Publications by authors named "Rémy Luthringer"

37 Publications

Evolution of life cycles and reproductive traits: Insights from the brown algae.

J Evol Biol 2021 Jul 23;34(7):992-1009. Epub 2021 Jun 23.

CNRS, Algal Genetics Group, Integrative Biology of Marine Models, Station Biologique de Roscoff, Sorbonne Université, UPMC Univ Paris 06, Roscoff, France.

A vast diversity of types of life cycles exists in nature, and several theories have been advanced to explain how this diversity has evolved and how each type of life cycle is retained over evolutionary time. Here, we exploited the diversity of life cycles and reproductive traits of the brown algae (Phaeophyceae) to test several hypotheses on the evolution of life cycles. We investigated the evolutionary dynamics of four life-history traits: life cycle, sexual system, level of gamete dimorphism and gamete parthenogenetic capacity. We assigned states to up to 77 representative species of the taxonomic diversity of the brown algal group, in a multi-gene phylogeny. We used maximum likelihood and Bayesian analyses of correlated evolution, while taking the phylogeny into account, to test for correlations between traits and to investigate the chronological sequence of trait acquisition. Our analyses are consistent with the prediction that diploid growth evolves when sexual reproduction is preferred over asexual reproduction, possibly because it allows the complementation of deleterious mutations. We also found that haploid sex determination is ancestral in relation to diploid sex determination. However, our results could not address whether increased zygotic and diploid growth are associated with increased sexual dimorphism. Our analyses suggest that in the brown algae, isogamous species evolved from anisogamous ancestors, contrary to the commonly reported pattern where evolution proceeds from isogamy to anisogamy.
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http://dx.doi.org/10.1111/jeb.13880DOI Listing
July 2021

Do Patterns of Instability or Severity of Psychopathology During Screening Predict Relapse in Schizophrenic Outpatient Subjects with Moderate to Severe Negative Symptoms Assigned to Placebo?

Innov Clin Neurosci 2020 Jan;17(1-3):27-29

Dr. Daniel is with Signant Health in Mclean, Virginia.

Patients with schizophrenia who, prior to inclusion in placebo-controlled trials, experience the most severe and/or unstable symptoms might be more likely to manifest symptomatic worsening upon antipsychotic discontinuation. This retrospective analysis included all randomized patients assigned to placebo (n=83) in a 12-week, double-blind, placebo-controlled outpatient trial of MIN-101 (roluperidone) for the treatment of negative symptoms in schizophrenia. The following risk factors were defined for exacerbation: instability between screening and baseline defined operationally as patients with the highest 10 percent of absolute change from the screening visit to baseline in the Positive and Negative Syndrome Scale (PANSS) total or one of the five PANSS Marder factors; screening or baseline severity in PANSS total or one of the five PANSS Marder factors; and gender and age. We used two operational criteria of relapse and the odds ratios of meeting the relapse criteria were calculated for each risk factor. The odds of meeting one of the operational thresholds for relapse after antipsychotic discontinuation were not statistically significantly increased in the subjects who were unstable on the PANSS total or on one of the five PANSS Marder factors before antipsychotic discontinuation. Further, the severity of PANSS total and Marder factor scores at screening and baseline were not statistically significantly associated with odds of relapse. Neither age nor gender had any effect on relapse rates. Mild to moderate symptomatic variations in the severity of symptoms during screening and more severe symptomology at baseline as measured by the PANSS were not predictive of increased risk of subsequent relapse in schizophrenic patients.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7239560PMC
January 2020

Network Analysis Indicates That Avolition Is the Most Central Domain for the Successful Treatment of Negative Symptoms: Evidence From the Roluperidone Randomized Clinical Trial.

Schizophr Bull 2020 07;46(4):964-970

Minerva Neurosciences, Waltham, MA.

A recent conceptual development in schizophrenia is to view its manifestations as interactive networks rather than individual symptoms. Negative symptoms, which are associated with poor functional outcome and reduced rates of recovery, represent a critical need in schizophrenia therapeutics. MIN101 (roluperidone), a compound in development, demonstrated efficacy in the treatment of negative symptoms in schizophrenia. However, it is unclear how the drug achieved its effect from a network perspective. The current study evaluated the efficacy of roluperidone from a network perspective. In this randomized clinical trial, participants with schizophrenia and moderate to severe negative symptoms were randomly assigned to roluperidone 32 mg (n = 78), 64 mg (n = 83), or placebo (N = 83). Macroscopic network properties were evaluated to determine whether roluperidone altered the overall density of the interconnections among symptoms. Microscopic properties were evaluated to examine which individual symptoms were most influential (ie, interconnected) on other symptoms in the network and are responsible for successful treatment effects. Participants receiving roluperidone did not differ from those randomized to placebo on macroscopic properties. However, microscopic properties (degree and closeness centrality) indicated that avolition was highly central in patients receiving placebo and that roluperidone reduced this level of centrality. These findings suggest that decoupling the influence of motivational processes from other negative symptom domains is essential for producing global improvements. The search for pathophysiological mechanisms and targeted treatment development should be focused on avolition, with the expectation of improvement in the entire constellation of negative symptoms if avolition is effectively treated.
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http://dx.doi.org/10.1093/schbul/sbz141DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7342174PMC
July 2020

Correction to: The selective orexin-2 antagonist seltorexant (JNJ-42847922/MIN-202) shows antidepressant and sleep-promoting effects in patients with major depressive disorder.

Transl Psychiatry 2019 Oct 2;9(1):240. Epub 2019 Oct 2.

Janssen Research and Development, Division of Janssen Pharmaceutica N.V., Beerse, Belgium.

In the original Article, Tables two and three had formatting issues which affected their clarity. This has been corrected in the PDF and HTML versions of this Article.
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http://dx.doi.org/10.1038/s41398-019-0585-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6775147PMC
October 2019

Effects of Roluperidone (MIN-101) on two dimensions of the negative symptoms factor score: Reduced emotional experience and reduced emotional expression.

Schizophr Res 2020 01 2;215:352-356. Epub 2019 Sep 2.

Minerva Neurosciences, Inc., Waltham, MA, USA.

Background: Recent research has suggested that negative symptoms (NS) can be considered in terms of two different dimensions: reduced expression (expressive deficit) and reduced experience (experiential deficit). Roluperidone, a compound with high affinities for 5 HT2A and sigma2 receptors, has previously shown superiority over placebo on improving NS in a prospective study in patients with schizophrenia. The objective here is to explore the effect of roluperidone compared to placebo, on the 2 domains of the Negative Symptoms.

Methods: This was a multi-national Phase 2b trial that enrolled 244 symptomatically stable patients with schizophrenia who had baseline scores ≥20 on the NS subscale of the PANSS. Patients were randomized to daily monotherapy with roluperidone 32 mg, roluperidone 64 mg, or placebo in a 1:1:1 ratio. All enrolled patients were Caucasian, and 137 (56%) were male. The 3 treatment groups were balanced on all demographic and illness-related baseline characteristics.

Results: Both doses of roluperidone were superior to placebo on both domains: Reduced Experience (p ≤ .006 for the 32 mg; p ≤ .001 for the 64 mg) with persistent superiority from Week 2 for the 64 mg dose and Week 8 for the 32 mg dose; Reduced Expression (p ≤ .003 for 32 mg; p ≤ .001 for 64 mg) with similar persistence.

Implications: Both doses of roluperidone previously improved PANSS negative symptoms in general and demonstrated tolerability in stable schizophrenia patients. The post hoc analysis reported here found the drug to work on both the reduced emotional experience and reduced emotional expression sub-scales empirically derived from the PANSS.
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http://dx.doi.org/10.1016/j.schres.2019.08.029DOI Listing
January 2020

The selective orexin-2 antagonist seltorexant (JNJ-42847922/MIN-202) shows antidepressant and sleep-promoting effects in patients with major depressive disorder.

Transl Psychiatry 2019 09 3;9(1):216. Epub 2019 Sep 3.

Janssen Research and Development, Division of Janssen Pharmaceutica N.V., Beerse, Belgium.

Excessive arousal has a role in the pathophysiology of major depressive disorder (MDD). Seltorexant (JNJ-42847922/MIN-202) is a selective antagonist of the human orexin-2 receptor (OX2R) that may normalize excessive arousal and thereby attenuate depressive symptoms. In this study, the effects of night-time arousal suppression on depressive symptoms were investigated. 47 MDD patients with a total Inventory of Depressive Symptomatology (IDS) score of ≥30 at screening were included in a randomized, double-blind, diphenhydramine-, and placebo-controlled multicentre study. Symptoms of depression were rated using the 17-item Hamilton Depression Rating Scale (HDRS). Effects on sleep were evaluated by polysomnography and by the Leeds Sleep Evaluation Questionnaire (LSEQ). To investigate the safety and tolerability of seltorexant, vital signs, suicidal ideation and adverse events were monitored. At baseline the severity of depressive symptoms correlated with sleep efficiency (SE), wake after sleep onset (WASO), duration of stage 2 sleep, and ruminations. Ten days of treatment with seltorexant (and not diphenhydramine) resulted in a significant improvement of core depressive symptoms compared to placebo; the antidepressant efficacy of seltorexant was maintained with continued treatment up to 28 days. Compared to placebo, the antidepressant efficacy of seltorexant coincided with an overall increase in (left posterior) EEG power and a relative increase in delta- and decrease in theta-, alpha- and beta power during stage 2 sleep. Treatment with seltorexant was associated with mild, self-limiting adverse drug reactions. Seltorexant affected core symptoms of depression in the absence of overt changes in the hypnogram; in contrast, diphenhydramine was not efficacious.
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http://dx.doi.org/10.1038/s41398-019-0553-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6722075PMC
September 2019

A key role for sex chromosomes in the regulation of parthenogenesis in the brown alga Ectocarpus.

PLoS Genet 2019 06 13;15(6):e1008211. Epub 2019 Jun 13.

Sorbonne Université, UPMC Univ Paris 06, CNRS, Algal Genetics Group, UMR 8227, Integrative Biology of Marine Models, Station Biologique de Roscoff, Roscoff, France.

Although evolutionary transitions from sexual to asexual reproduction are frequent in eukaryotes, the genetic bases of these shifts remain largely elusive. Here, we used classic quantitative trait analysis, combined with genomic and transcriptomic information to dissect the genetic basis of asexual, parthenogenetic reproduction in the brown alga Ectocarpus. We found that parthenogenesis is controlled by the sex locus, together with two additional autosomal loci, highlighting the key role of the sex chromosome as a major regulator of asexual reproduction. We identify several negative effects of parthenogenesis on male fitness, and different fitness effects of parthenogenetic capacity depending on the life cycle generation. Although allele frequencies in natural populations are currently unknown, we discuss the possibility that parthenogenesis may be under both sex-specific selection and generation/ploidally-antagonistic selection, and/or that the action of fluctuating selection on this trait may contribute to the maintenance of polymorphisms in populations. Importantly, our data provide the first empirical illustration, to our knowledge, of a trade-off between the haploid and diploid stages of the life cycle, where distinct parthenogenesis alleles have opposing effects on sexual and asexual reproduction and may help maintain genetic variation. These types of fitness trade-offs have profound evolutionary implications in natural populations and may structure life history evolution in organisms with haploid-diploid life cycles.
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http://dx.doi.org/10.1371/journal.pgen.1008211DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6592573PMC
June 2019

The selective orexin-2 receptor antagonist seltorexant improves sleep: An exploratory double-blind, placebo controlled, crossover study in antidepressant-treated major depressive disorder patients with persistent insomnia.

J Psychopharmacol 2019 02 15;33(2):202-209. Epub 2019 Jan 15.

6 Neuroscience Development, Janssen Research and Development, San Diego, CA, USA.

Background: Insomnia is common in patients with major depressive disorder. Although antidepressants improve mood, insomnia often persists as a result of physiological hyperarousal. The orexin-2 receptor is increasingly being recognized as a new target for the treatment of persistent insomnia in major depressive disorder .

Aim: This exploratory study investigated the effects of seltorexant on objective sleep parameters and subjective depressive symptoms in antidepressant treated major depressive disorder patients with persistent insomnia.

Methods: Twenty male and female patients received a single dose of 10, 20, 40 mg seltorexant and placebo with a washout period of seven days in a double-blind four-way crossover study. Effects on latency to persistent sleep, total sleep time and sleep efficiency were assessed with polysomnography. Subjective changes in mood were explored by the Quick Inventory of Depressive Symptomatology Self-Report. Safety was recorded and suicidal ideation and behavior were assessed with the Columbia Suicide Severity Rating Scale.

Results: Latency to persistent sleep was significantly shorter for all doses of seltorexant compared to placebo. Placebo least square mean was 61.05 min with least square mean ratios treatment/placebo (80% confidence interval) of 0.32 (0.24-0.44), 0.15 (0.11-0.2) and 0.17 (0.12-0.23) 19.69, 9.2, 10.15 for 10, 20 and 40 mg seltorexant respectively, (all p<0.001). Total sleep time was significantly longer for all doses of seltorexant compared to placebo. Sleep efficiency was significantly improved. The Quick Inventory of Depressive Symptomatology Self-Report demonstrated a trend to mood-improvement for the 40 mg group.

Conclusions: Seltorexant showed a statistically significant, dose-dependent decrease in latency to persistent sleep, and increase in total sleep time and sleep efficiency combined with a tendency toward subjectively improved mood.
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http://dx.doi.org/10.1177/0269881118822258DOI Listing
February 2019

Cognitive Effects of MIN-101 in Patients With Schizophrenia and Negative Symptoms: Results From a Randomized Controlled Trial.

J Clin Psychiatry 2018 May/Jun;79(3)

Minerva Neurosciences, Inc., Waltham, Massachusetts, USA.

Objective: Current dopamine-blocking antipsychotic drugs have little impact on the cognitive deficits associated with schizophrenia. We evaluated whether MIN-101, a molecule that combines sigma-2 antagonism and 5-HT2A antagonism, might improve cognitive deficits in individuals with moderate to severe negative symptoms in schizophrenia.

Methods: Individuals (N = 244) aged 18 to 60 years with stable symptoms of DSM-5-defined schizophrenia and moderate to severe negative symptoms were randomized to placebo (n = 83), MIN-101 32 mg (n = 78), or MIN-101 64 mg (n = 83) in a 12-week, phase 2b, prospective, double-blind, placebo-controlled, parallel-group trial between May 2015 and December 2015. In a post hoc analysis, mean z and T score changes from baseline at 12 weeks of treatment in the cognitive composite score and individual tests on the Brief Assessment of Cognition in Schizophrenia (BACS) Battery were compared between MIN-101 and placebo.

Results: A total of 79 patients (95.2%) from the placebo group, 76 (97.4%) from the MIN-101 32 mg group, and 79 (95.2%) from the MIN-101 64 mg group completed the BACS at baseline. The BACS token motor (P = .04), verbal fluency (P = .01), and composite z scores (P = .05) showed significant improvements in the MIN-101 32 mg group compared to the placebo group. At week 4, the clinical improvements from baseline in the Positive and Negative Syndrome Scale (PANSS) negative factor showed a significant correlation with improvements from baseline on the BACS composite in the 64 mg group (r = -0.292, P = .020). At week 12, improvement in the PANSS negative factor showed significant correlations with improvements in the BACS composite (r = -0.408, P = .002), Trail Making Test (r = -0.394, P = .003), and verbal memory (r = -0.322, P = .017) for the 64 mg group.

Conclusions: Results suggest a possible benefit of MIN-101 on cognitive performance in individuals with schizophrenia with stable positive symptoms and concurrent clinically significant negative symptoms.

Trial Registration: EU Clinical Trials Register identifier: 2014-004878-42​.
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http://dx.doi.org/10.4088/JCP.17m11753DOI Listing
August 2019

A randomized Phase 2 study to evaluate the orexin-2 receptor antagonist seltorexant in individuals with insomnia without psychiatric comorbidity.

J Psychopharmacol 2018 06 31;32(6):668-677. Epub 2018 May 31.

12 Minerva Neurosciences, Waltham, MA, USA.

Background: Seltorexant is a potent and selective antagonist of the orexin-2 receptor that is being developed for the treatment of insomnia and major depressive disorder.

Aims: The primary objective was to investigate the effect of seltorexant on sleep efficiency after single and multiple dose administration in subjects with insomnia disorder without psychiatric comorbidity. Secondary objectives included evaluation of total sleep time, latency to persistent sleep, and wake after sleep onset. Subjects received 40 mg of seltorexant for five days during Period 1 and placebo during Period 2 or vice versa in this randomized, two-way crossover study. Objective sleep parameters were evaluated by polysomnography over 8 h on Day 1/2 (single dose) and on Day 5/6 (multiple doses). Subjective sleep parameters were assessed by questionnaires.

Results: Twenty-seven subjects completed the study. The mean changes in sleep efficiency (% (SD)) of seltorexant from placebo at Day 1/2 were 5.8 (9.2), and 7.9 (9.8) at Day 5/6 ( p < 0.001 at both time points); in total sleep time (min (SD)) 27.7 (44.3) and 37.9 (47.1), respectively; in latency to persistent sleep (min (SD)) -18.8 (21.3) and -29.9 (27.7), respectively; and in wake after sleep onset (min (SD)) -11.1 (36.4) and -11.3 (46.5). The most common adverse events were headache and somnolence.

Conclusions: Sleep efficiency was increased with seltorexant treatment compared with placebo. Treatment with seltorexant resulted in a prolonged total sleep time, shorter latency to persistent sleep and wake after sleep onset. There were no unexpected safety findings.
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http://dx.doi.org/10.1177/0269881118773745DOI Listing
June 2018

The brief negative symptom scale (BNSS): Sensitivity to treatment effects.

Schizophr Res 2018 07 21;197:269-273. Epub 2017 Dec 21.

Minerva Neurosciences, Inc., Waltham, MA, USA.

The Brief Negative Symptom Scale (BNSS) grew out of a recommendation by the NIMH-sponsored Consensus Development Conference on Negative Symptoms that a scale based on contemporary concepts be developed. We assessed sensitivity to change of the BNSS in a trial of MIN-101, which showed efficacy for negative symptoms (PANSS pentagonal model) at daily doses of 32 and 64mg/day. Using mixed-effects model for repeated measures, we examined change in BNSS total score and in the BNSS factors of anhedonia/avolition/asociality (AAA), and expressivity (EXP). Compared to placebo, the 64mg group (N=83) showed a significant decrease in BNSS total score (effect size d [ES] 0.56, p<0.01) and both factor scores (AAA ES=0.48, EXP ES=0.46, p<0.02 for both). Patients in the trial had minimal depression and positive symptom scores; covarying for disorganization, positive symptoms, or anxiety/depression did not cause a meaningful change in the significance of the BNSS total or factor scores in this group. The 32mg group (N=78) did not differ significantly from placebo (N=83) on BNSS total score (ES=0.33, p<0.09), AAA (ES=0.25, p<0.20) or EXP (ES=0.30, p<0.12) scores. These results demonstrate the BNSS is sensitive to change.
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http://dx.doi.org/10.1016/j.schres.2017.11.031DOI Listing
July 2018

Efficacy and Safety of MIN-101: A 12-Week Randomized, Double-Blind, Placebo-Controlled Trial of a New Drug in Development for the Treatment of Negative Symptoms in Schizophrenia.

Am J Psychiatry 2017 12 28;174(12):1195-1202. Epub 2017 Jul 28.

From the Department of Psychiatry, Tel Aviv University Sackler School of Medicine, Tel Aviv, Israel; PPRS Research, Rouffach, France; Minerva Neurosciences, Waltham, Mass.; and the Louis and Gabi Weisfeld School of Social Work, Faculty of Social Sciences, Bar Ilan University, Ramat Gan, Israel.

Objective: The authors assessed the efficacy, safety, and tolerability of MIN-101, a compound with affinities for sigma-2 and 5-HT receptors and no direct dopamine affinities, in comparison with placebo in treating negative symptoms in stabilized patients with schizophrenia.

Method: The trial enrolled 244 patients who had been symptomatically stable for at least 3 months and had scores of at least 20 on the negative subscale of the Positive and Negative Syndrome Scale (PANSS). After at least 5 days' withdrawal from all antipsychotic medication, patients were randomly assigned to receive placebo or 32 mg/day or 64 mg/day of MIN-101 for 12 weeks. The primary outcome measure was the PANSS negative factor score (pentagonal structure model). Secondary outcome measures were PANSS total score and scores on the Clinical Global Impressions Scale (CGI), the Brief Negative Symptom Scale, the Brief Assessment of Cognition in Schizophrenia, and the Calgary Depression Scale for Schizophrenia.

Results: A statistically significant difference in PANSS negative factor score was observed, with lower scores for the MIN-101 32 mg/day and 64 mg/day groups compared with the placebo group (effect sizes, d=0.45 and d=0.57, respectively). Supporting these findings were similar effects on several of the secondary outcome measures, such as the PANSS negative symptom, total, and activation factor scores, the CGI severity item, and the Brief Negative Symptom Scale. There were no statistically significant differences in PANSS positive scale score between the MIN-101 and placebo groups. No clinically significant changes were observed in vital signs, routine laboratory values, weight, metabolic indices, and Abnormal Involuntary Movement Scale score.

Conclusions: MIN-101 demonstrated statistically significant efficacy in reducing negative symptoms and good tolerability in stable schizophrenia patients.
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http://dx.doi.org/10.1176/appi.ajp.2017.17010122DOI Listing
December 2017

Assessing sleep architecture and continuity measures through the analysis of heart rate and wrist movement recordings in healthy subjects: comparison with results based on polysomnography.

Sleep Med 2016 05 17;21:47-56. Epub 2016 Feb 17.

Index Ventures, Geneva, Switzerland.

Objective: The objective of the study was to evaluate the reliability of a new methodology for assessing sleep architecture descriptors based on heart rate and body movement recordings.

Methods: Twelve healthy male and female subjects between 18 and 40 years of age, without sleep disorders and not taking any drug or medication that could affect sleep, were recorded continuously during five consecutive nights. Together with the standard polysomnography, heart rate was recorded with a Holter and wrist movements by actimetry. Of the 60 recorded nights, 48 artifact-free nights were analyzed by two independent and well-trained visual scorers according to the rules of the American Academy of Sleep Medicine. Sleep stages were assigned to every 30-s epoch. In parallel, the same nights were analyzed by the new methodology using only heart rate and actimetry data, allowing a 1-s epoch sleep stage classification. Sleep architecture was measured for 48 nights, independently for the two manual scorings and the automatic analysis.

Results: Over 42 nights, the intra-class correlation coefficient, used to assess the consistency or reproducibility of quantitative measurements made by different observers, was classified as excellent when all 12 descriptors were combined. Analyses of the individual descriptors showed excellent interclass correlation for eight and good for four of the 12.

Conclusion: The automatic analysis of heart rate and body movement during sleep allows for the evaluation of sleep architecture and continuity that is equivalent to those obtained by manual scoring of polysomnography. The technique used here is simple and robust to allow for home sleep monitoring.
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http://dx.doi.org/10.1016/j.sleep.2016.01.015DOI Listing
May 2016

The Pseudoautosomal Regions of the U/V Sex Chromosomes of the Brown Alga Ectocarpus Exhibit Unusual Features.

Mol Biol Evol 2015 Nov 6;32(11):2973-85. Epub 2015 Aug 6.

Sorbonne Université, UPMC Univ Paris 06, CNRS, Algal Genetics Group, UMR 8227, Integrative Biology of Marine Models, Station Biologique de Roscoff, Roscoff, France

The recombining regions of sex chromosomes (pseudoautosomal regions, PARs) are predicted to exhibit unusual features due to their being genetically linked to the nonrecombining, sex-determining region. This phenomenon is expected to occur in both diploid (XY, ZW) and haploid (UV) sexual systems, with slightly different consequences for UV sexual systems because of the absence of masking during the haploid phase (when sex is expressed) and because there is no homozygous sex in these systems. Despite a considerable amount of theoretical work on PAR genetics and evolution, these genomic regions have remained poorly characterized empirically. We show here that although the PARs of the U/V sex chromosomes of the brown alga Ectocarpus recombine at a similar rate to autosomal regions of the genome, they exhibit many genomic features typical of nonrecombining regions. The PARs were enriched in clusters of genes that are preferentially, and often exclusively, expressed during the sporophyte generation of the life cycle, and many of these genes appear to have evolved since the Ectocarpales diverged from other brown algal lineages. A modeling-based approach was used to investigate possible evolutionary mechanisms underlying this enrichment in sporophyte-biased genes. Our results are consistent with the evolution of the PAR in haploid systems being influenced by differential selection pressures in males and females acting on alleles that are advantageous during the sporophyte generation of the life cycle.
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http://dx.doi.org/10.1093/molbev/msv173DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4610043PMC
November 2015

Sexual dimorphism and the evolution of sex-biased gene expression in the brown alga ectocarpus.

Mol Biol Evol 2015 Jun 27;32(6):1581-97. Epub 2015 Feb 27.

Sorbonne Université, UPMC Univ Paris 06, CNRS, Algal Genetics Group, UMR 8227, Integrative Biology of Marine Models, Station Biologique de Roscoff, CS 90074, F-29688, Roscoff, France

Males and females often have marked phenotypic differences, and the expression of these dissimilarities invariably involves sex differences in gene expression. Sex-biased gene expression has been well characterized in animal species, where a high proportion of the genome may be differentially regulated in males and females during development. Male-biased genes tend to evolve more rapidly than female-biased genes, implying differences in the strength of the selective forces acting on the two sexes. Analyses of sex-biased gene expression have focused on organisms that exhibit separate sexes during the diploid phase of the life cycle (diploid sexual systems), but the genetic nature of the sexual system is expected to influence the evolutionary trajectories of sex-biased genes. We analyze here the patterns of sex-biased gene expression in Ectocarpus, a brown alga with haploid sex determination (dioicy) and a low level of phenotypic sexual dimorphism. In Ectocarpus, female-biased genes were found to be evolving as rapidly as male-biased genes. Moreover, genes expressed at fertility showed faster rates of evolution than genes expressed in immature gametophytes. Both male- and female-biased genes had a greater proportion of sites experiencing positive selection, suggesting that their accelerated evolution is at least partly driven by adaptive evolution. Gene duplication appears to have played a significant role in the generation of sex-biased genes in Ectocarpus, expanding previous models that propose this mechanism for the resolution of sexual antagonism in diploid systems. The patterns of sex-biased gene expression in Ectocarpus are consistent both with predicted characteristics of UV (haploid) sexual systems and with the distinctive aspects of this organism's reproductive biology.
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http://dx.doi.org/10.1093/molbev/msv049DOI Listing
June 2015

A haploid system of sex determination in the brown alga Ectocarpus sp.

Curr Biol 2014 Sep 28;24(17):1945-57. Epub 2014 Aug 28.

Integrative Biology of Marine Models, CNRS UMR 8227, Sorbonne Universités, UPMC Université Paris 6, Station Biologique de Roscoff, CS 90074, 29688 Roscoff, France. Electronic address:

Background: A common feature of most genetic sex-determination systems studied so far is that sex is determined by nonrecombining genomic regions, which can be of various sizes depending on the species. These regions have evolved independently and repeatedly across diverse groups. A number of such sex-determining regions (SDRs) have been studied in animals, plants, and fungi, but very little is known about the evolution of sexes in other eukaryotic lineages.

Results: We report here the sequencing and genomic analysis of the SDR of Ectocarpus, a brown alga that has been evolving independently from plants, animals, and fungi for over one giga-annum. In Ectocarpus, sex is expressed during the haploid phase of the life cycle, and both the female (U) and the male (V) sex chromosomes contain nonrecombining regions. The U and V of this species have been diverging for more than 70 mega-annum, yet gene degeneration has been modest, and the SDR is relatively small, with no evidence for evolutionary strata. These features may be explained by the occurrence of strong purifying selection during the haploid phase of the life cycle and the low level of sexual dimorphism. V is dominant over U, suggesting that femaleness may be the default state, adopted when the male haplotype is absent.

Conclusions: The Ectocarpus UV system has clearly had a distinct evolutionary trajectory not only to the well-studied XY and ZW systems but also to the UV systems described so far. Nonetheless, some striking similarities exist, indicating remarkable universality of the underlying processes shaping sex chromosome evolution across distant lineages.
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http://dx.doi.org/10.1016/j.cub.2014.07.042DOI Listing
September 2014

A new sublingual formulation of zolpidem for the treatment of sleep-onset insomnia.

Expert Rev Neurother 2012 Feb;12(2):141-53

Unité d'Exploration des Rythmes Veille-Sommeil, Centre Hospitalier de Rouffach, Rouffach, France.

Insomnia is a very frequent complaint that periodically or permanently affects up to 60% of the general population. Valuable therapeutic options rely on pharmacological and nonpharmacological management of insomnia complaints. Zolpidem is one of the most popular hypnotic drugs used to treat insomnia. The drug was synthesized by Synthélabo Recherche in the early 1980s and has proved to be a suitable and well-tolerated drug, especially with regard to efficacy in sleep initiation. The present review focuses on an alternate delivery form of zolpidem, Edluar™, a new sublingual formulation of zolpidem that has been developed for the treatment of sleep-onset insomnia. Studies have shown that Edluar has a faster sleep-induction effect, whereas it did not differ from the oral formulation in terms of sleep maintenance or side effects. This review also discusses the mechanism of action of zolpidem and its pharmacokinetic profile in comparison to Edluar. Efficacy studies in specific settings (such as non-nightly use or use in combination with cognitive behavioral therapy) and particular safety issues encountered with zolpidem use are also discussed.
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http://dx.doi.org/10.1586/ern.11.197DOI Listing
February 2012

Pharmacokinetic profile of SKP-1041, a modified release formulation of zaleplon.

Biopharm Drug Dispos 2011 Dec 20;32(9):489-97. Epub 2011 Sep 20.

Program in Pharmacology and Experimental Therapeutics, Department of Molecular Physiology and Pharmacology, Tufts University School of Medicine and Tufts Medical Center, Boston, MA 02111, USA.

Objectives: Two investigations aimed to define the pharmacokinetic profile of a modified-release preparation of zaleplon (SKP-1041).

Methods: Protocol SOM001 was a 5-way crossover, double-blind, randomized trial comparing three novel modified-release formulations of zaleplon 15 mg (SKP-1041A, SKP-1041B, SKP-1041C) to placebo and immediate-release zaleplon 10 mg. Protocol SOM002 was a randomized, crossover, open-label trial to compare the pharmacokinetics of SKP-1041B after day and night administration. In SOM001, study drug was administered at 9:00 a.m. (fasted); blood samples were obtained beginning 1 h predose through 12 h postdose. In study SOM002, study drug was administered at 9:00 a.m. or 10:30 p.m.; blood samples were obtained beginning 1 h predose through 12 h postdose. Subjects were 19 (SOM001) and 23 (SOM002) healthy adults between ages 20-46.

Results: Dose-normalized total AUCs for modified-release preparations A, B, C and immediate-release zaleplon were not significantly different; peak plasma concentrations were similar for A and B, and both were significantly higher than C. Time to peak plasma concentration for A, B, and C were 4-5 h compared to 1.5 h for immediate-release zaleplon; mean terminal phase half-life was in the range 1-2 h for A, B and immediate-release zaleplon. No significant differences were noted between day and night administration in the SOM002 study.

Conclusions: Zaleplon, 15 mg, in a novel, modified-release formulation (SKP-1041) had a time to peak plasma concentrations at 4-5 h postdose compared to 1.5 h for immediate-release zaleplon, 10 mg. The pharmacokinetic profile suggests this formulation may be useful for treating middle-of-the-night awakening.
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http://dx.doi.org/10.1002/bdd.773DOI Listing
December 2011

One milligram of lorazepam does not decrease anxiety induced by CCK-4 in healthy volunteers: investigation of neural correlates with BOLD MRI.

J Psychopharmacol 2011 Jan 24;25(1):52-9. Epub 2010 May 24.

FORENAP, Rouffach, France.

Benzodiazepine effects on cholecystokinin tetrapeptide (CCK-4)-induced panic attack (PA) in humans are incompletely characterized, in particular on the neurofunctional level. This work explores the effects of lorazepam on brain activity and behavioral and physiological symptoms related to CCK-4-induced PA in healthy volunteers. Twenty-one male volunteers received 1 mg of lorazepam or placebo orally, 2 hours before an injection of 0.9% saline solution followed by 50 µg of CCK-4 during functional magnetic resonance imaging (fMRI) and heart rate recording. Panic attacks were defined using the panic symptom scale (PSS). In addition, the Y1-STAI (state anxiety) and the Bond & Lader Visual Analogue Scale (VAS) were used. Eleven subjects were classified as panickers. CCK-4 induced behavioral anxiety and cardiovascular effects along with cerebral activation in anxiety-related brain regions. Overall, lorazepam did not significantly modify the anxiogenic and cardiovascular effects of CCK-4. Regarding CCK-4-induced brain activation, lorazepam did not reduce activity in the insulae and cingulate gyrus of panickers. One milligram of lorazepam was not sufficient to reverse strong panicogenic effects, but decreased brain activity in the case of mild anxiety.
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http://dx.doi.org/10.1177/0269881110367449DOI Listing
January 2011

Nelotanserin, a novel selective human 5-hydroxytryptamine2A inverse agonist for the treatment of insomnia.

J Pharmacol Exp Ther 2010 Jan 19;332(1):281-90. Epub 2009 Oct 19.

Arena Pharmaceuticals, Inc., San Diego, California, USA.

5-Hydroxytryptamine (5-HT)(2A) receptor inverse agonists are promising therapeutic agents for the treatment of sleep maintenance insomnias. Among these agents is nelotanserin, a potent, selective 5-HT(2A) inverse agonist. Both radioligand binding and functional inositol phosphate accumulation assays suggest that nelotanserin has low nanomolar potency on the 5-HT(2A) receptor with at least 30- and 5000-fold selectivity compared with 5-HT(2C) and 5-HT(2B) receptors, respectively. Nelotanserin dosed orally prevented (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI; 5-HT(2A) agonist)-induced hypolocomotion, increased sleep consolidation, and increased total nonrapid eye movement sleep time and deep sleep, the latter marked by increases in electroencephalogram (EEG) delta power. These effects on rat sleep were maintained after repeated subchronic dosing. In healthy human volunteers, nelotanserin was rapidly absorbed after oral administration and achieved maximum concentrations 1 h later. EEG effects occurred within 2 to 4 h after dosing, and were consistent with vigilance-lowering. A dose response of nelotanserin was assessed in a postnap insomnia model in healthy subjects. All doses (up to 40 mg) of nelotanserin significantly improved measures of sleep consolidation, including decreases in the number of stage shifts, number of awakenings after sleep onset, microarousal index, and number of sleep bouts, concomitant with increases in sleep bout duration. Nelotanserin did not affect total sleep time, or sleep onset latency. Furthermore, subjective pharmacodynamic effects observed the morning after dosing were minimal and had no functional consequences on psychomotor skills or memory. These studies point to an efficacy and safety profile for nelotanserin that might be ideally suited for the treatment of sleep maintenance insomnias.
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http://dx.doi.org/10.1124/jpet.109.160994DOI Listing
January 2010

Rapid absorption of sumatriptan powder and effects on glyceryl trinitrate model of headache following intranasal delivery using a novel bi-directional device.

J Pharm Pharmacol 2009 Sep;61(9):1219-28

Forenap FRP, 27 rue du 4ème RSM, B.P. 27, 68250 Rouffach, France.

Objectives: The aim was to investigate the pharmacokinetics of intranasal sumatriptan (administered using a novel bi-directional powder delivery device) and study its effects on quantitative electroencephalography in patients with migraine. The safety profiles of the two formulations were also compared.

Methods: The pharmacokinetics of intranasal sumatriptan (10 mg and 20 mg) administered using a novel breath-actuated bi-directional powder delivery device were compared with subcutaneous sumatriptan (6 mg), along with an investigation of their effects on the electroencephalogram (EEG) following glyceryl trinitrate (GTN) challenge in 12 patients with migraine using a randomized, three-way cross-over design.

Key Findings: Following intranasal delivery, median t(max) was 20 min with both doses compared with 10 min after the subcutaneous dose. Mean +/- SD values for C(max) were 96 +/- 25, 11 +/- 7 and 16 +/- 6 ng/ml for subcutaneous, intranasal 10 mg and intranasal 20 mg formulations, respectively. Values for area under the curve were also lower with the intranasal doses. Intranasal and subcutaneous sumatriptan induced similar EEG changes characterized by reduced theta-power and increased beta-power. The majority of study participants were free of pain according to the headache severity score with all treatments from 15 min through to 8 h post-dose. All treatments were well tolerated and there were no reports of bitter aftertaste after intranasal delivery. Sumatriptan was rapidly absorbed after intranasal administration using the new device. Using the GTN challenge, sumatriptan powder delivered intranasally at a dose of 20 mg by the new device had effects similar to those of subcutaneous sumatriptan on EEG and reported headache pain, despite much lower systemic exposure.

Conclusions: Administration of sumatriptan intranasally at doses of 10 mg and 20 mg by the breath actuated bi-directional powder delivery device results in rapid absorption. Delivery to target sites beyond the nasal valve induced a similar EEG profile to subcutaneous sumatriptan 6 mg and prevented migraine attacks in patients following GTN challenge. Intranasal administration of sumatriptan powder with the breath actuated bi-directional powder delivery device was well tolerated.
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http://dx.doi.org/10.1211/jpp/61.09.0012DOI Listing
September 2009

The effect of prolonged-release melatonin on sleep measures and psychomotor performance in elderly patients with insomnia.

Int Clin Psychopharmacol 2009 Sep;24(5):239-49

FORENAP Pharma, Rouffach, France.

Objectives of this study were to investigate the effects of prolonged-release melatonin 2 mg (PRM) on sleep and subsequent daytime psychomotor performance in patients aged > or =55 years with primary insomnia, as defined by fourth revision of the Diagnostic and Statistical Manual of Mental Disorders of the American Psychiatric Association. Patients (N = 40) were treated nightly single-blind with placebo (2 weeks), randomized double-blind to PRM or placebo (3 weeks) followed by withdrawal period (3 weeks). Sleep was assessed by polysomnography, all-night sleep electroencephalography spectral analysis and questionnaires. Psychomotor performance was assessed by the Leeds Psychomotor Test battery. By the end of the double-blind treatment, the PRM group had significantly shorter sleep onset latency (9 min; P = 0.02) compared with the placebo group and scored significantly better in the Critical Flicker Fusion Test (P = 0.008) without negatively affecting sleep structure and architecture. Half of the patients reported substantial improvement in sleep quality at home with PRM compared with 15% with placebo (P = 0.018). No rebound effects were observed during withdrawal. In conclusion, nightly treatment with PRM effectively induced sleep and improved perceived quality of sleep in patients with primary insomnia aged > or =55 years. Daytime psychomotor performance was not impaired and was consistently better with PRM compared with placebo. PRM was well tolerated with no evidence of rebound effects.
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http://dx.doi.org/10.1097/YIC.0b013e32832e9b08DOI Listing
September 2009

The effect of aging on the inhibitory function in middle-aged subjects: a functional MRI study coupled with a color-matched Stroop task.

Int J Geriatr Psychiatry 2009 Oct;24(10):1062-71

FORENAP, Unité RMN, Rouffach, France.

Objective: The effects of aging on the inhibitory function are largely described in the neuroimaging literature but little data is available on the beginning of this age-related impairment.

Methods: In this study, we described the cortical activation of middle-aged (mean age +/- standard error to the mean, 51.7 +/- 3.1) subjects compared to young (26.8 +/- 3.4) and elderly subjects (62.8 +/- 3) while they performed a color-matched Stroop task during functional magnetic resonance imaging. The task consisted in identifying the printing color of a word regardless of its meaning. Three conditions were defined depending on the meaning of this word; neutral (no meaning), congruent (color name matching the printing color), incongruent (color name mismatching the printing color), with interference effect in the latter.

Results: Middle-aged subjects were as slow as elderly compared to young for all conditions and both were less accurate than young subjects during interference condition. Elderly showed an activity more bilateral and greater in the parietal lobule, the dorsolateral and ventrolateral prefrontal cortex (DLPFC, VLPFC) during both congruent and incongruent conditions compared to young. Middle-aged showed an intermediary level of activity between those of elderly and young subjects in the left DLPFC, VLPFC and parietal lobule only during incongruent condition.

Conclusion: These results suggested that the age-related impairment of the inhibitory process could already occur around the age of 50 years and consist in an increase of the activity in the left prefrontal and parietal cortex before increasing more and becoming bilateral around the age of 60 years.
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http://dx.doi.org/10.1002/gps.2222DOI Listing
October 2009

Test-retest reliability of a functional MRI anticipatory anxiety paradigm in healthy volunteers.

J Magn Reson Imaging 2008 Mar;27(3):459-68

FORENAP-FRP, Rouffach, France.

Purpose: To evaluate the reproducibility of neural activations induced by an anticipatory anxiety provocation challenge in healthy volunteers.

Materials And Methods: Fourteen healthy male volunteers participated in two separate functional MRI (fMRI) sessions in which they underwent a paradigm based on anticipation of aversive transcutaneous electrical nerve stimulations. This paradigm consisted of alternating presentation of red circles associated with the likelihood that aversive stimuli may be given and blue circles during which the subjects knew that no shock could be given. Anxiety state was compared before the fMRI sessions and during the threat periods using clinical scales (Hamilton, STAI-Y1), the Bond and Lader Visual Analogue Scale, and self-rating scales of apprehension and stimulus aversivity.

Results: The selected paradigm induced anticipatory anxiety of moderate intensity as suggested by clinical scales and apprehension rating, without any habituation to the somatosensory stimulus across sessions. Compared to rest periods, threat of the aversive stimulus induced clear brain activation in anticipatory anxiety-related areas: frontal/prefrontal cortex, insula, lentiform nucleus, temporal pole, and cingulate cortex. Anxiety symptoms and cerebral activity were reproducible across sessions.

Conclusion: The fMRI paradigm and its assessment method include all criteria to speed up the evaluation and the development of new anxiolytics.
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http://dx.doi.org/10.1002/jmri.21237DOI Listing
March 2008

A double-blind, placebo-controlled, randomized study evaluating the effect of paliperidone extended-release tablets on sleep architecture in patients with schizophrenia.

Int Clin Psychopharmacol 2007 Sep;22(5):299-308

Executive Department, Forenap Pharma, 27 rue du 4éme RSM, Rouffach 68250, France.

The effects of paliperidone extended-release on sleep architecture in patients with schizophrenia-related insomnia were evaluated in this multicenter, double-blind, randomized, placebo-controlled study. Patients received paliperidone extended-release 9 mg/day or matching placebo during the 14-day double-blind phase. Sleep architecture and sleep continuity were evaluated using polysomnograms. Subjective sleep measures were evaluated daily using the Leeds Sleep Evaluation Questionnaire. Efficacy and safety were also assessed. Thirty-six patients (17 on paliperidone extended-release, 19 on placebo; mean age 32.2 years) completed the study. Paliperidone extended-release treatment vs. placebo resulted in clinically and statistically significant differences in sleep measurements from baseline to endpoint including a reduction in: persistent sleep latency (41 min), sleep onset latency (35 min), number of awakenings after sleep onset (7), time awake in bed (50 min), and stage 1 sleep duration (12 min); prolongation in: total sleep time (53 min), sleep period time (42 min), stage 2 sleep duration (51 min), and rapid eye movement sleep duration (18 min); and an increase in sleep efficiency index (11%). Paliperidone extended-release, compared with placebo, did not exacerbate daytime somnolence and improved symptoms of schizophrenia. Paliperidone extended-release was well tolerated and improved sleep architecture and sleep continuity in patients diagnosed with schizophrenia and concomitant insomnia.
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http://dx.doi.org/10.1097/YIC.0b013e3281c55f4fDOI Listing
September 2007

Pharmacological models in healthy volunteers: their use in the clinical development of psychotropic drugs.

J Psychopharmacol 2007 May;21(3):272-82

Centre Hospitalier de l'Ardenne, Sainte Ode, Belgium.

Animal models of diseases are widely used in the preclinical phase of drug development. They have a place in early human clinical psychopharmacology as well, in order to get early clues that contribute to establish the proof of concept (POC) already in healthy volunteers (HV). Different types of models are available (pharmacological or non-pharmacological provocation, models based on age-related characteristics). This review is focused on pharmacological models in HV, with the aim to identify the main issues raised by their use in pharmaceutical trials. The available models unevenly fulfil the requirements of face validity, sufficient response rate, test-retest consistence and responsiveness to reference drugs. Most of them have been developed in the purpose of pathophysiology studies, using rating instruments validated for clinical practice. Substantial progress could be made by adapting models to the specific requirements of pharmaceutical trials, including wider use of biomarkers. Characteristics that make models, as well as biomarkers, suitabLe for use in drug development are proposed. Despite obvious limitations, human models can significantly enhance the way phase I studies contribute to establish the POC, provided they are integrated into adapted phase I development plans. Their use as industrial tools for drug evaluation requires specific, dedicated development.
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http://dx.doi.org/10.1177/0269881107077733DOI Listing
May 2007

Effects of acamprosate on sleep during alcohol withdrawal: A double-blind placebo-controlled polysomnographic study in alcohol-dependent subjects.

Alcohol Clin Exp Res 2006 Sep;30(9):1492-9

Unité d'Exploration des Rythmes Veille-Sommeil, FORENAP, Centre Hospitalier de Rouffach, Rouffach, France.

Background: Sleep disturbances are frequently encountered in alcohol-dependent patients. Drugs improving sleep during abstinence from alcohol may play an important role in the recovery process.

Methods: In the present study, the effects of acamprosate, a drug successfully used in maintaining abstinence following alcohol withdrawal, were assessed by polysomnographic recordings. A parallel double-blind placebo-controlled study was conducted in 24 male DSM-IV alcohol-dependent subjects aged 35.9+/-1.2 years. Treatments (2 tablets of 333 mg acamprosate vs placebo t.i.d.) were initiated 8 days before alcohol withdrawal and continued during the 15 days following alcohol withdrawal. Polysomnographic assessments were recorded during acute withdrawal (the first 2 nights following withdrawal) and during postwithdrawal abstinence (the last 2 nights of the trial).

Results: Results show that, compared with placebo, acamprosate decreased wake time after sleep onset and increased stage 3 and REM sleep latency (all treatment effects with a p < 0.05 significance). Withdrawal effects themselves were also demonstrated as sleep efficiency (p < 0.01) and total sleep time (p < 0.05) were lower in abstinence nights versus withdrawal nights, whereas no significant treatment x withdrawal effect could be evidenced. Acamprosate was well tolerated during the entire course of the study.

Conclusions: The present study shows that acamprosate ameliorates both sleep continuity and sleep architecture parameters classically described as disturbed in alcohol-dependent patients. From a clinical perspective, it suggests that an 8-day acamprosate prewithdrawal treatment is well tolerated and can attenuate the sleep disturbances engendered by alcohol withdrawal in alcohol-dependent subjects.
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http://dx.doi.org/10.1111/j.1530-0277.2006.00180.xDOI Listing
September 2006

Comparison of the effects of a 24-hour nicotine patch and a 16-hour nicotine patch on smoking urges and sleep.

Nicotine Tob Res 2006 Apr;8(2):193-201

Centre de Traitement des Addictions, Hôpital Emile Roux, Limeil Brevannes, France.

This randomized, open-label, crossover study was conducted to compare the effects of a 24-hr nicotine patch and a 16-hr nicotine patch on morning smoking urges and sleep quality of dependent smokers during a short period of cigarette abstinence. A total of 20 smokers (9 women and 11 men) smoking at least 20 cigarettes/day completed the two smoke-free study periods. For each period, cigarette abstinence started on the first evening and a nicotine patch was applied the next morning (for 16 or 24 hr), after baseline measures; a second patch was applied the next morning, 1 hr before the end of the experimental period. Smoking urges, mood and behavior self-reports, psychomotor performance, and polysomnographic recordings were compared between the two types of nicotine patch according to changes from baseline. Both patches decreased morning smoking urges, although results were significantly superior for the 24-hr patch. Furthermore, the 24-hr patch was more effective than the 16-hr patch in reducing the positive reinforcing dimension of smoking urges. Regarding polysomnographic recordings, the proportion of slow wave sleep was significantly increased from baseline with the 24-hr patch compared with the 16-hr patch. As for psychomotor performance measured through the critical flicker fusion test, significant improvement in morning alertness was observed in the 24-hr patch group. In conclusion, the 24-hr nicotine patch formulation is more effective than the 16-hr formulation in alleviating morning smoking urges and more specifically the positive reinforcing factor. The present findings do not support the idea that nicotine delivery during bedtime might disturb sleep, but rather it improves restorative sleep and postwaking arousal.
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http://dx.doi.org/10.1080/14622200500489989DOI Listing
April 2006

Functional magnetic resonance imaging characterization of CCK-4-induced panic attack and subsequent anticipatory anxiety.

Neuroimage 2006 Jul 5;31(3):1197-208. Epub 2006 Apr 5.

Forenap-Unité RMN, 27, rue du 4ème RSM, 68250 Rouffach, France.

The main objective of this work was to study the functional markers of the clinical response to cholecystokinin tetrapeptide (CCK-4). Twelve healthy male subjects were challenged with CCK-4 and simultaneously underwent functional magnetic resonance imaging (fMRI) recording. Since anticipatory anxiety (AA) is an intrinsic part of panic disorder, a behavioral paradigm, using the threat of being administered a second injection of CCK-4, has been developed to investigate induced AA. The study was composed of three fMRI scans according to an open design. During first and second scan, subjects were injected with placebo and CCK-4, respectively. The third scan was the AA challenge. CCK-4 administration induced physiological and psychological symptoms of anxiety that met the criteria for a panic attack in 8 subjects, as well as cerebral activation in anxiety-related brain regions. Clinical and physiological response intensity was consistent with cerebral activity extent and robustness. fMRI proved more sensitive than clinical assessment in evidencing the effects of the AA challenge. The latter induced brain activation, different from that obtained on CCK-4 and during placebo injection, that was likely related to anxiety. The method applied in this study is suitable for the study of anxiety using fMRI.
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http://dx.doi.org/10.1016/j.neuroimage.2006.01.035DOI Listing
July 2006
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