Kurs “ Allgemeine und systematische Pharmakologie und ... II_2.pdf · FEATURE ARTICLE Molecular...

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Kurs “ Allgemeine und systematische Pharmakologie und Toxikologie” Sommersemester 2018 Seminarthema II: Psychopharmaka Der Inhalt bzw. die Gliederung der Referate ist frühzeitig mit der/dem zuständigen Dozentin/en abzusprechen. Alle Referate sollten ca. 20 Minuten dauern und den Einsatz von Hilfsmitteln (Powerpoint-Präsentation) umfassen. Bei Wiederverwendung von Präsentationen von Kolleginnen/en vorangegangener Seminare werden keine Jokerpunkte (siehe Link "Creditsystem") vergeben. apl Prof. Dr. Barbara Möpps N 26-5208 Tel. 500-65505/65515 Referat I: Therapie der unipolaren Depression Millan, M.J., Goodwin, G.M., Meyer-Lindenberg, A., and S.O. Ogren (2015): Learning from the past and looking to the future: Emerging perspectives for improving the treatment of psychiatric disorders. Eur. Neuropsychopharmacol., http://dx.doi.org/10.1016/j.euroneuro.2015.01.016 (nur den Teil: Therapie der Depression) Bschor, T. and M. Adli (2008): Treatment of depressive disorders. Dtsch. Ärztebl. Int. 105: 782-792. Bleakley,S. (2013): Review of the choice and use of antidepressant drugs. Progress Neurology and Psychiatry. November/December. www.progressnp.com. Ihr Referat sollte folgende Punkte umfassen: - Monoaminhypothese, Mechanismen der Entstehung der Depression, Therapie der unipolaren Depression: trizyklische und heterozyklische Antidepressiva, MAO- und reuptake-Inhibitoren - Therapeutische Anwendung und Nebenwirkungen Referat II: Therapie der bipolaren Affekterkrankung Lenox, R.H., and Wang, L. (2003): Molecular basis of lithium action: integration of lithium- responsive signaling and gene expression networks. Mol. Psychatry 8: 135-144. Sie, M. (2014): Mood stabilizers in the management of bipolar affective disorder. Progress Neurology and Psychiatry. May/June. www.progressnp.com. S3-Leitlinie zur Diagnostik und Therapie bipolarer Störungen. www. Leitlinien-bipolar.de Ihr Referat sollte folgende Punkte umfassen: - Definition und Therapie der bipolaren Affekterkrankung - Molekulare und zelluläre Mechanismen der Wirkung von Lithiumionen sowie Pharmakokinetik und Pharmakodynamik von Lithium Referat III: Therapie der Schizophrenie Millan, M.J., Goodwin, G.M., Meyer-Lindenberg, A., and Ogren, S.O. (2015): Learning from the past and looking to the future: Emerging perspectives for improving the treatment of psychiatric disorders. Eur. Neuropsychopharmacol., http://dx.doi.org/10.1016/j.euroneuro.2015.01.016 (nur den Teil: Therapie der Schizophrenie) Burlon, M. (2007): Pharmakotherapie der Schizophrenie-“state of the art”. NeuroTransmitter 5, 59-70. Parker, C. (2013): Antipsychotics in the treatment of schizophrenia. Progress Neurology and Psychiatry.May/June. www.progressnp.com. Ihr Referat sollte folgende Punkte umfassen: - Pathogenese der Schizophrenie, neue Ansätze in der Therapie - Therapie: niederpotente versus hochpotente Antipsychotika typische (first) versus atypischen (second) Antipsychotika, NW

Transcript of Kurs “ Allgemeine und systematische Pharmakologie und ... II_2.pdf · FEATURE ARTICLE Molecular...

Page 1: Kurs “ Allgemeine und systematische Pharmakologie und ... II_2.pdf · FEATURE ARTICLE Molecular basis of lithium action: integration of lithium-responsive signaling and gene expression

Kurs “ Allgemeine und systematische Pharmakologie und Toxikologie” Sommersemester 2018

Seminarthema II: Psychopharmaka Der Inhalt bzw. die Gliederung der Referate ist frühzeitig mit der/dem zuständigen Dozentin/en abzusprechen. Alle Referate sollten ca. 20 Minuten dauern und den Einsatz von Hilfsmitteln (Powerpoint-Präsentation) umfassen. Bei Wiederverwendung von Präsentationen von Kolleginnen/en vorangegangener Seminare werden keine Jokerpunkte (siehe Link "Creditsystem") vergeben.

apl Prof. Dr. Barbara Möpps N 26-5208 Tel. 500-65505/65515

Referat I: Therapie der unipolaren Depression Millan, M.J., Goodwin, G.M., Meyer-Lindenberg, A., and S.O. Ogren (2015): Learning from the past and looking to the future: Emerging perspectives for improving the treatment of psychiatric disorders. Eur. Neuropsychopharmacol., http://dx.doi.org/10.1016/j.euroneuro.2015.01.016

(nur den Teil: Therapie der Depression) Bschor, T. and M. Adli (2008): Treatment of depressive disorders. Dtsch. Ärztebl. Int. 105: 782-792. Bleakley,S. (2013): Review of the choice and use of antidepressant drugs. Progress Neurology and Psychiatry. November/December. www.progressnp.com.

Ihr Referat sollte folgende Punkte umfassen: - Monoaminhypothese, Mechanismen der Entstehung der Depression, Therapie der

unipolaren Depression: trizyklische und heterozyklische Antidepressiva, MAO- und reuptake-Inhibitoren

- Therapeutische Anwendung und Nebenwirkungen Referat II: Therapie der bipolaren Affekterkrankung

Lenox, R.H., and Wang, L. (2003): Molecular basis of lithium action: integration of lithium-responsive signaling and gene expression networks. Mol. Psychatry 8: 135-144. Sie, M. (2014): Mood stabilizers in the management of bipolar affective disorder. Progress Neurology and Psychiatry. May/June. www.progressnp.com. S3-Leitlinie zur Diagnostik und Therapie bipolarer Störungen. www. Leitlinien-bipolar.de

Ihr Referat sollte folgende Punkte umfassen: - Definition und Therapie der bipolaren Affekterkrankung - Molekulare und zelluläre Mechanismen der Wirkung von Lithiumionen

sowie Pharmakokinetik und Pharmakodynamik von Lithium

Referat III: Therapie der Schizophrenie Millan, M.J., Goodwin, G.M., Meyer-Lindenberg, A., and Ogren, S.O. (2015): Learning from the past and looking to the future: Emerging perspectives for improving the treatment of psychiatric disorders. Eur. Neuropsychopharmacol., http://dx.doi.org/10.1016/j.euroneuro.2015.01.016

(nur den Teil: Therapie der Schizophrenie) Burlon, M. (2007): Pharmakotherapie der Schizophrenie-“state of the art”. NeuroTransmitter 5, 59-70. Parker, C. (2013): Antipsychotics in the treatment of schizophrenia. Progress Neurology and Psychiatry.May/June. www.progressnp.com.

Ihr Referat sollte folgende Punkte umfassen: - Pathogenese der Schizophrenie, neue Ansätze in der Therapie

- Therapie: niederpotente versus hochpotente Antipsychotika typische (first) versus atypischen (second) Antipsychotika, NW

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FEATURE ARTICLE

Molecular basis of lithium action: integration oflithium-responsive signaling and gene expressionnetworksRH Lenox and Le Wang

Molecular Neuropsychopharmacology Program, Department of Psychiatry, University of Pennsylvania School of Medicine,Philadelphia, PA, USA

The clinical efficacy of lithium in the prophylaxis of recurrent affective episodes in bipolardisorder is characterized by a lag in onset and remains for weeks to months afterdiscontinuation. Thus, the long-term therapeutic effect of lithium likely requires reprogram-ming of gene expression. Protein kinase C and glycogen synthase kinase-3 signaltransduction pathways are perturbed by chronic lithium at therapeutically relevant concentra-tions and have been implicated in modulating synaptic function in nerve terminals. Thesesignaling pathways offer an opportunity to model critical signals for altering gene expressionprograms that underlie adaptive responses of neurons to long-term lithium exposure. Whilethe precise physiological events critical for the clinical efficacy of lithium remain unknown, wepropose that linking lithium-responsive genes as a regulatory network will provide a strategyto identify signature gene expression patterns that distinguish between therapeutic andnontherapeutic actions of lithium.Molecular Psychiatry (2003) 8, 135–144. doi:10.1038/sj.mp.4001306

Keywords: lithium; gene; protein kinase C (PKC); glycogen synthase-3 (GSK-3); myristoylatedalanine-r ich C-k inase sustrate (MARCKS)

Introduction

Lithium (Liþ ) has been the standard pharmacologicaltreatment for bipolar disorder (BPD) (manic-depres-sive illness) over the last 50 years (see reviews:Goodwin and Ghaemi,1 Lenox and Manji,2 and Lenoxand Hahn3). Dysregulation of the balance of activationof signaling pathways in critical brain regions such aslimbic and associated cortical/subcortical areas mayunderlie the often-wild oscillations in the behavioralstates of mania and depression in patients geneticallypredisposed to BPD.4,5 Furthermore, it is thought thatonce the disease has been triggered and clinicallymanifest in the absence of treatment, long-termcompensatory changes in the central nervous systemset the stage for more frequent and severe affectiveepisodes over time.6 The clinical efficacy of lithiumin preventing recurrent affective episodes requires alag period for onset and is reversed upon disconti-nuation of treatment only after weeks or months.7–9 Byvirtue of its prophylactic properties, lithium isthought to target the underlying pathophysiologyof the disease, yet the precise molecular mechanismfor this therapeutic action remains elusive. Evi-

dence from both in vitro and in vivo studies hasdemonstrated that lithium exerts multiple effects onneurotransmitter/receptor-mediated signaling, iontransport, signal transduction cascades, hormonaland circadian regulation, and profoundly alters geneexpression patterns (see reviews Lenox and Hahn,3

Lenox et al,10 Manji and Lenox,11 Jope,12 Williams andHarwood,13 and Manji and Lenox14). Intense interesthas been focused upon phosphoinositide (PI) meta-bolism and glycogen synthase kinase-3 (GSK-3)-mediated signal transduction that are perturbed bychronic lithium at therapeutically relevant concentra-tions.13 Lithium acting through these pathways isthought to provide ‘initial signals’ that could elicitextensive reprogramming of gene expression, a para-digm necessary for the long-term therapeutic effect oflithium treatment.15 Furthermore, since the activity ofa given gene is likely regulated by a chain of proteinsencoded by other genes, a signature gene networkmay be used to better represent the reprogrammedlithium-responsive gene response. Identifying such alithium-responsive gene network in brain wouldallow us to distinguish between subsets of genesunderlying therapeutic and nontherapeutic actions oflithium. In this article, we discuss the rationale forusing a well-defined neurobiologically and pharma-cologically relevant target to identify a lithium-responsive element and critical transcription factor(s)that may ultimately define a network of genes

Received 3 July 2002; revised 23 October 2002; accepted 28October 2002

Correspondence: Dr RH Lenox, Mailstop: BWL-103A, CNS DrugDiscovery Program, Aventis Pharmaceuticals, Route 202-206North, Bridgewater, NJ 08807, USA.E-mail: [email protected]

Molecular Psychiatry (2003) 8, 135–144& 2003 Nature Publishing Group All rights reserved 1359-4184/03 $25.00

www.nature.com/mp

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implicated in mood stabilization for the treatment ofbipolar disorder.

Lithium and phosphoinositide/protein kinase Csignaling pathway

Lithium has been shown to be an inhibitor of anumber of structurally similar magnesium-dependentphosphomonoesterases at Ki values within thetherapeutically relevant range of concentrations(0.8–1.2 mM).16,17 It was recognized over two decadesago that lithium is a potent inhibitor of the intracel-lular enzyme, inositol monophosphatase (IMPase)(Ki¼ 0.8 mM), which converts inositol monopho-sphate to inositol.18–20 Biochemical and Geneticstudies subsequently identified the upstream inositolpolyphosphatase as an additional target for

lithium.21,22 Thus, receptor G-protein-coupled PIhydrolysis has been extensively investigated as a sitefor the action of lithium as a mood stabilizer (seereview Manji and Lenox;23 see Figure 1). Furthermore,since there is evidence that the mode of enzymeinhibition of IMPase is uncompetitive, the preferen-tial site of action for lithium was proposed to be themost overactive receptor-mediated neuronal path-ways undergoing the highest rate of phosphatidyl(4,5) bisphosphate (PIP2) hydrolysis.24,25 While it wasposited that lithium produces its therapeutic effectsvia a consequent reduction in relative concentrationsof myo-inositol and PIP2 concentrations, data-drivensupport for this hypothesis has been highly depen-dent upon the cell and animal models underinvestigation.26–31 Much of this inconsistency maybe related to the relatively small size of the signal-

Figure 1 Lithium-responsive signal transduction pathways focused on PI/PKC and GSK-3 signaling. Lithium directlyinhibits the enzyme inositol monophosphate phosphatase (IMPase; KiE0.8 mM). Binding of ligands to G-protein-coupledreceptors (GPCRs) activates PLC and causes hydrolysis of PIP2 to inositol-1,4,5 trisphosphate (IP3) and DAG. IP3 stimulatesCa2þ release from cellular store, and DAG activates DAG-dependent protein kinase C (PKC). In the presence of receptorligands, long-term inhibition of IMPase results in a depletion of myo-inositol (myo-I) and an accumulation of DAG followedby a downregulation of PKC isozymes a and e. On the other hand, lithium is a potent inhibitor of glycogen synthase kinase-3b(GSK-3b; KiE2 mM) leading to the stabilization of b-catenin, which enters the nucleus to activate LEF/TCF-dependent genes.Lithium-responsive gene network is hypothetically proposed to be activated through PKC and GSK-3 signaling pathways andtheir crosstalk at therapeutically relevant concentrations. Abbreviations: A, receptor agoinst; Akt/PKB, a serine/threoninekinase; APC, adenomatous polyposis protein; axin, a homolog of Drosophila product of the fused locus; CMP-PA, cytidinemonophosphate-phosphatidate; DAG, diacylglycerol; Dsh, dishevelled; G, G protein; GBP, GSK-3 binding protein; GSK-3,glycogen synthase kinase-3; IP3, inositol-1,4,5-trisphosphate; LEF/TCF, LEF(lymphoid enhancer element)/TCF(T cell factor-1) family transcription factors; LRE, lithium-responsive promoter element; MUNC, a synaptic protein that contains DAGbinding domain; PI, phosphatidylinositol; PIP2, phosphatidylinositol 4,5 bisphosphate; PP2A, protein phosphatase 2A; PLC,phospholipase C; Wnt, a secreted glycoprotein ligand for Wnt/b-catenin signaling pathway.

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dependent pools of myo-inositol and PIP2, as well asthe fact that the lithium-induced reduction of myo-inositol appears to be dependent upon multiplefactors including cell-type and tonic activity of thereceptor-coupled PI signaling pathway.31–33 It is ofinterest in this regard that a significant lithium-induced reduction in myo-inositol levels in the rightfrontal lobe has been observed in bipolar patientsprior to clinical response using proton magneticresonance spectroscopy.34 However, these and otherdata suggest that while inhibition of IMPase mayrepresent an initial effect of lithium, reducing myo-inositol levels may be more critical to the specificityof the cellular site of action for lithium than its long-term therapeutic efficacy (see review, Lenox andManji).2

Such data in turn supported the hypothesis thatshort-term lithium exposure in selective neuronalpopulations in brain undergoing heightened activa-tion would result in diacylglycerol (DAG)-mediatedactivation of protein kinase C (PKC), subsequentdownregulation of PKC isozymes, and long-termdownstream changes in brain.5,35 PKC isozymes havebeen implicated in the regulation of neurotransmitterrelease, neuronal excitability, and long-term changesin PKC-regulated protein function, neuroplasticity,and gene expression. PKC activity is tightly regulatedby virtue of not only the distinct distribution of itsfamily of isozymes, but its required translocation tothe membrane associated with phosphorylation andbinding to a receptor for activated C-kinase (RACK)proteins, and ultimate autocatalysis upon prolongedactivation. Several laboratories including our ownhave demonstrated that short-term lithium treatmentactivates PKC, and long-term lithium treatment down-regulates PKC isozymes in a PI-signaling-dependentmanner in brain.5,35 Studies of chronic lithium (1 mM)exposure in both in vivo and in vitro models from ourlaboratory and others have demonstrated a reductionin PKC isozymes a and e in rat subiculum and in CA1regions of the hippocampus, which has been repli-cated in immortalized hippocampal cell modelsystem.19,36,37 Furthermore, administration of myo-inositol to rats has been reported to reverse thedownregulation of PKCe in brain following chroniclithium. These studies have led to investigationsexamining PKC regulation in man (see reviews, Manjiand Lenox,19,35 Jope and Song,38 Wang et al,39 Soareset al40). Recent studies using human post-mortembrain homogenates revealed an increased associationof the receptor for activated C kinase-1 (RACK1) withPKC isozymes in frontal cortex of subjects with BPD,suggesting that interactions between these proteinsmay be also altered in bipolar disease.37 In addition,there is intriguing evidence that tamoxifen, a drugknown to inhibit PKC in vitro, was effective in aninitial clinical study of acutely manic patients withBPD.41 Thus, it appears that chronic lithium-depen-dent modulation of receptor-coupled PI–PKC signal-ing pathways may contribute to the long-term actionof lithium in the brain.

Lithium and Wnt signaling pathway

Glycogen synthase kinase 3b (GSK-3b) is a serine/threonine kinase that is constitutively active in cellsand negatively regulates its substrates, one of which isb-catenin, a downstream effector of the Wnt signalingpathway controlling dorsal–ventral axis specificationand cell fate determination in various organismsincluding Dictyostelium, sea urchins, zebrafish, andXenopus.17 GSK-3 activity is regulated through multi-ple proteins in a complex (Figure 1), where GSK-3 isactivated in the presence of axin, adenomatouspolyposis coli (APC), dishelveled (Dsh) and pro-motes phosphorylation of b-catenin for ubiquitin–proteosome-mediated degradation.43 On the contrary,GSK-3 binding protein (GBP), which is requiredfor axis formation in Xenopus, could join the comp-lex to inhibit GSK-3 activity, in part, by preventingaxin from binding GSK-3.44 When b-cateninaccumulates in cytoplasm, it translocates into nu-cleus and activates T-cell factor (TCF) and lymphoidenhancer element (LEF)-dependent gene transcrip-tion, through which the Wnt pathway controlsnumerous developmental processes. The full reper-toire of the genes containing LEF/TCF responsiveelements in their promoters has not been defined.Patterning genes Ultrabithorax in Drosophila, sia-mois, and nodal-related gene-3 in Xenopus,45–47 hu-man genes c-myc and cyclin D1,48–50 and connexin43and E-cadherin51,52 represent major LEF/TCF-respon-sive genes discovered to date. Other possibletargets of GSK-3 may include AP-1, CREB, NF-kB,heat shock protein 1, and CCAAT/enhancerbinding proteins.53 LEF1 was recently found to becritical to the generation of dentate gyrus granulecells and the development of the hippocampus inmice.45–47,54 In addition, GSK-3 could phosphorylateNF-AT, facilitating its export from the nucleus,and thus antagonizing NF-AT-dependent gene tran-scription.55

Lithium mimics Wnt signals by inhibition of GSK-3both in vitro and in vivo. This suggests that the often-observed developmental effects of lithium, whichcould not be explained by inhibition of IMPase, maybe in fact a result of inhibition of GSK-3b.56,57 Valproicacid also inhibits GSK-3,58 but its control over theb-catenin stability differs from lithium. While lithiumstabilizes b-catenin via inhibition of GSK-3, VPA-induced b-catenin accumulation is through increasedexpression of b-catenin rather than stabilization ofthe protein.59 GSK-3 has also been implicated insynaptic function. For example, GSK-3b inhibitioninduces the synapsin I clustering in the formation ofsynapses and neurotransmitter release.60 In addition,GSK-mediated phosphorylation of MAP-B and tauproteins regulate microtubule assembly and stabiliza-tion at synapses.57,61–63 Clinical studies have demon-strated that specific GSK-3 inhibitors mimic thetherapeutic action of mood stabilizers and mighttherefore be plausible drugs in treating bipolarpatients.64

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Crosstalk between PKC and GSK-3b signalingpathways

Certain PKC isoforms have been shown to phosphor-ylate and inactivate GSK-3b in vitro.65 However, Wnt-induced b-catenin accumulation is only partiallyinhibited in vivo by PKC inhibitors and by chronictreatment of cells with phorbol ester.66,67 This sug-gests that Wnt/b-catenin pathway may comprise twocomponents, one is mimicked by lithium and theother involves PKC. Further studies demonstratedthat some PKC isoforms (TPA-sensitive) are involvedin the Wnt-induced GSK-3b inactivation, whereasothers (atypical PKC) contribute to b-catenin degrada-tion.43,67 On the other hand, certain Wnt and Frizzledhomologs have been reported to regulate PKC differ-entially; i.e. some stimulate PKC but have no effect onexpression of b-catenin target genes, while others,capable of activating b-catenin target genes, do notactivate PKC.68 New data also establish that Frizzledsare bonafide G-protein-coupled receptors.69,70 Forexample, Frizzled-1 couples via G-protein Go and Gq

to the b-catenin–LEF-TCF pathway. Frizzled-2 cou-ples via Gq and Gt to downstream effectors includingCa2þ mobilization. In addition, the disheveled pro-teins may also mediate phosphoinositol signal trans-duction, leading to the activation of PKC.13 Thus, themutual interaction between several components ofPKC and GSK-3 signaling pathways suggests a modelof crosstalk between the two pathways (Figure 1). Inview of the fact that the relative Ki for lithiuminhibition of IMPase vs that for GSK-3b favors aninteraction of lithium in the PI/PKC signaling path-way in brain, chronic lithium might interact withGSK-3b in vivo by virtue of crosstalk at therapeuti-cally relevant concentrations.

Lithium and synaptic function

While there is evidence for effects of lithium on theexpression of numbers of genes in brain, includingthe DNA binding and transactivation of AP-1 tran-scription factors71 and both pro- and antiapoptoticgenes through the AKT/PKB signaling pathway,72,73

for the purpose of this discussion we will focus uponthe long-term action of lithium in the brain that stemsfrom its interaction with the PI/PKC signaling path-way. There is significant evidence that alterations indownstream targets in this pathway have functionalconsequences related to synaptic signaling in thebrain, which actually may be amplified throughcrosstalk with GSK-3b signaling as noted above.PKC isozymes have been implicated in neurotrans-mitter release, and a number of synaptic proteins arepossible substrates for PKC. Phorbol ester (PMA) hasbeen shown to evoke synaptic potentiation (PESP) atthe nerve terminal by presynaptic PKC acting on therelease machinery.74 Inhibition of protein kinase C atthe presynaptic terminal attenuates the phorbol ester-induced synaptic potentiation (PESP), supporting arole for PKC in synaptic potentiation.74 However,

chelating presynaptic Ca2þ does not significantlyaffect PESP, indicating that only certain PKC isoformssuch as PKCe, whose activation does not require Ca2þ ,are important in mediating the neurotransmitterrelease at nerve endings. In fact, chronic lithium-facilitated neurotransmitter release has been linked tothe isoform-specific decrease in PKC a and e in theabsence of significant alterations in other PKC iso-forms.23 Synaptic transmission is regulated by twomechanisms: an increase in the Ca2þ sensitivity ofexocytosis (release probability) and an increase in theamount of releasable synaptic vesicles (the pool size).DAG, which activates PKC, specifically increases thepool size but not the release probability. Recently, anew family of proteins, Munc13/unc13 proteins,initially identified in C. elegans, was found to containDAG receptor. This raises an interesting possibilitythat chronic lithium action in part may be mediatedthrough interaction of DAG with Munc proteins. Insupport of this hypothesis, presynaptic loading of asynthetic peptide with the sequence of the N-terminaldomain of Doc2a interacting with Munc13 attenuatesPESP.75 In addition, Munc18-1 was found to interactwith syntaxin1, a member of SNARE complex thatpromotes large dense-core vesicle docking.76 There-fore, lithium-induced changes in synaptic transmis-sion can be mediated by a complex network ofsynaptic proteins through both PKC and Muncsignaling pathways. In addition to direct modulationof Munc through DAG, lithium has also been shownto enhance the expression of a gene encoding cysteinestring proteins (CSPs) at therapeutically relevantconcentrations.77 CSPs are novel synaptic vesiclecomponents conserved in evolution,78 which alsointeract with the SNARE neurotransmitter releasecomplex.79

Lithium and MARCKS: a downstream targetfor PI/PKC signaling

Accumulating evidence over the past several yearshas identified a target in the brain for the action ofchronic lithium that is in the PI/PKC signalingcascade and possesses pharmacological characteris-tics consistent with the therapeutic properties oflithium in man. Activation of PKC results in the post-translational phosphorylation of various proteins,most prominent of which is the myristoylatedalanine-rich C-kinase substrate (MARCKS) in brain(Blackshear, 1993). MARCKS has been implicated inprocesses requiring signal-dependent changes inactin-membrane plasticity and cytoskeletal restruc-turing.80,81 It can crosslink actin, bind calcium/calmodulin, interact with the plasma membrane,and has been linked to organization of polypho-sphoinositide (PI (4,5)P2) signaling domains,82,83

regulation of phospholipase D,84 secretion,85,86 andphagocytosis.87 MARCKS is preferentially expressedin dendritic branches and axon terminals withinlimbic and limbic-associated regions of brain, as wellas neuronal growth cones necessary for normal brain

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development.88–90 Within brain and neurons in cul-ture, MARCKS protein is expressed in neurites andsynaptosomes, and is colocalized with synapticvesicles.91–93 PKC-MARCKS signaling has been im-plicated in vesicular trafficking of neurotransmitter inliving neurons,94 and in the regulation of variousprocesses including synaptic transmission at nerveterminals.80,81 Electrophysiological and behavioralstudies in heterozygote mutant mice have shown that50% reduction in MARCKS significantly affectslong-term potentiation (LTP) and hippocampallydependent behavior.95–97 These data indicate thatMARCKS plays an important role in the mediationof neuroplastic processes in the developing andmature CNS.

Chronic treatment with lithium at therapeuticallyrelevant concentrations significantly downregulatesMARCKS protein and mRNA (50%) in both rat brainand immortalized hippocampal cells.27,98,99 Directactivation of PKC by phorbol esters in immortalizedhippocampal cells also downregulates the MARCKSprotein,100 suggesting a role for PKC in the regulationof MARCKS gene (Macs) expression in brain. Thelithium-induced downregulation of MARCKS proteinis dependent upon the myo-inositol concentrationand the level of activation of receptor-coupled PIsignaling.31 Addition of inositol completely reversesthe lithium-induced downregulation of MARCKS,indicating that the downregulation of MARCKS wasmediated via the phosphoinositol pathway.31 Further-more, lithium-induced down regulation of MARCKSis only apparent after chronic, but not acute, admin-istration and persists beyond abrupt withdrawal ofthe drug for an extended period of time; parallelingthe clinical time course for the therapeutic effects oflithium during initial treatment as well as itsdiscontinuation. Of interest, the structurally unre-lated mood-stabilizer, valproic acid (VPA), shares theproperty of lithium in reducing the MARCKS expres-sion in hippocampus, but carbamazepine (CBZ) andother psychotropic agents (antianxiety, analgesic,antipsychotic, antidepressant, calcium-channelblocker) as well as other monovalent cations such asrubidium do not alter MARCKS regulation.101,102 Onthe other hand, VPA-induced downregulation ofMARCKS is inositol-independent, and has an addi-tive effect on MARCKS regulation, consistent withclinical data supporting greater efficacy of thecombined treatment in refractory bipolar patients.101

These findings point to a common mechanism, inwhich MARCKS may be a shared target for bothlithium and VPA. Thus, we have proposed that thereduction of MARCKS protein following long-termlithium administration alters pre/postsynaptic mem-brane structure and stabilizes aberrant neuronalsignaling in key brain regions of patients withBPD.3,5 The regulation of MARCKS expression repre-sents a highly valued target for the long-term action ofmood stabilizers, not only by virtue of its underlyingneurobiological properties but also in light of itspharmacological sensitivity and selectivity for struc-

turally unrelated drugs with efficacy in the prophy-lactic treatment of BPD. While MARCKS remains anattractive target for illustrative purposes in defining alithium-responsive gene network, it is evident thatother targets, such as prolyl oligopeptidase (POase),which appears to mediate the common effect oflithium, CBZ and VPA on growth cone stability andhas been implicated in affective disorders, may atsome point represent a similar opportunity.103

Perspective: linking the lithium-responsive genesas a network

The mechanisms underlying the prophylactic treat-ment of BPD by lithium are likely to be hardwired inthe genomic DNA. Despite all the reports of howindividual gene expression can be modulated inresponse to lithium’s exposure, there is as yet nostrategy available for the identification of the lithium-responsive genomic regulatory network in brain.Many studies have focused on determining the effectof lithium on one or a few genes at a time, anapproach that is not adequate for the analysis of largeregulatory control system organized as networks.Gene-specific expression is controlled by specificcis-regulatory target sequence embedded in promotersand the cognate binding transcription factors encodedby a set of regulatory genes. The functional linkages ofsuch a genomic regulatory network include elementsthat exhibit multiple interactions between the outputsof regulatory genes and corresponding cis-regulatorygenomic sequences. Thus, identifying networks oftranscription factors and the genes they regulate inresponse to lithium exposure is important to under-stand the biological responsiveness of an organism tolithium and the prophylactic properties of its actionin brain.

Studies in our laboratory have demonstrated thatthe lithium-induced reduction of MARCKS proteinwas accompanied by a downregulation of MARCKSmRNA with no evidence for a change in the half-lifeof the mRNA.99 Furthermore, synthesis of nascentRNA for MARCKS and the Macs promoter activitywere also found to be significantly reduced inchronic, but not acute, lithium-treated immortalizedhippocampal cells. Both reductions were signifi-cantly enhanced in the presence of activation ofreceptor-coupled PI signaling.99 We have identifiedfor the first time a lithium-responsive promotersequence located in the upstream region (�993/�713) of the Macs promoter.99 The mutant promoterlacking the �993/�713 fragment not only did notrespond to chronic lithium expose but also had asignificantly reduced promoter activity, suggestingthat chronic lithium represses the transcriptionalactivator(s) bound to this region. Until now, however,no lithium-responsive transcription factor directlybound to this region has been identified. Whilespecific transcription factors that bind to lithium-responsive promoter element (LRE) remain to beidentified (Figure 2), current data suggest that the

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mechanism by which chronic lithium represses theMacs gene transcription are likely through: (a)lithium-induced downregulation of DNA bindingactivity and/or expression of transcription activator(s)interacting with LRE; (b) lithium-induced down-regulation of activator function of transcriptionactivator(s) acting at LRE; (c) lithium-induced disrup-tion of the coordinate interaction between the distalactivating sequence-bound activator(s) and the prox-imal core promoter sequence-bound basal transcrip-tional machinery. The lithium-responsive �993/�713fragment contains significant enhancer/activator DNAelements that are necessary to sustain the optimalMacs gene transcription in cells.104 While an atypicalSp1 site, characterized by the presence of a prominentGA-rich sequence, was identified within the �993/�713, a classical Sp1 site was found in the middle ofthe GC-rich box close to a potential Z-DNA-formingsegment near the transcription initiation site.104

Presence of Z-DNA forming segment signifies bothcompositional and conformational changes influen-cing the genomic landscape, the accessibility of cis-acting elements, and the activation of gene transcrip-tion in the core promoter region.105 As summarized inFigure 2, Macs promoter lacks typical TATA box,and in the absence of a TATA box multiple Sp1 sitesin the promoter may control the transcription of Macsgene.

A recent microarray experiment further showedthat the expression of as many as 37 genes from 4132rat genes is altered during the chronic lithiumtreatment.106 If these data were extrapolated to theentire genome, there would be as many as 750 genesthat could potentially be regulated by lithium.However, the majority of such studies using differ-ential display and microarray analysis do not distin-guish between direct activation of target genes by atranscription factor and indirect effects resulting fromone transcription factor inducing the expression of asecond. Furthermore, the functional value of the vastmajority of these potential targets remains unknown.Using our knowledge regarding a high-value pharma-cologically relevant target such as MARCKS for theaction of chronic lithium in brain to identify lithium-responsive elements that could serve to link lithium-responsive genes as a regulatory network is bothintriguing and challenging. To establish such a genenetwork, some studies have coupled the overexpres-sion of a given transcription factor with microarrayexperiments. However, the genes affected by theoverexpressed transcription factors may not representthe true targets of those factors under physiologicalconditions. Recently, using finite perturbations ofgene expression in conjunction with microarrayexperiments that may mimic physiological conditionshas been advocated; thus differing from the drastic

Figure 2 Lithium-responsive promoter of the Macs gene. The Promoter region upstream of Macs is pharmacologicallyresponsive to chronic, but not acute, lithium exposure. A hypothetical activator complex binds to the upstream region ofMacs promoter and crosstalk with proteins in proximal promoter region including TBP, TAFs, Sp1, hypothetical tetheringproteins, etc. The gray rectangle box represents cis-regulatory enhancer elements (LRE) that may interact with specificlithium-responsive transcription factors. Long-term treatment with lithium is postulated to repress the Macs transcriptionthrough: (a) lithium-induced reduction in the DNA binding of the transcription activator(s) acting at the LRE; (b) lithium-induced alteration in the expression and/or the transactivation function of lithium-responsive transcription activator(s)acting at the LRE; (c) lithium-induced disruption of the interaction between enhancer complex formed at LRE and theproximal transcription initiator. In the figure, # refers to potential intermediary factors mediating the indirect action ofchronic lithium on the Macs promoter.

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changes incurred during transgenic overexpression orknockouts.107 In such studies, one can modulatesingle gene expression using techniques such asRNA interference (RNAi) one at a time and in asystematic fashion among all the genes of interest.Once the perturbed systems are in a new steady state,the levels of gene expression is measured against thatof reference by microarray or Taqman RCR. Theresulting data are arranged as a regulatory strengthmatrix, from which a regulatory network exhibitinggene–gene interactions could be inferred using ap-proaches adapted from metabolic control analysis.108

The method, however, lacks genome-wide efficiencyand does not provide direct evidence of in vivointeraction of given transcription factors with theirrespective cis-regulatory elements across the genome.To address these questions, a new technology knownas chIp–chip was developed, in which chromatinimmunoprecipitation (chIp) is coupled with micro-array experiment (chip) to accelerate the genome-wide detection of DNA–protein interactions in realtime and in real space. Using such a combinedapproach as chIp–chip, genome-wide mapping of

DNA binding sites for transcription factors (STE12,GAL4, RAP1, SCB, MCB, MCM1, SFF, and SW15) hasbeen achieved in yeast.109,110 This experimentalapproach has also been successfully extended tohuman genome, where DNA binding sites for E2Fand GATA-1 transcription factors are mapped genomewide.111–113

A lithium-responsive gene network will offer anopportunity to define a pathway associated with thelong-term prophylactic properties of lithium, distinctfrom its side-effect profile, which will drive thediscovery of novel agents for stabilization of moodin patients with BPD (Figure 3). Recently, a regulatorygene network that directs specific developmentalevents has been identified in developing sea urchinembryo.114,115 This provides a heuristic model forconstructing a lithium-responsive gene network asa means to identify signature genes that directthe therapeutic or nontherapeutic action of lithium.While chromosome immunoprecipitation could startwith antibodies against several known lithium-responsive transcription factors such as AP-1, CREB,NF-kB, LEF/TCF, these are general transcription

Figure 3 Model for a gene network for lithium-responsive genes: defining the therapeutic effect of chronic lithium. A genenetwork can be reconstructed by perturbation microarray and chlp–chip methods (see test for details). A lithium-responsivegene network will consist of a distinctive subset of genes that share a lithium-responsive element (LRE) as defined within theMacs gene which is regulated by specific transcription factors referred to as TFs that are yet to be identified. Such a lithium-responsive gene network (TF1) may subserve critical processes in the brain underlying cytoskeletal remodeling andregulation of synaptic signaling, while a different subset of genes defined by lithium-responsive elements regulated bytranscription factors (TF2, TF3) may underlie processes such as cell proliferation. Since these different network of genesunderlie different physiological sequela of chronic lithium, modulation of gene expression involved in the cytoskeletalrestructuring and neuroplasticity by lithium may prove to be fundamental to the mood-stabilizing properties of lithium in thebrain, whereas regulation of genes involved in cell proliferation and immune response may be linked to lithium’sleukocytotic and antiviral effects.

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factors that elicit far more gene expression thannecessary for the therapeutic action of lithium. Thus,identifying lithium-responsive transcription factorsor promoter elements from highly valued targets suchas the Macs gene becomes extremely desirable. Wedemonstrated that Macs promoter is pharmacologi-cally responsive to chronic, but not acute, lithiumtreatment at therapeutically relevant concentrations,and possesses pharmacological properties consistentwith its expressed protein and clinical properties oflithium.99 We further showed that the sites for lithiumresponsiveness lie within an enhancer element of thepromoter that has the potential to interact witha unique lithium-responsive activator complex(Figure 3).104 This raises the possibility that uniquetranscription factors sensitive to lithium treatmentmay be identifiable through this promoter. Whilegenes like Macs involved in the cytoskeletal restruc-turing, synaptic transmission, and neuroplasticitymay relate preferentially to the long-term mood-stabilizing properties of chronic lithium in the brain,genes underlying cell proliferation and immuneresponse may serve to identify pathways associatedwith lithium’s leukocytotic and antiviral effects(Figure 3). Thus, defining a lithium-responsive genenetwork will provide the data for pathway mapping ofnovel targets with better-defined mood-stabilizingproperties for the long-term treatment of BPD.

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The terms ‘melancholia’, ‘mania’, ‘depression’,‘manic depressive reaction’ and ‘manic depres-

sion’ have all been used to describe mood disorders.Mood disorders are now classified as either bipolaraffective disorder (BPAD) or unipolar affective disor-der. In this article, we focus on the use of mood sta-bilisers in BPAD. Treatment for unipolar affectivedisorder (depression) has already been consideredin a separate article in this series (see the NovemberDecember 2013 issue of Progress).

BPAD was first recognised as an illness as far backas ancient Greece where it was noted that melancho-lia appeared to be a part of mania.1 In modern med-icine its symptomatology was described in the firstDiagnostic Statistical Manual of Mental Disorders (DSM-I, 1952)2 where it was classified as a manic depressivereaction. The most recent edition (DSM-5) continuesto classify BPAD into two subsections: bipolar I disor-der, in which symptoms are predominantly manicepisodes but can include severe depressive episodes;and bipolar II disorder, where the episodes fluctuatebetween hypomania (a condition similar to mania butless severe) and depression.3 In DSM-5, there havebeen important amendments to the criteria formania/hypomania, which require that the moodchange must be accompanied by persistentlyincreased activity or energy levels, thereby excludingdiagnosis for some patients who would have met thecriteria in the previous manual (one of two moodsymptoms, elation/euphoria or irritable mood).4

In the WHO’s International Classification ofDisease (ICD-10), for a diagnosis of BPAD to be madethere must be evidence of two or more episodes inwhich there is significant disturbance to mood andactivity levels. The episodes must consist of hypo -mania or mania and depression; however, repeatedepisodes of hypomania or mania without depressionare also classified as bipolar.5

The prevalence of bipolar disorders in Europeranges between 0.1 per cent and 2.4 per cent6 and

they are estimated to cost the NHS £342 million annu-ally (at 2009/2010 prices);7 the costs to UK societywould be substantially more. Men and women areequally affected and the average age at onset isaround 17 years.8 BPAD is also related to an increasedrisk of suicide: around 25-50 per cent of adults admitto at least one suicide attempt throughout their ill-ness and 8 to 19 per cent take their own lives.9

Lithium was the first medication used for the treat-ment of mania and as maintenance treatment forBPAD. Lithium was first investigated as a treatmentoption for affective disorders by John Cade, anAustralian psychiatrist. During animal testing, he dis-covered lithium produced a calming effect. A furthertrial in patients with mania, published in 1949, foundthat it was an effective antimanic agent.10 Around thistime phenytoin was also observed to have an anti-manic effect. More recently phenytoin has again beeninvestigated in the prophylactic treatment of BPAD.11

Later, in the 1980s, carbamazepine was explored forthe treatment of rapid cycling.12 In the early 1990s,valproate was shown to be significantly more effectivethan placebo at treating acute mania13 and becamean alternative treatment choice to lithium. Otherantiepileptic treatments have been studied for effi-cacy in the treatment of BPAD.14

Evidence base supporting pharmacotherapy National guidelines have been produced by the NationalInstitute for Health and Care Excellence (NICE)6 andthe British Association for Psychopharmacology(BAP)14 on the treatment of bipolar disorder.

The most commonly used medicines in BPAD areantipsychotics, mood stabilisers, antidepressants andbenzodiazepines. A number of second generationantipsychotic medicines may now be classed as moodstabilisers as they prevent relapse into mania, depres-sion or both.14 The evidence to support their use inthe different stages of bipolar illness can vary, as cantheir licensed indications (see Table 1).

Review z Mood stabilisers for bipolar disorder

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As part of our series on the major psychiatric medication groups, produced in association withthe College of Mental Health Pharmacy (CMHP; www.cmhp.org.uk), Michele Sie discusses thechoice and use of medicines in the management of bipolar affective disorder. Pharmacology,interactions and side-effects, as well as information to give to patients, are described.

Mood stabilisers in the management ofbipolar affective disorderMichele Sie GPhC, MCMHP

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Treatment of acute mania Acute mania is characterised by elevated mood out ofkeeping with the patient’s circumstances, increasedenergy and physical overactivity, pressure of speech,poor attention, distractibility and a decreased need

for sleep. Grandiosity, overconfidence and flight ofideas are often present. Loss of normal social inhibi-tions may result in recklessness and sexual disinhibi-tion, placing the individual at risk. Psychoticsymptoms may or may not be present.15

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Medication Brand or Form available Licensed for Licensed for long-term mood stabilisationgeneric acute treatment

of mania

Lithium Priadel MR tablets, liquid Yes Yes(prescribe by brand) Camcolit Tablets, MR tablets

Liskonum Tablets

Valproate semisodium Depakote Tablets Yes* Yes*(valproic acid) Convulex Capsules No No

Sodium valproate Generic E/C tablets No NoLiquid

Epilim Chrono MR tablets No NoEpisenta MR capsules Yes* Yes*

Prolonged-release granules

Carbamazepine Generic Tablets No Yes if unresponsive to lithiumMR TabletsLiquid

Lamotrigine Lamictal Tablets No Yes – for prevention of depressive episodes in Dispersible tablets adults with bipolar I disorder who experience

predominantly depressive episodes

Olanzapine Generic Tablets Yes Yes if responded to olanzapine in acute episodeOrodispersible tabletsInjection

Aripiprazole Abilify Tablets Yes Yes if responded to aripiprazole in acute episodeOrodispersible tabletsOral solutionInjection

Quetiapine** Generic Tablets Yes Yes if responded to quetiapine in acute episodeMR Tablets

Risperidone Generic Tablets Yes+ NoOrodispersible tabletsLiquidLong-acting injection No No

Asenapine Sycrest Sublingual tablets Yes+ No

* Licensed for acute treatment of mania if lithium contraindicated or not effective and for the continuation of treatment after a manicepisode in patients who have responded for acute mania

** Quetiapine is also licensed for treatment of major depressive episodes in bipolar disorder+ Licensed for the treatment of moderate to severe manic episodes associated with bipolar disorder

Table 1. Medications licensed for bipolar affective disorder15

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Review z Mood stabilisers for bipolar disorder

Those presenting with mania should have blood teststo rule out thyroid disorders, blood disorders, infectionand electrolyte disturbances. Illicit substance use, suchas methamphetamine and cocaine, should be ruled outas possible precipitators.8 Certain medicines can causemania as an adverse effect, eg modafinil, disulfiram,some anti-viral drugs, steroids and antidepressants,15

and these should be reviewed and withdrawn where pos-sible. Some natural remedies are reported to induce orworsen mania, including St. John’s wort and ginseng.16

Excessive use of caffeine, eg guarana, coffee, cola, hasalso been associated with mania.17

Medications used in the treatment of acute maniaare classed as antimanic agents and these includelithium, valproate and antipsychotics.6 The second-generation antipsychotics, aripiprazole, asenapine,olanzapine, quetiapine and risperidone are licensedfor use in acute mania.15

The choice of treatment depends on the severity ofsymptoms, adverse effect profile (see Table 2), previousresponse to medication, future prophylactic treatment,concurrent medication (see Table 3) and patient pref-erence. First-line monotherapy treatment optionsinclude using an antipsychotic or valproate in severemania. Lithium or carbamazepine may also be consid-ered in less ill patients.6,14 Any antidepressants that thepatient is currently prescribed should also be stoppedas antidepressants can induce or worsen the manicpresentation. The speed at which the anti depressantis withdrawn depends on the clinical situation, and therisk of withdrawal effects.6 In acute mania, antidepres-sants are commonly stopped abruptly, as the risk ofworsening symptoms are perceived to outweigh the riskof the antidepressant withdrawal effects.

To reduce adverse effects it is recommended thatlithium is initiated at 400mg daily then increased everyfive to seven days while measuring blood plasma levels.Plasma levels should be measured 12 hours after thedose and the ideal level should be between 0.6mmolper litre and 1mmol per litre. Levels closer to 1mmolper litre are often needed in an acute manic episode.24

Depakote (valproate semisodium) and Episenta(sodium valproate) are the only available licensed val-proate preparations for the treatment of manicepisodes associated with bipolar disorder.15 Other val-proate preparations, although often used in BPAD,remain unlicensed.

Valproate semisodium allows for a rapid dose esca-lation starting at 750mg in divided doses on the firstday, and 1500mg on the second day titrated up to 20 to30mg per kg per day body weight. This rapid dose esca-lation has been shown to have significantly greatereffect than the standard valproate titration.25 Achieving

a higher blood level of valproate of at least 80mg perlitre is associated with a significantly greater improve-ment in mania by the third day of treatment.25

A multiple-treatments meta-analysis comparingthe efficacy and acceptability of antimanic medicinesin acute mania concluded that risperidone, olanzap-ine and haloperidol should be considered among thebest of the available options for the treatment ofmanic episodes. Gabapentin, lamotrigine and topira-mate were not significantly more effective thanplacebo in treating acute mania.26

Evidence also suggests that the addition of anti -psychotic treatment to established mood stabilisertreatment is more effective than mood stabiliser treat-ment alone.27 In addition to an antimanic medica-tion, the short-term use of a benzodiazepine forsedative and calming effects can also be useful in theacute manic phase of BPAD, particularly to promotesleep for agitated overactive patients.6,14

Asenapine, a second-generation antipsychotic, waslaunched in the UK in 2012 for the treatment of mod-erate to severe manic episodes associated with bipo-lar disorder and is not currently included in the NICEor British Association for Psychopharmacology (BAP)guidance. It has very low bioavailability (<2 per centin oral tablet form) and must be taken sublingually.Those prescribed asenapine must be counselled onthe use of the medication, covering the following:28

• tablets are fragile and absorb moisture from the air,as such they should not be removed from packaginguntil ready to use• hands should be dry when removing tablets frompackaging• The package tab should be peeled back to removethe tablet• The tablet should be placed under the tongue andallowed to dissolve; it should not be chewed or swallowed. • The patient should avoid eating and drinking for atleast 10 minutes after taking the tablet. • If other medication is taken at the same time, ase-napine should be taken last.

Treatment of mixed affective statesA mixed affective state is characterised by a mixtureof, or a rapid fluctuation between, hypomania, maniaand depressive symptoms.5 Evidence suggests that amixed affective state is a risk factor for suicide29 andthose experiencing it should be asked about suicidalideation, intention to act on these ideas and extentof plans, means or preparation for suicide.14

Treatment should follow that for an acute manicepisode and antidepressants should be avoided.6

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Medication: Lithium18,19 Valproate20 Carbamaze pine21 Lamotrigine22 Olanzapine23

Adverse effect

Somnolence Toxicity Common Very common Common Very commonTremor Very common Very common Uncommon Common XNausea/vomiting Very common Very common Very common Common XWeight gain Common Common Common X Very commonDry mouth Very common X Common Common CommonConstipation X X Uncommon X CommonThirst Very common X X X XBlurred vision Reported X Common Uncommon XDiplopia X X Common Uncommon XPeripheral oedema Common Uncommon Common X CommonHair loss X Common Very rare X UncommonElevated LFTs* X Common Rare – very rare* Very rare CommonBlood dyscrasias* Reported Common – Very common – Very rare Common –

rare* very rare* rare*Agitation Serotonin X Rare Common X

syndrome+

Dizziness Reported X Very common Common CommonRash Rare Rare Rare Very common CommonTachycardia Serotonin X Toxicity Common Rare

syndrome+

Headache Rare++ Common Common Very common XOrthostatic Reported X Rare X Very commonhypotensionRestlessness Toxicity X Rare X XInsomnia X X X Common XSeizures Toxicity X X X UncommonDiabetes mellitus X X X X UncommonNeuroleptic malignant ↑ risk when X Very rare X Raresyndrome given with

antipsychoticsRaised blood lipids X X Very rare X CommonRaised blood glucose X X X X CommonRenal impairment Reported with X Very rare X X

long term useAbnormal thyroid Common (↑ or ↓) Rare (↓) Very rare X Xfunction (↑TSH or ↓T4)

Extrapyramidal side-effectsAkathisia ↑ risk when X X X CommonParkinsonism given with Uncommon X Very rare CommonDystonia antipsychotics X Uncommon X UncommonTardive dyskinesia X X X Uncommon

Very common (>10 per cent), common (>1 and <10 per cent), uncommon (>0.1 and <1 per cent), rare (>0.01 and < 0.1 percent), very rare (< 0.01 per cent), reported: these events have been reported but the frequency is considered not known(cannot be estimated from the available data).X - not listed as a side-effect on the Summary of Product Characteristics * Dependent on specific blood cells/LFTs+ Serotonin syndrome has been reported with lithium ++ Persistent headache should be reported as it may be a sign of benign intracranial hypertension

Table 2. Comparison of adverse effects of mood stabilisers

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Olanzapine and quetiapine have been shown to haveeffects on both acute mania and acute bipolar depres-sion and as such may be good treatment choices inmixed states.14

Rapid cycling statesRapid cycling is characterised by four or more episodesof depression, mania, mixed affective state or hypoma-nia occurring in the last year.14 The interval betweenepisodes can fluctuate between days to months butbetween episodes the patient will be in remission.8

Antidepressants should be avoided in rapid cyclingas they can worsen symptoms. Hypothyroidism andsubstance misuse may also worsen rapid cycling andshould be assessed and treated as necessary.14 Alcoholis the most prevalent comorbid substance misused inpatients with BPAD.30

Treatment should depend on the presenting pole.Manic episodes should be treated as for acute maniaand depressive episodes as bipolar depression; com-binations of medicines may be required.

Bipolar depressionBipolar depression presents with similar characteris-tics to unipolar depression, although there are someimportant clinical differences that can help to distin-guish the two. In bipolar depression there are higherrates of psychomotor retardation, greater difficultythinking, more early morning awakening, moremorning worsening of mood and more frequent psy-chotic symptoms.31 For those not on mood stabilis-ing agents, quetiapine or lamotrigine should beconsidered as first-line options; an antidepressant incombination with an antimanic agent may also beconsidered. When psychotic symptoms are present,an antipsychotic may be prescribed.14

For those already on mood stabilising medication,the initial treatment is to optimise these agents, check-ing levels and compliance and increasing doses wherenecessary. If this is not effective, then the addition ofquetiapine, lamotrigine or cautious use of an anti -depressant would be suitable options. When using anantidepressant in BPAD, the SSRIs are recommendedfirst line as tricyclic antidepressants have been asso-ciated with an increased risk of switching to mania.32

Antidepressant-induced switching is less likely whenthe agent is co-prescribed with lithium, valproate oran antipsychotic.14 Any antidepressant used shouldbe started at a low dose and increased very slowly.Once depressive symptoms have been resolved, taper-ing and stopping treatment with an antidepressantshould be considered to prevent switching to a manicphase.6 Lamotrigine has been shown to be effective in

acute episodes of bipolar depression and in the long-term treatment of bipolar II disorder.

Although the BAP guideline concluded that que-tiapine has the most convincing evidence base for effi-cacy in bipolar depression,14 a recent meta-analysisfound that olanzapine and fluoxetine in combinationhad the best efficacy for bipolar depression and waswell tolerated, followed by quetiapine then val-proate.33 A comparative evaluation of quetiapine pluslamotrigine versus quetiapine monotherapy plus folicacid or placebo (CEQUEL trial) in bipolar depres-sion has been completed and the results are expectedto be published in October 2014.34

Long-term treatment of BPADThe aim of long-term treatment with mood stabilis-ers is to minimise the risk of a relapse of either adepressive or manic episode and to optimise qualityof life. Compared with placebo, mood stabilisers havebeen shown to be more effective at preventing relapseof any mood episode.14 They also reduce the severityof any relapses that occur and increase the time torelapse.35-37 Long-term treatment with lithium hasbeen shown to reduce the suicide rate in those withBPAD by 60 per cent compared with those not onlithium treatment.6,14,38

The NICE clinical guideline on bipolar disorder,published in 2006,6 recommends the use of lithium,valproate or olanzapine as monotherapy for first-linetreatment in acute episodes of illness and in the long-term management of BPAD. If these treatments arefound to be ineffective or only partially effective, it isrecommended that the medication should either beswitched to an alternative monotherapy or a combina-tion of two of these agents should be considered.Further options for treatment include either carba-mazepine or lamotrigine.6 Evidence suggests that lam-otrigine is particularly effective for those suffering fromdepression in bipolar II disorder.39 NICE also recom-mends that lithium should not be initiated routinely inprimary care for the treatment of BPAD.

The BAP guidelines, which were updated in2009,14 recommend long-term treatment based on thedominant pole and recognise that treatments differin their effectiveness at preventing mania and depres-sion. Where mania is dominant, lithium, ari piprazole,quetiapine, valproate or olanzapine should be consid-ered followed by carbamazepine. Where depressionis dominant, the recommended treatment is quetiap-ine or lamotrigine followed by lithium. The guidancealso makes further recommendations when treatmenthas failed, including consideration of the unlicenseduse of clozapine in treatment-refractory patients.

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There may, however, be some differences in effi-cacy between the mood stabilisers. Lithium preventsboth manic and, to a lesser extent, depressive relapses.Valproate is believed to prevent both manic and depres-sive episodes. Olanzapine is better at preventing mania

rather than depressive episodes, lamotrigine preventsdepressive episodes more than manic episodes, queti-apine prevents manic and depressive episodes and aripiprazole prevents manic relapse.14 Lithiummonotherapy and combination therapy with lithium

Drug Excretion/ Levels Levels Increases level of Decreases Other interactionsmetabolism increased by decreased by levels of

Lithium Excreted by the ACE inhibitors Sodium-containing Risk of ventricularkidneys unchanged Angiotensin II antacids arrhythmias with

receptor antagonists Smoking amiodarone or sertindoleNSAIDs Theophylline Increased risk of:COX-2 inhibitors • extra pyramidal side-Diuretics* effects with some Lithium toxicity is antipsychoticsworsened by sodium • CNS effects when used depletion; concurrent with SSRIsuse of diuretics(particularly thiazides) is hazardous and should be avoided

Valproate Metabolised by cimetidine carbamazepine carbamazepine Increased risk of CYP2B6, CYP2C9 lamotrigine neutropenia when Inhibits CYP2C9 used with olanzapine

Lamotrigine Metabolised by valproate rifampicin Active metabolite glucuronic acid carbamazepine of carbamazepineconjugation oestrogens

progestogens

Carbamaze pine Metabolised by clarithromycin rifabutin methadone Reduces effects of calcium- CYP1A2, CYP2B6, erythromycin efavirenz doxycycline channel blockersCYP2C9, CYP3A3/4 isoniazid telithromycin Increased risk of Induces CYP3A3/4, fluoxetine coumarins hyponatraemia when CYP2C9 fluvoxamine mianserin used with diuretics

antifungals mirtazapineritonavir paroxetinediltiazem tricyclic anti-verapamil depressantsacetazolamide lamotriginedanazol valproatecimetidine antipsychotics

antiviralsclonazepamciclosporincorticosteroidseplerenoneoestrogensprogestogens

Olanzapine Metabolised by fluvoxamine smoking Increased risk of: CYP1A2, CYP2D6 ritonavir carbamazepine • neutropenia with

valproate• CNS toxicity with sibutramine• enhanced hypotensiveeffects with general anaesthetics• antagonism of anti- convulsant effect of antiepileptic drugs

Table 3. Clinically significant interactions of mood stabilisers15,41

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plus valproate have been shown to be more effectiveat preventing relapse than valproate monotherapy.40

A number of treatments are now licensed for pre-venting recurrence in bipolar disorder (see Table 1),although some are only licensed for continuation treat-ment when they have been effective in treating a manicepisode. Carbamazepine is licensed for the prophylaxisof bipolar disorder unresponsive to lithium.15 If a med-ication is used outside its licensed indication, thepatient must be informed and their consent obtained.

Following an acute episode of either mania ordepression, maintenance treatment with a mood sta-biliser should continue for at least two years. If thereare risk factors for relapse, such as frequent episodes,co-morbid substance misuse and ongoing life stresses,then treatment should continue for five years orlonger depending on clinical need.6

Sudden cessation of lithium treatment has beenshown to increase the risk of relapse, particularlymania, by 50 per cent41 therefore it is imperativewhen trying to stop treatment that this is done in aplanned and consistent manner, tapering off the doseover a period of at least four weeks. Patients who reg-ularly stop their medication or remain non-compli-ant should receive an alternative mood stabiliser.

Pharmacology The aetiology of BPAD is still unclear, as is the mode ofaction of mood stabilising medications. There havebeen many hypotheses for a chemical imbalance inmania, which include raised levels of dopamine, sero-tonin, noradrenaline and glutamate42,43 as well as a

lowering of GABA (the inhibitory neurotransmitter).44

Depression is proposed to be caused by a decrease inserotonin, noradrenaline and dopamine levels,45 andhas also been associated with low levels of GABA,46 lowlevels of myoinositol47 and raised glutamate.48

Hypothetically, for mood stabilisers to be effec-tive it would seem that they would have to prevent ormodify some of these neurotransmitter changes.Lithium has been found to decrease glutamate lev-els within the brain as well as increasing myoinosi-tol.49 Valproate is thought to increase GABA byinhibiting its metabolism and increasing its synthe-sis.50 Lamotrigine and carbamazepine block voltage-dependent sodium channels, which then leads to areduction in release of excitatory neurotransmittersincluding glutamate.51,52 The antipsychotics havedopamine receptor antagonist activity, thereby reduc-ing dopamine activity in the brain.41

Blood monitoringLithium has a narrow therapeutic window, thereforeconsistent plasma levels are necessary (see Table 4).Once treatment has been initiated, lithium levelsshould be measured after four to seven days of treat-ment, then every week until dose and level remainconstant for four weeks. Once the patient is stabilisedon lithium, the measurements should be repeated atleast every three months and more frequently if thereis mild to moderate renal insufficiency; lithium iscontra indicated in patients with severe renal insuffi-ciency.15 It is imperative that blood levels are takenat the correct time of day and that enough time has

Medication Time to Form When to take level Therapeutic rangesteady state

Lithium 4-5 days MR tablets 12 hours post dose 0.6-1.0mmol per litreLiquid or ordinary Pre-dose (twice daily release tablets dosing)

Valproate 2-3 days MR tablets/ 12 hours post dose 50-125mg per litregranules (once daily dosing)Liquid or ordinary Pre-dose (twice daily release tablets dosing)

Carbamazepine 14 days MR tablets 12 hours post dose 6-12mg per litre(once daily dosing)

Liquid or ordinary Pre-dose (twice daily release tablets dosing)

Olanzapine 7 days Tablets 12 hours post dose 20-40µg per litreOrodispersible tablets

Table 4. Therapeutic drug level monitoring in maintenance treatment15,24,25

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elapsed between dose adjustments and blood samplesto ensure steady state plasma levels have beenachieved. Plasma levels above 1.0mmol per litre areassociated with toxicity and a reduction in dose is nec-essary. Lithium toxicity can be either acute or chronic.Acute toxicity is associated with an intentional orunintentional overdose, drug interaction or dehydra-tion, whereas chronic toxicity is associated with achange in kinetics: most commonly it is associatedwith dose changes and changes in elimination suchas a reducing renal function.53 The presenting symp-toms differ according to the type of toxicity (see Table5). Acute toxicity is generally less severe than chronictoxicity. As different brands of lithium do not havethe same bioavailability, prescriptions should clearlystate the brand intended.15

In 2009, the National Patient Safety Agency(NPSA) reporting and learning system reviewed inci-dents relating to lithium therapy and concluded thatlithium therapy, particularly monitoring, is an error-prone process. A number of recommendations weremade to improve: lithium monitoring, communica-tion of results, patient information and reducing con-current prescribing of interacting medicines. TheNPSA produced a patient pack,54 which includes alithium record book, lithium alert card and informa-tion booklet, which should be given to all patients pre-

scribed lithium. Patient should be regularly counselledon lithium treatment and recognising signs of toxicityand asked to carry their lithium record to all appoint-ments and their lithium alert card on their person.55

Therapeutic drug levels have also been establishedfor the use of valproate, carbamazepine and olanza-pine in mood stabilisation, but not for lamotrigine.24

It is recommended that carbamazepine levels aremeasured every six months to exclude toxicity,because there is a narrow window between therapeu-tic and toxic levels. 6 There is no recommended fre-quency for valproate drug level monitoring; it wouldappear to be useful during initiation of treatment toensure an adequate dose is achieved, if adverse effectsare present and if there is a lack of efficacy. Drug lev-els are also useful to help identify non-compliance.

Other monitoring requirementsLithiumRenal and thyroid function tests should be carriedout before lithium treatment and then every sixmonths.6 An ECG is also required before initiation oftreatment.24 A recent systematic review and meta-analysis has highlighted a high prevalence of hyper-parathyroidism in those on lithium and hasrecommended that calcium concentrations shouldbe checked before and during treatment.56

Medication Signs and symptoms of toxicity

Lithium Acute ChronicDiarrhoea Nausea and vomitingDizziness DizzinessNausea and vomiting DrowsinessDrowsiness AtaxiaAtaxia Slurred speechSlurred speech Increased thirst and polyuriaIncreased thirst and polyuria Severe tremor or twitchSevere tremor or twitch Movement disordersBlurred vision, diplopia Memory lossConfusionSeizureComaElectrocardiogram (ECG) changes

Valproate AtaxiaConfusionTremor

Lamotrigine AtaxiaConfusion

Carbamazepine AtaxiaConfusion

Table 5. Signs of toxicity with mood stabilisers15,53

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Valproate, carbamazepine and lamotrigineLiver function tests (LFTs) and full blood count(FBC) should be carried out before treatment, aftersix months treatment and when symptoms of liver orblood disorders occur (see Table 6).6,24 For carba-mazepine, it is also recommended to monitor ureaand electrolytes (U+Es) every six months, as acuterenal failure has occurred during carbamazepinetherapy.6

In rare cases, lamotrigine can cause bone marrowdepression, which may present as anaemia, bruisingor infection; presentation of these symptoms requiresurgent investigations. Carbamazepine and valproatehave both been associated with Drug Rash withEosinophilia and Systemic Symptoms (DRESS). Also,Stevens-Johnson syndrome is a rare adverse effect oflamotrigine and carbamazepine; if a rash develops,treatment should be stopped immediately. The riskof rash is increased if lamotrigine or carbamazepineis titrated rapidly so initiation should be in line withthe dosing recommendations in the BNF. If lamotrig-ine treatment is missed for more than five days, itmust be slowly re-titrated.15

OlanzapineFBC, U+Es and LFTs should be carried out before treat-ment and then at least yearly. Blood lipids should bemeasured before treatment and every three months forthe first year of treatment then yearly. Blood glucoseshould be measured before treatment, after one monthof treatment and then every four to six months.24

Use of pharmacological treatments in children andadolescentsThe diagnosis of BPAD in children and adolescentspresents a challenge as using current diagnostic crite-ria developed for adults has limitations. There is alsolimited evidence for the pharmacological treatmentof BPAD in this age group.6 The only medicines thatare licensed are lithium for mania and as a mood sta-biliser (from the age of 12 years) and aripiprazole for

the management of moderate to severe mania (fromthe age of 13 years) for a period of 12 weeks.15,57 Bothof these agents are recommended by NICE.6,57

All other treatments currently recommended foruse in BPAD in adults are not licensed for this indica-tion in children and adolescents. When these agentsare used in this younger age group, it is imperativethat relevant consent issues, involvement ofparent(s)/carer(s), and consideration of the youngperson’s capacity are addressed.

Children and adolescents should normally bemanaged by specialist clinicians only and treatmentshould follow the adult recommendations with thefollowing additions:6

• First-line treatment – an atypical antipsychotic thatis associated with lower weight gain and non-eleva-tion of prolactin levels such as aripiprazole• Second-line treatment in female patients – lithium • Second-line treatment in male patients – valproateor lithium.

Medicines should be started at lower doses thanin adults. Closer monitoring during treatment isrequired as children and adolescents may be moreprone to adverse effects of medication, includingsedation, obesity, extrapyramidal symptoms, meta-bolic changes and raised prolactin.

Women of childbearing ageNo mood stabiliser can be deemed completely safe inpregnancy. Valproate is not recommended by NICE inwomen of childbearing age as it has been associatedwith a 6 per cent rate of major malformations (two tothree times the rate expected).6 These malformationsinclude facial dysmorphias, distal digit hypoplasia,and a 1-2 per cent risk of neural tube defects (gen-eral population risk 0.06 per cent). Use of valproatein pregnancy has also been shown to affect postnatalcognitive function of the child, with a 22 per cent riskof low IQ (compared with a general population riskof 2 per cent).58

Carbamazepine has also been associated with ahigher rate of congenital abnormalities, includingfacial clefts, gastrointestinal tract problems, cardiacabnormalities and a 0.2 per cent risk of neural tubedefects. Neural tube defects may be attributed in partto valproate and carbamazepine’s effect on reducingserum folate, itself thought to be protective againstneural tube defects.58

Use of lamotrigine in pregnancy is associatedwith an increased risk of oral clefts. Lithium hasbeen associated with a higher incidence (seven timesthat expected) of congenital heart disease whenused in the first trimester with a risk of Ebstein’s

Liver disorders Common blood disorders

Onset is often abrupt: Symptoms are grouped according to Initial symptoms can include chills, blood cell affected:fever, rash, pruritus, arthralgia, Anaemia (low RBC) – fatigue, headache, abdominal pain, weakness and shortness of breathanorexia, nausea and vomiting Leukopenia (low WBC) – sore throat, These can progress to jaundice, fever, signs of infectiondark urine and an enlarged Thromobocytopenia (low platelets) and tender liver – bleeds or bruises easily

Table 6. Symptoms of drug-induced liver and blood disorders

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anomaly of 0.1-0.05 per cent (general populationrisk 0.005 per cent).58

In general, antipsychotic medicines have not beenshown to increase the risk of malformation when usedin pregnancy although data on individual medicationsare limited.58 As with all medication choices in preg-nancy, the latest advice should be sought and treat-ment should be tailored to individual circumstances.

All women of childbearing age should beinformed of the risks of medication use in pregnancy(including the risks of relapse, damage to the foetus,and the risks associated with stopping or changingmedication). They should also be offered advice oncontraception and be encouraged to discuss preg-nancy plans with their doctor.6

Although there is little known about the prevalenceof menstrual dysfunction and polycystic ovary syn-drome (PCOS) in women with BPAD, one-third ofwomen have reported irregular menstrual cycles dur-ing adolescence before they were treated.59 In womenwith BPAD, the use of valproate has been linked to a10-fold increase in risk of developing PCOS comparedwith women on non-valproate treatments,60 and maybe higher in women who were treated before theywere 20 years old. PCOS is also associated with fertil-ity problems. Because of this, there are concernsaround prescribing valproate in girls, female adoles-cents and young women. Valproate has also beenshown to increase the risk of hyperandrogenism inwomen, which may impact on fertility.59

Future developmentsThere are currently a number of new treatments inthe pipeline for mania and BPAD. These include:ramelteon, a melatonin-receptor agonist, which is cur-rently in Phase 3 trials for use as an adjunct in bipo-lar I disorder, and lurasidone, an atypicalantipsychotic that appears to have a lower potentialfor causing adverse weight and metabolic effects, forthe treatment of bipolar depression.61 Lurasidonealready has EMA approval for the treatment of schizo -phrenia in the EU. The NICE clinical guideline onbipolar disorder is currently being reviewed and isexpected to be published in September 2014, withthe antenatal and postnatal mental health guidelineupdate planned to be published in December 2014.

Summary Mood stabilisers are important treatments in the man-agement of BPAD and have been shown to be effec-tive in reducing the risk and severity of relapse. Inacute mania, lithium, valproate or one of the atypicalantipsychotics such as aripiprazole, quetiapine, olan-

zapine or risperidone are recommended. In mainte-nance treatment, lithium, valproate or olanzapine arefirst-line options. In the case of bipolar depression, itis recommended to first optimise the mood stabiliserthen cautiously use a low dose of an SSRI for a lim-ited time period. All patients being treated for BPADrequire close monitoring of physical health and reg-ular assessments of their medication for efficacy andcompliance. All healthcare professionals involved inthe treatment of BPAD have a duty to be aware of therequired monitoring to ensure the continued safetyof this vulnerable patient group.

Declaration of interestsNone declared.

Michele Sie is Chief Pharmacist at the West London MentalHealth NHS Trust, St. Bernard’s Hospital, Southall, London

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• Mood stabilisers can reduce the risk of relapse, andthe severity of relapse

• Always tell your doctor or pharmacist that you areon mood stabilising medications as these can inter-act with other prescribed medicines, medicines thatcan be purchased and herbal remedies

• If on lithium remember to carry your lithium alertcard and take your lithium record to appointments

• If required, attend regularly for blood tests to monitor levels and side-effects

• Adverse effects are more likely to occur at initiationof treatment and if blood levels are too high

• Do not stop taking a mood stabiliser suddenly (espe-cially lithium) as this may increase the risk of relapse

• If you develop signs of lithium toxicity (for examplefeeling shaky and wobbly on your feet, feeling extrasleepy and sluggish, blurred vision, feeling confused)you should seek immediate medical advice

• If you develop a rash or bruising (with lamotrigine,carbamazepine or valproate) stop your treatmentand tell your doctor as soon as possible

Table 7. Key information for patients

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