REVIEW

Neurodegenerative Aspects in Vulnerability to SchizophreniaSpectrum Disorders

Trevor Archer • Serafino Ricci • Danilo Garcia •

Max Rapp Ricciardi

Received: 8 January 2014 / Revised: 21 April 2014 / Accepted: 21 April 2014

� Springer Science+Business Media New York 2014

Abstract The neurodegenerative and neurotoxic aspects

of schizophrenia and/or psychosis involve genetic, epige-

netic, and neurotoxic propensities that impinge upon both

the symptom domains and the biomarkers of the disorder,

involving cellular apoptosis/excitotoxicity, increased reac-

tive oxygen species formation, viral and bacterial infec-

tions, anoxic birth injury, maternal starvation, drugs of

abuse, particularly cannabis, metabolic accidents, and other

chemical agents that disrupt normal brain development or

the integrity of brain tissues. Evidence for premorbid and

prodromal psychotic phases, aspects of neuroimaging,

dopamine, and psychosis vulnerability, and perinatal

aspects provide substance for neurodegenerative influ-

ences. Not least, the agencies of antipsychotic contribute to

the destructive spiral that disrupts normal structure and

function. The etiopathogenesis of psychosis is distin-

guished also by disruptions of the normal functioning of

the neurotrophins, in particular brain-derived neurotrophic

factor, dyskinesic aspects, immune system disturbances,

and metabolic aspects. Whether detrimental to neurode-

velopment or tissue-destructive, or an acceleration of

neurotoxic pathways, the notion of neurodegeneration in

the pathophysiology of schizophrenia spectrum and psy-

chotic disorders continues to gather momentum.

Keywords Apoptosis � Infection � Neurotoxin �Neurogenesis � Dopamine � Cannabis � Neurotrophins �Metabolism � Immune system � Neurodevelopment

Introduction

The status of the neurodegenerative influence in the

development of schizophrenic psychoses has not been

considered straightforward and perhaps may even seem

tenuous. Nevertheless, the plausibility of evidence from

laboratory animal models studies, neuroimaging studies,

and postmortem assays together with a neurodevelopmen-

tal viewpoint of disorder etiopathogenesis does imply that

neurodegenerative processes may contribute to heightened

predisposition and susceptibility to the precipitation of

symptom domains through a staging notion (Archer et al.

2010a, b). For example, in a five-day repeated ketamine

administration animal model of schizophrenia, Faizi et al.

(2014) observed increased reactive oxygen species pro-

duction, mitochondrial membrane potential collapse,

mitochondrial swelling, and cytochrome c release in

mitochondria of schizophrenia group. Genetic risk factors

may impact upon or disrupt developmental trajectories

(Dauvermann et al. 2012, 2013; Sullivan et al. 2003). There

is much support for the notion that schizophrenia spectrum

disorders have their origin during gestation and/or in early

infancy (Graff et al. 2011; Sawa and Snyder 2002). Insults,

during the early infancy or perinatal period, or even during

the course of early-to-late childhood and adolescence, are

implicated in the etiopathogenesis of the marked structural

T. Archer (&) � D. Garcia � M. R. Ricciardi

Department of Psychology, University of Gothenburg, Box 500,

40530 Gothenburg, Sweden

e-mail: trevor.archer@psy.gu.se

T. Archer � D. Garcia � M. R. Ricciardi

Network for Empowerment and Well-Being, Lund, Sweden

S. Ricci

Department of Anatomy, Histology, Forensic Medicine and

Orthopaedics, Sapienza University, Rome, Italy

D. Garcia

Center for Ethics, Law and Mental Health (CELAM), University

of Gothenburg, Gothenburg, Sweden

123

Neurotox Res

DOI 10.1007/s12640-014-9473-0

and functional abnormalities that distinguish the symptoms

of disorder (Cannon et al. 2002a, b; Fontes et al. 2011;

Geddes et al. 1999).

The eventual contribution of neurodegenerative pro-

cesses affecting the disorder must take into account the

plethora of interactive factors and agents that include

inherited and acquired attributes (Elia et al. 2011; Jablonka

and Raz 2009). The disorder pathophysiology may involve

the influences of several contributory process, including

cellular apoptosis/excitotoxicity, viral and bacterial infec-

tions, anoxic birth injury, maternal starvation, drug abuse

in particular cannabis, trauma, and other conditions exert-

ing detrimental effects on neurogenesis. Both neurogenetic

and epigenetic forces arising from gene-environment

interactions affecting developmental trajectories impart

levels of predisposing vulnerability that may or may not

lead to the manifestation of schizophrenic symptoms

(Gratacos et al. 2007; Hoenicka et al. 2010), or those of

related conditions (Bergman et al. 2011; Jacob et al. 2010).

Whether or not the neurodegenerative aspect of the disor-

der may be neurogenetic or epigenetic, there compelling

evidence exists for expressions of the disruptive influences

affecting normal development. In the present treatise, the

available evidence supporting the notion of neurodegen-

erative impacts of liability to psychosis is reviewed criti-

cally. Recent studies showing that psychosis is usually

predated by a prodromal phase characterized by dramatic

neurobiological and psychopathological changes are

reviewed. Then, the imaging findings supporting neurode-

generative impacts in the development of psychosis with

some specific insight into molecular and structural studies

are examined. Following this, dopamine and psychosis

vulnerability, perinatal agents, cannabis abuse, neurotro-

phin disruption, dyskinetic movement, brain insulin dys-

regulation, and cytokine imbalance aspects are discussed.

Throughout, it ought to be considered that (i) histopathol-

ogical features are suggestive of apoptotic rather than

necrotic processes, and (ii) loss of structure and function in

disorder progression, and (iii) the presence of infections

and/or adverse environmental conditions that perturb the

course of normal development resulting in unsuitable

developmental trajectories.

The Evidence for a Prodromal Psychotic Phases

Over the recent two decades, accumulating evidence has

showed that psychosis onset is usually preceded by a

prodromal phase (Fusar-Poli et al. 2013a). This period is

spanning childhood and adolescence and is characterized

by profound neurodevelopmental changes. Subjects expe-

riencing putative prodromal signs or symptoms of psy-

chosis have a greater risk of developing the disease (from

18 % at 6 months up to 36 % after 3 years) over time

(Fusar-Poli et al. 2012a). The majority of the subjects who

will develop a psychotic disorder later on will transit

toward schizophrenic psychoses rather than to affective

psychoses (Fusar-Poli et al. 2013b). Furthermore, the pre-

sence of putative prodromal symptoms per se is associated

with significant psychosocial impairment, decreased qual-

ity of life, and subtle cognitive deficits (Borgwardt et al.

2006, 2010, 2011; Buschlen et al. 2011; Fusar-Poli et al.

2011a, b, c, 2012b; Haller et al. 2009; Koutsouleris et al.

2012; Mechelli et al. 2011; Rothlisberger et al. 2012;

Shenton et al. 2001; Smieskova et al. 2012a, b). At a

neurobiological level, the prodromal psychotic phase is

characterized by significant alterations in the structure

(Buehlmann et al. 2010; Crossley et al. 2009; Fusar-Poli

et al. 2007, 2011a, b, c; Smieskova et al. 2010a, b, 2012c),

function (Fusar-Poli et al. 2010, 2011a, b, c; Fusar-Poli and

Meyer-Lindenberg 2013a), connectivity (Fusar-Poli and

Meyer-Lindenberg 2013b), and neurochemistry (Howes

et al. 2007; Lyon et al. 2011; McGuire et al. 2008; Meyer-

Lindenberg et al. 2002; Miyake et al. 2011) of the brain

(Laruelle et al. 1996). The presence of a subtle prepsy-

chotic phase is the clinical ground on which neurodegen-

erative factors can be tested. As evident from genetic risk

Table 1 Putative neurodegenerative factors influencing vulnerability

and altered developmental trajectory

Imaging

Volumetric loss

Loss of connectivity

Catecholamine metabolite alterations

Tissue loss

Thalamic gray matter

Glutamate-transmission integrity

Temporal lobe and Inferior frontal gyrus

Dopamine

Presynaptic alterations

Synthesis and turnover

Perinatal

Ventral HPL lesion

MAM neurotoxicity

Adverse childhood experience

Infection

Neurotrophin

BDNF loss/reduction

Insulin

Brain insulin dysregulation

Immune system disturbance

Cytokine imbalance

HPF hippocampus, MAM methylazoxymethanol, BDNF brain-

derived neurotrophic factor

Neurotox Res

123

factors and risk factors linked to childhood ill health/

adversity, the developmental trajectories of the afflicted

individuals are not optimal (Arango and Fraguas 2013).

Some of the stronger pieces of evidence supporting the

notion of neurodegenerative aspects in liability to psy-

chosis (cf. Pasternak et al. 2012) are considered below

(Table 1).

Imaging Aspects

At first sight, the accumulated evidence for progressive

volumetric loss, e.g., in cortical volume/thickness (Gold-

man et al. 2009; Honea et al. 2008) and loss of functional

connectivity (Meyer-Lindenberg et al. 2005; Yu et al.

2011), argues for the aspect of neurodegeneration in

schizophrenia; yet, the possible impacts of peristaltic and

environmental agents must needs to be understood prior to

a reliable conclusion (Meyer-Lindenberg 2011). For

example, Goto et al. (2010) compared 18 patients (nine

males, nine females; age range: 13–52 years) with 18

healthy volunteers (nine males, nine females; age range:

15–49 years) with no current or past psychiatric history,

using magnetic resonance spectroscopy (MRS). They

found that levels of N-acetylaspartate/Cr in the left basal

ganglia and parieto-occipital lobe, but not in the frontal

lobe, were significantly lower in patients with first-episode

schizophrenia psychosis than in control subjects. No dif-

ferences were observed between the serum brain-derived

neurotrophic factor (BDNF) levels of patients with first-

episode schizophrenia psychosis and the healthy control

subjects. The plasma levels of catecholamine metabolites,

plasma 3-methoxy-4-hydroxyphenylglycol, but not homo-

vanillic acid, were significantly lower in the patients with

first-episode psychosis than in control subjects. In addition,

a significantly positive correlation was observed between

the levels of N-acetylaspartate/Cr of the left basal ganglia

and plasma MHPG in all the subjects. The authors con-

cluded that brain N-acetylaspartate levels in the left basal

ganglia and plasma 3-methoxy-4-hydroxyphenylglycol

levels were significantly reduced at the first-episode of

schizophrenia psychosis, indicating that neurodegeneration

via noradrenergic neurons might be associated with the

initial progression of the disease.

Increased prefrontal gyrification (cortical folding) and

increased local short range prefrontal connectivity and

reduced long range connectivity have been observed in high-

genetic risk subjects (Dauvermann et al. 2012); gyrification

and connectivity are disrupted in Schizopsychotic disorders.

Dauvermann et al. (2013) have found that Bayesian Model

Selection analysis has demonstrated significantly lower

connection strength of the thalamocortical connection with

nonlinear modulation from the mediodorsal thalamus in

high-risk subjects with psychotic symptoms, and those

individuals who subsequently developed schizophrenia.

Aspects of Tissue Loss

Regional loss of glutamate and glutamine in schizophrenic

patients (Tayoshi et al. 2009) may offer evidence of an

excitotoxic process in the disorder pathophysiology. The

loss of parvalbumin-containing cells, an observation that

has been reported consistently in postmortem analysis of

the brains of schizophrenic patients) following NMDA

receptor blockade offers support for this notion (Adell et al.

2012; Dean et al. 2011). Aoyama et al. (2011) have dem-

onstrated that the loss of thalamic glutamate in the brain of

schizophrenia patients correlated significantly with loss a

gray matter in the middle and inferior frontal gyrus and

temporal pole. Thalamic gray matter and glutamate losses

were observed in individuals at risk for developing

schizophrenia (see also Aoyama et al. 2013; Stone et al.

2009). Correlations between glutamate and glutamine

ratios in the frontal cortices of adolescents at risk for the

disorder and performance scores on the Global Assessment

of Functioning Scale have been observed (Tibbo et al.

2004). It has been suggested that the elevated glutamine

levels in never-treated patients followed by the decreased

level of thalamic glutamine and gray-matter loss in con-

nected regions may be indicative of either neurodegener-

ation or a plastic response to reduced subcortical activity

(Theberge et al. 2007). There appears to be a consensus of

sorts for an excitotoxic contribution primarily in early-

stage schizophrenia (Bustillo et al. 2010). Glutamatergic

alterations and loss of cortical gray matter originating from

basal ganglia-corticothalamic circuits may be the expres-

sions of excitotoxicity through these regions. First-episode

schizophrenic patients have exhibited increased membrane

breakdown in a magnetic resonance spectroscopy by

applying labeled phosphorous (Miller et al. 2009). Takei

et al. (2013) have demonstrated reduced functional per-

formance activation in both the temporal lobes and the

right inferior frontal gyrus during task performance (mea-

sured by mean [oxyhemoglobin] changes). Reduced acti-

vation in the left temporal lobe was negatively correlated

with the Positive and Negative Syndrome Scale disorga-

nization and negative symptoms sub-scores; right inferior

frontal gyrus activation was negatively correlated with

illness duration, Positive and Negative Syndrome Scale

disorganization, and negative symptom sub-scores. Their

results imply that brain dysfunction in schizophrenia dur-

ing a conversation task is related to functional deficits in

both the temporal lobes and the right inferior frontal gyrus

with manifestation primarily in the form of disorganized

thinking and negative symptomatology.

Neurotox Res

123

Dopamine and Psychosis Vulnerability

Over the past two decades, new neurochemical imaging

techniques have enabled the subcortical dopaminergic

system to be carefully investigated in vivo (McGuire et al.

2008). In particular, the development of new radiotracers

combined with single-photon emission computed tomog-

raphy (SPECT) or positron emission tomography (PET)

techniques has allowed accurate investigations of striatal

presynaptic dopaminergic alterations in schizophrenia (for

reviews see Howes et al. 2007; Lyon et al. 2011; Miyake

et al. 2011). Different indexes of presynaptic dopamine

neurotransmission such as dopamine synthesis capacity

studies (Meyer-Lindenberg et al. 2002) and dopamine

release (Laruelle et al. 1996), or depletion (Kegeles et al.

2010) studies have suggested significant alterations in the

striatal presynaptic dopaminergic function in schizophre-

nia. For the sake of the present discussions, it ought to be

noted, however, that elevated dopamine synthesis and

release is also seen in subjects at risk for schizophrenia

(Huttunen et al. 2008) and in the prodromal state (Mechelli

et al. 2011), suggesting that they are part of the risk

architecture of schizophrenia. The original neurodegener-

ative model of schizophrenia proposed that functional

alterations in dopamine neurotransmission are secondary to

a change in the number or density of striatal dopamine

terminals over the course of the illness (Lieberman et al.

1990, 1997). Two recent meta-analyses have recently tes-

ted this hypothesis (Fusar-Poli and Meyer-Lindenberg

2013a, b). The authors found that dopamine synthesis

capacity was increased of 14 % in patients with schizo-

phrenia as compared to controls, while there were no dif-

ferences in structural indexes of neuronal integrity (such as

measures of Dopamine Active Transporter). The functional

alterations observed during the psychosis onset can be

related to a number of environmental factors such as

perinatal insults, reviewed below here.

Perinatal Aspects

Several perinatal insults have been shown to induce

schizophrenia-like symptoms in laboratory setting (Archer

2010; Powell et al. 2012). Bilateral excitotoxin-induced

lesions, administering ibotenic acid to the ventral hippo-

campus typically to 7-day-old rat pups, induce disruptions

of prepulse inhibition (PPI) to the acoustic startle response,

a model of sensory gating in rodents, hyper-responsiveness

to stressful stimuli, supersensitivity to dopamine (DA)

agonists, and N-methyl-D-aspartic acid (NMDA) antago-

nists (Lipska et al. 1992, 1995, 2001); additionally, per-

sistent deficits in working memory and spatial navigational

learning (O’Donnell et al. 2002), together with hyper-

responsiveness to stimulation of the ventral tegmental area

(Lillrank et al. 1999; Lipska and Weinberger 1994) have all

been observed in neonatal ventral hippocampus-lesioned

rats. Prenatal administration of methylazoxymethanol

(MAM) disrupted early brain development with structural

and functional abnormalities in the cortex and hippocam-

pus, many of which bear similarities to schizophrenia,

expressed in the adult rats (Flagstad et al. 2005; Lodge and

Grace 2008; Mohammed et al. 1986a, b; Moore et al.

2006). The utility of prenatal MAM as an animal model of

the disorder highlights the neurodegenerative aspect (Chen

and Hillman 1986), particularly with regard to the neuro-

cognitive deficits (Fiore et al. 2004; Gourevitch et al. 2004;

Lee et al. 2011; Leng et al. 2005). Similar to patients

presenting cognitive deficit profiles in schizophrenia

spectrum disorder (Maat et al. 2012), MAM-treated marked

deficits on an attentional-shift task (analogous to the Wis-

consin Card Sorting Task), and on a differential rein-

forcement of low rate of responding (DRL-20 performance,

analogous to continuous performance) task (Featherstone

et al. 2007). Prenatal MAM administration disrupts early

cortical development causing deficits in medial prefrontal

functions at adult ages (Goto and Grace 2006). These

effects of the neurotoxin interrupt normal neuronal devel-

opment, stress and immune response systems, and signal

transduction mechanisms (Ciani et al. 2003; Ferrer et al.

1997; Lafarga et al. 1997; Rice and Barone 2000).

Traumatic/adverse experiences during infancy and early

childhood compromise healthy brain development in sev-

eral domains, including cognitive, emotional, and motor.

Traumatic environmental confrontation during early neu-

rodevelopment, such as parental loss (maternal separation),

that induces a marked provocation of the hypothalamic–

pituitary–adrenal (HPA) axis was found to cause schizo-

phrenia-like, e.g., impairments of sensory-gating, symp-

toms in the rats as adults (Ellenbroek et al. 1998), as well

as other expression of the disorder (Furukawa et al. 1998).

Rosenberg et al. (2007) surveyed 569 adults presenting

schizophrenia with regard adverse childhood events

(including physical abuse, sexual abuse, parental mental

illnesses, loss of a parent, parental separation or divorce,

witnessing domestic violence, and foster or kinship care),

evaluating the relationships between cumulative exposure

to these events and psychiatric, physical, and functional

outcomes. They found that increased exposure to adverse

childhood events was strongly related to psychiatric prob-

lems in both cognitive and emotional domains (suicidal

thinking, hospitalizations, distress, and posttraumatic stress

disorder), substance abuse, physical health problems (HIV

infection), medical service utilization (physician visits),

and poor social and daily care functioning (homelessness

or criminal justice involvement). Ellman et al. (2009)

observed genetic and/or environmental factors linked to

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123

psychosis that caused fetal brains to be particularly vul-

nerable to the effects of influenza B, leading to poorer

cognitive performance even before symptom onset. Simi-

larly but related to sorrow, Morgan et al. (2007) observed

that separation from, and/or the death of, one parent prior

to the age of 16 were both strongly associated with a two-

to three-fold increases in the risk of psychosis. It was

shown that the strength of these associations were similar

for White British and Black Caribbean (but not for Black

African) subjects, although separation from (but not death

of) a parent was more common among Black Caribbean

controls than White British controls. Finally, a 10-year

cohort of high secure hospital patients who had either a

personality disorder or schizophrenia found a rate of child-

parent separation of 178/289 (62 %) in the schizophrenia

group compared with a rate of 119/147 (81 %) in the

personality disorder group of patients that had been sepa-

rated from one or both parents before the age of 16 years

(Pert et al. 2004). Chew et al. (2013) imply that cellular

abnormalities extend to glial cells since oligodendroglial,

microglial, and astrocyte activity alternations in SSDs are

associated with neonatal brain injury.

Neurotrophin Disruption

Brain-derived neurotrophic factor is essential for the main-

tenance of functional neurons, regulating growth, differen-

tiation, synaptic connectivity, neurorepair, and longevity

(Altar et al. 1997; Niu and Yip 2011). BDNF, central for the

survival and differentiation of midbrain dopamine neurons

(Hyman et al. 1991), and phenotypic differentiation of locus

coeruleus noradrenergic neurons (Traver et al. 2006), has

emerged as an important biomarker for schizophrenia

spectrum disorder (Favalli et al. 2012; Pae et al. 2012; Zhang

et al. 2012). In 63 patients presenting schizophrenia com-

pared to 52 age- and sex-matched healthy controls were

examined with neuropsychological tests, Niitsu et al. (2011)

found that although there were no significant differences in

serum BDNF levels between normal controls and schizo-

phrenic patients, serum BDNF levels for normal controls,

but not schizophrenic patients, showed negative correlations

with verbal working memory. On the other hand, serum

BDNF levels of schizophrenic patients indicated positive

correlations with the scores of the Scale for the Assessment

of Negative Symptoms (SANS) and the Information subtest

scores of Wechsler Adult Intelligence Scale Revised

(WAIS-R). Serum BDNF levels were related with the

impairment of verbal working memory and negative symp-

toms in patients with schizophrenia. In 22 acute schizo-

phrenic patients and 22 age-matched healthy volunteers, Lee

et al. (2011) observed significantly reduced serum levels in

the unmedicated schizophrenic patients (n = 22;

4.38 ± 2.1 ng/mL) compared to the age-matched healthy

volunteers. The percentage change of BDNF (increase,

173 % ± 110) correlated negatively with the percentage

change of PANSS score with BDNF increase during psy-

chotic treatment, as shown by several others (Pedrini et al.

2011; Yoshimura et al. 2007, 2010). Reduced BDNF con-

centrations have been reported in chronic antipsychotic-

treated patients (Grillo et al. 2007; Ikeda et al. 2008; Rizos

et al. 2010), neuroleptic-free (Palomino et al. 2006), and

neuroleptic-naıve (Chen and Huang 2011; Rizos et al. 2008)

patients.

Dyskinesic Aspects

Long-term administration of antipsychotic agents induces

tardive dyskinesias (TDs), a syndrome composed of invol-

untary, hyperkinetic, and abnormal movements often

expressed through excessive chewing or dancing/foot shuf-

fling behaviors (Jafari et al. 2012; Correll and Schenk 2008).

Lower serum concentrations of BDNF, inversely correlated

with Abnormal Involuntary Movement Scale (AIMS) scores,

have been observed in patients presenting TDs (Tan et al.

2005). Additionally, associations between TD and BDNF

polymorphisms have accumulated (Park et al. 2009; Zai et al.

2009). Yang et al. (2011) compared serum BDNF levels in

schizophrenic patients with (n = 129) and without (n = 235)

TDs with healthy controls (n = 323), with concurrent

assessment of AIMS and the Positive and Negative Symptoms

Scale (PANSS). Schizophrenic patients presenting TDs

showed lower BDNF concentrations than those without and

healthy controls. Lower BDNF serum concentrations corre-

lated with higher PANSS negative sub-scores, but not with

AIMS scores. The authors concluded that reduced BDNF

concentrations may be associated with greater TD patho-

physiology and negative symptoms in schizophrenia. Zhang

et al. (2010) have indicated that schizophrenic patients with

TD presented higher serum levels of S100B, a calcium-

binding protein, than normal, healthy controls, and those

patients without TD. The serum S100B levels were positively

correlated with AIMS scores in patients with TD. The authors

concluded from these results that increased S100B levels may

be related to the neurodegenerative aspect of disorder, asso-

ciated with TD pathophysiology. TDs are generally indicative

of neurodegenerative pathologies (Miller and Chouinard

1993).

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123

Cannabis Abuse

Growing research evidence suggests that cannabis use

leads to more frequent psychotic relapses, impairs cogni-

tive performance and is associated generally with a poor

prognosis in vulnerable individuals (Borgwardt et al.

2006). A long-term association between treatment adher-

ence, type of first admission, and long cannabis use by first-

episode patients and high-risk juveniles (Barbeito et al.

2013; Gill et al. 2013). Additionally, there is a great

interest in the hypothesis that cannabis use plays a causal

role in the development of psychosis (Borgwardt et al.

2007; Haller et al. 2009). Analyses of prospective birth

cohort and population studies suggest that cannabis use is

indeed associated with an earlier age at onset of psychotic

disorders, particularly schizophrenia (Smieskova et al.

2012a, b, c; Borgwardt et al. 2011; Buschlen et al. 2011;

Rothlisberger et al. 2012). The potential role as risk factor

played by cannabis in the development of psychotic dis-

orders has been recently investigated during the early

prepsychotic phases of the illness. Cannabis abuse can

impact the neurobiological alterations observed in poten-

tially prodromal individuals (Smieskova et al. 2012a, b, c;

Borgwardt et al. 2010; Bossong et al. 2013; Garakani et al.

2013; Morgan et al. 2013), with daily use, especially of

high-potency cannabis, drives the earlier onset of psychosis

in cannabis users (Di Forti et al. 2013). Imaging research in

the healthy brain has consistently indicated cannabis abuse

can modulate the neuroanatomical and neurofunctional

areas which are implicated in psychosis onset (Buehlmann

et al. 2010; Crossley et al. 2009; Fusar-Poli et al. 2007,

2010, 2011a, b, c; Smieskova et al. 2010a, b, 2012a, b, c).

Finally, in a first population-based study mapping the

association between lifetime cannabis use, psychosis, and

schizotypal personality traits, Davis et al. (2013) have

observed marked relationships between these factors.

Stefanis et al. (2013) have shown that the use of cannabis

may induce some cumulative toxic effects on those indi-

viduals abusing the drug, thereby placing them on the road

to developing psychosis, the manifestation and debut of

this condition are delayed for *7–8 years, independent of

the age at which cannabis use was initiated.

Metabolic Aspects

The glycogen synthase kinase-3s (GSK, a and b), involved

in glycogen metabolism, are expressed ubiquitously over

various tissues and are abundant in brain tissue (Jaworski

et al. 2011). Kaidanovich-Beilin and Woodgett (2011) have

discussed the fundamental roles for these protein kinases in

memory, behavior, and neuronal fate determination. It has

been argued that disrupted in Schizophrenia-1 (DISC1)

provides a candidate gene for neuropsychiatric disorders

and an influential involvement during brain structural and

functional development. Singh et al. (2011) have observed

that DISC1 variants are implicated in the loss of function in

Wnt/GSK3b signaling, and thereby interrupt the course of

brain development. Common DISC1 polymorphisms

(variants) are associated with neuropsychiatric phenotypes

including altered cognition, brain structure, and function.

The contribution of the DISC1 gene to neural development

and the eventual neurodevelopment of schizophrenia risk

has been studied (Wexler and Geschwind 2011). GSK-3, a

regulator of a wide range of cellular processes, plays a key

dual role in apoptosis with putative contribution to

schizophrenia neuropathology (Emamian et al. 2004) and

other neurodegenerative disorders (Avila et al. 2004; Ber-

ger et al. 2005; Onishi et al. 2011). Its role in the apoptotic

signaling underlying excessive cell death may imply a

neurodegenerative involvement in schizophrenia spectrum

disorders, at least during the early stages of development

(Gomez-Sintes et al. 2011). Astrocytic glycogenolysis and

glycogen mobilization are implicated in normal brain

function (Brown and Ransom 2007; Brown et al. 2003;

Swanson 1992), and neuronal energy requirements (Brown

et al. 2003; Wender et al. 2000), and not least in the

necessities of cognitive function (Gibbs et al. 2006; Hertz

et al. 2003; Suzuki et al. Suzuki et al. 2011). The links

between glycogen metabolism and the glutathione (GSH)

system have been studied: Shinohara et al. (2010) have

shown that activation of GSK-3beta is a key mediator of

the initial phase of acetaminophen-induced liver injury

through modulating glutamate cysteine ligase (GCL) and

myeloid cell leukemia sequence-1 degradation. GSH defi-

cits occur both in neurodegenerative conditions and

schizophrenia (Ballatori et al. 2009; Do et al. 2009; Drin-

gen and Hirrlinger 2003), and a GCL gene polymorphism,

affecting GSH synthesis, is associated with the disorder

(Tosic et al. 2006). In this regard, Lavoie et al. (2011) have

found that glucose metabolism and glycogen utilization are

dysregulated in astrocytes showing chronic deficit in GSH

implying dysfunctional brain energy metabolism in

schizophrenia.

It ought to be noted that Saitohin, an intronless gene

nested within the human tau gene, that contains a single

nucleotide polymorphism (A/G) may be involved in the

pathophysiology of neurodegenerative disorders (Combar-

ros et al. 2003). In a sample of 48 schizophrenic patients

and 47 healthy controls, Bosia et al. (2011) tested the role

of saitohin polymorphism as a concurring factor of cog-

nitive decline among these patients using the Wisconsin

Card Sorting Test for executive functioning. They observed

a significantly greater frequency of G allele among patients

with frontotemporal dementia and schizophrenic patients

presenting impaired Wisconsin Card Sorting Test

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123

performance. They concluded that Saitohin gene products

affected core frontal executive function deterioration likely

through mechanisms occurring through neurodevelopment

with neurodegenerative outcome (Bosia et al. 2011).

Finally, there exists shared susceptibility for type 2 dia-

betes and schizophrenia (Lin and Shuldiner 2010).

Brain Insulin Dysregulation

There are several indications that risk factors for psychosis are

associated with cardiometabolic disease risk factors, and vice

versa (Galletly et al. 2012). Insulin, a major factor in cardio-

metabolic disease risk, is involved in several physiological

function of the brain such as food intake and weight control,

reproduction, learning and memory, neuromodulation and

neuroprotection development, and progression of neurode-

generative and neuropsychiatric disorders (Bloemer et al.

2014; de la Monte and Tong 2013). In individuals afflicted by

dysregulation of insulin the risk of brain plasticity derailment

emerges (Deutsch et al. 2006; Ghasemi et al. 2012; Huang and

Lee 2010). Graham et al. (2008) have observed in a group of

patients presenting first-episode psychosis, 6-month treatment

with second generation antipsychotics was associated with the

exacerbation of pre-existing and emergence of new CVD and

diabetes risk factors. Foley et al. (2013) have observed car-

diometabolic risk factors/indicators distinguished those indi-

viduals presenting psychosis from the general population,

through a number of factors including age, gender, obesity,

etc., in a population of 1,642 psychosis-diagnosed Australians

(aged 18–64 years) compared with a national comparator

sample of 8,866 controls (aged 25–64 years) from the general

population. From age 25, psychotic individuals presented a

significantly higher mean BMI, waist circumference, tri-

glycerides, glucose [women only], and diastolic blood pres-

sure, and significantly lower HDL-cholesterol than control

individuals. With the exception of triglycerides at age 60? in

men, and glucose in women at various ages, these differences

were present at every age. Differences in BMI and waist cir-

cumference between samples, although dramatic, could not

explain all differences in diastolic blood pressure, HDL-cho-

lesterol, or triglycerides, but did explain differences in glu-

cose. They have postulated that psychosis shows the

hallmarks of insulin-resistance by at least in the age of 25.

Similarly, Chen et al. (2013) have shown that schizophrenia-

related psychopathology was associated with insulin-resis-

tance and/or dyslipidemia in Chinese patients with antipsy-

chotic-naıve first-episode schizophrenia patients were more

prone to insulin-resistance and dyslipidemia as compared to

the healthy population, which was correlated negatively to

positive symptoms.

Immune System Imbalance

Finally, there exists much evidence implicating cytokine

imbalance in schizophrenia spectrum/schizopsychotic dis-

orders. For example, Song et al. (2013) showed that drug

naıve, first-episode schizophrenic patients presenting nor-

mal weight indicated up-regulated inflammatory status

associated with elevated levels of the cytokines, IL-1b, IL-

6, and TNF-a. Furthermore, inflammatory cytokine mark-

ers, such as IL-1Ra and sTNF-R1, are associated with both

general disease severity and psychotic features (Hope et al.

2013; Kirkpatrick and Miller 2013). Dimitrov et al. (2013)

observed that levels of GRO, MCP-1, MDC, and sCD40L

were elevated significantly and that levels of IFN-c, IL-2,

IL-12p70, and IL-17 were reduced significantly in schizo-

phrenia patients compared to controls; positive correlations

between cytokine levels and disorder severity, assessed

with Positive and Negative Symptoms Scale (PANSS)

scores in schizophrenic subjects, for G-CSF, IL-1b, IL1ra,

IL-3, IL-6, IL-9, IL-10, sCD40L, and TNF-b. Bergink et al.

(2013a) observed that postpartum psychosis patients failed

to show the postpartum T cell level elevations of healthy

women, but rather marked elevations of monocyte levels,

and up-regulation of several immune-related monocyte

genes. Notably, Di Nichola et al. (2013) found markedly

higher serum levels of IL-1a, IL-1b, IL-8, and TNF-a as

well as the tendency for higher IL-6 serum levels in

comparison with controls; Leukocyte m-RNA levels of IL-

1a, IL-6, and TNF-a, but not IL-1b and IL-8, were sig-

nificantly higher in patients also. Childhood trauma was

associated with greater TNF-a levels with recent stressful

life events linked to greater TNF-a m-RNA levels in

leukocytes.

Bergink et al. (2013b) have described a scenario through

which both infection and environmental stressors interact

during gestation/early life period to activate microglia

thereby disturbing the fine balance neuronal and/or regio-

nal development; this concatenation of adverse events sets

the stage for the burgeoning vulnerability for later psy-

chotic disorders. As the adverse scenario unfolds, endo-

crine changes, stress, or infection, may activate microglia

alterations further, leading to functional abnormalities of

the neuronal circuitry in the brain and the expressions of

psychosis. Borovcanin et al. (2012) have shown reduced

levels of pro-inflammatory markers, IL-17 and IL-17/TGF-

b ratio, in patients presenting psychosis. They indicate that

the presence of enhanced anti-inflammatory/immunosup-

pressive activity in schizophrenic patients express attempts

of the patients’ immune system to counteract or limit

ongoing pro-inflammatory processes and down-regulating

chronic inflammatory processes (see also Borovcanin et al.

2013).

Neurotox Res

123

Conclusions

Neurodegenerative aspects contributing to the pathophysi-

ology of psychotic disorders appear, by and large, to exert

their influences through interruption of the normal struc-

tural–functional trajectories of brain development and/or

by neurotoxic destruction of tissue integrity. Not least is

structural-functional integrity compromised by the pre-

sence of motor deficits (Singh et al. 2014). Observations of

neuropathological structural/functional abnormalities in the

postmortem brains of schizophrenic patients have been

shown to occur over a wide range of brain areas (as shown,

for example, by reduction in the volume of cerebral cortex

and/or thalamus, and an increase in the volume of the

ventricles) and nevertheless there are more reports

describing the temporal lobe and frontal lobe compared to

those describing other areas of the brain; all these sug-

gesting degeneration of developmental origin. Intrauterine

infection and inflammation are known risk factors for brain

damage in the neonate irrespective of the gestational age.

Infection-induced maternal immune activation leads to a

fetal inflammatory response mediated by cytokines that has

been implicated in the development of not only periven-

tricular leukomalacia and cerebral palsy but also a spec-

trum of neurodevelopmental disorders, such as autism and

schizophrenia (Burd et al. 2012; Ricci et al. 2013). The

specific timing of the immune challenge with respect to the

gestational age and neurologic development of the fetus

may be crucial in the elicited response, which are the

neuropsychiatric disorders associated with intrauterine

inflammation appears to be the evidence for immune dys-

regulation in the developing brain. Laboratory model

studies of maternal gestational inflammation provide crit-

ical roles for the elucidation of mechanisms involved in

fetal brain injury associated with exposure to the maternal

milieu. These animal models present different expressions

of fetal microglial activation, neurotoxicity in combination

with motor deficits and behavioral abnormalities in the

offspring. The vulnerability bestowed through genetic and

epigenetic (i.e., gene-environment interactions) forces

exacerbate the deficits expressed through symptom profiles

and biomarkers. In this respect, Kirkbride et al. (2012) have

proposed that maternal prenatal nutrition can influence

offspring schizophrenia risk via epigenetic effects. It

appears that the prenatal nutrition may be linked to epi-

genetic outcomes in offspring and schizophrenia in off-

spring, and that schizophrenia is associated with these

observed epigenetic changes. Disorder progression in the

brains of patients was found to be characterized by pro-

gressive gray-matter volume decreases and lateral ven-

tricular volume increases (Fusar-Poli et al. 2013a, b, c),

possibly related to treatment. Further, increased levels of

dopamine synthesis capacity in the dorsal striatum region

present a robust feature of individuals at ultra-high risk for

psychosis (Egerton et al. 2013). Finally, the prevailing and

potential risks for disorder, that influence developmental

trajectories, yet, render distinctions within the spectrum

vague, provoke activation of the immune system, and

acting in parallel with underlying genetic liability, are

linked with imperfect regulation of the genome mediating

these prenatal or early postnatal environmental events

(Jenkins 2013).

Acknowledgments The development of this manuscript was sup-

ported by the Bliwa Stiftelsen.

Conflict of interests The authors declare that they have no com-

peting interests.

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