Oxidative biology: new intervention opportunities in psychiatry

Oxidative biology is an area that is

emerging from the shadows as being

a potential mechanism of disease and

a consequent therapeutic option. Oxida-

tive biology has a long history in psychi-

atry. The first paper examining oxidative

biology in psychiatry appeared as early as

1934. In that paper, Looney andChilds (1)

showed lowered levels of glutathione in

people with major psychiatric disorders.

Glutathione is one of the dominant free

radical scavengers, and is a key compo-

nent of endogenous redox pathways in

many tissues including the brain. There

have been sporadic attempts to modulate

oxidative biology in psychiatry. Perhaps

the best known of these are the attempts to

utilize conventional antioxidants such as

vitamin E in the treatment of schizophre-

nia, particularly in extrapyramidal side

effects such as tardive dyskinesia. These

have had relatively mixed successes. The

focus, however, has shifted from exoge-

nous antioxidants such as vitamin E to the

endogenous antioxidant pathways, par-

ticularly the glutathione pathway.

There are now a number of studies that

have looked at peripheral markers of

oxidative biology in major psychiatric

disorders, including schizophrenia (2–4),

bipolar disorder (4,5), autism (6–9) and

unipolar major depression (5,10). In

essence, there is a concordance of findings

emanating from these studies showing

alterations redox status in a multitude of

psychiatric disorders. Such findings

include dysregulation of peripheral gluta-

thione function as well as disruptions of

other components of the antioxidant

cascade, including enzymes with a key role

in oxidative biology such as catalase. In

general, these studies support increased

oxidative stress in association with acute

phases of illness. Such stress has been

shown to be reduced by therapy of the

particular disorder, for example with

antidepressants in depression (10), and

have been shown to be greatest in those

individuals with the highest symptom

rating scores. There is also novel genetic

data that there are polymorphisms of the

gene glutathione cysteine ligase, a key

component of the glutathione metabolic

pathway, that may be a vulnerability

factor for schizophrenia (11).

There is further evidence that current

psychotropic agents may have a role in

oxidative biology. Some such as haloper-

idol have pro-oxidative effects (12),

whereas others, particularly lithium and

valproate have significant in vitro antiox-

idant effects. Some authors (13) have

postulated that this may one of the

therapeutic mechanisms of mood stabil-

izers in bipolar disorder. Dopamine, a key

transmitter implicated in schizophrenia

has oxidative potential, and this may be

a factor in hyperdopaminergic states such

as psychosis and mania. There is a single

neuroimaging study with magnetic reso-

nance spectroscopy, showing that levels of

glutathione in the brain in people with

schizophrenia are indeed reduced (14).

Studies have also shown evidence of the

secondary effects of oxidative stress, in

particular increased levels of lipid perox-

idation that is documented in major

psychiatric disorders. Such lipid peroxi-

dation affects neuronal membrane func-

tion and viability (15). Oxidative stress has

also been shown to be a pathway to

apoptosis, which is a mechanism of pro-

grammed cell death thatmay be part of the

mechanism of the tissue loss evident in

many disorders. The notion of increased

oxidative stress in the acute phases of

illness indirectly suggests that this may be

a common pathway related to the findings

of neurostructural and neurofunctional

change that is documented in major

psychiatric disorders. This link may open

the path to interventions that may have

a neuroprotective role.

These data are converging to suggest

that dysregulation of oxidative biology

with resultant oxidative stress may be

a significant pathophysiological finding in

people with major psychiatric disorders as

well as suggesting that attempts to mod-

ulate oxidative biology may be fruitful.

Glutathione itself is not orally bioavail-

able; however, its precursor cysteine is

effectively replenished by using N-acetyl-

cysteine, which is bioavailable and does

cross the blood–brain barrier. There are

a handful of preliminary studies that

suggest that N-acetyl-cysteine may have

some effects in people with psychiatric

disorders. Small studies (16) have ap-

peared in the literature examining N-

acetyl-cysteine in cocaine use as well as in

gambling. Attempts to study the effects of

modulations of oxidative biology in pri-

mary major psychiatric disorders includ-

ing schizophrenia and bipolar disorder are

well underway and should be available

shortly. N-acetyl-cysteine is already

widely available for indications including

paracetamol overdose and as a renal pro-

tectant and has an established safety and

tolerability profile. There is renewed hope

that it might be a useful adjunct in clinical

situations where current therapies are

suboptimal.

Michael Berk1,2,31Department of Clinical and Biomedical Sciences:

Barwon Health, University of Melbourne,Geelong, Victoria, Australia

2ORYGEN Youth Health, Melbourne, Victoria, Australia3Mental Health Research Institute, Melbourne, Victoria,

Australia

259

Professor Michael BerkDepartment of Clinical and Biomedical Sciences,

Swanston Centre – Barwon Health,University of Melbourne,

PO Box 281,Geelong, VIC 3220,

AustraliaTel: 161 3 5226 7450;Fax: 161 3 5246 5165;

E-mail: mikebe@barwonhealth.org.au

Acta Neuropsychiatrica 2007: 19:259–260

� 2007 The Author

Journal compilation � 2007 Blackwell

Munksgaard

DOI: 10.1111/j.1601-5215.2007.00224.x

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