Special Issue: Neuropsychiatric Disorders

Mood-stabilizing drugs: mechanisms

of action
Robert J. Schloesser
1
, Keri Martinowich
2
and Husseini K. Manji
3
1
Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA
2
Laboratory of Molecular Pathophysiology, National Institute of Mental Health, Bethesda, MD, USA
3
Johnson & Johnson Pharmaceutical Research and Development, Titusville, NJ, USA
Mood-stabilizing drugs are the most widely prescribed
pharmacological treatments for bipolar disorder, a dis-
ease characterized by recurrent episodes of mania and
depression. Despite extensive clinical utilization, signi-
cant questions concerning their mechanisms of action
remain. In recent years, a diverse set of molecular and
cellular targets of these drugs has been identied. Based
on these ndings, downstream effects on neural and
synaptic plasticity within key circuits have been pro-
posed. Here, we discuss recent data, identify current
challenges impeding progress and dene areas for future
investigation. Further understanding of the primary tar-
gets and downstream levels of convergence of mood-
stabilizing drugs will guide development of novel thera-
peutic strategies and help translate discoveries into
more effective treatments with less burdensome ad-
verse-effect proles.
Introduction
Signicant questions remain in understanding the neuro-
biological mechanisms underlying bipolar disorder. Bipo-
lar disorder pathophysiology is thought to arise from
interactions between genetic risk factors and environmen-
tal inuences, which include exposure to adverse childhood
experiences, chronic stress and trauma. As with other
major neuropsychiatric disorders, a neurodevelopmental
component probably contributes to disease pathophysiolo-
gy. A prominent theory suggests that bipolar disorder
arises from alterations in neural and synaptic plasticity
[1]. Neuroplastic changes that occur during critical devel-
opmental windows may contribute to structural and func-
tional changes in key circuits, which can have long-lasting
effects on adult brain function. Underlying decits in
plasticity may be aggravated or unmasked later in life
by exposure to stressful events, a key risk factor in mood
disorder development [2]. The theory that alterations in
neural and synaptic plasticity contribute to disease pathol-
ogy is supported by reports of structural and functional
changes in both neuroimaging and postmortem studies of
individuals with bipolar disorder [3].
The most important pharmacological treatments for
patients with bipolar disorder are mood-stabilizing drugs,
which comprise a diverse group of compounds, including
lithium salts as well as the anticonvulsants valproate,
carbamazepine and lamotrigine. All mood stabilizers ame-
liorate symptoms of mania and some (e.g. lithium and
lamotrigine) have documented antidepressant properties
[46]. Most importantly, mood stabilizers decrease episode
recurrence (phase prophylaxis) and lithium decreases sui-
cide risk [7] Use of lithium as a successful treatment for
bipolar treatment was rst publishedin1949[8], but didnot
gainUSFoodandDrug Administrationapproval until 1970.
Several medications developed for other indications (e.g.
anticonvulsants for epilepsy or antipsychotics for schizo-
phrenia) were subsequently approved for bipolar disorder
treatment, but no novel medications have been introduced
specically for bipolar disorder since the introduction of
lithium over 60 years ago. By providing an efcacious
treatment for millions of patients, lithium therapy was a
signicant breakthrough in neuropsychopharmacology.
However, lithium monotherapy is often insufcient, and a
majority of patients require combination therapy [9,10].
Approval of a variety of additional pharmacological treat-
ments, including the anticonvulsants discussed above, as
well as numerous atypical antipsychotic agents, has in-
creased the chances of identifying a successful combination
therapy. Despite these advances, current treatment options
are less thanadequate intreating many facets of the illness.
In addition, many patients cannot tolerate the adverse-
effect proles of existing therapies (e.g. changes in weight
andappetite, tremor, blurredvision, dizziness, etc.), leading
to frequent medication changes and high rates of non-ad-
herence [11]. Hence, there is a critical unmet need for new
treatments with greater efcacy, faster onset and better
tolerability. A more thorough understanding of bipolar dis-
order pathophysiology, as well as the molecular-, cellular-
and systems-level mechanisms mediating the effects of
currently utilized treatments, will facilitate development
of novel therapeutics.
Overview of bipolar disorder
Bipolar disorder is common, with approximately 1% of the
populationaffected[1214]. The disorder is characterizedby
the Diagnostic and Statistical Manual of Mental Disorders
(DSM)-IV as severe bouts of recurring mania and depres-
sion. Up to 5% of the population falls under either the
diagnostic category of bipolar II disorder [12], which is
characterizedby severe bouts of depressionand hypomania,
or a bipolar spectrum disorder, including cyclothymic
Review
Corresponding author: Manji, H.K. ([email protected]).
Keywords: bipolar disorder; mood-stabilizing drugs; neurotrophic factors; synaptic
plasticity; mania; lithium.
36 0166-2236/$ see front matter 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.tins.2011.11.009 Trends in Neurosciences, January 2012, Vol. 35, No. 1
disorder. Although patients with bipolar disorder II have
milder manic episodes (hypomania), their disease is not
considered less serious. Cyclothymic disorder is character-
ized by less extreme mood uctuations that range frommild
depressionto hypomania. Bipolar disorder is amajor, world-
wide health problem with devastating consequences for
affected individuals, their families and society. The poor
prognosis of these patients is illustrated by high rates of
relapse, lingering residual symptoms, cognitive impair-
ments and diminished quality of life [15,16]. Patients with
bipolar disorder are prone to coexisting medical conditions,
including cardiovascular disease, diabetes mellitus and
thyroid dysfunction [1720]. Underscoring severity, it is
estimated that patients with bipolar disorder I have a 5
17-fold higher suicide rate than the general population [21].
Symptoms of bipolar disorder I typically commence in
young adulthood. Patients cycle between states of mania or
depression interspersed with symptom-free intervals of
variable length. Mania is characterized by increased irrita-
bility, hyperactivity, euphoric and/or delusional thinking,
promiscuity, heightened risk-taking, decreased sleep, de-
creasedneedfor sleepand, insome patients, is accompanied
by psychosis. During depressive episodes, patients experi-
ence feelings of hopelessness, guilt, decreased libido, suicid-
al thoughts and decreased ability to experience reward and
happiness. The process of switching betweenopposing mood
states is a core feature of bipolar disorder, which uniquely
distinguishes it from other neuropsychiatric disorders with
which it shares many common symptoms (e.g. depressed
mood, sleep disturbances, anxiety, and changes in weight
andappetite) (Box1). Inadditiontodistinct periods of mania
or depression, some patients experience mixed states. A
subset of patients with either bipolar disorder I or II show
rapid cycling, which is dened as more than four episodes of
either mania or depression within 1 year. In untreated
patients, the disease typically worsens owing to cycle accel-
eration; the frequency of episodes increases owing to short-
ening of the lengthof symptom-free intervals. Individuals in
episode-free intervals were classically described as in resti-
tutio ad integrum, but this viewhas been challenged in light
of credible evidence that an increase in the number of
episodes correlates with decreased cognitive abilities and
decits in social functioning.
Mechanisms of action of mood-stabilizing drugs
Synaptic plasticity and neurotransmission
Historical perspectives postulated that mood disorders
arise from ionic shifts and changes in membrane perme-
ability, which led to direct impairments in neural excit-
ability and transmission [13]. Given that lithium was one
of the few options for successful treatment of bipolar
disorder treatment, numerous studies investigated its
effects on neurotransmitter chemistry. Early studies docu-
mented effects of lithium on many neurotransmitter and
neuromodulator systems, including the monoaminergic,
serotonergic, cholinergic and GABAergic systems [22
24]. One of the prevailing hypotheses speculated that
lithiuminterfered with the sodiumpotassiumelectrogenic
pump, and that the direct effects of this alteration on
synaptic transmission led to the observed secondary effects
in specic neurotransmitter systems [25,26].
More recent evidence suggests that mood disorders,
including bipolar disorder, affect intracellular signaling
cascades that lead to impairments in structural and func-
tional neural plasticity as well as alterations in glutama-
tergic neurotransmission [2,27]. Glutamate, the most
abundant excitatory neurotransmitter, is integral for syn-
aptic transmission in brain circuitry, and is a key regulator
of synaptic strength and plasticity, which play major roles
in the neurobiology of learning, memory and general cog-
nition [28]. Altered glutamate levels in plasma, serum and
cerebrospinal uid have been observed in human studies of
individuals with mood disorders [29]. Moreover, NMR
spectroscopy studies have shown altered levels of gluta-
mate and related metabolites in diverse brain regions of
patients with bipolar disorder [29].
Accumulating evidence indicates that lithiumhas direct
effects on glutamatergic neural transmission. In particu-
lar, several lines of evidence suggest that lithium alters
neuronal excitability at hippocampal CA1 synapses, lead-
ing to enhanced excitatory postsynaptic potentials [3033]
(Figure 1a,c). The ability of lithium to enhance synaptic
transmission in hippocampal CA1 has been attributed to
an increase in presynaptic excitability as well as increases
in synaptic efciency. A recent report has also shown that
its effect on synaptic enhancement at CA1 synapses may
arise from its ability to potentiate currents through the
AMPA subtype of ionotropic glutamate receptors by selec-
tively increasing the probability of channel opening [34].
These effects on hippocampal synaptic transmission may
be of particular relevance for mood disorder treatment
because the hippocampus is a key component of the limbic
systemnetwork, and is implicated in emotional regulation,
cognition and memory. Hence, dysfunctional hippocampal
signaling may contribute to behavioral disturbances in
mood disorders, a hypothesis further supported by consis-
tent ndings of declarative memory decits in patients
with mood disorders [3537]. As the last relay in the
Box 1. The switch process in bipolar disorder
The phenomenon of switching between the polarities of depression
and mania or hypomania, singularly distinguishes bipolar disorder
from other neuropsychiatric disorders. Hence, understanding this
process is critical for a full understanding of bipolar disorder
pathophysiology. Switching from a depressive to a manic state can
occur spontaneously, but can also be influenced by exposure to
stress and sleep deprivation as well as illicit drug use [125]. In
addition, electroconvulsive therapy, antipsychotics and some anti-
depressant therapies can induce switching [125]. Individual genet-
ics, especially in genes that regulate monoaminergic transmission
and circadian rhythms, may also influence predisposition towards
state switching [126,127]. Understanding these processes is im-
portant because individuals with patterns of switching have a
poorer clinical outlook and carry greater risk for substance abuse
and suicide [125,128,129].
Lack of knowledge about state switching has contributed to delays
in research progress because the cyclic nature presents an extreme
challenge for rodent modeling. Although considerable caution needs
to be taken in applying animal models to complex neuropsychiatric
disorders, they are invaluable tools for exploring underlying cellular
and molecular biology. Most animal models that have been used for
bipolar disorder research have focused on either mania or depres-
sion, rather than modeling both behaviors within the same individual
[14]. Understanding the biology underlying the switch process could
allow for modeling induction of different states, which would be an
invaluable tool for the development of new therapeutics.
Review Trends in Neurosciences January 2012, Vol. 35, No. 1
37

CA1
DG
CA3
(a)
(c) CA3CA1 synaptic plasticity
(b) CA1-subicular output
(d) Cellular morphology changes
(e) Hippocampal
neurogenesis
CA3 pyramidal cell
CA1 pyramidal cell


Hilar
interneuron
Subgranular zone
Dentate granule cell
(c)
presynapse postsynapse
Glu
BDNF
NMDAR
TrkB
mGluR
AMPAR
CA1 pyramidal
cell dendrite
CA3 pyramidal
cell axon
L
ithium treatm
e
n
t
S
t
r
e
s
s
/
g
lu
cocorticoi d
s
(d) CA3 pyramidal cell
remodeling
(e)
Progenitor cell
Migrating
neuroblast
Mature
granule cell
Postmitotic Proliferation
(b)
CA1
CA3
mPFC
Amygdala
Striatum
Hypothalamus
DG
S
ubiculum
M
ossy fiber pathway
M
a
tu
ration/differentia
tio
n
S
c
h
a
f
f
e
r

c
o
l
l
a
t
e
r
a
l
s
TRENDS in Neurosciences
Figure 1. Roles of the hippocampal trisynaptic circuit in bipolar disorder and therapeutic mechanisms of mood-stabilizer action. (a) The trisynaptic circuit comprises the
dentate gyrus (DG, blue), which is also the site of the subgranular zone (SGZ), one of the two germinal zones of the brain that retains ongoing neurogenesis throughout life.
DG cells (green) are glutamatergic cells whose axons form the mossy fiber pathway, which projects into the CA3 regions. DG cells synapse onto both glutamatergic CA3
pyramidal cells as well as GABAergic interneurons that reside in CA3. CA3 pyramidal cells project axons that form the Schaffer collaterals, synapsing onto CA1 pyramidal
cells. CA1 pyramidal cells provide the major output of the hippocampal circuit, which is to the subiculum. (b) Control of hippocampal output via the subiculum. The main
output of the hippocampus is the subiculum, which in turn sends major projections to both cortical and subcortical targets. Projections to the medial prefrontal cortex
(mPFC), amygdala, striatum and hypothalamus are of primary interest in relation to functional roles of the hippocampus in stress-related disorders and in mood-stabilizer
treatment. (c) Mood stabilizer-induced changes in hippocampal strength and synaptic plasticity. Lithium increases presynaptic excitability as well as synaptic efficiency at
hippocampal CA1 synapses, leading to enhancement of excitatory postsynaptic potentials [3033]. The effects of lithium on synaptic enhancement at CA1 synapses may
arise from its ability to potentiate currents through the AMPA subtype of ionotropic glutamate receptors by selectively increasing the probability of channel opening [34].
Lithium and valproate have documented effects on increasing levels of the neurotrophin brain-derived neurotrophic factor (BDNF) [4347], which is also implicated in
certain forms of long-term potentiation (LTP) at the CA3CA1 synapse [52]. (d) Cellular remodeling in response to stress and mood-stabilizer treatment. Exposure to stress
and excessive glucocorticoids leads to dendritic retraction and induction of apoptotic cell signaling [91]. Lithium treatment prevents and/or reverses stress-induced
hippocampal dendritic atrophy of hippocampal principal cells [88]. In patients with bipolar disorder, volume is decreased in hippocampal subfields, whereas chronic lithium
treatment leads to an increase [7680]. (e) Effects of mood stabilizers on adult hippocampal neurogenesis and potential roles in therapeutic response. Adult neurogenesis
encompasses the proliferation of progenitor cells as well as their subsequent differentiation, maturation and integration into the existing hippocampal circuitry. Newly born
granule cells project axons into the hilus, where they synapse primarily with interneurons or into the CA3 subfield. Mood stabilizers have documented effects on increasing
rates of adult neurogenesis [5961]. Adult neurogenesis contributes to normal hippocampal function, including the ability of the hippocampus to provide negative feedback
regulation over the HPA axis [6466].
Review
Trends in Neurosciences January 2012, Vol. 35, No. 1
38
tripartite hippocampal circuit, alterations in synaptic plas-
ticity in CA1 pyramidal neurons could effect changes in
hippocampal and/or subicular modulation of several key
target structures, including the prefrontal cortex (PFC),
amygdala and striatum, as well as hippocampal control
over hypothalamic endocrine regulation (Figure 1a,b). This
is particularly interesting in light of prominent theories
suggesting that dysfunction in the neural circuit linking
the hippocampus, PFCand anterior cingulate cortex (ACC)
are tightly linked to the affective and cognitive abnormali-
ties seen in mood disorders [38] (Figure 3).
Direct effects on neural transmission have also been
documented for mood stabilizers classied as anticonvul-
sants. Valproate decreases high-frequency action potential
ring by enhancing inactivation of voltage-gated sodium
channels and indirectly enhances GABAergic function [39].
Lamotrigine blocks both voltage-gated sodium channels
and L-type calciumchannels, which can lead to substantial
effects on baseline neurotransmission [40]. In addition,
both valproate and lamotrigine upregulate excitatory ami-
no acid transporter activity, leading to enhanced gluta-
mate clearance [41,42]. Hence, these mood stabilizers may
indirectly inuence excitatory neurotransmission by mod-
ulating the rate of glutamate uptake.
Intracellular signaling cascades
Studies over the past 15 years have led to the hypothesis
that mood disorders may not only be attributable to direct
cellular impairments in neural excitability and transmis-
sion, but also to impairments in cellular signaling cascades
that mediate structural and functional changes in neural
and synaptic plasticity. Preclinical studies have pointed to
decits in intracellular signaling cascades associated with
cell survival, growth and metabolism. As such, recent stud-
ies have attempted to identify common effects of chemically
divergent mood stabilizers with the intent of elucidating
functional targets of efcacious treatment response.
Both preclinical and clinical studies have suggested that
lithium exerts neurotrophic and neuroprotective effects,
and recent research has identied specic roles for lithium
inactivating relevant intracellular signaling cascades. Lith-
ium leads to upregulation of the neurotrophin, brain-de-
rived neurotrophic factor (BDNF) [4347] as well as the
neuroprotective protein, B-cell lymphoma/leukemia-2 (Bcl-
2) [48,49]. It has been suggested that diminished levels of
Bcl-2 contribute to ndings of reduced hippocampal pyra-
midal cell size [50], and decreasedlevels of BDNFhave been
identied in bipolar disorder [51]. In addition to its neuro-
trophic effects, BDNFplays a key role inregulating synaptic
plasticity and, in particular, is required for specic forms of
long-termpotentiation at the CA3CA1 synapse (Figure 1c)
[52]. Enhanced Bcl-2 expression counteracts deleterious
effects of stress on neurons, suggesting that its pharmaco-
logical inductionhas utility incases of compromised cellular
resiliency. In addition to antagonizing cell-death signaling,
Bcl-2 stimulates axonal regeneration following trauma [53].
At the cellular level, Bcl-2 plays a key role in controlling
intracellular calcium dynamics, which is of special interest
because impaired calcium signaling regulation has been
repeatedly recognized as a cellular abnormality in bipolar
disorder [54]. Interestingly, intracellular calcium signaling
alsoplays animportant regulatoryroleinsynaptic plasticity
cascades, including mediating activity-dependent tran-
scription of BDNF [55]. A single nucleotide polymorphism
in the Bcl-2 gene (rs956572) is associated with increased
bipolar disorder risk, and is functionally linked to: (i) re-
duced Bcl-2 expression in human lymphoblasts; and (ii)
decreased gray matter volume in the ventral striatum, an
areaimplicatedinthe neurobiologyof rewardandemotional
processing [56]. Further supporting a role for Bcl-2 function
in bipolar disorder, this polymorphism signicantly affects
intracellular calcium homeostasis via regulation of endo-
plasmic reticulum release in lymphoblasts derived from
patients with bipolar disorder [57,58].
Recent evidence, which may be relevant for the clinical
effects of lithium, showed that it promotes neurite out-
growth and stimulates adult hippocampal neurogenesis in
rodents [5961]. Given that newborn neurons integrate
into the existing circuitry, where they display enhanced
plasticity in behaviorally relevant circuits [62,63], this
could be signicant for hippocampal function in mood
regulation (Figure 1a,e). It has been reported that hippo-
campal neurogenesis contributes to negative feedback reg-
ulation of the hypothalamicpituitaryadrenal (HPA) axis
[64,65]. Supporting the view that newborn neurons may be
involved in HPA axis feedback regulation, these cells
contribute to the antidepressant-induced improvement
in stress integration [66]. Thus, in a depressive state,
facilitating hippocampal neurogenesis may restore proper
control over the stress response system. This is particular-
ly interesting because there is robust evidence of HPA axis
abnormalities in bipolar disorder (discussed below).
Several enzymes havebeenshownto bedirectlyinhibited
by lithium at therapeutically relevant concentrations [14].
These include inositol monophosphatase (IMPase); inositol
polyphosphate a-phosphatase; bisphosphate 3
0
-nucleotid-
ase; fructose 1,6-bisphophatase; glycogen synthase kinase
3 (GSK3) and phosphoglucomutase [6769]. Evidence from
numerous studies has also implicated protein kinase C
(PKC) inbipolar disorder pathophysiology, andbothlithium
and valproate decrease PKC levels as well as PKC activity.
Lithium interacts with the phosphoinositolPKC pathway
through inhibition of IMPase, which results in decreased
free myo-inositol and production of diacylglycerol. These
actions converge to result in decreased PKC levels and
enzyme activity [70]. Valproate also results in decreased
PKClevels andactivity, but the mechanismby whichit does
so is distinct fromthat of lithium[71]. The reader is directed
to other sources for a more thorough discussion of the
extensive literatures on these topics [13,14].
Pinpointing levels of convergence
Structurefunction alterations in bipolar disorder and
effects of mood stabilizers
In vivo human studies reporting decreased gray matter
volumes in bipolar disorder that are either attenuated
or increased by lithium treatment have provided strong
support for its neuroprotective and neurotrophic effects
[7286] (Figure 2). Although consistent evidence of de-
creased hippocampal volume was identied in major de-
pressive disorder, initial studies suggested no differences
in bipolar disorder [87]. However, using a ne-mapping
Review Trends in Neurosciences January 2012, Vol. 35, No. 1
39

Lithium-induced volumetric changes

Cortical (gray matter) [72, 73, 74, 75, 76]
Brain region Refs
Cortical (ROI) [76, 82, 83, 84, 85, 86]
Hippocampus [76, 77, 78, 79, 80]
Amygdala [76, 78, 81]
(a) (b) (i)
(ii)
(d)
(c)
(e)
7.0
6.5
6.0
5.5
5.0
5.5
5.0
4.5
4.0
3.5
Healthy subjects (n = 298)
Healthy subjects (n = 255)
Bipolar not on lithium (n = 85)
T
o
t
a
l

a
m
y
g
d
a
l
a

v
o
l
u
m
e

(
m
l
)
T
o
t
a
l

h
i
p
p
o
c
a
m
p
a
l


v
o
l
u
m
e
(
m
m
3
)
Bipolar not on lithium (n = 111)
Bipolar on lithium (n = 100)
Bipolar on lithium (n = 104)
X = -3
Significance
Significance
(i)
Cortical GMD differences as a function of lithium treatment
Bipolar Li+ versus controls
Bipolar Li-versus controls
<0.01
<0.01
0.05
0.05
(ii)
>0.1
>0.1
Y = 31
C.C.
p < 0.001
p < 0.05
350
300
250
200
150
100
50
0
Controls
n = 21
L
e
f
t

s
u
b
g
e
n
u
a
l

v
o
l
u
m
e

(
m
m
3
)
Bipolar off
chronic Li/VPA
n = 15
Bipolar on
chronic Li/VPA
n = 6
MDD
n = 21
-5.5 -2.8 0
t-Value
Subgenual PFC
TRENDS in Neurosciences
Figure 2. Neuroimaging studies in bipolar disorder. (a) Predicted volumetric changes in the hippocampus (i) and amygdala (ii) for healthy subjects, individuals with bipolar
disorder not on lithium therapy, and individuals with bipolar disorder on lithium therapy, in an international collaborative mega-analysis of adult patient data [72]. Mean
predicted volumes are presented from linear mixed models while adjusting for gender, research center and age. Highly significant differences between the three groups are
present for both hippocampus (F = 11.32, P = 0.0001) and amygdala (F = 8.904, P = 0.0002). Individuals with bipolar disorder on lithium show greater volumes compared
with both those not on lithium [hippocampus (F = 9.53, P = 0.002)] [amygdala (F = 6.33, P = 0.013)] and healthy subjects [hippocampus (F = 12.96, P = 0.0004)] [amygdala
(F = 10.97, P = 0.001)]. Healthy subjects show greater mean volumes than individuals with bipolar disorder not on lithium [hippocampus (F = 7.81, P = 0.005)] [amygdala
(F = 5.13, P = 0.024)]. (b) Cortical gray matter differences (GMD) as a function of lithium treatment. (i) Differences in gray matter volume in patients treated with lithium only
(Li+; n = 20) versus control subjects (n = 28). Widespread areas of gray matter concentration can be observed across the cortex. Differences are particularly striking in the left
cingulated and paralimbic association cortices and bilaterally in the visual association cortex. (ii) No significant differences were observed in this study in gray matter
densities between patients who were not taking lithium (Li; n = 8) and control subjects. (c) Gray matter volume in the subgenual prefrontal cortex (PFC) [i.e. anterior
cingulated cortex (ACC) ventral to the genu of the corpus callosum] was found to be abnormally reduced in patients with bipolar disorder or major depressive disorder
(MDD) compared with control subjects [85]. Demonstration of this effect was made by acquisition of magnetic resonance imaging-based morphometric measures that were
guided by positron emission tomography (PET) images showing a reduction of cerebral blood flow and glucose metabolism in the subgenual area of the PFC. Voxel by
voxel analysis of neurophysiological data from depressed versus control subjects was used to localize the differential activity more specifically to the subgenual PFC. (d)
Subgenual PFC volumes of patients with bipolar disorder or MDD are decreased compared with control subjects. However, bipolar individuals treated with lithium (Li) or
valproic acid (VPA) are comparable to control subjects. (e) Lithium-induced volumetric changes. This table provides selected references that compare volumetric changes in
response to lithium treatment in patients with bipolar disorder not on lithium treatment versus those on lithium therapy versus healthy controls. Meta-analyses are denoted
in bold. Abbreviation: ROI, region of interest. Reproduced, with permission, from [76] (a), [82] (b) and [89] (c); modified, with permission, from [83] (d).
Review
Trends in Neurosciences January 2012, Vol. 35, No. 1
40
three-dimensional technique, a recent study discerned
structural abnormalities in patients with bipolar disorder
that roughly correspond to the hippocampal CA1 subelds
[79]. Several additional reports and meta-analyses have
documented increased total hippocampal volume in
patients treated with lithium compared with unmedicated
patients [7678,80]. In line with these ndings, it is inter-
esting that lithium treatment reverses hippocampal den-
dritic atrophy induced in an animal model of chronic stress
[88] (Figure 1d). Ina recent mega-analysis to systematically
identify regional volumetric decits and effects of lithium
administration in bipolar disorder, pooled imaging data
showed cerebral volume reductions that were signicantly
associated with illness duration. Individuals with bipolar
disorder who were not on lithium therapy showed signi-
cant decrease in cerebral and hippocampal volumes, where-
as patients treated with lithium showed signicantly
increased hippocampal and amygdala volumes [76]. Data
onamygdala volumes inpatients withbipolar disorder have
been conicting, but recent studies using high-resolution
magnetic imaging resonance (MRI) have convincingly
shown that amygdala volume is smaller in unmedicated
patients with bipolar disorder and larger in patients
with bipolar disorder on mood-stabilizer treatment [81].
Together with data in the above-referenced mega-analysis,
it appears that lithium does have trophic effects in the
amygdala [76,81]. Prominent volumetric abnormalities
have been reported in bipolar disorder in the ACC
[83,89,90], and chronic treatment with lithium or valproic
acid has been associated with increased gray matter
volumes in this region [82,83]. Preclinical studies showing
that lithium and valproate increase the expression of mole-
cules involved in synaptic plasticity, cytoskeleton remodel-
ing and cellular resilience may explain why these imaging
studies have found increased volumes in patients with
lithium-treated bipolar disorder [3,91]. Hence, the existent
data point to neurotrophic and neuroprotective actions of
lithium in multiple areas of the limbic and/or prefrontal
network by increasing cellular resiliency, enhancing synap-
tic plasticity and modulating neuronal morphology.
Functional neuroimaging studies have been invaluable
in identifying putative misregulated brain circuits in mood
disorders. Combined with data from structural and volu-
metric studies, researchers have identied key brain
regions within limbic, striatal and PFC loops that are
thought to underlie cognitive and behavioral manifesta-
tions. These regions include the amygdala and related
limbic structures, ACC, orbital and medial PFCs, ventro-

Medial prefrontal cortex

Anterior cingulate cortex
Thalamus
Orbifrontal cortex
Hypothalamuspituitary
Hippocampus
Amygdala
() Regulation of emotion and assessment of
consequence in decision-making; extensive
connections with limbic areas, including
hippocampus and amygdala
(#) Altered CBF and glucose
metabolism in primary depression [3,90]
() Sensory relay,
extensive connections
with limbic system and
mood-related circuitry
(#) Depressed individuals
with MDD and BD show
increased metabolism and
CBF in the mediodorsal
nucleus of the thalamus [3]
() Learning, memory and
cognition; site of ongoing adult
neurogenesis; negative
regulation over HPA axis
(#) Reduction in gray matter
volume in patients with BD,
with increased volumes in
such patients on lithium
treatment [7680]; decreased
number of synapses and
synaptic proteins; declarative
memory deficits [3537]
() Evaluation of experience/stimuli
with strong emotional valence,
acquisition and expression of
emotionally related memories
(#) Decreased volumes in patients with
BD, with increased volumes in such
patients on lithium treatment [76,78,81],
elevated resting CBF and glucose
metabolism [3,90]
() Links nervous system to endocrine system;
synthesizes and secretes, neurohormones, including
corticotropin-releasing hormone, an important
component of the stress system; key structure in
controlling HPA axis function
(#) Hypercortisolemia, HPA axis abnormalities
() Integration of multi-modal stimuli and
assessment of stimulus value and/or
reward, extinction of unreinforced responses
to stimuli [3,90]
(#) Volume reductions, increased metabolism [90]
() This region has extensive connections
with brain structures implicated in the
modulation of emotional behavior, and
participates as part of this extended
network in emotional processing and
regulation of autonomic response
(#) Reduction in gray matter volume in MDD
and BD [89,90], although not seen in these
studies [76,82], gray matter volumetric
increases in patients with lithium-treated
bipolar disorder [82,83], but not evidenced
in this analysis [76], alterations in metabolic
activity [3,8990], decreased glial cell density
[83,90], altered glutamate levels [29]
TRENDS in Neurosciences
Figure 3. Prefrontallimbic system circuitry important in mood disorders. Circuitry connecting key brain regions, including the prefrontal cortex, amygdala, hippocampus
and hypothalamicpituitary endocrine system, that are believed to be important in mood disorders and are probably targeted by mood-stabilizing drugs. (*) Basic functions
of each individual region as well as (#) pertinent findings in mood disorders or mood-stabilizing drug mechanisms of action are described. Abbreviations: BD, bipolar
disorder; CBF, cerebral blood flow; HPA, hypothalamicpituitaryadrenal axis; MDD, major depressive disorder.
Review Trends in Neurosciences January 2012, Vol. 35, No. 1
41
medial striatum, the medial thalamus and related regions
of the basal ganglia [3,90] (Figure 3). As opposed to a
localized lesion in an isolated region, disrupted signaling
within interconnected circuits is thought to result in dis-
ease susceptibility and behavioral manifestation of mood
disorder symptoms (see [3,90,92] for more details).
Intersection with the glucocorticoid system and affective
resilience
Increasing evidence suggests that limbic system abnormal-
ities intersect with disturbances in glucocorticoid signaling
in mood disorders. Rates of hippocampal neurogenesis are
negatively affected by increased levels of circulating gluco-
corticoids and chronic stress [93,94]. Conversely, recent
evidence suggests that adult hippocampal neurogenesis
plays a role in regulating the stress response system
[6466]. This is of considerable interest in light of: (i) the
structural and volumetric decits in the hippocampus of
unmedicated patients with bipolar disorder (Figure 2); and
(ii) the effects of lithium on hippocampal circuitry and
neurogenesis (Figure 1c,d,e). Changes inHPAaxis feedback
regulation are one of the most robust biological abnormali-
ties observed in affective disorders [9598] (Box 2).
Moreover, the subtypes of depression most frequently asso-
ciated with HPAaxis hyperactivation are the most likely to
be associatedwithhippocampal volume reductions [99,100].
The functional importance of these disturbances is
highlighted by studies showing that normalization of
HPA axis activity parallels remission from depressive epi-
sodes and reduces relapse [101104]. Furthermore, chronic
treatment with lithiumand valproate can enhance recovery
from both the depressive and manic episodes associated
with exogenous or endogenous (i.e. Cushings disease)
elevations of glucocorticoids [91]. Importantly, it has been
demonstrated that lithium and valproic acid (VPA) elevate
levels of the bcl-2-associated athanogene, BAG-1, a co-
chaperone protein that inhibits glucocorticoid receptor
(GR) activation [49]. Together, the available data suggest
that interactions between GR and BAG1 counteract delete-
rious effects of hypercortisolemia in bipolar disorder and
Box 2. HPA axis and glucocorticoid receptor signaling in bipolar disorder
The glucocorticoid cortisol, which is released from the adrenal gland,
is the end product of the HPA axis, which comprises the hypothala-
mus, pituitary gland and adrenal cortices (Figure I). Neurosecretory
cells within the paraventricular nucleus of the hypothalamus secrete
corticotropin-releasing hormone (CRH) and arginine vasopressin
(AVP) into the circulatory system of the pituitary. This causes release
of adrenocorticotropic hormone (ACTH) from the anterior lobe of the
pituitary, which leads to cortisol release from the adrenals. Cortisol
has numerous cellular effects, which are mediated via the GR and the
mineralocorticoid receptor (MR).
The hippocampus regulates the endocrine system stress system by
modulating hypothalamic paraventricular nucleus activity. Chronic
dysregulation of the HPA axis in response to stress is associated with
impaired glucocorticoid function and inhibition of negative feedback
via the GR [130]. Importantly, reduced levels of GR have been observed
in patients with bipolar disorder or depression. Considerable evidence
shows that stress exposure is associated with mood disorder develop-
ment. Dysregulated HPA axis activation probably plays a key role in
mood disorder development because stress-induced neuronal atrophy
is prevented by adrenalectomy [99,100]. This is noteworthy given that a
significant percentage of patients with mood disorders display some
manifestations of HPA axis dysfunction, and patients with HPA axis
dysfunction are most likely to be associated with volumetric reductions
in the hippocampus [3,99,100]. A significant effect of long-term
exposure to excessive glucocorticoids is a reduction in cellular
resiliency, rendering neurons more vulnerable to other noxious insults,
including excitotoxicity and oxidative stress [3,91,131]. Whether
varying intracellular signaling cascades, particularly those associated
with neuroprotective and neurotrophic signaling cascades, within the
stress response system can provide resiliency or attenuate suscept-
ibility to stressful stimuli remains an open question. Ongoing and
future studies aimed at targeting BAG-1, which mediates GR trafficking,
may help to determine whether these interventions can provide
resiliency from GR-related stress effects [91].
Hypothalamus
CRH
ACTH
AVP
GRs
GRs
Anterior pituitary
Adrenal cortex
Cortisol/
corticosterone
Hippocampus
MRs and GRs
TRENDS in Neurosciences
Figure I. The response to stress includes activation of the hypothalamicpituitary
adrenal (HPA) axis. Activation of the HPA axis leads to corticotrophin-releasing
hormone (CRH) and arginine vasopressin (AVP) production in the paraventricular
nucleus of the hypothalamus. These hormones are released into the bloodstream,
leading to secretion of adrenocorticotrophic hormone (ACTH) from the anterior
pituitary. ACTH stimulates the synthesis and release of glucocorticoids (cortisol in
humans, corticosterone in rodents) from the adrenal cortex into the bloodstream.
Cellular effects of glucocorticoids are mediated via glucocorticoid receptor (GRs)
and mineralocorticoid receptor (MRs). Regulatory control over the HPA axis is
mediated via negative feedback loops at the level of the pituitary as well as from
other regions of the brain, including the hippocampus.
Review
Trends in Neurosciences January 2012, Vol. 35, No. 1
42
contribute to affective resilience [91]. As such, treatments
aimed at direct modulation of this pathway are the focus of
considerable research interest [105], and efforts to identify
therapeutics that enhance hippocampal neurogenesis may
have utility in promoting glucocorticoid-related affective
resilience. The ndings pertaining to glucocorticoid regula-
tion are particularly noteworthy because: (i) glucocorticoids
represent one of the few agents capable of inducing both
manic and depressive episodes in susceptible individuals;
and(ii) glucocorticoids playimportant roles inmediatingthe
stress response as well as modulating cellular and affective
resilience (reviewed in [91]).
New strategies and novel therapeutics
A major treatment goal is prophylaxis, decreasing the
episode severity and increasing the inter-episode interval.
Despite treatment, a signicant number of patients expe-
rience recurrent episodes. The onset of crippling depres-
sions is particularly troublesome because administration
of most currently utilized therapeutics have a lag time to
achieve efcacy; only a fraction of patients meet response
criteria by the end of the rst treatment week [106108].
This leaves patients highly vulnerable to self-harm and
suicide, which is reected by high rates of mortality during
this latency period [109,110]. Thus, it is encouraging that
recent studies have demonstrated that glutamatergic mod-
ulators and brain stimulation paradigms may hold promise
as fast-acting therapeutics [109,111].
Glutamatergic modulators
Growing appreciation of abnormal glutamatergic
signaling in mood disorder pathophysiology has pointed
to glutamatergic modulators as promising areas for re-
search development. As such, compounds targeting gluta-
mate release, ionotropic glutamate receptors and
glutamate transporters are under study. Initial studies
identifying fast-acting antidepressant properties for keta-
mine, a non-competitive, high-afnity NMDA receptor
antagonist, generated signicant interest. In vitro, keta-
mine increases glutamatergic neuron ring rate and pre-
synaptic glutamate release [112], effects that are thought
to contribute to its robust and rapid antidepressive effects
[111]. Adding substantial proof-of-concept validation to
earlier clinical studies [113115], a recent double-blind
placebo controlled study on patients with treatment-resis-
tant bipolar disorder replicated the robust, fast-acting
antidepressant response of ketamine [115]. Preclinical
studies have suggested that the antidepressant effects of
ketamine are mediated by enhanced AMPA receptor activ-
ity. Enhanced glutamatergic signaling via AMPAreceptors
is thought to occur as a result of increased extracellular
glutamate, which preferentially favors signaling via
AMPA receptors owing to NMDA receptor blockade
[112,116]. Subsequent studies in rodents have demonstrat-
ed that the mammalian target of rapamycin (mTOR) sig-
naling pathway [117] is involved in mediating the fast-
acting antidepressant effects of ketamine, and this is
dependent on rapid translation of BDNF via deactivation
of the eukaryotic elongation factor 2 (eEF2) [118] (see also
[119] in this Issue). Despite these encouraging results,
long-term efcacy and safety remain to be addressed. A
full elucidation of the molecular and cellular mechanisms
that underlie the ability of ketamine to mediate both fast-
acting and sustained antidepressive effects is expected to
Box 3. Outstanding questions
What causes the observed volumetric loss in brains of patients
with bipolar disorder, and how is lithium able to rescue these
deficits?
In brain areas of rodents that are homologous to regions where
gray matter reductions have been observed (e.g. ventromedial PFC
and hippocampus), exposure to stress results in dendritic atrophy
and cell loss [91]. Significant dendritic atrophy would result in
decreased neuropil volume, which accounts for a significant
portion of gray matter volume. Studies of rodent models of chronic
stress have suggested that similar processes of stress sensitivity
and glucocorticoid excess underlie the gray matter volume reduc-
tions observed in patients [91]. Other hypotheses have pointed to a
role for abnormal mitochondrial signaling and oxidative stress
leading to apoptotic processes that ultimately result in cell death
[131]. The ability of lithium treatment to increase levels of bcl-2 and
BDNF may counteract or reverse the early stages of apoptotic cell
signaling in the brains of patients with bipolar disorder.
What are the key biological mechanisms underlying the antimanic
and mood-stabilizing effects of diverse mood-stabilizing agents?
Can more efficacious and selective drugs be developed, with
fewer adverse effects? As discussed in the main text, at least some
of the therapeutic effects of mood-stabilizing drugs appear to be
induced by activating neurotrophic and neuroprotective pathways,
and related intracellular signaling pathways. However, it remains a
challenge to make causal associations between these signaling
pathways, which have been identified in animal and cell culture
models, and therapeutic effects observed in patients. Increased
access to patient samples, including postmortem human data,
genome-wide association studies of bipolar disorder and treatment
response groups, new methods of utilizing patient material [i.e.
neurons derived from induced pluripotent stem cells (iPSCs)] and
the ability to cross-integrate these data, will help in testing
hypotheses of mood-stabilizer mechanisms of action.
Can neurophysiological or blood and/or peripheral tissue biomar-
kers be identified to measure or predict treatment response
objectively?
Biomarkers that can reliably aid in diagnosis or indicate success-
ful treatment response are not yet available for bipolar disorder.
The advent and decreasing relative cost of applying new molecular
biology and proteomic techniques, genome-wide sequencing and
functional neuroimaging should aid in the identification of biomar-
kers for diagnosis, as well as in personalized medicine and
treatment with pharmacogenomics. The use of patient lympho-
blasts and iPSCs may allow investigation of the putative signaling
pathways discussed here (i.e. energy metabolism and mitochon-
drial signaling, GSK3 signaling, BDNF, Bcl-2 and calcium signaling),
especially in conjunction with genetic risk alleles that have been
identified for bipolar disorder [132,133].
Can better animal models be developed?
Although considerable caution needs to be taken in applying
animal models to complex neuropsychiatric disorders, they can be
invaluable tools for understanding the underlying pathologies and,
hence, for developing better treatments. An ideal model for bipolar
disorder would include oscillations between depressive-like and
manic behaviors and would be responsive to mood-stabilizer
treatments. The progressive and cyclic nature of bipolar disorder
presents an incredible challenge for modeling in rodents. Indeed,
most models have tended to focus on modeling either mania or
depression, with the majority focusing on stress-related depression
[14]. However, as discussed in Box 1, understanding the nature of
this switch phenomenon may be central to understanding the
disorder and for the development of better treatments.
Review Trends in Neurosciences January 2012, Vol. 35, No. 1
43
be valuable in advancing rational drug development for
future antidepressant agents.
Brain stimulation
Recent strides inunderstandingthemisregulationof critical
neural circuits have raised the prospect of direct, therapeu-
tic targeting by using brain stimulation to promote in vivo
neural plasticity. Non-invasive methods, including tran-
scranial magnetic stimulation and transcranial direct cur-
rent stimulation, as well as an invasive form of deep brain
stimulation (DBS) that targets brain areas via implanted
electrodes, have been proposed [120]. In theory, this stimu-
lation could elicit circuit-level modications that can
improve symptoms. The application of DBS as a successful
therapy in Parkinsons disease [121,122] has led to in-
creased interest in its potential utility for treatment of
severe mood disorders [121,122]. Functional neuroimaging
data coupled with previous lesion data in rodents have been
used to identify putative target regions and neural circuits
that are associated with mood disorders, and exciting pre-
liminary studies targeting the limbiccortical circuit have
shown promise in ameliorating symptoms in treatment-
resistant depression [123,124].
Concluding remarks
A growing body of evidence suggests that neuroplastic
changes at the structural, functional and cellular levels
underlie the misregulation of key circuits that contribute
to bipolar disorder. Changes at the cellular and circuit level
include impairments in neurotrophic and neuroprotective
signaling cascades, altered glutamatergic and glucocorti-
coid signaling and changes in the rates of adult neurogen-
esis. Although several novel interventions and therapies
aimed at targeting neural plasticity and cellular resilience
have been identied, many issues remain (Box 3).
The development of novel mood stabilizers with faster
onset of action, increased efcacy and less burdensome
adverse-effect proles, would have enormous impact on
public health and, as such, it is a priority to move both basic
andclinical studies forward. Vertical movement will require
closer interaction between basic and clinical researchers to
identify targets of neural and synaptic plasticity that can be
used in developing interventions and therapeutics in mood
disorders. A better understanding of mechanisms ranging
from molecules to synapses, to circuits and nally to behav-
ior, will be required to achieve this goal.
Disclosure statement
H.K.M. is a paid employee of Johnson&Johnson Pharma-
ceutical Research and Development.
Acknowledgements
Support was provided by the National Institute of Mental Health
Intramural Research Program. The gures and illustrations were
designed and created by Anne K. Schlosser.
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