Prevention of oxidative stress-mediated neuropathology and improved clinical outcome by adjunctive...

International Review of Psychiatry, April 2006; 18(2): 119–131

Prevention of oxidative stress-mediated neuropathology and improvedclinical outcome by adjunctive use of a combination of antioxidantsand omega-3 fatty acids in schizophrenia

SAHEBARAO P. MAHADIK1,2,, ANILKUMAR PILLAI1,2, SADHANA JOSHI3,

& ADRIANA FOSTER1

1Department of Psychiatry and Health Behavior, Medical College of Georgia, Augusta, GA, 2Medical Research Service

Line, Veterans Affairs Medical Center, Augusta, GA, USA, and 3Interactive Research School for Health Affairs,

Bharati Vidhyapeeth, Pune, India

SummarySchizophrenia is associated with a broad range of neurodevelopmental, structural and behavioral abnormalities that oftenprogress with or without treatment. Evidence indicates that such neurodevelopmental abnormalities may result fromdefective genes and/or non-genetic factors such as pre-natal and neonatal infections, birth complications, famines, maternalmalnutrition, drug and alcohol abuse, season of birth, sex, birth order and life style. Experimentally, these factors have beenfound to cause the cellular metabolic stress that often results in oxidative stress, such as increased cellular levels of reactiveoxygen species (ROS) over the antioxidant capacity. This can trigger the oxidative cell damage (i.e., DNA breaks, proteininactivation, altered gene expression, loss of membrane lipid-bound essential polyunsaturated fatty acids [EPUFAs] andoften apoptosis) contributing to abnormal neural growth and differentiation. The brain is preferentially susceptible tooxidative damage since it is under very high oxygen tension and highly enriched in ROS susceptible proteins, lipids and poorDNA repair. Evidence is increasing for increased oxidative stress and cell damage in schizophrenia. Furthermore,treatments with some anti-psychotics together with the lifestyle and dietary patterns, that are pro-oxidant, can exacerbatethe oxidative cell damage and trigger progression of neuropathology. Therefore, adjunctive use of dietary antioxidants andEPUFAs, which are known to regulate the growth factors and neuroplasticity, can effectively improve the clinical outcome.The dietary supplementation of either antioxidants or EPUFAs, particularly omega-3 has already been found to improvesome psychopathologies. However, a combination of antioxidants and omega-3 EPUFAs, particularly in the early stages ofillness, when brain has high degree of neuroplasticity, potentially may be even more effective for long-term improved clinicaloutcome of schizophrenia.

Introduction

Schizophrenia is a devastating disorder that affects

almost 1% population in every culture around the

world (Craig, Siegel, Hopper, Lin, & Sartorius,

1997; Jablensky et al., 1992). Its symptomatology

becomes evident in adolescence and most of the

subjects often progressively deteriorate throughout

the rest of their lives. Neuropathological studies

indicate that it involves abnormal neurodevelopment

that progresses to a broad range of structural (i.e.,

regional size and shape, and neural cell growth and

differentiation) and functional (i.e., multitransmitter

signal transduction) changes (Bender, 1947; Catts &

Catts, 2000; DeLisi, Hoff, Kushner, Calev,

& Stritzke, 1997; Fish, Marcus, Hans, Auerbach, &

Perdue, 1992; Garey et al., 1998; Gur et al., 1998;

Heckers, 1997; Keller et al., 2003; Lawrie &

Abukmeil, 1998; Lieberman, 1999; Lieberman,

Bogerts, Degreef, & Ashtari, 1992; Mathalon,

Sullivan, Lim, & Pfefferbaum, 2001; Niznikiewicz,

Kubicki, & Shenton, 2003; Selemon, Rajkowska, &

Goldman-Rakic, 1995; Senitz & Winkelmann, 1991;

Weinberger, 1987; Weinberger, Berman, & Zec,

1986). Several etiological factors, both genetic and

non-genetic, have been suggested primarily based

on epidemiological studies (Harrison & Weinberger,

2005; McDonald & Murray, 2000). However, the

proposed biochemical mechanisms do not explain

the neuropathological complexity. Over 50 years ago,

Hoffer, Osmond and Smythies (1954) proposed that

schizophrenia may be associated with free radical

(i.e., reactive oxygen species, ROS) mediated pathol-

ogy. Presently, this approach has quietly gained

broad acceptance due to: (1) evidence in patients of

Correspondence: Sahebarao P. Mahadik, Medical Research Service (242), Veterans Affairs Medical Center, 5B-103,1 Freedom Way, Augusta, GA 30904, USA. Tel: þ1 706 733 0188 ext. 2490. Fax: þ1 706 823 3977.E-mail: [email protected]

ISSN 0954–0261 print/ISSN 1369–1627 online/06/020119–13 � Institute of PsychiatryDOI: 10.1080/09540260600581993

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increased generation of ROS, dysregulated antiox-

idant defense, increased lipid peroxidation, and

increased apoptotic markers; and (2) most of the

non-genetic factors that have been associated with

schizophrenia (Cannon, Jones, & Murray, 2002;

Urakubo, Jarskog, Lieberman, & Gilmore, 2001)

are found to increase the oxidative stress and

oxidative cell damage in animals and some even in

humans. Furthermore, evidence suggests that oxida-

tive cell injury can be prevented and corrected by

a combination of antioxidants and omega-3 fatty acid

supplementation. Some studies have already

reported beneficial effects of these supplements.

Recently, several extensive reviews and chapters

have been published on this topic (Das, 2004;

Horrocks & Farooqui, 2004; Mahadik & Evans,

1997; Mahadik, Evans, & Lal, 2001; Peet,

Laugharne, Mellor, & Ramchand, 1996; Peet &

Stokes, 2005). This review will provide a brief

summary of evidence for oxidative stress and

oxidative cell injury in schizophrenia, and possible

prevention and improved clinical outcome with

dietary supplementation of antioxidants and omega-

3 fatty acids, particularly at early stages of illness.

Oxidative stress and oxidative brain pathology

Oxidative stress is the situation where cellular levels

of ROS exceed the antioxidant capacity. This can

result either by sudden increase in cellular metabo-

lism, toxicity or by altered antioxidant defense

system that involves altered antioxidant enzyme

gene expression and/or reduced intake of dietary

antioxidants. Oxidative stress leads invariably to

oxidative cell damage, namely, DNA breaks and

protein inactivation resulting in altered gene expres-

sion, peroxidative loss of membrane phospholipids

causing abnormal cell growth and differentiation

and/or even apoptotic cell death. Starting from

conception, the time and magnitude of oxidative

stress and the pre-natal and post-natal environment

(anti- or pro-oxidant) will influence the degree and

magnitude of neurodevelopmental deficits. It is

physiologically unusual that although the brain uses

over 20% of the body oxygen and it generates very

large levels of ROS it has poor endogenous anti-

oxidant defense system and relies on the dietary

intake of antioxidants and life style to support it.

Reactive oxygen species (ROS)

Levels of cellular ROS, predominantly superoxide

(�O2), hydroxyl (�OH), nitric oxide (NO�), and

nitrite (NOO�) radicals are generated from mole-

cular oxygen (O2) during oxidative metabolism.

These are generated predominantly in mitochondria

during rapid oxidative phosphorylation and by the

actions of mixed function oxidases (e.g., amino acid

oxidase, cytochrome oxidase, monoamine oxidase,

and xanthine oxidase), auto-oxidation of transition

metals like iron and copper, and by phytochemical

oxidations. In addition, hydrogen peroxide (H2O2)

is generated intra-cellularly by the metalloenzyme,

superoxide dismutase, which is then either converted

to toxic peroxide under acidic conditions or con-

verted to �OH by the Haber-Weiss reaction. NO�

is formed by action of the enzyme, nitric oxide

synthase. This can interact with superoxide under

acidic conditions forming unstable peroxynitrous

acid that spontaneously generate �OH and NOO�.

Therefore, under excessive stress (i.e., physical,

behavioral and chemical) the cellular oxidative

metabolism increases very rapidly creating a sudden

increase in the levels of ROS and thus an increase

in oxidative stress. Note that although ROS are

generally dangerous and lethal for cell growth and

survival, they also play a vital role in some

neurodevelopmental processes (Allen & Balin,

1989; Montague, Gancayco, Winn, Marchase, &

Friedlander, 1994) and vascular performance

(Colavitti et al., 2002; Dawson, Dawson, & Snyder,

1992).

Antioxidant defense system

Antioxidant defense system (AODS) includes

enzymes (superoxide dismutases [SODs]; catalase,

[CAT] and glutathione peroxidase [GPx]), and

non-enzymatic, primarily dietary antioxidants and

uric acid. The SODs convert superoxide radicals to

H2O2. There are two major SODs, copper-zinc-SOD

present in the cytosol and manganese-SOD present

in the mitochondria. Mitochondrial SOD comprises

almost 60% of the total SOD, because twice as much

superoxide is produced in mitochondria compared to

the cytosol. Catalase, an iron-containing enzyme

found primarily in peroxisomes, lysosomes, and

mitochondria and glutathione peroxidase, a sele-

nium-containing enzyme found predominantly in

cytosol with low levels in mitochondria help to

remove hydrogen peroxide formed by SOD.

Among the non-enzymatic cellular antioxidants,

reduced glutathione (GSH) is probably the most

important antioxidant. Mitochondria cannot synthe-

size GSH but import it from the cytosol using

a carrier protein embedded in the membrane

surrounding the mitochondria. There are many

antioxidants that are ingested through diet, among

them the most common and popular are, vitamin E

(�-tocopherols), vitamin C (ascorbate), �-carotenesand coenzyme Q. Vitamin E is present in vegetable

oils and wheat germ. It is a lipid soluble antioxidant

and therefore effectively prevents plasma membrane

120 S. P. Mahadik et al.

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lipid peroxidation. Vitamin C is a water-soluble

antioxidant and present in high concentrations in

fruits and vegetables. It has multiple antioxidant

properties, both in plasma and cytosol, including

regeneration of oxidized vitamin E (Frei, England,

& Ames, 1989; Halliwell & Gutteridge, 1990).

Mechanism(s) of oxidative neural cell injury

Reactive oxygen species live for milliseconds but

due to their instant interactions with a wide range of

chemicals with susceptible structures, they can

inactivate or destroy cellular proteins, lipids and

DNA and RNA, in addition to small bioactive

molecules such as hormones, neurotransmitters and

precursors synthesized locally or ingested in diet.

The brain is selectively vulnerable to oxidative

cellular damage since in addition to high oxidative

metabolism and poor antioxidant defense, it contains

more susceptible proteins (high disulfide bonds) and

lipids (enriched with essential polyunsaturated fatty

acids, EPUFAs), and very little DNA repair through

cell proliferation (Cui, Luo, Xu, & Ven Murthy,

2004; Halliwell, 2001; Muller, 1997; Olanow, 1993;

Reiter, 1995). These interactions of ROS can affect

significantly the cell proliferation and differentiation

during early development, and membrane lipid-

mediated neurotransmitter signal transduction and

thereby information processing and even neural cell

survival. Oxyradical-mediated lipid peroxidation has

been implicated in altered synaptic transmission,

decreased transport of dopamine and �-aminobuty-

ric acid (GABA) in synaptosomes (Rafalowska, Liu,

& Floyd, 1989) and decreased GABA receptor-gated

chloride flux in synaptic vesicles (Schwartz, Skolnick,

& Paul, 1988) in rat brain. Since these cellular

processes are critical for normal brain and behavioral

development, and survival throughout life of an

individual, ROS-mediated cellular damage can con-

tribute at varying degrees to the observed neuro-

pathology of schizophrenia (see later).

Oxidative stress in schizophrenia

Since the first suggestion that free radical pathology

may have role in etiopathogenesis of schizophrenia

by Hoffer et al. (1954), a large number of studies

have been published to support it. These studies have

generally reported altered indices of oxidative stress

(increased cellular levels of ROS, altered antioxidant

balance and increased oxidative damage) in blood,

CSF and post-mortem brains from schizophrenic

patients compared with matched normal controls

(reviewed by Cadet & Perumal, 1990; Mahadik et al.,

1999b; 2001; Mahadik & Mukherjee, 1996; Reddy

& Yao, 1996; Yao, Reddy, & van Kammen, 2001).

Studies in drug-naı̈ve patients at the onset of

psychosis and chronic patients with years of treat-

ment clearly indicate that oxidative stress is part of

the illness and it is exacerbated by some treatments

and a variety of factors related to life style and

socioeconomic status.

Altered ROS generation

Direct measure of ROS is not possible since these

are short lived; however, levels of nitric oxide and

superoxides (NO� and �O2) can be determined

indirectly as nitrite (NO�2 ) and nitrate (NO�

3 ).

Reaction between NO� and �O2 leads to formation

of peroxynitrite that becomes peroxynitrous acid

at neutral pH. Peroxynitrous acid then sponta-

neously decomposes generating a hydroxyl radical

and nitrate. Higher levels of nitrates are reported in

serum (Taneli, Pirildar, Akdeniz, Uyanik, & Ari,

2004), red blood cells (RBC; Herken, Uz, Ozyurt,

& Akyol, 2001a) and post-mortem brain (Yao et al.,

2004) but not in CSF (Ramirez, Garnica, Boll,

Montes, & Rios, 2004) from schizophrenic patients,

compared to controls. Nitric oxide is made by the

enzyme, nitric oxide synthase (NOS) using

L-arginine as substrate. Therefore, NO� increase

may support some of the reports on increased

neuronal-NOS activity (Bernstein et al., 2001;

Karson et al., 1996). NO� can be toxic if generated

in large quantities (e.g., neuronal excitotoxicity due

to high glutamate). However, NO� is an important

neural signal messenger as well as it plays a critical

role in regulation of blood flow. It acts as vasodilator

to increase the blood flow for increased neural

demand of nutrition and oxygen for energy produc-

tion (Dawson et al., 1992; Faraci & Brian, 1994).

Altered antioxidant defense system

Alterations in the antioxidant defense mechanism

have been reported in patients with schizophrenia.

The role of antioxidant enzymes in schizophrenia has

been thoroughly studied, but results are inconsistent.

Various reports from different research groups

indicated increase (Reddy, Keshavan, & Yao, 1991;

Zhang, Zhou, Cao, Zhang, & Wu, 2003), decrease

(Ranjekar et al., 2003) or no change (Yao et al.,

1998a) in the levels of RBC SOD in patients with

schizophrenia. Levels of GPx were also found

inconsistent in patients with schizophrenia (Herken,

Uz, Ozyurt, Sogut, Virit, & Akyol, 2001b; Ranjekar

et al., 2003). The results in the measure of CAT are

also contradictory, with lower (Reddy et al., 1991),

elevated (Herken et al., 2001b) or normal (Yao et al.,

1998a) activities in schizophrenia patients. However,

studies in drug-naı̈ve first-episode psychotic patients

as well as chronic patients on and off antipsychotic

Prevention of oxidative stress-mediated neuropathology 121

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treatment suggest that defects in AODS predate the

illness and antipsychotic treatments may differen-

tially alter it depending the duration of treatment

(Evans et al., 2003; Mukherjee, Mahadik, Scheffer,

Correnti, & Kelkar, 1996; Reddy et al., 1991, 2003;

Reddy & Yao, 1996; Yao et al., 2001). Post-mortem

analysis in patients with schizophrenia indicated an

increase in Mn SOD with no change in Cu, Zn-SOD

in the frontal and temporal cortex in the brain

(Loven, James, Biggs, & Little, 1996). However, a

recent report found increased levels of Cu, Zn- and

Mn-SOD in frontal cortex and substantia innomi-

nata but not in rest of the brain (Michel et al., 2004).

In addition, plasma levels of vitamin E (McCreadie,

MacDonald, Wiles, Campbell, & Paterson, 1995),

vitamin C (Suboticanec, Folnegovic, Korbar,

Mestrovic, & Buzina, 1990), albumin (Yao, Reddy,

& van Kammen, 2000b), and uric acid (Yao, Reddy,

& van Kammen, 1998b) are reported lower in

schizophrenic patients.

Indices of oxidative neural cell injury

The most often used index of oxidative cell injury

is the increased levels of lipid peroxides in the brain

tissue. Naturally, increased lipid peroxides correlate

with the decreased levels of membrane EPUFAs.

These follow with DNA breaks and apoptosis, and

increased protein oxidation. Unfortunately in schizo-

phrenic patients, most of these indices are studied in

blood, and very rarely in CSF. However, since the

oxidative stress is systemic and some of the oxidative

products from brain do end up in the blood,

peripheral measures have been found to be relevant

for the assessment of brain oxidative cell injury.

Increased lipid peroxides. Changes in the peripheral

levels of thiobarbituric acid reactive substances

(TBARS), which are catabolic products of peroxida-

tion, have been reported in patients with schizo-

phrenia. Increased plasma (Peet, Laugharne,

Rangarajan, & Reynolds, 1993) and CSF (Lohr,

Underhill, Moir, & Jeste, 1990; Pall, Williams,

Blake, & Lunec, 1987; Tsai et al., 1998) TBARS

have been reported in some chronic schizophrenic

patients treated with neuroleptics and in plasma of

chronic patients who were not treated with neuro-

leptics (McCreadie et al., 1995), as well as in drug-

naive patients at the onset of psychosis (Mahadik,

Mukherjee, Correnti, Scheffer, & Mahadik, 1998).

Increased levels of TBARS were found in

plasma/serum in both patients with chronic and

never medicated first episode schizophrenia

(Arvindakshan et al., 2003b; Khan et al., 2002;

Mahadik et al., 1998) and in patients with tardive

dyskinesia (Peet et al., 1993). The levels of TBARS

were also found to correlate with the severity of

abnormal involuntary movements (Peet et al., 1993),

with negative symptoms, and with RBC glutathione

peroxidase (Mahadik et al., 1998). Plasma levels of

malondialdehyde (MDA), a lipid peroxidation

marker, were significantly increased in patients

treated with first generation antipsychotics (FGAs)

for three weeks compared to some second generation

antipsychotics (SGAs such as amisulpride, clozapine

and quetiapine) (Kropp et al., 2005).

Reduced membrane phospholipid EPUFAs. Increased

lipid peroxidation can result in a reduction in the

levels of plasma membrane esterified PUFAs and

thereby phospholipids. A number of studies have

reported low levels of phospholipids (Keshavan,

Mallinger, Pettegrew, & Dippold, 1993; Rotrosen

& Wolkin, 1987), esterified phospholipid PUFAs,

particularly arachidonic and docosahexaenoic acids

(AA and DHA respectively) (Glen et al., 1994;

Mukherjee et al., 1994; Yao, van Kammen, &

Welker, 1994) in erythrocyte membranes and in

brain homogenates (Horrobin, Manku, Hillman,

& Glen, 1991) from patients with schizophrenia.

Reduced levels of phosphatidylcholine and phospha-

tidylethanolamine were also found in post-mortem

brain tissue from schizophrenia patients (Yao,

Leonard, & Reddy, 2000a). More recently, reduced

levels of particularly AA and DHA with increased

levels of lipid peroxides have been reported in drug-

naı̈ve first episode patients at early stages of psychosis

(Evans et al., 2003; Khan et al., 2002). However,

similar studies in patients from India showed

decreased levels of RBC DHA but not AA, and

also no increase in plasma lipid peroxides

(Arvindakshan et al., 2003b). Studies in chronic

patients also from India found that the levels of RBC

DHA were lower but not AA, and also no increase

in plasma lipid peroxides (Arvindakshan et al.,

2003b; Ranjekar et al., 2003). This indicates that

plasma lipid peroxides are primarily related to AA

levels. Antipsychotic effects on membrane EPUFAs

are also very important. The membrane AA and

DHA levels were higher in patients treated with

SGAs as compared to FGAs (Arvindakshan et al.,

2003b; Evans et al., 2003; Khan et al., 2002). This is

consistent with the reduced oxidative stress discussed

earlier as well as possible inhibition of phospholipase

A2 (PLA2) with SGAs.

Increased phospholipase A2. Increased oxidative

stress-mediated lipid peroxidation has been found

to be associated with parallel increase in the

phospholipase A2 levels as a compensatory mechan-

ism to repair peroxidated lipids in several organs in


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animals (Burgess & Kuo, 1996). We have found that

plasma levels of lipid peroxides correlated with the

levels of PLA2 (Scheffer, Bradley, & Mahadik,

1999), consistent with the suggested restorative role

for PLA2 following increased lipid peroxidation

(Smalheiser & Swanson, 1998; Van Den Berg,

Op Den Kamp, Lubin, & Kuypers, 1993). This

increased PLA2 may exaggerate further the loss of

membrane essential fatty acids. This suggests that the

reduced levels of EPUFAs in schizophrenia may

be primarily a result of an increased peroxidative

breakdown, which may be exaggerated by lower

dietary intake (Mahadik & Evans, 1997; Mahadik,

Mulchandani, Hegde, & Ranjekar, 1999a; Mahadik,

Sitasawad, & Mulchandani, 1999b). However, the

higher levels of phospholipase A2 are considered

pathological in schizophrenia as a cause for the

reported lower levels of membrane EPUFAs (Gattaz,

Hubner, Nevalainen, Thuren, & Kinnunen, 1990;

Gattaz, Schmitt, & Athanasios, 1995; Mahadik &

Mukherjee, 1996; Noponen et al., 1993; Reddy &

Yao, 1996; Ross, Hudson, Erlich, Warsh, & Kish,

1997). Moreover, the increase in phospholipase A2

is inconsistent (Katila, Appleberg, & Rimon, 1997)

and is considered a generalized ‘stressor’ response

(Noponen et al., 1993).

DNA damage and apoptosis. Reactive oxygen

species are known to trigger DNA breaks and

apoptosis (Wood & Youle, 1994). Oxidative stress

mediated DNA damage can be determined by a well-

established comet assay method (Collins, Dusinska,

Gedik, & Stetina, 1996). Using such assay, one study

did not find DNA damage in lymphocytes from

subjects suffering from schizophrenia (Psimadas

et al., 2004). There are some reports regarding

increased apoptotic markers in CSF and post-

mortem brain of schizophrenic patients that have

led to propose the apoptotic (cellular, as well as

dendritic) mechanisms triggered by oxidative stress

in the pathology of schizophrenia (Catts, V. S., &

Catts, S. V., 2000; Jarskog, Glantz, Gilmore, &

Lieberman, 2005; Margolis, Chung, & Post, 1994).

Treatments of schizophrenia and oxidative stress

Neuroleptics have both pro-oxidant and antioxidant

properties (Jeding et al., 1995). First generation anti-

psychotics (FGAs) such as haloperidol and fluphe-

nazine administered to animals have been found to

increase the oxidative stress by altering the levels of

antioxidants, and cause oxidative injury, including

apoptosis through mitochondrial action, in the brain

(Cadet & Perumal, 1990) and in culture (Behl,

Rupprecht, Skutella, & Holsboer, 1995; Noh et al.,

2000). However chlorpromazine has been found to

increase the activity of antioxidant enzymes but

reduces the lipid peroxidation (Roy, Pathak, &

Singh, 1984). Based on these studies and the

increased lipid peroxidation in CSF and plasma of

tardive dyskinesia (TD) patients (see later), neuro-

leptic treatment mediated oxidative injury was

suggested for TD (Cadet & Lohr, 1987). However,

since increased lipid peroxidation has now been

found in drug-naive patients at the onset of psychosis

(Mahadik et al., 1998) as well as in drug-naive

chronic patients with TD (McCreadie et al., 1995) it

can be suggested that oxidative injury, while possibly

exacerbated by certain neuroleptics, is indeed part of

the primary illness. This last point is very important

since several studies indicate that the longer the

duration of untreated illness, the poorer the prog-

nosis and it takes longer to respond to anti-psychotics

(Perkins et al., 2004; Wyatt, 1995), possibly suggest-

ing that a florid psychotic state, if not controlled

quickly, may be ‘pathogenic’ perhaps by exacerbation

of pre-existing oxidative stress or by yet unknown

mechanisms.

Recently, very systematically designed temporal

studies with FGAs such as haloperidol and chlor-

promazine and second generation anti-psychotics

(SGAs) such as risperidone, olanzapine and cloza-

pine have provided a much clearer picture of

antipsychotic effects on oxidative stress. Short-term

(<14 days) treatment with both FGAs and SGAs

does not alter the antioxidant defense enzymes nor

levels of lipid peroxides, whereas continued treat-

ment with FGAs but not the SGAs until 90 days,

altered the antioxidant enzymes and increased the

lipid peroxides in rat brain (Parikh et al., 2003a;

Pillai, Parikh, Terry, & Mahadik, unpublished data).

However continued treatment beyond 90 days up

to 180 days altered the antioxidant defense even by

SGAs (Pillai et al., unpublished data). It was also

notable that switching animals on FGAs after 90 days

to SGAs, significantly normalized the levels of

antioxidant enzymes, with parallel reduction in

levels of lipid peroxides. In addition, anti-psychotic

treatment differentially alters the glutamatergic

transmission, brain free iron, caloric intake, and

energy metabolism that are known to increase the

oxidative stress (supra). Thus, the anti-psychotic

response of a neuroleptic may depend on its pro- or

antioxidant properties, duration of treatment and the

level of pre-existing oxidative stress in the patient.

Exacerbation of oxidative stress by life style and

socioeconomic status

Among many factors that are associated with the life

style and socioeconomic status of schizophrenics are

heavy smoking (Leon, 1996), high caloric intake

(Strassnig, Brar, & Ganguli, 2003), sedentary life,


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and frequent use of alcohol and drugs of abuse

(Fammy, Streissguth, & Unis, 1998; Gerding,

Labbate, Meason, Santos, & Arano, 1999) which

increase the risk for oxidative stress and oxidative

neural injury (Brown, Birtwistle, Roe, & Thompson,

1999). Cigarette smoke is found to contain very high

levels of both ROS and NO radicals (Pryor & Stone,

1993) and smokers have high levels of lipid

peroxides, compared to non-smokers (Morrow

et al., 1995). Caloric restriction has been shown to

reduce the brain oxidative cellular damage (Sohal,

Ku, Agarwal, Forster, & Lal, 1994) and improve

learning and memory (Pitsikas & Algeri, 1992),

compared to normal ad libidum food intake.

Furthermore, oxidative stress and oxidative neural

injury have also been shown to be a primary

mechanism of complications of alcohol action, such

as increased glutamate activity (Hungund &

Mahadik, 1993).

Neuropathological and clinical implications

The mechanisms of ROS-mediated cellular damage

and the changes in the indices of oxidative cell

damage in schizophrenia discussed earlier very

strongly support the broad range of diffuse neuro-

developmental abnormalities (Degreef et al., 1992;

DeLisi, Hoff, Kushner, Calev, & Stritzke,

1992; Lawrie & Abukmeil, 1998; Lieberman et al.,

1992; Suddath, Christison, Torrey, Casanova, &

Weinberger, 1990) as well as post-mortem neuro-

pathology (Arnold et al., 1998; Heckers, 1997;

Selemon et al., 1995) observed in schizophrenia.

Children with schizophrenia have a broad range of

structural brain abnormalities (Lawrie et al., 1999),

and post-mortem neuropathological changes consis-

tent with effects of ROS mediated cellular damage.

These changes are associated with clinical features,

like impaired psychomotor and neuropsychological

development (‘neurointegrative defect’) in children

genetically at risk for schizophrenia (Fish et al.,

1992), pre-morbid dysfunction (Cannon et al.,

1997), and minor physical anomalies (Gupta

et al., 1995; Lane et al., 1997). These studies have

particularly indicated the differential reductions in

volumes of several brain regions, disorganized

neuronal networks, and increased ventricular size.

All of these changes likely predate (i.e., begin during

neurogenesis) the onset of illness, and these regions

may progressively deteriorate by way of proposed

increased ‘pruning’ (excessive removal of nerve

endings and processes) but not by classical degen-

eration (Keshavan, Anderson, & Pettegrew, 1994).

It is also important to indicate that oxidative stress

and associated damage is generally systemic and

affects the whole body, with brain as the most

susceptible region for reasons discussed earlier. Even

without anti-psychotic treatment that may exacerbate

the risk for metabolic disturbance, schizophrenics

have a higher prevalence of obesity, diabetes (sum-

marized by Mahadik & Mukherjee, 1996), cardio-

vascular disease (Hanson & Gottesman, 2005),

dementias (including Parkinson’s) and even reduced

life span (Horrobin, 1991; 1996; Mahadik et al.,

1999b). Thus it is important to prevent the oxidative

stress and associated pathologies in schizophrenia.

Prevention of oxidative injury and improvedclinical outcome

Studies in animals and humans have indicated that

the dietary intake of antioxidants is effective in the

prevention of oxidative cell injury, and that the intake

of EPUFAs may correct such injury throughout the

body, but predominantly in the brain. An epidemio-

logical report by Christinsen, O. & Christinsen, E.

(1988) showed an association (r¼ 0.97) of higher

intake of fat from fish and vegetables (highly enriched

in !3 EPUFAs and antioxidants) in patients with

a better outcome of schizophrenia.

Supplementation of antioxidants

The choice of antioxidant(s) type and its amount

and length of treatment may depend on the type and

levels of oxyradicals, the nature (e.g., lipids or

proteins or DNA oxidation) and extent of cell

injury, and the contribution of pharmacotherapy for

the primary disease (Rice-Evans & Diplock, 1993).

In schizophrenia, many of these factors have not been

investigated. However, since there is increased lipid

peroxidation, the use of vitamin E, a hydrophobic

antioxidant, should theoretically be preferable. In

addition, since potency of vitamin E is maintained

by vitamin C, which can also prevent the intracellular

peroxidation, parallel use of vitamin C could be of

value. It is important to point out that only one in 10

Americans are believed to have adequate intake of

both antioxidants, and that the situation may be even

worse in schizophrenic patients including pregnant

schizophrenic women. The most common dietary

antioxidants are the vitamins A, E and C, �-carotene,ubiquinones and flavonoids; trace elements such as

zinc (Zn), copper (Cu) and selenium (Se), are part

of the antioxidant enzymes.

Based on the nature of oxidative stress and indices

of oxidative stress (Mahadik & Evans, 1997;

Mahadik & Gowda, 1996; Mahadik & Mukherjee,

1996; Reddy & Yao, 1996), a combination of a

hydrophobic agent such as vitamin E, to protect

membranes, and a hydrophilic agent such as vitamin

C in intracellular protection, provide complete

antioxidant defense. A total of 14 studies have been


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done using primarily vitamin E (800–1600 IU daily)

supplement in chronic schizophrenic patients with

TD (Adler et al., 1993; 1999; Mahadik & Gowda,

1996; Reddy & Yao, 1996). All but two studies

(Adler et al., 1999; Shriqui, Bradjewejn Annable,

& Jones, 1992) have found vitamin E beneficial in

controlling some symptoms of TD and psycho-

pathology. These studies clearly indicate that vitamin

E (a daily dose of 800–1600 IU) is efficacious, if

given to patients <45 years and within five years

of TD. This observation has been interpreted as

indicating that the use of antioxidant supplements

may prevent the deteriorating course at early stages

of illness (Mahadik & Gowda, 1996; Mahadik &

Scheffer, 1996; Peet et al., 1993). Lifestyle and

socio-economic status, factors like high caloric

intake, smoking and use of alcohol and drugs of

abuse can be obstacles for an effective antioxidant

treatment of schizophrenia.

Supplementation of essential fatty acids

Boosting lower levels of membrane phospholipid-

EPUFAs, predominantly AA (20 : 4n-6, !6-EPUFA)

and DHA (22 : 6n-3, !3-EPUFA) by dietary supple-

mentation in schizophrenia is an attractive approach.

These EPUFAs make almost 25% of the brain weight

and their turnover is very rapid. AA is adequately

available in the diet, but adequate brain DHA must

come from diet (Anderson, Connor, & Corliss, 1990;

Connor, Lin, & Neuringer, 1993).

Clinical trials of !6 and !3 fatty acid supplemen-

tation in schizophrenia have been summarized

(Fenton, Hibbelin, & Knable, 2000; Mahadik &

Evans, 1997; Peet et al., 2002). All the supplement

studies are done as adjunctive treatment with a

variety of antipsychotics with doctor’s choice. Studies

by Vaddadi, Courtney, Gilleard, Manku and

Horrobin (1989), in a placebo controlled clinical

trial of individuals with mainly schizophrenia admi-

nistered a mixture of fatty acids (linoleic acid and

gamma-linolenic acid) showed improvement in

psychopathological scores (p<0.002) and Wechsler

Memory scores (p<0.012), however, there was no

improvement in TD scores (abnormal involuntary

movement scale, AIMS). More recently, eicosapen-

taenoic acid (EPA) as ethyl-EPA or EPA plus DHA

supplements in double-blind placebo-controlled

trials have been found more effective than

!6-EPUFAs in reducing the Positive And Negative

Syndrome Scale (PANSS) or SAPS/SANS (SAPS,

Scale of Assessment of Positive Symptoms; SANS,

Scale of Assessment of Negative Symptoms) in

chronic patients on neuroleptics (Mellor,

Laugharne, & Peet, 1995; Peet et al., 1996; Peet

& Mellor, 1998; Shah, Vankar, Telang, Ramchand,

& Peet, 1998). These supplements were found to

improve the levels of RBC membrane EPUFAs and

the psychopathology, particularly negative symptoms

(Peet et al., 1996; Peet & Mellor, 1998).

Clinical trials are also going on in drug-free

patients with recent onset of psychosis (Ho et al.,

2000). It is also important to point out that, in all the

supplementation studies, the levels of RBC mem-

brane EPUFAs (e.g., AA, EPA and DHA) were

found to inversely correlate with the severity of

psychopathology: increased EPUFAs with reduced

psychopathology. A recent dose-ranging study with

ethyl-EPA (1, 2, or 4 gm/day) or placebo (4 gm/day

of liquid paraffin) for 12 weeks in patients with

schizophrenia on clozapine or SGAs (olanzapine,

risperidone or quetiapine) or one of the FGAs has

reported 2 gm/day as the maximum effective dose

and no improvement was seen on the PANSS and its

sub-scales in patients on either FGAs or SGAs over

patients on placebo (Peet & Horrobin, 2002). The

elevated levels of membrane EPA or DHA did not

show correlation with the clinical improvements, but

levels of AA did show strong correlation. Since most

of the published studies that have reported thera-

peutic effects of EPUFA supplementation in schizo-

phrenia have been done by a small group of

investigators, it will be very important to have

replication studies done by many other investigators.

Supplementation of a combination of antioxidants

and essential fatty acids

Since increased oxidative stress mediated EPUFA

peroxidative degradation as well as defective phos-

pholipid-EPUFA metabolism exists in schizophrenia,

the use of a combination of EPUFAs and antiox-

idants (e.g., vitamins E and C) for supplementation

may be preferable (Mahadik et al., 2001). Earlier

studies have also used only vitamin E and supple-

mentation with vitamin C, an effective intracellular

antioxidant, has not yet been tried.

Recently, one study has reported that a four-

month supplementation of a combination of

EPA :DHA (360 : 240) and vitamins E :C

(800 IU : 1 gm) per day in two equal doses in 34

chronic schizophrenic patients on stable medications

(both FGAs and SGAs), was very efficacious

(Arvindakshan, Ghate, Ranjekar, Evans, &

Mahadik, 2003a). All the patients showed over

25% reductions in most of the psychopathological

scores, and these effects were significantly sustained

up to four months after termination of supplementa-

tion. This study did not have a placebo group,

however, the membrane EPA and DHA levels were

elevated from baseline, to equal or even slightly

higher than the levels in matched normal controls

without any change in the plasma lipid peroxides.

This indicated that the low dose EPUFA treatment


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is adequate to correct the pre-existing membrane

EPUFA deficits and probably antioxidants prevented

the degradation. The AA levels pre-treatment were

similar to normal controls, were significantly reduced

post-treatment, and returned to pre-treatment levels

following four months of termination of supplemen-

tation. This suggests that supplementation of !3EPUFAs such as EPA alone (Peet & Horrobin,

2002) or a mixture of EPA and DHA as in this study,

probably reduces AA incorporation in membranes

by competition. Further placebo-controlled supple-

mentation studies with a combination of EPUFAs

(EPAþDHA) and a mixture of vitamins E and C

should be considered. Although EPA is found

effective in reducing some symptoms, it is not a

major membrane fatty acid. Levels of its metabolites

such as eicosanoids may increase at high doses.

These metabolites have not been found to be

therapeutic and may have some unwanted effects.

Furthermore, the reduction of membrane AA either

by competition for incorporation or by inhibition

of PLA2 is not a good idea since it is vital for

membrane receptor-mediated signal transduction of

several neurotransmitters and growth factors in

schizophrenia.

Conclusions and future perspectives

In summary, oxidative stress and cell damage likely

exist at very early stages of schizophrenia and if not

treated early, it can trigger progressive deterioration

of neuropathology and thereby symptomatology;

dietary antioxidants and omega-3 fatty acids are

found to effectively prevent and restore the oxidative

neuropathology and improve the outcome under

a variety of situations. Moreover, these supplements

are also found to prevent or cure important medical

morbidities such as obesity, hypertension, diabetes

and cardiovascular abnormalities that are often

associated with the illness and its treatment.

Therefore, it is tempting to suggest that the dietary

supplementation of a combination of antioxidants

and omega-3 fatty acids with current conventional

pharmacotherapy is timely.

We do not wish to detract from the importance of

developing safer and more efficient anti-psychotics.

As discussed earlier, in vitro and in vivo studies in

animals indicate that treatment with some SGAs may

be neuroprotective against oxidative cell injury by

inducing antioxidant defense (Li et al., 1999; Parikh

et al., 2003a; Pillai et al., unpublished data).

However, conventional pharmacotherapy is limited

in reducing the negative symptoms and improving

cognitive performance and it alone might not be

sufficient to contain the deteriorating course over a

very long-term period. The nature of neuropathology

of schizophrenia clearly indicates that its treatment

by anti-psychotics needs vital augmentation by

agents that will stop one of the key bases of

neuropathology, namely, oxidative stress. Omega-3

fatty acid has been shown to repair neuropathology

and trigger neuroplasticity through regulation of a

variety of growth factors such as nerve growth factor

(NGF) and brain derived neurotrophic factor

(BDNF) (Ikemoto et al., 2000; Wu, Ying, &

Gomez-Pinilla, 2004). This is important since these

growth factors are critical for brain growth and

cognitive performance, and these are found altered

in schizophrenia (Parikh et al., 2003b).

The role of omega-3 fatty acids in preservation

and performance of brain and body has been well

documented (Simopoulos, 1991). There is also need

for a study in a large number of first episode drug-

naı̈ve patients and well matched controls for dietary

and socio-economic status in addition to usual age,

gender, and ethnic origin, which is very difficult to

design in a community setup. Some obvious obsta-

cles in designing such a study are the apparent ethnic

differences in measures of oxidative stress and the

possible impact of alternative medicine (a

MicroMedex search revealed over 2,800 products

containing Vitamin E). Such a study may be partly

possible in cohorts from USA Army personnel or

better yet in cohorts in countries, such as India and

China, where population is racially homogeneous,

reasonably stable and with similar lifestyle.

Furthermore, it is important to establish the relation-

ship between biochemical indices of oxidative stress

and oxidative phospholipid-EPUFA degradation,

and psychopathology at base line and intermittently

over a two-year follow-up period. It is also necessary

to investigate the effects of current medications on

these indices. Regarding the molecular nature of

pathology, although evidence points to the involve-

ment of endogenous antioxidant enzyme genes,

phospholipases, fatty acid carrier proteins and

desaturases, systematic studies are warranted.

A more important issue is also the time of initiation

of pathology. If it has prenatal origin, it may be ideal to

have dietary supplementation during this period. The

benefits of supplementation in adult may be limited

since adult brain may be difficult to remodel.

References

Adler, L. A., Peselow, E., Rotrosen, J., Duncan, E., Lee, M.,

Rosenthal, M., et al. (1993). Vitamin E treatment of tardive

dyskinesia. American Journal of Psychiatr, 150, 1405–1407.

Adler, L. A., Rotrosen, J., Edson, R., Lavori, P., Lohr, J.,

Hitzemann, R., et al. (1999). Vitamin E treatment for tardive

dyskinesia. Archives of General Psychiatry, 56, 836–841.


Int R

ev P

sych

iatr

y D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y U

nive

rsity

of

Mel

bour

ne o

n 03

/13/

13Fo

r pe

rson

al u

se o

nly.

Allen, R. G., & Balin, A. K. (1989). Oxidative influence on

development and differentiation: An overview of a free radical

theory of development. Free Radical Biology & Medicine, 6,

631–661.

Anderson, G. J., Connor, W. E., & Corliss, J. D. (1990).

Docosahexaenoic acid is the preferred dietary n-3 fatty acid

for the development of the brain and retina. Pediatric Research,

27, 89–97.

Arnold, S. E., Trojanowski, J. Q., Gur, R. E., Blackwell, P.,

Han, L.-Y., & Choi, C. (1998). Absence of neurodegenerative

and neural injury in the cerebral cortex in a sample of elderly

patients with schizophrenia. Archives of General Psychiatry, 55,

225–232.

Arvindakshan, M., Ghate, M., Ranjekar, P. K., Evans, D. R., &

Mahadik, S. P. (2003a). Supplementation with a combination

of omega-3 fatty acids and antioxidants (vitamins E and C)

improves the outcome of schizophrenia. Schizophrenia Research,

62, 195–204.

Arvindakshan, M., Sitasawad, S., Debsikdar, V., Ghate, M.,

Evans, D., Horrobin, D. F., et al. (2003b). Essential

polyunsaturated fatty acid and lipid peroxide levels in never-

medicated and medicated schizophrenia patients. Biological

Psychiatry, 53, 56–64.

Behl, C., Rupprecht, R., Skutella, T., & Holsboer, F. (1995).

Haloperidol-induced cell death—mechanism and protection

with vitamin E in vitro. NeuroReport, 7, 360–364.

Bender, L. (1947). Childhood schizophrenia: Clinical study of

100 schizophrenic children. American Journal of Psychiatry, 17,

40–56.

Bernstein, H. G., Krell, D., Braunewell, K. H., Baumann, B.,

Gundelfinger, E. D., Diekmann, S., et al. (2001). Increased

number of nitric oxide synthase immunoreactive Purkinje cells

and dentate nucleus neurons in schizophrenia. Journal of

Neurocytology, 30, 661–670.

Brown, S., Birtwistle, J., Roe, L., & Thompson, C. (1999). The

unhealthy lifestyle of people with schizophrenia. Psychological

Medicine, 29, 697–701.

Burgess, J. R., & Kuo, C.-F. (1996). Increased calcium-

dependent phospholipase A2 activity in vitamin E, and

selenium-deficient rat lung, liver and spleen cytosol is time-

dependent and reversible. The Journal of Nutritional

Biochemistry, 7, 366–374.

Cadet, J. L., & Lohr, J. B. (1987). Free radicals and the

developmental pathophysiology of schizophrenic burnout.

Integrative Psychiatry, 5, 40–48.

Cadet, J. L., & Perumal, A. S. (1990). Chronic treatment with

prolixine causes oxidative stress in rat brain. Biological


Cannon, M., Jones, P., Gilvarry, C., Rifkin, L., Mckenzie, K.,

Foerster, A., et al. (1997). Premorbid social functioning in

schizophrenia and bipolar disorder: Similarities and differences.

American Journal of Psychiatry, 154, 1544–1550.

Cannon, M., Jones, P. B., & Murray, R. M. (2002). Obstetric

complications and schizophrenia: Historical and meta-analytic

review. American Journal of Psychiatry, 159, 1080–1092.

Catts, V. S., & Catts, S. V. (2000). Apoptosis and schizophrenia:

Is the tumor suppressor gene, p53, a candidate susceptibility

gene? Schizophrenia Research, 41, 405–415.

Christinsen, O., & Christinsen, E. (1988). Fat consumption and

schizophrenia. Acta Psychiatrica Scandinavica, 78, 587–591.

Colavitti, R., Pani, G., Bedogni, B., Anzevino, R., Borrello, S.,

Waltenberger, J., et al. (2002). Reactive oxygen species as

downstream mediators of angiogenic signaling by vascular

endothelial growth factor receptor-2/KDR. The Journal of

Biological Chemistry, 277, 3101–3108.

Collins, A. R., Dusinska, M., Gedik, C. M., & Stetina, R. (1996).

Oxidative damage to DNA: Do we have a reliable biomarker?

Environmental Health Perspectives, 104, 465–469.

Connor, W. E., Lin, D. S., & Neuringer, M. (1993). The

Docosahexaenoic Acid (Dha. 22:6n-3) contents of erythrocytes

a marker for the DHA content of brain phospholipids?

The FASEB Journal, 7, A152.

Craig, T. J., Siegel, C., Hopper, K., Lin, S., & Sartorius, N.

(1997). Outcome in schizophrenia and related disorders

compared between developing and developed countries. A

recursive partitioning re-analysis of the WHO DOSMD data.

The British Journal of Psychiatry, 170, 229–233.

Cui, K., Luo, X., Xu, K., & Ven Murthy, M. R. (2004). Role of

oxidative stress in neurodegeneration: Recent developments

in assay methods for oxidative stress and nutraceutical

antioxidants. Progress in Neuropsychopharmacology & Biological


Das, U. N. (2004). Can perinatal supplementation of long-chain

polyunsaturated fatty acids prevent schizophrenia in adult life?

Medical Science Monitor, 10, HY33–HY37.

Dawson, T. M., Dawson, V. L., & Snyder, S. H. (1992). A novel

neuronal messenger molecule in brain: The free radical, nitric

oxide. Annals of Neurology, 32, 297–311.

Degreef, G., Ashtari, M., Bogerts, B., Bilder, R., Jody, D. N.,

Alvir, J. M. J., et al. (1992). Volumes of ventricular system

subdivisions measured from magnetic resonance images in first-

episode schizophrenic patients. Archives of General Psychiatry,

49, 531–537.

DeLisi, L. E., Sakuma, M., Tew, W., Kushner, M., Hoff, A. L.,

& Grimson, R. (1997). Schizophrenia as a chronic active brain

process: A study of progressive brain structural change

subsequent to the onset of schizophrenia. Psychiatry Research,

74, 129–140.

DeLisi, L. E., Hoff, A., Kushner, M., Calev, A., & Stritzke, P.

(1992). Ventricular enlargement at the onset of psychosis is

associated with diagnostic outcome. Biological Psychiatry, 32,

199–201.

Evans, D. R., Parikh, V. V., Khan, M. M., Coussons, C.,

Buckley, P. F., & Mahadik, S. P. (2003). Red blood cell

membrane essential fatty acid metabolism in early psychotic

patients following antipsychotic drug treatment. Prostaglandins,

Leukotrienes, and Essential Fatty Acids, 69, 393–399.

Fammy, C., Streissguth, A. P., & Unis, A. S. (1998). Mental

illness in adults with fetal alcohol syndrome or fetal alcohol

effects. American Journal of Psychiatry, 155, 552–554.

Faraci, F. M., & Brian Jr, J. E. (1994). Nitric oxide and the

cerebral circulation. Stroke, 25, 692–703.

Fenton, W. S., Hibbelin, J., & Knable, M. (2000). Essential

fatty acids, lipid membrane abnormalities, and the

diagnosis and treatment of schizophrenia. Biological Psychiatry,

47, 8–21.

Fish, B., Marcus, J., Hans, S., Auerbach, J. G., & Perdue, S.

(1992). Infants at risk for schizophrenia: Sequelae of a genetic

neuro-integrative defect. Archives of General Psychiatry, 49,

221–235.

Frei, B., England, L., & Ames, B. N. (1989). Ascorbate is an

outstanding antioxidant in human blood plasma. Proceedings of

the National Academy of Sciences of the United States of America,

86, 6377–6381.

Garey, L. J., Ong, W. Y., Patel, T. S., Kanani, M., Davis, A.,

Mortimer, A. M., et al. (1998). Reduced dendritic spine

density on cerebral cortical pyramidal neurons in schizo-

phrenia. Journal of Neurology, Neurosurgery and Psychiatry, 65,

446–453.

Gattaz, W. F., Hubner, C. K., Nevalainen, T. J., Thuren, T., &

Kinnunen, P. K. J. (1990). Increased serum phospholipase A2

activity in schizophrenia: A replication study. Biological


Gattaz, W. F., Schmitt, A., & Athanasios, M. (1995). Increased

platelet phospholipase A2 activity in schizophrenia.

Schizophrenia Research, 16, 1–6.


Int R

ev P

sych

iatr

y D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y U

nive

rsity

of

Mel

bour

ne o

n 03

/13/

13Fo

r pe

rson

al u

se o

nly.

Gerding, L. B., Labbate, L. A., Meason, M. O., Santos, A. B., &

Arano, G. W. (1999). Alcohol dependence and hospitalization

in schizophrenia. Schizophrenia Research, 38, 71–75.

Glen, A. I. M., Glen, E. M. T., Horrobin, D. F., Vaddadi, K. S.,

Spellman, M., Morse-Fisher, N., et al. (1994). A red cell

membrane abnormality in a sub-group of schizophrenic patients:

Evidence for two diseases. Schizophrenia Research, 12, 53–61.

Gupta, S., Andreasen, N. C., Arndt, S., Flaum, M., Schultz, S.

K., Hubbard, W. C., et al. (1995). Neurological soft signs in

neuroleptic-naive and neuroleptic treated schizophrenic

patients and normal comparison subjects. American Journal of


Gur, R. E., Cowell, P., Turetsky, B. I., Gallacher, F., Cannon, T.,

Bilker, W., et al. (1998). A follow-up magnetic resonance

imaging study of schizophrenia. Relationship of neuroanatomi-

cal changes to clinical and neurobehavioral measures. Archives

of General Psychiatry, 55, 145–152.

Halliwell, B., & Gutteridge, J. M. C. (1990). Antioxidants of

human extracellular fluids. Archives of Biochemistry and

Biophysics, 280, 1–8.

Halliwell, B. (2001). Role of free radicals in the neurodegenerative

diseases: Therapeutic implications for antioxidant treatment.

Drugs & Aging, 18, 685–716.

Hanson, D. R., & Gottesman, I. I. (2005). Theories of

schizophrenia: A genetic-inflammatory-vascular synthesis.

BMC Medical Genetics, 11, 6–7.

Harrison, P. J., & Weinberger, D. R. (2005). Schizophrenia genes,

gene expression, and neuropathology: On the matter of their

convergence. Molecular Psychiatry, 10, 40–68.

Heckers, S. (1997). Neuropathology of schizophrenia:

Cortex, thalamus, basal ganglia, and neurotransmitter-specific

projection system. Schizophrenia Bulletin, 23, 403–421.

Herken, H., Uz, E., Ozyurt, H., & Akyol, O. (2001a). Red blood

cell nitric oxide levels in patients with schizophrenia.


Herken, H., Uz, E., Ozyurt, H., Sogut, S., Virit, O., & Akyol, O.

(2001b). Evidence that the activities of erythrocyte free radical

scavenging enzymes and the products of lipid peroxidation are

increased in different forms of schizophrenia. Molecular


Ho, L., Pasinetti, G. M., Horrocks, L. A., Farooqui, A. A.,

Horrobin, D. F., Peet, M., et al. (2000). Eicosanoid pathways

and psychiatric disorders. Biological Psychiatry, 47, 114S.

Hoffer, A., Osmond, H., & Smythies, J. (1954). Schizophrenia;

a new approach. II. Result of a year’s research. The Journal of

Mental Science, 100, 29–45.

Horrobin, D. F. (1991). Is the main problem in free radical

damage caused by radiation, oxygen, and other toxins the loss of

membrane essential fatty acids rather than the accumulation of

toxic materials? Medical Hypotheses, 35, 23–36.

Horrobin, D. F. (1996). Schizophrenia as a membrane lipid

disorder which is expressed throughout the body.

Prostaglandins, Leukotrienes, and Essential Fatty Acids, 55, 3–8.

Horrobin, D. F., Manku, M. S., Hillman, S., & Glen, I. A. M.

(1991). Fatty acid levels in brains of schizophrenics and normal

controls. Biological Psychiatry, 30, 795–805.

Horrocks, L. A., & Farooqui, A. A. (2004). Docosahexaenoic acid

in the diet: Its importance in maintenance and restoration of

neural membrane function. Prostaglandins, Leukotrienes, and

Essential Fatty Acids, 70, 361–372.

Hungund, B. L., & Mahadik, S. P. (1993). Role of gangliosides in

behavioral and biochemical actions of alcohol: Cell membrane

structure and function. Alcoholism, Clinical and Experimental

Research, 17, 329–339.

Ikemoto, A., Nitta, A., Furukawa, S., Ohishi, M., Nakamura, A.,

Fujii, Y., et al. (2000). Dietary n-3 fatty acid deficiency

decreases nerve growth factor content in rat hippocampus.

Neuroscience Letters, 285, 99–102.

Jablensky, A., Sartorius, N., Ernberg, G., Anker, M., Korten, A.,

Cooper, J. E., et al. (1992). Schizophrenia: Manifestations,

incidence and course in different cultures. A World Health

Organization 10-country study. Psychological Medicine.

Monograph Supplement, 20, 1–97.

Jarskog, L. F., Glantz, L. A., Gilmore, J. H., & Lieberman, J. A.

(2005). Apoptotic mechanisms in the pathophysiology of

schizophrenia. Progress in Neuropsychopharmacology &

Biological Psychiatry, 29, 846–858.

Jeding, I., Evans, P. J., Akanmu, D., Dexter, D., Spencer, J. D.,

Aruoma, O. I., et al. (1995). Characterization of the potential

antioxidant and pro-oxidant actions of some neuroleptic drugs.

Biochemical Pharmacology, 49, 359–365.

Karson, C. N., Griffin, W. S., Mrak, R. E., Husain, M.,

Dawson, T. M., Snyder, S. H., et al. (1996). Nitric oxide

synthase (NOS) in schizophrenia: Increases in cerebellar

vermis. Molecular and Chemical Neuropathology, 27, 275–284.

Katila, H., Appleberg, B., & Rimon, R. (1997). No differences

in phospholipase-A2 activity between acute psychiatric patients

and controls. Schizophrenia Research, 26, 103–105.

Keller, A., Castellanos, F. X., Vaituzis, A. C., Jeffries, N. O.,

Giedd, J. N., & Rapoport, J. L. (2003). Progressive loss of

cerebellar volume in childhood-onset schizophrenia. American

Journal of Psychiatry, 160, 128–133.

Keshavan, M. S., Anderson, S., & Pettegrew, J. W. (1994). Is

schizophrenia due to excessive synaptic pruning in the

prefrontal cortex? The Feinberg Hypothesis revisited. Journal

of Psychiatric Research, 28, 239–265.

Keshavan, M. S., Mallinger, A. G., Pettegrew, J. W., &

Dippold, C. (1993). Erythrocyte membrane phospholipids in

psychotic patients. Psychiatry Research, 49, 89–95.

Khan, M. M., Evans, D. R., Gunna, V., Scheffer, R. E., Parikh, V.

V., & Mahadik, S. P. (2002). Reduced erythrocyte membrane

essential fatty acids and increased lipid peroxides in schizo-

phrenia at the never-medicated first-episode of psychosis and

after years of treatment with anti-psychotics. Schizophrenia

Research, 58, 1–10.

Kropp, S., Kern, V., Lange, K., Degner, D., Hajak, G.,

Kornhuber, J., et al. (2005). Oxidative stress during treatment

with first- and second- generation anti-psychotics. The Journal

of Neuropsychiatry and Clinical Neuroscience, 17, 227–231.

Lane, A., Kinsella, A., Murphy, P., Byrne, M., Keenan, J.,

Colgan, K., et al. (1997). The anthropometric assessment of

dysmorphic features in schizophrenia as an index of its

developmental origins. Psychological Medicine, 27, 1155–1172.

Lawrie, S. M., & Abukmeil, S. S. (1998). Brain abnormality in

schizophrenia: A systematic and quantitative review of volu-

metric magnetic resonance imaging studies. The British Journal

of Psychiatry, 172, 119–120.

Lawrie, S. M., Whalley, H., Kestelman, J. N., Abukmeil, S. S.,

Byrne, M., Hodges, A., et al. (1999). Magnetic resonance

imaging of brain in people at high risk of developing

schizophrenia. Lancet, 353, 30–33.

Leon, J. D. (1996). Smoking and vulnerability for schizophrenia.

Schizophrenia Bulletin, 22, 405–409.

Li, X. M., Chan-Forney, J., Julio, A. V., Bennett, V. L.,

Shrikhande, S., Keegan, D. L., et al. (1999). Differential effects

of olanzapine on the gene expression of superoxide dismutase

and the low affinity nerve growth factor receptor. Journal

of Neuroscience Research, 56, 72–75.

Lieberman, J. A. (1999). Is schizophrenia a neurodegenerative

disorder? A clinical and neurobiological perspective. Biological


Lieberman, J., Bogerts, B., Degreef, G., & Ashtari, A. J. (1992).

Qualitative assessment of brain morphology in acute and

chronic schizophrenia. American Journal of Psychiatry, 149,

784–794.


Int R

ev P

sych

iatr

y D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y U

nive

rsity

of

Mel

bour

ne o

n 03

/13/

13Fo

r pe

rson

al u

se o

nly.

Lohr, J. B., Underhill, S., Moir, S., & Jeste, D. V. (1990).

Increased indices of free radical activity in the cerebrospinal

fluid of patients with tardive dyskinesia. Biological Psychiatry,

28, 535–539.

Loven, D. P., James, J. F., Biggs, L., & Little, K. Y. (1996).

Increased manganese-superoxide dismutase superoxide dismu-

tase activity in postmortem brain from neuroleptic-treated

psychotic patients. Biological Psychiatry, 40, 230–232.

Mahadik, S. P., & Evans, D. (1997). Essential fatty acids in the

treatment of schizophrenia. Drugs of Today, 33, 5–17.

Mahadik, S. P., Evans, D., & Lal, H. (2001). Oxidative stress and

role of antioxidant and omega-3 essential fatty acid supple-

mentation in schizophrenia. Progress in Neuropsychopharmacol-

ogy & Biological Psychiatry, 25, 463–493.

Mahadik, S. P., & Gowda, S. (1996). Antioxidants in the

treatment of schizophrenia. Drugs of Today, 32, 1–13.

Mahadik, S. P., & Mukherjee, S. (1996). Free radical pathology

and the antioxidant defense in schizophrenia. Schizophrenia


Mahadik, S. P., & Scheffer, R. E. (1996). Oxidative injury and

potential use of antioxidants in schizophrenia. Prostaglandins,

Leukotrienes, and Essential Fatty Acids, 55, 45–54.

Mahadik, S. P., Mukherjee, S., Correnti, E. E., Scheffer, R., &

Mahadik, J. (1998). Elevated plasma lipid peroxides at the onset

of non-affective psychosis. Biological Psychiatry, 43, 674–679.

Mahadik, S. P., Mulchandani, M., Hegde, M. V., & Ranjekar, P.

K. (1999a). Cultural and socioeconomic differences in dietary

intake of essential fatty acids and antioxidants: Effects on the

outcome. In D. Horrobin, A. L. Glen & M. Peet (Eds.),

Phospholipid Spectrum Psychiatric Disorders (p. 167). Carnforth,

UK: Marius Press.

Mahadik, S. P., Sitasawad, V., & Mulchandani, M. (1999b).

Membrane peroxidation and the neuropathology of schizo-

phrenia. In D. Horrobin, A. L. Glen & M. Peet (Eds.),

Phospholipid Spectrum Psychiatric Disorders (p. 99). Carnforth,

UK: Marius Press.

Margolis, R. L., Chung, D.-M., & Post, R. M. (1994).

Programmed cell death: Implications for neuropsychiatric

disorders. Biological Psychiatry, 35, 946–956.

Mathalon, D. H., Sullivan, E. V., Lim, K. O., & Pfefferbaum, A.

(2001). Progressive brain volume changes and the clinical

course of schizophrenia in men: A longitudinal magnetic

resonance imaging study. Archives of General Psychiatry, 58,

148–157.

McCreadie, R. G., MacDonald, E., Wiles, D., Campbell, G., &

Paterson, J. R. (1995). The Nithsdale Schizophrenia Surveys.

XIV: Plasma lipid peroxide and serum vitamin E levels in

patients with and without tardive dyskinesia, and in normal

subjects. The British Journal of Psychiatry, 167, 610–617.

McDonald, C., & Murray, R. M. (2000). Early and late

environmental risk factors for schizophrenia. Brain Research.

Brain Research Reviews, 31, 130–137.

Mellor, J. E., Laugharne, J. D. E., & Peet, M. (1995).

Schizophrenic symptoms and dietary intake of n-3 fatty acids.


Michel, T. M., Thome, J., Martin, D., Nara, K., Zwerina, S.,

Tatschner, T., et al. (2004). Cu, Zn- and Mn-superoxide

dismutase levels in brains of patients with schizophrenic

psychosis. Journal of Neural Transmission, 111, 1191–1201.

Montague, P. R., Gancayco, C. D., Winn, M. J., Marchase, R. B.,

& Friedlander, M. J. (1994). Role of NO production in NMDA

receptor-mediated neurotransmitter release in cerebral cortex.

Science, 263, 973–977.

Morrow, J. D., Frei, B., Longmire, A. W., Gaziano, J. M.,

Lynch, S. N., Shyr, Y., et al. (1995). Increase in circulating

products of lipid peroxidation (F2-isoprostanes) in smokers:

Smoking as a cause of oxidative damage. The New England

Journal of Medicine, 332, 1198–1203.

Mukherjee, S., Mahadik, S. P., Scheffer, R., Correnti, E. E., &

Kelkar, H. (1996). Impaired antioxidant defense at the onset

of psychosis. Schizophrenia Research, 19, 19–26.

Mukherjee, S., Mahadik, S. P., Horrobin, D. F., Jenkins, K.,

Correnti, E., & Scheffer, R. (1994). Membrane fatty acid

composition of fibroblasts from schizophrenic patients.

Biological Psychiatry, 35, 700.

Muller, D. P. R. (1997). Neurological disease. In H. Sies (Ed.),

Antioxidants in Disease Mechanisms and Therapy (p. 557).

New York: Academic Press.

Niznikiewicz, M., Kubicki, M., & Shenton, M. (2003). Recent

structural and functional imaging findings in schizophrenia.

Current Opinion in Psychiatry, 16, 123–147.

Noh, J. S., Kang, H. J., Kim, E. Y., Sohn, S., Chung, Y. K.,

Kim, S. U., et al. (2000). Haloperidol-induced neuronal

apoptosis: Role of p38 and c-Jun-NH(2)-terminal protein

kinase. Journal of Neurochemistry, 75, 2327–2334.

Noponen, M., Sanfilipo, M., Samanich, K., Ryer, H., Angrist, B.,

Wolkin, A., et al. (1993). Elevated PLA2 activity in

schizophrenics and other psychiatric patients. Biological


Olanow, C. W. (1993). A radical hypothesis for neurodegenera-

tion. Trends in Neurosciences, 16, 439–444.

Pall, H. S., Williams, A. C., Blake, D. R., & Lunec, J. (1987).

Evidence of enhanced lipid peroxidation in the cerebrospinal

fluid of patients taking phenothiazines. Lancet, 2, 596–599.

Parikh, V., Evans, D. R., Khan, M. M., & Mahadik, S. P. (2003b).

Nerve growth factor in never-medicated first-episode psychotic

and medicated chronic schizophrenic patients: Possible impli-

cations for treatment outcome. Schizophrenia Research, 60,

117–123.

Parikh, V., Khan, M. M., & Mahadik, S. P. (2003a). Differential

effects of anti-psychotics on expression of antioxidant enzymes

and membrane lipid peroxidation in rat brain. Journal of

Psychiatric Research, 37, 43–51.

Peet, M., Horrobin, D. F., & the E-E Multicentre Study Group.

(2002). A dose-ranging exploratory study of the effects of ethyl-

eicosapentaenoate in patients with persistent schizophrenic

symptoms. Journal of Psychiatric Research, 36, 7–18.

Peet, M., Laugharne, J., Rangarajan, N., & Reynolds, G. P.

(1993). Tardive dyskinesia, lipid peroxidation, and sustained

amelioration with vitamin E treatment. International Clinical

Psychopharmacology, 8, 151–153.

Peet, M., Laugharne, J. D., Mellor, J., & Ramchand, C. N.

(1996). Essential fatty acid deficiency in erythrocyte membranes

from chronic schizophrenic patients, and the clinical effects of

dietary supplementation. Prostaglandins, Leukotrienes, and

Essential Fatty Acids, 55, 71–75.

Peet, M., & Stokes, C. (2005). Omega-3 fatty acids in the

treatment of psychiatric disorders. Drugs, 65, 1051–1059.

Peet, M., & Mellor, J. (1998). Double blind placebo

controlled trial of n-3 polyunsaturated fatty acids as an

adjunct to neuroleptics. Ninth Schizophrenia Winter Workshop

(p. 54).

Perkins, D., Lieberman, J., Gu, H., Tohen, M., McEvoy, J.,

Green, A., et al. (2004). Predictors of anti-psychotic treatment

response in patients with first-episode schizophrenia, schizo-

affective and schizophreniform disorders. The British Journal of


Pillai, A., Parikh, V., Terry Jr, A. V. & Mahadik, S. P. Long-term

antipsychotic treatments and crossover studies in rats:

Differential effects of typical and atypical agents on the

expression of antioxidant enzymes and lipid peroxidation in

adult rat brain. Journal of Psychiatric Research. In press.

Pitsikas, N., & Algeri, S. (1992). Deterioration of spatial and

nonsocial reference working memory in aged rats: Protective

effect of life-long caloric restriction. Neurobiology of Aging, 13,

369–373.


Int R

ev P

sych

iatr

y D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y U

nive

rsity

of

Mel

bour

ne o

n 03

/13/

13Fo

r pe

rson

al u

se o

nly.

Pryor, W. A., & Stone, K. (1993). Oxidants in cigarette

smoke: Radicals hydrogen peroxide, peroxinitrate, and

peroxinitrate. Annals of the New York Academy of Sciences,

1012, 12–28.

Psimadas, D., Messini-Nikolaki, N., Zafiropoulou, M.,

Fortos, A., Tsilimigaki, S., & Piperakis, S. M. (2004). DNA

damage and repair efficiency in lymphocytes from schizophrenic

patients. Cancer Letters, 204, 33–40.

Rafalowska, U., Liu, G.-J, & Floyd, R. A. (1989). Peroxidation

induced changes in synaptosomal transport of dopamine and

�-aminobutyric acid. Free Radical Biology & Medicine, 6,

485–492.

Ramirez, J., Garnica, R., Boll, M. C., Montes, S., & Rios, C.

(2004). Low concentration of nitrite and nitrate in the

cerebrospinal fluid from schizophrenic patients: A pilot study.


Ranjekar, P. K., Hinge, A., Hegde, M. V., Ghate, M., Kale, A.,

Sitasawad, S., et al. (2003). Decreased antioxidant enzymes

and membrane essential polyunsaturated fatty acids in schizo-

phrenic and bipolar mood disorder patients. Psychiatry

Research, 121, 109–122.

Reddy, R., Keshavan, M., & Yao, J. K. (2003). Reduced plasma

antioxidants in first-episode patients with schizophrenia.


Reddy, R., & Yao, J. (1996). Free radical pathology in schizo-

phrenia: A review. Prostaglandins, Leukotrienes, and Essential

Fatty Acids, 55, 33–43.

Reddy, R., Mahadik, S. P., Mukherjee, S., & Murthy, J. N.

(1991). Enzymes of the antioxidant defense system in chronic

schizophrenic patients. Biological Psychiatry, 30, 309–312.

Reiter, R. J. (1995). Oxidative processes and anti-oxidative

defense mechanisms in the aging brain. The FASEB Journal,

9, 526–533.

Rice-Evans, C. A., & Diplock, A. T. (1993). Current status

of antioxidant therapy. Free Radical Biology & Medicine, 15,

77–96.

Ross, B. M., Hudson, C., Erlich, J., Warsh, J. J., & Kish, S. J.

(1997). Increased phospholipid breakdown in schizophrenia:

Evidence for the involvement of a calcium-dependent

phospholipase A2. Archives of General Psychiatry, 54, 487–494.

Rotrosen, J., & Wolkin, A. (1987). Phospholipid and prostaglan-

din hypotheses of schizophrenia. In H. Y. Meltzer (Ed.),

Psychopharmacology: The Third Generation of Progress (p. 759).

New York: Raven Press.

Roy, D., Pathak, D. N., & Singh, R. (1984). Effects of

chlorpromazine on the activities of antioxidant enzymes and

lipid peroxidation in the various regions of aging rat brain.

Journal of Neurochemistry, 42, 628–633.

Scheffer, R. D., Bradley, J., & Mahadik, S. P. (1999).

Elevated lipid peroxidation and phospholipase A2:

Possible mechanism of the lower cell membrane essential

polyunsaturated fatty acids in schizophrenia. Biological

Psychiatry, 43, 101.

Schwartz, R. D., Skolnick, P., & Paul, S. M. (1988). Regulation

of gamma-aminobutyric acid/barbiturate receptor gated

chloride ion flux in brain vesicles by phospholipase A2:

Possible role of oxygen radicals. Journal of Neurochemistry, 50,

565–571.

Selemon, L. D., Rajkowska, G., & Goldman-Rakic, P. S. (1995).

Abnormally high neuronal density in the schizophrenic cortex.

Archives of General Psychiatry, 52, 805–818.

Senitz, D., & Winkelmann, E. (1991). Neuronal structure

abnormality in the orbito-frontal cortex of schizophrenics.

Journal fur Hirnforschung, 32, 149–158.

Shah, S., Vankar, G. K., Telang, S. D., Ramchand, C. N., &

Peet, M. (1998). Eicosapentaenoic acid (EPA) as an adjunct

in the treatment of schizophrenia. Schizophrenia Research,

29, 158.

Shriqui, C. L., Bradjewejn, J., Annable, L., & Jones, B. D. (1992).

Vitamin E in the treatment of tardive dyskinesia: A double-blind

placebo-controlled study. American Journal of Psychiatry, 149,

391–393.

Simopoulos, A. P. (1991). Omega-3 fatty acids in health and

disease, and in growth and development. The American Journal

of Clinical Nutrition, 54, 438–463.

Smalheiser, N. R., & Swanson, D. R. (1998). Calcium-dependent

phospholipase A2 and schizophrenia. Letter to the Editor.


Sohal, R. S., Ku, H.-H., Agarwal, S., Forster, M. J., & Lal, H.

(1994). Oxidative damage, mitochondrial oxidant generation

and antioxidant defenses during aging, and in response to food

restriction in the mouse. Mechanisms of Ageing and Development,

74, 121–133.

Strassnig, M., Brar, J. S., & Ganguli, R. (2003). Nutritional

assessment of patients with schizophrenia: A preliminary study.

Schizophrenia Bulletin, 29, 393–397.

Suboticanec, K., Folnegovic, V., Korbar, M., Mestrovic, B., &

Buzina, R. (1990). Vitamin C status in chronic schizophrenia.

Biological Psychiatry, 28, 959–966.

Suddath, R. L., Christison, G. W., Torrey, E. F., Casanova, M.

F., & Weinberger, D. R. (1990). Anatomical abnormalities in

the brains of monozygotic twins discordant for schizophrenia.

The New England Journal of Medicine, 322, 789–794.

Taneli, F., Pirildar, S., Akdeniz, F., Uyanik, B. S., & Ari, Z.

(2004). Serum nitric oxide metabolite levels and the effect of

antipsychotic therapy in schizophrenia. Archives of Medical

Research, 35, 401–405.

Tsai, G., Goff, D. C., Chang, R. W., Flood, J., Baer, L., &

Coyle, J. T. (1998). Markers of glutaminergic neurotransmis-

sion and oxidative stress associated with tardive dyskinesia.

American Journal of Psychiatry, 155, 1207–1213.

Urakubo, A., Jarskog, L. F., Lieberman, J. A., & Gilmore, J. H.

(2001). Prenatal exposure to maternal infection alters cytokine

expression in the placenta, amniotic fluid, and fetal brain.


Vaddadi, K. S., Courtney, P., Gilleard, C. J., Manku, M. S., &

Horrobin, D. F. (1989). A double-blind trial of essential fatty

acids supplementation in patients with tardive dyskinesia.

Psychiatry Research, 27, 313–323.

Van Den Berg, J. J. M., Op Den Kamp, J. A. F., Lubin, B. H., &

Kuypers, F. A. (1993). Conformational changes in oxidized

phospholipids and their preferential hydrolysis by phospholipase

A2: A monolayer study. Biochemistry, 32, 4962–4967.

Weinberger, D. R. (1987). Implications of normal brain develop-

ment for the pathogenesis of schizophrenia. Archives of General


Weinberger, D. R., Berman, K. F., & Zec, R. F. (1986).

Physiologic dysfunction of dorsolateral prefrontal cortex in

schizophrenia. I. Regional cerebral blood flow evidence.


Wood, K. A., & Youle, R. J. (1994). Apoptosis and free

radicals. Annals of the New York Academy of Sciences, 738,

400–407.

Wu, A., Ying, Z., & Gomez-Pinilla, F. (2004). Dietary omega-3

fatty acids normalize BDNF levels, reduce oxidative damage,

and counteract learning disability after traumatic brain injury

in rats. Journal of Neurotrauma, 21, 1457–1467.

Wyatt, R. J. (1995). Early intervention of schizophrenia:

Can the course of the illness be altered? Biological Psychiatry,

38, 1–3.

Yao, J. K., Leonard, S., & Reddy, R. D. (2000a). Membrane

phospholipid abnormalities in postmortem brains from schizo-

phrenic patients. Schizophrenia Research, 42, 7–17.

Yao, J. K., Leonard, S., & Reddy, R. D. (2004). Increased nitric

oxide radicals in postmortem brain from patients with schizo-

phrenia. Schizophrenia Bulletin, 30, 923–934.


Int R

ev P

sych

iatr

y D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y U

nive

rsity

of

Mel

bour

ne o

n 03

/13/

13Fo

r pe

rson

al u

se o

nly.

Yao, J. K., Reddy, R., McElhinny, L. G., & van Kammen, D. P.

(1998a). Effects of haloperidol on antioxidant defense system

enzymes in schizophrenia. Journal of Psychiatric Research, 32,

385–391.

Yao, J. K., Reddy, R., & van Kammen, D. P. (2000b). Abnormal

age-related changes of plasma antioxidant proteins in schizo-

phrenia. Psychiatry Research, 97, 137–151.

Yao, J. K., Reddy, R., & van Kammen, D. P. (1998b). Reduced

level of plasma antioxidant uric acid in schizophrenia. Psychiatry


Yao, J. K., Reddy, R. D., & van Kammen, D. P. (2001). Oxidative

damage and schizophrenia: An overview of the evidence and its

therapeutic implications. CNS Drugs, 15, 287–310.

Yao, J. K., van Kammen, D. P., & Welker, J. A. (1994). Red cell

membrane dynamics in schizophrenia. II. Fatty acid composi-

tion. Schizophrenia Research, 13, 217–226.

Zhang, X. Y., Zhou, D. F., Cao , L. Y., Zhang, P. Y., & Wu, G. Y.

(2003). Elevated blood superoxide dismutase in neuroleptic-

free schizophrenia: Association with positive symptoms.

Psychiatry Research, 117, 85–88.


Int R

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sych

iatr

y D

ownl

oade

d fr

om in

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ahea

lthca

re.c

om b

y U

nive

rsity

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Mel

bour

ne o

n 03

/13/

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