SPECIAL ARTICLE

The underlying neurobiology of bipolar disorder

HUSSEINI K. MANJI, JORGE A. QUIROZ, JENNIFER L. PAYNE, JASKARAN SINGH, BARBARA P. LOPES,
JENILEE S. VIEGAS, CARLOS A. ZARATE
Laboratory of Molecular Pathophysiology, Mood and Anxiety Disorders Program, National Institute of Mental Health, 49 Convent Dr., Bethesda,
MD 20892-4405, USA

Clinical studies over the past decades have attempted to uncover the biological factors mediating the pathophysiology of bipolar disorder (BD) utilizing a variety of biochemical and neuroendocrine strategies. Indeed, assessments of cerebrospinal fluid chemistry, neuroendocrine responses to pharmacological challenge, and neuroreceptor and transporter binding have demonstrated a number of abnormalities in the amine neurotransmitter systems in this disorder. However, recent studies have also implicated critical signal transduction pathways as being integral to the pathophysiology and treatment of BD, in addition to a growing body of data suggesting that
impairments of neuroplasticity and cellular resilience may also underlie the pathophysiology of the disorder. It is thus noteworthy that
mood stabilizers and antidepressants indirectly regulate a number of factors involved in cell survival pathways - including MAP kinases, CREB, BDNF and bcl-2 protein - and may thus bring about some of their delayed long-term beneficial effects via underappreciated
neurotrophic effects.
Key words: Mania, norepinephrine, dopamine, acetylcholine, serotonin, glutamate, neuroplasticity, CREB, BDNF, ERK MAP kinase, bcl-2

Although genetic factors play a major, unquestionable

role in the etiology of bipolar disorder (BD), the biochemical abnormalities underlying the predisposition to and the
pathophysiology of BD remain to be fully elucidated. Early
biologic theories regarding the pathophysiology of BD have
focused upon various neurotransmitters, in particular the
biogenic amines. In recent years, however, advances in our
understanding of the cellular mechanisms underlying neuronal communication have focused research into the role of
post-receptor sites. Indeed, the molecular medicine revolution has resulted in a more complete understanding of the
etiology and pathophysiology of a variety of medical disorders (1,2). However, in contrast to the progress that has
been made in elucidating the etiology and/or pathophysiology of a variety of medical conditions, we have yet to identify the specific abnormal genes or proteins in BD. The
behavioral and physiological manifestations of BD are complex and must account not only for the profound changes in
mood, but also for the constellation of neurovegetative and
psychomotor features. The pathophysiology is undoubtedly
mediated by a network of interconnected limbic, striatal
and fronto-cortical neurotransmitter neuronal circuits, and
the interacting cholinergic, catecholaminergic and serotonergic neurotransmitter systems thus represent very attractive candidates. Thus, it is not surprising that clinical studies over the past 40 years have for the most part rested upon
the conceptual foundation that monoamine signaling and
hypothalamic-pituitary-adrenal (HPA) axis disruption are
integral to the pathophysiology of both depression and
mania (3,4).
A true understanding of the pathophysiology of BD must
address its neurobiology at different physiological levels, i.e.
molecular, cellular, systems, and behavioral. Abnormalities
in gene expression undoubtedly underlie the neurobiology
136

of the disorder at the molecular level and this will become

evident as we identify the susceptibility and protective
genes for BD in the coming years. Once this has been
accomplished, however, the even more difficult work must
begin to examine the impact of the faulty expression of
these gene-products (proteins) on integrated cell function.
It is at these levels that some compelling protein candidates
have been identified as the targets for the actions of mood
stabilizing agents; however, the precise manner in which
these candidate molecular and cellular targets may or may
not relate to the faulty expression of susceptibility geneproducts is yet to be determined. The task becomes even
more daunting when one considers the possibility that a
major component of the pathophysiology of BD may stem
from discordant biological rhythms ranging from ultradian
to infradian that ultimately drive the periodic recurrent
nature of the disorder (5-7). The subsequent challenge for
the basic and clinical neuroscientist will be the integration
of these molecular/cellular changes to the systems and ultimately to the behavioral level wherein the clinical expression of BD becomes fully elaborated. However, considerable progress has been made in our understanding of this
fascinating but devastating mental disorder. This article will
focus upon recent data linking signaling abnormalities and
impairments of neuroplasticity with the underlying neurobiology of BD. Space limitations necessitate the citing of
review articles in many instances. A full reference list upon
which this article is based is available upon request.

CLASSICAL MONOAMINERGIC NEUROTRANSMITTER

AND NEUROENDOCRINE SYSTEMS
The stimulus for the study of the biogenic amines in
patients with BD was provided by the discovery of effecWorld Psychiatry 2:3 - October 2003

tive pharmacologic treatments for depression and mania

(3). In addition to these compelling pharmacological data,
the biogenic amine neurotransmitter systems are distributed extensively in the limbic system, which is implicated
in the regulation of sleep, appetite, arousal, sexual function, endocrine function, and emotional states such as fear
and rage. The clinical picture of BD involves disruption of
behavior, circadian rhythms, neurophysiology of sleep,
neuroendocrine and biochemical regulation within the
brain (3,8). These complex illness manifestations are
undoubtedly mediated by a network of interconnected
neurotransmitter pathways; the monoamine neurotransmitter systems are ideally placed to mediate such complex
behavioral effects, and thus represent attractive candidate
systems underlying the pathophysiology of BD (9).

Noradrenergic system
Despite methodological difficulties in assessing central
nervous system (CNS) noradrenergic (NE) functions in
humans, extensive investigation supports the presence of
NE systems abnormalities in BD (3,10,11). Postmortem
studies have shown an increased NE turnover in the cortical and thalamic areas of BD subjects (12,13), whereas in
vivo studies have found plasma levels of NE and its major
metabolite, 3-methoxy-4-hydroxyphenylglycol (MHPG),
to be lower in bipolar than unipolar depressed patients,
and higher in bipolar patients when manic than when
depressed (3,11). The same occurs with urinary MHPG
levels, which are lower in bipolar depressed patients,
while longitudinal studies show that MHPG excretion is
higher in the manic compared to depressed state
(3,4,10,11). Finally, in a consistent mode, cerebrospinal
fluid (CSF) NE and MHPG are also reported to be higher
in mania than in depression.
Other paradigms studying NE receptor function tend to
suggest the possibility of an altered sensitivity of 2- and
2-adrenergic receptors in mood disorders (10,11). Genetics studies have also been carried out, showing that polymorphic variation of enzymes involved in amine metabolism (i.e. tyrosine hydroxylase, catechol-O-methyltransferase) could confer different susceptibility to develop
bipolar symptomatology (14-16). However, although
promising, these findings need to be replicated and subgroups of bipolar patients to whom these alterations may
apply need to be identified.

Serotonergic system
There is a consistent body of data from CSF studies, neuroendocrine challenge studies, serotonin receptor and reuptake site binding studies, pharmacologic studies, and most
recently, brain imaging studies supporting a role for alterations of serotonergic neurotransmission in major depressive episodes (3,17,18). Overall, investigators have reported
reduced levels of 5-hydroxyindoleacetic acid (5-HIAA) in a

subgroup of patients, especially those with impulsivity,

aggression and suicide attempts. In BD subjects, studies of
CSF 5-HIAA in manic patients have generally produced
variable and inconsistent results (3,19). Thus, baseline CSF
5-HIAA levels in manic patients, compared to nondepressed controls, have been reported as decreased in four
studies, unchanged in nine studies, and increased in three
studies; by contrast, most studies find no difference in the
levels of CSF 5-HIAA between manic and depressed
patients. Of the four studies that examined CSF 5-HIAA
accumulation following administration of probenecid in
manics, depressives and controls, two reported that both
manic and depressed patients have diminished CSF 5HIAA formation compared to controls, and one reported
that manic patients have significantly lower CSF 5-HIAA
accumulation than depressives and controls (3).
Studies have also reported decreased radioligand binding to the serotonin transporter (which takes up serotonin
from the synaptic cleft) both in platelets and in the midbrain of depressed patients (17,18). Most recently, an
intriguing preliminary positron emission tomography
(PET) study reported decreases in 5-hydroxytryptamine (5HT)1A receptor binding potential in raphe and hippocampus-amygdala of brain in depressed patients, in particular
in bipolar depressives and in unipolar patients with bipolar relatives (20). One factor which may contribute to the
reduction in 5-HT1A receptor binding in depression is
increased cortisol secretion (known to occur in many
depressed patients, vide infra), since postsynaptic 5-HT1A
receptor mRNA expression is under tonic inhibition by
corticosteroid receptor stimulation in some brain regions.
The magnitude of the reduction in 5-HT1A receptor density and mRNA levels induced by stress-induced glucocorticoid secretion in rodents is similar to that of the differences
between depressed and healthy humans. For example, in
rats, chronic unpredictable stress reduced 5-HT1A receptor
density an average of 22% across hippocampal subfields,
similar to the 25% reduction in hippocampal 5-HT1A
receptor binding potential found in depression. Similarly,
in tree shrews, chronic social subordination stress (for 28
days) decreased the density of 5-HT1A receptors in the posterior cingulate, parietal cortex, prefrontal cortex (PFC),
and hippocampus (by 11% to 34%), similar to the magnitude of reduced 5-HT1A receptor binding potential found
by Sargent et al (21) and Drevets et al (22) in these regions.
Neurotransmitter depletion models, specifically in this
case tryptophan depletion to lower serotonin levels, permit
a more direct strategy to clarify the involvement of serotonergic systems in mood disorders. Tryptophan depletion
(achieved by the ingestion of preparations containing high
levels of other aminoacids, but devoid of tryptophan)
results in reversal of the response to certain antidepressant
medications and recurrence of depression; however, depletion in healthy subjects without evidence of mental illness
and in nonmedicated patients with depression does not
consistently cause or intensify depression (23). These stud137

ies again substantiate the underlying complexity of neurobiologic systems not only in depression but by analogy in BD.
With respect to BD, recent studies have investigated the
effect of tryptophan depletion in lithium-treated euthymic
patients and have generally found no recurrence of symptoms (24). Thus, although lithium has often been postulated to exert many of its beneficial effects via an enhancement
of serotonergic function, the tryptophan depletion studies
suggest that other mechanisms may be more important.
Most recently, investigators have explored the possibility that sensitivity to the deleterious mood and cognitive
effects of lowered serotonin may represent an endophenotype for BD, by studying unaffected relatives of BD
patients. In a double-blind, crossover design, 20 unaffected
relatives from multiple bipolar families and 19 control subjects underwent acute tryptophan depletion (ATD) (25).
Unlike the control subjects, unaffected relatives experienced a lowering of mood during ATD but not with the
placebo. Furthermore, unaffected relatives tended to show
increased impulsivity in the ATD condition. Measurements
obtained before ingestion of the aminoacids drink indicated that, relative to control subjects, unaffected relatives
exhibited lower serotonin platelet concentrations, lower
affinity, and fewer binding sites of the serotonin transporter
for imipramine; these differences were unaffected by tryptophan depletion. In more recent studies, Sobczak et al
(26) investigated the effects of ATD on cognitive performance in healthy first-degree relatives of bipolar patients
(FH) (N= 30) and matched controls (N= 15) in a placebocontrolled, double-blind crossover design. Performances
on planning, memory and attention tasks were assessed at
baseline and 5 hours after ATD. They found that speed of
information processing on the planning task following
ATD was impaired in the FH group but not in the control
group. Furthermore, FH subjects with a bipolar disorder
type I (BD-I) relative showed impairments in planning and
memory, independent of ATD. In all subjects, ATD
impaired long-term memory performance and speed of
information processing. ATD did not affect short-term
memory or focused and divided attention. Together, these
results suggest that vulnerability to reduced tryptophan
availability may represent an endophenotype for BD and
warrants further investigation.
Studies assessing the sensitivity of the serotonergic system by exploring changes in plasma levels of prolactin and
cortisol after administration of d-fenfluramine in manic
patients have shown contradictory results (27,28). More
consistent results have been found after administration of
sumatriptan (a 5-HT1D agonist): the growth hormone (GH)
response is blunted in manic compared with depressed
patients (29), revealing a subsensitivity of 5-HT function.

Dopaminergic system
Several lines of evidence point to a role of dopamine
(DA) system in mood disorders. A relevant preclinical
138

model derives from the crucial role of mesoaccumbens DA

in the neural circuitry of reward and/or incentive motivational behavior (30). Loss of motivation is one of the central features of depression and indeed anhedonia is one of
the defining characteristics of melancholia. Thus, a deficiency of DA systems stands out as a prime candidate for
involvement in the pathophysiology of depression (31,32).
The strongest direct finding from clinical studies implicating DA in depression is reduced homovanillic acid (HVA,
the major DA metabolite) in the CSF; indeed, this is one
of the most consistent biochemical findings in depression
(3,11). There is also evidence for a decreased rate of CSF
HVA accumulation in subgroups of depressed patients,
including those with marked psychomotor retardation
versus agitation (33). Furthermore, depression occurs in
up to 40% of patients with idiopathic Parkinsons disease
and may precede motor symptoms. Interestingly, some
case reports have documented abolition of symptoms of
Parkinsons disease during a manic episode (34,35).
The pharmacological bridge also supports the notion
that manipulation of the dopaminergic system is capable
of modulating the illness. Thus, DA agonists appear to be
effective antidepressants and are able to precipitate mania
in some bipolar patients (3,11). Most recently, investigators have utilized a catecholamine depletion strategy (via
use of the tyrosine hydroxylase inhibitor -methylparatyrosine, AMPT) in lithium-treated, euthymic BD patients
(36). Intriguingly, they did not observe any mood-lowering
effects of AMPT, but observed a rebound hypomania in a
significant percentage of the patients. Although preliminary, these results are compatible with a dysregulated signaling system wherein the compensatory adaptation to
catecholamine depletion results in an overshoot due to
impaired homeostatic mechanisms. Most recently,
McTavish et al (37) reported that a tyrosine-free mixture
lowered both subjective and objective measures of the
psychostimulant effects of methamphetamine and manic
scores. These preliminary studies suggest that tyrosine
availability to the brain attenuates pathological increases
in dopamine neurotransmission following methamphetamine administration and putatively in mania.
In more recent neuroimaging studies, the concentration
of the vesicular monoamine transporter protein (VMAT2)
was quantified with (+)[11C]dihydrotetrabenazine (DTBZ)
and PET (38). Sixteen asymptomatic BD-I patients who
had a prior history of mania with psychosis (nine men and
seven women) and individually matched healthy subjects
were studied. VMAT2 binding in the thalamus and ventral
brainstem of the bipolar patients was higher than in the
comparison subjects. In a follow-up study, the same
research group attempted to assess the diagnostic specificity of the findings, by comparing VMAT2 concentrations between euthymic BD-I (N=15) patients, schizophrenic patients (N=12), and age-matched healthy volunteers (N=15) (38). They found that VMAT2 binding in the
thalamus was higher in BD-I patients than in control subWorld Psychiatry 2:3 - October 2003

jects and schizophrenic patients. The authors interpreted

the intriguing findings of increased VMAT2 expression in
euthymic BD-I patients as representing trait-related
abnormalities in the concentration of monoaminergic
synaptic terminals. However, chronic lithium treatment
has recently been demonstrated to increase VMAT2 protein in rat frontal cortex (the only region examined) (39),
raising the possibility that the PET human studies may
have been confounded by treatment effects.
Most recently, Yatham et al (40) assessed presynaptic
dopamine function in 13 neuroleptic- and mood-stabilizernaive nonpsychotic first-episode manic patients by measuring [18F]6-fluoro-L-DOPA (18F-DOPA) uptake in the
striatum by PET. No significant differences in 18F-DOPA
uptake rate constants in the striatum were found between
the manic patients and the comparison subjects; however,
treatment with valproate (VPA) significantly reduced 18FDOPA uptake rate.

magnetic resonance imaging (MRI) studies have also

revealed reduced hippocampal volumes in patients with
Cushing disease and post-traumatic stress disorder (other
conditions associated with hypercortisolemia). Indeed,
one of the most consistent effects of stress on cellular morphology is atrophy of the CA3 hippocampal neurons
(47,48), which also occurs upon exposure to high levels of
glucocorticoids, suggesting that activation of the HPA axis
likely plays a major role in mediating the stress-induced
atrophy (48). Thus, recurrent stress (and presumably
recurrent mood episodes which are often associated with
hypercortisolemia) may lower the threshold for cellular
death/atrophy in response to a variety of physiological
(e.g. aging) and pathological events, likely involving the
inhibition of glucose transport (diminishing the capability
for energy production and augmenting susceptibility to
conditions which place a high demand or load on the neuron), and the abnormal enhancement of glutamatergic signaling leading to excitotoxicity (48).

Cholinergic system
Much of the evidence supporting the involvement of
the cholinergic system in mood disorders comes from neurochemical, behavioral and physiologic studies in
response to pharmacologic manipulations. These studies,
carried out in the early 1970s, showed that the relative
inferiority of noradrenergic compared to cholinergic tone
was associated with depression, while the reverse was
associated with mania (41). Additional support is found
from a study on the central cholinesterase inhibitor
physostigmine (administered intravenously), in which
transient modulation of symptoms in manic cases and
induction of depression in euthymic bipolar patients stabilized with lithium were observed.
A decrease in the cholinergic tone during mania has
also been described when increased requirements of the
cholinergic agonist pilocarpine were needed to elicit
pupillary constriction: consistently, this responsiveness
increased after lithium or VPA treatment (42,43), adding
evidence on the effects of lithium perhaps potentiating
brain cholinergic systems (44,45). However, the therapeutic responses observed with antidepressant and antimanic
pharmacological agents are not reliably matched with
effects on the cholinergic system.

Stress and glucocorticoids modulate neural plasticity:

implications for mood disorders
Numerous reports document HPA axis hyperactivity in
drug-free depressed (46) and bipolar depressed patients.
With respect to BD, increased HPA activity has been associated with mixed manic states, depression, and less consistently with classical manic episodes (3,18). Chronic
stress or glucocorticoid administration has been demonstrated to produce atrophy and death of vulnerable hippocampal neurons in rodents and primates. In humans,

SIGNALING NETWORKS: THE CELLULAR COGWHEELS

UNDERLYING LONG-TERM NEUROPLASTICITY
More recently, research into the pathophysiology and
treatment of mood disorders has moved from a focus on
neurotransmitters and cell surface receptors to intracellular signaling cascades.
Multicomponent, cellular signaling pathways interact at
various levels, thereby forming complex signaling networks
which allow the cell to receive, process, and respond to
information (49-51). These networks facilitate the integration of signals across multiple time scales, the generation of
distinct outputs depending on input strength and duration,
and regulate intricate feed-forward and feedback loops (4951). Given their widespread and crucial role in the integration and fine-tuning of physiologic processes, it is not surprising that abnormalities in signaling pathways have now
been identified in a variety of human diseases (2,52,53).
Furthermore, signaling pathways represent major targets for
a number of hormones, including glucocorticoids, thyroid
hormones, and gonadal steroids (2,52). These biochemical
effects may play a role in mediating certain clinical manifestations of altered hormonal levels in mood disorder subjects (e.g. the frequent onset of bipolar disorder in puberty,
triggering of episodes in the postpartum period, association
of depression and potentially rapid cycling with hypothyroidism, and triggering of affective episodes in response to
exogenous glucocorticoids).
Complex signaling networks may be especially important in the CNS, where they weigh and integrate diverse
neuronal signals and then transmit these integrated signals
to effectors, thereby forming the basis of a complex information processing network (49-51). The high degree of
complexity generated by these signaling networks may be
one mechanism by which neurons acquire the flexibility
for generating the wide range of responses observed in the
139

nervous system. These pathways are thus undoubtedly

involved in regulating such diverse vegetative functions as
mood, appetite and wakefulness and are therefore likely to
be involved in the pathophysiology of BD. We now turn to
a discussion of the direct and indirect evidence supporting
a role for abnormalities in signaling pathways in the
pathophysiology and treatment of BD.

The Gs/cAMP generating signaling pathway

Several independent laboratories have now reported
abnormalities in G protein subunits in BD (54,55). Postmortem brain studies have reported increased levels of the
stimulatory G protein (Gs) accompanied by increases in
post-receptor stimulated adenylyl cyclase (AC) activity in
BD (55,56). Several studies have also found elevated Gs
protein levels and mRNA levels in peripheral circulating
cells in BD, although the dependency on clinical state
remains unclear (45,55,57-60). It should be emphasized,
however, that there is at present no evidence to suggest that
the alterations in the levels of Gs are due to a mutation in
the Gs gene itself (61). There are numerous transcriptional and post-transcriptional mechanisms which regulate the
levels of G protein subunits, and the elevated levels of Gs
could potentially represent the indirect sequelae of alterations in any one of these other biochemical pathways
(54,55,57,62).
There is growing consensus that the ability of a simple
monovalent cation like lithium to treat multiple aspects of
an illness as complex as BD arises from its major effects on
intracellular signaling pathways, rather than on any single
neurotransmitter system per se (9,44,60). Although it
appears that the lithium ion (at therapeutic concentrations) does not directly affect G protein function, there is
considerable evidence that chronic lithium administration
affects that function (9,44). Although some studies have
reported modest changes in the levels of G protein subunits, the preponderance of the data suggests that chronic
lithium does not modify G protein levels per se, but rather
modifies G protein function (62,63). Although speculative, it might be postulated that these G protein effects which would theoretically attenuate excessive signaling
through multiple pathways - likely contribute to lithiums
long-term prophylactic efficacy in protecting susceptible
individuals from spontaneous-, stress-, and drug (e.g. antidepressant, stimulant)- induced cyclic affective episodes.

The protein kinase C signaling pathway

Protein kinase C (PKC) exists as a family of closely related subspecies, has a heterogenous distribution in brain
(with particularly high levels in presynaptic nerve terminals), and, together with other kinases, appears to play a
crucial role in the regulation of synaptic plasticity and various forms of learning and memory (64-67). PKC is one of
the major intracellular mediators of signals generated upon
140

external stimulation of cells via a variety of neurotransmitter receptors (including muscarinic M1, M3, M5 receptors,
noradrenergic 1 receptors, metabotropic glutamatergic
receptors, and serotonergic 5-HT2A receptors), which
induce the hydrolysis of various membrane phospholipids.
To date, there have only been a limited number of studies directly examining PKC in BD (68). Although
undoubtedly an over-simplification, particulate (membrane) PKC is sometimes viewed as the more active form
of PKC, and thus an examination of the subcellular partioning of this enzyme can be used as an index of the
degree of activation. Friedman et al (69) investigated PKC
activity and PKC translocation in response to serotonin in
platelets obtained from BD subjects before and during
lithium treatment. They reported that the ratios of platelet
membrane-bound to cytosolic PKC activities were elevated in the manic subjects. In addition, serotonin-elicited
platelet PKC translocation was found to be enhanced in
those subjects. With respect to brain tissue, Wang and
Friedman (70) measured PKC isozyme levels, activity and
translocation in post-mortem brain tissue from BD
patients; they reported increased PKC activity and translocation in BD brains compared to controls, effects which
were accompanied by elevated levels of selected PKC
isozymes in cortices of BD subjects.
Evidence accumulating from various laboratories has
clearly demonstrated that lithium, at therapeutically relevant concentrations, exerts major effects on the PKC signaling cascade. Currently available data suggest that
chronic lithium attenuates PKC activity, and downregulates the expression of PKC isozymes and in frontal cortex and hippocampus (62,71). Chronic lithium has also
been demonstrated to dramatically reduce the hippocampal levels of a major PKC substrate, MARCKS (myristoylated alanine rich C kinase substrate), which has been
implicated in regulating long-term neuroplastic events
(62,71). Although these effects of lithium on PKC isozymes
and MARCKS are striking, a major problem inherent in
neuropharmacologic research is the difficulty in attributing
therapeutic relevance to any observed biochemical finding.
It is thus noteworthy that the structurally dissimilar antimanic agent VPA produces very similar effects as lithium
on PKC and isozymes and MARCKS protein (63,71).
Interestingly, lithium and VPA appear to bring about their
effects on the PKC signaling pathway by distinct mechanisms. These biochemical observations are consistent with
the clinical observations that some patients show preferential response to one or other of the agents, and that one
often observes additive therapeutic effects in patients when
the two agents are co-administered.
In view of the pivotal role of the PKC signaling pathway
in the regulation of neuronal excitability, neurotransmitter
release, and long-term synaptic events (68,72), it was postulated that the attenuation of PKC activity may play a
role in the antimanic effects of lithium and VPA. In a pilot
study it was found that tamoxifen (a non-steroidal antieWorld Psychiatry 2:3 - October 2003

strogen known to be a PKC inhibitor at higher concentrations (73)) may, indeed, possess antimanic efficacy (74).
Clearly, these results have to be considered preliminary,
due to the small sample size thus far. In view of the preliminary data suggesting the involvement of the PKC signaling system in the pathophysiology of BD, these results
suggest that PKC inhibitors may be very useful agents in
the treatment of mania. Larger double-blind placebo-controlled studies of tamoxifen and of novel selective PKC
inhibitors in the treatment of mania are warranted.

Abnormalities of calcium signaling

Calcium ions play a critical role in regulating the synthesis and release of neurotransmitters, neuronal
excitability, and long-term neuroplastic events, and it is
thus not surprising that a number of studies have investigated intracellular Ca2+ in peripheral cells in BD (54,75).
These studies have consistently revealed elevations in
both resting and stimulated intracellular Ca2+ levels in
platelets, lymphocytes and neutrophils of patients with
BD. The regulation of free intracellular Ca2+ is a complex,
multi-faceted process, and the abnormalities observed in
BD could arise from abnormalities at a variety of levels
(54). Ongoing studies should serve to delineate the specific regulatory sites at which the impairment occurs in BD.

IMPAIRMENTS OF NEUROPLASTICITY
AND CELLULAR RESILIENCE
Structural imaging studies have demonstrated reduced
gray matter volumes in areas of the orbital and medial
PFC, ventral striatum and hippocampus, and enlargement
of third ventricle in patients with mood disorders relative
to healthy controls (76). Complementary post mortem
neuropathological studies have shown abnormal reductions in cortex volume, glial cell counts, and/or neuronal
densities/sizes in the subgenual PFC, orbital cortex and
dorsal anterolateral PFC in unipolar and bipolar patients.
However, many of these preliminary reports, although
extremely interesting, require further replication.
The marked reduction in glial cells in these regions is
particularly intriguing in view of the growing appreciation
that glia plays critical roles in regulating synaptic glutamate
concentrations and CNS energy homeostasis, and in releasing trophic factors that participate in the development and
maintenance of synaptic networks formed by neuronal and
glial processes (77). Abnormalities of glial function could
thus prove integral to the impairments of structural plasticity and overall pathophysiology of mood disorders.
It is not presently known whether this evidence of neuronal deficits constitutes developmental abnormalities
that may confer vulnerability to abnormal mood episodes,
compensatory changes to other pathogenic processes, the
sequelae of recurrent affective episodes or other factors
that are difficult to control in patient populations.

Underlying mechanism for cell loss

Activation of the HPA axis appears to play a critical role
in mediating hippocampal atrophy, as was already discussed. In addition to directly causing neuronal atrophy,
stress and glucocorticoids also appear to reduce cellular
resilience, thereby making certain neurons more vulnerable to other insults, such as ischemia, hypoglycemia, and
excitatory aminoacid toxicity.
The reduction in the resilience of hippocampal neurons
may also reflect the propensity for various stressors to
decrease the expression of brain derived neurotrophic factor (BDNF) in this region (78). BDNF and other neurotrophic factors are necessary for the survival and function of neurons, implying that a sustained reduction of
these factors could affect neuronal viability. Increasing
evidence suggests that neurotrophic factors inhibit cell
death cascades by (in large part) activating the mitogen
activated protein (MAP) kinase signaling cascade, and
upregulating major cell survival proteins such as bcl-2
(79). Bcl-2 is now recognized as a major neuroprotective
protein, since bcl-2 overexpression protects neurons
against diverse insults, including ischemia, the neurotoxic
agent methyl-phenyl-tetrahydropyridine (MPTP), -amyloid, free radicals, excessive glutamate, and growth factor
deprivation (80). Accumulating data suggests that bcl-2 is
not only neuroprotective, but also exerts neurotrophic
effects and promotes neurite sprouting, neurite outgrowth
and axonal regeneration (80). If enhanced bcl-2 expression appears to be capable of offsetting the potentially
deleterious consequences of stress-induced neuronal
endangerment (81), then, pharmacologically induced
upregulation of bcl-2 may have considerable utility. Overall, it is clear that the neurotrophic factors/MAP
kinase/bcl-2 signaling cascade plays a critical role in cell
survival in the CNS, and that there is a fine balance maintained between the levels and activities of cell survival and
cell death factors. Modest changes in this signaling cascade or in the levels of the bcl-2 family of proteins (potentially due to genetic, illness or insult-related factors) may
therefore profoundly affect cellular viability.

Do antidepressants and mood stabilizers

have neurotrophic properties?
Neuroplasticity subsumes diverse processes of vital
importance by which the brain perceives, adapts and
responds to a variety of internal and external stimuli. The
manifestations of neuroplasticity in the adult CNS have
been characterized as including alterations of dendritic
function, synaptic remodeling, long-term potentiation
(LTP), axonal sprouting, neurite extension, synaptogenesis, and even neurogenesis (82).
There are several reports supporting the hypothesis that
antidepressant treatment produces neurotrophic-like
effects (78). Chronic administration of an atypical antidepressant, tianeptine, was reported to block the stress141

induced atrophy of CA3 pyramidal neurons (83) and to

block other stress-induced changes in brain structure and
neurochemistry (84). Male tree shrews subjected to a
chronic psychosocial stress paradigm were found to have
decreased N-acetylaspartate (NAA), a putative marker of
neuronal viability (85), measured in vivo by 1H-magnetic
resonance spectroscopy (MRS), decreased granule cell
proliferation in the dentate gyrus of the hippocampus and
a reduction in hippocampal volume as compared to nonstressed animals. All these stress-induced effects were prevented/reversed in the animals treated concomitantly with
tianeptine (84). However, the generalizability of these
effects to other classes of antidepressants is unclear.
Elegant recent studies have demonstrated that another
pathway involved in cell survival and plasticity, the cyclic
adenosine monophosphate (cAMP)-cAMP response element binding protein (CREB) cascade, is up-regulated by
antidepressant treatment (86). Up-regulation of CREB, a
gene promoter, and one of its major targets, BDNF, occurs
in response to several different classes of antidepressant
treatments, and occurs in a time frame consistent with the
therapeutic action of antidepressants (87). Furthermore,
chronic, but not acute, antidepressant treatments have been
found to increase the number of new neurons in the dentate
gyrus granule cell layer. These effects have been observed
with different classes of antidepressants, but not with several other psychotropic medications investigated (87). A role
for the cAMP-CREB cascade and BDNF in the actions of
antidepressant treatment is also supported by studies
demonstrating that up-regulation of these pathways has
effects similar to antidepressant medications in behavioral
models of depression such as the learned helplessness and
forced swim test models (88-90).
Several endogenous growth factors, including nerve
growth factor (NGF) and BDNF, exert many of their neurotrophic effects via the MAP kinase signaling cascade.
The net result of stimulation of this cascade is an increase
in the transcription and/or activity of a number of cell survival proteins, such as bcl-2 and BDNF. It is thus noteworthy that recent studies have demonstrated that chronic lithium and VPA robustly activate the MAP kinase cascade in cells of human neuronal origin and in rat frontal
cortex and hippocampus (91,92). Consistent with this
activation, both treatments produced a doubling of bcl-2
levels in frontal cortex, an effect primarily due to a marked
increase in the number of bcl-2 immunoreactive cells in
layers II and III of frontal cortex (93). Interestingly, the
importance of neurons in layers II-IV of the frontal cortex
in mood disorders has recently been emphasized, since
primate studies indicate that these areas are important for
providing connections with other cortical regions, and
that they are targets for subcortical input (94). Furthermore, chronic lithium also increases bcl-2 levels in the
mouse hippocampus (95) and in cerebellar granule cells in
culture (96), as well as VPA increases bcl-2 levels in
human cells of neuronal origin (91).
142

Consistent with the neurotrophic and neuroprotective

effects of MAP kinase activation and bcl-2 upregulation,
lithium, at therapeutically relevant concentrations, has
been shown to exert neuroprotective effects in a variety of
preclinical paradigms. Consistently, VPA has been demonstrated to exert neuroprotective actions in cellular models
as well, including glutamate toxicity, -amyloid toxicity,
and following exposure to other toxins (97-100).

Glycogen synthase kinase:

a common target for mood stabilizers
Lithium and VPA regulate the activity of a crucial kinase
that functions as an intermediary in numerous intracellular
signaling pathways, the enzyme glycogen synthase kinase-3
(GSK-3), suggesting the importance of this enzyme in BD
research (101,102). While lithium inhibits GSK-3 - a constitutively active and a highly conserved enzyme in evolution by direct competition with magnesium for a binding site, the
precise mechanisms by which VPA exerts its action is still
uncertain (102-104). Other signals deactivating GSK-3 arise
from insulin stimulation, developmental signals, and numerous growth factors (e.g. NGF and BDNF). Thus, growth factors may bring about many of their neurotrophic/neuroprotective effects, at least in part, by GSK-3 inhibition. Rapidly
increasing evidence suggests that GSK-3 also plays important roles in regulating neuroplasticity and cellular
resilience. GSK-3 phosphorylates - and thereby inactivates transcription factors and cytoskeletal proteins (such as the
Alzheimers protein tau). Furthermore, changes in GSK-3
mediate MAP-1B (a cytoskeletal protein) phosphorylation,
associated with the loss and/or unbundling of stable axonal
microtubules. Finally, GSK-3 inhibition results in the accumulation of synapsin I, a protein involved in synaptic vesicle
docking and release, at growth cone-like areas.
This evidence suggests that lithiums and VPAs effect on
GSK-3 may play important roles in regulating processes
such as synaptic plasticity and cell survival in the mature
CNS. It is thus interesting that all of these processes have
been implicated in the pathophysiology and treatment of
BD (102).

Glutamatergic interventions:
do they represent a neurotrophic strategy?
Another neurotransmitter system that has been implicated in regulating neuronal plasticity and cellular
resilience in a variety of neuropsychiatric disorders is the
highly complex glutamatergic system. In fact, glucocorticoids can induce the release of glutamate in the hippocampal CA3 region, and very high levels of type II corticosteroid receptor activation markedly increase calcium
currents and lead to increased expression of N-methyl-Daspartate (NMDA) receptor (a subtype of glutamatergic
ionotropic receptor) on hippocampal neurons, that could
predispose to neurotoxicity and finally atrophy. InterestWorld Psychiatry 2:3 - October 2003

ingly, NMDA blockade can prevent stress-induced atrophy in that region and it is thus noteworthy that recent
preclinical studies have shown that the glutamatergic system represents a target (often indirect) for the actions of
antidepressants and mood stabilizers (105).
Further evidence of the glutamatergic system involvement in mood disorders comes from brain imaging studies.
These have shown that glucose metabolic signal, which
correlates tightly with regional cerebral blood flow (CBF)
during physiological activation, is likely to predominantly
reflect glutamatergic transmission (106). PET imaging studies of BD patients have demonstrated abnormalities of
CBF and glucose metabolism and, since projections from
the regions involved in these abnormalities are glutamatergic, depression- and mania-related hypo/hyperactivity may
be suggestive of either decreased (depression) or increased
(mania) activation of glutamatergic cortico-limbic pathways. Thus, the hypothesis that a mood-stabilizing drug
might modulate glutamate release or the consequences of
glutamate release could be consistent with these data from
functional neuroimaging studies.
There are a number of glutamatergic plasticity enhancing strategies which may be of considerable utility in the
treatment of mood disorders. Presently, lamotrigine and
ketamine, two anti-glutamatergic agents, have shown to
have antidepressant properties in bipolar and unipolar
depression. Other agents - including NMDA antagonists,
glutamate release reducing agents, and alpha-amino-3hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)
receptors potentiators - are under development or currently being clinically tested (107).

Human evidence for the neurotrophic effects

of mood stabilizers
While the body of preclinical data demonstrating neurotrophic and neuroprotective effects of mood stabilizers is
striking, considerable caution must clearly be exercised in
extrapolating to the clinical situation with humans. In view
of lithiums and VPAs robust effects on the levels of the
cytoprotective protein bcl-2 in the frontal cortex, Drevets
et al re-analyzed older data demonstrating ~40% reductions in subgenual PFC volumes in familial mood disorder
subjects (108). Consistent with neurotrophic/neuroprotective effects of lithium and VPA, they found that the patients
treated with chronic lithium or VPA exhibited subgenual
PFC volumes that were significantly higher than the volumes in non-treated patients, and not significantly different from controls (109). It should be noted that, in contrast
to mood stabilizers, chronic treatment of patients with
selective serotonin reuptake inhibitors did not have any
effect on gray matter volumes. In a more recent study,
Drevets and colleagues have investigated glial cell densities
in mood disorder patients. Although the sample sizes are
quite small, they made the intriguing observation that
unipolar patients exhibited reduced glial cell densities,

whereas only the bipolar patients off chronic lithium or

VPA exhibited similar reductions (110). Considerable caution is warranted in view of the small sample sizes and
cross-sectional nature of the studies.
To investigate the potential neurotrophic effects of lithium in humans more definitively, a longitudinal clinical
study was undertaken using proton MRS to quantitate
NAA levels. It was found that chronic lithium increased
NAA concentration in the human brain in vivo (111).
These findings provide intriguing indirect support for the
contention that chronic lithium increases neuronal viability/function in the human brain. Furthermore, a ~0.97
correlation between lithium-induced NAA increases and
regional voxel gray matter content was observed, thereby
providing evidence for co-localization with the regional
specific bcl-2 increases observed in the rodent brain cortices. These results suggest that chronic lithium may not
only exert robust neuroprotective effects (as it has been
demonstrated in a variety of preclinical paradigms), but
also exert neurotrophic effects in humans.
In follow-up studies to the NAA findings, it was
hypothesized that, in addition to increasing functional
neurochemical markers of neuronal viability, lithiuminduced increases in bcl-2 would also lead to neuropil
increases, and thus to increased brain gray matter volume
in BD patients. In this clinical research investigation,
brain tissue volumes were examined using high resolution
three dimensional MRI and validated quantitative brain
tissue segmentation methodology to identify and quantify
the various components by volume, including total brain
white and gray matter content. Measurements were made
at baseline (medication free, after a minimum 14 day
washout) and then repeated after 4 weeks of lithium at
therapeutic doses. This study revealed that chronic lithium significantly increases total gray matter content in the
human brain of patients with BD (112). No significant
changes were observed in brain white matter volume, or
in quantitative measures of regional cerebral water content, thereby providing strong evidence that the observed
increases in gray matter content are likely due to neurotrophic effects as opposed to any possible cell swelling
and/or osmotic effects associated with lithium treatment.
A finer grained sub-regional analysis of this brain imaging
data is ongoing. The increased gray matter finding has
recently been replicated in a cross-sectional MRI study:
Sassi et al (113) found that lithium treated bipolar
patients had a statistically higher cortical gray matter volume when compared either to non-treated bipolar
patients or control subjects.

CONCLUDING REMARKS
A considerable body of data confirms that the amine
neurotransmitter systems are dysfunctional in BD,
explaining why they have become a common target for
pharmacological interventions. However, conceptual and
143

experimental evidence suggests that abnormalities in the

regulation of signal transduction cascades and neuroplasticity could more primarily underlie the pathophysiology
of BD. This concept is becoming increasingly important
when considering that, for many refractory patients with
this disorder, new drugs simply mimicking the traditional
medications which directly or indirectly alter neurotransmitter levels and those which bind to cell surface receptors may be of limited benefit (114). Therefore, the existence of abnormalities in signal transduction pathways
suggests that, for patients refractory to conventional medications, improved therapeutics may only be obtained by
the direct targeting of post-receptor sites (e.g. CREB/
BDNF/MAP kinase/bcl-2). Strategies to enhance neurotrophic factor signaling are currently under research and
they hold much promise for the development of novel
therapeutics for the long-term treatment of severe BD.

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