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Contents lists available at ScienceDirect

Asian Journal of Psychiatry

journal homepage: www.elsevier.com/locate/ajp

Review

Do schizophrenia patients age early?

Venkataram Shivakumar a,b,*, Sunil V. Kalmady a,b, Ganesan Venkatasubramanian a,b,
Vasanthapuram Ravi c, Bangalore N. Gangadhar a
a
The Schizophrenia Clinic, Department of Psychiatry, National Institute of Mental Health & Neurosciences (NIMHANS), Bangalore, India
b
Translational Psychiatry Laboratory, Cognitive Neurobiology Division, Neurobiology Research Centre, National Institute of Mental Health & Neurosciences,
Bangalore, India
c
Department of Neurovirology, National Institute of Mental Health & Neurosciences (NIMHANS), Bangalore, India

A R T I C L E I N F O A B S T R A C T

Article history: The etiopathogenesis of schizophrenia is poorly understood. Within the proposed ‘‘neurodegeneration
Received 1 November 2013 paradigm’’, observations have been put forth for ‘‘accelerated aging’’ in this disorder. This proposition is
Received in revised form 17 February 2014 largely based on the neuroscience research that demonstrates progressive changes in brain as well as
Accepted 22 February 2014
other systemic abnormalities supportive of faster aging process in patients with this disorder. In this
Available online xxx
review, we have summarized the literature related to the concept of early aging in schizophrenia. These
studies include P300 abnormalities & visual motion discrimination, neuroimaging findings, telomere
Keywords:
dynamics as well as neuropathology of related brain regions. We also propose a role of vitamin D,
Aging
neuroimmunological changes and elevated oxidative stress as well as mitochondrial dysfunction in
IL-6
Oxidative stress addition to the above factors with ‘vitamin-D deficiency’ as the central paradox. Put together, the
P300 evidence supporting early aging in schizophrenia is compelling and this requires further systematic
Schizophrenia studies.
Telomere ß 2014 Elsevier B.V. All rights reserved.
Vitamin-D

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
2. Aging and schizophrenia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
3. Age-related physiological abnormalities and metabolic syndromes in schizophrenia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
4. Evidences from neuroimaging studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
5. Neuropathology findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
6. P300 and visual motion perception abnormalities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
7. Telomere dynamics in schizophrenia and aging. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
8. Immune system in schizophrenia and aging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
9. Vitamin-D in schizophrenia and aging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
10. Oxidative damage, mitochondrial dysfunction in schizophrenia & aging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
11. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000

1. Introduction

Schizophrenia is a complex neuropsychiatric disorder charac-

terized by delusions, hallucinations, formal thought disorder,
* Corresponding author at: Department of Psychiatry, National Institute of personality disturbance, and cognitive dysfunction (APA, 1994). It
Mental Health & Neurosciences (NIMHANS), Bangalore, India. affects 1% of the world population (Bresnahan et al., 2000). It also
Tel.: +91 080 26995256; fax: +91 80 26564830.
E-mail address: shvdgrt@gmail.com (V. Shivakumar).
has a tremendous socioeconomic impact (Kaplan and Sadock,

http://dx.doi.org/10.1016/j.ajp.2014.02.007
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Please cite this article in press as: Shivakumar, V., et al., Do schizophrenia patients age early? Asian J. Psychiatry (2014), http://
dx.doi.org/10.1016/j.ajp.2014.02.007
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2006). The World Health Organization ranks it among the top ten
disabling disorders (WHO, 2001). The etiopathogenetic basis of
schizophrenia is yet to be ascertained (Keshavan et al., 2011).
Among the different causes, genetic basis has gained consider-
able evidence from family and monozygotic twin studies (Brown,
2011). However, genetic theories alone cannot explain schizo-
phrenia completely, since the concordance rate in monozygotic
twins is only 50%. Moreover, specific gene isolation has not been
possible yet (McGuffin et al., 1995). Consequently it is tempting to
postulate that environmental factors play a role in the pathogene-
sis (Brown, 2011). Environmental factors such as infections during
pregnancy (Brown et al., 2004), and birth related complications
(Mittal et al., 2008), Rh-factor incompatibility (Cannon et al., 2002),
immunological factors, winter births and vitamin-D deficiency
(McGrath, 1999) have been implicated. However, the contribution
of these factors toward pathogenesis of schizophrenia is yet to be
definitively established; nonetheless, it is important to note that
most of these factors are linked with immune aberrations and an
immune mediated pathogenesis is among the leading hypotheses
for schizophrenia (Canetta and Brown, 2012; Horvath and Mirnics,
2014; Smith et al., 2007).
Prenatal immune abnormalities can result in persistent pro-
inflammatory state that can adversely impact further neurodeve-
lopment (Canetta and Brown, 2012). Indeed, it has been strongly
hypothesized that schizophrenia could be due to a neurodevelop-
mental abnormality of brain (Fatemi and Folsom, 2009). The
evidence for this is provided by the imaging studies which have
largely demonstrated enlarged ventricles, smaller medial temporal
lobes, and smaller cortical volume in first episode cases as well as
in high-risk individuals. The fact that these brain changes are
present even before the manifestation of illness, suggests a
possible neurodevelopmental basis (Steen et al., 2006). Postmor-
tem neuropathological studies have confirmed these imaging
findings (Harrison, 2004). However, some researchers also
hypothesize that schizophrenia could be due to progressive
neurodevelopmental pathology (Woods, 1998).
2. Aging and schizophrenia
Kirkpatrick et al. (2008) in their review termed it as ‘pathological
aging’ or ‘accelerated aging process’, because of increased incidence
of premature onset of age-related physiological abnormalities and
mortality. Papanastasiou et al. (2011), considered schizophrenia as
‘segmental progeria’ i.e., viewing schizophrenia as a whole body
disorder rather than psychological disorder alone. The main driving
factor in considering schizophrenia as an accelerated aging process
is the early onset of aging changes in schizophrenia patients
compared to their healthy counterparts. The factors in support of
this hypothesis of accelerated aging in schizophrenia are the
increased occurrence of structural and functional brain abnormali-
ties as seen in elderly, increased incidence of aging-associated
physiological abnormalities and disease (Fernandez-Egea et al.,
2009b). Early cognitive decline and shorter natural life span than
general population also support accelerated aging (Kirkpatrick et al.,
2008). This is further supported by altered telomere dynamics seen
in schizophrenia patients (Kao et al., 2008). Electrophysiological and
visual motion discrimination abnormalities noted as in the elderly
and absence of gliosis being attributed to apoptotic changes, provide
a clue that neurodegenerative processes may be operative in this
disorder. In this review an attempt has been made to collate all the
evidences and relate them to the proposed hypothesis. Extending
these postulates further, we also propose a role for vitamin-D,
elevated oxidative stress & mitochondrial dysfunction and neu-
roimmunological changes as a common risk factor for both
schizophrenia and aging thus adding the evidence base for
‘‘accelerated aging’’ in schizophrenia.
Please cite this article in press as: Shivakumar, V., et al., Do schizophrenia patients age early? Asian J. Psychiatry (2014), http://
dx.doi.org/10.1016/j.ajp.2014.02.007
3. Age-related physiological abnormalities and metabolic
syndromes in schizophrenia
Schizophrenia is associated with an increased incidence of age-
related metabolic abnormalities like impaired glucose tolerance,
insulin resistance and type II diabetes mellitus (Ryan and Thakore,
2002). It may be argued that these metabolic abnormalities could
be secondary to antipsychotic usage; but these abnormalities were
reported even prior to the advent of neuroleptics. However, studies
have reported increased insulin resistance and glucose intolerance
in antipsychotic-naı̈ve schizophrenia patients compared to their
healthy counterparts (Fernandez-Egea et al., 2009a; Ryan et al.,
2003; Venkatasubramanian et al., 2007). Patients of schizophrenia
have increased pulse pressure (Kirkpatrick et al., 2008); a risk
factor for cardiovascular diseases, which commonly appears as age
advances due to arterial stiffness. Indeed, pulse pressure changes
are associated with insulin resistance and glucose intolerance
(Sengstock et al., 2005). The prevalence of metabolic syndrome,
though appears to be very common in schizophrenia, might be
possibly due to the adverse impact of antipsychotic treatment
(Mitchell et al., 2013). However, recent meta-analysis of preva-
lence of metabolic syndrome in schizophrenia reports a rate of
20.2% in un-medicated patients (Mitchell et al., 2013).
Schizophrenia is also associated with an increased mortality
rate compared to normal population with cardiovascular disease
accounting for many of the excessive deaths (Lwin et al., 2011).
Though other factors like suicide, poor health care and medication
side effects are considered the main cause of mortality, the
metabolic abnormalities and resulting cardiovascular diseases
cannot be neglected (Henderson et al., 2005; Venkatasubramanian
et al., 2007).
Apart from this, efforts have been made to study other
hormones which might act as aging indicators, in schizophrenia.
One such hormone is androgen, which progressively declines with
age (Kaufman and Vermeulen, 2005). Interestingly, a study
conducted in male antipsychotic-naı̈ve schizophrenia patients
found that testosterone levels were significantly reduced (Fer-
nandez-Egea et al., 2011). This adds to the line of evidences
supporting the accelerated aging hypothesis.
4. Evidences from neuroimaging studies
Neuroimaging studies have reported significant decrease in the
brain volume with advancing age (Fjell et al., 2009). Common
findings include ventricular dilatation, volume loss in prefrontal and
temporal cortices as well as reduction in hippocampal volume
(Lemaitre et al., 2005). Interestingly, imaging studies in schizophre-
nia have also reported similar changes in these regions (Steen et al.,
2006). Moreover, hippocampus, one of the prime structures
implicated in schizophrenia (Whitworth et al., 2005), shows atrophy
at a faster rate than any other structure in normal aging process
(Lemaitre et al., 2005). Even within hippocampus, the CA1 and CA3
subfields are affected in healthy aging, age-related diseases like
Alzheimer’s as well as in schizophrenia (Small et al., 2011).
One might wonder how, the mere presence of these structural
brain changes qualify for being an evidence for neurodegenerative
process. Primarily these changes seem to progress over time even
after the onset of illness, which support neurodegeneration theory
in schizophrenia. This is vindicated in recent voxel-based
morphometric studies (Mane et al., 2009). Earlier longitudinal
studies did not indicate any progressive deterioration of the brain
early in schizophrenia. However, a recent meta-analysis has
demonstrated that patients with schizophrenia, compared with
healthy controls, show a significantly higher progressive reduction
in cortical gray matter volume over time with a moderate effect
size of 0.5 (Olabi et al., 2011).
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DeLisi et al. (1998) in their four year longitudinal study reported
a clear reduction in the hemispheric volume. This was further
replicated by Sporn et al. (2003), who reported a striking loss of
gray matter volume in early onset schizophrenia. Chakos et al.
(2005) showed that patients with schizophrenia had smaller
hippocampal volumes than the controls. This volume reduction
was larger in older patients than in young, compared with age-
matched controls. Jacobsen et al. (1998) reported a significantly
greater volume decreases in right temporal lobe, bilateral superior
temporal gyrus and posterior superior temporal gyrus, right
anterior superior temporal gyrus, and left hippocampus during the
follow-up interval. They also documented a 7% reduction in
hippocampus volume per year.
Enlarged ventricles have been one of the earliest findings noted
in schizophrenia. Interestingly, ventricular volume was found to
increase with time in schizophrenia. Mathalon et al. (2001)
reported nearly 13% increase in the size of lateral ventricle every
year resulting in doubling of the size roughly in an 8 year span. This
study corroborated the findings of Rapoport et al. (1999), who
reported a 10% increase in ventricular volume per year.
Progressive brain volume loss in schizophrenia is approximately
twice that found in healthy people due to normal aging and the loss
is more pronounced in the frontal and temporal areas (Hulshoff Pol
and Kahn, 2008). Greater clinical severity was associated with faster
rates of fronto-temporal brain volume changes (Mathalon et al.,
2001). Not only structural changes, but also functional studies have
reported similarities between schizophrenia and aging (Buchsbaum
and Hazlett, 1997). Both have decreased cerebral blood flow and
metabolism in the region of frontal lobe, which also explains
impaired executive functioning in both cases.
Multiple lines of evidences demonstrating progressive loss of
brain volume in schizophrenia after the onset of illness and their
association with the clinical severity raise serious concerns about
discarding the neurodegenerative processes which might be active
in schizophrenia, resulting in accelerated aging changes.
5. Neuropathology findings
Neuropathology studies examining postmortem brains of
schizophrenia patients corroborate the brain changes found in
Magnetic Resonance Imaging (MRI) studies (Harrison, 1999). They
however support neurodevelopmental cause by ruling out gliosis,
which is usually present in an ongoing pathological process.
However, some studies have reported significant gliosis (Bruton
et al., 1990). The drawbacks of the gliosis hypothesis however are,
firstly there is a lack of consistent methodology adopted across
studies to determine the presence or absence of gliosis (Harrison,
1999). Secondly, proponents of neurodegenerative theories have
suggested that the absence of gliosis and evidence of cell
degeneration could be due to the fact that the pathophysiology
involves a graded apoptosis rather than a fulminant necrotic
process (Margolis et al., 1994). Apoptosis is a form of cell death that
occurs in many neurodegenerative disorders in which intra- or
extracellular physiologic events trigger a programmed sequence of
cellular actions resulting in cell destruction and evacuation
(Bredesen, 1995). When apoptosis is triggered at synapses due
to various neurochemical events like calcium influx, glutamate
stimulation or due to reactive oxygen species; it produces
neurodegenerative synapse loss or synaptic remodeling (Mattson
et al., 1998). This type of apoptotic cell injury might compromise
cell function and alter brain morphology without any serious cell
damage or gliosis (Lieberman, 1999).
Studies have reported decreased neuronal size in layer III of the
cortex with cytoplasmic atrophy accompanied by reduced neuropil
and cortical thinning as well as increased density of neurons
indicating that the cell processes and synaptic connections are
Please cite this article in press as: Shivakumar, V., et al., Do schizophrenia patients age early? Asian J. Psychiatry (2014), http://
dx.doi.org/10.1016/j.ajp.2014.02.007
3
indeed reduced in schizophrenia (Casanova, 1997; Goldman-Rakic
and Selemon, 1997). This is also evident with the finding of
decreased concentrations of synaptic proteins in schizophrenia
(Eastwood et al., 2001; Karson et al., 1999).
Researchers also argue that there could be a subtype of
schizophrenia which is directly associated with an inflammatory
or neurodegenerative pathology (Harrison, 1999). Therefore mere
absence of gliosis does not rule out neurodegeneration of the brain.
6. P300 and visual motion perception abnormalities
Electrophysiological abnormalities in schizophrenia also have
resemblance with findings in normal aging. P300 component of
event-related potentials ERP which reflects task-related cognitive
processes like attention, context updating, speed and efficiency of
cognitive processing has decreased amplitude and increased
latency both in aging and schizophrenia (Mathalon et al., 2000).
Visual motion processing studies in normal aging revealed a
significant deterioration in the ability of the older observers to
perceive differences in speed (Norman et al., 2003). The same finding
has also been reported in neurodegenerative disorders (Kavcic et al.,
2011). Schizophrenia also showed similar changes in visual motion
processing as that of normal aging; patients showed significantly
increased thresholds i.e., degraded performance for velocity
discrimination compared to healthy control (Bidwell et al., 2006).
7. Telomere dynamics in schizophrenia and aging
Telomeres are specialized structures at the terminal part of the
chromosomes. It is widely agreed that telomere length correlates
with aging process, as telomeres shorten with every cell division
due to end-replication losses (Aubert and Lansdorp, 2008). Hence it
could serve as a reliable biomarker for assessment of aging.
Lymphocytes are considered ‘the windows to brain’, the aging-
related changes in them is believed to reflect the aging changes in
the brain (Gladkevich et al., 2004). In one study lymphocytes of
schizophrenia patients were aged to the equivalent of 25 years
older than lymphocytes derived from healthy controls and the rate
of telomere loss was more than doubled (Kao et al., 2008).
Telomere length in schizophrenia has also been correlated with
response to treatment, and patients with short telomere length
were poor responders (Yu et al., 2008). At least one study has
reported decreased telomerase levels in peripheral blood lym-
phocytes of schizophrenia patients (Porton et al., 2008). Findings
on telomere data are challenged by either a lack of association of
telomere length (Mansour et al., 2011) or even longer telomeres in
schizophrenia patients (Nieratschker et al., 2013). Possible
confounding effect of antipsychotics however cannot be excluded
(Savolainen et al., 2012). Studies related to telomere dynamics are
few in number; but there is a need for more intense research in this
area.
Thus there are multiple evidences in favor of the accelerated
aging hypothesis in schizophrenia which has been highlighted by
many researchers (Kirkpatrick et al., 2008; Papanastasiou et al.,
2011). We believe that there are a few more factors which are
important in the context of this hypothesis. Normal aging is
explained by many theories. The ones which appear to be
operating both in schizophrenia and aging process are the
‘inflammatory theory of aging’, ‘vitamin-D deficiency’ and oxida-
tive stress & mitochondrial dysfunction.
8. Immune system in schizophrenia and aging
Research into immune abnormalities in schizophrenia (Horvath
and Mirnics, 2014) has provided valuable insights into treatment-
related aspects arguing for approaches based on immunomodulation
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(Debnath and Venkatasubramanian, 2013). An increased level of
pro-inflammatory markers in both peripheral and cerebral systems
has been consistently documented in schizophrenia (Fan et al.,
2007). Among the pro-inflammatory cytokines, interleukin-6 (IL-6)
plays a vital role in schizophrenia pathology. The compelling role of
IL-6 in the pathogenesis of schizophrenia is emphasized by the
following factors: (i) meta-analytic studies supporting significantly
higher serum levels of IL-6 in schizophrenia patients that correlate
with symptom severity (Potvin et al., 2008); (ii) association of
schizophrenia with IL-6 gene polymorphism (Paul-Samojedny et al.,
2010); (iii) potential influence serum IL-6 on hippocampus;
hippocampus being the most important brain regions implicated
in schizophrenia (Marsland et al., 2008); (iv) IL-6 playing a vital role
in ‘ketamine model’ of schizophrenia (Behrens et al., 2008); (v) role of
IL-6 in fetal pathogenetic model of neurodevelopmental aberrations
in schizophrenia (Smith et al., 2007). Interestingly, it has been
hypothesized that immune mediated pathogenesis can result in
increased free radicals leading to oxidative stress mediated damage
in schizophrenia (Sirota et al., 2003). Indeed, studies related to
oxidative stress and cytokines in schizophrenia supports this view
(Zhang et al., 2009). Also, various lines of evidence suggest oxidative
stress abnormalities in schizophrenia which is discussed subse-
quently.
Thus, immunopathological role of interleukin-6 is one among
the comprehensive approaches to understand Schizophrenia.
Studies in aging have provided strong evidence linking increase
in IL-6 levels with advancing age (Ferrucci et al., 2005). It is
regarded as one of the key factors responsible for premature
induction of aging at a cellular level (Tsirpanlis, 2009).
9. Vitamin-D in schizophrenia and aging
Vitamin-D helps in growth of brain by inducing various growth
factors. A possible linkage of low vitamin-D to schizophrenia is also
hypothesized (McCann and Ames, 2008). The evidence to this
includes the association of schizophrenia with winter births, its
greater frequency in dark-skinned migrants to cold climates, and
the variation in incidence and prevalence of schizophrenia with
latitude (McGrath, 1999). Recent meta-analysis on vitamin-D and
psychosis reported a moderately significant reduction in the serum
levels of vitamin-D in schizophrenia patients compared to healthy
controls and a trend for lower levels compared to other psychoses
(Belvederi Murri et al., 2013). The effects of vitamin-D insufficiency
on central nervous system has been demonstrated by the fact that
vitamin-D deprived rats showed brain morphological changes like
enlarged ventricles and thinner cortex, which are seen in brains of
schizophrenia patients (Eyles et al., 2003). Low maternal vitamin-D
has been proposed to adversely affect the developing fetal brain,
leaving the affected offspring at an increased risk of adult-onset
schizophrenia (McGrath, 1999). With respect to its role in aging,
animal experiments have demonstrated a direct relationship
between abnormal vitamin-D levels and premature aging and
metabolic syndromes (Hayes, 2010; McGill et al., 2008; Tuohimaa,
2009). In humans too low serum vitamin-D levels are related to
aging (Perez-Lopez et al., 2011). There is also considerable
evidence that vitamin-D has a significant impact on the immune
system (McCann and Ames, 2008). Vitamin-D has been shown to
decrease the production of pro-inflammatory cytokines and
increase the production of anti-inflammatory cytokines (McCann
and Ames, 2008). Similarly, vitamin-D plays an important role in
reducing oxidative stress and related damage (Halicka et al., 2012).
Therefore this could be one of the pathogenetic mechanisms
resulting in accelerated aging changes in vitamin-D deprived rats.
These evidences point toward the close relationship between
schizophrenia, premature aging, and vitamin D.
Please cite this article in press as: Shivakumar, V., et al., Do schizophrenia patients age early? Asian J. Psychiatry (2014), http://
dx.doi.org/10.1016/j.ajp.2014.02.007
10. Oxidative damage, mitochondrial dysfunction in
schizophrenia & aging
Oxidative stress abnormalities have been proposed to play an
important role in the pathogenesis of schizophrenia (Jiang et al.,
2013). Evidence points to the role of mitochondrial dysfunction
and elevated levels of oxidative damage as potential pathogenetic
mechanisms in schizophrenia (Prabakaran et al., 2004). Indepen-
dent studies have provided evidence to this in the form of genetic
and functional impairment in schizophrenia patients to synthesize
glutathione, an antioxidant molecule (Gysin et al., 2007). Apart
from glutathione and total antioxidant levels, some researchers
have reported increased levels of neopterin in schizophrenia
(Chittiprol et al., 2010). High neopterin production is associated
with increased production of reactive oxygen species by stimulat-
ed immunocompetent cells and it has also been proposed that
neopterin may not only be an indicator of oxidative stress resulting
from immune activation, but may also contribute to the oxidative
stress by modulating reactive oxygen species (Murr et al., 2002).
Magnetic resonance spectroscopy imaging studies in neuroleptic-
naı̈ve schizophrenia patients have demonstrated lower phospho-
creatine/total phosphorus and phosphocreatine/total ATP ratios in
basal ganglia, which could be due to reduced synthesis, perhaps
related to mitochondrial dysfunction (Gangadhar et al., 2004). The
translational evidence to the oxidative damage theory has been
provided by Berk et al. (2008) in their randomized, multicenter,
double-blind, placebo-controlled study, which demonstrated the
beneficial effects of administration of antioxidants like N-
acetylcysteine, a precursor of Glutathione.
Interestingly, elevated levels of oxidative stress and mitochon-
drial decay are considered one of the main causes of aging
(Shigenaga et al., 1994), where glutathione and other reactive
oxygen species play an important role. Neopterin is reported to
increase with advancing age (Spencer et al., 2010). In fact oxidative
damage to the nucleic acids has been suspected to play a major role
in aging as well as associated physiological abnormalities like
atherosclerosis and cardiovascular abnormalities (Vogiatzi et al.,
2009). These are also seen at an early age in schizophrenia and
neurodegeneration (Nunomura et al., 2012). A recent study
examining the oxidative stress on cellular constituents by
measuring the urinary excretion of markers of DNA and RNA
oxidation found that there was a 20% increase in the excretion of
these markers in schizophrenia when compared to controls
(Jorgensen et al., 2013). Thus DNA damage might be one of the
reasons for shortened telomere length found in schizophrenia
Fig. 1. Vitamin-D centered accelerated aging hypothesis in pathogenesis of
schizophrenia.
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Table 1
Common features noted between schizophrenia and normal aging.

Parameters Schizophrenia Normal aging

Metabolism Increased rates of obesity, abnormalities in glucose
tolerance years before the introduction of antipsychotic
medication (Ryan and Thakore, 2002)
Hormonal Decreased levels of testosterone (Fernandez-Egea et al.,
2011)
Brain changes Gray matter loss in hippocampus, temporal and frontal
cortices and volume enlargements in ventricular system,
subarachnoid space (Steen et al., 2006)
Nerve conduction P300 component of ERP which reflects efficiency of
cognitive processing has decreased amplitude and
increased latency in and schizophrenia (Mathalon et al.,
2000)
Ocular Degraded performance for velocity discrimination (Bidwell
et al., 2006)
Telomere dynamics Rate of telomere loss is more than doubled (Kao et al., 2008)
and Reduced telomerase activity (Porton et al., 2008).
Immune system Increase in the serum levels of various cytokines with a
special emphasis on IL-6 (Potvin et al., 2008)
Vitamin-D Reduced vitamin-Din schizophrenia patients (Belvederi
Murri et al., 2013) and offspring’s of vitamin-D deprived
mothers at more risk of developing schizophrenia
(McGrath, 1999)
Oxidative stress & Increased level of ROS and oxidative stress generation
mitochondrial dysfunction within the prefrontal cortex of the schizophrenia
(Prabakaran et al., 2004)
20% increase in the excretion of DNA and RNA oxidation
markers (Jorgensen et al., 2013)
The risk of metabolic syndrome increases with older age
(Kraja et al., 2006)
Aging is associated with a progressive decline in
testosterone levels in men (Kaufman and Vermeulen, 2005)
Similar changes in the identical areas are noted in aging
brains (Lemaitre et al., 2005)
Reduced amplitude of P300 & increased latency are also
seen in normal aging (Iragui et al., 1993)
Visual motion discrimination abnormalities are common in
aging (Norman et al., 2003)
Telomeres shorten with age due to end-replication losses
(Aubert and Lansdorp, 2008)
Interleukin-6 is one of the factors responsible for premature
induction of aging at cellular level (Tsirpanlis, 2009)
Low vitamin-D levels associated with aging in humans
(Perez-Lopez et al., 2011) and premature aging and
metabolic syndromes in animal experiments (Hayes, 2010)
Elevated levels of oxidative stress and mitochondrial decay
cause of aging (Shigenaga et al., 1994)
Oxidative damage to the nucleic acids play a major role in
aging, aging-associated metabolic syndrome (Vogiatzi et al.,
2009)

patients. These converging evidences point toward one other
pathogenetic mechanism i.e. elevated levels of oxidative stress and
mitochondrial dysfunction commonly operating in schizophrenia
and aging.
11. Conclusion
Though most of the research in schizophrenia is focused from
the neurodevelopmental view point, there are certain factors
which remain unexplained. Considering the latency of onset of
schizophrenia, its chronic and deteriorating course (at least in a
subset of population), relative refractoriness of negative symptoms
to treatment and progressive brain structural changes indicate that
schizophrenia might have an ongoing neurodegenerative course
resulting in appearance of accelerated aging changes as mentioned
above.
The immune system abnormalities, vitamin-D deficiency as
well as elevated oxidative stress and mitochondrial dysfunction,
appears to act in synchrony forming a vicious cycle of events
although, the precise triggering factor remains unknown. Compil-
ing all the evidences described above, there appears to be one
central paradox which is involved in regulating the other major
pathways. This central paradox is vitamin-D deficiency, which is
probably contributing to accelerated aging in schizophrenia.
Vitamin-D, as discussed earlier seems to play a vital role in
immune system regulation as well as in reducing oxidative stress
and mitochondrial decay. Chronic reduction in vitamin-D levels
could be detrimental to the structural integrity and functioning of
the brain. Based on the available evidences and given the versatile
role of vitamin-D, we hypothesize that neurodegenerative course
could be operative in certain subset of schizophrenia population
and vitamin-D could be the driving factor. These observations are
summarized in the following figure (Fig. 1).
In this article we highlight some of the factors supporting our
hypothesis (summarized in Table 1) of accelerated aging as one of
the critical components in the pathogenesis of schizophrenia.
Neurodegeneration may not be the sole pathophysiology operating
in schizophrenia. It could be operating in conjunction with
neurodevelopmental process or it could be a predominant
pathogenetic mechanism in a subgroup of individuals with
schizophrenia who exhibit accelerated aging changes.
Though the factors supporting the neurodegenerative theory
appear to be convincing, the evidences highlighted in this review
needs further replication through systematic studies. The hypoth-
esis, placing vitamin-D as a central paradox also requires rigorous
testing and validation. Moreover, there might be other factors too,
operating independently or in association with the accelerated
aging pathways directly or indirectly and this merits further
research.
Further, correlating the symptom profile of the patient with the
aging parameters might provide new insights into the pathophys-
iology of the illness. Moreover, there is a need for studies to
concentrate on the metabolic abnormalities and other physiologi-
cal abnormalities associated with the illness. Thus, understanding
schizophrenia demands a multipronged approach to unravel the
complex interactions among various critical pathogenetic path-
ways.
Conflict of interest
None.
Role of contributors
All the authors were involved in the conceptualization of the
study. Authors VS & SVK managed the literature search. VS
prepared the initial draft. All the authors reviewed and have
approved the final manuscript.
Role of the funding source
This is a part of PhD (PhD in Clinical Neurosciences) work of the
author VS, supported by Indian Council of Medical Research (ICMR)

Please cite this article in press as: Shivakumar, V., et al., Do schizophrenia patients age early? Asian J. Psychiatry (2014), http://
dx.doi.org/10.1016/j.ajp.2014.02.007
G Model
AJP-565; No. of Pages 7
6 V. Shivakumar et al. / Asian Journal of Psychiatry xxx (2014) xxx–xxx
and partially supported by Wellcome Trust/DBT (500236/Z/11/Z)
India Alliance Senior Fellowship research grant to GV.
Ethical statement
Not applicable.
Acknowledgements
VS is supported by the Indian Council of Medical Research. SVK
is supported by the Wellcome Trust/DBT India Alliance.
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