Thierry Danel

Chronobiology of Alcohol: From Chronokinetics to Alcohol-related Alterations of the Circadian System

The development of concepts in chronobiology is intimately linked to studies on alcohol, as a number of these are based on chronobiological variations observed in the metabolism of ethanol. This concerns circadian differences in its metabolism (chronokinetics) and effects (chronoefficacy and chronotoxicity) and also inherent circadian rhythmicity in the sensitivity of target organs to its effects (chronesthesy). Chronobiologic discoveries are also fertile grounds for understanding the biological and psychotropic effects of alcohol. Confusing effects, which are difficult to explain by conventional homeostatic theory, are easy to understand when considered in the context of the concepts of chronopharmacology, and thereby uncovering new pathways of investigation. Beyond the studies that have elucidated the rhythm-dependent variation in ethanol, chronobiology is opening new explanatory pathways concerning the attributes of the alcohol withdrawal syndrome and effects of alcohol on the development of the central nervous system, particularly the development of the internal clock, and on the alcohol-dependency syndrome. The concepts of chronopharmacology and chronotoxicology are of equal importance to the fields of occupational medicine and industry medicine.

Inversion of Melatonin Circadian Rhythm in Chronic Alcoholic Patients during Withdrawal: Preliminary Study on Seven Patients

AIMS The inversion of melatonin circadian rhythm secretion in some alcoholics during both intake and acute withdrawal has been widely reported. In the same way, what happens to this inversion when these patients are in long-term withdrawal is not known. To document this abnormality in alcoholics after withdrawal we investigated melatonin secretion observed during chronic alcoholization and after withdrawal. METHODS We measured the urinary 6-sulfatoxymelatonin (6SM) (6SM/creatinine ratio), main metabolite of the hormone, in two fractions, one diurnal and the other nocturnal, in seven alcohol-dependent patients presenting with this abnormality during alcoholization at two times: in acute withdrawal phase (under benzodiazepines) and 15 days after beginning of withdrawal (free of any psychotropic treatment). RESULTS Our results show that this reversed rhythm of melatonin secretion as seen by the diurnal excretion of 6SM (6SM/creatinine ratio) persists during acute withdrawal in more than half of the patients and is still present 15 days after withdrawal in three patients. CONCLUSION It is remarkable that the inversion of the melatonin rhythms gets corrected in four out of seven patients after withdrawal. But, the circadian disorganization of melatonin secretion in three patients could underline a desynchronization in some alcoholic patients and may indicate more widespread circadian temporal structure disturbances in these patients.

Safety and drinking outcomes among patients with comorbid alcohol dependence and borderline personality disorder treated with high-dose baclofen: a comparative cohort study.

In France, the off-label use of high-dose baclofen (HDB) for alcohol dependence is spreading. HDB induces frequent neuropsychiatric adverse events (AEs). Borderline personality disorder (BPD) is a major axis-two psychiatric disorder that exposes to frequent comorbid alcohol dependence and increased risky behaviors. We investigated the drinking and safety outcomes of patients with BPD treated with HDB for comorbid alcohol dependence. In a prospective cohort of 204 patients with alcohol dependence treated by HDB, 23 patients fulfilled the Diagnostic and Statistical Manual of Mental Disorders, 4th ed. criteria for BPD. We paired two control participants without a psychiatric history with each BPD patient according to age and sex. We compared the average lengths of follow-up, average doses of baclofen received, rates of heavy drinking days, rates of serious AEs, and rates of AEs resulting in baclofen withdrawal. Between BPD patients (n=23) and controls (n=46), there were no significant differences in mean age (45.3±11.2 vs. 45.2±11.2 years), sex ratio (43.5% women), mean duration of follow-up (8.0±4.0 vs. 7.7±4.2 months; P=0.77), and average daily dose of baclofen (102.2±42.7 vs. 94.6±9.7 mg/day; P=0.44). However, the mean rate of heavy drinking days (74.3±25.3 vs. 41.7±33.3%; P<10E−4), the rate of serious AEs (65.2 vs. 6.5%; P<10E−4), and the rate of treatment discontinuation after AEs (52.2 vs. 8.6%; P<10E−4) were significantly higher in BPD. The benefit/risk balance of HDB appears to be unfavorable in comorbid BPD patients compared with nonpsychiatric patients.

Fetal alcohol-induced hyperactivity is reversed by treatment with the PPARα agonist fenofibrate in a rat model

IntroductionExposure to alcohol in utero is linked to the development of a wide range of psychobehavioral changes, notably hyperactivity and attention deficit, with complex underlying pathological and functional mechanisms. Although the currently available treatments for hyperactivity have been studied in children exposed to alcohol in utero, the efficacy of these compounds is subject to debate and has prompted efforts to identify new pharmacological targets.MethodIn a rat model of early alcohol exposure (i.e., in utero and during lactation), we studied the effect of the lipid-lowering peroxisome proliferator-activated receptor (PPAR) alpha activator fenofibrate on psychobehavioral impairments.ResultsIn the young rat, early exposure to alcohol perturbs locomotor behavior and induces prepubertal hyperactivity and postpubertal hypoactivity. The hyperactivity, usually observed at the end of the fifth week of life, was prevented by the administration of fenofibrate, which also had a beneficial effect on the accompanying attention deficit by reinforcing sustained attention.ConclusionOur results with fenofibrate suggest that the pharmacological modulation of nuclear receptors such as PPAR-alpha may constitute a new therapeutic approach to managing the psychobehavioral disorders associated with early alcohol exposure.

A case-comparison study of executive functions in alcohol-dependent adults with maternal history of alcoholism

INTRODUCTION As executive dysfunctions frequently accompany alcohol dependence, we suggest that reports of executive dysfunction in alcoholics are actually due, in some case to a maternal history of alcohol misuse (MHA+). A history of maternal alcohol dependence increases the risk for prenatal alcohol exposure to unborn children. These exposures likely contribute to executive dysfunction in adult alcoholics. To assess this problem, we propose a case-comparison study of alcohol-dependent subjects with and without a MHA. METHODS Ten alcohol-dependent subjects, with a maternal history of alcoholism (MHA) and paternal history of alcoholism (PHA), were matched with 10 alcohol-dependent people with only a paternal history of alcoholism (PHA). Executive functions (cancellation, Stroop, and trail-making A and B tests) and the presence of a history of three mental disorders (attention deficit hyperactivity disorder, violent behavior while intoxicated, and suicidal behavior) were evaluated in both populations. RESULTS Alcohol-dependent subjects with MHA showed a significant alteration in executive functions and significantly more disorders related to these functions than PHA subjects. The major measures of executive functioning deficit are duration on task accomplishment in all tests. Rates of ADHD and suicidality were found to be higher in MHA patients compared to the controls. CONCLUSION A history of MHA, because of the high risk of PAE (in spite of the potential confounding factors such as environment) must be scrupulously documented when evaluating mental and cognitive disorders in a general population of alcoholics to ensure a better identification of these disorders. It would be helpful to replicate the study with more subjects.

Les facteurs qui influencent la consommation intensive et régulière de médicaments psychotropes

The article attempts to construct a typology to the use of psychoactive drugs and the study of the various factors linked to their use, whether heavy or regular. The results draw on the exploitation of databases containing medicines presented for reimbursement by medical insurance in the Nord - Pas-de-Calais region. In 2007 and 2008, 20.7% of the insured population (764,650 people) benefited from reimbursements for this type of medication. Among the beneficiaries, about a third (30.5%) had an intense consummation. Age, the CMUs benefits and the fact that a person is or not followed by a psychiatrist are the most influential variables on the intensity and the regularity of intake. The observed regularity of the recourse to benzodiazepines does not conform with the current recommendations.

Autobiographical Memory Deficits in Alcohol-Dependent Patients with Short- and Long-Term Abstinence

BACKGROUND Autobiographical memory (AM) enables the storage and retrieval of life experiences that allow individuals to build their sense of identity. Several AM impairments have been described in patients with alcohol abuse disorders without assessing whether such deficits can be recovered. This cross-sectional study aimed to identify whether the semantic (SAM) and episodic (EAM) dimensions of AM are affected in individuals with alcohol dependence after short-term abstinence (STA) or long-term abstinence (LTA). A second aim of this study was to examine the factors that could disrupt the efficiency of semantic and episodic AM (the impact of depression severity, cognitive functions, recent or early traumatic events, and drinking history variables). METHODS After clinical and cognitive evaluations (alcohol consumption, depression, anxiety, IQ, memory performance), AM was assessed with the Autobiographical Memory Interview in patients with recent (between 4 and 6 weeks) and longer (at least 6 months) abstinence. Participants were asked to retrieve the number and nature of traumatic or painful life experiences in recent or early life periods (using the Childhood Traumatic Events Scale). RESULTS The 2 abstinent groups had lower global EAM and SAM scores than the control group. These scores were comparable for both abstinent groups. For childhood events, no significant differences were observed in SAM for both groups compared with control participants. For early adulthood and recent events, both STA and LTA groups had lower scores on both SAM and EAM. Moreover, there was a negative correlation between the length of substance consumption and SAM scores. CONCLUSIONS This study highlighted a specific AM disorder in both episodic and semantic dimensions. These deficits remained after 6 months of abstinence. This AM impairment may be explained by compromised encoding and consolidation of memories during bouts of drinking.

Heart rate variability changes and emotion regulation abilities in short- and long-term abstinent alcoholic individuals

INTRODUCTION Difficulties in identifying and regulating emotion are recognized as major factors of relapse in alcohol use disorders (AUD). This study aimed to evaluate the differences of emotion regulation processes in AUD patients with short-term (STA, less than one month) and long-term abstinence (LTA, at least six months) by recording the high frequency of Heart Rate Variability (HF-HRV) in response to emotional and neutral stimuli. METHOD Emotional induction constituted the presentation of highly emotional and neutral pictures (IAPS data base) presenting human interactions. HF-HRV was recorded before (at rest), during (pictures) and after emotional induction (recovery). RESULTS The results showed higher phasic HF-HRV in the STA group in comparison to the LTA and C groups for negative, positive and neutral stimuli. In the LTA group, we observed a normalization of HRV, in response to emotional stimuli. However, for negative valence stimuli in the recovery period, LTA participants are no more different from STA group. A main positive correlation was observed for both patient groups between craving scores and increased HF-HRV during and after the emotion induction. CONCLUSION The data support the hypothesis of emotion regulation impairment after STA but also show a partial improvement with prolonged abstinence. This impairment in patients may correspond to the maintenance of negative feedback that accentuates the difficulties in the emotional physiological process and limits the ability to engage in or maintain other processes. HF-HRV is a good indicator of emotion regulation processes related to the intensity of the craving even after long-term abstinence.

The System of Medical Treatment for Addiction in France

ABSTRACT The French Addictions Treatment system was recently reformed. The ministerial memo was clearly inspired by professionals and from the clinical reality of patients. The main purpose of this reform was to reorganize the treatments (fighting against the historical split of the different structures) but also to fight against the substances approach in favor of a global approach. Thus, this new plan allows addiction treatment professionals to be concerned with the prevention and the detection of addictive behaviors (abuse and risk use), which was relatively new in the French medical profession. We present a brief history of the evolution of the system of treatment for addiction, and we describe the new system of treatment for addiction as it is now defined in France.

Combining brief contact interventions (BCI) into a decision-making algorithm to reduce suicide reattempt: the VigilanS study protocol

Introduction The early postattempt period is considered to be one of the most at-risk time windows for suicide reattempt or completion. Among the postcrisis prevention programmes developed to compensate for this risk, brief contact interventions (BCIs) have been proven to be efficient but not equally for each subpopulation of attempters. VigilanS is a region-wide programme that relies on an algorithmic system to tailor surveillance and BCI provisions to individuals discharged from the hospital after a suicide attempt. Aim VigilanS’ main objective is to reduce suicide and suicide reattempt rates both at the individual level (patients included in VigilanS) and at the populational level (inhabitants of the Nord–Pas-de-Calais region). Methods and analysis At discharge, every attempter coming from a participating centre is given a crisis card with an emergency number to contact in case of distress. Patients are then systematically recontacted 6 months later. An additional 10-day call is also given if the index suicide attempt is not the first one. Depending on the clinical evaluation during the phone call, the call team may carry out proportionated crisis interventions. Personalised postcards are sent whenever patients are unreachable by phone or in distress. On the populational level, mean suicide and suicide attempt rates in Nord–Pas-de-Calais will be compared before and after the implementation of the programme. Here/there cross-sectional comparisons with a control region will test the spatial specificity of the observed fluctuations, while time-series analyses will be performed to corroborate the temporal plausibility of imputing these fluctuations to the implementation of the programme. On the individual level, patients entered in VigilanS will be prospectively compared with a matched control cohort by means of survival analyses (survival curve comparisons and Cox models). Discussion VigilanS interventional components fall under the ordinary law care regime, and the individuals’ general rights as patients apply with no addendums or restrictions for their participation in the programme. The research section received authorisation from the Ethical Committee of Lille Nord-Ouest under the caption ‘Study aimed at evaluating routine care’ and is registered in ‘Clinical Trials’. The French Ministry of Health plans to extend the experimentation to other regions and probe the relevance of this type of ‘bottom–up’ territorial prevention policy at the national level. Trial registration number NCT03134885.