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Special Issue: Neuropsychiatric Disorders

Mood-stabilizing drugs: mechanismsof actionRobert J. Schloesser1, Keri Martinowich2 and Husseini K. Manji3

1 Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA2 Laboratory of Molecular Pathophysiology, National Institute of Mental Health, Bethesda, MD, USA3 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, signifi-

cant questions concerning their mechanisms of action

remain. In recent years, a diverse set of molecular andcellular targets of these drugs has been identified. Based

on these findings, 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 define 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 profiles.

Introduction

Significant 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 influences, 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 deficits inplasticity 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 first published in 1949 [8], but did not

gainUS Foodand Drug Administration approvaluntil 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

specifically for bipolar disorder since the introduction of

lithium over 60 years ago. By providing an efficacious

treatment for millions of patients, lithium therapy was a

significant breakthrough in neuropsychopharmacology.

However, lithium monotherapy is often insufficient, 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 than adequate in treating many facets of the illness.

In addition, many patients cannot tolerate the adverse-

effect profiles of existing therapies (e.g. changes in weight

and appetite, tremor, blurred vision, 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 efficacy, 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 characterized by

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

characterized by severe bouts of depression and 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
mailto:[email protected]://dx.doi.org/10.1016/j.tins.2011.11.009http://dx.doi.org/10.1016/j.tins.2011.11.009mailto:[email protected]

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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 fluctuations that range from mild

depression to hypomania. Bipolar disorderis a major, 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 ofrelapse, 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-

creasedneed for sleepand, in some patients, is accompaniedby 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 between opposing 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

and appetite) (Box1).In additionto distinctperiodsof mania

or depression, some patients experience mixed states. A

subset of patients with either bipolar disorder I or II show

rapid cycling, which is defined as more than four episodes of

either mania or depression within 1 year. In untreatedpatients, the disease typically worsens owing to cycle accel-

eration; the frequency of episodes increases owing to short-

ening of the length of symptom-free intervals. Individuals in

episode-free intervals were classically described as inresti-

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

deficits 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

lithium interfered with the sodiumpotassium electrogenic

pump, and that the direct effects of this alteration on

synaptic transmission led to the observed secondary effects

in specific 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 fluid have been observed in human studies ofindividuals 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 lithium has 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 efficiency. A recent report has also shown thatits 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

system network, 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 findings of declarative memory deficits 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 couldallow 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

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[

CA1

DG

CA3

(a)

(c)CA3CA1 synaptic plasticity

(b)CA1-subicular output

(d) Cellular morphology changes

(e) Hippocampalneurogenesis

CA3 pyramidal cell

CA1 pyramidal cell

Hilarinterneuron

Subgranular zone

Dentate granule cell

(c)

presynapse postsynapse

Glu

BDNF

NMDAR

TrkB

mGluR

AMPAR

CA1 pyramidalcell dendrite

CA3 pyramidalcell axon

Lithiumtreatm

en

t

Stress/glucocort icoid

s

(d) CA3 pyramidal cellremodeling

(e)

Progenitor cell

Migratingneuroblast

Maturegranule cell

PostmitoticProliferation

(b)CA1

CA3

mPFC

Amygdala

Striatum

Hypothalamus

DG

Subiculum

Mossyfiberpathway

Maturation/differentiation

Sch

affe

rcoll

ate

rals

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-stabilizertreatment. (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].


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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 linkingthe hippocampus, PFC and 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 classified as anticonvul-

sants. Valproate decreases high-frequency action potential

firing by enhancing inactivation of voltage-gated sodium

channels and indirectly enhances GABAergic function [39].

Lamotrigine blocks both voltage-gated sodium channels

and L-type calcium channels, 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 mayindirectly influence 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

deficits in intracellular signaling cascades associated with

cell survival, growth and metabolism. As such, recent stud-

ies have attempted to identify common effects of chemicallydivergent mood stabilizers with the intent of elucidating

functional targets of efficacious treatment response.

Both preclinical and clinical studies have suggested that

lithium exerts neurotrophic and neuroprotective effects,

and recent research has identified specific roles for lithium

in activating 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 findings of reduced hippocampal pyra-

midal cell size [50], anddecreased levels of BDNF have been

identified in bipolar disorder[51]. In addition to its neuro-

trophic effects, BDNFplays a key role in regulating synaptic

plasticity and, in particular, is required for specific forms of

long-term potentiation at the CA3CA1 synapse (Figure 1c)

[52]. Enhanced Bcl-2 expression counteracts deleterious

effects of stress on neurons, suggesting that its pharmaco-

logical induction has utility in cases 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 an important regulatory rolein synapticplasticity

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

areaimplicated in the neurobiology of reward and emotionalprocessing[56]. Further supporting a role for Bcl-2 function

in bipolar disorder, this polymorphism significantly 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 significant 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).

Severalenzymeshave beenshown to be directlyinhibited

by lithium at therapeutically relevant concentrations [14].

These include inositol monophosphatase (IMPase); inositol

polyphosphate a-phosphatase; bisphosphate 30

-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) in bipolar disorder pathophysiology, and bothlithium

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

PKC levels andactivity, but themechanism by which it does

so is distinct from that of lithium [71]. The readeris 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 identified in major de-

pressive disorder, initial studies suggested no differences

in bipolar disorder [87]. However, using a fine-mapping


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[

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)

Totalamygdalavolume(ml)

To

talhippocampalvolume

(mm

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

0.1

Y = 31

C.C.

p < 0.001

p< 0.05

350

300

250

200

150

100

50

0Controls

n = 21

Leftsubgenualvolume(mm

3)

Bipolar off

chronic Li/VPAn= 15

Bipolar on

chronic Li/VPAn= 6

MDD

n= 21-5.5 -2.8 0t-Value

Subgenual PFC


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 arepresent 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).


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three-dimensional technique, a recent study discerned

structural abnormalities in patients with bipolar disorder

that roughly correspond to the hippocampal CA1 subfields

[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 findings, it is inter-

esting that lithium treatment reverses hippocampal den-dritic atrophy induced in an animal model of chronic stress

[88] (Figure1d). In a recent mega-analysis to systematically

identify regional volumetric deficits and effects of lithium

administration in bipolar disorder, pooled imaging data

showed cerebral volume reductions that were significantly

associated with illness duration. Individuals with bipolar

disorder who were not on lithium therapy showed signifi-

cant decrease in cerebral and hippocampal volumes, where-

as patients treated with lithium showed significantly

increased hippocampal and amygdala volumes [76]. Data

on amygdalavolumes in patients with bipolar disorder have

been conflicting, but recent studies using high-resolution

magnetic imaging resonance (MRI) have convincingly

shown that amygdala volume is smaller in unmedicatedpatients 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 identified 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; extensiveconnections with limbic areas, includinghippocampus and amygdala(#) Altered CBF and glucosemetabolism in primary depression [3,90] () Sensory relay,

extensive connectionswith limbic system andmood-related circuitry(#) Depressed individualswith MDD and BD showincreased metabolism andCBF in the mediodorsalnucleus of the thalamus [3]

(

) Learning, memory andcognition; site of ongoing adultneurogenesis; negativeregulation over HPA axis(#) Reduction in gray mattervolume in patients with BD,with increased volumes insuch patients on lithiumtreatment [7680]; decreasednumber of synapses andsynaptic proteins; declarativememory deficits [3537]

() Evaluation of experience/stimuliwith strong emotional valence,acquisition and expression ofemotionally related memories(#) Decreased volumes in patients withBD, with increased volumes in suchpatients on lithium treatment [76,78,81],

elevated resting CBF and glucosemetabolism [3,90]

() Links nervous system to endocrine system;synthesizes and secretes, neurohormones, includingcorticotropin-releasing hormone, an importantcomponent of the stress system; key structure incontrolling HPA axis function(#) Hypercortisolemia, HPA axis abnormalities

() Integration of multi-modal stimuli andassessment of stimulus value and/orreward, extinction of unreinforced responsesto stimuli [3,90](#) Volume reductions, increased metabolism [90]

() This region has extensive connectionswith brain structures implicated in themodulation of emotional behavior, andparticipates as part of this extendednetwork in emotional processing andregulation of autonomic response(#) Reduction in gray matter volume in MDDand BD [89,90], although not seen in thesestudies [76,82], gray matter volumetricincreases in patients with lithium-treatedbipolar disorder [82,83], but not evidencedin this analysis [76], alterations in metabolic

activity [3,8990], decreased glial cell density[83,90], altered glutamate levels [29]


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.


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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 deficits 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 in HPA axis 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 HPA axis hyperactivation are the most likely to

be associated with hippocampalvolume 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 lithium and 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. Cortisolhas 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]. Thisis 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-termexposure 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 mediatesGR 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


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 inhumans, 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.


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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 findings 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 in mediating the

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 significant 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 efficacy; only a fraction of patients meet response

criteria by the end of the first treatment week[106108].

This leaves patients highly vulnerable to self-harm and

suicide, which is reflected 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-affinity NMDA receptorantagonist, generated significant interest. In vitro, keta-

mine increases glutamatergic neuron firing 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 AMPA receptors

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 efficacy 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 significantportion 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 achallenge 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 molecularbiology 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-stabilizertreatments. 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.


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be valuable in advancing rational drug development for

future antidepressant agents.

Brain stimulation

Recent strides in understanding the misregulation of 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 modifications 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 identified, many issues remain (Box 3).The development of novel mood stabilizers with faster

onset of action, increased efficacy and less burdensome

adverse-effect profiles, would have enormous impact on

public health and, as such, it is a priority to move both basic

and clinicalstudies forward. Verticalmovement 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 finally 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.

AcknowledgementsSupport was provided by the National Institute of Mental Health

Intramural Research Program. The figures and illustrations were

designed and created by Anne K. Schlosser.

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