Dynamic Functional Connectivity in Adolescence-Onset Major Depression: Relationships With Severity and Symptom Dimensions.

BACKGROUND: The spatial functional chronnectome is an innovative mathematical model designed to capture dynamic features in the organization of brain function derived from resting-state functional magnetic resonance imaging data. Measurements of dynamic functional connectivity have been developed from this model to quantify the brain dynamical self-reconfigurations at different spatial and temporal scales. This study examined whether two spatiotemporal dynamic functional connectivity quantifications were linked to late adolescence-onset major depressive disorder (AO-MDD), and scaled with depression and symptom severity measured with the Montgomery-Åsberg Depression Rating Scale. METHODS: Thirty-five patients with AO-MDD (21 ± 6 years of age) and 53 age- and sex-matched healthy young participants (20 ± 3 years of age) underwent 3T magnetic resonance imaging structural and resting-state functional magnetic resonance imaging acquisitions. The chronnectome here comprised seven individualized functional networks portrayed along 132 temporal overlapping windows, each framing 110 seconds of resting brain activity. RESULTS: Based on voxelwise analyses, patients with AO-MDD demonstrated significantly reduced temporal variability within the bilateral prefrontal cortex in five functional networks including the limbic network, default mode network, and frontoparietal network. Furthermore, the limbic network appeared to be particularly involved in this sample and was associated with Montgomery-Åsberg Depression Rating Scale scores, and its progressive dynamic inflexibility was linked to sadness. Default mode network and frontoparietal network dynamics scaled with negative thoughts and neurovegetative symptoms, respectively. CONCLUSIONS: This triple-network imbalance could delay spatiotemporal integration, while across-subject symptom variability would be network specific. Therefore, the present approach supports that brain network dynamics underlie patients' symptom heterogeneity in AO-MDD.

Lower midbrain dopamine transporter availability in depressed patients: Report from high-resolution PET imaging.

BACKGROUND: A reduced presynaptic dopamine neurotransmission has long been implicated in major depressive disorder (MDD). However, molecular imaging studies that assessed the dopamine transporter (DAT) availability have led to inconsistent results, partly due to methodological considerations, and to exclusive focus on the striatum, precluding findings in extra-striatal regions. METHODS: Herein, we leveraged our database of high-resolution Positron Emission Tomography (PET) images acquired with a highly selective radiotracer, [11C]PE2I, to assess striatal and extra-striatal DAT availability in eight patients treated for depression compared to twenty-four healthy controls. RESULTS: Statistical parametric mapping and voxel-based analyses of PET images detected a significant lower DAT availability in depressed patients within the superior part of the midbrain (right, pFWE = 0.002; left, pFWE = 0.006), a region including the ventral tegmental area and the substantia nigra from where the mesocorticolimbic and nigrostriatal dopamine pathways originate. A similar difference was found in the right dorsal putamen (pFWE = 0.012). LIMITATIONS: The statistical power was limited to detect only large effects, due to the size of the patients' sample. CONCLUSIONS: The findings support the hypothesis that a reduced presynaptic dopamine function plays a role in the pathophysiology of depression, and that extra-striatal dopamine function should be further investigated.

Tailored-Dose Baclofen in the Management of Alcoholism: A Retrospective Study of 144 Outpatients Followed for 3 Years in a French General Practice.

Background: More information is needed about the efficacy and safety of long-term baclofen in the treatment of alcohol use disorders. The objective of this study was to assess the effect of treatment with tailored-dose baclofen on alcohol consumption in patients with alcohol use disorders followed for 3 years after first initiating baclofen treatment. Methods: This retrospective descriptive cohort included outpatients followed in a French general practice clinic for 3 years and treated with tailored-dose baclofen to reduce or eliminate alcohol consumption. At 3 years, treatment was considered successful if alcohol consumption was at or below levels defined as low-risk by the WHO (≤ 40 g/d in men and ≤ 20 g/d in women). Results: The study population included 144 patients (88 men and 56 women). The participants' mean age was 46 ± 11 years and mean daily alcohol intake before treatment was 167 ± 77 grams. At the end of the study, treatment was successful for 91 (63.2%) patients. Participants' mean dose of baclofen at the end of study period was 100 ± 101 mg/d. We identified 75 (52.1%) patients for whom treatment was successful at each annual follow-up appointment: at 1, 2, and 3 years. The mean maximum dose of baclofen over follow-up of the 144 patients was 211 ± 99 mg/d (dose range: 40 mg/d to 520 mg/d). Conclusion: In this study, tailored-dose baclofen appears to be an effective treatment in patients with alcohol use disorders, with sustainable effect over time (3 years). There are many adverse effects but they are consistent with those already described in the literature.

Dopamine Transporter and Reward Anticipation in a Dimensional Perspective: A Multimodal Brain Imaging Study.

Dopamine function and reward processing are highly interrelated and involve common brain regions afferent to the nucleus accumbens, within the mesolimbic pathway. Although dopamine function and reward system neural activity are impaired in most psychiatric disorders, it is unknown whether alterations in the dopamine system underlie variations in reward processing across a continuum encompassing health and these disorders. We explored the relationship between dopamine function and neural activity during reward anticipation in 27 participants including healthy volunteers and psychiatric patients with schizophrenia, depression, or cocaine addiction, using functional magnetic resonance imaging (fMRI) and positron emission tomography (PET) multimodal imaging with a voxel-based statistical approach. Dopamine transporter (DAT) availability was assessed with PET and [11C]PE2I as a marker of presynaptic dopamine function, and reward-related neural response was assessed using fMRI with a modified Monetary Incentive Delay task. Across all the participants, DAT availability in the midbrain correlated positively with the neural response to anticipation of reward in the nucleus accumbens. Moreover, this relationship was conserved in each clinical subgroup, despite the heterogeneity of mental illnesses examined. For the first time, a direct link between DAT availability and reward anticipation was detected within the mesolimbic pathway in healthy and psychiatric participants, and suggests that dopaminergic dysfunction is a common mechanism underlying the alterations of reward processing observed in patients across diagnostic categories. The findings support the use of a dimensional approach in psychiatry, as promoted by the Research Domain Criteria project to identify neurobiological signatures of core dysfunctions underling mental illnesses.

Population pharmacokinetics of oral baclofen at steady-state in alcoholic-dependent adult patients.

Baclofen has been proposed for few years to help treating alcohol dependence at higher doses than those used in neurology. Baclofen pharmacokinetics has been previously well described at low oral or intravenous doses but remains poorly investigated with such high oral doses. We here describe dose regimens of baclofen in 143 alcohol-dependent patients treated with steady-state oral doses of baclofen. Plasma baclofen levels were measured in blood samples using liquid chromatography coupled with tandem mass spectrometry. One hundred and forty-nine baclofen concentrations were sampled 30 min to 15 h after the last dose, and baclofen pharmacokinetics was determined using population pharmacokinetics approach. Our population, whose average age and BMI were 51.5 years and 25.5 kg/m2 , respectively, was composed of two-thirds of men. Daily baclofen doses ranged from 15 to 250 mg and 26% were higher than 120 mg. A one-compartment model with first-order absorption and elimination allowed to determine mean values for clearance (CL/F), volume of distribution (V/F) and absorption rate constant at 8.0 L/h, 44.5 L and 2.23 h-1 , respectively. Inter-individual variability on CL/F and V/F was 27.4 and 86% for the parameters. None of the demographic and biological covariates significantly decreased inter-individual variability. A proportional relationship between oral dose and plasma baclofen exposure indicated a linear pharmacokinetics of baclofen even at doses over 120 mg/day. Our large population study evidenced a linear pharmacokinetics of oral baclofen even at high daily doses with an inter-individual variability of baclofen exposure that could not be explained by demographic and biological data.

Amygdala and regional volumes in treatment-resistant versus nontreatment-resistant depression patients.

BACKGROUND: Although treatment-resistant and nontreatment-resistant depressed patients show structural brain anomalies relative to healthy controls, the difference in regional volumetry between these two groups remains undocumented. METHODS: A whole-brain voxel-based morphometry (VBM) analysis of regional volumes was performed in 125 participants' magnetic resonance images obtained on a 1.5 Tesla scanner; 41 had treatment-resistant depression (TRD), 40 nontreatment-resistant depression (non-TRD), and 44 were healthy controls. The groups were comparable for age and gender. Bipolar/unipolar features as well as pharmacological treatment classes were taken into account as covariates. RESULTS: TRD patients had higher gray matter (GM) volume in the left and right amygdala than non-TRD patients. No difference was found between the TRD bipolar and the TRD unipolar patients, or between the non-TRD bipolar and non-TRD unipolar patients. An exploratory analysis showed that lithium-treated patients in both groups had higher GM volume in the superior and middle frontal gyri in both hemispheres. CONCLUSIONS: Higher GM volume in amygdala detected in TRD patients might be seen in perspective with vulnerability to chronicity, revealed by medication resistance.

Striatal and Extrastriatal Dopamine Transporter Availability in Schizophrenia and Its Clinical Correlates: A Voxel-Based and High-Resolution PET Study.

Neuroimaging studies investigating dopamine (DA) function widely support the hypothesis of presynaptic striatal DA hyperactivity in schizophrenia. However, published data on the striatal DA transporter (DAT) appear less consistent with this hypothesis, probably partly due to methodological limitations. Moreover, DAT in extrastriatal regions has been very poorly investigated in the context of schizophrenia. In order to address these issues, we used a high resolution positron emission tomograph and the selective DAT radioligand [11C]PE2I, coupled with a whole brain voxel-based analysis method to investigate DAT availability in striatal but also extra-striatal regions in 21 male chronic schizophrenia patients compared to 30 healthy male controls matched by age. We found higher DAT availability in schizophrenia patients in midbrain, striatal, and limbic regions. DAT availability in amygdala/hippocampus and putamen/pallidum was positively correlated with hallucinations and suspiciousness/persecution, respectively. These results are consistent with an increase of presynaptic DA function in patients with schizophrenia, and support the involvement of both striatal and extrastriatal DA dysfunction in positive psychotic symptoms. The study also highlights the whole brain voxel-based analysis method to explore DA dysfunction in schizophrenia.

Liquid chromatography high resolution mass spectrometry for the determination of baclofen and its metabolites in plasma: Application to therapeutic drug monitoring.

Baclofen is used to manage alcohol dependence. This study describes a simple method using liquid chromatography coupled to high-resolution mass spectrometry (LC-HR-MS) developed in plasma samples. This method was optimized to allow quantification of baclofen and determination of metabolic ratio of its metabolites, an oxidative deaminated metabolite of baclofen (M1) and its glucuronide form (M2). The LC-HR-MS method on Exactive® apparatus is a newly developed method with all the advantages of high resolution in full-scan mode for the quantification of baclofen and detection of its metabolites in plasma. The present assay provides a protein precipitation method starting with 100 µL plasma giving a wide polynomial dynamic range (R2 > 0.999) between 10 and 2000 ng/mL and a lower limit of quantitation of 3 ng/mL for baclofen. Intra- and inter-day precisions were <8.1% and accuracies were between 91.2 and 103.3% for baclofen. No matrix effect was observed. The assay was successfully applied to 36 patients following baclofen administration. Plasma concentrations of baclofen were determined between 12.2 and 1399.9 ng/mL and metabolic ratios were estimated between 0.4 and 81.8% for M1 metabolite and on the order of 0.3% for M2 in two samples.

The haloperidol story.

Haloperidol was synthesized on the 11th of February 1958 at the Janssen Laboratories, in Belgium. Soon after its synthesis and animal studies, which suggested to Paul Janssen and his colleagues that this butyrophenone drug would be of great interest as its action was similar but much more powerful than that of chlorpromazine, haloperidol was administered to humans at the Liege hospital. The subsequent clinical studies confirmed that this new drug was particularly active against delusions and hallucinations. The introduction of haloperidol in the United States of America was difficult for clinical and legal reasons. For many years, haloperidol had been widely used in western countries, until the introduction of "new antipsychotics."