “…What
is the best way to communicate the idea of a ‘risk profile’, and
how might this affect personal identity? Given that human
behavior and psychiatric disorders arise from a complex set of
factors, how can this complexity be respected when using
biomarker information in the clinic and community? And what
issues might arise from commercialization of biomarkers, and
how should they be addressed” [56]?
So far most putative biomarkers of psychiatric disorders that
have been identified have been “descriptive” (also considered to
be “distal” or symptomatic biomarkers which have not been
validated so far [57]). It is hoped that biomarkers in psychiatry
will lead to new therapeutics, such as those being used in the
treatment of cardiovascular disease where lipid biomarkers are
used for phenotyping disease processes as well as for develop-
ing treatment strategies [57,58]. Although applying this para-
digm to clinical psychiatry is challenging, it is a goal worth
pursuing. Imaging genomics and related emerging technologies
are also moving forward rapidly as biomarkers in psychiatry
and hold the greatest promise for making biological system-
based evaluations in psychiatry.
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