The British Journal of Psychiatry (2001) 178: s107-s119
© 2001 The Royal College of Psychiatrists
Bipolar disorder: leads from the molecular and cellular mechanisms of action of mood stabilisers
HUSSEINI K. MANJI, FRCPC,
GREGORY J. MOORE, PhD and
GUANG CHEN, PhD
Laboratory of Molecular Pathophysiology, Wayne State University School of
Medicine, Detroit, Michigan, USA
Correspondence:
Dr Husseini K. Manji, Director, Laboratory of Molecular Pathophysiology,
National Institute of Mental Health, Bld 49, Room BIEEI6, 49 Convent Drive,
MSC 4405, Bethesda, MD 20892, USA. Tel: + 1 301 496 0373; fax + 1 301 480
0123; e-mail:
manjih{at}intra.nimh.nih.gov
Declaration of interest Support from the National Institute of
Mental Health, The Stanley Foundation, NARSAD and the Joseph Young Sr
Foundation.
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ABSTRACT
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Background New research is dramatically altering our understanding
of the molecular mechanisms underlying neuronal communication.
Aim To elucidate the molecular mechanisms underlying the therapeutic
effects of mood stabilisers.
Method Results from integrated clinical and laboratory studies are
reviewed.
Results Chronic administration of lithium and valproate produced a
striking reduction in protein kinase C (PKC) isozymes in rat frontal cortex
and hippocampus. In a small study, tamoxifen (also a PKC inhibitor) had marked
antimanic efficacy. Both lithium and valproate regulate the DNA binding
activity of the activator protein 1 family of transcription factors. Using
mRNA differential display, it was also shown that chronic administration of
lithium and valproate modulates expression of several genes. An exciting
finding is that of a robust elevation in the levels of the cytoprotective
protein, bcl-2.
Conclusions The results suggest that regulation of signalling
pathways may play a major part in the long-term actions of mood stabilisers.
Additionally, mood stabilisers may exert underappreciated neuroprotective
effects.
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INTRODUCTION
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Despite well-established genetic diatheses and extensive research, the
biochemical abnormalities underlying the predisposition to and the
pathophysiology of bipolar disorder have yet to be clearly established. Early
biological explanations of bipolar disorder implicated neurotransmitters, in
particular the biogenic amines. However, advances in our understanding of the
cellular mechanisms underlying neuronal communication have shifted the focus
of research onto the role of post-receptor sites. Indeed, the ‘molecular
medicine revolution’ has increased our understanding of the
pathophysiological basis of a variety of medical disorders. This remarkable
progress is largely attributable to the elucidation of the basic mechanisms of
signal transduction, and the application of the powerful tools of molecular
biology to the study of human disease. Hundreds of guanine-nucleotide-binding
(G) protein-coupled receptors and over a dozen G proteins and effectors have
now been characterised at the molecular and cellular level
(Spiegel, 1998). This has
allowed the study of a variety of human diseases which are caused by loss- and
gain-of-function mutations; studies of such diseases offer unique insights
into the physiological and pathophysiological functioning of many cellular
transmembrane signalling pathways.
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BACKGROUND
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The role of G protein-coupled signal transduction pathways in human
disease
G proteins are a ubiquitous family of proteins that serve the critical role
of transducers of information across the plasma membrane, coupling receptors
to various effectors. It has been estimated that about 80% of all known
hormones, neurotransmitters and neuromodulators elicit cellular responses
through G proteins coupled to a variety of intracellular effectors.
Given their widespread and crucial roles in the regulation of physiological
functions, it is not surprising that alterations in G protein-coupled signal
transduction pathways have been implicated in a variety of pathophysiological
states: the interested reader is referred to Spiegel et al
(1993), Shenker
(1995) and Spiegel
(1998) for excellent reviews.
Loss- and gain-of-function mutations in G protein-coupled receptors have been
identified in such diverse conditions as retinitis pigmentosa, nephrogenic
diabetes insipidus, familial adrenocorticotrophic hormone (ACTH) resistance,
congenital bleeding, Hirschsprung's disease, hypergonadotrophic ovarian
failure, central hypothyroidism, growth hormone deficiency and familial male
precocious puberty (reviewed in Shenker,
1995; Spiegel,
1998). Furthermore, a variety of clinical conditions have been
demonstrated to arise from alterations in the functioning of G protein
subunits (Table 1)
(Weinstein & Shenker,
1993; Weinstein,
1994a,b).
It should be noted that G protein dysfunction appears to be the primary
initiating event in Albright's hereditary osteodystrophy,
McCune—Albright syndrome and some endocrine tumors. In several other
conditions (including hyper- and hypothyroidism, and states associated with
altered glucocorticoid or gonadal steroid levels), the G protein abnormalities
are probably secondary, but none the less are implicated in the
pathophysiology of the condition (Manji,
1992; Weinstein &
Shenker, 1993; Weinstein,
1994a,b).
For example, hypothyroidism is associated with increased levels of the
inhibitory G protein (Gi) and decreased levels of the stimulatory G
protein (Gs) in most tissues examined, including brain
(Manji, 1992;
Weinstein,
1994a,b).
These biochemical changes are thought to be responsible (at least in part) for
the impaired lipolysis and thermogenesis observed in hypothyroidism, and may
also have a role in the cognitive/psychological symptoms frequently observed.
Indeed, the major effects that many hormones (including thyroid,
glucocorticoids and gonadal steroids) have on signalling pathways suggest that
these biochemical effects may mediate some of the observed clinical features
of bipolar disorder (e.g. onset in puberty, triggering of episodes in the
post-partum period, association with alterations in endogenous thyroid hormone
levels and response to exogenous glucocorticoids).
The G protein-coupled signalling pathways first amplify and
‘weight’ extracellularly generated neuronal signals and then
transmit these integrated signals to effectors, thereby forming the basis for
a complex information processing network
(Ross, 1989;
Manji, 1992;
Bourne & Nicoll, 1993).
Since a single receptor subtype can be coupled to a number of G proteins, and
several G proteins can converge to activate or inactivate a single effector
(Ross, 1989;
Taylor, 1990;
Manji, 1992;
Bourne & Nicoll, 1993),
these signalling pathways form complex networks. These networks facilitate the
integration of signals across multiple time-scales, the generation of distinct
outputs depending on input strength and duration, and regulate feed-forward
and feedback loops (Bhalla & Lyengar, 1999;
Weng et al, 1999).
The complexity generated by the interactions of G protein-coupled receptors
may be one mechanism by which neurons acquire the flexibility for generating
the wide range of responses observed in the nervous system. This has led to
the proposal that G protein-coupled signal transduction pathways may be
critically involved in the neuronal circuits regulating such diverse
vegetative functions as mood, appetite and wakefulness and, by extrapolation,
in the cellular mechanisms of action of mood-stabilising agents.
In contrast to the progress that has been made in elucidating many other
medical conditions, we have yet to identify the specific abnormal genes or
proteins in bipolar disorders. Genetic linkage studies suggesting the
involvement of specific genes and gene products in bipolar disorder have
elicited considerable excitement about the possibilities for improved
treatment of this condition (Gurling
et al, 1995; Gelerntner, 1995;
Berrettini et al,
1997; Nurnberger & Berrettini, 1998;
Barondes, 1998). Like other
common and complex diseases such as diabetes
(Davies et al, 1994;
Aitman & Todd, 1995) and
hypertension (Thibonnier & Schork,
1995; O'Connor et
al, 1996), the transmission of bipolar disorder appears to be
multi-factorial in nature rather than the result of simple Mendelian
inheritance (discussed in Philbert et
al, 1997). A recent study has even provided evidence for a
locus for mental health wellness, on chromosome 4p at D4S2949, in pedigrees
exhibiting high rates of bipolar disorder
(Ginns et al, 1998). These data suggest that the bipolar disorder phenotype may arise from a
complex interplay of not only genetic and environmental risk factors, but also
genetic and environmental protective factors. Moreover, differences in
diagnostic criteria and aetiological heterogeneity may account for the failure
to replicate many older linkage studies in bipolar disorder. More recently,
several independent research groups have reported linkage of bipolar disorder
to disparate chromosomal regions — 4p
(Blackwood et al,
1996), 6p, 13q and 15q (Ginns
et al, 1996) and 18q
(Freimer et al,
1996). An accompanying commentary by Risch & Botstein
(1996) attributed much of the
uneven findings to the complex genetic mechanisms underlying the disease.
Linkage studies will undoubtedly continue to be an important means of
exploring the aetiology and potentially the selective treatment responsiveness
of bipolar disorder; nevertheless, there is a growing consensus that other
methods are needed to identify the biochemical pathways underlying the
pathophysiology of what is arguably the most complex of all neuropsychiatric
disorders. Indeed, it is becoming increasingly apparent that a true
understanding of the pathophysiology of bipolar disorder must address its
neurobiology at different physiological levels — molecular, cellular,
systemic and behavioural (Manji &
Lenox, 2000). Abnormalities in gene expression undoubtedly
underlie the neurobiology of the disorder at the molecular level, and this
will become evident from identification of the susceptibility and protective
genes for bipolar disorder in the coming years. This must be followed by the
even more difficult task of examining the impact of the faulty expression of
these gene products (proteins) on integrated cell function. It is at these
levels that recent studies have identified certain proteins as potential
targets for the actions of mood-stabilising drugs.
There are, however, several impediments to the elucidation of the molecular
and cellular mechanisms of action of mood stabilisers. First, no suitable
experimental model of bipolar disorder is available, and many studies are of
necessity conducted in normal rodents. Animal models of drug dependence have
probably been instrumental in the pace of research on their molecular
mechanisms (Hyman & Nestler,
1996). Second, a problem in the identification of therapeutically
relevant target genes for the actions of mood stabilisers is the lack of
easily detectable phenotypic changes induced by these agents
(Ikonomov & Manji, 1999). This makes the task of ascribing functional significance to the multiple
treatment-induced changes at the genomic level daunting. Moreover,
establishing the genetic basis of mood as a quantitative trait is still at its
inception (Flint & Corley,
1996) and we therefore cannot focus on a group of already known
genes. Finally, there is the dearth of knowledge concerning the neuronal
circuits and pathways involved in the pathophysiology of what is probably a
group of complex, heterogeneous disorders with overlapping symptom clusters,
subsumed under the rubric of ‘manic—depressive illness’ or
‘bipolar disorder’.
Despite these formidable obstacles, progress is being made, using advanced
cellular and molecular biological strategies to identify changes in signalling
pathways and gene expression that may have therapeutic relevance in the
long-term treatment of bipolar disorder. This article looks at recent research
on the molecular mechanisms underlying the therapeutic effects of mood
stabilisers. For discussion of some of the other signalling pathways that have
been implicated in the pathophysiology and treatment of bipolar disorder,
readers are referred to reviews by Wang et al,
(1997); Jope
(1999); Li et al
(2000); Post et al
(2000) and Warsh et
al (2000).
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LITHIUM AS A MOOD STABILISER IN THE TREATMENT OF BIPOLAR
DISORDER
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Our research laboratory has been extensively involved in the identification
of specific proteins and regulatory processes involved in the action of
mood-stabilising agents, particularly the monovalent cation that has had a
profound effect on the lives of millions — lithium
(Goodwin & Jamison, 1990; Baldessarini & Tondo,
2000). The discovery of lithium's efficacy as a mood-stabilising
agent revolutionised the treatment of patients with bipolar disorder —
indeed, it has reshaped not only medical and scientific ideas, but also
popular concepts of severe mental illness
(Manji et al,
2000a). After nearly three decades of use in North
America, lithium continues to be the mainstay of treatment for bipolar
disorder, both for the acute manic phase and as prophylaxis for recurrent
manic and depressive episodes (Goodwin
& Jamison, 1990; Baldessarini et al,
1997; Davis et al,
1999; Baldessarini & Tondo,
2000). Numerous placebo-controlled studies have strongly suggested
the efficacy of lithium in the long-term prophylactic treatment of bipolar
disorder, and the beneficial effects appear to involve a reduction in the
number of episodes as well as in their intensity (reviewed in
Goodwin & Jamison, 1990;
Davis et al, 1999;
Baldessarini & Tondo,
2000). There is compelling evidence that adequate lithium
treatment, particularly when given in the context of a specialist clinic, also
reduces the excessive mortality observed in the illness
(Muller-Oerlinghausen et al,
1992; Baldessarini et
al, 1997; Nilsson,
1999).
Despite lithium's role as one of psychiatry's most important treatments,
the cellular and molecular basis for its beneficial effects have yet to be
elucidated (Bunney & Garland-Bunney,
1987; Jope & Williams,
1994; Manji et al,
2000a). Although a number of acute effects of lithium
have been identified in vitro, its therapeutic effects in the
treatment of bipolar disorder are only seen after chronic administration,
thereby precluding any simple mechanistic interpretations based on its acute
biochemical effects. The search for the mechanisms of action of
mood-stabilising agents has been facilitated by a growing appreciation that,
rather than any single neurotransmitter system being responsible for
depression or mania, many interacting and overlapping systems are involved in
regulating mood, and the most effective drugs are unlikely to work on any
particular neurotransmitter system in isolation but, rather, affect the
functional balance between interacting systems. Signal transduction pathways
are therefore an attractive target to explain lithium's efficacy in treating
multiple aspects of bipolar disorder (Jope
& Williams, 1994; Manji
et al, 2000a), and consequently recent research
into the effects of mood-stabilising agents has focused upon second-messenger
generating systems and gene expression
(Mork et al, 1992;
Jope & Williams, 1994;
Wang et al, 1997;
Jope, 1999; Manji et
al, 1999,
2000a;
Li et al, 2000;
Warsh et al,
2000).
Lithium and the phosphoinositide cycle: is the inositol depletion
hypothesis a valid model?
In the 1990s research on the cellular mechanisms underlying lithium's
therapeutic effects focused extensively upon receptor-coupled hydrolysis of
phosphatidylinositol 4,5-bisphosphate (PIP2). Although inositol
phospholipids are relatively minor components of cell membranes, they have a
major role in receptor-mediated signal transduction pathways, and are involved
in a diverse range of responses in the central nervous system (reviewed in
Baraban et al, 1989;
Berridge & Irvine, 1989;
Catt & Balla, 1989; Chuang, 1989;
Rana & Hokin, 1990;
Fisher et al, 1992).
Activation of a variety of neurotransmitter receptor subtypes (including
muscarinic M1, M3 and M5, noradrenergic
1, serotonergic 5-HT2 and several metabotropic
glutamatergic receptors) induces the hydrolysis of membrane phospholipids. In
brief, agonists such as acetylcholine, noradrenalin (noradrenalin), serotonin
or glutamate bind to specific cell surface receptors, which interact with G
proteins to stimulate phospholipase Cß (PLCß). Activated PLC
catalyses the conversion of PIP2 to two second messengers, inositol
1,4,5-trisphosphate (IP3) and diacylglycerol (DAG): IP3
stimulates the mobilisation of intracellular calcium ions, while DAG activates
protein kinase C (PKC). The trisphosphate can be phosphorylated and
dephosphorylated, leading to other inositol phosphate compounds or to
unphosphorylated inositol. Inositol is then converted to phosphatidylinositol
(PI), which in turn is phosphorylated to phosphatidylinositol phosphate (PIP)
and PIP2 (Fig.
1).
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Fig. 1 The phosphoinositide cycle. The binding of a hormone or agonist (H) to
receptor (R) activates G proteins which stimulate phospholipase C (PLC); PLC
hydrolyses phosphatidylinositol 4,5-bisphosphate (PIP2) to the two
second messengers diacylglycerol (DAG) and inositol 1,4,5-trisphosphate
(Ins(1,4,5)P3). Ins(1,4,5)P3 stimulates the mobilisation
of calcium [Ca2+]il and DAG activates protein kinase C
(PKC). Ins(1,4,5)P3 can be further phosphorylated to
Ins(1,3,4,5)P4 or dephosphorylated to Ins(1,4)P2.
Subsequent dephosphorylations recycle inositol phosphates to inositol. Two
phosphatases are inhibited uncompetitively by lithium, inositol
polyphosphate-1-phosphatase (which dephosphorylates Ins(1,3,4)P3
and Ins(1,4)P2 to Ins(3,4)P2 and Ins(4)P), and inositol
monophosphatase (which dephosphorylates inositol monophosphates Ins(1)P,
Ins(3)P, and Ins(4)P to inositol). Free inositol (along with cytidine
monophosphate phosphatidate (CMP-PA)) is essential for the synthesis of
phosphatidylinositol (PI) and PIP2; CDP, cytidine
5'-diphosphate.
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The ability of a cell to maintain sufficient supplies of
myo-inositol (mI) is crucial to the resynthesis of the
phosphoinositides, and the maintenance and efficacy of signalling. Lithium, at
therapeutically relevant concentrations, is an inhibitor of inositol
monophosphatase (Ki 0.8 mmol/L), and results in an
accumulation of inositol 1-monophosphate as well as a reduction in free
inositol (Allison & Stewart,
1971; Hallcher & Sherman,
1980). Lithium also inhibits inositol polyphosphate-1-phosphatase,
which is involved in recycling inositol polyphosphates to inositol.
Furthermore, since the mode of enzyme inhibition is uncompetitive, lithium's
effects have been postulated to be most pronounced in systems undergoing the
highest rate of PIP2 hydrolysis (see reviews by Nahorski et
al, 1991,
1992). Thus, Berridge and
associates first proposed that the physiological consequence of lithium's
action is derived through a depletion of free inositol, and that its
selectivity could be attributed to its preferential action (due to the
uncompetitive nature of the inhibition) on the most overactive
receptor-mediated neuronal systems (Berridge et al,
1982,
1989). However, numerous
studies have examined the effects of lithium on receptor-mediated PI
responses, and although some report a reduction in agonist-stimulated
PIP2 hydrolysis in rat brain slices following acute or chronic
lithium administration, these findings have often been small and inconsistent,
and subject to numerous methodological differences — see Jope &
Williams (1994) for an
excellent review. Additionally, several lines of evidence suggest that the
action of chronic lithium treatment may not simply be directly manifested in
receptor-mediated PI turnover. While investigators have observed that the
levels of inositol in brain remain reduced in rats receiving chronic lithium,
it has been difficult to demonstrate that this results in a reduction in the
resynthesis of PIP2, which is the substrate for agonist-induced PI
turnover (reviewed in Jope & Williams,
1994).
A series of studies have recently been undertaken to determine if lithium
does indeed reduce the levels of mI in critical brain regions of
individuals with bipolar disorder (despite the attractiveness of the inositol
depletion hypothesis, it has never been demonstrated to occur in human brain),
and if so, whether these reductions are associated with its therapeutic
effects.
Proton magnetic resonance spectroscopy (MRS) spectra were acquired from 8cc
regions of interest (ROIs) in the frontal, temporal, parietal and occipital
lobes, with an acquisition time of 5 min/ROI (STEAM pulse sequence TE 30 ms,
TM 13.7 ms, TR 2000 ms (Frahm et
al, 1987) Fig.
2). Using proton MRS, we have been able to quantitate regional
brain mI concentrations with excellent reliability
(Moore et al, 1999).
Using a test—retest design (scan interval range 1-12 weeks) in six
healthy volunteer subjects, the brain mI concentration (expressed in
units of mI x 104/brain water and reported as the
mean (standard error)) was 2.57 (0.28) v. 2.50 (0.24) with a mean
difference of 0.07 or ±3% of the mI measure, demonstrating
that the temporal stability and test—retest reliability of this measure
are remarkably good. In order to evaluate the interrater reliability of this
method, two trained individuals analysed the in vivo magnetic
resonance data with MRUI-VARPRO time domain spectral analysis software
(Van den Boogaart et al,
1994; de Beer et al,
1992). The individuals were masked to the study information and to
each other's results. Intraclass correlation coefficient analysis revealed an
interrater reliability of more than 98%.
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Fig. 2 Brain regions examined and typical proton magnetic resonance spectrum
(MRS). Regions of interest: (a) frontal lobe, (b) temporal lobe, (c) parietal
lobe, (d) occipital lobe. Lower panes: frontal lobe proton MRS from a bipolar
disorder patient. PPM, parts per million, ml, myo-inositol;
cho, choline compounds; Cr, creatine compounds; Glx, glutamate/glutamine/GABA;
NA, N-acetyl compounds.
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After extensive validation for in vivo measurement of regional
brain mI concentration as well as careful determination that the 1.5
T mI resonance is indeed predominately mI (
80%)
(Moore et al, 1999), this method has been applied in studies of bipolar disorder. Following
medication wash-out (2 weeks), MRS scans were performed in patients at
three time points: baseline; after 5 days of lithium treatment; and after 4
weeks of lithium treatment. It was found that therapeutic administration of
lithium did indeed produce significant reductions in mI levels in
brain regions that had previously been implicated in the pathophysiology of
bipolar disorder (Moore et al,
1999). However, the major lithium-induced mI reductions
are observed after only 5 days of lithium administration, at a time when the
patient's clinical state is completely unchanged.
Consequently, although lithium does reduce mI levels
(Jope & Williams, 1994), this reduction per se is not associated with a therapeutic response.
Although the inositol depletion hypothesis as originally articulated does not
receive support from this longitudinal human study, it remains an attractive
working hypothesis that some of the initial actions of lithium may occur with
the relative depletion of mI
(Godfrey et al, 1989;
Pontzer & Crews, 1990;
Kofman & Beimaker, 1990, 1993;
Tricklebank et al,
1991). This relative depletion of mI may initiate a
cascade of secondary changes at different levels of the signal transduction
process and gene expression in the central nervous system, effects that are
ultimately responsible for lithium's therapeutic efficacy
(Manji & Lenox, 1999). Studies are in progress to determine if the lithium-induced reductions in
mI levels are associated with components of ultimate therapeutic
response.
Lithium, valproate and the PKC signalling cascade: implications for
the development of novel drugs for bipolar disorder
The PKC signalling pathway is also a target for the actions of chronic
lithium (reviewed in Hahn & Friedman,
1999; Jope, 1999;
Manji & Lenox, 1999,
2000). PKC is highly enriched
in brain, and plays a major role in regulating pre- and post-synaptic aspects
of neurotransmission (Huang,
1989; Stabel & Parker,
1991; Nishizuka,
1992). It is now known to exist as a family of closely related
sub-species, has a heterogeneous distribution in brain (with particularly high
levels in presynaptic nerve terminals) and plays a major part in the
regulation of neuronal excitability, neurotransmitter release and long-term
alterations in gene expression and plasticity
(Huang, 1989;
Stabel & Parker, 1991;
Nishizuka, 1992). Evidence
accumulating from various laboratories has demonstrated that lithium exerts
significant effects on PKC in a number of cell systems including the brain
(reviewed in Hahn & Friedman,
1999; Jope, 1999;
Manji & Lenox, 1999,
2000). Most of the currently
available data suggest that chronic lithium exposure results in an attenuation
of phorbol ester-mediated responses, which may be accompanied by a
downregulation of PKC isozymes in the brain (reviewed in
Hahn & Friedman, 1999; Jope, 1999; Manji & Lenox,
1999,
2000). Using quantitative
autoradiographic techniques, it has been demonstrated that chronic lithium
administration results in a significant decrease in membrane-associated PKC in
several hippocampal structures. This is accompanied by isozyme-specific
decreases in PKC- and -
(which have been particularly implicated
in facilitating neurotransmitter release), in the absence of significant
alterations in PKC-ß, PKC-
, PKC-
or PKC-
(Manji et
al, 1993,
2000a). Concomitant
studies carried out in immortalised hippocampal cells in culture exposed to
chronic lithium show a similar reduction in the expression of both the
PKC- and - isozymes in the cell as determined by immunoblot
(Manji & Lenox, 1999).
Chronic lithium has also been demonstrated to dramatically reduce the
hippocampal levels of a major PKC substrate myristoylated alanine-rich C
kinase substrate (MARCKS), which has been implicated in regulating long-term
neuroplastic events (Lenox et al,
1992). Do these effects of lithium on PKC isozymes have any
clinical relevance? Given the key role of PKC isozymes in the regulation of
neuronal excitability and in neurotransmitter release, the possibility that
inhibition of these isozymes represents the biochemical effect most
therapeutically relevant for lithium's antimanic effects is a heuristic and
testable hypothesis (discussed in more detail below). Although these effects
of lithium on PKC isozmes and MARCKS are striking, a major problem inherent in
neuropharmacological research is the difficulty in attributing therapeutic
relevance to any observed biochemical finding. It is thus noteworthy that the
structurally dissimilar antimanic agent, valproate, produces very similar
effects to those of lithium on PKC- and - isozymes and MARCKS
protein (Chen et al,
1994; Watson et al,
1998; Manji & Lenox,
1999; Manji et al,
2000a). Interestingly, lithium and valproate appear to
act on the PKC signalling pathway by different mechanisms
(Manji & Lenox, 1999);
these biochemical observations are consistent with the clinical observations
that some patients show a preferential response to one or other of the agents,
and that additive therapeutic effects are often observed when the two agents
are co-administered (Freeman & Stoll,
1998).
Are PKC inhibitors effective in the treatment of acute mania?
To date, only a few studies have directly examined PCK in bipolar disorder
(Hahn & Friedman, 1999).
Friedman and associates investigated PCK activity and PKC translocation in
response to serotonin in platelets obtained from patients with bipolar
disorder before and during lithium treatment
(Friedman et al,
1993). The ratios of platelet membrane-bound to cytosolic PKC
activities were elevated in the manic group, in whom serotonin-elicited
platelet PKC translocation was also enhanced. With respect to brain tissue,
Wang & Friedman (1996)
measured PKC isozyme levels, activity and translocation in post-mortem brain
tissue from patients who had bipolar disorder; PKC activity and translocation
were greater than in control samples, as were cortical levels of selected PKC
isozymes.
In view of the pivotal role of the PKC signalling pathway in the regulation
of neuronal excitability, neurotransmitter release and long-term synaptic
events (Nishizuka, 1992;
Stabel & Parker, 1991; Huang, 1989;
Conn & Sweatt, 1994), it
was postulated that the attenuation of PKC activity may have a major role in
the antimanic effects of lithium and valproate. There was thus a clear need to
investigate the efficacy of PKC inhibitors in the treatment of mania. There is
currently only one relatively selective PKC inhibitor available for human use
— tamoxifen. This is a synthetic, nonsteroidal antioestrogen widely used
in the treatment of breast cancer
(Catherino & Jordan, 1993;
Jordan, 1994). A number of the
effects of tamoxifen are due to oestrogen-receptor antagonism
(Jordan, 1994), but it has
become clear in recent years that it is also a potent PKC inhibitor at
therapeutically relevant concentrations
(Couldwell et al,
1993). A pilot study investigating the efficacy of tamoxifen in
the treatment of acute mania found that this agent does indeed possess
antimanic efficacy (Bebchuk et al,
2000) (Fig. 3).
Despite the small sample size, the results are intriguing, and support the
hypothesis that the antimanic effects of lithium and valproate are mediated by
PKC inhibition. In view of the apparent involvement of the PKC signalling
system in the pathophysiology of bipolar disorder
(Friedman et al,
1993; Wang & Friedman,
1996), these results indicate that PKC inhibitors may be useful
agents in its treatment. Larger, double-blind, placebo-controlled studies of
tamoxifen and of novel selective PKC inhibitors in the treatment of mania are
clearly warranted.
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Fig. 3 Effects of tamoxifen in the treatment of acute mania. Tamoxifen was
administered to 10 subjects with acute mania in blinded form; raters were
blind to the treatment regimen. Main outcome measures included the Young Mania
Rating Scale (YMRS), the Clinician Administered Rating Scale for Mania and the
Hamilton Rating Scale for Depression. Tamoxifen resulted in a significant
decrease in manic symptomatology rated by the YMRS (*P
< 0.05).
Figure reproduced, with permission, from data in Bebchuk et al
(2000).
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EFFECTS OF MOOD STABILISERS ON TRANSCRIPTION FACTORS AND GENE
EXPRESSION
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It has become increasingly appreciated that biochemical models proposed for
the effects of many psychotropic drugs (including mood stabilisers,
antidepressants and anti-psychotics) must attempt to account for their special
temporal clinical profile — in particular, that the therapeutic effects
require a lag period for onset of action, and are generally not immediately
reversed upon discontinuation (Hyman &
Nestler, 1996; Duman et
al, 1997; Jope,
1999; Manji et al,
1999,
2000a). Patterns of
effects requiring such prolonged administration of the drug suggest
alterations at the genomic level (Manji
et al, 1995; Human & Nestler, 1996;
Duman et al, 1997).
To investigate the putative effects of mood stabilisers on gene expression,
their effects on the DNA binding activity of transcription factors, especially
the activator protein 1 (AP-1) family of transcription factors, were examined.
The AP-1 factors are a collection of homodimeric and heterodimeric complexes
composed of products from two transcription factor families, Fos and Jun.
These products bind to a common DNA site, known as the
12-O-tetradecanoyl-phorbol-13-acetate (TPA) response element (TRE),
in the regulatory domain of the gene, and activate gene transcription in
response to PKC activators, growth factors, cytokines and other agents
(including neurotransmitters) (Karin &
Smeal, 1992; Hughes &
Dragunow, 1995). Induction of c-fos is rapid and
transient: Fos protein reaches its maximal levels within 30 minutes, and
decreases to low levels within 1-2 hours
(Hughes & Dragunow, 1995).
Induction of c-jun is longer-lasting and varies from a few hours to
several days, depending on the cell type and the stimulus
(Hughes & Dragunow, 1995). The c-jun gene is subject to positive autoregulation through an AP-1
binding site in its promoter. The genes known to be regulated by the AP-1
family of transcription factors in the brain include genes for various
neuropeptides, neurotrophins, receptors, transcription factors, enzymes
involved in neurotransmitter biosynthesis and proteins that bind to
cytoskeletal elements (Hughes &
Dragunow, 1995).
Several independent laboratories have demonstrated that lithium, at
therapeutically relevant concentrations, regulates AP-1 DNA binding activity
(Williams & Jope, 1995;
Jope & Song, 1997; Ozaki & Chuang, 1997;
Unlap & Jope, 1997; Yuan et al, 1998;
Chen et al,
1999a). The effects of lithium and valproate on the DNA
binding activity of AP-1 were examined using methods verified by both
competition assay with cold and mutant TRE oligos and supershift assay with
antibodies against AP-1 transcription factors
(Yuan et al, 1998;
Chen et al,
1999a). Both lithium and valproate at therapeutically
relevant concentrations, produced a time- and concentration-dependent increase
in the DNA binding of TRE to AP-1 transcription in rat brain ex vivo,
and in cultured human neuroblastoma cells factors
(Yuan et al, 1998;
Chen et al,
1999a). It was further confirmed that these effects on
AP-1 DNA binding activity do, in fact, translate into changes at the gene
expression level. Effects of lithium on gene expression were first studied in
cells transiently transfected with the pGL2 control vector. The reporter gene,
luciferase in the pGL2 control vector, is driven by simian virus 40 (SV40)
promoter, which has two characterised AP-1 sites. Using this reporter gene
transfection system, the role of the AP-1 sites in mediating valproate's
effects on gene expression was further examined by eliminating the AP-1 sites
by mutagenesis. Lithium increased the expression of the luciferase reporter
gene driven by an SV40 promoter/enhancer containing TREs
(Yuan et al, 1998;
Chen et al,
1999a); this increase was time- and
concentration-dependent. Furthermore, mutations in the TRE sites of the
reporter gene promoter markedly attenuated these effects. These data indicate
that lithium may stimulate gene expression (at least in part) through the AP-1
transcription factor pathway, effects that may play an important part in its
long-term clinical actions (Fig.
4).
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Fig. 4 Effects of lithium and valproate (VPA) on luciferase reporter gene activity
in cultured cells: (a) time and (b) dose dependency. Cells were cultured,
transfected with the pGL2 control vector and then incubated with lithium or
valproate at the concentrations indicated in (a) for 24 hours, or with lithium
(1.0 mol/l) or VPA (1.0 mol/l) for the times indicated in (b) as described in
Yuan et al (1998)
and Chen et al
(1999a). Luciferase
activity was assayed in the whole cell lysates using the Promega kit. Data are
means (s.e.). *P < 0.05 compared to control. (c)
Attenuation of the lithium- or valproate-induced increases in luciferase
activity by TRE mutations. The mutations on the TRE sites were made using the
QuikChange site directed mutagenesis kit. Cells were transfected with either
pGL2 control or mutant pGL2 control and then incubated with 1.0 mmol/l lithium
or 0.6 mmol/l valproate for 24 hours. Luciferase activity was assayed using
the Promega kit. The values in the bar graphs are the means (s.e.) of three or
more experiments. Reproduced from Yuan et al
(1998) and Chen et
al (1999c) with
permission.
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To ascribe therapeutic relevance to the observed biochemical findings it is
necessary to demonstrate that they do, in fact, also occur in critical regions
of the central nervous system in vivo. It is well established that
the expression of tyrosine hydroxylase (TH) is largely mediated by the AP-1
family of transcription factors (Kumer
& Vrana, 1996). The effects of acute and chronic lithium on
the levels of TH in three brain areas that have been implicated in the
pathophysiology of mood disorders — the frontal cortex, hippocampus and
striatum — were therefore examined
(Goodwin & Jamison, 1990; Drevets et al, 1992,
1997;
Ketter et al, 1997;
Soares & Mann, 1997). It
was found that chronic lithium treatment significantly increased the levels of
TH in all three brain areas (Chen et
al, 1998). Future in situ hybridisation studies or
immunohistochemistry studies are needed to determine if lithium also increases
the expression of TH in areas of brain known to contain the cell bodies of the
major noradrenergic and dopaminergic systems, namely the locus caeruleus,
ventral tegmental area and substantia nigra. The results clearly show that in
addition to increasing AP-1 DNA binding activity and the expression of the
luciferase reporter gene in vitro, chronic lithium administration
increases the TH levels in areas of rat brain ex vivo. These effects
are compatible with an effect on the DNA binding of TRE to the AP-1 family of
transcription factors, and have the potential to regulate patterns of gene
expression in critical neuronal circuits
(Boyle et al, 1991;
Lin et al, 1993). In
view of the key roles of these nuclear transcription regulatory factors in
longterm neuronal plasticity and cellular responsiveness, and the potential to
regulate patterns of gene expression in critical neuronal circuits
(Boyle et al, 1991;
Lin et al, 1993),
these effects may be important in the therapeutic efficacy of lithium and
valproate, and are worthy of further study. The precise mechanisms by which
lithium regulates AP-1 DNA binding activity still need to be fully delineated,
but may involve effects on PKC isozymes
(Yuan et al, 1999).
Furthermore, as we discuss in greater detail below, lithium, at clinically
relevant concentrations, has been demonstrated to inhibit the activity of
glycogen synthase kinase-3ß (GSK-3ß) (Hedgepeth et al,
1997; Klein & Melton,
1996; Stambolic et
al, 1996). This enzyme is known to phosphorylate
c-jun at three sites adjacent to the DNA binding domain, thereby
reducing TRE binding (Lin et al,
1993; Stambolic et
al, 1996).
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GLYCOGEN SYNTHASE KINASE
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Is GSK-3ß a therapeutically relevant target for mood-stabilising
agents?
In the late 1990s a completely unexpected target for the action of lithium
was identified. Klein & Melton
(1996) were the first to
demonstrate that lithium, at therapeutically relevant concentrations, is an
inhibitor of GSK-3ß. This is an evolutionarily highly conserved kinase,
originally identified as a regulator of glycogen synthesis, and is now known
to have an important role in the central nervous system, by regulating various
cytoskeletal processes through its effects on tau and synapsin I, as well as
long-term nuclear events by phosphorylation of c-jun, and nuclear
translocation of ß-catenin (Klein
& Melton, 1996; Wagner
et al, 1996; Yost
et al, 1996; Ikeda
et al, 1997; Lucas
& Salinas, 1997). However, lithium is known to bring about a
variety of biochemical effects (Bunney
& Garland-Bunney, 1987; Mork et al, 1992;
Chang et al, 1996;
Jope, 1999) (see
Table 2), and it is unclear if
inhibition of GSK-3ß is therapeutically relevant. A series of studies
were therefore undertaken to determine if valproate, like lithium, also
regulates GSK-3; it was found that valproate inhibits both GSK-3 and
GSK-3ß in a concentration-dependent manner, with significant effects
observed at concentrations similar to those attained clinically
(Chen et al,
1999b) (Fig.
5).
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Fig. 5 Effects of valproate (VPA) on glycogen synthase kinase 3 (GSK-3). (a, b)
Effects of VPA on GSK-3 activity. The reaction was carried out using
purified or recombinant GSK-3, and 150 µmol/l MgATP (as described in
Chen et al,
1999b) with VPA, either in the absence (a) or presence
(b) of additional Mg2+ (20 mmol/l). Data are means (s.e.) from
three experiments. (c, d) Effects of VPA on GSK-3ß activity (as described
in Chen et al,
1999b) in the absence (c) or presence (d) of additional
Mg2+ (20 mmol/l). Data are means (s.e.) from three experiments. VPA
inhibited GSK-3 and GSK-3ß in a concentration-dependent manner,
both in the absence and presence of Mg2+; *P
< 0.05 compared to control (e, f). Additivity of the effects of VPA and
lithium on GSK-3 activity. The reaction was carried out at room temperature
for 20 minutes utilising 0.5 U GSK-3 or GSK-3ß, with either VPA
alone (0.6 mmol/l), or VPA (0.6 mmol/l) plus lithium (1.0 mmol/l). Data are
means (s.e.) from three experiments. The addition of lithium resulted in
further significant reductions in the activity of both GSK-3 and
GSK-3ß; *P < 0.05 compared to VPA alone. Figure
modified, and reproduced, with permission from Chen et al
(1999b).
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Incubation of intact human neuroblastoma SH-SY5Y cells with valproate
resulted in an increase in the subsequent in vitro recombinant
GSK-3ß-mediated 32P incorporation into two putative GSK-3
substrates (approximate molecular weights 85 and 200), compatible with
inhibition of endogenous GSK-3ß by valproate. Consistent with GSK-3ß
inhibition, incubation of SH-SY5Y cells with valproate results in a
significant time-dependent increase in both cytosolic and nuclear
ß-catenin levels. Since GSK-3ß plays a critical role in the central
nervous system by regulating various cytoskeletal processes as well as
long-term nuclear events, and is a common target for both lithium and
valproate, its inhibition may underlie some of the long-term therapeutic
effects of mood-stabilising agents, and represents an exciting area of future
research.
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MESSENGER RNA DIFFERENTIAL DISPLAY STUDIES
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Regulation of long-term changes in gene expression by
mood-stabilising agents
Although several specific genes that are the targets of long-term lithium
and/or valproate have been identified, it has been estimated that
approximately 10 000-15 000 genes may be expressed in a given cell at any
time, and thus new methods are required to study the complex pattern of gene
expression changes induced by chronic drug treatment
(Hyman & Nestler, 1996;
Jope, 1999; Manji et
al, 1999,
2000b). New
methodologies have evolved to identify the differential expression of multiple
genes (e.g. in pathological v. normal tissue, or in control
v. treated tissue). The pool of transcribed mRNAs in a given cell is
termed a ‘transcriptome’, and underlies the cell phenotype. The
transcriptome, which includes the transcribed genes and the corresponding
number of mRNA copies, changes under both physiological and pathological
conditions, as well as in response to treatments. Identifying the genes whose
transcription is altered in the transition from one functional state to
another is central to defining the precise molecular events that regulate cell
phenotype and function. A series of studies utilising the technique of mRNA
differential display, based on reverse transcription and the polymerase chain
reaction, to identify changes in gene expression associated with the
therapeutic efficacy of mood stabilisers, investigated the effects of lithium
and valproate (the only two medications approved by the US Food and Drug
Administration for the treatment of bipolar disorder). Although these two
agents are unlikely to exert their therapeutic effects by precisely the same
mechanisms, identifying the genes that are regulated in concert by these
structurally highly dissimilar agents may provide important clues to the
molecular mechanisms underlying mood stabilisation
(Ikonomov & Manji, 1999).
Inbred male Wistar Kyoto rats (selected to reduce potential false positives
due to individual differences) were treated chronically with lithium,
valproate or saline. Ribonucleic acid was extracted from the frontal cortices
to study gene expression using mRNA differential display
(Liang & Pardee, 1992;
Liang et al, 1995).
One hundred and fifty reactions were performed with the combination of three
one-base anchored 3' primers and fifty 5' arbitrary primers
(Liang & Pardee, 1992;
Liang et al, 1995);
on average, 270 bands were obtained in each reaction. Clones were sequenced
from T7 and M13 priming sites using an automated sequencer; BLAST searches
were conducted for each clone obtained, and the homology with known sequences
in the GenBank database was further evaluated using the BESTFIT program from
the Genetic Computer Group's sequence analysis software package. To date, we
have identified a number of mRNA species whose expression is markedly
increased or decreased by both treatments.
One of the genes whose expression is markedly increased by both lithium and
valproate (clone 12; GenBank accession number AF087437) is 355 base pairs
long, contains a poly(A)tail, and shows high sequence homology with the
3' end of the ß subunit of the mouse (92% identical sequences) and
human (85%) transcription factor, polyomavirus enhancer binding protein 2
(PEBP2)ß, also known as core-binding factor (CBF) ß and acute
myelogenous leukaemia 1 (AML1) ß (Liu
et al, 1993; Wang
et al, 1996; Kanno
et al, 1998). In the absence of available antibodies to
PEBP2-ß, we next sought to determine if the treatments induced functional
changes in PEBP2 transcription factor activity. Treatment with both lithium
and valproate increased the DNA binding activity of PEBP2-ß in the
frontal cortex (Chen et al,
1999c). To determine if these effects are specific for
mood stabilisers, we investigated the effects of chronic D-amphetamine
sulphate and chlordiazepoxide; neither of these treatments produced any
detectable changes in PEBP2-ß DNA binding activity. We therefore
investigated putative targets of the PEBP2 transcription factor, which may be
of therapeutic relevance in the treatment of bipolar disorder.
The promoter of the B-cell lymphoma protein 2 (bcl-2) gene (both rat and
human genes) has a PEBP2 binding site, and this site has been clearly
demonstrated to increase the expression of a reporter gene driven by the bcl-2
promoter (Klampfer et al,
1996). A neuroprotective role for bcl-2 is well established, and
constitutive expression of high levels of bcl-2 protein enhances the survival
of cells when exposed to adverse stimuli
(Jacobson & Raff, 1995;
Merry & Korsmeyer, 1997).
Additionally, the delivery in vivo of a bcl-2 expression vector
protects neurons against focal ischaemia
(Lawrence et al,
1996), and bcl-2 has also been demonstrated to promote neuronal
regeneration (Chen et al,
1997). In this context, it is noteworthy that mood disorders,
including bipolar disorder, are associated with volumetric changes on magnetic
resonance imaging and computed tomography, suggestive of neuronal atrophy or
loss (Elkis et al,
1995; Drevets et al,
1997; Ketter et al,
1997). Furthermore, both brain imaging studies and postmortem
morphometric three-dimensional cell counting studies have implicated the
frontal cortex as a site of neuronal atrophy or loss in bipolar disorder
(Dreets et al, 1997; Rajkowska
et al, 1999;
Rajkowska, 2000). We
therefore investigated whether the treatment-induced increase in
PEBP2-ß DNA binding activity in the frontal cortex was accompanied
by changes in the levels of the neuroprotective protein, bcl-2. Chronic
treatment of rats with both lithium and valproate resulted in a doubling of
bcl-2 levels in the frontal cortex, effects that were accompanied by a marked
increase in the number of bcl-2 immunoreactive cells in layers 2 and 3 of the
frontal cortex. It is noteworthy that neuroprotective effects have recently
been reported for both lithium and valproate
(Bruno et al, 1995;
Nonaka et al, 1998);
the robust increases in the levels of bcl-2 that we have demonstrated may have
a major role in mediating these effects, and suggest that mood-stabilising
agents may bring about some of their long-term beneficial effects via hitherto
underappreciated neuroprotective effects
(Smith et al, 1995;
Duman et al, 1997;
Manji et al,
1999).
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CONCLUSION
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Regulation of signal transduction and gene expression within critical
regions of the brain affects the intracellular signal generated by a number of
neurotransmitter systems; these effects thus represent attractive putative
mediators of the therapeutic actions of mood stabilisers, effects that are
probably mediated via their effects on a network of interconnected
neurotransmitter pathways (Fig.
6). It is becoming increasingly clear that for many refractory
patients with these disorders, new drugs simply mimicking the
‘traditional’ drugs that directly or indirectly alter
neurotransmitter levels or bind to cell surface receptors may be of limited
benefit. This is because such strategies implicitly assume that the target
receptors are functionally intact, and that altered synaptic activity will
thus be transduced to modify the postsynaptic ‘throughput’ of the
system. However, the possible existence of abnormalities in signal
transduction pathways suggests that for patients refractory to conventional
medications, benefit may only be obtained by the direct targeting of
post-receptor sites (Nestler,
1998; Manji et al,
2000a,
2001). Recent discoveries
concerning a variety of mechanisms involved in the formation and inactivation
of second messengers offer the promise for the development of novel
pharmacological agents designed to ‘site-specifically’ target
signal transduction pathways. Although clearly more complex than the
development of receptor-specific drugs, it may be possible to design novel
agents to selectively affect second-messenger systems because they are
heterogeneous at the molecular and cellular level, are linked to receptors in
a variety of ways, and are expressed in different stoichiometries in different
cell types. Additionally, since signal transduction pathways display certain
unique characteristics depending on their activity state, e.g. rate of guanine
nucleotide exchange, G protein conformational states, GTP hydrolysis,
interaction with different regulators of G protein signalling (RGS) proteins,
cytosol to membrane translocation of PKC isozymes and receptor kinases, they
offer built-in targets for relative specificity of action, depending on the
‘set point’ of the substrate. It is our strong conviction that it
is at the cellular and molecular level that some of the most exciting advances
in our understanding of the long-term therapeutic action of lithium will take
place in the coming years (Manji & Lenox,
1999,
2000). Current studies of
long-term lithium-induced changes to the PKC signalling pathway (including PKC
isozyme regulation, post-translational modification of important
phosphoproteins, and PKC-mediated gene expression) are a most promising avenue
for future investigation. An exciting recent finding is the hitherto
completely unexpected demonstration that lithium robustly increases the levels
of the major neuroprotective protein bcl-2
(Manji et al, 1999).
This upregulation of bcl-2 is accompanied by neurotrophic effects of lithium
in both preclinical and clinical studies
(Manji et al,
2000b; Moore et
al,
2000a,b).
In view of the recent brain imaging studies and postmortem morphometric
three-dimensional cell counting studies demonstrating neuronal atrophy or loss
in bipolar disorder (Rajkowska et
al, 1999), these results raise the intriguing possibility
that mood-stabilising agents may bring about some of their long-term
beneficial effects by their underappreciated neuroprotective action (Duman
et al, 1997,
2000; Manji et al,
1999,
2000b)
(Fig. 7). These recent
observations also suggest that impairments of neuroplasticity and cellular
resilience may contribute to the pathophysiology of mood disorders, and the
poor long-term outcome observed in many patients
(Manji et al,
2000b). Strategies are being investigated to develop
small molecule switches for protein—protein interactions, which have the
potential to regulate the activity of growth factors, MAP kinase cascades and
interactions between homodimers and heterodimers of the bcl-2 family of
proteins (Guo et al,
2000); the development of treatments that directly target
molecules involved in critical neuronal survival and cell death pathways would
have the potential to enhance neuroplasticity and cellular resilience, and
thereby modulate the long-term course and trajector of these devastating
illnesses.
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Fig. 6 Effects of mood stabilisers on signalling pathways and gene expression.
Abbreviations as follows: receptors coupled to stimulation (Rr) or
inhibition (Ri) of adenylate cyclase (AC); G proteins mediating
stimulation (G5) or inhibition (Gi) of adenylate
cyclase; receptors (Rq) coupled to the G protein, Gqll;
phospholipase C ß isozyme (PLCß); receptor tyrosine kinase (TrK);
phosphatidylinositol 4,5-bisphosphate (PIP2); diacylglycerol, DAG;
inositol 1,4,5-trisphosphate (IP3); protein kinase C (PKC); mitogen
activated protein kinase (MAPK); mitogen activated protein kinase kinase
(MAPKK); glycogen synthase kinase 3 (GSK-3); cyclic AMP response element
binding protein (CREB); lithium (Li); carbamazepine (CBZ); valproate
(VPA).
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Fig. 7 Four principal levels of lithium effects. Lithium exerts its primary
biochemical effects at the molecular and cellular levels. These effects bring
about changes in critical interacting neuronal circuits, thereby regulating
affective, cognitive and motor systems, effects that are ultimately
responsible for bringing about long-term stabilisation of mood. GSK-3ß,
glycogen synthase kinase 3ß; mRNA, messenger RNA; PKC, protein kinase
C.
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Clinical Implications and Limitations
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CLINICAL IMPLICATIONS
- Greater understanding of the molecular and cellular mechanisms of action
of mood-stabilising agents will enhance the rationale for the development of
new treatments targeting intracellular targets.
- The long-term therapeutic effects of mood-stabilising agents may involve
underappreciated neurotrophic effects.
LIMITATIONS
- As yet, there are no phenotypical changes in rodent studies that are
clearly associated with treatment response.
- Most of the studies have been conducted in ‘normal’
rodents.
- Bipolar disorder undoubtedly represents a heterogeneous group of
disorders, and current studies do not adequately address this.
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ACKNOWLEDGMENTS
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The authors' research is supported in part by the National Institute of
Mental Health, the Theodore and Vada Stanley Foundation, National Association
for Research on Schizophrenia and Depression and the Joseph Young Senior
Foundation. The authors would also like to acknowledge the valuable
contributions of Joseph M. Bebchuk, MD; Debra Glitz, MD; the nursing staff of
the Neuropsychiatric Research Unit; and Ms Celia Knobelsdorf for providing
outstanding editorial assistance.
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TOP
ABSTRACT
INTRODUCTION
