Systemic serum protein alterations and molecular mechanisms in alcohol dependence

Perceived Effectiveness of Medications Among Mental Health Service Users With and Without Alcohol Dependence

Cortical Inhibition in Alcohol Dependence

Addolorato et al. [1] recently published a welcome review article in CNS Drugs, entitled ‘‘Management of alcohol dependence in patients with liver disease’’. Alcoholic liver disease (ALD) is too often forgotten within the numerous review articles that are regularly published on alcoholdependence medications, whereas cirrhosis is one of the most dramatic consequences of alcohol dependence and can deeply affect the safe use of numerous medications. Addolorato and colleagues [2] state that the gamma amino-butyric acid type B (GABAB) receptor agonist baclofen should be currently preferred in ALD because baclofen was the sole drug that had a good efficacy/safety profile in ALD patients with alcohol dependence in a study whose results were published in The Lancet. Albeit relevant, this conclusion is relatively ironic in the sense that an off-label treatment for alcohol dependence has exhibited higher evidence in ALD than any of the currently approved medications. This indicates to what extent this field of research has been neglected until now. Although baclofen is definitely one of the most promising drugs for treating alcohol dependence in ALD patients, several important safety concerns remain in using this drug in ALD. The findings of the study in The Lancet were obtained from patients with no psychiatric history and who had undergone permanent monitoring by close relatives throughout the trial period. Moreover, as baclofen was particularly effective in maintaining abstinence, only nine patients within the baclofen group experienced relapse, and the amounts of alcohol drinking were not detailed. Thus, possible interactions between baclofen and alcohol intoxication were difficult to identify. Additionally, no patient presented with hepatic encephalopathy, although this condition has been hypothesized to result from GABArelated mechanisms [3]. For all of these reasons, despite the important advances provided by this study, several safety concerns still persist for baclofen because the patient profiles and monitoring conditions in this study were not comparable to those of real-life patients, in whom significant psychiatric co-morbidities; persisting or recurrent alcohol abuse; or ALD complications, such as encephalopathy, may be found. We believe that the question of dose is even more crucial. In the aforementioned study, baclofen was tested at 30 mg/day. Addolorato’s Roman team has published many articles using this dose, which has thus made the dose the most studied and most supported by evidence in the offlabel use of baclofen for abstinence maintenance. However, a dose–response effect of baclofen has been suspected in alcohol dependence [4], and this drug has recently been used in clinical practice at very high doses, i.e., up to 300 mg/day or more, and notably more with a purpose of temperance than of abstinence [5–8]. Although several of these uses have been limited to last-resort situations by hospital teams that could provide enhanced patient monitoring [9, 10], there also exists certain spreading, albeit less visible, practices of prescribing of high-dose baclofen, notably in France [10]. The possible hepatic toxicity of B. Rolland (&) A. Louvet O. Cottencin R. Bordet University of Lille Nord de France, 59045, Lille, France e-mail: benjrolland@gmail.com; benjamin.rolland@chrulille.fr

Dopamine receptors are associated with reward and dependence towards alcohol. The polymorphisms of dopamine D2 receptor (DRD2) genes have been reported to be involved in susceptibility to alcoholism. Therefore, we investigated the association of three single-nucleotide polymorphisms (SNPs) in DRD2 and ankyrin repeat and kinase domain containing one (ANKK1) genes with alcohol dependence in Korean subjects, who were classified by the criteria of the Lesch typology. The DRD2 -141C (Insertion (Ins)/Deletion (Del)), exon8 (A/G) and the ANKK1 TaqIA (A1/A2) polymorphisms were genotyped in a case-control sample consisting of 245 alcohol-dependent (AD) patients and 110 healthy controls. AD patients were classified into four subtypes by the Lesch typology. The majority of them (77.1%) were Lesch type 1. Differences in genotype and allele frequencies were examined between the AD patients and the controls. Also those analyses were done between the Lesch type 1 group and the controls. There were significant differences in the genotype and allele frequencies of -141C Ins/Del and TaqIA A1/A2 between the AD patients and the controls. However, there were no significant differences in genotype or allele frequencies of exon8 A/G between the AD patients and the controls. The -141C Ins/Ins and TaqIA A1+ variants were associated with Lesch type 1 AD patients. When analysing haplotypes of three SNPs, the odds ratio of -141C Ins-A-A1 was 2.286, while the odds ratio of -141C Del-G-A2 was 0.323. The present study showed a significant difference in DRD2 -141C and ANKK1 TaqIA polymorphisms between the AD patients and the controls. Our findings suggest that -141C Ins and TaqIA A1 alleles can be a predisposing factor for alcohol dependence in the Korean population.

Commitment strength, alcohol dependence and HealthCall participation: Effects on drinking reduction in HIV patients

Aim:To assess personality disorder (PD), emotional intelligence (EI), and locus of control of alcohol dependent (AD) patients and its comparison with normal controls.Materials and Methods:Based on purposive sampling technique, 33 AD patients were selected from the De-Addiction Ward of Ranchi Institute of Neuro-Psychiatry and Allied Sciences (RINPAS) and 33 matched normal subjects were selected from Ranchi and nearby places. Both the groups were matched on various sociodemographic parameters, that is, age, gender, and socioeconomic level. All participants were assessed with Millon Clinical Multiaxial Inventory-III, Mangal EI Inventory, and Locus of Control scale. Obtained responses were scored by using standard scoring procedures and subsequently statistically analyzed by using Chi-square test.Results:AD patients have more comorbid pathological personality traits and disorders in comparison to their normal counterparts. Depressive, narcissistic, and paranoid PDs were prominent among AD group; followed by schizotypal, antisocial, negativistic, dependent, schizoid, sadistic, masochistic, and borderline PD. In comparison to normal participants, AD patients were significantly deficient in almost all the areas of EI and their locus of control was externally oriented.Conclusion:Patients with AD have significantly higher PDs, low EI, and an external orientation on the locus of control. Identification and management of these comorbid conditions are likely to improve the management and outcome of AD.

The increased vulnerability to alcohol dependence (AD) seen in individuals with childhood adversity (CA) may result in part from CA-induced epigenetic changes. To examine CA-associated DNA methylation changes in AD patients, we examined peripheral blood DNA methylation levels of 384 CpGs in promoter regions of 82 candidate genes in 279 African Americans [AAs; 88 with CA (70.5% with AD) and 191 without CA (38.2% with AD)] and 239 European Americans [EAs; 61 with CA (86.9% with AD) and 178 without CA (46.6% with AD)] using Illumina GoldenGate Methylation Array assays. The effect of CA on methylation of individual CpGs and overall methylation in promoter regions of genes was evaluated using a linear regression analysis (with consideration of sex, age, and ancestry proportion of subjects) and a principal components-based analysis, respectively. In EAs, hypermethylation of 10 CpGs in seven genes (ALDH1A1, CART, CHRNA5, HTR1B, OPRL1, PENK, and RGS19) were cross validated in AD patients and healthy controls who were exposed to CA. P values of two CpGs survived Bonferroni correction when all EA samples were analyzed together to increase statistical power [CHRNA5_cg17108064: Padjust = 2.54×10−5; HTR1B_cg06031989: Padjust = 8.98×10−5]. Moreover, overall methylation levels in the promoter regions of three genes (ALDH1A1, OPRL1 and RGS19) were elevated in both EA case and control subjects who were exposed to CA. However, in AAs, CA-associated DNA methylation changes in AD patients were not validated in healthy controls. Our findings suggest that CA could induce population-specific methylation alterations in the promoter regions of specific genes, thus leading to changes in gene transcription and an increased risk for AD and other disorders.

There are a number of epidemiological studies concerning the gender differences in the genetic etiology of alcohol dependence (AD), with ADH2 and ALDH2 being strong candidates. The purpose of this study was to investigate gender differences in frequencies of ADH2 and ALDH2 genotypes in AD patients and in a normal control (NC) group of Koreans. Study subjects consisted of 228 AD patients (180 males, 48 females) and 138 NC (79 males, 59 females). For both male and female subjects, the frequency of the ADH2*1/1 genotype was significantly higher in AD patients compared to the NC group. However, the effect size of the ADH2*1/1 genotype on AD was much larger in females than in males. Furthermore, the ALDH2*1/1 genotype was positively associated with AD in male subjects but negatively associated with AD in female patients. Interestingly, AD in males was primarily determined by ALDH2 enzyme activity (92%), whereas female AD was primarily determined by ADH2 enzyme activity (60.4%). These results suggest that risk for the development of AD in males is mainly associated with the ALDH2*1/1 genotype, while in female patients, the ADH2*1/1 genotype was more highly associated with risk of AD. Overall, it is evident that gender differences associated with genetic risks for AD are present.

Hyperreactivity and impaired sensory gating of the acoustic startle response in alcohol dependence has been suggested to reflect a residual effect of previous detoxifications, increasing the severity of subsequent withdrawal episodes. Previous studies on the acoustic startle only included early-onset alcohol-dependent patients. The observed abnormalities may therefore also be specific for this subtype of alcohol dependence. We investigated the acoustic startle response in alcohol-dependent patients and healthy controls and hypothesized that (i) early-onset alcohol-dependent patients show increased acoustic startle responses compared with late-onset alcohol-dependent patients and healthy controls, and (ii) the duration of alcohol dependence or the number of prior detoxifications would not explain the differences in the acoustic startle between early- and late-onset alcohol dependence. The acoustic startle reflex was assessed in detoxified, male alcohol-dependent patients (N = 83) and age-matched healthy male controls (N = 86). Reflex eye blink responses to an auditory startle stimulus were measured by means of electromyographic recordings over the right orbicularis oculi muscle. Reflex amplitudes and levels of prepulse inhibition (PPI) were analyzed. There was no association between number of previous withdrawals and the startle response or PPI. Early-onset alcohol-dependent patients showed higher acoustic startle amplitudes compared with late-onset alcohol-dependent patients and healthy controls [75/105 dB: F(2, 166) = 9.2, p < 0.001; 85/105 dB: F(2, 166) = 12.1, p < 0.001; 95 dB: F(2, 166) = 8.2, p < 0.001; 105 dB: F(2, 166) = 9.7, p < 0.001], and there were no differences in PPI. Increased acoustic startle response in detoxified early-onset alcohol-dependent patients may reflect a trait marker specifically involved in early-onset alcohol dependence. The findings of the current study do not support the hypothesis that the increased startle response is a residual state marker.

Long-term use of methamphetamine could induce psychosis, but consequences with regards to intelligence have seldom been investigated. Long-term use of alcohol could also result in intellectual deterioration. The IQ of 34 methamphetamine-induced psychosis (MIP) patients (age, 28.7 +/- 6.1 years) and 34 alcohol-dependent (AD) patients (age, 40.7 +/- 7.3 years) was compared using the Chinese version of the Wechsler Adult Intelligence Scale-Third Edition (WAIS-III). The average full-scale IQ, verbal IQ, performance IQ, verbal comprehension index, working memory index, perceptual organization index, and processing speed index was 82.3 +/- 10.8, 84.3 +/- 11.9, 81.9 +/- 12.1, 85.5 +/- 11.9, 84.7 +/- 12.5, 85.4 +/- 13.6, and 78.5 +/- 12.7 in MIP patients and 90.5 +/- 12.0, 95.2 +/- 11.3, 86.0 +/- 13.7, 95.5 +/- 11.0, 87.1 +/- 14.5, 96.2 +/- 13.1, and 84.5 +/- 15.0 in AD patients, respectively. There were six MIP patients (17.6%) whose full-scale IQ was <70 and 13 (38.2%) whose full-scale IQ was <85 and >70, while one AD patient had a full-scale IQ <70 (2.9%) and 10 (22%) had full-scale IQ <85 and >70. Long-term use of methamphetamine can result not only in psychosis, but also in mentality deterioration. Intelligence deterioration is more severe in clinical MIP patients than AD patients. Assessment of the mentality of MIP patients is suggested to help with the implementation of rehabilitative programs for these patients.

Complex neurobiological models based on animal research have been formulated in an attempt to explain the cyclic pattern of nonREM and REM sleep. The "reciprocal interaction model" of nonREM and REM sleep regulation, which has been updated to incorporate new evidence is still the most convincing. Therefore it is reasonable to apply this model also to REM sleep abnormalities such as shortened REM latency and increased REM density, observed in patients with depression and alcohol dependency. In a retrospective analysis baseline data from 40 subjects with primary alcohol dependency are compared with a group of 40 patients diagnosed with major depression (diagnoses according to DSM-III-R) and healthy subjects. All alcohol dependent patients were examined in the sleep laboratory during subacute withdrawal at least 7 days off medication and after at least 14 days of abstinence. The patients with major depression (at least 7 days off psychoactive medication) and the healthy subjects had been examined previously by polysomnography during the last few years in the context of various studies and were assembled from our database to match the group of alcohol dependent patients with respect to age and sex. Alcohol dependent patients exhibited similar disturbances in sleep continuity and REM sleep as depressed patients in comparison to healthy controls while parameters of sleep architecture were even more strongly disturbed in alcohol dependence. While enhanced sensitivity of cholinergic receptors is the most likely explanation for the increase in "REM pressure" in depressives, this appears not to apply to alcoholics, who rather exhibit a decreased response to cholinergic stimulation. Thus, according to the reciprocal interaction model of nonREM- and REM sleep regulation and in contrast to the interpretation of the findings in depressed patients, an impaired aminergic rather than an increased cholinergic neurotransmission might be responsible for the increased REM sleep pressure in alcohol dependent patients. Alternatively or in addition the REM anomalies in alcoholic patients could also be due to adaptive regulatory processes during chronic alcohol consumption that lead to downregulation of GABA(A)- and upregulation of NMDA-receptors or their intracellular signalling and become apparent with alcohol withdrawal. Such adaptive counterregulation might also explain the alterations in slow wave sleep found in alcoholics that are even more pronounced in these patients than in patients with major depression.

Regional gray matter deficits in alcohol dependence: A meta-analysis of voxel-based morphometry studies

BackgroundAlcohol dependence is a mental disorder with a high relapse rate. However, specific neuroimaging biomarkers have not been determined for alcohol dependence and its relapse. We conducted data-driven research to investigate resting-state functional magnetic resonance imaging (rs-fMRI) during early abstinence from alcohol dependence and its potential ability to predict relapse.MethodsParticipants included 68 alcohol-dependent patients and 68 healthy controls (HCs). The regional homogeneity (ReHo) and fractional amplitude of low-frequency fluctuations (fALFF) were compared between the alcohol dependence group and the HCs and between the relapse group and the nonrelapse group. The brain regions that presented significantly different ReHo and/or fALFF between the alcohol-dependent patients and HCs and/or between the relapsed and nonrelapsed patients were selected as the seeds to calculate the functional connectivities (FCs).ResultsDuring a 6-month follow-up period, 52.24% of alcohol-dependent patients relapsed. A regression model for differentiating alcohol-dependent patients and HCs showed that reductions in ReHo in the left postcentral region, fALFF in the right fusiform region, and FC in the right fusiform region to the right middle cingulum were independently associated with alcohol dependence, with an area under the receiver operating characteristic curve (AUC) of 0.841. The baseline FC of the left precentral to the left cerebellum of the relapse group was significantly lower than that of the nonrelapse group. The AUC of this FC to predict relapse was 0.774.ConclusionsOur findings contribute to advancing research on the neurobiological etiology and predictive biomarkers for relapse associated with alcohol dependence.

Some addicted patients have social cognition deficits that require therapists to have special skills to ensure treatment success. Specific remediation techniques that teach addicted patients to look at the relevant emotional cues when interacting with people should be tested as adjunctive treatment. Almost two decades after the first studies reporting reduced ability to read non-verbal signals in alcohol dependence 1, Bora & Zorlu's meta-analysis confirms further that social cognitive impairments comprise an important research topic in the field of addiction 2. Social abilities are fundamental to human behaviour. Patterns of body language, including facial expressions and body postures, translate into a tuned ballet between interacting partners that binds and bonds people together 3. In this context, it appears inevitable that difficulties decoding non-verbal inputs could lead to interpersonal difficulties in alcohol-dependent patients 4. Bora & Zorlu evoke possible aetiologies to explain social cognitive deficits in alcohol-dependent patients. A toxic effect of chronic alcohol consumption on connectivity between brains areas devoted to social cues decoding has been described 5. However, social cues decoding difficulties have also been seen in other substance-related addictions (e.g. opiates 6). Additionally, non-verbal emotion decoding impairments have been highlighted recently in pathological gambling; that is, an addiction without a substance 7. This suggests that non-verbal emotion decoding impairments in addiction could occur in the absence of any toxic effect of a substance on the brain. In this commentary, I propose that attachment styles could impact significantly upon alcohol-dependent patients’ ability to decode non-verbal emotions. Insecure attachment is associated with alcohol dependence and constitutes a risk factor for its development 8. The majority of alcohol-dependent patients display an abnormal attachment style and experience difficulties in securing stable interpersonal relationships 9. Because impaired interpersonal attachment is associated with an inability to buffer life's emotional turmoil effectively 9, alcohol might be used as a coping strategy. Attachment problems impair emotion decoding in faces, as they are associated with gaze avoidance towards informative cues in childhood. Children with callous/unemotional traits show low levels of eye contact towards their mothers; in other words, they fail to attend to the eyes of attachment figures 10. Impaired ability to seek out and make use of the eye regions is also present in autism, and improves with oxytocin administration 11. Specific neuronal structures are considered important in the monitoring of gaze: amygdala regions are involved in the processing of gaze and eye fixation, as illustrated by deficits of facial emotion processing in patients with amygdala lesions 12. Interestingly, alcohol-dependent patients have been shown to exhibit lowered amygdalar responses when looking at emotional faces 13. This pattern of activation has also been found among young people with a high risk of alcoholism (i.e. from families with a history of alcohol dependence 14, 15). This supports the idea that non-verbal language processing difficulties might partly precede the development of an addiction. Consequently, we encourage future studies on alcohol dependence to examine the association between attachment styles and patterns of eye movements during facial emotion decoding. On a therapeutic level, addicted patients’ social cognition deficits could interfere significantly with psychotherapeutic interventions. Patients with addiction show a very high level of dropout from treatment, which might partly reflect attachment problems. The effectiveness of treatment relies heavily upon strong interpersonal skills, independently of theoretical psychotherapeutic background 16. It is therefore important that the therapist is aware of patients’ lowered ability to decode non-verbal emotional states and finds ways of interacting with them despite these difficulties. Indeed, high emotional tuning characterizes psychotherapies with higher symptom reduction 17, and might be difficult to achieve with some addicted patients. As well as psychotherapeutic interventions, cognitive remediation procedures could help to improve social cognition deficits in addiction, and should also be examined in future studies. For instance, training patients to look at the right cues when decoding emotional faces (i.e. the eyes and the mouth) has been shown to be effective in the treatment of impaired emotion decoding in child psychopathy 10 and in schizophrenia 18. Moreover, an emotion perception intervention combined with cognitive remediation has been shown to improve both emotion recognition and social functioning in chronic schizophrenia 19. In summary, we need further research to explore the relationship between social cognition deficits and abnormal attachment styles in addiction. Improving these deficits in adult addicted patients might still be possible through effective psychotherapeutic interventions and specific cognitive remediation procedures, aiming at a positive impact upon their social life and their substance use. None.

DIAGNOSIS AND MANAGEMENT OF ALCOHOL PROBLEMS