| 1. |
- Lissek, T, et al.
(författare)
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Building Bridges through Science
- 2017
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Ingår i: Neuron. - : Elsevier BV. - 1097-4199 .- 0896-6273. ; 96:4, s. 730-735
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Tidskriftsartikel (refereegranskat)
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| 2. |
- Guiraud, J., et al.
(författare)
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Sodium oxybate for the maintenance of abstinence in alcohol-dependent patients: An international, multicenter, randomized, double-blind, placebo-controlled trial
- 2022
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Ingår i: Journal of Psychopharmacology. - : SAGE Publications. - 0269-8811 .- 1461-7285. ; 36:10
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Tidskriftsartikel (refereegranskat)abstract
- Background: Sodium oxybate (SMO) has been shown to be effective in the maintenance of abstinence (MoA) in alcohol-dependent patients in a series of small randomized controlled trials (RCTs). These results needed to be confirmed by a large trial investigating the treatment effect and its sustainability after medication discontinuation. Aims: To confirm the SMO effect on (sustained) MoA in detoxified alcohol-dependent patients. Methods: Large double-blind, randomized, placebo-controlled trial in detoxified adult alcohol-dependent outpatients (80% men) from 11 sites in four European countries. Patients were randomized to 6 months SMO (3.3-3.9 g/day) or placebo followed by a 6-month medication-free period. Primary outcome was the cumulative abstinence duration (CAD) during the 6-month treatment period defined as the number of days with no alcohol use. Secondary outcomes included CAD during the 12-month study period. Results: Of the 314 alcohol-dependent patients randomized, 154 received SMO and 160 received placebo. Based on the pre-specified fixed-effect two-way analysis of variance including the treatment-by-site interaction, SMO showed efficacy in CAD during the 6-month treatment period: mean difference +43.1 days, 95% confidence interval (17.6-68.5; p = 0.001). Since significant heterogeneity of effect across sites and unequal sample sizes among sites (n = 3-66) were identified, a site-level random meta-analysis was performed with results supporting the pre-specified analysis: mean difference +32.4 days, p = 0.014. The SMO effect was sustained during the medication-free follow-up period. SMO was well-tolerated. Conclusions: Results of this large RCT in alcohol-dependent patients demonstrated a significant and clinically relevant sustained effect of SMO on CAD.
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| 3. |
- Littleton, JM, et al.
(författare)
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Challenges to medications development in treating alcohol dependence: An international perspective - Summary of a symposium held at the ESBRA Congress, Prague, 13 September 2003
- 2004
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Ingår i: Alcohol and Alcoholism. - : Oxford University Press (OUP). - 1464-3502. ; 39:4, s. 271-275
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Tidskriftsartikel (refereegranskat)abstract
- Few medications for treating alcohol dependence exist. Greater partnership is needed between academia and the pharmaceutical industry to develop, licence and market efficacious medications for treating alcohol dependence. Methodologies that span the divide between preclinical and large-scale clinical studies need to be developed in order to provide sufficient information on safety, toleration, drug-interaction profile and efficacy, with which to guide development decisions. Due to the heterogeneous nature of alcohol dependence, the effort of developing an efficacious medication is likely to be enhanced by clearer choices about the characteristics of the population. Careful consideration of potential mechanism of action of the putative therapeutic medication should enable the appropriate choice of drinking endpoint. The pharmaceutical industry in collaboration with academia might need to develop new approaches to determining appropriate treatment endpoints with regulatory bodies. The investment risk to industry should be appraised not only in terms of the rather poor results of previous marketing efforts but with a view to the opportunity to penetrate a potentially enormous and largely untapped market.
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| 4. |
- Bernardi, R. E., et al.
(författare)
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A gene-by-sex interaction for nicotine reward: evidence from humanized mice and epidemiology
- 2016
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Ingår i: Translational Psychiatry. - : NATURE PUBLISHING GROUP. - 2158-3188. ; 6:e861
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Tidskriftsartikel (refereegranskat)abstract
- It has been proposed that vulnerability to nicotine addiction is moderated by variation at the mu-opioid receptor locus (OPRM1), but results from human studies vary and prospective studies based on genotype are lacking. We have developed a humanized mouse model of the most common functional OPRM1 polymorphism rs1799971_A4G (A118G). Here we use this model system together with a cohort of German youth to examine the role of the OPRM1 A118G variation on nicotine reward. Nicotine reinforcement was examined in the humanized mouse model using i.v. self-administration. Male (n = 17) and female (n = 26) mice homozygous either for the major human A allele (AA) or the minor G allele (GG) underwent eight daily 2 h sessions of nicotine self-administration. Furthermore, male (n = 104) and female (n = 118) subjects homozygous for the A allele or carrying the G allele from the Mannheim Study of Children at Risk were evaluated for pleasurable and unpleasant experiences during their initial smoking experience. A significant sex-by-genotype effect was observed for nicotine self-administration. Male 118GG mice demonstrated higher nicotine intake than male 118AA mice, suggesting increased nicotine reinforcement. In contrast, there was no genotype effect in female mice. Human male G allele carriers reported increased pleasurable effects from their first smoking experience, as compared to male homozygous A, female G and female homozygous A allele carriers. The 118G allele appears to confer greater sensitivity to nicotine reinforcement in males, but not females.
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| 5. |
- Guiraud, J., et al.
(författare)
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Treating alcohol dependence with an abuse and misuse deterrent formulation of sodium oxybate: Results of a randomised, double-blind, placebo-controlled study
- 2021
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Ingår i: European Neuropsychopharmacology. - : Elsevier BV. - 0924-977X. ; 52, s. 18-30
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Tidskriftsartikel (refereegranskat)abstract
- Sodium oxybate (SMO) has been approved in Italy and Austria for the maintenance of abstinence in alcohol dependent (AD) patients. Although SMO is well tolerated in AD patients, cases of abuse and misuse have been reported outside the therapeutic setting. Here we report on a phase IIb double-blind, randomized, placebo-controlled trial for the maintenance of abstinence in AD patients with a new abuse and misuse deterrent formulation of SMO. A total of 509 AD patients were randomized to 12 weeks of placebo or one of four SMO doses (0.75, 1.25, 1.75 or 2.25 g t.i.d.) followed by a one-week medication-free period. The primary endpoint was the percentage of days abstinent (PDA) at end of treatment. An unexpectedly high placebo response (mean 73%, median 92%) was observed. This probably compromised the demonstration of efficacy in the PDA, but several secondary endpoints showed statistically significant improvements. A post-hoc subgroup analysis based on baseline severity showed no improvements in the mild group, but statistically significant improvements in the severe group: PDA: mean difference +15%, Cohen's d = 0.42; abstinence: risk difference +18%, risk ratio = 2.22. No safety concerns were reported. Although the primary endpoint was not significant in the overall population, several secondary endpoints were significant in the intent-to-treat population and post-hoc results showed that treatment with SMO was associated with a significant improvement in severe AD patients which is consistent with previous findings. New trials are warranted that take baseline severity into consideration. (C) 2021 The Authors. Published by Elsevier B.V.
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| 6. |
- Scherrer, B., et al.
(författare)
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Baseline severity and the prediction of placebo response in clinical trials for alcohol dependence: A meta-regression analysis to develop an enrichment strategy
- 2021
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Ingår i: Alcoholism-Clinical and Experimental Research. - : Wiley. - 0145-6008 .- 1530-0277. ; 45:9, s. 1722-1734
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Tidskriftsartikel (refereegranskat)abstract
- Background There is considerable unexplained variability in alcohol abstinence rates (AR) in the placebo groups of randomized controlled trials (RCTs) for alcohol dependence (AD). This is of particular interest because placebo responses correlate negatively with treatment effect size. Recent evidence suggests that the placebo response is lower in very heavy drinkers who show no "spontaneous improvement" prior to treatment initiation (high-severity population) than in a mild-severity population and in studies with longer treatment duration. We systematically investigated the relationship between population severity, treatment duration, and the placebo response in AR to inform a strategy aimed at reducing the placebo response and thereby increasing assay sensitivity in RCTs for AD. Methods We conducted a systematic literature review on placebo-controlled RCTs for AD.We assigned retained RCTs to high- or mild-severity groups of studies based on baseline drinking risk levels and abstinence duration before treatment initiation. We tested the effects of population severity and treatment duration on the placebo response in AR using meta-regression analysis. Results Among the 19 retained RCTs (comprising 1996 placebo-treated patients), 11 trials were high-severity and 8 were mild-severity RCTs. The between-study variability in AR was lower in the high-severity than in the mild-severity studies (interquartile range: 7.4% vs. 20.9%). The AR in placebo groups was dependent on population severity (p = 0.004) and treatment duration (p = 0.017) and was lower in the high-severity studies (16.8% at 3 months) than the mild-severity studies (36.7% at 3 months). Conclusions Pharmacological RCTs for AD should select high-severity patients to decrease the magnitude and variability in the placebo effect and and improve the efficiency of drug development efforts for AD.
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| 7. |
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| 8. |
- Guiraud, J., et al.
(författare)
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Sodium Oxybate for Alcohol Dependence: A Network Meta-Regression Analysis Considering Population Severity at Baseline and Treatment Duration
- 2023
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Ingår i: Alcohol and Alcoholism. - : Oxford University Press (OUP). - 0735-0414 .- 1464-3502. ; 58:2, s. 125-133
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Tidskriftsartikel (refereegranskat)abstract
- Aims: The estimated effect of sodium oxybate (SMO) in the treatment of alcohol dependence is heterogeneous. Population severity and treatment duration have been identified as potential effect modifiers. Population severity distinguishes heavy drinking patients with <14 days of abstinence before treatment initiation (high-severity population) from other patients (mild-severity population). Treatment duration reflects the planned treatment duration. This study aimed to systematically investigate the effect of these potential effect moderators on SMO efficacy in alcohol-dependent patients. Methods: Network meta-regression allows for testing potential effect modifiers. It was selected to investigate the effect of the above factors on SMO efficacy defined as continuous abstinence (abstinence rate) and the percentage of days abstinent (PDA). Randomized controlled trials for alcohol dependence with at least one SMO group conducted in high-severity and mild-severity populations were assigned to a high-severity and mild-severity group of studies, respectively. Results: Eight studies (1082 patients) were retained: four in the high-severity group and four in the mild-severity group. The high-severity group was associated with larger SMO effect sizes than the mild-severity group: abstinence rate risk ratio (RR) 3.16, P = 0.004; PDA +26.9%, P < 0.001. For PDA, longer treatment duration was associated with larger SMO effect size: +11.3% per extra month, P < 0.001. In the high-severity group, SMO showed benefit: abstinence rate RR 2.91, P = 0.03; PDA +16.9%, P < 0.001. In the mild-severity group, SMO showed benefit only in PDA for longer treatment duration: +23.9%, P < 0.001. Conclusions: In the retained studies with alcohol-dependent patients, high-severity population and longer treatment duration were associated with larger SMO effect sizes.
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| 9. |
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| 10. |
- Rodriguez Parkitna, J, et al.
(författare)
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Loss of the serum response factor in the dopaminesystem leads to hyperactivity
- 2010
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Ingår i: The FASEB Journal. - : Federation of American Societies for Experimental Biology. - 0892-6638 .- 1530-6860. ; 24, s. 2427-2435
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Tidskriftsartikel (refereegranskat)abstract
- The serum response factor (SRF) is a key regulator of neural development and cellular plasticity, which enables it to act as a regulator of long-term adaptations in neurons. Here we performed a comprehensive analysis of SRF function in the murine dopamine system. We found that loss of SRF in dopaminoceptive, but not dopaminergic, neurons is responsible for the development of a hyperactivity syndrome, characterized by reduced body weight into adulthood, enhanced motor activity, and deficits in habituation processes. Most important, the hyperactivity also develops when the ablation of SRF is induced in adult animals. On the molecular level, the loss of SRF in dopaminoceptive cells is associated with altered expression of neuronal plasticity-related genes, in particular transcripts involved in calcium ion binding, formation of the cytoskeleton, and transcripts encoding neuropeptide precursors. Furthermore, abrogation of SRF causes specific deficits in activity-dependent transcription, especially a complete lack of psychostimulant-induced expression of the Egr genes. We inferred that alterations in SRFdependent gene expression underlie the observed hyperactive behavior. Thus, SRF depletion in dopaminoceptive neurons might trigger molecular mechanisms responsible for development of psychopathological conditions involving hyperactivity.
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