Abstract Brain morphological alterations in schizo-

phrenic patients have led to the neurodevelopmental

hypothesis of schizophrenia. On the other hand, a

progressive neurodegenerative process has also been

suggested and some follow-up studies have shown

progressive morphological changes in schizophrenic

patients. Several neurotransmitter systems have been

suggested to be involved in this disorder and some of

them could lead to neuronal death under certain

conditions. This review discusses some of the bio-

chemical pathways that could lead to neurodegener-

ation in schizophrenia showing that neuronal death

may have a role in the etiology or natural course of

this disorder.

Keywords Dopamine � Antipsychotics �Nitric oxide � NMDA antagonist � Excitotoxicity �Apoptosis

Introduction

The etiology of schizophrenia has not been clearly

understood although several hypotheses have been

developed. Morphological alterations in the brains

from schizophrenic patients have been found, mainly in

the cerebellum [1–4], frontal and temporal lobes [5, 6],

nucleus accumbens [7, 8], mediodorsal thalamus [7]

and other brain regions [9, 10] as compared to control

subjects, although inconsistent results have also been

reported [1, 11, 12]. Evidence of neurodegeneration

has been found in some studies ([1, 13]; but see also

[14, 15]). Discrepancies may arise from the heteroge-

neity of the disorder.

In this regard, there is an intense discussion about

possible neurodegeneration in schizophrenia which

raises the question of which biochemical pathway

could be underlying such a degenerative process. In

this review, the reader will explore the possible

mechanisms of neurodegeneration that could be

involved in schizophrenia. The neurobiological evi-

dence about the developmental theory will not be

discussed since it has been extensively reviewed in the

literature [16].

Brain morphological abnormalities in schizophrenia

An altered neurodevelopment may account for the

morphological alterations in the brains from schizo-

phrenic patients but does not explain that at least some

of those alterations show a progressive course [1, 11],

which suggests an active neurodegenerative process.

On the other hand, both hypotheses (neurodevelop-

ment and neurodegeneration) may be related to each

I. Perez-Neri � S. Montes � C. Rıos (&)Department of Neurochemistry, National Institute ofNeurology and Neurosurgery, Insurgentes Sur 3877 Col. LaFama. Tlalpan, 14269 Mexico City, Mexicoe-mail: crios@correo.xoc.uam.mx

J. Ramırez-BermudezDepartment of Clinical Research, National Institute ofNeurology and Neurosurgery, Insurgentes Sur 3877 Col. LaFama. Tlalpan, 14269 Mexico City, Mexico

J. Ramırez-BermudezDepartment of Psychiatry, National Institute of Neurologyand Neurosurgery, Insurgentes Sur 3877 Col. La Fama.Tlalpan, 14269 Mexico City, Mexico

Neurochem Res (2006) 31:1279–1294

DOI 10.1007/s11064-006-9162-3

123

OVERVIEW

Possible Mechanisms of Neurodegeneration in Schizophrenia

Ivan Perez-Neri Æ Jesus Ramırez-Bermudez ÆSergio Montes Æ Camilo Rıos

Accepted: 31 August 2006 / Published online: 28 September 2006� Springer Science+Business Media, LLC 2006

other. Reduced neurotrophic factor signaling, for

example, could lead to both an altered development

of the central nervous system (CNS) and neuronal

death because neurotrophic factors are involved in

CNS development and neuronal survival. So, hypoth-

eses for neurodegeneration and an altered CNS devel-

opment in schizophrenia are not mutually exclusive

and they even could be complementary.

The major brain morphological abnormalities

observed in schizophrenic patients are the loss of cortical

gray matter, the reduced volume of the amygdala, the

hippocampus [17], the frontal and temporal lobes [1, 5,

11, 18] and ventricular enlargement [1, 5, 11, 17, 19]. A

complete description of those alterations is beyond the

scope of this review. Some of the pathological findings

may be observed since the earlier psychotic episodes

and thus they are not likely to be due to chronic

antipsychotic medication [1, 11] and they are more

evident in patients who have suffered multiple epi-

sodes of the disease [5]. It has also been reported a

general decrease of brain mass from the onset of the

disorder [17, 20–22]. Some follow-up neuroimaging

studies have reported a progressive ventricular

enlargement in schizophrenic patients [1, 11]. This

finding may also be observed during physiological

ageing [23] but in schizophrenia it occurs earlier than in

normal subjects.

The interpretation of pathological findings in schizo-

phrenia should be taken with caution since several

factors (such as reduced neuronal size or neuropil,

changes in glial cell number or volume) may be

responsible for the reduced volume observed in some

brain regions in schizophrenic patients. Neuronal loss

is one of those factors. Reduced number of neurons has

been reported in the anterior cingulate cortex [10],

nucleus accumbens [1], hippocampus [1, 10] and

thalamus [24–26] from people who died with schizo-

phrenia. Other studies have failed to replicate those

results [1, 10] but it should be considered that total

neuron numbers could mask significant decreases in

the number of specific cell types within a brain nucleus.

In fact, reduced number in specific cell groups such as

striatal cholinergic interneurons [27], cortical parval-

bumin-containing and calbindin-containing c-aminobu-

tyric acid-(GABA)-ergic cells [28], non-pyramidal

neurons in hippocampal sector CA2 [29], cortical

NADPH-diaphorase positive neurons [30, 31] and

hypothalamic nitric oxide synthase-containing neurons

[32], has also been reported in schizophrenia. The

medication status of the patients included in those

studies is a confounding factor although reduced

number of hippocampal neurons is not likely to be

due to neuroleptic exposure at the time of death [29]

and could be associated to the reduced brain regional

volume in first-episode schizophrenics [1, 11] and thus

neuronal loss in schizophrenia may be related to

disease rather than to medication.

If neurodegeneration is involved in the pathophys-

iology of schizophrenia, biochemical or histopatholog-

ical changes indicative of cell death are expected to be

present in schizophrenic brains. Gliosis has been

reported in schizophrenia for at least 20 years [1].

Glial proliferation has been found in the subiculum

and orbitofrontal cortex of the brains from people with

schizophrenia and dementia compared to those from

people with schizophrenia without dementia, indepen-

dently of neuroleptic exposure, although none of those

subgroups were significantly different from control

samples [13], suggesting that a neurodegenerative

process leading to gliosis could be present in a subset

of schizophrenic patients (those with severe cognitive

impairment). It is also possible that astrocytosis is an

epiphenomenon to schizophrenia but it remains to be

determined if the co-morbidity of dementia is respon-

sible for neuronal death (leading to gliosis) in this

disorder or if the pathophysiology of schizophrenia

could in some patients lead to neurodegeneration

manifested as dementia.

However, most studies have failed to find gliosis in

schizophrenic brains [14, 15, 25] at least partially due to

methodological differences between them [1]. Apop-

totic mechanisms have also been suggested to occur in

schizophrenia [8]. In this regard, significantly reduced

content of the antiapoptotic protein Bcl-2 [33] and

increased Bax/Bcl-2 ratio (associated to susceptibility

for apoptotic death) in Brodmann’s Area (BA) 21 [34]

and ultrastructural changes in oligodendroglial cells

suggestive of apoptotic death [35] have been found in

the brains from people who died with schizophrenia.

Those results are not likely to be due to antipsychotic

medication [33–35].

In spite of the discrepancies between studies, brain

histopathological findings in schizophrenia suggest that

neurodegeneration may occur in a subset of patients

with this disorder.

Glutamatergic hypofunction

Excitotoxicity

An excitotoxic hypothesis for schizophrenia has been

recently reviewed [36]. Some post-mortem studies have

found either increased or decreased expression of

ionotropic glutamatergic receptors in some brain

regions from people who died with schizophrenia

1280 Neurochem Res (2006) 31:1279–1294

123

[18, 36–39]. Those results may be influenced by

antipsychotic drugs since they increase the expression

of those receptors [40]. Increased expression could be

a compensatory mechanism related to the glutamater-

gic hypofunction suggested to occur in schizophrenia

[40, 41] since this effect has also been reported

following N-methyl-D-aspartate receptor (NMDAR)

blockade in rats [42] and primary forebrain cultures

[43].

Decreased expression of ionotropic glutamatergic

receptors found in some studies could be related to

neurotoxicity. Brake and co-workers [44] have reported

that excitotoxic lesions of the prefrontal cortex of

neonate rats lead to an increased dopaminergic

response in the nucleus accumbens when they reach

adulthood. This neurochemical response is similar to

that suggested to occur at the onset of schizophrenia.

Glutamatergic neurons in the medial prefrontal

cortex project to the nucleus accumbens [45] and

reduce dopamine release in this limbic region through

action on metabotropic glutamate receptors (mGluR)

[46, 47] although activation of NMDAR leads to the

opposite effect [48]. In fact, both increases and

decreases in dopamine release have been reported

using different agonists for some mGluR subtypes, as

well as different experimental conditions [49]. On the

other hand, reduced binding to glutamate uptake

sites, indicative of glutamatergic innervation, has been

reported to be decreased in the nucleus accumbens

and other brain regions (unchanged in BA 9 [50]) of

schizophrenic brains, independently of chronic halo-

peridol or clozapine treatment [51]. Excitatory amino

acid transporters are also reduced at the mRNA level

in the ventral striatum in schizophrenia brains post-

mortem [52]. Thus, diminished prefrontal cortical

projections to the nucleus accumbens possibly due

to neuronal death may increase dopamine release in

this nucleus by disinhibition from glutamatergic

modulation.

Mitochondrial dysfunction

It seems contradictory to suggest the involvement of

excitotoxic cell death in schizophrenia when cerebro-

spinal fluid (CSF) glutamate concentration has been

reported to be reduced [53, 54] or unchanged [55, 56] in

schizophrenic patients compared to controls. But it

should be considered that deficiencies in energetic

metabolism, which have also been suggested to occur

in schizophrenia [57, 58], may sensitize neurons to the

physiological glutamate concentrations in the extracel-

lular fluid leading to excitotoxic cell death [59]. This is

related to the fact that reduced ATP availability during

mitochondrial dysfunction decreases Na+/K+ ATPase

activity which in turn maintains membrane potential,

leading to a prolonged depolarization and extruding

magnesium from the NMDAR channel, thus increasing

the receptor’s activity (Fig. 1) [57].

Reduced Na+/K+ ATPase activity during mitochon-

drial dysfunction may also alter glutamate uptake since

an energy failure leading to ATP depletion and

intracellular sodium accumulation leads to the reverse

transport of glutamate [60–62]. Regarding schizophre-

nia, decreased glutamate uptake in subcortical brain

regions is likely to occur due to decreased expression

of glutamate transporters [51, 52], possibly associated

to neuroleptic medication [63], although it may be

further reduced if mitochondrial function is compro-

mised.

Other studies further support that mitochondrial

dysfunction is associated to excitotoxicity. Mitochon-

drial toxin-induced neurotoxicity in vitro is attenuated

with co-incubation with a non-competitive NMDAR

antagonist [64] although in vivo studies are not

completely consistent with those results [65]. Reduced

mitochondrial volume and number in oligodendroglial

cells have been reported in both prefrontal cortex (BA

10) and caudate nucleus from schizophrenic brains [35]

although those results should be taken with caution

since they only suggest a reduced mitochondrial

function. In addition, other studies supporting

mitochondrial dysfunction have been reported in

schizophrenia, as discussed in a later section.

GABAergic dysfunction and NMDAR antagonism

neurotoxicity

In the cerebral cortex, glutamatergic neurons stimulate

GABAergic interneurons through NMDAR [66, 67].

Those GABAergic interneurons inhibit pyramidal

neurons in the frontal cortex [66, 68, 69]. Some authors

have suggested that NMDAR blockade reduces corti-

cal inhibitory tone, thus increasing the firing rate of

glutamatergic neurons leading to excitotoxic death at

postsynaptic (i.e. GABAergic) neurons through non-

NMDAR [36, 70]. The association between NMDAR

hypofunction and neurodegeneration by cortical disin-

hibition was proposed at least 10 years ago [66]. If a

similar mechanism occurs in schizophrenia it should be

expected to produce an increased NMDAR and

decreased non-NMDAR expressions. In fact, those

results have been found in some studies [37].

Support for the hypothesis that NMDAR antago-

nism leads to increased glutamatergic function through

non-NMDAR arise from studies showing that

ketamine, a non-competitive NMDAR antagonist,

Neurochem Res (2006) 31:1279–1294 1281

123

increases glutamate release in the rat prefrontal cortex

[71]; also, the biochemical (dopamine release) and

behavioral (locomotor hyperactivity) effects of a com-

petitive NMDAR antagonist (D-AP5) are reduced by

co-administration of a non-NMDAR antagonist [72].

Dizocilpine (MK-801), a selective NMDAR antag-

onist, decreases both amplitude and frequency of

inhibitory postsynaptic currents in pyramidal neurons

and excitatory postsynaptic currents in GABAergic

interneurons from the rat cerebral cortex [67] support-

ing the hypothesis that this kind of glutamatergic

antagonists are able to decrease cortical inhibitory tone

and increase the firing rate of glutamatergic neurons.

It should also be considered that acute NMDAR

blockade is neuroprotective in several models of

neuronal damage [73–77]; however, it has been

reported that pretreatment with the selective non-

competitive NMDAR antagonist phencyclidine (PCP)

sensitizes neurons to excitotoxic death and thus, sub-

threshold concentrations of N-methyl-D-aspartate may

induce apoptosis in cultured forebrain neurons [43].

Those results may be related to the increased expres-

sion of the NMDAR following treatment with its

antagonists [42, 43] then, although acute NMDAR

blockade is neuroprotective, the chronic treatment

with NMDAR antagonists leads to an increased

NMDAR expression that could predispose to excito-

toxic damage.

Blockade of NMDAR leads to neurodegeneration

associated to excessive glutamate release that can be

attenuated by administration of GABAergic agonists,

such as muscimol [70] and sodium thiopental [78],

supporting the hypothesis that NMDAR antagonist-

induced cell death involves diminished GABAergic

neurotransmission, which has also been suggested to

occur in schizophrenia [10, 12, 79–83].

Wang and co-workers [42] have demonstrated that

different brain regions are not equally sensitive to the

neurotoxic effect of NMDAR antagonists. PCP admin-

istration significantly increases TUNEL-positive

(apoptotic) cells in the dorsolateral frontal cortex but

not in the hippocampus, the nucleus accumbens, the

cerebellum nor the anterior cingulate cortex. Mitchell

and co-workers [84] have also shown that acute PCP

administration induces apoptosis in the rat corpus

striatum but not in the nucleus accumbens.

It remains to be determined if neurodegeneration

induced by high-affinity NMDAR antagonists is also

induced by the endogenous antagonists of this recep-

tor, i.e. N-acetylaspartylglutamate (NAAG) and ky-

nurenic acid. NAAG reduces NMDAR-mediated

responses [85] and some studies have found increased

hippocampal NAAG concentration in the brains of

neuroleptic-treated schizophrenic patients [86],

although other studies have found reduced concentra-

tion of this peptide in the temporal cortex (BA 22) [87]

Fig. 1 Some metabolic pathways that could lead to neurode-generation in schizophrenia by overstimulation or blockade ofglutamatergic neurotransmission. Glutamate stimulation ofNMDA receptors mediates Akt phosphorylation which protectsagainst apoptosis. Selective NMDA antagonists interfere with

this survival pathway. Mitochondrial dysfunction reduces Na+/K+

ATPase activity increasing membrane depolarization. NMDAreceptor then becomes voltage-activated and magnesium isextruded from the ion channel permitting calcium influx whichin excess may lead to excitotoxic death. Glu, glutamate

1282 Neurochem Res (2006) 31:1279–1294

123

and the CSF [88] from schizophrenic patients. Differ-

ences in the regions studied may explain such discrep-

ancies. On the other hand, kynurenic acid

concentration has been shown to be increased in BA

9 of schizophrenic brains [89] and the CSF from young

male schizophrenic patients, most of them drug-naıve

[90].

Antiapoptotic signaling

Although the biochemical pathways leading to the

neurotoxic effects of NMDAR antagonists have not

been completely elucidated, evidence of apoptotic

death induced by those antagonists suggests the

participation of this subtype of glutamatergic receptor

in antiapoptotic signaling. It has been reported that

glutamate concentrations below the threshold for

excitotoxic death induce Akt (protein kinase B,

PKB) phosphorylation [91, 92], most likely through

calcium/calmodulin dependent kinase (CaMK) kinase,

inducing the activation of this protein [93]. Akt

activation is part of an antiapoptotic pathway [93–95]

and thus NMDAR blockade may interfere with the

signaling for cell survival (Fig. 1).

The gene encoding Akt has been linked to schizo-

phrenia in European [96, 97] and Japanese populations

[98]. Furthermore, Akt protein levels are decreased in

lymphocytes, frontal cortex and hippocampus from

patients with schizophrenia independently of age,

gender and haloperidol treatment [96] suggesting that

Akt-mediated signaling pathways are altered in this

disorder.

Reduced expression of brain-derived neurotrophic

factor (BDNF) and its receptor [80] could also contrib-

ute to an enhanced susceptibility for apoptotic death in

schizophrenia since this neurotrophin possesses neuro-

protective properties [99]. Reduced BDNF content has

been reported in the prefrontal cortex (BA’s 9 [80] and

46 [100]) from schizophrenic brains and reduced [101] or

unchanged [102] in serum from schizophrenic patients.

All those results are likely to be independent of

antipsychotic medication. Glutamatergic hypofunction

could lead to reduced BDNF expression since activation

of non-NMDAR leads to a 10-fold increase in BDNF

mRNA content in hippocampal neurons [103]. Also,

kynurenic acid (an endogenous antagonist of glutama-

tergic receptors [104, 105]) blocks the increased mRNA

BDNF content induced by the activation of glutama-

tergic receptors in hippocampal neurons [103], and thus

glutamatergic hypofunction could also be related to the

decreased BDNF expression.

In summary, mitochondrial dysfunction has been

suggested to occur in schizophrenia [57, 58] and may

lead to an increased susceptibility for excitotoxic

damage [59] (Fig. 1). On the other hand, NMDAR

antagonism leads to neurodegeneration and GABAer-

gic neurotransmission may have protective effects

against those insults [70, 78]; however, it has been

hypothesized to be decreased in this disorder [12,

79–81, 83] and may contribute to excitotoxic damage

by disinhibiting pyramidal neurons [36, 66–70]. Fur-

thermore, glutamatergic hypofunction could also lead

to decreased antiapoptotic signaling mediated by Akt

(Fig. 1) [93–95] and BDNF [106] since both are

regulated by glutamatergic receptors [91, 92, 103].

Dopaminergic overstimulation

Mitochondrial dysfunction and oxidative stress

Evidence supporting dopaminergic hypofunction in the

cerebral cortex and hyperfunction in subcortical brain

regions in schizophrenia has been elsewhere reviewed

[10, 107].

Dopaminergic overstimulation leads to cell death

under certain conditions (Fig. 2) [58, 108–112]. Intra-

striatal injection of dopamine induces parenchymal

damage [113] that may be associated to mitochondrial

dysfunction since dopamine inhibits mitochondrial

respiration [114–116]. In fact, mitochondrial cyto-

chrome c oxidase activity has been shown to be

reduced in the caudate nucleus from schizophrenic

brains [117]. Since some typical antipsychotics inhibit

mitochondrial respiration [118–120], it remains to be

determined if cytochrome c activity in schizophrenia is

influenced by neuroleptic drugs.

On the other hand, an energetic failure may

decrease the activity of the dopamine transporter

(DAT) maintaining the neurotransmitter in the

extracellular fluid for a longer time. Drugs impairing

ATP synthesis, which may also induce cell death [i.e.

1-methyl-4-phenylpyridinium (MPP+)], significantly

diminish dopamine uptake in vitro by a mechanism

that is not dependent on competition for the DAT or

synaptosomal integrity [121]. Similar results have

been obtained with other mitochondrial toxins [122].

However, the mechanism underlying those effects is

still to be determined since this inhibition of dopa-

mine uptake is neither dependent on ATP depletion

nor reactive oxygen species (ROS) generation [122].

Also, in vivo studies are not completely consistent

with those in vitro results. Administration of the

mitochondrial toxin 3-nitropropionic acid to rats

increases dopamine turnover [65] which is not con-

sistent with inhibition of dopamine uptake since

Neurochem Res (2006) 31:1279–1294 1283

123

blockade of DAT reduces the concentration of

dopamine metabolites [123].

Some iron (III)–catechol complexes are superoxide

anion scavengers [124] which may be underlying the

protective effect of dopamine against iron-induced

lipid peroxidation [114]; however, dopamine-induced

toxicity is associated to the production of ROS [111,

125, 126]. This is due to an interaction between iron (a

lipid peroxidant [77, 127, 128]) and hydrogen peroxide

(the product of monoamine oxidase (MAO) activity

[129, 130]) leading to oxidative damage [131, 132] since

it may be independently reduced by iron chelation

[114], catalase activity [115] or MAO inhibition

[114–116].

Dopaminergic receptor-induced cell death

and excitotoxicity

Selective dopamine D1 receptor agonists potentiate

serum deprivation-induced apoptosis [133] and induce

activation of caspase 3 [134], although neuroprotective

effects of selective D1 (but not D2) receptor agonists

against FeCl2 treatment or glutathione depletion have

also been reported [133]; thus, stimulation of D1

receptors may lead to neuroprotection or toxicity

depending on the neurotoxic insult (oxidative stress

vs serum-deprivation).

Incubation of cell cultures with high dopamine

concentrations (above 100 lM) reduces intracellular

ATP levels [58] and concentrations above 200 lM

reduce cell viability [58, 111]. Cell death may be

prevented by addition of selective D1 receptor antag-

onists [135]. In contrast, D2 receptor agonists have

shown neuroprotective effects (Fig. 2) [136] associated

to Akt activation [137], although inconsistent results

have also been reported [138].

Interactions between dopaminergic and glutamater-

gic neurotransmitter systems and their relevance to

psychopathology have been reviewed elsewhere [139].

Dopamine-induced cell death may also involve sec-

ondary excitotoxicity since activation of D1 receptors

potentiates NMDAR-mediated currents in prefrontal

cortical neurons [140, 141], most likely through a

protein kinase A-(PKA)-dependent mechanism [142].

In fact, dopamine-induced cell loss is attenuated by a

competitive NMDAR antagonist [76, 112]. Further-

more, dopamine-induced apoptosis involves excitotox-

icity mediated by non-toxic extracellular glutamate

concentrations [112] suggesting that dopamine leads to

an increased sensitivity to the neurotoxic effects of

glutamate.

Antiapoptotic signaling

Cortical dopaminergic hypofunction, as suggested to

partially occur in schizophrenia [107], may lead to

reduced BDNF levels since the transduction mecha-

nisms activated by D1 receptor stimulation enhances

adenylate cyclase activity [143] and cAMP response

element-binding protein-(CREB)-mediated signaling

are important for BDNF expression [144]. A complex

interaction between dopaminergic and glutamatergic

receptors may occur in this regard since dopamine-

induced CREB phosphorylation is reduced by

NMDAR antagonists [145]. CREB phosphorylation is

part of a signaling cascade in which dopaminergic

receptor activation leads to increased NMDAR

activity [140, 141], which in turn produces CREB

Fig. 2 Differential role ofdopaminergic receptorsubtypes in cell death andsurvival. D1 receptorstimulation may lead toapoptotic cell death by amechanism that partiallyrequires NO biosynthesis. NOdiffuses across plasmamembrane and inhibitsdopamine transporterincreasing receptorstimulation by dopamine. D2

receptor stimulation may beprotective against dopamine-induced apoptosis. DAT,dopamine transporter; NO,nitric oxide

1284 Neurochem Res (2006) 31:1279–1294

123

phosphorylation mediated by CaMK [146]; then,

CREB activation by this mechanism may be altered

during glutamatergic hypofunction. On the other hand,

reduced BDNF levels could lead to an increased

subcortical dopaminergic response since chronic BDNF

depletion in heterozygote knock-out mice leads to an

age-related increase in striatal dopamine content [147,

148] which is likely to reflect reduced dopamine release

to produce sensitization of postsynaptic receptors, since

those mice show an increased sensitivity to the loco-

motor-stimulating effect of methamphetamine [148].

On the other hand, dopamine may also alter

antiapoptotic signaling mediated by Akt as phosphor-

ylation of this protein is reduced by stimulation

[149, 150] while increased by blockade [150] of D2

dopaminergic receptors, which is consistent with a

PKA-dependent Akt activation mechanism [93, 151].

Akt knock-out mice showed increased sensitivity to the

disrupting effects of amphetamine on prepulse inhibi-

tion of the acoustic startle response [96] which is a

behavioral model to study sensorimotor gating in

schizophrenia [152–154].

In summary, dopamine may induce cell death by

mechanisms that may be dependent or independent on

dopaminergic receptors (Fig. 2) [58, 108–113]. The

mitochondrial respiratory chain is altered in the brains

of at least a subset of schizophrenic patients [117] and

may be inhibited by dopamine [114–116]. Mitochon-

drial dysfunction leads in turn to dopaminergic over-

activity by decreasing dopamine uptake [121, 122].

Also, dopamine catabolism by MAO leads to the

generation of hydrogen peroxide [129, 130] which

reacts with free iron (II) leading to oxidative damage

[131, 132]. Activation of D1 receptors initiates a

signaling cascade to produce an increased NMDAR

activity [140, 141] and secondary excitotoxicity [76,

112] mediated by non-toxic extracellular glutamate

concentrations [112]. Since BDNF expression is med-

iated by CREB [144] which is activated by dopami-

nergic receptors, reduced cortical dopaminergic

neurotransmission may alter trophic factor signaling

which is important for neuronal survival [99]. Further-

more, BDNF deficiency increases dopaminergic

response [148]. On the other hand, subcortical dopa-

minergic overstimulation of D2 receptors decreases

Akt activation [149, 150] which has antiapoptotic

properties [93, 94].

Reduced nitric oxide biosynthesis

Nitric oxide (NO) is synthesized by the enzyme NO

synthase (NOS) after NMDAR activation [155, 156].

This is due to the fact that the N-terminus of type I

NOS (nNOS) encodes a PDZ domain that interacts

with PSD 95, which in turn associates to the C-

terminus of the NR1/NR2 subunits of the NMDAR

[157–159].

NO is associated to both neurotoxic and neuropro-

tective effects [160]. NO is responsible for the gluta-

mate-induced activation of guanylate cyclase [155, 161]

which is considered its physiological target, but is

associated to glutamate neurotoxicity [156, 162] and

dopamine-induced cell-death.

D1 receptor stimulation may induce cell death

through a mechanism that requires, at least in part,

NOS activation [135] (Fig. 2). Since dopamine recep-

tor stimulation increases NMDAR activity and

excitotoxicity (Section ‘‘Dopaminergic receptor-

induced cell death and excitotoxicity’’), this mecha-

nism could be involved in dopamine-induced NO

biosynthesis.

The genes encoding NOS [163] and NOS binding

proteins (CAPON) [164] have been linked to

schizophrenia in Chinese but not British [165]

populations. NO is able to reduce dopamine reup-

take [166, 167] increasing the extracellular concen-

tration of this neurotransmitter and thus increasing

the activation of its receptors, which may lead to

cell death (Fig. 2).

Some studies have found evidence for a significant

reduction in NO biosynthesis measured as constitu-

tive NOS activity in post-mortem prefrontal cortex

(BA 9) [168] and nitrite plus nitrate concentration in

the CSF [169, 170] and plasma [171] from patients

with schizophrenia. These results are not likely to be

due to antipsychotic medication since CSF nitrite/

nitrate concentrations were reported in first-episode

schizophrenics [169, 170]. In this regard, other studies

have led to inconsistent results [172–176] but meth-

odological issues regarding the analysis of nitrite and

nitrate in biological samples should be considered

[177–179].

Since excessive NO concentrations are associated

to neuronal damage [135, 156, 162] and inhibition of

the mitochondrial respiratory chain [180, 181],

reduced NOS activity in schizophrenia may be

neuroprotective against certain mechanisms of neu-

ronal damage. However, reduced NO biosynthesis

may lead to some susceptibility for neuronal death

since NO has also been associated to neuroprotective

effects [160, 182, 183] related to an increased

expression of the antiapoptotic proteins Bcl-2 and

Bcl-xL, reduced serum deprivation-induced caspase-3

activity [184], Akt activation [185] and to antioxidant

mechanisms [183].

Neurochem Res (2006) 31:1279–1294 1285

123

Oxidative stress

ROS have been implicated in the pathophysiology of

most neurodegenerative disorders [128, 186–192].

Some studies have suggested that oxidative stress

may also play a role in schizophrenia [193], especially

associated to the development of tardive dyskinesia

[88]. Increased 8-hydroxy 2¢-deoxyguanosine, a marker

of oxidative DNA damage, has been found in the

hippocampus from schizophrenic brains [194]. Markers

for cell cycle activation were found in the same study

[194] as have also been found in apoptotic cells [195–

197], although the influence of antipsychotic treatment

could not be completely ruled out.

Reduced total glutathione content has been

reported in the CSF and prefrontal cortex of schizo-

phrenic patients, most of them drug-naıve [54], which

may reflect reduced antioxidant defenses and oxidative

stress. Plasma peroxidation products have been shown

to be increased in first-episode (drug-naıve) schizo-

phrenic patients and were significantly and positively

correlated with the Brief Psychiatric Rating Scale

negative symptom scores [198]. Other studies have

failed to find a significant difference in the concentra-

tion of oxidation products in the CSF [88] and

fibroblasts [171] from medicated schizophrenic

patients.

Both increased plasma xanthine oxidase activity

[175], which generates superoxide anions, and

decreased superoxide dismutase (SOD) activity

[175, 199] have been found in the plasma from neuro-

leptic-treated schizophrenic patients, suggesting the

presence of oxidative stress which may lead to cell

death [200], although CSF SOD activity in schizophrenic

patients was reported not significantly different com-

pared to control levels [88]. Polymorphisms in the SOD

gene have been linked to schizophrenia [201]. SOD is an

antioxidant enzyme with neuroprotective effects in

neurodegenerative challenges such as glutamate excito-

toxicity [202], 1-methyl-4-phenyl-1,2,3,6-tetrahydro-

pyridine [203] and MPP+ [204] neurotoxicities.

Catalase and glutathione peroxidase activities have

also been shown to be decreased in schizophrenic

patients [199]. On the other hand, Sirota and

co-workers [205] have found that neutrophils isolated

from schizophrenic patients release an increased

amount of superoxide radicals in response to stimula-

tion compared to neutrophils isolated from control

patients; they also found a positive and statistically

significant correlation between neutrophil superoxide

anion generation and negative symptom scores [205].

Other studies have found that glutathione peroxidase

activity correlates with psychotic symptom severity in

patients with schizophrenia [206]. Results from both

studies are independent of pharmacological treatment.

The presence of oxidative stress in schizophrenia

should be taken carefully since it has been demon-

strated haloperidol-induced ROS generation in neuro-

nal cultures [207] that may be associated to

mitochondrial complex I inhibition [118–120]. Similar

results are obtained by chronic administration of

risperidone [119] and fluphenazine [120]. Both inhibi-

tion [119] and a lack of effect [120] on complex I

activity have been reported for clozapine. In this

regard, oxidative stress in schizophrenic patients could

be associated to pharmacological treatment; however,

studies with first-episode, drug-naıve patients suggest

that oxidative stress may play a role in the pathophys-

iology of schizophrenia.

On the other hand, oxidative stress has been

associated to impaired learning [190] and may be

involved in the cognitive deficit of patients with

schizophrenia; this may involve reduced glutamatergic

neurotransmission since the oxidation of the redox-

sensitive site in the NMDAR reduces the activation of

this receptor [105, 208, 209].

However, although ROS generation has been asso-

ciated to the induction of cell death in several studies,

the possible impairment in the oxidant/antioxidant

balance in schizophrenic patients should be taken

carefully since some free radicals have important

physiological roles [210, 211].

Neuroprotective effect of atypical antipsychotics

Some neuroimaging studies have observed that brain

morphological abnormalities are less evident when

schizophrenic patients are taking pharmacological

treatment [11].

In contrast to typical antipsychotics such as halo-

peridol which have been associated to ROS generation

[207] and other neurotoxic effects [212], atypical

antipsychotics such as clozapine and olanzapine have

shown antiapoptotic effects in several studies. In spite

of the possible haloperidol-induced oxidative stress,

this drug has been shown to increase Akt phosphor-

ylation [96] which may signal an antiapoptotic pathway

[93–95]. Furthermore, both haloperidol and sulpiride

increase Nerve Growth Factor mRNA [213] and

protein content [214] in the hippocampus, the striatum

and the nucleus accumbens; thus, those drugs may

enhance trophic factor signaling.

Olanzapine protects against methamphetamine-in-

duced neurotoxicity [215] and reduces apoptotic cell

death induced by trophic factor withdrawal [216].

1286 Neurochem Res (2006) 31:1279–1294

123

Wang and co-workers [42] showed that olanzapine

pretreatment significantly decreases the number of

apoptotic cells and the expression of the proapoptotic

protein Bax induced by PCP administration to neonate

rats. Similar results have been reported for the chronic

administration of quetiapine [217]. Furthermore, both

clozapine and olanzapine increase Bcl-2 protein and

mRNA levels in the frontal cortex and hippocampus

[218, 219]; this protein is protective against neuronal

death induced by several mechanisms [116, 220–222]

and has been shown to be decreased in the temporal

cortex of brains from patients who died with schizo-

phrenia [33]. Quetiapine attenuates PCP-induced

increased Bax and decreased Bcl-XL levels in the

posterior cingulate cortex [217]. Furthermore, olanza-

pine reduces the methamphetamine-induced decrease

in the levels of Bcl-2 in the caudate/putamen [215].

The antiapoptotic activity of olanzapine and zipr-

asidone involves Akt phosphorylation [216] and may

also involve trophic factor signaling since chronic

administration of those drugs increase BDNF expres-

sion in the rat hippocampus [219]. BDNF has been

associated to cell survival [223] and has been shown to

be decreased in schizophrenia (See section ‘‘Glutama-

tergic hypofunction’’ under subsection ‘‘Antiapoptotic

signaling’’) independently of pharmacological treat-

ment since BDNF levels are not different in BA 9 and

46 in haloperidol-treated monkeys respect to their

controls [80].

Other trophic factors are also modulated by atypical

antipsychotics. The administration of clozapine

increases Fibroblast Growth Factor-2 mRNA levels

in the rat prefrontal [224] and parietal [225] cortices,

striatum and nucleus accumbens [225].

The neuroprotective properties of some atypical

antipsychotics (such as clozapine, ziprasidone, olanza-

pine and quetiapine) may be related to their agonistic

properties on 5-HT1A receptors [226–229] since selec-

tive agonists of this subtype of serotoninergic receptor

protect against excitotoxic damage [73, 230–232],

MPP+ neurotoxicity [73], traumatic [233] and ischemic

brain injury [234, 235]; also, those drugs have been

shown to reduce caspase 3 activation [73], stauro-

sporine-induced apoptosis [236, 237], serum depriva-

tion-induced cell death [238] and to increase BDNF

mRNA and protein levels [239].

The involvement of serotoninergic neurotransmis-

sion in the pathophysiology of schizophrenia and the

modulatory role of antipsychotic drugs on serotonin-

ergic receptors have been previously reviewed [240,

241]. Reduced activation of 5-HT1A receptors could

represent some susceptibility for neuronal death and

may lead to an increased expression of this receptor as

has been reported in BA 46 of brains from people who

died with schizophrenia [242].

Since excessive extracellular glutamate concentra-

tions may lead to neuronal damage, some of the

neuroprotective effects of atypical antipsychotics may

be associated to the inhibitory effect of 5-HT1A

receptor activation on evoked glutamate release

[243]. Haloperidol leads to an increased basal gluta-

mate concentration in the striatum and nucleus

accumbens [244]. Also, the chronic administration of

clozapine increases depolarization-induced glutamate

release in the nucleus accumbens [244].

In other studies [245], it has been reported that the

administration of the antipsychotic zotepine reduces

the neuronal vacuolization associated to the neuro-

toxic effect of dizocilpine. On the other hand,

chlorpromazine and trifluoperazine reduce NADPH-

induced lipid peroxidation [246], suggesting that at

least some atypical antipsychotics protect against

oxidative stress.

For those reasons it may be hypothesized that at least

part of the therapeutic effect of atypical antipsychotics

may be due to their neuroprotective effect against

neurodegeneration in patients with schizophrenia.

Conclusions

For decades, schizophrenia has been considered by

most clinicians and researchers as a non-degenerative

disease; however, some follow-up neuroimaging stud-

ies show progressive morphological alterations sugges-

tive of degeneration occurring at least in a subset of

schizophrenic patients. As the development of schizo-

phrenia does not exclude the possibility of comorbid

degenerative diseases, it must be determined if

neurodegeneration in some schizophrenic patients is

associated to schizophrenia itself or if it is just an

independent process, or if those degenerative disorders

actually diagnosed as schizophrenia are indeed, as

suggested by Harrison [1], ‘‘an as yet unrecognized

novel neurodegenerative disorder’’. Discussion about

the possible neurodegeneration in schizophrenia has

both diagnostic and therapeutic implications.

On the other hand, the hypothesis of neurodegen-

eration in schizophrenia should be supported on

biochemical mechanisms that explain cell death in

the context of this disorder. Scientific literature about

this issue shows that the main developed hypotheses

regarding the pathophysiology of schizophrenia

involve possible mechanisms of neurodegeneration,

and thus neuronal death may be associated to the

etiology and/or the course of this disorder.

Neurochem Res (2006) 31:1279–1294 1287

123

Acknowledgements We thank Dr Mario Trevino-Villegas(CINVESTAV-IPN) for his valuable comments about thisreview. I. Perez-Neri receives a grant from the NationalCouncil for Science and Technology (CONACyT, No. 186343).

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