Pierre Alexis Geoffroy

Frank Bellivier

Marion Leboyer

Bruno Etain

Can the response to mood stabilizers be predicted in bipolar disorder?

Bipolar disorder (BD) is a severe chronic multifactorial disease that requires maintenance therapy with mood stabilizers (MS). Even with medications, the rate of response among patients with BD is low and the risk of relapse is high. Therefore, in this context of the urgent need for reliable and reproducible predictors of individual responses to MS, pharmacogenetics research is expected to provide helpful progress. Most pharmacogenetic studies of MS have focused on the response to lithium with several good putative candidate genes but informative results are sparse. There have been few studies on valproate, lamotrigine or atypical antipsychotics. Overall, the results of pharmacogenomics studies have not provided sufficient data to change daily practices in BD significantly and further investigation is warranted to identify highly relevant genetic predictors of response their roles. Although progress still remains to be made, the clinical assessment of a subject including the identification of specific individual phenotypic and pharmacogenetic characteristics is likely to become a powerful instrument for the development of personalized therapies.

INTRODUCTION

Bipolar disorder (BD) is a chronic multifactorial psychiatric disorder that is characterized by recurrent alternating episodes of mania/hypomania and depression interspaced with euthymic periods variably affected by residual symptoms and dysfunction [START_REF] Leboyer | Bipolar disorder: new perspectives in health care and prevention[END_REF]. BD causes impairment in functioning and health-related quality of life, and BD patients require maintenance therapy [START_REF] Pa Geoffroy | Combination Therapy for Manic Phases: A Critical Review of a Common Practice[END_REF]. The lifetime prevalence of BD is about 1% for the traditional BD I subtype and up to 6.5% if all BD spectrum subtypes are included; thus, it is evidence that BD is a major public health problem [START_REF] Angst | The emerging epidemiology of hypomania and bipolar II disorder[END_REF][START_REF] Kr Merikangas | Lifetime and 12-month prevalence of bipolar spectrum disorder in the National Comorbidity Survey replication[END_REF]. Indeed, BD is seventh most major cause of disability-adjusted life-years according to the World Health Organization (WHO) [START_REF] Murray | The Global Burden of Disease. A Comprehensive Assessment of Morbidity and Disability From Diseases, Injuries and Risk Factors in 1990 and Projected to 2020[END_REF].

The etiological determinants of BD remain poorly understood; similarly, the mechanisms of action of psychotropic drugs have not been described in detail, and indeed the exact targets are still to be definitively identified. Current guidelines advocate the use one of a group of variably similar treatment algorithms for all patients, such that the clinical, pathophysiological, and lifetime heterogeneity of BD is not taken into accounts, because of the lack of evidence [START_REF] Pa Geoffroy | Combination Therapy for Manic Phases: A Critical Review of a Common Practice[END_REF]. Thus, personalized therapeutic strategies with targeted interventions -taking into account both individual characteristics and the characteristics of the clinical expression of the disorder in a given individual-are clearly required to improve prognosis. Pharmacogenomics can be exploited to identify key biomarkers and therefore drive innovation in this field of personalized medicine.

Numerous studies have attempted to identify genetic markers that could be used to predict drug efficacy and safety in several fields of medicine. Pharmacogenetics is -the study of variability in drug response due to heredity‖, and may thus be contribute to the development of ‗personalized' treatment strategies in medicine, and including BD. However to date, there is only one US FDA-approved commercial pharmacogenetic test available (Roche Diagnostic, AmpliChip CYP450) which allows genotyping for the two cytochrome P450 genes (CYP2D6 and CYP2C19). Using this chip, patients can be genotyped to help predict the metabolizer status of patients, which may influence choice and dose of antipsychotic or antidepressant medication [START_REF] De Leon | The AmpliChip CYP450 genotyping test: Integrating a new clinical tool[END_REF]. No clear genetic biomarker for use in routine clinical care in BD has been described. This is particularly unfortunate because BD patients show a low rate of response, a high risk of relapse and several side effects to MS that are unfortunately not predictable. Indeed, survival analysis of BD patients indicates a 5-year risk of relapse into mania or depression of 73% despite continual and adequate MS medication [START_REF] Mj Gitlin | Relapse and impairment in bipolar disorder[END_REF]. Even for those who do not relapse, considerable affective morbidity is observed [START_REF] Mj Gitlin | Relapse and impairment in bipolar disorder[END_REF]. The large EMBLEM prospective study with BD I patients shows that 64% achieved remission and 34% achieved functional recovery at 2 years [START_REF] Haro | 2-Year course of bipolar disorder type I patients in outpatient care: factors associated with remission and functional recovery[END_REF]. A naturalistic observation study of the response to MS described very low rates of full response to individual MS: lithium 30%, carbamazepine 0%, valproate 13%, lamotrigine 11%, and olanzapine 25% [START_REF] Garnham | Prophylactic treatment response in bipolar disorder: results of a naturalistic observation study[END_REF]. The predictors were few and uncertain: lithium responders were more likely to be bipolar II with earlier onset of illness, and responders to valproate presented higher rates of psychosis [START_REF] Garnham | Prophylactic treatment response in bipolar disorder: results of a naturalistic observation study[END_REF]. Various evidence indicates that the response to long-term lithium treatment is a familial trait and clusters in families [START_REF] Grof | Is response to prophylactic lithium a familial trait?[END_REF]. Also, the mode of inheritance of BD responsive to lithium appears to conform to a recessive model with sex-specific penetrance of transmission [START_REF] Alda | Autosomal recessive inheritance of affective disorders in families of responders to lithium prophylaxis[END_REF]. Evidence for such heritability is consistent with the relevant genes exerting a high-magnitude effect on the response to long-term lithium treatment. Thus, the response to long-term prophylactic treatment with mood stabilizers (MS) has been suggested to be a clinical trait that could be exploited to identify homogeneous subgroups of BD and to map genes relevant to both treatment response and BD itself [START_REF] Alda | Genetic factors and treatment of mood disorders[END_REF][START_REF] Ha Mansour | Pharmacogenetics of bipolar disorder[END_REF][START_REF] Squassina | Pharmacogenomics of mood stabilizers in the treatment of bipolar disorder[END_REF][START_REF] Gm Macqueen | The phenotypes of bipolar disorder: relevance for genetic investigations[END_REF]. Therefore, informative and helpful results are expected from pharmacogenomics research in this context of the urgent need to find reliable and reproducible predictors of individual responses to MS and MS safety [START_REF] Squassina | Pharmacogenomics of mood stabilizers in the treatment of bipolar disorder[END_REF][START_REF] Smith | Predicting response to lithium in bipolar disorder: a critical review of pharmacogenetic studies[END_REF][START_REF] Mccarthy | Pharmacogenetics of lithium response in bipolar disorder[END_REF][START_REF] Serretti | Pharmacogenetics of lithium long-term treatment: focus on initiation and adaptation mechanisms[END_REF].

We review the current state of, and perspectives for, pharmacogenetic research on MS treatments in BD. First, we consider issues pertaining to the diagnosis of BD patients, sample selection and definitions of treatment response phenotypes used in various pharmacogenetic studies. Then, we review existing evidence for genetic predictors of the response of BD patients to MS treatment. Finally, we discuss the possible challenges and future directions for pharmacogenetics in BD.

METHODS

We conducted in March 2013 an extensive review on the pharmacogenomics studies exploring MS treatment in BD. The publications were obtained from the PubMed electronic database. The literature search was performed using the Mesh heading: -Bipolar Disorder‖ AND ("genetics" OR "gene" OR -pharmacogenomics‖ OR -pharmacogenetics‖) AND ("mood stabilizer" OR "lithium" OR "valproate" OR "valproic acid" OR "lamotrigine‖ OR "carbamazepine‖ OR "oxcarbazepine‖ OR "topiramate‖ OR "gabapentin‖ OR "antipsychotic‖). We also used the related articles function of the PubMed database, the reference list of retained studies and searched Google Scholar to identify additional articles. We included only published data written in English.

PHENOTYPIC FEATURES AND DEFINITIONS

A research in pharmacogenetics is confronted by a methodological question: should the response to MS treatment in all BD subjects be studied, or should phenotypically defined subgroups of subjects with BD be studied?

The genetic and phenotypic heterogeneity of BD clearly cloud the identification of its biological determinants [START_REF] Leboyer | Psychiatric genetics: search for phenotypes[END_REF]. The use of valid and consensual definitions for all steps of studies is essential for reliable and comparable results to be obtained. Rigorous definitions of the probands and clear criteria for the definition of treatment are needed to detect causative determinants of differences in response to medication.

Which phenotype should be assessed for subjects with BD?

Investigations of drug responders [START_REF] Alda | Investigating responders to lithium prophylaxis as a strategy for mapping susceptibility genes for bipolar disorder[END_REF] and the comparison of patients responsive to different drugs [START_REF] Mj Passmore | Phenotypic spectra of bipolar disorder in responders to lithium versus lamotrigine[END_REF] have led to promising results. Responsive patients that differ with respect to course of the disease, comorbidity and family history, may represent distinct subtypes of BD. There is now evidence to suggest that lithium-responsive BD is a core bipolar phenotype [START_REF] Alda | Investigating responders to lithium prophylaxis as a strategy for mapping susceptibility genes for bipolar disorder[END_REF]: responders to lithium show a family history of BD and a familial response to lithium consistent with genetic factors having a prominent role [START_REF] Alda | Investigating responders to lithium prophylaxis as a strategy for mapping susceptibility genes for bipolar disorder[END_REF]. Also, family histories and some clinical characteristics differ between responders to lithium and responders to other MS [START_REF] Alda | Investigating responders to lithium prophylaxis as a strategy for mapping susceptibility genes for bipolar disorder[END_REF].

BD is a broad-large spectrum with wide range of symptoms. Defining intermediate phenotypes, or homogeneous subgroups within the BD population may be useful. Indeed, the early genetic research with the whole BD spectrum, or even with the traditional BD I subgroup, failed to obtain significant and relevant results [START_REF] Leboyer | Psychiatric genetics: search for phenotypes[END_REF]. Consequently, recent studies focus on more homogeneous subgroups, and there has been substantial effort directed towards phenotypic refinement. The purpose of phenotypic refinement is to select subgroups that differ from the whole BD population as concerns clinical presentation, course of the disease, family history, comorbidities and/or possibly long-term response to treatment [START_REF] Pa Geoffroy | Reconsideration of bipolar disorder as a developmental disorder: Importance of the time of onset[END_REF]. Alda proposed a classification based on three main subtypes of BD: (1) classical, (2) psychosis spectrum and (3) 'characterological' which includes cases with distinct clinical characteristics and specific patterns of drug treatment response that might lead to more targeted treatment [START_REF] Alda | The phenotypic spectra of bipolar disorder[END_REF].

Such phenotype selection of BD populations aims to increase the probability of identifying genes of interest. They highlight the importance of careful diagnostic assessment of BD cases, with attention to specific clinical features, family history, comorbidities and clinical course as these factors may be closely linked to the treatment response phenotype.

How should treatment response phenotypes be assessed?

Assessment of treatment response phenotypes is central to identifying the role of genetic factors in determining a subject's response to a drug or the onset of adverse drug reactions (ADR). The definitions of treatment response used in the literature are often not clear and divergent between pharmacogenetic studies. Defining treatment response phenotypes is expected to be highly complex, largely because the clinical quantification of the response to treatment is complex.

The simplest phenotype is dichotomous (responders/non-responders) and has been used in most pharmacogenetic studies of MS [START_REF] Squassina | Pharmacogenomics of mood stabilizers in the treatment of bipolar disorder[END_REF]. Nevertheless, a binary trait of this type does not allow correct measurement of the response to a drug, which is, constitutively, a quantitative trait. Indeed, such binary measurement does not reflect the clinical reality because most patients show partial responses and very few of presented a full response to MS [START_REF] Garnham | Prophylactic treatment response in bipolar disorder: results of a naturalistic observation study[END_REF]. If a categorical approach is used, partial responses to a drug can be usefully assessed in addition to the classical traits of responders/non-responders. Applying a dimensional approach, the response to MS is studied as a quantitative trait, and this may facilitate the identification of genetic variants and their expression associated with a wide range of intermediate phenotypes. The dimensional approach allows the degree of variation in the treatment response phenotype to be studied, and this contrasts with the dichotomous approach that only the two extreme points of the dimensional gradient into account. Moreover, combining assessment of the response to treatment as measured from the improvement of BD symptoms, with assessment of treatment side effects, as with the Clinical Global Impressions Scale (CGI), might be useful to separate out the two effects [START_REF] Mk Spearing | Modification of the Clinical Global Impressions (CGI) Scale for use in bipolar illness (BP): the CGI-BP[END_REF]. The method of -extreme discordant phenotype‖ (EDP) may increase the statistical power and consequently the probability of detecting gene variants associated with drug efficacy or toxicity [START_REF] Dw Nebert | Extreme discordant phenotype methodology: an intuitive approach to clinical pharmacogenetics[END_REF]. Alternatively, individual trait values, for example treatment response, can be used as indices for phenotype selection, and selective genotyping has been proven to be effective for mapping quantitative trait loci (QTL) [START_REF] Zhang | Statistical power of association using the extreme discordant phenotype design[END_REF].

The definition of treatment response is complex, especially in BD: several factors have to be considered, including the long-term response to MS, the severity and the duration of episodes before and after the introduction of the MS, the presence of possible confounders, for example multiple pharmacotherapy, and the degree of compliance. Thus, stringent definitions are tricky to establish, and several tools have been proposed. The average Affective Morbidity Index and the Illness Severity Index are both analytical tools [START_REF] Coppen | A double-blind comparison of lithium carbonate and maprotiline in the prophylaxis of the affective disorders[END_REF] [START_REF] Maj | Prediction of affective psychoses response to lithium prophylaxis. The role of socio-demographic, clinical, psychological and biological variables[END_REF]. They each provide a quantitative evaluation of the improvement under MS and take into account both severity and duration of episodes before and after the introduction of MS treatment. However, they suffer limitations because they do not take the presence of confounders into account, such as compliance or poly-pharmacotherapy. Grof et al. recently compared response to long-term lithium treatment in bipolar relatives of BD lithium responders and BD controls, and proposed a more complete rating scale referred to as the -Alda scale‖ [START_REF] Grof | Is response to prophylactic lithium a familial trait?[END_REF]. It is a quantitative scale for measuring the degree of improvement under MS taking the presence of confounders into account. As well as allowing improvement due to MS only to be observed, it also permits both an intermediate phenotype approach (partial response to MS) and an EDP approach [START_REF] Grof | Is response to prophylactic lithium a familial trait?[END_REF]. This approach involves rating the degree of response on a 10-point scale (-A‖ criteria) and the number of episodes off the treatment, the frequency of episodes off the treatment, the duration of treatment, the compliance during period (s) of stability, and the use of additional medications during the periods of stability (-B‖ criteria); a total score from 0 to 10 is then obtained by subtracting B from A criteria [START_REF] Grof | Is response to prophylactic lithium a familial trait?[END_REF].

However, irrespective of the definition used, we observed that the rate of response to various MS treatments in monotherapy is always close to 50% (and about 30% for placebo), with an incremental benefit of about 20% when adding a second MS agent [START_REF] Gajwani | Treatment-refractory bipolar disorder: classification to aid in clinical management[END_REF]. Thus, treatment refractoriness in BD remains a substantial medical challenge. We believe therefore that it is very important to identify markers that are predictive of the response to MS treatments; this may involve the identification of genetic variant patterns that can be used to help choose between different molecules available as treatment in routine practice.

PHARMACOGENOMICS OF MOOD STABILIZERS

Lithium

Lithium salts are the best studied MS and remain a cornerstone of treatment in BD. Pharmacogenetic studies have for the most part focused on the response to lithium prophylaxis as a way to define a more homogeneous population (Table 1).

Linkage studies on the response to lithium

Linkage studies on the response to lithium were the first to generate relevant and informative results. Analysis of the Faroese population with eight lithium-responsive BD probands provided evidence of increased haplotype sharing on the distal part of chromosome 18q23, confirming the preliminary findings for this region by Freimer et al. [START_REF] Ewald | A haplotype-based study of lithium responding patients with bipolar affective disorder on the Faroe Islands[END_REF]. A linkage study focused on this region of chromosome 18: in the sample of lithium-responsive BD probands including only unilineal families, two chromosomal regions with modestly positive LOD scores were found at D18S53 and at D18S61 for maternal and paternal pedigrees, respectively [START_REF] Turecki | Lithium responsive bipolar disorder, unilineality, and chromosome 18: A linkage study[END_REF]. Further linkage studies using a temperament-based measure (cyclothymic temperament) as a quantitative intermediate phenotype found the highest linkage on chromosome 18p11 and weaker linkage for chromosomes 3 and 7 [START_REF] Evans | Suggestive linkage of a chromosomal locus on 18p11 to cyclothymic temperament in bipolar disorder families[END_REF]. Consequently, chromosome 18 is a potential region of interest and quantitative measures may lead to the detection of loci for BD and maybe for the response to lithium. Work with a very large pedigree derived from a homogeneous population in Quebec from Saguenay-Lac-St-Jean area found the chromosome 12q23-q24 region to be linked with the response to lithium in a BD population [START_REF] Morissette | Genome-wide search for linkage of bipolar affective disorders in a very large pedigree derived from a homogeneous population in quebec points to a locus of major effect on chromosome 12q23-q24[END_REF]. Linkage to chromosome 12q24 was confirmed later in a larger study in the same population, and other regions of lower interest were found on chromosomes 2, 5, 7, 9, 10, 17 and 20 [START_REF] Shink | A genome-wide scan points to a susceptibility locus for bipolar disorder on chromosome 12[END_REF]. Evidence for linkage was found in 31 BD families identified as excellent lithium responders with loci on chromosomes 15q14 and 7q11.2 [START_REF] Turecki | Mapping susceptibility genes for bipolar disorder: a pharmacogenetic approach based on excellent response to lithium[END_REF]; considering response phenotype, this study also suggests that chromosome 7q11.2 may be more involved in the response to lithium than chromosome 15q14, which was implicated in the etiology of BD [START_REF] Turecki | Mapping susceptibility genes for bipolar disorder: a pharmacogenetic approach based on excellent response to lithium[END_REF]. These observations highlight how it is important to pay attention to the interpretation of studies of this type. Indeed, comparing responders to non-responders allows treatment response genes to be identified, whereas studying BD responders alone only allows conclusions about genes associated with the disease. A very relevant recent linkage study considered 36 families recruited through responsive probands to long-term lithium treatment; it involved an initial linkage study followed by fine mapping and gene expression analysis. Exploiting these two complementary strategies, the authors found evidence of linkage to lithium-responsive BD in 3p25, 3p14 and 14q11 regions; they also found significantly deregulated synaptic and mitochondrial genes in these regions [START_REF] Lopez De Lara | Implication of synapse-related genes in bipolar disorder by linkage and gene expression analyses[END_REF].

These linkage studies on the response to lithium generated enthusiastic results and should also be performed in the future on the -non-response‖ phenotype. Moreover, some methodological issues, such as spontaneous remission of the illness, will have to be addressed.

The candidate gene approach 5.1.2.1. The inositol pathway

Selecting candidate genes for pharmacogenetic investigation is difficult because the exact mechanism of action of lithium remains unclear [START_REF] Toker | Gene-expression studies in understanding the mechanism of action of lithium[END_REF]. Lithium inhibits the activity of several enzymes including those involved in the phosphatidylinositol cycle and in phospholipase C signal transduction that may be responsible for mood stabilization. Williams RS et al. reported that the effects of MS (including valproate and carbamazepine as well as lithium) are mediated through action on inositol depletion [START_REF] Williams | A common mechanism of action for three mood-stabilizing drugs[END_REF]. They demonstrate that all three drugs inhibit the collapse of sensory neuron growth cones and increase growth cone area, and that this action is reversed by inositol [START_REF] Williams | A common mechanism of action for three mood-stabilizing drugs[END_REF]. Consequently, numerous candidate gene studies on the response to lithium prophylaxis have addressed inositol-related genes.

The hypothesis that inositol polyphosphate 1-phosphatase (INPP1) in the phospholipase C signaling pathway is a putative target of lithium has been investigated: several pharmacogenetic studies have tested for associations between polymorphisms in the INPP1 gene and the response to lithium of BD patients. An association between the C973A variant of the INPP1 gene and good efficacy of lithium in BD has been reported [START_REF] Vm Steen | The polymorphic inositol polyphosphate 1phosphatase gene as a candidate for pharmacogenetic prediction of lithium-responsive manic-depressive illness[END_REF], but not subsequently confirmed by Michelon et al. [START_REF] Michelon | Association study of the INPP1, 5HTT, BDNF, AP-2beta and GSK-3beta GENE variants and restrospectively scored response to lithium prophylaxis in bipolar disorder[END_REF].

Candidate genes studies have drawn attention to the myo-inositol monophosphatase 2 (IMPA2) that encodes an enzyme of the phosphatidylinositol signaling system and is inhibited by lithium [START_REF] Dimitrova | Association study of myo-inositol monophosphatase 2 (IMPA2) polymorphisms with bipolar affective disorder and response to lithium treatment[END_REF]. One study compared good responders to lithium treatment with the poor responders among 237 parent-offspring trios, 174 cases and 170 controls: this study reported a trend for significant associations in predicting the response to lithium treatment for two polymorphisms [START_REF] Dimitrova | Association study of myo-inositol monophosphatase 2 (IMPA2) polymorphisms with bipolar affective disorder and response to lithium treatment[END_REF]. The two polymorphisms of IMPA2 on chromosome 18p11.2 were confirmed in a supplementary study [START_REF] Sjøholt | Examination of IMPA1 and IMPA2 genes in manic-depressive patients: association between IMPA2 promoter polymorphisms and bipolar disorder[END_REF]. Two studies found no association between the polymorphisms of myo-inositol monophosphatase 1 (IMPA1) on chromosome 8q21.13-21.3 with variation in the response to lithium treatment in cases of BD [START_REF] Sjøholt | Examination of IMPA1 and IMPA2 genes in manic-depressive patients: association between IMPA2 promoter polymorphisms and bipolar disorder[END_REF][START_REF] Vm Steen | Lack of genetic variation in the coding region of the myo-inositol monophosphatase gene in lithium-treated patients with manic depressive illness[END_REF]. Generally, preliminary studies implicate several enzymes related to inositol phosphate metabolism and therefore the genes of this pathway may be suitable targets for studies of the action of lithium.

Diacylglycerol kinase eta (DGKH) is a key protein in the lithium-sensitive phosphatidyl inositol pathway responsible for the recycling and degradation of diacylglycerol (DAG). A recent genome-wide association study implicates the diacylglycerol kinase eta gene (DGKH), and found the strongest association signal at a marker within the first intron of DGKH [START_REF] Baum | A genome-wide association study implicates diacylglycerol kinase eta (DGKH) and several other genes in the etiology of bipolar disorder[END_REF]. However, study of a sample of 199 Sardinian BD patients characterized for the response to lithium therapy did not replicate the association with DGKH polymorphisms [START_REF] Manchia | Interacting genes in lithium prophylaxis: preliminary results of an exploratory analysis on the role of DGKH and NR1D1 gene polymorphisms in 199 Sardinian bipolar patients[END_REF], and an additional study in 91 subjects characterized for lithium response did not find an association but the sample was too small to detect anything other than large, strong effects [START_REF] Squassina | The diacylglycerol kinase eta gene and bipolar disorder: a replication study in a Sardinian sample[END_REF].

Several studies have tested the phospholipase C-gamma 1 (PLCG1) gene that codes for a gamma-1 isozyme of phospholipase (PLC), an enzyme of the inositol pathway second messenger system. One study reported a positive association for one PLCG1 polymorphism in 136 excellent lithium responders compared to 163 controls [START_REF] Turecki | Evidence for a role of phospholipase C-gamma1 in the pathogenesis of bipolar disorder[END_REF]. The same authors screened the PLCG1 gene for functional polymorphisms and identified three polymorphic sites in three different exons (exons 9, 26, 31); however, none of the markers was found to be associated with BD in a sample of 133 excellent responders to lithium and 99 healthy controls [START_REF] Ftouhi-Paquin | Identification of three polymorphisms in the translated region of PLC-gamma1 and their investigation in lithium responsive bipolar disorder[END_REF]. Because of the absence of a comparison non-responder group, these two studies only show that the PLCG1 gene is associated with BD. A recent study tried to confirm the findings that bipolar patients with an excellent response to lithium treatment have a higher frequency of a specific dinucleotide repeat allele in the PLCG1 genomic region; however, this was not replicated in a sample of Norwegian lithium-treated bipolar patients sub-classified as lithium responders, non-responders, or partial-responders/unclassified [START_REF] Løvlie | The phospholipase C-gamma1 gene (PLCG1) and lithium-responsive bipolar disorder: re-examination of an intronic dinucleotide repeat polymorphism[END_REF]. Only a PLCG1-8 repeat was more frequent among lithium responders than controls when analysing according to presence or absence of different dinucleotide alleles [START_REF] Løvlie | The phospholipase C-gamma1 gene (PLCG1) and lithium-responsive bipolar disorder: re-examination of an intronic dinucleotide repeat polymorphism[END_REF]. Although further studies are needed to explain these contradictory results, work in the inositol pathway shows promise and generates helpful findings.

The circadian signaling system

There is interest in variants of genes associated with the molecular clock, as some of these genes encode enzymes that are inhibited by lithium, for example glycogen synthase kinase 3 alpha and beta (GSK3α and GSK3β). Lithium acts on these enzymes either by direct inhibition or indirectly by regulating other mechanisms like the formation of a signaling complex comprised of beta-arrestin 2 (βArr2) and Akt. [START_REF] Freland | Inhibition of GSK3 by lithium, from single molecules to signaling networks[END_REF]. Benedetti et al. studied the association of GSK3β (-50 T/C) polymorphism with the therapeutic response to lithium among 88 bipolar type I patients: the recurrence index for homozygotes for the wild variant (C/C) did not change under treatment, whereas carriers of the mutant allele showed improvement. This thus suggests that the long-term response to lithium in bipolar illness is influenced by the GSK3β -50 T/C polymorphism [START_REF] Benedetti | A glycogen synthase kinase 3-beta promoter gene single nucleotide polymorphism is associated with age at onset and response to total sleep deprivation in bipolar depression[END_REF]. However, contradictory results have been reported: one study concluded that this polymorphism is not related to the response to prophylactic lithium [START_REF] Szczepankiewicz | Association study of the glycogen synthase kinase-3beta gene polymorphism with prophylactic lithium response in bipolar patients[END_REF] and another found no association [START_REF] Michelon | Association study of the INPP1, 5HTT, BDNF, AP-2beta and GSK-3beta GENE variants and restrospectively scored response to lithium prophylaxis in bipolar disorder[END_REF]. GSK3β also phosphorylates and stabilizes the orphan nuclear receptor REV-ERBα, one of the principal components of the circadian rhythm system that is involved in the cyclic regulation of Brain and Muscle Arnt-like protein-1 (BMAL1). Lithium induces degradation of REV-ERBα and BMAL1 gene expression, implicating REV-ERBα as a target of lithium in its mechanism of action [START_REF] Yin | Nuclear receptor Rev-erbalpha is a critical lithium-sensitive component of the circadian clock[END_REF]. The association of the gene encoding for REV-ERBα (NR1D1) and the response to lithium prophylaxis in BD patients has been investigated in a sample of 199 Sardinian BD patients characterized for the response to lithium therapy; the interaction analysis did not show any significant effect of any NR1D1 polymorphisms [START_REF] Manchia | Interacting genes in lithium prophylaxis: preliminary results of an exploratory analysis on the role of DGKH and NR1D1 gene polymorphisms in 199 Sardinian bipolar patients[END_REF]. However, more recently, Campos-de-Sousa et al. observed a significant association between the variant rs2314339 in NR1D1 and the response to lithium [START_REF] Campos-De-Sousa | Nuclear receptor rev-erb-{alpha} circadian gene variants and lithium carbonate prophylaxis in bipolar affective disorder[END_REF]. Further evidence of a role for REV-ERBα in the therapeutic mechanism of lithium has recently been described. McCarthy et al. conducted a candidate gene association study for 16 variants in seven circadian clock genes and the response to lithium of 282 Caucasian patients with BD [START_REF] Mccarthy | Functional genetic variation in the Rev-Erbα pathway and lithium response in the treatment of bipolar disorder[END_REF]. They found that a variant in the promoter of NR1D1 (rs2071427) and a variant in cryptochrome-1 (CRY1; rs8192440) were nominally associated with the response to lithium [START_REF] Mccarthy | Functional genetic variation in the Rev-Erbα pathway and lithium response in the treatment of bipolar disorder[END_REF]. Also, GSK3β and NR1D1 genotypes considered together predicted the response to lithium robustly and additively; the response was proportional to the number of response-associated alleles [START_REF] Mccarthy | Functional genetic variation in the Rev-Erbα pathway and lithium response in the treatment of bipolar disorder[END_REF].

Glucocorticoid receptors are regulators of the circadian rhythm. A polymorphism of the glucocorticoid receptor gene (NR3C1) on chromosome 5q31-32 is associated with lithium responder status [START_REF] Szczepankiewicz | Glucocorticoid receptor polymorphism is associated with lithium response in bipolar patients[END_REF]. Although the mechanism of action of lithium is not understood, it clearly interferes with the expression of circadian genes and this is involved in its mood stabilizing effect [START_REF] Yin | Nuclear receptor Rev-erbalpha is a critical lithium-sensitive component of the circadian clock[END_REF]. These first results from pharmacogenetic studies with the circadian system are promising but still preliminary and further replications are required.

The neurotransmitter system: serotonin, dopamine and GABA pathways

Serretti et al. explored the dopamine, GABA and serotonin pathways and did not find any association between the efficacy of lithium and polymorphisms at the genes of any of the following: the D2 receptor (57), the D3 receptor [START_REF] Serretti | Dopamine receptor D3 gene and response to lithium prophylaxis in mood disorders[END_REF], the D4 receptor [START_REF] Serretti | Dopamine receptor D2 and D4 genes, GABA (A) alpha-1 subunit genes and response to lithium prophylaxis in mood disorders[END_REF], the γ-aminobutyric acid (GABA) type A receptor α-1 subunit (57), and the 5-HT2A, 2C and 1A receptors [START_REF] Serretti | Serotonin receptor 2A, 2C, 1A genes and response to lithium prophylaxis in mood disorders[END_REF]. The same authors found an association between a functional polymorphism in the upstream regulatory region of the serotonin transporter gene (5-HTTLPR) and the prophylactic efficacy of lithium: 5-HTTLPR s/s variants were associated with a worse response to lithium than either l/s and l/l variants (60). These 5-HTTLPR s/s and l/s variants showed a significant epistatic interaction with the Val/Val genotype of brain-derived neurotrophic factor (BDNF) and response to lithium prophylaxis in a sample of 107 BD patients [START_REF] Jk Rybakowski | Response to lithium prophylaxis: interaction between serotonin transporter and BDNF genes[END_REF]. In the study by Michelon et al., the 5-HTTLPR gene and BDNF gene variants were not predictive factors for the response to lithium prophylaxis [START_REF] Michelon | Association study of the INPP1, 5HTT, BDNF, AP-2beta and GSK-3beta GENE variants and restrospectively scored response to lithium prophylaxis in bipolar disorder[END_REF]. Manchia et al. investigated several polymorphisms of genes of the neurotransmitter system, including the DRD1, DRD2, DRD3, DAT1, 5-HTTLPR and HTR2A genes, for association with response to lithium prophylaxis in a sample of 155 Sardinian BD probands [START_REF] Manchia | No association between lithium full responders and the DRD1, DRD2, DRD3, DAT1, 5-HTTLPR and HTR2A genes in a Sardinian sample[END_REF]. No association was found between the polymorphisms of these genes and the response to lithium treatment [START_REF] Manchia | No association between lithium full responders and the DRD1, DRD2, DRD3, DAT1, 5-HTTLPR and HTR2A genes in a Sardinian sample[END_REF]. A recent association study involving DRD1 showed an association between allele G at -48 A/G and a worse response to lithium [START_REF] Jk Rybakowski | Dopamine D1 receptor gene polymorphism is associated with prophylactic lithium response in bipolar disorder[END_REF]. An additive association analysis of 5-HT2A and 5-HT2C serotonin receptor gene polymorphisms and the response of BD patients to lithium prophylaxis found no association (64). To summarize, four studies have reported associations between genotypes carrying the 5-HTTLPR s allele and a worse response to lithium [START_REF] Serretti | Serotonin transporter gene associated with lithium prophylaxis in mood disorders[END_REF][START_REF] Jk Rybakowski | Response to lithium prophylaxis: interaction between serotonin transporter and BDNF genes[END_REF][START_REF] Serretti | Further evidence for a possible association between serotonin transporter gene and lithium prophylaxis in mood disorders[END_REF][START_REF] Jk Rybakowski | Prophylactic effect of lithium in bipolar affective illness may be related to serotonin transporter genotype[END_REF]. An association and linkage study confirmed the absence of association between the response to lithium and GABRA3, GABRA5 and GABRB3 subunits of the GABAA receptor [START_REF] Duffy | Association and linkage studies of candidate genes involved in GABAergic neurotransmission in lithium-responsive bipolar disorder[END_REF].

Enzymes involved in the synthesis/catabolism of amines, including neurotransmitters, may be of relevance. Serretti et al. did not find any association between the prophylactic efficacy of lithium in mood disorders and the following variants of enzymes in the corresponding pathways: catechol-O-methyltransferase (COMT) G158A, monoamine oxidase A (MAO-A) 30-bp repeat, and G-protein beta 3-subunit (Gβ3) C825T [START_REF] Serretti | Pharmacogenetics of lithium prophylaxis in mood disorders: analysis of COMT, MAO-A, and Gbeta3 variants[END_REF]. A further association and linkage study found no association between MAO-A and the response to lithium [START_REF] Turecki | MAOA: association and linkage studies with lithium responsive bipolar disorder[END_REF]. The prophylactic efficacy of lithium may depend in part on variants of the tryptophan hydroxylase (TPH) gene, which is a serotonin-related gene. Subjects with the TPH A/A variant showed a trend toward a worse response to lithium than subjects with either TPH A/C or TPH C/C variants [START_REF] Serretti | Tryptophan hydroxylase gene and response to lithium prophylaxis in mood disorders[END_REF]. An association study focused on the gene encoding tyrosine hydroxylase (TH), the rate-limiting enzyme in catecholamine synthesis: it revealed no association in 54 patients with the long-term response to lithium monotherapy [START_REF] Cavazzoni | Lithium-responsive affective disorders: no association with the tyrosine hydroxylase gene[END_REF].

To conclude, the serotonin-related genes of the neurotransmitter system, and in particular the serotonin transporter gene, show the strongest evidence of interactions with the response to lithium prophylaxis.

The BDNF/TrkB signaling pathway

BDNF-related genes have been implicated in the pathogenesis of BD and in the mechanism of action of lithium. Rybakowski et al. showed extreme differences in response to lithium prophylaxis between subjects according to their BDNF polymorphisms [START_REF] Jk Rybakowski | Response to lithium prophylaxis: interaction between serotonin transporter and BDNF genes[END_REF]. Subsequent studies tended to validate this result and the Val/Met BDNF genotype at the Val66Met functional polymorphism showed a positive association with better response to lithium in a sample of 88 BD patients [START_REF] Jk Rybakowski | Prophylactic lithium response and polymorphism of the brain-derived neurotrophic factor gene[END_REF]. The same authors provided a supplementary study investigating the association in the BDNF gene and polymorphisms in the gene encoding the neurotrophic tyrosine kinase receptor type 2 (NTRK2) [START_REF] Dmitrzak-Weglarz | Association studies of the BDNF and the NTRK2 gene polymorphisms with prophylactic lithium response in bipolar patients[END_REF]. Among the four BDNF polymorphisms tested, two (C/G (rs988748) and G/A (rs6265)) showed an association with the response to lithium prophylaxis [START_REF] Dmitrzak-Weglarz | Association studies of the BDNF and the NTRK2 gene polymorphisms with prophylactic lithium response in bipolar patients[END_REF]. No association was found between the response to lithium and either the interaction of BDNF and NTRK2 genes or polymorphism of the NTRK2 gene alone [START_REF] Dmitrzak-Weglarz | Association studies of the BDNF and the NTRK2 gene polymorphisms with prophylactic lithium response in bipolar patients[END_REF]. The Michelon et al and Masui et al studies did not find such results for BNDF [START_REF] Michelon | Association study of the INPP1, 5HTT, BDNF, AP-2beta and GSK-3beta GENE variants and restrospectively scored response to lithium prophylaxis in bipolar disorder[END_REF][START_REF] Masui | Lithium response and Val66Met polymorphism of the brain-derived neurotrophic factor gene in Japanese patients with bipolar disorder[END_REF].

Lithium inhibits glutamatergic transmission via NMDA receptors, and the src-family tyrosine kinases (FYN) belong to the protein kinase family that phosphorylates NMDA receptor subunits, participating in the BDNF/TrkB signal transduction pathway. A marginal association between FYN polymorphisms and a worse response to lithium in 101 BD patients has been reported [START_REF] Szczepankiewicz | The association study of three FYN polymorphisms with prophylactic lithium response in bipolar patients[END_REF]. The same authors investigated the association between three polymorphisms in the NMDA receptor 2B subunit (GRIN2B) gene and the response to lithium but did not find a significant association [START_REF] Szczepankiewicz | No association of three GRIN2B polymorphisms with lithium response in bipolar patients[END_REF].

These various findings suggest that the BDNF/TrkB signal transduction pathway may play a key role in the response to lithium prophylaxis.

Other signaling pathways

Lithium may affect the cyclic adenosine monophosphate (cAMP) pathway of signal transduction. The first relevant genetic study of BD found significant associations with the CREB1, CREB2 and CREB3 genes of this pathway [START_REF] Mamdani | Lithium response and genetic variation in the CREB family of genes[END_REF]. In a BD sample of 180 lithium responders and 69 non-responders, and 127 controls, the same authors found that two CREB1 polymorphisms may be associated with BD and/or the response to lithium [START_REF] Mamdani | Lithium response and genetic variation in the CREB family of genes[END_REF]. In the same sample, there was no association between the propyl endopeptidase (PREP) gene l and the response to lithium [START_REF] Mamdani | No association between the PREP gene and lithium responsive bipolar disorder[END_REF].

The endoplasmic reticulum (ER)-stress response, a potential pathophysiological mechanism of BD, involves various molecules including the X-box-binding protein 1 (XBP1). An association between the response to lithium and -116C/G polymorphism of XBP1 has been reported in Japanese BD patients [START_REF] Kakiuchi | Lithium response and -116C/G polymorphism of XBP1 in Japanese patients with bipolar disorder[END_REF]. In the same BD Japanese population, this association was further confirmed, with -116C allele carriers showing a better response than -116G homozygotes to lithium [START_REF] Masui | A possible association between the -116C/G single nucleotide polymorphism of the XBP1 gene and lithium prophylaxis in bipolar disorder[END_REF]. The same authors found a significant association between the breakpoint cluster region (BCR) gene and the response to lithium, observing that the allele frequency of the Asn796Ser single-nucleotide polymorphism was significantly higher in non-responders than in responders [START_REF] Masui | A possible association between missense polymorphism of the breakpoint cluster region gene and lithium prophylaxis in bipolar disorder[END_REF].

The protein kinase C (PKC) pathway is an important mediator of several intracellular responses to neurotransmitter signaling. It has therefore been the subject of investigation, but a recent study failed to show any positive association between the response to lithium and PDLIM5 (PDZ and LIM domain 5), an adaptor protein that selectively binds the isozyme PKC (epsilon) to N-type Ca (2+) channels in neurons [START_REF] Squassina | The PDLIM5 gene and lithium prophylaxis: an association and gene expression analysis in Sardinian patients with bipolar disorder[END_REF]. Silberberg et al. investigated the calcium channel gamma-2 subunit (CACNG2, Stargazin) gene on 22q13.1 and found that three single nucleotide polymorphisms (rs2284017, rs2284018, rs5750285) were significantly associated with the response to lithium [START_REF] Silberberg | Stargazin involvement with bipolar disorder and response to lithium treatment[END_REF].

These preliminary results need to be replicated before any conclusions can be drawn. Polymorphisms of the genes for activating enhancer-binding protein 2 beta 3 (AP2-B), the myristoylated alanine-rich C-kinase substrate (MARKS) and the betaadrenergic receptor kinase 2 (GRK3, BARK2) have been found not be to associated with the response to lithium [START_REF] Michelon | Association study of the INPP1, 5HTT, BDNF, AP-2beta and GSK-3beta GENE variants and restrospectively scored response to lithium prophylaxis in bipolar disorder[END_REF][START_REF] Bremer | The pharmacogenetics of lithium response depends upon clinical co-morbidity[END_REF]. Rybakowski et al., who had previously reported an association between BD and a functional polymorphism of matrix metalloproteinase-9 (MMP-9) gene, tested for its involvement in the response to lithium and were unable to find any such association [START_REF] Jk Rybakowski | Functional polymorphism of matrix metalloproteinase-9 (MMP-9) gene and response to lithium prophylaxis in bipolar patients[END_REF].

Recently, Rybakowski et al. aimed to replicate some of these earlier findings and tested the association of 14 gene polymorphisms with the quality of the response to lithium prophylaxis [START_REF] Jk Rybakowski | Clinical and pathogenic aspects of candidate genes for lithium prophylactic efficacy[END_REF]. The authors confirmed an association between the response to lithium and the polymorphisms of 5HTTLPR, DRD1, COMT, BDNF and FYN genes, but not those of 5HT2A, 5HT2C, DRD2, DRD3, DRD4, GSK-3, NTRK2, GRIN2B and MMP-9. A list of these pharmacogenetic studies is provided in Table 1.

Genome Wide Association Studies (GWAS) on the response to lithium

An international consortium on lithium genetics (ConLiGen, www.conligen.org) is currently driving an international effort to elucidate the genetic underpinnings of the response of BD patient to lithium. The consortium aims to establish the largest ever sample of cases of BD characterized for their response to lithium treatment suitable for genome-wide studies [START_REF] Tg Schulze | The International Consortium on Lithium Genetics (ConLiGen): an initiative by the NIMH and IGSLI to study the genetic basis of response to lithium treatment[END_REF]. In particular, there is a particular effort to develop stringent definitions for the response phenotypes. This consortium has not yet published or made available any results, but the scientific community is awaiting the findings with high hopes.

An early report described a sample of 359 BD patients characterized for the response to lithium and who were participants in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) cohort [START_REF] Rh Perlis | A genomewide association study of response to lithium for prevention of recurrence in bipolar disorder[END_REF]. The associations identified did not reach genome-wide significance, but the findings for two regions, on chromosome 10p15 (rs10795189) and chromosome 4q32 including a gene coding for the glutamate/alpha-amino-3-hydroxy-5-methyl-4-isoxazolpropionate (AMPA) receptor GRIA2, indicate that they deserve further examination [START_REF] Rh Perlis | A genomewide association study of response to lithium for prevention of recurrence in bipolar disorder[END_REF]. Squassina et al. performed a GWAS in a sample of 204 Sardinian patients with BD characterized for response to lithium and found an association, supported by quantitative trait analysis, for a single nucleotide polymorphism (SNP) in intron 1 of the amiloride-sensitive cation channel 1 neuronal (ACCN1) gene [START_REF] Squassina | Evidence for association of an ACCN1 gene variant with response to lithium treatment in Sardinian patients with bipolar disorder[END_REF]. This cation channel has high affinity for sodium and is permeable to lithium and consequently is a putative genetic marker of lithium efficacy for patients with BD (89). However, this possibility needs to be confirmed. McCarthy et al. used a multi-level approach focusing on associations between circadian clock genes and BD compared to controls, and also considered the response to lithium [START_REF] Mccarthy | A survey of genomic studies supports association of circadian clock genes with bipolar disorder spectrum illnesses and lithium response[END_REF]. They reconciled discordant results from earlier GWAS and candidate gene studies by identifying recognized and previously unrecognized associations between clock genes and BD-spectrum illnesses [START_REF] Mccarthy | A survey of genomic studies supports association of circadian clock genes with bipolar disorder spectrum illnesses and lithium response[END_REF].

The results of these various approaches and the findings generated argue for continued GWAS of the response to lithium in BD patients.

Pharmacogenomics of other mood stabilizers

Almost all pharmacogenetic studies of MS have focused on the response to lithium but informative results are sparse. The situation for other MS is similarly, in addition to fewer reported studies. Thus, there is little evidence available for valproate and even less for lamotrigine. Lastly, we will review current evidence about atypical antipsychotics' pharmacogenetics.

5.2.1.Valproate (VPA)

The mechanism of action of valproate (VPA) is poorly understood and several hypotheses exist. The X-box-binding protein 1 (XBP1) is involved in the endoplasmic reticulum (ER)-stress response, and the 116C/G polymorphism in the promoter region of the corresponding gene is known to be associated with BD. An association between this polymorphism and the response to VPA has been reported [START_REF] Kim | Preliminary evidence on the association between XBP1-116C/G polymorphism and response to prophylactic treatment with valproate in bipolar disorders[END_REF]: in a sample of 51 BD patients the G allele was associated with a better response to VPA than the C allele [START_REF] Kim | Preliminary evidence on the association between XBP1-116C/G polymorphism and response to prophylactic treatment with valproate in bipolar disorders[END_REF]. The transcription activity of XBP1 was lower for the G allele than for the C allele. Thus VPA increases the endoplasmic reticulum (ER)-stress response, which is compromised by the G allele. Similarly, association between the -116C/G polymorphism and the clinical efficacy of lithium has been observed consistent with the notion that the XBP1 gene product is involved in the response to MS [START_REF] Kim | Preliminary evidence on the association between XBP1-116C/G polymorphism and response to prophylactic treatment with valproate in bipolar disorders[END_REF].

The Val158Met polymorphism in the COMT gene is another candidate gene in the response to VPA and to lithium; its role was examined in a sample of 144 BDI patients and 157 controls [START_REF] Lee | Catechol-O-methyltransferase Val158Met polymorphism affects therapeutic response to mood stabilizer in symptomatic manic patients[END_REF]. The study found that the Met/Met genotype was more frequent in non-responders than in responders to MS (either lithium, VPA or carbamazepine), whereas no differences were detected between BD patients and controls. Unfortunately, the sample was pooled for types of MS and therefore the study is uninformative about the role of COMT Val66Met in the response to individual mood stabilizers [START_REF] Lee | Catechol-O-methyltransferase Val158Met polymorphism affects therapeutic response to mood stabilizer in symptomatic manic patients[END_REF]. Further studies with a larger numbers of subjects are required to elucidate the role of COMT gene polymorphism in the therapeutic response of BD patients to mood stabilizer.

Lamotrigine (LTG)

A pharmacogenetic study based on the response to LTG has been performed in 85 LTG-treated BD I depression patients. Polymorphisms in the dopamine D2 receptor (DRD2), dopamine β-hydroxylase (DBH), glucocorticoid receptor (NR3C1), histamine H1 receptor (HRH1) and melanocortin 2 receptor (MCR2) genes were associated with the response to treatment [START_REF] Rh Perlis | Genetic association study of treatment response with olanzapine/fluoxetine combination or lamotrigine in bipolar I depression[END_REF]. As far as we are aware, this is the only pharmacogenetic study addressing LTG to be reported, no other results of studies of this type, relevant to conventional MS, have been published. Several pathways seem to be involved in the response to LTG, and might be, at least in part, shared by lithium and other conventional MS.

Atypical antipsychotics (AAP)

Antipsychotic medication is widely used, being prescribed to between 72% and 92% of patients with mania [START_REF] Cookson | Use of antipsychotic drugs and lithium in mania[END_REF]. Despite this extensive use of AAP in the treatment of BD, pharmacogenetic studies are again lacking and very few studies have investigated the genetic underpinnings of the therapeutic response. Furthermore, these few studies only included patients during acute phases of BD.

Perlis et al. investigated common genetic variations for association with clinical improvement in a cohort of 88 BD I depression patients following treatment with an olanzapine/fluoxetine combination (OFC) [START_REF] Rh Perlis | Genetic association study of treatment response with olanzapine/fluoxetine combination or lamotrigine in bipolar I depression[END_REF]. They found significant associations between polymorphisms in the dopamine D (3) receptor (DRD3) and HRH1 genes, and response to OFC [START_REF] Rh Perlis | Genetic association study of treatment response with olanzapine/fluoxetine combination or lamotrigine in bipolar I depression[END_REF]. Subsequently, in the same population, they found an association between the response to OFC and polymorphisms in the norepinephrine transporter (SLC6A2) gene, the melanocortin 3 receptor (MC3R) gene and the tryptophan hydroxylase 2 (TPH2) gene [START_REF] Jp Houston | Association of common variations in the norepinephrine transporter gene with response to olanzapine-fluoxetine combination versus continued-fluoxetine treatment in patients with treatment-resistant depression: a candidate gene analysis[END_REF]. Furthermore, Dávila et al. investigated the role of the COMT Val158Met polymorphism in the plasma concentration of catecholamine metabolites and clinical features in 42 BD I patients [START_REF] Dávila | .a.geoffroy@gmail.com alanine-rich C-kinase substrate; group D, member 1; MMP-9: matrix metalloproteinase-9; NR1D1: nuclear receptor subfamily 1, group D, member 1; NR3C1: nuclear-receptor subfamily 3, group C, member 1 ; NTRK2: neurotrophic tyrosine kinase, receptor, type 2; PDLIM5: PDZ and LIM domain 5; PLCG1: phospholipase C, gamma 1; PREP: propyl endopeptidase; TH: tyrosine hydroxylase; TPH: tryptophan hydroxylase; XBP1: X-box-binding protein 1[END_REF]. Authors found no significant association with the response to olanzapine treatment or with any of the markers tested, including the plasma concentrations of metabolites of dopamine (homovanillic acid; HVA) and of noradrenaline (3-methoxy-4-hydroxyphenylglycol; MHPG). Nevertheless, in the homozygous Val-Val group, a non-significant aggregation of BD patients presenting with psychosis was found; and clinical improvement significantly correlated with the plasma concentration of MHPG prior to treatment. The preliminary findings of these two studies are of interest and further work on these issues would be fruitful. Table 2 presents published pharmacogenetic studies of the response to various mood-stabilizing medications. In view of the widespread and increasing prescription of antipsychotics to patients with BD further research efforts in pharmacogenetics to identify possible genetic predictors of response would be extremely valuable.

SUMMARY AND PERSPECTIVES

To prescribe MS appropriately to patients, predictors of the response are required. Various genetic markers are considered to be promising candidates. In this review, we present diverse findings that are promising, and further investigation is warranted for confirmation. It seems very likely that the response to MS has a complex genetic heritability. Candidate genes associated with BD display relatively low odds ratios (OR) and minor allele frequencies (MAF), and therefore it is unlikely that the response to MS is determined by common variants with large effect-sizes. Furthermore, specific clinical features, family history, comorbidities and clinical course are factors that may be closely linked to the MS response phenotype and thus may help to understand its complex genetic heritability. For example, A. Bremer et al observed that polymorphisms in NTRK2 and INPP1 genes were associated with the response to lithium, and also with both suicidal ideation and post-traumatic stress disorder; this indicates that the response to lithium in BD and clinical co-morbidities share, at least partly, genetic determinants [START_REF] Bremer | The pharmacogenetics of lithium response depends upon clinical co-morbidity[END_REF].

This review leads us to suggest several putative goals for pharmacogenomics research in BD: genetic research in mood disorders can be reasonably expected to contribute in the following areas associated with treatment effects: 1) prediction of treatment response in individual patients; 2) prediction of side effects; 3) development of personalized therapies; 4) identification of homogeneous clinical subgroups of BD for genetic studies; 5) identification of causative determinants of BD; 6) identification of new treatment pathways; 7) development of gene therapy for BD; and 8) findings that are relevant to other psychiatric diseases. Some of the goals that we believe are important for pharmacogenomics research in BD are summarized in Figure 1.

These approaches are however subject to several limitations, and as a consequence of some of them, the interpretation of pharmacogenetic results can be difficult (summarized in Table 1 as relevant to the efficacy of lithium prophylaxis). First, diagnostic heterogeneity in patient groups prevents rigorous comparison between studies. The definitions of the response to MS (see table 1 and2) are not consensual and differ between studies. Clearly, valid and consensual definitions of probands and clear criteria for the definition of the response to MS are needed for results to be reliable and comparable. Also, most of the candidate genes studied were chosen for their possible association with mood disorders, rather than for their putative role in the mechanism of action of lithium or other MS. Future studies on biological and genetic factors associated with lithium response will have to consider potential confounders such as compliance and co-administration of circadian rhythm therapy, other psychotropic drugs or psychotherapy. Finally, sample sizes in these studies are often small; prospective studies with larger samples are required to study the response to MS.

CONCLUSION

To date, the results from pharmacogenomics studies are not sufficiently abundant, informative or conclusive to have significantly changed daily practice in the management of BD. The clinical assessment of a subject with the identification of specific individual phenotypic and pharmacogenetics data may nevertheless become a powerful approach for the development of personalized therapies. Further pharmacogenomics studies are needed to validate reliable and reproducible predictors of individual responses to MS and MS safety. Advances made in pharmacogenomics may help the clinician select appropriate effective treatment and monitoring, leading to more personalized treatment algorithms that are currently lacking for BD. BD: bipolar disorder; MD: major depression; RU: recurrent unipolar; ER: excellent responders; FR: full responders; R: responders; PR: partial or poor responders; NR: non responders; UN: unclassified. 5-HT1A: 5-hydroxytryptamine receptor 1A; 5-HT2A: 5-hydroxytryptamine receptor 2A; 5-HT2C: 5-hydroxytryptamine receptor 2C; 5-HTT: solute-carrier family 6 member 4 (serotonin transporter); 5-HTTLPR: serotonin-transporter-linked promoter region; AP2-B: activating enhancer-binding protein 2 beta 3; BCR: breakpoint cluster region; BDNF: brain-derived neurotrophic factor; CREB1: cAMP-responsive element-binding protein 1; COMT: catechol-O-methyl transferase; CREB2: cAMP-responsive element-binding protein 2; CREB3: cAMPresponsive element-binding protein 3; CRY1: cryptochrome-1 ; DAT1: dopamine transporter 1; DGKH: diacylglycerol kinase, eta; DRD1: dopamine receptor D1; DRD2: dopamine receptor D2; DRD3: dopamine receptor D3; DRD4: dopamine receptor D4; GABRA1: gamma-aminobutyric acid A receptor, alfa 1; GABRA3: gamma-aminobutyric acid A receptor, alfa 3; GABRA5: gamma-aminobutyric acid A receptor, alfa 5; GABRB3: gamma-aminobutyric acid A receptor, beta 3; Gβ3: G protein beta 3; GRIN2B: NMDA receptor 2B subunit ; GRK3: beta-adrenergic receptor kinase 2 (BARK2); GSK3B: glycogen synthase kinase 3 beta; FYN: Src-family tyrosine kinases; IMPA1: inositol(myo)-1(or 4)-monophosphatase 1; IMPA2: inositol(myo)-1(or 4)monophosphatase 2; INPP1: inositol polyphosphate-1-phosphatase; MAO-A: monoamine oxidase A; MARKS: myristoylated

Table 1. Pharmacogenetic studies on the response to lithium in bipolar disorder

Gene

  responders'': no recurrence of impairing symptoms, or recurrence of mild symptoms, promptly controlled by adjusting the lithium dose or with short courses of benzodiazepines but no other medication. PR : lithium level ≥0.6 mEq/l with improvement of the recurrence pattern in spite of being mildly depressed or hypomanic while on monotherapy. responders'': patients recruited for genetic association studies had clearly shown a good response to lithium ‗‗Poor responders'': some of these patients experienced no benefit at retrospectively according to the clinical history, with comparison of the frequency, duration and severity of episodes before and after treatment b) demonstrated -long and complete remission‖ on lithium alone retrospectively according to the clinical history, with comparison of the frequency, duration and severity of episodes before and after treatment b) demonstrated -long and complete remission‖ on lithium alone[START_REF] Sjøholt | Examination of IMPA1 and IMPA2 genes in manic-depressive patients: association between IMPA2 promoter polymorphisms and bipolar disorder[END_REF]

  Each patient had to fulfill the following criteria: A) Diagnosis of primary episodic bipolar disorder based on SADS-L (lifetime version) interview and Research Diagnostic Criteria (RDC) ; B) High recurrence risk ; and C) Unequivocal response to lithium NR: had to experience at least two recurrences during lithium treatment with confirmed therapeutic levels of lithium Good responders'': no recurrence of impairing symptoms, or recurrence of mild symptoms, promptly controlled by adjusting the lithium dose or with short courses of benzodiazepines but no other medication. PR: lithium level ≥0.6 mEq/l with improvement of the recurrence pattern in spite of being mildly depressed or hypomanic while on monotherapy.

		NR) 41MD			episode index recurrence index NR: showed <50% reduction, no change, or worsening of
	5-HT2C	101 BD 124 patients characterized	No No	Retrospective Prospective	ER: no affective episodes on lithium Efficacy evaluated as the difference between a pre-lithium the episode index.	(86) (59)
		(24ER, 51PR, (102BD; for lithium 101 BD	No	Retrospective	PR: 50% reduction in the episode index, defined as number treatment recurrence index and an on-lithium treatment ER: no affective episodes on lithium	(86)
		26NR) 22MD) response) (24ER, 51PR,			of episodes per year compared to the pre-lithium period recurrence index PR: 50% reduction in the episode index, from that during
	TPH	92 BD 108 patients 26NR)	No Yes	Retrospective Prospective	NR: < 50% reduction, no change or worsening of the ER: no affective episodes on lithium Efficacy evaluated as the difference between a pre-lithium the pre-lithium period	(64) (70)
		(24ER, 48PR, (90BD + 18MD			episode index PR: 50% reduction in the episode index, defined as number treatment recurrence index and an on-lithium treatment NR: < 50% reduction, no change or worsening of the
	DRD3	155 BD 20NR) characterized	No	Retrospective	The response to lithium was assessed using the scale of episodes per year compared to the pre-lithium period recurrence index episode index	(45)
	(43R, 112PR + for lithium Other signaling pathways			developed by Grof et al. (24) NR: < 50% reduction, no change or worsening in the
	CREB1	NR) response) 249 BD (180R,	Yes	Prospective	episode index, defined as number of episodes per year ER: Each patient had to fulfill several criteria: A)	(77)
	TH	55 patients 54 BD lithium 69NR)	No No	Prospective Retrospective	Efficacy evaluated as the difference between a pre-compared to the pre-lithium period. ER: patients judged to have a high risk of recurrence on the Diagnosis of primary episodic bipolar disorder based on	(58) (71)
		(43BD; 12MD) 101 BD responders (48 and 127	No	Retrospective	treatment index and an ongoing treatment index ER: no affective episodes on lithium basis of the number and frequency of episodes before the SADS-L (lifetime version) interview and Research	(86)
		101 BD (24ER, 51PR, BD and 6 RU) controls	No	Retrospective	ER: no affective episodes on lithium PR: 50% reduction in the episode index, defined as number lithium therapy. Maintained on lithium monotherapy for ≥3 Diagnostic Criteria (RDC); B) High recurrence risk; and C)	(86)
		(24ER, 51PR, 26NR) 94 controls			PR: 50% reduction in the episode index, defined as number of episodes per year compared to the pre-lithium period years, at plasma levels ≥0.6 mEq/l, with no further Unequivocal response to lithium
		26NR)			of episodes per year compared to the pre-lithium period NR: < 50% reduction, no change or worsening of the episodes of the illness while on adequate treatment. No NR: had to experience at least two recurrences during
					NR: < 50% reduction, no change or worsening of the episode index additional biological or pharmacological interventions lithium treatment with confirmed therapeutic levels of
	5-	201 patients	Yes	Prospective	episode index Efficacy evaluated as the difference between a pre-lithium allowed. lithium	(60)
	DRD4 HTTLPR The BDNF/TrkB signaling pathway 125 patients No (167BD, (s/s and CREB2 249 BD (180R, No	Prospective Prospective	Efficacy evaluated as the difference between a pre-treatment recurrence index and an on-lithium treatment ER: Each patient had to fulfill the following criteria: A)	(57) (77)
	BDNF CREB3	(100BD; 34MD) 88 BD 69NR)	worse Yes	Retrospective	treatment index and an ongoing treatment index recurrence index ER: had no affective episodes on lithium; Diagnosis of primary episodic bipolar disorder based on	(45)
		25MD) characterized and 127	response)		PR: showed 50% reduction in the episode index (number the SADS-L (lifetime version) interview and Research
		101 BD 83 BD for response to controls	No Yes	Retrospective Prospective	ER: no affective episodes on lithium Efficacy evaluated as the difference between a pre-lithium of episodes per year relative to that during the pre-lithium Diagnostic Criteria (RDC) ; B) High recurrence risk ; and	(86) (65)
		(24ER, 51PR, (36R, 47NR) lithium	(l/s and		PR: 50% reduction in the episode index, defined as number treatment recurrence index and an on-lithium treatment period); C) Unequivocal response to lithium
		26NR)	better		of episodes per year compared to the pre-lithium period recurrence index NR : showed <50% reduction, no change, or worsening of NR: had to experience at least two recurrences during
			response)		NR: < 50% reduction, no change or worsening of the the episode index. lithium treatment with confirmed therapeutic levels of
		67 BD 108 BD	Yes Yes	Retrospective Retrospective	episode index ER: no affective episodes on lithium ER: had no affective episodes on lithium; lithium	(66) (73)
	DAT1 PREP	155 BD (18ER, 35PR, (25ER, 55PR, 249 BD (180R,	No (s/s and s No	Retrospective Prospective	The response to lithium response was assessed using the PR: 50% reduction in the episode index, defined as number PR: showed 50% reduction in the episode index (number ER: (78) (45)
		(43R, 112PR + 14NR) 28NR) 69NR)	and worse		scale developed by Grof et al. (24) of episodes per year compared to pre-lithium period of episodes per year relative to that during the pre-lithium
		NR) and 127	response)		NR: < 50% reduction, no change or worsening of the period);
	GABRA1	125 patients controls	No	Prospective	Efficacy evaluated as the difference between a pre-episode index, defined as number of episodes per year NR: showed <50% reduction, no change, or worsening of	(57)
		(100BD;			treatment index and an ongoing treatment index compared to the pre-lithium period. the episode index.
		25MD) 121 BD 134 BD I	Interaction No	Retrospective Retrospective	ER: no affective episodes R ‗‗ Good responders'': no recurrence of impairing	(61) (40)
	GABRA3	a) 138 BDI (31ER, 54PR,	a) No between	Prospective	Patients were stabilized on lithium monotherapy PR: 50% reduction in the number of episodes per year symptoms, or recurrence of mild symptoms, promptly	(67)
		lithium 26NR)	b) No BDNF and		compared to the pre-lithium period controlled by adjusting the lithium dose or with short
	XBP1	responders and 66 BD	5HTTLPR Yes	Retrospective	courses of benzodiazepines but no other medication. R: Less frequent and/or severe relapse, including no	(80)
		108 controls	polymorphis		PR: lithium level ≥0.6 mEq/l with improvement of the relapse, than during the period before the initiation of
		b) 24 families	m and the		recurrence pattern in spite of being mildly depressed or lithium treatment
	BCR	ascertained 161 BD (43R,	response to Yes	Retrospective	hypomanic while on monotherapy. R: full response without any affective episode during	(81)
		through 184 BD 118NR)	lithium No	Retrospective	The response to lithium was rated retrospectively from lithium treatment (=ER).	(84)
	AP2-B	lithium-134 BD I (92R, 92NR) 134 BD I	No No	Retrospective Retrospective	R ‗‗ Good responders'': no recurrence of impairing standardized interviews and medical records R ‗‗ (40) (40)
		responsive BD 121 BD	Yes	Retrospective	symptoms, or recurrence of mild symptoms, promptly ER: had no affective episodes on lithium;	(61)
		probands (31ER, 54PR,			controlled by adjusting the lithium dose or with short PR: showed 50% reduction in the episode index (number
	GABRA5	a) 138 BDI 26NR)	a) No	Prospective	Patients were stabilized on lithium monotherapy courses of benzodiazepines but no other medication. of episodes per year relative to that during the pre-lithium	(67)
		lithium	b) No		PR: lithium level ≥0.6 mEq/l with improvement of the period);
		responders and			recurrence pattern in spite of being mildly depressed or NR: showed <50% reduction, no change, or worsening of
		108 controls			hypomanic while on monotherapy. the episode index.
	PDLIM5	b) 24 families 155 BD 161 BD 155 BD	No No No	Retrospective Retrospective Retrospective	The response to lithium was assessed using the scale R: Less frequent and/or severe relapses, including no The response to lithium was assessed using the scale	(45) (74) (82)
		ascertained (43R, 112PR + (43R, 112PR +			developed by Grof et al. (24) relapse, by comparison with the period before the initiation developed by Grof et al. (24)
		through NR) NR)			of lithium treatment
	CACNG2	lithium-101 BD 101 BD a) 213 BD I	Yes Yes a) Yes	Retrospective Retrospective Retrospective	ER: no affective episodes on lithium ER: no affective episodes on lithium NR: no improvement or worsening of illness	(86) (86) (83)
		responsive BD (24ER, 51PR, (24ER, 51PR, b) 170 BD	b) Yes		PR: 50% reduction in the episode index, defined as number PR: 50% reduction in the episode index, defined as number PR: minor or modest improvement in frequency of
		probands 26NR) 26NR)			of episodes per year compared to the pre-lithium period of episodes per year, since the pre-lithium period episodes or admissions; significant morbidity
	GABRB3	a) 138 BDI	a) No	Prospective	Patients were stabilized on lithium monotherapy NR: < 50% reduction, no change or worsening of the NR: < 50% reduction, no change or worsening of the R: partial good response (marked improvement but not	(67)
		lithium	b) No		episode index episode index episode-free)
	COMT NTRK2	responders and 201 patients 108 BD	No No	Prospective Retrospective	Efficacy evaluated as the difference between a pre-lithium ER: had no affective episodes on lithium; FR: good response (complete remission).	(68) (73)
	MMP-9	108 controls (160 BD + (25ER, 55PR, 109 BD (26ER,	No	Prospective	treatment recurrence index and an on-lithium treatment PR: showed 50% reduction in the episode index (relative to ER: no affective episodes during lithium treatment;	(85)
		b) 24 families 41MD 28NR) 55PR, 28NR)			recurrence index that during the pre-lithium period); PR: 50% or more reduction in the episode index;
	DGKH PLCG1 Gβ3 GRIN2B FYN 5-HT2A MAO-A 5-HT1A	21 BD patients ascertained characterized through for lithium (7R, 7NR, 91 BD lithium responders 199 BD lithium responders a) 136 BD lithium responders 163 controls b) 32 families ascertained through 133 BD lithium responders (160 BD + 28NR) 26NR) 201 patients (24ER, 53PR, (24ER, 51PR, probands 105 BD probands 101 BD responsive BD responsive BD lithium-lithium-through 26NR) ascertained (24ER, 51PR, 20NR) b) 25 families 101 BD (24ER, 48PR, 108 controls 92 BD a) 138 BD and NR) response) 26NR) (43R, 112PR + for lithium (24ER, 51PR, 155 BD characterized 101 BD 142PR+NR) 22MD) 41MD (57FR, (102BD; (160 BD + 124 patients 201 patients 26NR) 22MD) (24ER, 51PR, 67PR+NR) (102BD; 101 BD (24FR, 124 patients 26NR) probands (24ER, 51PR, 26NR) responsive BD 101 BD (92R, 92NR) (24ER, 51PR, 7UN) lithium-response) 184 BD 101 BD	No No No No No a) Yes b) Yes considered) were Yes families b) No unilineal No a) No (when No Yes No No No No No No ideation) suicidal Yes (in BD with Yes No	Retrospective Prospective Prospective Retrospective Retrospective Retrospective Retrospective Prospective Prospective Retrospective Retrospective Retrospective Prospective Prospective Retrospective Retrospective Prospective Retrospective Retrospective Retrospective	classified retrospectively according to the clinical history NR: showed <50% reduction, no change, or worsening of NR: less than 50% reduction, no change or worsening of the episode index. the episode index. Patients were stabilized on lithium monotherapy for an NR: < 50% reduction, no change or worsening of the treatment recurrence index and an on-lithium treatment during the pre-lithium period); average of 14.4 ± 9 years of episodes per year compared to the pre-lithium period Efficacy evaluated as the difference between a pre-lithium PR: showed 50% reduction in the episode index (from that PR: 50% reduction in the episode index, defined as number ER: had no affective episodes on lithium; ER: no affective episodes on lithium episode index compared to the pre-lithium period. NR: < 50% reduction, no change or worsening of the episode index, defined as number of episodes per year the pre-lithium period NR: < 50% reduction, no change or worsening of the PR: 50% reduction in the episode index, from that during of episodes per year compared to the pre-lithium period ER: no affective episodes on lithium PR: 50% reduction in the episode index, defined as number an average follow-up of 14.4 ± 6.8 years. the episode index. ER: no affective episodes on lithium The response to lithium was evaluated prospectively with NR: showed <50% reduction, no change, or worsening of Response to lithium was evaluated prospectively with an during the pre-lithium period); average follow-up of 14.4 ± 6.8 years. scale developed by Grof et al. (24) PR: showed 50% reduction in the episode index (from that The response to lithium response was assessed using the ER: had no affective episodes on lithium; recurrence index recurrence index episode index Response to lithium: assessed using the scale of Grof et al. treatment recurrence index and an on-lithium treatment treatment recurrence index and an on-lithium treatment NR: < 50% reduction, no change or worsening of the (24). Efficacy evaluated as the difference between a pre-lithium Efficacy evaluated as the difference between a pre-lithium the pre-lithium period recurrence index episode index PR: 50% reduction in the episode index, from that during treatment recurrence index and an on-lithium treatment NR: < 50% reduction, no change or worsening of the ER: no affective episodes on lithium episode index Response to lithium: assessed using the scale of Grof et al. Efficacy evaluated as the difference between a pre-lithium of episodes per year compared to pre-lithium period NR: < 50% reduction, no change or worsening of the (24). PR: 50% reduction in the episode index, defined as number lithium period ER: no affective episodes on lithium standardized interviews and medical records PR: 50% reduction in the episode index, since the pre-The response to lithium was rated retrospectively from a ER: no affective episodes on lithium	(43) (68) (48) (76) (86) (86) (64) (69) (47) (45) (75) (59) (68) (45) (86) (59) (46) (86) (84) (86)
	20

ACKNOWLEDGEMENTS

P.A. Geoffroy has received a prize from Bayer for being Laureate of the medical university of Lille. F. Bellivier has received honoraria and financial support as an independent symposium speaker from Sanofi-Aventis, Lundbeck, AstraZeneca, Eli Lilly, Bristol-Myers Squibb and Servier. M. Leboyer has received honoraria and financial support as an independent symposium speaker from AstraZeneca and Servier. B. Etain has received honoraria and financial support as an independent symposium speaker from Sanofi-Aventis, Lundbeck, AstraZeneca, Eli Lilly, Bristol-Myers Squibb and Servier.

Running title: Predicting response to mood stabilizers


MD Pierre Alexis Geoffroy
email: pierre.a.geoffroy@gmail.com

Vincent Laprevote

Pierre Thomas

Renaud Jardri
email: renaud.jardri@chru-lille.fr

Somatotopy and bodily hallucinations

Hallucinations are commonly defined as "perceptual experiences in the absence of sensory input".

Hallucinations, one of the major first-rank symptoms of schizophrenia (SZ) spectrum disorders, include bodily hallucinations (BH), which may encompass tactile, somatic, visceral, proprioceptive, kinesthetic, vestibular, coenesthetic, nociceptive, sexual or thermal experiences. Although the underlying mechanisms of BH have not been established, four neuroimaging case reports have preliminarily described likely pathophysiological correlates of BH [START_REF] Bär | Transient activation of a somatosensory area in painful hallucinations shown by fMRI[END_REF][START_REF] Geoffroy | Anatomofunctional correlates of delusional parasitosis[END_REF][START_REF] Jardri | A case of fMRI-guided rTMS treatment of coenesthetic hallucinations[END_REF][START_REF] Shergill | Modality specific neural correlates of auditory and somatic hallucinations[END_REF]. According to these case reports, three patients had SZ [START_REF] Bär | Transient activation of a somatosensory area in painful hallucinations shown by fMRI[END_REF][START_REF] Jardri | A case of fMRI-guided rTMS treatment of coenesthetic hallucinations[END_REF][START_REF] Shergill | Modality specific neural correlates of auditory and somatic hallucinations[END_REF] and the fourth patient had delusional parasitosis [START_REF] Geoffroy | Anatomofunctional correlates of delusional parasitosis[END_REF]. In each report, per-hallucinatory functional magnetic resonance imaging (fMRI) revealed increased functional activation of the somatosensory cortices during BH.

Two fMRI raw datasets were made available by the authors after email contacts [START_REF] Geoffroy | Anatomofunctional correlates of delusional parasitosis[END_REF][START_REF] Jardri | A case of fMRI-guided rTMS treatment of coenesthetic hallucinations[END_REF]. Strikingly, poor overlaps were observed between the identified overactive areas when the available functional maps for BH were projected onto a unique normalized template (Figure 1).

Figure 1. Functional brain activations during bodily hallucinations.

Per-hallucinatory functional magnetic resonance imaging (fMRI) findings were obtained from two published case reports of bodily hallucinations (BH) relative to the method described in the article by [START_REF] Jardri | The neurodynamic organization of modalitydependent hallucinations[END_REF] These two functional maps were projected onto a unique normalized template. The Penfield sensory homunculus is presented above in the same coronal plane. Activations within the somatosensory cortex (z-maps with corrected p <10 -4 ) were color-coded according to the reference paper (purple: [START_REF] Jardri | A case of fMRI-guided rTMS treatment of coenesthetic hallucinations[END_REF]green: Geoffroy et al., 2012). Purple clusters were obtained from a patient who suffered from BH that manifested as "electric shocks" and alien "objects" moving inside his thorax, abdomen and pelvis. Green clusters were obtained from a patient who suffered from BH that manifested as "tingling" and "movement" sensations behind both ears from the temporal, mastoid and mandibular regions. The resulting cortical activations perfectly overlap the homunculus regions involved in sensations of the abdominal and temporal body parts.

This observation supports the concept that BH phenomenology is linked to the cortical somatotopic organization. This clinical-functional correspondence is interesting for several reasons. First, it allows the construction of a model that may account for BH beyond the conventional misattribution hypothesis, which was essentially developed in the auditory modality. The misattribution hypothesis stated that hallucinations might rely on the aberrant attribution of internal events to alien sources. However, although modality-specific hallucinations may share several common pathways, they may likely rely on specific neural dysfunctions transducing the hallucinatory content of the experience. Notably, this explanation has been suggested in casereports of not only the visual hallucinations that are characteristic of Charles-Bonnet syndrome or schizophrenia but also multisensory hallucinations [START_REF] Jardri | The neurodynamic organization of modalitydependent hallucinations[END_REF].

Furthermore, we believe that the reported findings nicely highlight the potential contribution of casereports towards the exploration of subjective experiences. Figure 1 demonstrates how a specific functional pattern can be superimposed onto the somatotopic brain areas responsible for the body parts involved in the abnormal sensations that patients describe perceiving during BH. Because of the high inter-individual variability attributed to various possible hallucinations, group studies may suffer from two major shortcomings. First, group analyses usually reveal clusters formed by shared activated voxels across all of the participants. These clusters must survive thresholding strategies that are used to correct multiple comparisons in fMRI. The second point is directly linked to the first one because averaging the fMRI signal at the group level may result in an impoverished clinical-functional relationship revealed by the subject-level analysis (i.e., a somatotopic organization of BH). By illustrating two non-overlapping functional patterns linked with BH, Figure 1 highlights the complementarities of case reports with group studies. These findings constitute the first step that must be confirmed in larger samples; however, the number is valid only if it is appropriately used. Grouping patients with BH would be futile if these hallucinatory experiences are not suitably assessed to constitute specific sub-populations. The likelihood that some BH experiences may be unique or limited to few patients must be considered.

The general argument that has been developed has nothing to do with a promotion of low statistical power in research on hallucinations, which may lead to erroneous conclusions and poor reproducibility. On the contrary, recent developments in fMRI technology has allowed for an exploration of these symptoms on a case-by-case basis, which may have significant bench-to-bedside implications. First, growing knowledge in this field has contributed toward reducing the stigma directed at patients suffering from hallucinations. Second, individual fMRI may contribute to innovative treatments for refractory BH, which for example facilitates identifying the

target over specific somatosensory areas during repetitive transcranial magnetic stimulation (rTMS) protocols [START_REF] Jardri | A case of fMRI-guided rTMS treatment of coenesthetic hallucinations[END_REF]. The exact role that individual fMRI plays in assisting clinicians in decision-making, therapy and follow-up will need to be defined and adequately developed within the medical toolbox. However, this strategy may pave the way for personalized therapy in mental health.