International Review of Psychiatry, August 2009; 21(4): 410–413

Valproate and neuroprotective effects for bipolar disorder

MURAD ATMACA

F|rat University, School of Medicine, Department of Psychiatry, Elazig, Turkey

AbstractValproate is an anticonvulsant drug but also a mood stabilizer commonly used to treat bipolar disorder. It has a structureof short-chain fatty acid and is becoming a first line treatment for bipolar disorder. The effect mechanism of the vaproatehas not been completely established but it has been suggested that alterations in gene expression may be involved inchronic treatment. On the other hand, a growing body of evidence emphasizes that valproate has neuroprotective andneurotrophic actions. Neuroimaging studies that examine neurochemistry in the living brain provide further support forthe hypothesis that bipolar disorder is related to changes in neuronal viability and function. In cellular view of point, it wasshowed that valproate protected rat cerebral cortical and cerebellar granule cells from glutamate-related excitotoxicity, andapoptotic death of the endoplasmic reticulum in C6 glioma cells and PC 12 cells. At the genetic level, growing datasuggest that the long-term treatment of mood disorders may involve the regulation of signalling pathways and geneexpression in critical neuronal circuits. It has been shown that lithium and valproate produce some changes in basal andstimulated DNA binding to activator protein 1 (AP-1) transcription factors, considering that strategic changes in geneexpression in critical neuronal circuits may be important in the treatment of a variety of psychiatric disorders. So, agrowing body of evidence establishes its neuroprotective and neurotrophic actions in bipolar disorder.

Introduction

Bipolar disorder is classified as a mood disorder in

the Diagnostic and Statistical Manual of Mental

Disorders Fourth Version (DSM-IV) and affects

approximately 1.5% of the population. It is char-

acterized by episodes of mania and depression with

significant morbidity and mortality. Bipolar disorder

is also associated with many other deleterious health-

related effects, and the costs associated with disability

and premature death represent an economic burden

of hundreds of billions of dollars annually in the

world. Although extensive research has been per-

formed for two decades, the biochemical, neuro-

anatomical and genetic etiopathogenesis underlying

the predisposition to and the pathophysiology of the

disorder remain unclear; moreover, the term good

prognostic disorder when compared to psychotic

disorders has changed along last one decade in the

light of the data evaluated.

On the other hand, neurodegeneration and the

changes in cellular architecture have been empha-

sized. In a postmortem investigation, Rajkowska

et al. (2001) suggested the first histopathological

evidence that changes in both neurons and glial cells

underlie the neuropathology of bipolar disorder.

Using a stereological three-dimensional cell counting

method, they (Rajkowska et al., 2001) have

demonstrated that area 9 from bipolar disordered

patients was characterized by significant reductions

in glial density, increases in size, and changes in

shape of glial nuclei as compared to normal control

subjects. On the other hand, in the same investiga-

tion (Rajkowska et al., 2001), glial alterations are

accompanied by reductions in neuronal density in

the same cortical layers (III and V). Valproic acid

(VPA) is an anticonvulsant drug but also a mood

stabilizer commonly used to treat bipolar disorder.

It has a structure of short-chain fatty acid and is

becoming a first line treatment for bipolar disorder

(McElroy et al., 1992; Bowden, 1996). The effect

mechanism of the vaproate has not been completely

established but it was suggested that alterations in

gene expression may be involved in chronic treat-

ment (Post, 1992; Hyman & Nestler, 1996).

On the other hand, a growing body of evidence

emphasizes that valproate has neuroprotective and

neurotrophic actions. It was demonstrated that

chronic treatment with valproate decreased the

brain volume reductions in bipolar disorder

(Drevets, 2000). Neuroimaging studies that examine

neurochemistry in the living brain provide further

support for the hypothesis that bipolar disorder is

related to changes in neuronal viability and function.

Proton magnetic resonance spectroscopy (1H-MRS),

Correspondence: Murad Atmaca, MD, Associate Professor of Psychiatry, Firat (Euphrates) Universitesi, Firat Tip Merkezi, Psikiyatri Anabilim Dali,

23119 Elazig, Turkey. Tel: (90) 424 233 3555/1578. Fax: (90) 424 238 7688. E-mail: matmaca_p@yahoo.com

ISSN 0954–0261 print/ISSN 1369–1627 online � 2009 Institute of Psychiatry

DOI: 10.1080/09540260902962206

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a recent development in MR technology, allows bio-

chemical constituents to be directly assayed in vivo,

such as choline-containing compounds (CHO),

an index of membrane metabolism, creatineþ

phosphocreatine (CRE), involved in cell energetic

metabolism, and n-acetyl-containing compounds

(especially N-acetylaspartate : NAA). While CHO

and CRE are present in neurons and in glial cells,

NAA is found primarily in neurons (Urenjak et al.,

1993) and in highest concentrations in pyramidal

glutamatergic neurons (Moffett & Namboodiri,

1995). NAA was thought to represent a marker of

neuronal structural integrity. However, a number of

more recent studies have demonstrated that NAA

reductions are reversible, suggesting that NAA is

sensitive to processes affecting the functioning of

neurons (Richards, 1991; Cendes et al., 1997). It

also appears that NAA is sensitive to mitochondrial

oxidative phosphorylation and that it may correlate

highly with tissue glutamate levels (Jenkins et al.,

2000; Petroff et al., 2002). Low NAA is thought to

represent loss of neurons and/or axons, reduction of

interneuronal neuropil, and neuronal or axonal

metabolic dysfunction or damage (Baxter et al.,

1989; Drevets, 1999). 1H MRS studies concerning

bipolar disorder have focused on dorsolateral pre-

frontal cortex (DLPFC) and hippocampal regions. A1H MRS study showed significant reductions of

NAA peaks in the DLPFC of adult bipolar disorder

subjects (Winsberg et al., 2000), whereas two other

MRS studies (Hamakawa et al., 1999; Bertolino

et al., 2003) did not find any differences in DLPFC

or frontal lobes. Chang et al. (2003) reported

reduced NAA levels in DLPFC in a sample of

pediatric bipolar patients who had a parent with

bipolar disorder. Studies using high resolution MRS

reveal that unmedicated patients with bipolar disor-

der have decreased levels bilaterally of NAA in the

hippocampus (Bertolino et al., 2003), as compared

with healthy control subjects. Moreover, therapeutic

doses of lithium reverse these decreased levels of

NAA in their brain (Moore et al., 2000). Deicken

et al. (2003) found low NAA bilaterally in the

absence of smaller hippocampal volume as measured

by MRI, supporting the idea that NAA might be a

more sensitive marker of neuronal damage or loss

than quantitative MRI measurements of tissue loss.

Quetiapine is an atypical antipsychotic with estab-

lished efficacy in the treatment of schizophrenia. It

also shows efficacy in the treatment of acute mania

and depression associated with bipolar disorder

(Dando & Keating, 2005). Quetiapine, either as

monotherapy or in combination with lithium or

divalproex sodium is generally well tolerated and

effective in reducing manic symptoms in patients

with acute bipolar mania, and is approved for use in

adults for this indication (Dando & Keating, 2005;

Gao & Calabrese, 2005; McIntyre et al., 2005). We

wondered the effects of mood stabilizer alone and the

combination of mood stabilizer and atypical anti-

psychotic, quetiapine on hippocampal neurochem-

ical markers of bipolar disordered patients who first

applied, those ongoing mood stabilizer, valproate,

those on valproate plus atypical antipsychotic,

quetiapine treatment concurrently. In that study

(Atmaca et al., 2007) we obtained several important

results: (1) Drug-free patients had significantly lower

NAA/CHO and NAA/CRE ratios compared with

valproate and valproate plus quetiapine groups and

healthy controls. Lower NAA/CHO and NAA/CRE

remained statistically significant even after covarying

for age or whole brain volume compared with

valproate and valproate plus quetiapine groups and

healthy controls; (2) in post-hoc comparisons, a

significant difference was found between the valpro-

ate plus quetiapine group and the valproate group in

regard to only NAA/CHO, but was not found

between the valproate group and healthy controls,

or the valproate plus quetiapine group and healthy

controls for NAA/CRE and CHO/CRE.

In another similarly designed investigation

(Atmaca et al., 2007) we assessed the subregions of

the cingulate gyrus; left anterior cingulate (LAC), left

posterior cingulate (LPC), right anterior cingulate

(RAC), and right posterior cingulate (RPC) in bip-

olar patients that are either unmedicated (n¼ 10), on

valproate monotherapy (n¼ 10) or on valproate plus

quetiapine (n¼ 10) versus healthy comparisons

(n¼ 10). We demonstrated that drug-free patients

had significantly smaller LAC and LPC volumes

compared with the valproate and valproate plus

quetiapine groups and healthy controls even after

correcting for age, whole brain volume and disease

duration, whereas both treated groups did not differ

from the controls. In addition, the LAC volume

showed a trend for larger values in the group with

combined valproate-quetiapine treatment compared

with the group treated with valproate only. In cellular

view of point, it was shown that valproate protected

rat cerebral cortical and cerebellar granule cells from

glutamate-related excitotoxicity (Kanai et al., 2004),

and apoptotic death of the endoplasmic reticulum in

C6 glioma cells and PC 12 cells (Bown et al., 2002;

Hiroi et al., 2005). In an experimental model,

valprote administration was shown to decrease

ischemia-induced brain damage and related neuro-

logical deficits (Ren et al., 2004).

On the other hand, it was demonstrated that

valprote could enhance some neuron protective

factors and proteins such as Akt (De Sarno et al.,

2002), extracellular signal-regulated protein kinase

(Yuan et al., 2001), Bcl-2 (Chen et al., 1999), Grp78

(Bown et al., 2002) and brain-derived neurotro-

phic factor (BDNF) (Fukumoto et al., 2001).

Valproate in bipolar disorder 411

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Glutathione has a key role in cellular antioxidant

defence mechanism in the brain via reacting with

peroxides and conjugating with oxidized products

(Dringen & Hirrlinger, 2003). In their study, Cui

et al. (2007) examined in primary cultured rat

cerebral cortical cells whether glutathione depletion

inhibited the neuroprotective effects of lithium and

valproate and whether chronic treatment with

lithium and valproate and could regulate glutathione

values, and found that chronic treatment with

lithium and valproate inhibited reactive oxygen

metabolite H2O2-induced cell death in primary

cultured rat cerebral cortical cells. Valproate has

also been shown to promote neurogenesis in the

dentate gyrus of the hippocampus and could be

considered as a potential drug for treating some

neurodegenerative diseases (Chuang, 2005; Hao

et al., 2004). At the genetic level, growing data

suggest that the long-term treatment of mood

disorders may involve the regulation of signalling

pathways and gene expression in critical neuronal

circuits (Lenox et al., 1998; Manji et al., 1995; Wang

et al., 1999). It was shown that lithium and valproate

produce some changes in basal and stimulated DNA

binding to activator protein 1 (AP-1) transcription

factors (Asghari et al., 1999; Chen et al., 1999; Ozaki

& Chuang, 1999), considering that strategic changes

in gene expression in critical neuronal circuits may

be important in the treatment of a variety of

psychiatric disorders. Moreover, recently valproate

was reported to inhibit histone deacetylase (HDAC),

an enzyme that catalyzes the removal of acetyl group

from lysine residues of histones, triggering changes in

the expression of distinct genes (Gottlicher et al.,

2001; Phiel et al., 2001).

Finally, although the effect mechanism of valpro-

ate has not been completely established, it was

demonstrated that chronic treatment with valproate

decreased the brain volume reductions and changed

the neuronal viability and function in bipolar

disorder. On the other hand, valproate could directly

enhance some neuron protective factors and proteins

like Akt, extracellular signal-regulated protein kinase,

Bcl-2, Grp78 and BDNF, and regulate the signalling

pathways and gene expression in critical neuronal

circuits in bipolar disorder. So, a growing body of

evidence establishes its neuroprotective and neuro-

trophic actions.

Declaration of interest: The author reports no

conflicts of interest. The author alone is responsible

for the content and writing of the paper.

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Valproate in bipolar disorder 413

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