We describe the efficacy and safety of as-needed use of nalmefene in the subgroup of patients with a high drinking risk level (DRL; men:>60g/day; women:>40g/day); i.e. a group of patients with a great unmet medical need for.

To evaluate the 6 month efficacy and safety of as-needed use of nalmefene 18mg versus placebo in a subgroup of alcohol-dependent patients with high DRL from a randomised controlled trial [NCT00812461].

All patients received a motivational and adherence-enhancing intervention (BRENDA) in combination with either nalmefene or placebo. Number of heavy drinking days (HDDs) and total alcohol consumption (TAC) were measured using the Timeline Follow-back method. Additionally, data on clinical improvement, liver function and safety were collected throughout the study.

The study population consisted of 317 patients: placebo N=162; nalmefene N=155 (mean age 44.8±10.3 years; 69% men; mean HDDs: 22±6.2/month; mean TAC 111±47.9g/day). Mean number of HDDs decreased to 10 days/month and mean TAC decreased to 43g/day at month 6 in the nalmefene group. There was a superior effect of nalmefene compared to placebo in reducing the number of HDDs (-2.7 [95% CI: -5.0;-0.3];p=0.0253) and TAC -10.3 [-20.2;-0.5];p=0.0404). Improvements in clinical status and alanine amino transferase were greater in the nalmefene group compared to the placebo group (p< 0.05). Adverse events were more common with nalmefene; incidence of adverse events leading to dropout was at the placebo level.

As-needed nalmefene was efficacious in reducing alcohol consumption in patients with high risk for alcoholrelated harm.

We describe the efficacy and safety of as-needed use of nalmefene in the subgroup of patients with a high drinking risk level (DRL; men:>60g/day; women:>40g/day); i.e. a group of patients with a great unmet medical need for treatment.

To evaluate the 1 year efficacy and safety of as-needed use of nalmefene 18mg versus placebo in a subgroup of alcohol dependent patients with high DRL from a randomised controlled trial [NCT00811941].

All patients received a motivational and adherence-enhancing intervention (BRENDA) in combination with either nalmefene or placebo. Number of heavy drinking days (HDDs) and total alcohol consumption (TAC) were measured using the Timeline Follow-back method. Additionally, data on clinical improvement, liver function and safety were collected throughout the study.

The study population consisted of 187 patients: placebo N=42; nalmefene N=145 (mean age 46.2±11.9 years; 78% men; mean HDDs 19±6.3/month; mean TAC 101±45.0 g/day). Mean number of HDDs decreased to 7 days/month and mean TAC decreased to 33g/day at 1 year in the nalmefene group. At 1 year, there was a superior effect of nalmefene compared to placebo in reducing the number of HDDs (-3.6 [95% CI:-6.5;-0.7]; p=0.0164) and TAC -17.3 [-30.9;-3.8]; p=0.0129). Improvements in clinical status and in liver enzymes from baseline were larger in the nalmefene compared to the placebo group. Adverse events and adverse events leading to dropout were more common with nalmefene than placebo.

As-needed nalmefene was efficacious in reducing alcohol consumption in patients with high risk for alcoholrelated harm.

Although neuroimaging studies suggest brain regional abnormalities in depressive disorders, it remains unclear whether abnormalities are present at illness onset or reflect disease progression.

We hypothesized that cerebral variations were present in adolescents with subthreshold depression known to be at high risk for later full-blown depression.

We examined brain structural and diffusion-weighted magnetic resonance images of adolescents with subthreshold depression.

The participants were extracted from the European IMAGEN study cohort of healthy adolescents recruited at age 14. Subthreshold depression was defined as a distinct period of abnormally depressed or irritable mood, or loss of interest, plus two or more depressive symptoms but without diagnosis of Major Depressive Episode. Comparisons were performed between adolescents meeting these criteria and control adolescents within the T1-weighted imaging modality (118 and 475 adolescents respectively) using voxel-based morphometry and the diffusion tensor imaging modality (89 ad 422 adolescents respectively) using tract-based spatial statistics. Whole brain analyses were performed with a statistical threshold set to p< 0.05 corrected for multiple comparisons.

Compared with controls, adolescents with subthreshold depression had smaller gray matter volume in caudate nuclei, medial frontal and cingulate cortices; smaller white matter volume in anterior limb of internal capsules, left forceps minor and right cingulum; and lower fractional anisotropy and higher radial diffusivity in the genu of corpus callosum.

The findings suggest that adolescents with subthreshold depression have volumetric and microstructural gray and white matter changes in the emotion regulation frontal-striatal-limbic network.

The phase 3 programme investigating nalmefene for reduction of alcohol consumption in alcohol dependent patients comprised two 6-month studies (ESENSE1 and 2) and one 12-month study (SENSE), conducted in 19 European countries.

To investigate the tolerability and safety of as-needed use of 18 mg nalmefene.

1997 patients with a diagnosis of alcohol dependence were recruited. Adverse events (AEs) and other safety variables were recorded.

797 patients in the placebo group and 1144 patients in the nalmefene group received study medication; patients took study medication on 62% and 51% of the days, respectively. The incidence of AEs was high in both the placebo and the nalmefene group (62.7% and 74.7%, respectively), and was not dependent on the drinking risk level at baseline. While mostly mild or moderate, these AEs did lead to dropout in some patients: 47 patients (6%) in the placebo group and 149 patients (13%) in the nalmefene group. Patients continuing in the studies seemed to develop tolerance with time for the most frequent AEs. Median time to event and median duration of these AEs were generally shorter for nalmefene than for placebo (many started after 1st dose). 35 patients (4.4%) in the placebo group and 57 patients (5.0%) in the nalmefene group had serious adverse events (SAEs). The majority of SAEs were not related to study medication and no apparent trends with respect to overall incidence or distribution across organ systems were noted.

Nalmefene was well-tolerated and no major safety issues were identified.

To investigate distinguishing features between bipolar I, II and unipolar depression, and impulsivity/aggression traits in particular.

Six hundred and eighty-five (n = 685) patients in a major depressive episode with lifetime Unipolar (UP) depression (n = 455), Bipolar I (BP-I) disorder (n = 151), and Bipolar II (BP-II) (n = 79) disorder were compared in terms of their socio-demographic and clinical characteristics.

Compared to unipolar patients, BP-I and BP-II depressed patients were significantly younger at onset of their first depressive episode, and were more likely to experience their first depressive episode before/at age of 15. They also had more previous affective episodes, more first- and second-degree relatives with history of mania, more current psychotic and subsyndromal manic symptoms, and received psychopharmacological and psychotherapy treatment at an earlier age. Furthermore, BP-I and BP-II depressed patients had higher lifetime impulsivity, aggression, and hostility scores. With regard to bipolar subtypes, BP-I patients had more trait-impulsivity and lifetime aggression than BP-II patients whereas the latter had more hostility than BP-I patients. As for co-morbid disorders, Cluster A and B Personality Disorders, alcohol and substance abuse/dependence and anxiety disorders were more prevalent in BP-I and BP-II than in unipolar patients. Whereas the three groups did not differ on other socio-demographic variables, BP-I patients were significantly more often unemployed that UP patients.

Our findings comport with major previous findings on differences between bipolar and unipolar depression. As for trait characteristics, bipolar I and II depressed patients had more life-time impulsivity and aggression/hostility than unipolar patients. In addition, bipolar I and II patients also differed on these trait characteristics.

Aberrant activity of the subcallosal cingulate (SCC) is a common theme across pharmacologic treatment efficacy prediction studies. The functioning of the SCC in psychotherapeutic interventions is relatively understudied, as are functional differences among SCC subdivisions. We conducted functional connectivity analyses (rsFC) on resting-state functional magnetic resonance imaging (fMRI) data, collected before and after a course of cognitive behavioral therapy (CBT) in patients with major depressive disorder (MDD), using seeds from three SCC subdivisions.

Resting-state data were collected from unmedicated patients with current MDD (Hamilton Depression Rating Scale-17 > 16) before and after 14-sessions of CBT monotherapy. Treatment outcome was assessed using the Beck Depression Inventory (BDI). Rostral anterior cingulate (rACC), anterior subcallosal cingulate (aSCC), and Brodmann’s area 25 (BA25) masks were used as seeds in connectivity analyses that assessed baseline rsFC and symptom severity, changes in connectivity related to symptom improvement after CBT, and prediction of treatment outcomes using whole-brain baseline connectivity.

Pretreatment BDI negatively correlated with pretreatment rACC ~ dorsolateral prefrontal cortex and aSCC ~ lateral prefrontal cortex rsFC. In a region-of-interest longitudinal analysis, rsFC between these regions increased post-treatment (p < 0.05FDR). In whole-brain analyses, BA25 ~ paracentral lobule and rACC ~ paracentral lobule connectivities decreased post-treatment. Whole-brain baseline rsFC with SCC did not predict clinical improvement.

rsFC features of rACC and aSCC, but not BA25, correlated inversely with baseline depression severity, and increased following CBT. Subdivisions of SCC involved in top-down emotion regulation may be more involved in cognitive interventions, while BA25 may be more informative for interventions targeting bottom-up processing. Results emphasize the importance of subdividing the SCC in connectivity analyses.