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The Wnt Signaling Pathway in Bipolar Disorder

Todd D. Gould and Husseini K. Manji
Neuroscientist 2002 8: 497
DOI: 10.1177/107385802237176

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 PROGRESS IN CLINICAL NEUROSCIENCE ■

The Wnt Signaling Pathway in Bipolar Disorder

TODD D. GOULD and HUSSEINI K. MANJI
Laboratory of Molecular Pathophysiology
National Institute of Mental Health
Bethesda, Maryland

The Wnt signaling pathway is a highly conserved pathway critical for proper embryonic development.
However, recent evidence suggests that this pathway and one of its key enzymes, glycogen synthase
kinase 3β, may play important roles in regulating synaptic plasticity, cell survival, and circadian rhythms in
the mature CNS—all of which have been implicated in the pathophysiology and treatment of bipolar disor-
der. Furthermore, two structurally highly dissimilar medications used to treat bipolar disorder, lithium and
valproic acid, exert effects on components of the Wnt signaling pathway. Together, these data suggest that
the Wnt signaling pathway may play an important role in the treatment of bipolar disorder. Here, the authors
review the modulation of the Wnt/GSK-3β signaling pathway by mood-stabilizing agents, focusing on two
therapeutically relevant aspects: neuroprotection and modulation of circadian rhythms. The future devel-
opment of selective GSK-3β inhibitors may have considerable utility not only for the treatment of bipolar
disorder but also for a variety of classical neurodegenerative disorders. NEUROSCIENTIST 8(5):497–511,
2002: DOI: 10.1177/107385802237176
KEY WORDS Wnt signaling, Glycogen synthase kinase, Lithium, Valproic acid, Neuroprotection, Circadian rhythms, Bipolar disorder

Bipolar disorder (BD, also referred to as manic-depressive
illness) is a common, chronic, and often life-threatening
illness (Goodwin and Jamison 1990). The disease is
equally prevalent in men and women and can occur at
any age, with the early twenties being the median age of
onset (Goodwin and Jamison 1990; Angst and Sellaro
2000). Two almost diametrically opposite mood states
characterize BD: mania and depression. Mania is char-
acterized by a hyperaroused state (either euphoric or
dysphoric), increases in motor activity, racing thoughts,
impaired judgment, decreased sleep, and an apparent
decreased need for sleep. The depressive phases of the
illness, which occur in the same individuals, are charac-
terized by depressed mood, suicidal ideation, anhedonia,
impaired sleep, reduced psychomotor activity, and
impaired memory and concentration. Although exact
figures are difficult to obtain, suicide is estimated to be
the cause of death in upwards of 15% of individuals with
BD, and many other deleterious health-related effects are
increasingly being recognized (Jamison 1986; Goodwin
and Jamison 1990). The lifetime cost estimate of dis-
ability and general medical care of persons with onset of
bipolar disorder in 1998 is projected to be $24 billion in
Peter S. Klein, University of Pennsylvania, provided invaluable com-
ments regarding the substance and style of this review. Sarah K. Tsou
provided excellent editorial assistance. The National Institute of
Mental Heath and the Theodore and Vada Stanley Foundation support
our research. Space limitations necessitated the citing of review papers
in many cases; a full reference list upon which this article was based
is available upon request.
Address correspondence to: Husseini K. Manji, Laboratory of
Molecular Pathophysiology, Bldg 49, Room B1EE16, NIMH, NIH, 49
Convent Dr., Bethesda, MD 20892 (email: manjih@intra.nimh.nih.gov).
the United States alone (Begley and others 2001). It is
thus not altogether surprising that the Global Burden of
Disease Study has identified BD as one of the leading
causes of disability worldwide (Murray and Lopez
1996).
Despite the devastating impact BD has on the lives of
millions worldwide, little is known about its etiology or
pathophysiology. As is the case with most psychiatric ill-
nesses, the etiology of BD was once thought to be due
solely to environmental and social causes; however,
there is now incontrovertible evidence that genetic fac-
tors play a major role. Whereas BD has an overall life-
time incidence of about 1%, first-degree relatives and
monozygotic twin siblings of a patient with BD develop
the disorder about 7% and 60% percent of the time,
respectively (Goodwin and Jamison 1990; Craddock and
Jones 1999; Potash and DePaulo 2000). Although bio-
logical factors portend a predisposition for the develop-
ment of BD, environmental factors also affect the out-
come. For example, sleep deprivation, drug use, and
changes in hormonal levels (i.e., during the postpartum
period) are all documented precipitants of mania in sus-
ceptible individuals (Goodwin and Jamison 1990). In a
consolidated view, current models for BD—and other
diseases with complex genetics—suggest that an inter-
play between genetic, environmental, and epigenetic fac-
tors causes the disease (Craddock and Jones 2001;
Petronis 2001).
The brain systems that have heretofore received the
greatest attention in neurobiologic studies of BD have
been the monoaminergic neurotransmitter systems,
which were implicated by discoveries that effective anti-
depressant drugs exerted their initial biochemical effects
by regulating the intrasynaptic concentrations of sero-

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tonin and norepinephrine. Antihypertensives that deplet-
ed these monoamines sometimes precipitated depressive
episodes in susceptible individuals (Delgado and others
1999). Furthermore, the monoaminergic systems are
extensively distributed throughout the network of limbic,
striatal, and prefrontal cortical neuronal circuits thought
to support the behavioral and visceral manifestations of
mood disorders (Drevets 2000b). Thus, clinical studies
over the past 40 years have utilized assessments of cere-
brospinal fluid chemistry, neuroendocrine responses to
pharmacological challenge, and neurotransmitter recep-
tor and transporter binding, demonstrating a number of
abnormalities of the serotonergic, noradrenergic, and
other neurotransmitter and neuropeptide systems in BD
(Maes and Meltzer 1995; Schatzberg and Schildkraut
1995; Garlow and others 1999). Although such investi-
gations have been heuristic over the years, they have
been of limited value in elucidating the unique neurobi-
ology of BD. More recently, there has been a growing
appreciation that although dysfunctions within the
monoaminergic neurotransmitter systems are likely to
play important roles in mediating many facets of the
pathophysiology of BD, they likely represent the down-
stream effects of other, more primary abnormalities
(Bowden 1997; Manji and Lenox 2000). Consequently,
recent evidence demonstrating that impairments of neu-
roplasticity and cellular resilience may underlie the
pathophysiology of BD and that mood stabilizing agents
exert major effects on signaling pathways that regulate
critical neuroplastic events and cell survival has generat-
ed considerable excitement among the clinical neuro-
science community and is reshaping views about the
neurobiological underpinnings of these disorders. In this
perspectives paper, we review the emerging data sug-
gesting that the Wnt signaling pathway and one of its key
intermediaries, GSK-3β, may play an important role in
the pathophysiology and treatment of BD and that strate-
gic targeting of this pathway may assist in the develop-
ment of improved therapeutics for this devastating neu-
ropsychiatric disorder.
The Wnt Signaling Pathway: An Overview
The Wnt signaling pathway is highly conserved and
plays a critical role in normal development in diverse
species from Drosophila to human. In humans, the Wnt
protein family is composed of at least 15 secreted glyco-
proteins (Wodarz and Nusse 1998). These proteins bind
to the frizzled family of extracellular receptors, resulting
in a signal that is transduced via an intracellular protein,
disheveled. Signaling through disheveled results in inhi-
bition of the enzyme glycogen synthase kinase (GSK),
which is also evolutionarily conserved, is found in
species ranging in diversity from Dictyostelium to
humans, and is found in two forms in mammals: 3α and
3β. Both GSK isozymes were originally identified based
on their ability to phosphorylate—and thereby inacti-
vate—glycogen synthase, resulting in stimulation of the
formation of glycogen. Although most research has
focused on the 3β isoform, available evidence suggests
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that the two forms may have very similar—though not
identical—biological properties (Plyte and others 1992;
Ali and others 2001).
GSK-3β is a serine/threonine kinase that is believed to
be, in general, constitutively active in cells. Phosphory-
lation of GSK-3β by other kinases (including PKC and
Akt) generally results in a decrease in its activity. Thus,
the activity of GSK-3β can be regulated by the action of
a variety of other cellular signaling mechanisms, which
may serve to fine-tune this constitutively active
enzyme’s activity (Woodgett 2001). One of GSK-3β’s
major substrates is β-catenin, which is found in two
functional reservoirs within the cell—a cytoplasmic and
a membrane-associated pool. The cytoplasmic pool is
involved in transmitting the Wnt signal to the nucleus,
whereas the membrane-associated pool interacts with
cadherin to provide structural support in cell adhesions.
Phosphorylation of β-catenin by GSK-3β is regulated by
a complex that includes axin, adenomatous polyposis
coli (APC), frequently rearranged in T-cell lymphoma
(FRAT1), disheveled, casein kinase Iε, and protein phos-
phatase-2A (Peifer and Polakis 2000) (Fig. 1).
Phosphorylation of β-catenin by GSK-3β results in its
degredation in a ubiqitin-dependent manner, thereby
terminating/inhibiting the actions of this important
mediator of the Wnt signaling pathway (Peifer and
Polakis 2000; Sharpe and others 2001). β-catenin binds
with the T-cell factor/lymphoid enhancer factor (tcf/lef)
transcription factor that translocates to the nucleus and
acts as a transcription factor at lef/tcf sites in the pro-
moter of a number of genes (Novak and Dedhar 1999;
Harwood 2001). Activation of the Wnt pathway in early
development modulates organizers, which are groups of
cells that provide instructions for early development and
organization of the surrounding tissue, and thereby reg-
ulates cell fate determination and body patterning
(Cadigan and Nusse 1997; Wodarz and Nusse 1998).
Although this linear description of Wnt signaling—
the canonical pathway—has received the most attention,
recent evidence suggests that Wnt signal may interact
with other signaling pathways. For example, at least in
certain systems, phosphatidyl inositol and Ca2+ signaling
appear to be activated by Wnt-stimulation of the frizzled
family of receptors (Kuhl and others 2000; Patapoutian
and Reichardt 2000).
Wnt Signaling in the Mature CNS
GSK-3β is highly expressed in the adult brain (Ali and
others 2001) and is known to phosphorylate a number of
important cytoskeletal proteins, including three major
microtubule-associated proteins: Tau, MAP-1B, and
MAP-2 (Salinas and Hall 1999). Recent studies have
suggested that changes in GSK-3β-mediated MAP-1B
phosphorylation are associated with the loss and/or
unbundling of stable axonal microtubules (Lucas and
others 1998). Furthermore, GSK-3β inhibition results in
the accumulation of synapsin I, a protein involved in
synaptic vesicle docking and release, at growth cone-like
areas (Lucas and Salinas 1997). Wnt-7a may mimic
Wnt and Bipolar Disorder
Fig. 1. The canonical Wnt pathway. Signaling through Wnt glycoproteins and frizzled receptors activates disheveled. Disheveled acti-
vation results in inhibition of glycogen synthase kinase-3β (GSK-3β). Phosphorylation of β-catenin by GSK-3β results in its degrada-
tion by ubiquitin. Nondegraded (nonphosphorylated) β-catenin binds to lef/tcf transcription factors, targeting transcription of specific
genes. Lithium competes with Mg++ to inhibit GSK-3β (Ryves and Harwood 2001). Valproic acid (VPA) may be an inhibitor of GSK-3β.
Alternately, it may exert its action on Wnt signaling through inhibition of histone deacetylase, by its known actions on c-Jun, through
up-regulation of β-catenin mRNA, or by its action on the Ras/RSK pathway (Chen and others 1997, 1999; Phiel and others 2001; Yuan
and others 2001).

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many of these actions, as this protein has recently been
shown to induce axon and growth cone remodeling (Hall
and others 2000). Although additional research is clear-
ly required, these data suggest that Wnt signaling
through GSK-3β plays important roles in axonal remod-
eling and regulation of synaptic connectivity.
In addition to its apparent role in regulating synapse
formation and axonal growth in developing systems,
there has been considerable recent excitement regarding
the role of GSK-3β in regulating cell death in mature
neuronal tissue, and for the development of GSK-3β
inhibitors as novel therapeutic agents for neurodegener-
ative diseases. Although it was initially reported in 1993
that GSK-3β activity was required for β-amyloid-
induced neurotoxicity in primary hippocampal neurons
(Takashima and others 1993), these observations were
not followed up until very recently. Indeed, it is quite
likely that the demonstration in 1996 that GSK-3β is a
target for lithium’s actions (Klein and Melton 1996;
Phiel and Klein 2001) has greatly contributed to the
resurgence in interest of GSK-3β as a potential thera-
peutic target. Recent studies have demonstrated that
GSK-3β may regulate cell death beyond its role in β-
amyloid-induced toxicity. For example, GSK-3β overex-
pression was found to induce apoptosis in Rat-1 and PC-
12 cells; additionally, dominant negative GSK-3β
mutants prevented apoptosis following inhibition of PI
3-kinase in these cells (Pap and Cooper 1998).
Furthermore, the expression of FRAT-1, a protein that is
thought to interact with the β-catenin/axin/GSK-3β
complex and inhibit GSK-3β in a substrate-specific
manner, also rescues primary sympathetic neurons from
PI 3-kinase inhibition-induced cell death (Crowder and
Freeman 2000). A number of endogenous growth factors
(e.g., nerve growth factor and brain-derived neurotroph-
ic factor [BDNF]) utilize the PI 3-kinase signaling cas-
cade as a major effector system. Thus, growth factors
may bring about many of their neurotrophic/neuropro-
tective effects, at least in part, by GSK-3β inhibition.
Consistent with such a contention, serum deprivation or
PI 3-kinase-induced apoptosis is attenuated by either a
dominant negative form of GSK-3β or an inhibitory
GSK-3β binding protein (Hetman and others 2000).
Neuronal apoptosis in all three of these experiments was
decreased following exposure to either a dominant neg-
ative form of GSK-3β or an inhibitory GSK-3β binding
protein. In this regard, as discussed later in this review,
lithium is neuroprotective in many preclinical models
(Manji and others 1999b).
Although the study of the effects of selective small
molecule GSK-3β inhibitors is still in its infancy, the
available data suggest that pharmacological inhibition of
GSK-3β also exerts neuroprotective effects. Two novel
inhibitors of GSK-3β have been demonstrated to protect
primary sensory and granule neurons from potassium
deprivation or phosphatidylinositol 3-kinase-induced
cell death (Cross and others 2001).
As discussed already, GSK-3β is the target of multiple
signaling systems, and the demonstration of GSK-3β’s role
in neuronal survival and apoptosis does not necessarily
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implicate the canonical Wnt signaling cascade per se in
mediating these effects (Jope and Bijur 2000). In an attempt
to address the specific role of Wnt in the regulation of
apoptosis, a recent study reported that Rat-1 cell lines
stable expressing Wnt-1 were resistant to vincristine- and
vinblastine-regulated apoptosis and that these findings
appeared to be mediated by Tcf-mediated transcription
(Chen and others 2001). By contrast, another study sug-
gested pro-apoptotic effects of up-regulation of components
of the Wnt pathway (van Gijn and others 2001). Although
additional studies are clearly needed, these findings sug-
gest that the precise manner in which the Wnt signaling
pathway regulates cell survival/cell death may be both
development stage and cell line/cell type specific.
Perhaps the strongest evidence suggesting that the
Wnt signaling pathway may play a major role in cell sur-
vival comes from the observations that mutations in Wnt
pathway genes are associated with a large number of
tumors. For example, more than 80% of colorectal carci-
nomas have mutations in the APC or β-catenin genes
(Miyoshi and others 1992; Polakis 2000). APC and β-
catenin mutations are also found in medulloblastomas
and neuroectodermal tumors, albeit at a much lower per-
centage (Huang and others 2000; Koch and others 2001).
Finally, Turcot’s syndrome, characterized clinically by
the co-occurrence of primary brain tumors and multiple
colorectal adenomas, appears to be caused in most cases
by defects in the APC gene (Hamilton and others 1995).
At this point, it should be acknowledged that all the
evidence thus far regarding the neuroprotective proper-
ties of the Wnt pathway has come from primary and
immortalized cell culture studies. Thus, it is not com-
pletely clear to what extent this signaling pathway exerts
a neurotrophic/neuroprotective role in models of health
and disease in the adult CNS. Nevertheless, as we dis-
cuss in greater detail later, the possibility that this system
can be manipulated pharmacologically to provide neuro-
protection is compelling and is an active area of
research.
GSK-3β and Circadian Rhythms
Another role for GSK-3β that may be of considerable
importance in the pathophysiology and treatment of BD
is the regulation of circadian rhythms. Emerging work
from Drosophila suggests that the ortholog of GSK-3β
in this species, SHAGGY, may play a very important
role in regulating circadian rhythms (Martinek and oth-
ers 2001). Specifically, this group found that overex-
pression of SHAGGY results in a shortening of the peri-
od of the Drosophila circadian locomotor activity cycle,
a predictable measure of circadian rhythmicity in this
species. Furthermore, a reduction of SHAGGY activity
resulted in a lengthening of the period. SHAGGY
appears to act by modulating phosphorylation of the
TIMELESS protein, an action that advances the nuclear
entry of the TIMELESS/PERIOD dimer, thus promoting
the shortening of the Drosophila circadian cycle
(Martinek and others 2001) (Fig. 2). Knowledge regard-
ing human circadian physiology is not as advanced as
Wnt and Bipolar Disorder
Fig. 2. The circadian cycle in Drosophila. The CYCLE/CLOCK dimer initiates transcription of both period and timeless genes in the
early part of the day, and mRNA levels reach their peak at the beginning of the night. PERIOD accumulates at a faster rate but earli-
er in the day and is marked for degradation when phosphorylated by DOUBLETIME. As levels of TIMELESS increase in the cytoplasm,
unphosphorylated PERIOD binds with the phosphorylated form of TIMELESS, resulting in this dimmer translocating to the nucleus
and inhibiting the transcription of TIMELESS and PERIOD (Williams and Sehgal 2001). SHAGGY/ZESTY WHITE, the Drosophila
ortholog of glycogen synthase kinase-3β (GSK-3β), appears to be the enzyme that phosphorylates TIMELESS (Martinek and others
2001). TIMELESS is light sensitive and breaks down at sunrise. This leads to the breakdown of unbound PERIOD, thus allowing the
cycle to renew itself (Williams and Sehgal 2001). Many patients with bipolar disorder have abnormalities in circadian physiology (Wehr
and others 1983). Furthermore, lithium lengthens the circadian cycle in diverse species (Klemfuss 1992). The action of lithium on GSK-
3β may help to explain this finding.

that in Drosophila; however, although a true TIMELESS
ortholog has not been identified, orthologs of many of
the proteins are present in humans, likely operate in a
very similar manner, and may therefore play important
roles in the regulation of human circadian rhythms
(Wager-Smith and Kay 2000; Reppert and Weaver
2001). Furthermore, CKIε, which we have previously
mentioned as an enzyme that interacts with GSK-3β, is
mutated in the autosomal dominant circadian mutant in
Syrian hamsters, is the doubletime circadian mutant in
flies, and also interacts with GSK-3β and the Wnt sig-
naling pathway, suggesting that these occurrences may

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be linked (Price and others 1998; Peters and others 1999;
Sakanaka and others 1999; Lowrey and others 2000;
Vielhaber and Virshup 2001).
We now turn to a discussion of the Wnt signaling
pathway in the pathophysiology and treatment of BD.
The Wnt Signaling Pathway
Is a Target of Lithium
The discovery of lithium’s efficacy as a mood-stabilizing
agent revolutionized the treatment of patients with BD;
indeed, it is likely that the remarkable efficacy of lithium
has, in fact, served to spark a revolution that has, over
time, reshaped not only medical and scientific but also
popular concepts of severe mental illnesses. After 3
decades of use in North America, lithium continues to be
one of the mainstays of treatment for this disorder, both
for the acute manic phase and as a prophylaxis for recur-
rent manic and depressive episodes (Goodwin and
Jamison 1990; Manji and Lenox 2000). Adequate lithi-
um treatment, particularly in the context of a lithium
clinic, is also reported to reduce the excessive mortality
observed in the illness (Vestergaard and Aagaard 1991;
Muller-Oerlinghausen and others 1992; Tondo and oth-
ers 1997), and it has been estimated that in most indus-
trialized countries, 0.1% of the population is undergoing
lithium treatment (Schou 1991). The effect on the broad-
er community is highlighted by the estimation that the
use of lithium saved the United States $4 billion during
the years 1969 to 1979 by reducing associated medical
costs and restoring productivity (Reifman and Wyatt
1980). However, despite its role as one of psychiatry’s
most important treatments, the biochemical basis for
lithium’s antimanic and mood-stabilizing actions
remains to be elucidated (Jope 1999; Manji and Lenox
2000).
Until fairly recently, there had been only one clear
biochemical target of lithium at a concentration of ~1
mM (similar to the therapeutic plasma levels). It has
been known for many years that lithium, at therapeuti-
cally relevant concentrations, inhibits inositol
monophosphatases (IMPases) (Berridge and others
1982, 1989), and other monoesterases; however, the
“inositol depletion hypothesis” of lithium’s actions has
received limited direct experimental support (Jope and
Williams 1994; Jope 1999; Phiel and Klein 2001). Thus,
there was considerable excitement generated 5 years ago
by the identification of a novel target for lithium’s
actions. Klein and Melton (1996) were the first to report
that lithium was an inhibitor of GSK-3β in vitro. These
studies arose out of their observation that lithium’s
effects on the dorsalization of the Xenopus embryo are
similar to the effects following activation of the Wnt sig-
naling pathway. They further showed that the selective
inhibition of IMPase with other agents did not mimic
lithium’s effects in Xenopus, leading to their studies
demonstrating that lithium, at therapeutically relevant
concentrations, is a direct inhibitor of GSK3β (Klein and
Melton 1996). This original study was followed by addi-
tional reports confirming and extending these findings
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(Stambolic and others 1996; Hedgepeth and others
1997). Although some indirect in vivo effects should not
be entirely excluded at this point (Chalecka-Franaszek
and Chuang 1999), lithium inhibits GSK-3β in vitro by
direct competition with magnesium, an ion that has a
similar hydrated ionic radius to that of lithium (Ryves
and Harwood 2001). The action is specific to lithium, as
other group I metal ions—sodium, potassium, cesium,
and rubidium—have no effect on GSK-3β in vitro activ-
ity (Klein and Melton 1996; Ryves and Harwood 2001).
Importantly, in addition to the in vitro findings, lithium
has also been demonstrated to inhibit the phosphoryla-
tion of GSK-3β substrates, tau, and MAP-1B in vivo
(Stambolic and others 1996; Hedgepeth and others
1997; Lucas and others 1998).
Lithium exerts profound developmental effects in
diverse organisms, and the identification of GSK-3β as
a target for lithium’s actions has provided a clear cellular
basis for many of the observed phenotypes; indeed,
many of the phenotypes are replicated by activation of
the Wnt pathway (Phiel and Klein 2001). For example,
treating Dictyostelium with lithium results in the diver-
sion of presumptive spore cells to the stalk cell fate, and
loss of GSKA, the GSK-3β homologue in this species,
results in a remarkably similar phenotype (Maeda 1970;
Harwood and others 1995). In Xenopus and zebrafish,
lithium administration mimics the activation of the Wnt
pathway by ectopic expression of Wnt, β-catenin, domi-
nant negative GSK-3β administration, or inhibitory
forms of axin with expansion of the dorsal mesoderm
and duplication of the dorsal axis (Kao and Elinson
1988; McMahon and Moon 1989; Yost and others 1996;
Zeng and others 1997; Yost and others 1998; Hedgepeth
and others 1999).
As expected from a direct GSK-3β inhibitor, lithium
administration leads to the accumulation of β-catenin in
diverse species such as Xenopus embryos, sea urchin
embryos, and cultured mammalian epithelial cells and
neurons (Stambolic and others 1996; Hedgepeth and
others 1997; Lucas and Salinas 1997; Emily-Fenouil and
others 1998; Wikramanayake and others 1998; Chen and
others 2000; Phiel and Klein 2001). Most relevant to the
potential therapeutic relevance of pharmacologic inhibi-
tion of GSK-3β, chronic (3-week) lithium administra-
tion at therapeutic concentrations increases β-catenin
expression in the rat hippocampus (Guang Chen and H.
K. Manji, unpublished observation). Finally, lithium also
increases transcription from lef/tcf reporter constructs
(Staal and others 1999; Vonica and others 2000; Phiel
and others 2001).
In sum, as described by Phiel and Klein, the evidence
that GSK-3β is a target of lithium includes the follow-
ing: 1) in vitro inhibition, 2) in vivo inhibition, 3) lithi-
um phenocopying of GSK-3β loss of function, 4) alter-
native inhibitors of GSK-3β mimic lithium action, and
5) elevations of the levels of GSK-3β reverse the pheno-
typic effects of lithium (Phiel and Klein 2001) (Table 1).
Although the evidence that lithium is an inhibitor of
GSK-3β is compelling, a major problem inherent in BD
research is the ability to ascribe therapeutic relevance to
Wnt and Bipolar Disorder
Table 1. Effects of lithium and valproate on the Wnt pathway.

Lithium Valproate

Directly inhibits GSK-3β by competition with Magnesium
Inhibits the phosphorylation of GSK-3β substrates in cell
culture
Mimics the effects of Wnt stimulation on development of
diverse species
Increases β-catenin protein levels in cell culture
Increases β-catenin protein levels in rat hippocampus
Inhibits GSK-3β mediated potentiation of staurosporine-
induced apoptosis in cell culture
Decreases platelet activating factor mediated increases
in GSK-3β activity in cell culture
Increases transcription from lef/tcf reporter constructs
Inhibits GSK-3β in some in vitro experiments, but not in
others.
Increases back-phosphorylation of a putative GSK-3β
substrate (GSK-3β enzyme is added to lysate after
incubation with valproate)
Increases β-catenin protein levels in cell culture
Increases β-catenin mRNA expression in cell culture
Increases β-catenin protein levels in rat hippocampus
Inhibits GSK-3β mediated potentiation of staurosporine-
induced apoptosis in cell culture
Decreases platelet activating factor mediated increases
in GSK-3β activity in cell culture
Increases transcription from lef/tcf reporter constructs

Both lithium and valproic acid have effects on the Wnt pathway. See text and the following references: Maeda (1970); Kao and Elinson
(1988); McMahon and Moon (1989); Harwood and others (1995); Klein and Melton (1996); Stambolic and others (1996); Yost and oth-
ers (1996); Hedgepeth and others (1997); Lucas and Salinas (1997); Emily-Fenouil and others (1998); Lucas and others (1998);
Wikramanayake and others (1998); Yost and others (1998); Chen and others (1999); Hedgepeth and others (1999); Staal and others
(1999); Bijur and others (2000); Chen and others (2000); Vonica and others (2000); Grimes and Jope (2001); Phiel and Klein (2001);
Phiel and others (2001); Ryves and Harwood (2001); Tong and others (2001); Li and others (in press).

any observed biochemical finding. There are not clear
phenotypic changes associated with treatment response,
and the available animal models are less than ideal.
Indeed, numerous extracellular and intracellular effects
have been documented for lithium (Wang and others
1997; Manji and others 1999a). Whereas some of these
effects are likely related to the treatment efficacy of
these drugs, others may cause the numerous side effects,
or simply be epiphenomenon, with no clinical signifi-
cance. An approach some laboratories have undertaken
to locate potentially therapeutic targets involves identi-
fying targets that are common to structurally dissimilar
agents belonging to the same therapeutic class (e.g.,
mood stabilizers) (Chen and others 1994; Lenox and
others 1996; Manji and others 1996). Thus, although
chemically distinct agents likely do not work through
identical mechanisms, identification of targets that they
regulate in concert in appropriate paradigms may great-
ly serve to validate their therapeutic relevance. In this
context, it is noteworthy that the two most efficacious
and most widely used agents in the treatment of BD,
lithium and valproic acid (VPA), are structurally highly
dissimilar. It is thus not altogether surprising that recent
studies have begun to explore the possibility that the Wnt
signaling pathway may represent a convergent pathway
for the treatment of BD by investigating the effects of
VPA on this signaling pathway.
The Wnt Signaling Pathway Is Also a Target
for the Actions of Valproic Acid
Chen and others (1999) first described VPA as an acti-
vator of the Wnt pathway. They observed that incubation
of human neuroblastoma SH-SY5Y cells with 0.6 mM
VPA caused an increase in the subsequent in vitro
recombinant GSK-3β mediated 32P incorporation into
two putative GSK-3β substrates (Chen and others 1999).
Furthermore, 1-day (and longer) treatment of SH-SY5Y
cells with a therapeutically relevant concentration of
VPA (0.6 mM) resulted in a significant increase in both
nuclear and cytoplasmic β-catenin protein levels.
Additionally, similar to the effects of lithium, VPA also
increased β-catenin levels in the rat hippocampus after
chronic (3-week) VPA treatment at therapeutic concen-
trations (Guang Chen and H. K. Manji, unpublished
observation). Further supporting an action of VPA on
Wnt signaling, VPA has recently been demonstrated to
increase lef/tcf-mediated reporter gene expression in
Neuro 2A cells (Phiel and others 2001). Additionally,
both VPA and lithium attenuate a platelet-activating-
factor-mediated increase in GSK-3β activity (Tong and
others 2001) (Table 1).
Although the mechanism of lithium’s effect on the
Wnt pathway appears to be due in large part (if not
exclusively) to direct inhibition of GSK-3β, it is less
clear precisely how VPA inhibits this pathway—both
direct and indirect mechanisms may be operative. Thus,
Chen and others (1999) reported in vitro inhibition of
GSK-3β and –3α mediated phosphorylation of a CREB
peptide. Furthermore, a recent finding by Grimes and
Jope supports a direct inhibitory effect of VPA on GSK-
3; they found that VPA inhibits the ability of immuno-
precipitated GSK-3β to phosphorylate recombinant
human tau in vitro (Grimes and Jope 2001). By contrast,
Phiel and others found that VPA did not inhibit the in
vitro phosphorylation of glycogen synthase peptide or
the phosphorylation of tau in cell culture (Phiel and oth-
ers 2001). VPA also inhibits the phosphorylation of
MAP-1B by GSK-3β in vivo, but not in vitro, suggest-
ing that VPA inhibits the GSK-3β-mediated phosphory-

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Table 2. Neuroprotective and neurotrophic effects of lithium.
Cultured Cells (human and rodent) Rodent Brain In Vivo
Protects cells against a number of Reduces behavioral deficits and
toxic stimuli including choline acetyltransferase activity
induced by cholinergic lesions
Glutamate Protects against radiation injury
NMDA Protects against cellular and behav-
Calcium ioral changes after middle cereb-
MPP+ ral artery occlusion
Thapsigarin Protects against quinolinic acid
β-amyloid toxicity
Ouabain Enhances hippocampal neurogenesis
Age
Phenytoin
Carbamazepine
KCI deprivation
Serum deprivation
NGF deprivation
GSK-3β + staurosporin
or heat shock
Both preclinical (in cell culture and in intact animals) and clinical evidence suggests that lithium has neuroprotective effects. See Manji
and others (1999b, 2000a, 2000b) and the references found within.
lation of MAP-1B indirectly in intact neurons (Patricia
Salinas, personal communication). Thus, VPA inhibition
of GSK-3β may be substrate specific, or possibly due to
differences in assay conditions (Phiel and Klein 2001).
At present, the degree to which VPA directly inhibits
GSK-3β, and its potential substrate specificity, requires
further delineation. Nevertheless, it is clear that VPA
increases a downstream target of Wnt signaling, β-
catenin. Further recent data have identified an addition-
al pathway—isolated from GSK-3β—by which VPA may
activate the Wnt signaling cascade. VPA is an inhibitor
of histone deacetylase (HDAC) (IC50 = 0.4 mM) and
increases β-catenin mRNA expression in Neuro 2A cell
lines (Phiel and others 2001). It is noteworthy that other
HDAC inhibitors—butyrate (like VPA, a small fatty
acid) and trichostatin-A—also increase the transcription
of tcf reporter constructs in cell culture (Bordonaro and
others 1999); thus, VPA’s effects on β-catenin mRNA, β-
catenin protein levels, and tcf transcriptional activity
may be mediated in part by HDAC inhibition.
A final mechanism by which VPA may indirectly
inhibit GSK-3β and regulate β-catenin is through the
ERK/MAP kinase/RSK pathway. This pathway has
recently been demonstrated to be robustly activated by
VPA (Yuan and others 2001). Furthermore, GSK-3β can
be phosphorylated by Rsk, suggesting a mechanistic link
between the actions of VPA and the regulation of GSK-
3β and β-catenin (Sutherland and others 1993;
Stambolic and Woodgett 1994; Eldar-Finkelman and
others 1995; Kleijn and Proud 2000; Desbois-Mouthon
and others 2001).
Overall, although they may regulate the Wnt signaling
pathway by nonidentical mechanisms, it is striking that
these two structurally highly dissimilar agents exert sim-
504 THE NEUROSCIENTIST
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Human Effects
Increases N-acetyl asparate (NAA)
levels in the brains of BD
patients
Increases gray matter volume in the
brains of BD patients
BD patients chronically
treated with either lithium or val-
proate do not show reduced
PFCx volumes
ilar effects (at therapeutically relevant concentrations)
on this important signaling pathway known to regulate
synaptic plasticity, circadian rhythms, and neuronal sur-
vival (Table 1).
Preclinical and Clinical Studies Suggest That
Mood Stabilizers Have Neurotrophic Effects
The evidence reviewed above suggests that GSK-3β and
β-catenin are targets for the actions of both lithium and
VPA. Do these effects, in fact, have the potential to
translate into therapeutic effects in patients? There is
now a large body of data that shows that lithium, at con-
centrations similar to its IC50 for GSK-3 inhibition,
exerts neurotrophic and neuroprotective effects in a vari-
ety of preclinical and clinical paradigms (Table 2)
(Chuang and others 2002; Jope and Bijur 2002). For
example, lithium protects cerebellar granule cells
against glutamate-, NMDA receptor-, low potassium-,
and toxic level of anticonvulsant-induced cell death
(Nonaka and others 1998a, 1998b; Manji and others
2000b). In addition to the demonstration of protective
effects in vitro, a number of studies have also investigat-
ed lithium’s neuroprotective effects in vivo. In this con-
text, lithium has been shown to protect against a variety
of excitotoxic and ischemic insults (Pascual and
Gonzalez 1995; Nonaka and Chuang 1998; Arendt and
others 1999; Manji and others 1999b, 2000b). Please see
Table 2 and references contained within Manji and oth-
ers (2000b) and Manji and others (1999b) for a complete
review of lithium’s neuroprotective effects.
Although not as well studied, VPA also exerts neuro-
protective actions in several paradigms (Bruno and oth-
ers 1995; Mark and others 1995; Mora and others 1999;
Wnt and Bipolar Disorder
Fig. 3. Neuroprotective effects of lithium and valproic acid (VPA) in human SH-SY5Y neuroblastoma cells. Cells were incubated with
either lithium (1.0 mM) or VPA (1.0 mM) for 3 days and then exposed to two different toxins—thapsigarin (which mobilizes intracellu-
lar calcium; 0.5 mM for 16 h) or MPP+ (25 uM for 16 h). The mitochondrial dehydrogenase activity that cleaves 3-(4,5-dimethylthiazol-
2-yl)-2,5-diphenyl tetrazolium bromide (MTT) was used to determine cell survival in a quantitative colormetric assay. Three days of
lithium or VPA treatment exerted significant protective effects against both toxins. *P < 0.05. (Copied with permission from Manji and
others 2000a.)

Manji and others 2000b). In a direct comparison, Manji
and others (2000a) reported the neuroprotective effects
of lithium and VPA. Lithium and VPA protected
human neuroblastoma SH-SY5Y cells from both thapsi-
garin- and MPP+-induced apoptosis at therapeutically
relevant concentrations. Furthermore, at therapeutic
concentrations, the degree of protection from both drugs
was similar (Fig. 3). VPA and lithium also protect SH-
SY5Y cells from staurosporine-induced apoptosis in
cells stably transfected with GSK-3β in a model that
has been shown to have the same results after treatment
with lithium, thus linking the neuroprotective effects of
these medications with the Wnt/GSK-3β pathway
(Bijur and others 2000; Li and others 2002). Inhibition
of GSK-3β and/or the activation of the Wnt signaling
pathway is an attractive mechanism to explain these
findings.
Are the Neurotrophic and Neuroprotective Effects
of Mood Stabilizers Possibly Therapeutically
Relevant in the Long-Term Treatment of BD?
Mood disorders have traditionally been conceptualized
as neurochemical disorders, but there is now evidence
from a variety of sources demonstrating regional reduc-
tions in CNS volume, as well as reductions in the num-
bers and/or size of glia and neurons in discrete brain
areas (Manji and others 2000b). Although the precise
cellular mechanisms underlying these morphometric
changes remain to be elucidated, the data suggest that
mood disorders are associated with impairment of struc-
tural plasticity and cellular resilience. Structural imag-
ing studies have demonstrated reduced gray matter vol-
ume in areas of the orbital and medial prefrontal cortex
(PFC), ventral striatum and hippocampus, and enlarge-

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ment of third ventricles in mood disordered relative to
healthy control samples (Drevets and others 1999; Manji
and Duman 2001). Complementary postmortem neu-
ropathological studies have shown abnormal reductions
in cortex volume, glial cell counts, and/or neuron size in
the subgenual PFC, orbital cortex, dorsal anterolateral
PFC, and amygdala (Manji and others 2000b;
Rajkowska in press). Finally, a recent study found a
decrease in N-acetyl-aspartate (NAA, a putative marker
of neuronal viability [Tsai and Coyle 1995]), in the dor-
solateral prefrontal cortex in patients with BD compared
to healthy control subjects (Winsberg and others 2000).
At present, it is not known whether these deficits consti-
tute developmental abnormalities that may confer vul-
nerability to abnormal mood episodes, compensatory
changes to other pathogenic processes, or the sequelae of
recurrent affective episodes. Understanding these issues
will partly depend upon experiments that delineate the
onset of such abnormalities within the illness course and
determination if they antedate depressive episodes in
individuals at high familial risk for mood disorders
(Drevets and others 1999). The hypothesis that dysfunc-
tion of these regions may contribute to the development
of at least some symptoms of BD is consistent with evi-
dence that lesions (e.g., strokes or tumors) involving
either the PFC or the striatum (a major target of efferent
projections from the PFC), and degenerative diseases
affecting the striatum (e.g., Parkinson’s and Huntington’s
diseases), are associated with increased risk for develop-
ing depression (Drevets and others 1999). Overall, what-
ever the precise underlying mechanisms, the impairment
of structural plasticity in regions of the brain most asso-
ciated with the pathophysiology of BD suggests that neu-
rotrophic and neuroprotective effects of mood disorders
may play a major role in the long-term treatment of BD.
Although the body of preclinical data demonstrating
neurotrophic and neuroprotective effects of lithium and
VPA is impressive, considerable caution must clearly be
exercised in extrapolating to the clinical situation with
humans. In a retrospective analysis, Drevets and associ-
ates reanalyzed their data demonstrating ~40% reduc-
tions in subgenual PFC volumes in familial mood disor-
der subjects (Drevets and others 1997). Consistent with
neurotrophic/neuroprotective effects of lithium and
VPA, they found that the patients treated with chronic
lithium or VPA exhibited subgenual PFC volumes that
were significantly higher than the volumes in nonlithi-
um- or VPA-treated patients, and not significantly dif-
ferent from controls (Drevets 2000a). To prospectively
investigate if lithium also exerts neurotrophic/neuropro-
tective effects in the human brain in vivo, a longitudinal
clinical study was undertaken utilizing proton magnetic
resonance spectroscopy to quantitate NAA levels (Moore
and others 2000a). Chronic lithium administration was
found to significantly increase NAA concentration, and
furthermore, a striking ~0.97 correlation between lithi-
um-induced NAA increases and regional voxel gray mat-
ter content was observed, thus suggesting that lithium
may be exerting these effects by targeting gray matter
(Fig. 4). Further-more, a follow-up high-resolution volu-
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metric MRI study demonstrated that 4 weeks of lithium
treatment also significantly increased total gray matter
content in the human brain (Moore and others 2000b)
(Fig. 5). Taken together, these clinical data support the
hypothesis that mood stabilizers may exert hitherto
underappreciated neurotrophic/neuroprotective effects
in humans, effects that are likely due, at least in part, to
their effects on GSK-3β and/or Wnt pathway regulation.
Does Lithium Also Regulate Circadian Rhythms
via Its Effects on GSK-3β?
Abnormalities in circadian physiology are common in
patients with BD (Wehr and others 1983) and have been
hypothesized to reflect an endophenotype of the illness
(Lenox and others 2002). Many patients have changes in
the circadian period of temperature, melatonin, and
other hormones, with unclear clinical significance
(Souetre and others 1988; Healy and Waterhouse 1995;
Pacchierotti and others 2001). Most patients with BD
have sleep cycle abnormalities and other changes asso-
ciated with circadian physiology during both the depres-
sive and manic stages of the illness (Kasper and Wehr
1992). Furthermore, alteration of biological rhythms
through interventions like sleep deprivation exerts a
major effect in BD. Partial or total sleep deprivation is
capable of inducing a rapid antidepressant effect in
~40% to 60% of depressed BD patients (Wu and Bunney
1990; Wirz-Justice and Van den Hoofdakker 1999). The
antidepressant effect is transient and reverses after a full
night of sleep, thereby making it impractical as a routine
therapeutic intervention. Although sleep deprivation
clearly has to be considered as more than just a circadi-
an rhythm manipulation, the striking and rapid effect
(much faster than pharmacologic interventions) points to
the potential critical role of circadian rhythms in the
pathophysiology and treatment of BD. In further support
of such a contention, there is considerable evidence that
sleep deprivation is capable of inducing mania in many
patients with BD, leading to the hypothesis that sleep
deprivation and mania affect each other in a reciprocal
fashion, with one increasing the intensity of the other
(Wehr and others 1987).
These clinical findings add important substance to the
observation that lithium increases free-running (organ-
ism is without external time cues) circadian period
length in humans and many other species including uni-
cellular organisms, plants, insects, and mice (Klemfuss
1992). Hitherto, a biological target for this action has
been lacking (Klemfuss 1992; Ikonomov and Manji
1999). However, as discussed already, the Drosophila
ortholog of GSK-3β, SHAGGY, was recently identified
as a mediator of circadian rhythms in this species
(Martinek and others 2001). Tissue-specific overexpres-
sion of SHAGGY resulted in a shortening of the period
of the Drosophila circadian locomotor activity cycle.
Furthermore, a reduction of SHAGGY activity resulted
in a lengthening of the period (Martinek and others 2001),
precisely the effect that lithium has on free-running cir-
cadian length in most organisms studied (Fig. 2). Thus,
Wnt and Bipolar Disorder
Fig. 4. Brain N-Acetyl-Aspartate (NAA) is increased following 4 weeks of lithium administration at therapeutic levels. Quantitative pro-
ton (1H) magnetic resonance spectroscopy (MRS) was utilized to measure brain NAA level at baseline and after 4 weeks of lithium
administration. Voxel placement for each region investigated a) frontal lobe, b) parietal lobe, c) occipital lobe, d) temporal lobe. Chronic
lithium increases brain NAA content in the regions investigated (left). ■, occipital; ●, temporal; ▲, frontal; ◆, parietal. Four weeks of
lithium adminstration resulted in a small (5%) but significant (P = 0.02) increase of total brain NAA concentration. NAA increases cor-
relate with percentage of gray matter content (right). (Modified and reproduced with permission from Moore and others 2000a.)

lithium’s inhibition of GSK-3β represents a putative
cellular mechanism for the ability of this simple monova-
lent cation to alter circadian physiology in diverse organ-
isms. This also raises the possibility that GSK-3β inhibitors
may have broad utility in the treatment of disorders
associated with abnormalities of circadian rhythms.
Conclusions and Prospects
Although some indirect in vivo effects should not be
excluded (Chalecka-Franaszek and Chuang 1999), lithi-
um does directly target GSK-3β—thereby stimulating
the Wnt pathway—at therapeutic concentrations (Klein
and Melton 1996). Similarly, VPA targets the Wnt path-
way and may also have more specific effects on GSK-3β
(Chen and others 1999). Although GSK-3β’s role as a
mediator of many cellular processes leaves the quest for
putative downstream physiological targets wide open,
we have focused on two targets that have been a focus of
BD research in the past: regulation of neuroplastic
changes and modulation of circadian rhythms. As dis-
cussed in this review, increasing preclinical and clinical
evidence implicates changes in neuroplasticity and cel-
lular resiliency in both the pathophysiology and treat-
ment of mood disorders (Jope 1999; Manji and others
2000b). Similarly, evidence accumulated over the past 3
decades suggests that changes in, or the modulation of,
circadian rhythms may underlie both the underlying
cause of BD and an explanation for why some treatments
for the disorder are efficacious (Kasper and Wehr 1992).
Although both these areas of focus are certainly strong-
ly correlated with BD, it remains to be seen with cer-
tainty what the true underlying causes are.
To date, although there is strong suggestive evidence
that Wnt/GSK-3β regulation may be related to BD treat-
ment efficacy, there is no direct evidence that abnormal-
ities of Wnt signaling are present in BD. Although post-
mortem brain studies are fraught with methodological
problems—including long postmortem delays, ante-
mortem medication and drug use, causes of death that

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Fig. 5. Brain gray matter volume is increased following 4 weeks of lithium administration at therapeutic levels in patients with bipolar
disorder (BD). a) A slice of three-dimensional volumetric magnetic resonance imaging (MRI) data that was segmented by tissue type
using quantitative methodology to determine tissue volumes at each scan time point. Brain tissue volumes were examined using high-
resolution three-dimensional MRI (124 1.5 mm-thick coronal T1-weighted spoiled gradient echo images) and validated quantitative
brain tissue segmentation methodology to identify and quantify the various components by volume, including total brain white and
gray matter content. Measurements were made at baseline (medication free, after a minimum 14-day washout) and then repeated after
4 weeks of lithium at therapeutic doses. b and c, Chronic lithium significantly increases total gray matter content in the human brain
of patients with BD. No significant changes were observed in brain white matter volume or in quantitative measures of regional cere-
bral water. (Modified and reproduced with permission from Moore and others 2000b.)

have variable effects on brain tissue, and the inability to
adequately study posttranslational modifications—two
studies have recently quantitated GSK-3β protein levels
in the frontal cortex in BD patients, finding no differ-
ences from controls (Lesort and others 1999; Kozlovsky
and others 2000). However, studies have found altered
levels of GSK-3—or other molecules in the Wnt
pathway—in postmortem brains or peripheral cells from
patients with another neuropsychiatric disorder, schizo-
phrenia (Yang and others 1995; Cotter and others 1998;
Miyaoka and others 1999; Kozlovsky and others 2000;
Beasley and others 2001). In this regard, it is noteworthy
that a leading hypothesis posits that early neurodevelop-
mental changes predispose to the development of schiz-
ophrenia in adulthood (Weinberger 1997). Clearly addi-
tional studies are required to investigate these findings
further, as well as to pursue the possibility that there may
be alterations in other mediators of the Wnt pathway in
patients with BD.
Recently, selective small molecule GSK inhibitors have
been developed (Coghlan and others 2000; Cross and oth-
ers 2001; Smith and others 2001); these molecules have
been used successfully to protect cerebellar granule cells
from toxic stimuli (Cross and others 2001). Future research
may examine these molecules for efficacy in the treatment
of BD. Even more promising may be the development of
drugs that, similar to FRAT1, inhibit GSK-3β-mediated
phosphorylation of specific substrates (e.g., unprimed
substrates such as β-catenin and axin) but not substrates
requiring pre-phosphorylation, such as glycogen syn-
thase, thus being specific for the Wnt-mediated effects
of this multitalented enzyme (Thomas and others 1999).
This approach may make it possible to discern which
GSK-3β pathway is relevant for the treatment of BD.

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 Lithium and VPA have numerous effects on G-proteins
and second messenger systems with undetermined clini-
cal significance (Gould and Manji 2002; Manji and oth-
ers 1996; Wang and others 1997). These studies make it
clear that lithium does not target only GSK-3β in cells.
It therefore remains to be seen if the effects of lithium
and VPA on the Wnt signaling pathway and GSK-3β are
truly important for the treatment and/or the pathophysi-
ology of BD. The findings presented in this review could
be related to the numerous side effects of these medica-
tions. However, the putative roles are intriguing and sug-
gest that future research into the role of the Wnt pathway
in BD could provide valuable clues both for understand-
ing the underlying pathophysiology of the disorder and
for developing valuable potential therapies.
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