Using admixture analysis to examine birth-cohort effects on age at onset of bipolar disorder.

OBJECTIVE: It is suggested that age at onset (AAO) of bipolar I disorder (BP-I) is decreasing. We tested for a birth-cohort effect on AAO using admixture analysis. METHOD: A clinical sample of 3896 BP-I cases was analysed using two approaches: (i) in a subsample with untruncated AAO × birth year distribution (n = 1865), we compared the best-fitting model for the observed AAO in patients born ≤1960 and >1960, (ii) to control for potential confounders, two separate subsamples born ≤1960 and >1960 were matched for age at interview (n = 250), and a further admixture analysis was undertaken. RESULTS: The two approaches indicated that the proportion of cases in the early AAO category was significantly greater in cases born >1960; manic onsets were also more frequent in the early onset BP-I cases born >1960. CONCLUSION: The decrease in AAO of BP-I in recent birth-cohorts appears to be associated with an increase in the proportion of cases in the early onset subgroup; not with a decrease in the mean AAO in each putative subgroup. This could indicate temporal changes in exposure to risk factors for mania.

[Hyperthymic and cyclothymic temperaments: attenuated forms of bipolar disorder?]. / Tempéraments hyperthymique et cyclothymique: expressions atténuées du trouble bipolaire?

A temperament is described as a temporally stable dimension, biologically determined. Several temperaments have been described (hyperthymic, depressive, cyclothymic, irritable and anxious) and could represent premorbid characteristics of an affective disorder. Some temperaments could thus correspond to chronic sub-affective states expressed as attenuated forms of mood disorder. Several studies suggest that a large proportion of bipolar patients have a hyperthymic or cyclothymic temperament. Moreover, temperaments seem to influence the clinical caracteristics of bipolar disorders. Future investigations will evaluate whether temperaments represent a predisposing factor, an attenuated form of bipolar disorders or a distinct entity.

Drug metabolic enzyme genotype-phenotype discrepancy: High phenoconversion rate in patients treated with antidepressants.

Cytochromes from the P450 family (CYP) play a central role in the primary metabolism of frequently prescribed antidepressants, potentially affecting their efficacy and tolerance. There are however important differences in the drug metabolic capacities of each individual resulting from a combination of intrinsic and environmental factors. This variability can present an important risk for patients and increases the difficulty of drug prescription in clinical practice. Pharmacogenetic studies have uncovered a number of alleles defining the intrinsic metabolizer status, however, additional factors affecting cytochrome activity can modify this activity and result in a phenoconversion. The present study investigates the discrepancy between the genetically predicted and actually measured activities for the six most important liver cytochromes (CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6 and CYP3A4) in a cohort of patients under antidepressant treatment, previously shown to have a high proportion of patients with low metabolizing activities. We now performed the genetic characterization of this cohort to determine the extent of the genetic versus environmental contribution in these decreased activities. For all enzyme tested, we observed an important rate of phenoconversion, affecting between 33 % and 65 % of the patients, as well as a significant (p < 1E-06) global reduction in the effective but not predicted activities of CYP2D6, CYP2C9 and CYP2C19 compared to the general population. Our results highlight the advantages of phenotyping versus genotyping as well as the increased risk of treatment failure or adverse effect occurrence in a polymedicated population.

[Bipolar disorder and attention deficit/hyperactivity disorder in adults: differential diagnosis or comorbidity]. / Trouble déficit d'attention-hyperactivité et trouble bipolaire chez l'adulte: diagnostic différentiel ou comorbidité?

Attention deficit/hyperactivity disorder (ADHD) can sometimes coexist with bipolar disorder (BD). Despite controversies about the coexistence of the two disorders, recent clinical as well as biological studies support the concept of comorbid adult ADHD and BD. Although there is some overlapping symptomatology between both disorders, ADHD can be diagnosed in patients suffering from with BD after a detailed clinical evaluation. Clinicians should be particularly attentive to specific symptoms in order to treat adequately both disorders since untreated ADHD comorbidity with BD is associated with poor clinical and socio-professional outcome.

[Psychiatry]. / Psychiatrie.

Methods of brain stimulation such as transcranial magnetic stimulation, deep brain stimulation and vagus nerve stimulation may have a place in the treatment of depression or severe anxiety disorders resistant to conventional treatments. Several advances in chronotherapy as well as developments in treatment protocols have helped to prolong the antidepressant effect of sleep deprivation. The clinical applications of these methods in depressive episodes and especially in bipolar depression are discussed. The complete remission of a depressive episode and the maintenance of therapeutic benefit beyond the mere reduction of symptoms, have become important issues. The persistence of residual depressive symptoms is associated with increased risk of relapse: their recognition and treatment are illustrated in this article.

Functional N-methyl-D-aspartate receptors in O-2A glial precursor cells: a critical role in regulating polysialic acid-neural cell adhesion molecule expression and cell migration.

The capacity for long-distance migration of the oligodendrocyte precursor cell, oligodendrocyte-type 2 astrocyte (O-2A), is essential for myelin formation. To study the molecular mechanisms that control this process, we used an in vitro migration assay that uses neurohypophysial explants. We provide evidence that O-2A cells in these preparations express functional N-methyl-D-aspartate (NMDA) receptors, most likely as homomeric complexes of the NR1 subunit. We show that NMDA evokes an increase in cytosolic Ca2+ that can be blocked by the NMDA receptor antagonist AP-5 and by Mg2+. Blocking the activity of these receptors dramatically diminished O-2A cell migration from explants. We also show that NMDA receptor activity is necessary for the expression by O-2A cells of the highly sialylated polysialic acid-neural cell adhesion molecule (PSA-NCAM) that is required for their migration. Thus, glutamate or glutamate receptor ligands may regulate O-2A cell migration by modulating expression of PSA-NCAM. These studies demonstrate how interactions between ionotropic receptors, intracellular signaling, and cell adhesion molecule expression influence cell surface properties, which in turn are critical determinants of cell migration.

[Screening for bipolar disorders: a review of the literature]. / Dépistage des troubles bipolaires: une revue de la littérature.

OBJECTIVE: The aim of this article is to review the major instruments proposed for screening for bipolar disorder among clinical or general, adult or paediatric populations. They were developed in order to improve the detection of this illness which, far too often, remains unrecognized. Several of these screening instruments are already translated into several languages and validated. METHODOLOGY: A systematic review of the literature published on this topic up to July 2007 was carried out, using the main electronic data base (Medline). The keywords employed included bipolar disorder, screening, questionnaire, diagnosis and early recognition. RESULTS: The studies reported here examine whether screening instruments perform similarly in various clinical and non-clinical samples. Different forms of the same questionnaire (like self-report or parent report used in paediatric samples) are sometimes compared, usually showing that parent reports supersede the adolescent self-report form. This is namely the case for the Mood Disorder Questionnaire (MDQ) which is a brief and widely tested tool, available both in adult and adolescent versions. The MDQ exhibits good psychometric properties in relation to sensitivity and specificity in adult psychiatric samples, but these are more limited in the general population. Moreover, it yields better sensitivity for BP type I than for other bipolar subtypes. This is also true for other screening instruments like the hypomania check list (HCL-32). In order to optimize the sensitivity for bipolar II disorders, proposals for changing the MDQ screening algorithm have been tested. DISCUSSION: Even though it does not replace a thorough clinical interview, the use of screening tools for bipolar disorder is widely advocated. We discuss the need for clinicians to rely upon instruments allowing for a rapid and economically feasible identification of this disorder. Involving family members in the evaluation process may also increase the rate of recognition. More studies are still required in order to improve diagnostic efficiency of the screening instruments.

Corticotropin releasing factor receptor 1-deficient mice display decreased anxiety, impaired stress response, and aberrant neuroendocrine development.

Corticotropin releasing factor (CRF) is a major integrator of adaptive responses to stress. Two biochemically and pharmacologically distinct CRF receptor subtypes (CRFR1 and CRFR2) have been described. We have generated mice null for the CRFR1 gene to elucidate the specific developmental and physiological roles of CRF receptor mediated pathways. Behavioral analyses revealed that mice lacking CRFR1 displayed markedly reduced anxiety. Mutant mice also failed to exhibit the characteristic hormonal response to stress due to a disruption of the hypothalamic-pituitary-adrenal (HPA) axis. Homozygous mutant mice derived from crossing heterozygotes displayed low plasma corticosterone concentrations resulting from a marked agenesis of the zona fasciculata region of the adrenal gland. The offspring from homozygote crosses died within 48 hr after birth due to a pronounced lung dysplasia. The adrenal agenesis in mutant animals was attributed to insufficient adrenocorticotropic hormone (ACTH) production during the neonatal period and was rescued by ACTH replacement. These results suggest that CRFR1 plays an important role both in the development of a functional HPA axis and in mediating behavioral changes associated with anxiety.

Bactericidal and virucidal activity of the alkalophilic P395D/L241V/T343A mutant of vanadium chloroperoxidase.

AIMS: Vanadium chloroperoxidase and its directed evolution mutant P395D/L241V/T343A were investigated for their antibacterial and antiviral potential at slightly alkaline pH and at a H(2)O(2) concentration that is low compared to current nonenzymatic formulations. METHODS AND RESULTS: Two bacteria (the Gram-negative Pseudomonas aeruginosa and the Gram-positive Staphylococcus aureus) and two viruses (the enveloped Herpes Simplex Virus and the nonenveloped Coxsackievirus B4) were incubated with the P395D/L241V/T343A mutant, 10 mmol l(-1) H(2)O(2) and 100 mmol l(-1) Br(-) at pH 8. Strong microbial reduction was observed and bactericidal and virucidal activities of the mutant were three to six orders of magnitude higher than for the wild-type enzyme. CONCLUSIONS: The P395D/L241V/T343A mutant of vanadium chloroperoxidase has a broad antimicrobial activity at alkaline conditions. SIGNIFICANCE AND IMPACT OF THE STUDY: For many disinfection formulations, antimicrobial activity at slightly alkaline pH values is required. To date, only the wild-type vanadium chloroperoxidase has been studied for its antibacterial activity, and only at acidic to neutral pH values. Its antiviral activity (e.g. useful for the cleaning of medical equipment) was not studied before. The observed activity for the alkalophilic P395D/L241V/T343A mutant is an important step forward in the application of this robust enzyme as a component in disinfection formulations.

Frequency of dysphoria and mixed states.

BACKGROUND: Mixed states are a complex entity in the field of mood disorders. Dysphoria has been advocated as an important clinical dimension of mixed states. The objective of this work is to study the frequency of dysphoria within a population of patients with DSM-IV major depressive and/or manic episodes and to determine if it may help establish diagnostic criteria for subthreshold cases of depressive or manic mixed states. SAMPLING AND METHODS: A total of 165 patients were assessed using the Mini International Neuropsychiatric Interview complemented by a section defining dysphoria as a constellation of 3 among 4 symptoms (inner tension, irritability, aggressive behavior and hostility). RESULTS: When classifying patients according to the number of symptoms of the opposite polarity, changes in the frequency of dysphoria revealed a clear contrast between the 2 opposite manic and depressive poles and the full mixed state (DSM-IV definition). The frequency of dysphoria was 17.5% in pure depression, 22.7% in pure mania and 73.3% in full mixed state. Two threshold effects were identified: (1) the frequency of dysphoria increased from 17.5 to 61.1% (p = 0.002) when the number of manic symptoms in DSM-IV depressed patients increased from 0 to 1, and (2) dysphoria increased from 14.3 to 69.2% (p = 0.057) when the number of depressive symptoms increased from 2 to 3 in DSM-IV manic patients. CONCLUSION: Dysphoria is strongly but not necessarily associated with mixed states. When used as a clinical marker for mixed states, dysphoria confirms the modern delimitations of sub-threshold mixed states by specifying the required number of symptoms of the opposite polarity (which could be lower for depressive mixed states than for manic mixed states). The study has limitations related to the inclusion of patients who are not drug-free, to the definition of dysphoria and to the sample size.

The EACN scale for oil classification revisited thanks to fish diagrams.

The phase behavior of C(10)E(4)-oil-water systems at constant o/w ratio and variable temperature (fish diagram) has been investigated for several homologous oil families. The temperature T( *) and surfactant concentration C( *) at the critical point were determined for 10 n-alkanes varying from C(6) to C(28) as well as for a series of alkylcyclohexanes and alkylbenzenes. On the basis of T( *), equivalent alkane carbon numbers (EACN) were assigned to nonlinear alkanes, alkylbenzenes, and alkylcyclohexanes. The consistency of the method was shown by corroborating that the EACN values of oils previously investigated with other C(i)E(j) (dibutyl ether, squalane, isopropyl myristate, and dodecylbenzene) are the same when determined with C(10)E(4). The fact that two oils of different nature but with the same EACN (i.e., the same T( *)) do not exhibit the same C( *) is discussed in terms of monomeric solubility of the surfactant in the oil (CMC(oil)).

[Psychiatry]. / Psychiatrie.

Introduced this year on the Swiss market, duloxetine (Cymbalta) is a new antidepressant which inhibits the reuptake of noradrenaline and serotonin. Clinical studies have shown its efficacy in depression as well as in neuropathic pains (60-120 mg/day) with a good tolerability. In this paper are also included short reviews about the two large American studies developed by the National Institute of Mental Health in the fields of the treatment for depression (STAR-D) and of the antipsychotic treatments for schizophrenia (CATIE study). Its also reviews two questions of present interest: the use of the second generation antipsychotics for the treatment of bipolar depression and the concept of bipolar disorders in children.

A stepwise drug treatment algorithm to obtain complete remission in depression: a Geneva study.

QUESTIONS UNDER STUDY/PRINCIPLES: We describe the proportion of severely depressed outpatients reaching complete remission at the different stages of a drug treatment algorithm. We compare several treatment options for SSRI (selective serotonin reuptake inhibitor) non-responders and test the feasibility of the algorithm in clinical conditions. METHODS: Patients with severe depressive disorders (ICD-10; MADRS > or = 25) admitted to an academic outpatient clinic were enrolled in this algorithm-guided sequential treatment protocol (starting with an SSRI and ending with a tricyclic, lithium, triodothyronine combination). The general principle of the algorithm was to boost the drug therapy in the event of non-response. RESULTS: 135 patients entered the study and 131 were eligible for analysis. From this group, 86 patients dropped out (65.6%), 40 reached complete remission (30.5%) and 5 patients did not reach remission at all (3.8%). In the 117 patients to whom a last observation carried forward approach was applied, the median improvement of the MADRS score was 48.0% (range -20.7%-100%), with 48.7% of patients considered responders, 23.1% partial responders and 28.2% non-responders. Median retention time was 8 weeks (range 2-34). CONCLUSIONS: This algorithm-guided antidepressant treatment was acceptable for clinicians and resulted in an elevated final response rate among study completers. However, the dropout rate was high, mainly due to treatment interruption or non-observance.

Resting-state functional connectivity of emotion regulation networks in euthymic and non-euthymic bipolar disorder patients.

BACKGROUND: Previous functional magnetic resonance imaging studies in bipolar disorder (BD) have evidenced changes in functional connectivity (FC) in brain areas associated with emotion processing, but how these changes vary with mood state and specific clinical symptoms is not fully understood. METHODS: We investigated resting-state FC between a priori regions of interest (ROIs) from the default-mode network and key structures for emotion processing and regulation in 27 BD patients and 27 matched healthy controls. We further compared connectivity patterns in subgroups of 15 euthymic and 12 non-euthymic patients and tested for correlations of the connectivity strength with measures of mood, anxiety, and rumination tendency. No correction for multiple comparisons was applied given the small population sample and pre-defined target ROIs. RESULTS: Overall, regardless of mood state, BD patients exhibited increased FC of the left amygdala with left sgACC and PCC, relative to controls. In addition, non-euthymic BD patients showed distinctive decrease in FC between right amygdala and sgACC, whereas euthymic patients showed lower FC between PCC and sgACC. Euthymic patients also displayed increased FC between sgACC and right VLPFC. The sgACC-PCC and sgACC-left amygdala connections were modulated by rumination tendency in non-euthymic patients, whereas the sgACC-VLPFC connection was modulated by both the current mood and tendency to ruminate. CONCLUSION: Our results suggest that sgACC-amygdala coupling is critically affected during mood episodes, and that FC of sgACC play a pivotal role in mood normalization through its interactions with the VLPFC and PCC. However, these preliminary findings require replication with larger samples of patients.

[Psychiatry]. / Psychiatrie.

The main innovation of the year 2004 was the introduction of a new, second-generation antipsychotic drug with a new mechanism of action (partial dopamine agonist), encouraging first clinical results, and an advantageous clinical tolerance profile. Additionally, three new galenic forms are presented: an oral, extended-release form of methylphenidate that could be useful in the treatment of attention-deficit/hyperactivity disorders; an intramuscular depot form of a second-generation antipsychotic drug (risperidone) with the advantage of improving adherence; and an intramuscular form of a second generation antipsychotic (olanzapine) that is valuable in emergency situations. Finally, we will briefly give an update on the advantages of lamotrigine in bipolar depression.

Borderline personality disorder and childhood maltreatment: a genome-wide methylation analysis.

Early life adversity plays a critical role in the emergence of borderline personality disorder (BPD) and this could occur through epigenetic programming. In this perspective, we aimed to determine whether childhood maltreatment could durably modify epigenetic processes by the means of a whole-genome methylation scan of BPD subjects. Using the Illumina Infinium® HumanMethylation450 BeadChip, global methylation status of DNA extracted from peripheral blood leucocytes was correlated to the severity of childhood maltreatment in 96 BPD subjects suffering from a high level of child adversity and 93 subjects suffering from major depressive disorder (MDD) and reporting a low rate of child maltreatment. Several CpGs within or near the following genes (IL17RA, miR124-3, KCNQ2, EFNB1, OCA2, MFAP2, RPH3AL, WDR60, CST9L, EP400, A2ML1, NT5DC2, FAM163A and SPSB2) were found to be differently methylated, either in BPD compared with MDD or in relation to the severity of childhood maltreatment. A highly relevant biological result was observed for cg04927004 close to miR124-3 that was significantly associated with BPD and severity of childhood maltreatment. miR124-3 codes for a microRNA (miRNA) targeting several genes previously found to be associated with BPD such as NR3C1. Our results highlight the potentially important role played by miRNAs in the etiology of neuropsychiatric disorders such as BPD and the usefulness of using methylome-wide association studies to uncover such candidate genes. Moreover, they offer new understanding of the impact of maltreatments on biological processes leading to diseases and may ultimately result in the identification of relevant biomarkers.

Endotoxin decreases corticotropin-releasing factor receptor 1 messenger ribonucleic acid levels in the rat pituitary.

Bacterial endotoxins produce profound activation of the hypothalamo-pituitary-adrenal axis, mediated by stimulation of hypothalamic CRF neurons. Although a number of studies have described direct pituitary actions of inflammatory mediators, the effects of inflammatory stimuli on the sensitivity of corticotropes to CRF remain to be elucidated. The aim of this study was to determine the effects of inflammatory stress on the CRF receptor 1 (CRF-R1) messenger RNA (mRNA) levels in the rat pituitary. The systemic injection of endotoxin [lipopolysaccharide (LPS); 50 microg/kg, i.v.] increased plasma concentrations of ACTH and corticosterone. Ribonuclease protection analysis of total RNA isolated from individual whole pituitaries indicated that LPS produced a significant decrease in CRF-R1 mRNA that was evident by 2 h after injection (to 57% of control) and more marked by 6 h (to 38% of control). To evaluate whether the decrease in CRF-R1 mRNA was dependent upon increased exposure to CRF and/or vasopressin (AVP), LPS was injected with an anti-CRF antiserum, a CRF receptor antagonist (Astressin), or anti-AVP antiserum. A strong inhibition of the ACTH response to LPS was produced by pretreatment with anti-CRF antiserum, Astressin, or anti-AVP antiserum. However, these treatments had no effect on the decrease in CRF-R1 mRNA produced by LPS, indicating that neither CRF nor AVP are obligatory mediators of this pituitary response. The hypothesis that LPS might have direct pituitary effects on CRF-R1 mRNA levels was tested in vitro. Indeed, decreases in CRF-R1 mRNA to 43% and 53% of the control level were observed in rat anterior pituitary cell cultures that were treated with either LPS itself or the inflammatory mediator interleukin-1beta, respectively. Collectively, these results show that CRF receptor mRNA levels in the pituitary of the rat are markedly reduced by systemic LPS treatment and that this decrease is not dependent upon increased exposure of the pituitary to CRF or AVP, but may involve direct effects within the pituitary of either LPS itself or ensuing cytokine production.

Stress-induced increase in vasopressin and corticotropin-releasing factor expression in hypophysiotrophic paraventricular neurons.

The concerted action of CRF and vasopressin (VP) plays a critical role in regulating ACTH release from anterior pituitary cells. In this study, we have explored the expression of these neurohormones in hypophysiotropic paraventricular neurons after repeated exposure of rats to immobilization stress. Cell by cell quantitative in situ hybridization was used to evaluate the steady state level of mRNAs coding for VP and CRF. We found that 16 daily stress exposures resulted in a significant increase in the average cellular level of CRF and VP mRNAs (150% and 200% of control levels, respectively). Moreover, in the repeatedly stressed group, the number of VP-expressing parvicellular neurons was approximately doubled relative to the control value. Using quantitative immunoelectron microscopy, VP- and CRF-immunoreactive sites were assessed in the dense core vesicle compartment of CRF axon terminals in the external zone of the median eminence. We found that after repeated stress, the immunolabeling of VP was augmented, while that of CRF was slightly decreased. Concurrently, we observed a significant increase in the proportion of CRF nerve terminals that were VP positive (from 50% in controls to 90% in stressed animals). We conclude that the observed changes in CRF neurons may represent a physiological response to increased functional demand and may lead to alterations in the composition of the ACTH-releasing signal.

Stress-induced changes in messenger RNA levels of N-methyl-D-aspartate and AMPA receptor subunits in selected regions of the rat hippocampus and hypothalamus.

The postsynaptic AMPA/kainate and N-methyl-D-aspartate-selective glutamate receptors are formed by several different subunits and the overall subunit composition of the receptor appears to determine its physiological and pharmacological properties. Although glutamatergic mechanisms have been implicated in various forms of hippocampal stress responses, the impact of stress on glutamate receptor subunit composition has not yet been elucidated. We have used cell-by-cell quantitative in situ hybridization to assess stress-induced changes in transcript levels of N-methyl-D-aspartate and AMPA receptor subunit genes in subdivisions of the rat hippocampus and hypothalamus that are implicated in the stress response. We found that 24 h after a single immobilization stress there was a significant increase in the cellular level of NR1 subunit messenger RNA (about 35-45% above control values) in hippocampal CA3 and CA1 pyramidal cells as well as in neurons of the hypothalamic supraoptic and paraventricular nuclei. Moreover, in the CA3 area we have detected a concomitant increase (50% above controls) in the level of NR2B subunit messenger RNA, while the expression of NR2A subunit gene did not change after stress. Stress induced a selective decrease in the level of AMPA receptor subunit glutamate receptor A messenger RNA in neurons of both the CA3 and CA1 areas (18 and 24%, respectively, below control values). These results suggest that the regulation of specific subunit messenger RNAs of the N-methyl-D-aspartate and AMPA receptors may be involved in altered hippocampal and hypothalamic responsiveness to glutamate and thus could play a critical role in stress-induced changes in their function.

Coexpression of dopamine D2 and substance P (neurokinin-1) receptor messenger RNAs by a subpopulation of cholinergic neurons in the rat striatum.

Amongst different intrinsic and extrinsic inputs, cholinergic striatal interneurons receive afferents from the dopaminergic nigrostriatal projection and from local collaterals of striatonigral cells containing substance P. The following study demonstrates that both dopamine D2 and substance P (neurokinin-1) receptors are expressed by a large proportion of cholinergic interneurons. Using in situ hybridization on triplet adjacent sections with radioactive probes specific for choline acetyltransferase, substance P receptor, and D2 receptor long-splicing form messenger RNAs, we show that these interneurons can be divided into four subpopulations in terms of substance P and D2 receptor expression. A majority of these neurons coexpress both receptors (76%), while other minor subpopulations express either one (respectively, 16% and 2%) or none of them (6%). Our results also show that substance P receptor is expressed by striatal neurons that are not cholinergic. These findings are in agreement with the concept that striatal cholinergic interneurons are heterogeneous in terms of input-output connections and the type of receptors expressed. Moreover, the presence of substance P and D2 receptors on a majority of these neurons is relevant to a putative role of cholinergic interneurons in several conditions such as various neurodegenerative disorders or antipsychotic drug administration, where substance P and dopamine inputs are modified.