App-based maintenance treatment for alcohol use disorder after acute inpatient treatment: Study protocol for a multicentre randomized controlled trial.

BACKGROUND: Alcohol use disorder, a prevalent and disabling mental health problem, is often characterized by a chronic disease course. While effective inpatient and aftercare treatment options exist, the transferal of treatment success into everyday life is challenging and many patients remain without further assistance. App-based interventions with human guidance have great potential to support individuals after inpatient treatment, yet evidence on their efficacy remains scarce. OBJECTIVES: To develop an app-based intervention with human guidance and evaluate its usability, efficacy, and cost-effectiveness. METHODS: Individuals with alcohol use disorder (DSM-5), aged 18 or higher, without history of schizophrenia, undergoing inpatient alcohol use disorder treatment (N = 356) were recruited in eight medical centres in Bavaria, Germany, between December 2019 and August 2021. Participants were randomized in a 1:1 ratio to either receive access to treatment as usual plus an app-based intervention with human guidance (intervention group) or access to treatment as usual plus app-based intervention after the active study phase (waitlist control/TAU group). Telephone-based assessments are conducted by diagnostic interviewers three and six weeks as well as three and six months after randomization. The primary outcome is the relapse risk during the six months after randomization assessed via the Timeline Follow-Back Interview. Secondary outcomes include intervention usage, uptake of aftercare treatments, AUD-related psychopathology, general psychopathology, and quality of life. DISCUSSION: This study will provide further insights into the use of app-based interventions with human guidance as maintenance treatment in individuals with AUD. If shown to be efficacious, the intervention may improve AUD treatment by assisting individuals in maintaining inpatient treatment success after returning into their home setting. Due to the ubiquitous use of smartphones, the intervention has the potential to become part of routine AUD care in Germany and countries with similar healthcare systems.

Lower Emotion Regulation Competencies Mediate the Association between Impulsivity and Craving during Alcohol Withdrawal Treatment.

There is evidence that craving mediates the relationship between Impulsive Personality Traits (IPTs) and relapse during the treatment of an Alcohol Use Disorder (AUD). To provide tailored interventions, a deeper understanding of the relation between IPTs and craving, namely mediating processes, is important. Based on previous literature, we proposed that lower emotion regulation competencies mediate the relation between attentional as well as non-planning IPTs and craving. To investigate these interrelations, we used data from the baseline assessment (n = 320) of the SmartAssistEntz project (pre-registered in the German Clinical Trials Register [DRKS00017700]). Inpatients with a primary AUD diagnosis were interviewed using standardized self-report measures (IPTs: BIS-15, emotion regulation competencies: ERSQ, craving: OCDS-G short version) during their withdrawal treatment. Indirect effects were calculated using the SPSS macro PROCESS v3.5. Attentional as well as non-planning, but not motor, IPTs were associated with craving. Emotion regulation competencies mediated the relationship between attentional as well as non-planning IPTs and craving. Given their mediating role in the present study, it is interesting to investigate if addressing emotion regulation competencies can mitigate the negative influences of attentional and non-planning IPTs. The direct effect of attentional IPTs implicates alternate mediating processes, which should also be investigated in future research.

Association of impulsivity with quality of life and well-being after alcohol withdrawal treatment.

OBJECTIVES: Impulsivity is related to a higher risk of relapse in alcohol use disorders. However, besides drinking behavior, other recovery outcomes like physical and mental health-related quality of life are at least as important. The present study aimed to fill a research gap regarding the association of different impulsivity facets with health-related quality of life and well-being in alcohol use disorder. METHODS: Individuals with a primary alcohol use disorder diagnosis (n = 167) were interviewed with standardized self-report measures at the progressed stage of their withdrawal treatment and 6 weeks thereafter. Multiple regression models were calculated to examine the association of impulsivity, craving, and drinking patterns with health-related quality of life and well-being 6 weeks after withdrawal treatment, as well as the predictive role of impulsivity assessed during withdrawal for these two outcomes. RESULTS: Craving was associated with health-related quality of life and well-being 6 weeks after withdrawal. Likewise, non-planning and attentional impulsivity were associated with well-being 6 weeks after withdrawal. Motor impulsivity during withdrawal treatment predicted health-related quality of life 6 weeks thereafter. CONCLUSION: Impulsivity seems to be negatively related to health-related quality of life and well-being in the first weeks after alcohol withdrawal treatment, probably to a higher extent than drinking patterns, but differentiating between its facets seems to be important. These findings emphasize the importance of treatment approaches aiming at reduced impulsivity in the early recovery process.

Effects of Psychoactive Massage in Outpatients with Depressive Disorders: A Randomized Controlled Mixed-Methods Study.

The clinical picture of depressive disorders is characterized by a plethora of somatic symptoms, psychomotor retardation, and, particularly, anhedonia. The number of patients with residual symptoms or treatment resistance is high. Touch is the basic communication among humans and animals. Its application professionally in the form of, e.g., psychoactive massage therapy, has been shown in the past to reduce the somatic and mental symptoms of depression and anxiety. Here, we investigated the effects of a specially developed affect-regulating massage therapy (ARMT) vs. individual treatment with a standardized relaxation procedure, progressive muscle relaxation (PMR), in 57 outpatients with depression. Patients were given one ARMT or PMR session weekly over 4 weeks. Changes in somatic and cognitive symptoms were assessed by standard psychiatric instruments (Hamilton Depression Scale (HAMD) and the Bech-Rafaelsen-Melancholia-Scale (BRMS)) as well as a visual analogue scale. Furthermore, oral statements from all participants were obtained in semi-structured interviews. The findings show clear and statistically significant superiority of ARMT over PMR. The results might be interpreted within various models. The concept of interoception, as well as the principles of body psychotherapy and phenomenological aspects, offers cues for understanding the mechanisms involved. Within a neurobiological context, the significance of C-tactile afferents activated by special touch techniques and humoral changes such as increased oxytocin levels open additional ways of interpreting our findings.

The "DGPPN-Cohort": A national collaboration initiative by the German Association for Psychiatry and Psychotherapy (DGPPN) for establishing a large-scale cohort of psychiatric patients.

The German Association for Psychiatry and Psychotherapy (DGPPN) has committed itself to establish a prospective national cohort of patients with major psychiatric disorders, the so-called DGPPN-Cohort. This project will enable the scientific exploitation of high-quality data and biomaterial from psychiatric patients for research. It will be set up using harmonised data sets and procedures for sample generation and guided by transparent rules for data access and data sharing regarding the central research database. While the main focus lies on biological research, it will be open to all kinds of scientific investigations, including epidemiological, clinical or health-service research.

Atrial natriuretic peptide, arginine vasopressin peptide and cortisol serum levels in opiate-dependent patients.

Preclinical studies suggest that chronic drug abuse profoundly alters stress-responsive systems. The best studied of the stress-responsive systems in humans is the hypothalamic-pituitary-adrenal (HPA) axis. Apart from cortisol, arginine vasopressin peptide (AVP), and atrial natriuretic peptide (ANP) are known to directly impact upon the HPA axis in addictive behavior. We investigated alterations in ANP, AVP and cortisol serum levels in opiate-dependent patients who received diacetylmorphine treatment within a structured opiate maintenance program. ANP serum levels were significantly increased in opiate-dependent patients as compared to healthy controls, whereas AVP and cortisol serum levels were reduced. The ANP, AVP and cortisol serum levels were not significantly associated with the psychometric dimensions of heroin craving. In conclusion, chronic drug abuse profoundly alters stress-responsive systems like the HPA axis. Alterations of AVP, ANP and cortisol appear to constitute an important component in the neurobiology of opiate-dependent patients.

Methylation matters? Decreased methylation status of genomic DNA in the blood of schizophrenic twins.

Studies of schizophrenia inheritance in identical twins show a concordance of about 50%, which supports an epigenetic model. In our present study we investigated methylation of genomic DNA and promoter methylation of Reelin and SOX10 genes in peripheral blood of twins suffering from schizophrenia. Global DNA methylation was reduced (52.3%) in schizophrenic twins if compared with healthy control twins (65.7%). The reduced methylation was significant in males only. We also found a similar hypomethylation in the non-affected twins of discordant pairs and a mixed group of psychiatric controls. In discordant twins there was a relative hypermethylation of the SOX10 promoter. Within-pair-difference of methylation of Reelin promoter was significantly lower in monozygotic twins than in dizygotic twins.

Association of nerve growth factor and vascular endothelial growth factor A with psychometric measurements of opiate dependence: results of a pilot study in patients participating in a structured diamorphine maintenance program.

Preclinical study results suggest that neurotrophic peptides like nerve growth factor (NGF) and vascular endothelial growth factor A (VEGF-A) may be associated with symptoms of addictive behavior like withdrawal symptoms and rewarding effects. We investigated alterations in NGF and VEGF-A serum levels in opiate-dependent patients (25 male patients), who received diamorphine (DAM, heroin) treatment within a structured opiate maintenance program, and compared the results with the NGF and VEGF-A serum levels of healthy controls (23 male controls). NGF and VEGF-A serum levels were assessed before and after DAM administration twice a day (in the morning (16 h after last application--t1) and in the afternoon (7 h after last application--t3)) in order to detect a possible immediate or summative (in the afternoon) heroin effect on these two neuropeptides. Moreover, we investigated possible associations between the serum levels of these neurotrophic growth factors and psychometric dimensions of addictive behavior, e.g. craving, withdrawal, depression. Whereas there was no direct effect of DAM application on the serum levels of both neurotrophic growth factors neither in the morning nor in the afternoon, the NGF serum levels of the patient group were found to be significantly increased at all four time points of investigation compared with the healthy controls. In contrast, VEGF-A serum levels did not differ significantly in the patient and control groups. We found a significant positive association between the NGF serum levels and several items of the short opiate withdrawal scale as well as a negative association between self-reported mood (measured by visual analogue scale) and mood before heroin application (in the morning as in the afternoon). Moreover, we found a significant positive association between the NGF serum levels (t1 and t3) and the self-reported craving for methadone. In contrast, we found a negative association between the VEGF-A serum levels and avoidance, anxiety, suicide intentions of the SCL-90 as well as a positive association between the VEGF-A serum levels and the subscales of the heroin craving questionnaire measuring the rewarding effects of heroin. In conclusion, the results of this pilot study show that there might be an association between symptoms of opiate dependence and withdrawal and serum levels of VEGF-A and NGF.

Alpha-synuclein and heroin craving in opiate-dependent patients on injectable heroin maintenance.

Research suggests that alpha-synuclein (SNCA) and NACP-Rep1, a polymorphic complex microsatellite repeat ~10 kb upstream of the SNCA gene translational start, may be involved in substance-use behaviors and craving. This study was the first to examine the effects of diacetylmorphine (DAM) on peripheral SNCA protein expression along with craving in opiate-dependent patients and to compare their NACP-Rep1 allele lengths with those of healthy controls. Using an experimental design, opiate-dependent patients on injectable heroin maintenance were investigated at four time points, twice pre- and post-injection of DAM. SNCA protein levels of 30 DAM-maintained patients were measured using enzyme-linked immunosorbent assay. Participant-rated effects were assessed in 42 patients by Tiffany's Heroin Craving Questionnaire (HCQ), Gossop's Short Opiate Withdrawal Scale and Visual Analogs. NACP-Rep1 alleles of 42 patients and 101 controls were analyzed. One-way repeated-measures ANOVAs provided significant overall effects for SNCA protein content (P = 0.028), craving (P < 0.001), withdrawal symptomatology (P < 0.001) and mood (P < 0.001), indicating that DAM injections may not only reduce craving but also SNCA protein expression. However, there was no association between protein expression and craving. Relative to controls, patients had significantly longer NACP-Rep1 alleles (P < 0.001). NACP-Rep1 allele lengths correlated positively with HCQ total scores averaged across all time points (r = 0.420; P = 0.006) as well as with post-DAM HCQ total scores in the morning (r = 0.488, P = 0.001) and afternoon (r = 0.423, P = 0.005). The findings provide evidence of a contributory role of SNCA and NACP-Rep1 for opiate dependence.

Serum levels of BDNF are associated with craving in opiate-dependent patients.

Preclinical study results suggest that brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) are involved in the modulation of addictive behaviour. We investigated alterations in serum levels of BDNF and GDNF in opiate-dependent patients (28 males) who received diacetylmorphine treatment within a structured opiate maintenance programme. BDNF (T = 2.735, p = 0.009) serum levels were significantly increased in the opiate-dependent patients as compared with healthy controls (21 males), whereas GDNF serum levels (T = 1.425, p = 0.162) did not differ significantly from GDNF serum levels of the healthy controls. BDNF serum levels were significantly associated with craving for heroin (measured by the Heroin Craving Questionnaire (r = 0.420, p = 0.029) and by the General Craving Scale (r = 0.457, p = 0.016), whereas GDNF serum levels were not associated with psychometric dimensions of heroin craving. In conclusion, our results show a positive association between BDNF serum levels and opiate craving in opiate-dependent patients.

Differences and similarities on neuronal activities of people being happily and unhappily in love: a functional magnetic resonance imaging study.

BACKGROUND: Brain activity was studied in grief following frustrated love compared to romantic love, and it was hypothesized that unhappy lovers compared to happy lovers would have decreased brain activity in regions specific to emotional and reward circuits, such as frontal brain areas, anterior cingulate cortex (ACC), bilateral insula or posterior cingulate cortex (PCC). METHODS: Twelve volunteers intensely in love and 12 volunteers recently separated from their romantic partners were scanned performing 3 runs of functional magnetic resonance imaging acquisition. Subjects viewed partner pictures versus erotic pictures during the first run of the scanning process, autobiographical pictures versus neutral pictures during the second and autobiographical texts versus neutral texts during the third run. The Passionate Love Scale (PLS) and the Beck Depression Inventory (BDI) were additionally recorded. RESULTS: Decreased brain activity in unhappy lovers compared to happy lovers occurred in frontal areas, ACC and PCC and bilateral insula. Unhappy lovers also revealed clinical depressive symptoms in the BDI. CONCLUSION: Unhappy lovers compared to happy lovers exhibited clinical depressive symptoms and reduced blood oxygen level dependency changes in a brain network which has been described as being involved in major depression. This might be a cue for the close relationship between grief and depression.

Distinct intracellular vesicle transport mechanisms are selectively modified by spastin and spastin mutations.

Spastin is a microtubule severing ATPase that regulates intracellular and axonal transport of vesicles. Intracellular vesicle trafficking was analyzed in differentiated SH-SY5Y-neuroblastoma cells, transfected with spastin wild-type and three spastin mutations (ΔN, K388R, S44L) to investigate spastin-mediated effects on the velocity of vesicles, stained with LysoTracker Red®. The vesicle velocity varied considerably between mutations and detailed analysis revealed up to five distinct velocity classes. Microtubule severing by overexpressed wild-type spastin caused reduced vesicle velocity. S44L and ΔN mutations, which were functionally impaired, showed similar velocities as control cells. K388R-transfected cells exhibited an intermediate velocity profile. The results support the idea that spastin mutations not only alter axonal transport, but in addition regulate intracellular trafficking in the cell soma as well.

Antidepressant drugs modulate growth factors in cultured cells.

BACKGROUND: Different classes of antidepressant drugs are used as a treatment for depression by activating the catecholinergic system. In addition, depression has been associated with decrease of growth factors, which causes insufficient axonal sprouting and reduced neuronal damage repair. In this study, antidepressant treatments are analyzed in a cell culture system, to study the modulation of growth factors. RESULTS: We quantified the transcription of several growth factors in three cell lines after application of antidepressant drugs by real time polymerase chain reaction. Antidepressant drugs counteracted against phorbolester-induced deregulation of growth factors in PMA-differentiated neuronal SY5Y cells. We also found indications in a pilot experiment that magnetic stimulation could possibly modify BDNF in the cell culture system. CONCLUSION: The antidepressant effects antidepressant drugs might be explained by selective modulation of growth factors, which subsequently affects neuronal plasticity.

Association of the long allele of the 5-HTTLPR polymorphism with compulsive craving in alcohol dependence.

AIMS: Various studies have reported a role of the serotonin transporter-linked polymorphic region (5-HTTLPR) in alcoholism. METHOD: The present study investigated an association of this polymorphism with obsessive-compulsive alcohol craving in 124 male patients admitted for alcohol detoxification treatment. RESULTS: We found significantly higher compulsive craving in patients with the long allele of the 5-HTTLPR polymorphism [at admission: analysis of variance (ANOVA): F = 3.48, P = 0.034, general linear model: F = 3.92, P = 0.023; after 7 days: ANOVA: F = 3.12, P = 0.049]. CONCLUSIONS: Our results suggest that the long variant of the 5-HTTLPR polymorphism is associated with higher compulsive alcohol craving at the beginning of alcohol withdrawal.

Daily variations of homocysteine concentration may influence methylation of DNA in normal healthy individuals.

The regulation of genetic expression is tightly controlled and well balanced in the organism by different epigenetic mechanisms such as DNA methylation and histone modifications. DNA methylation occurring after embryogenesis is seen mainly as an irreversible event. Even small changes in genomic DNA methylation might be of biological relevance, and several factors influencing DNA methylation have been identified so far, one being homocysteine. In this study, genomic DNA methylation was analyzed and homocysteine plasma levels were measured over a 24 h period in 30 healthy students (15 males and 15 females) exposed to a standard 24 h regime of daytime activity alternating with nighttime sleep. Plasma homocysteine concentrations were measured using HPLC detection. DNA was extracted from whole EDTA blood, and genomic DNA methylation was assessed by fluorescently labeled cytosine extension assay. Both homocysteine and DNA methylation showed 24 h variation. Homocysteine showed a significant daily rhythm with an evening peak and nocturnal nadir in all subjects (p<0.001). Males showed higher overall homocysteine levels compared to females (p=0.002). Genomic DNA methylation showed a significant rhythm with increased levels at night (p=0.021), which was inverse to plasma homocysteine levels.

Homocysteine regulates expression of Herp by DNA methylation involving the AARE and CREB binding sites.

Herp (homocysteine-induced endoplasmic reticulum protein) is an ER-resident membrane protein, which has a ubiquitin-like domain at its N-terminus. Expression of Herp protein is up-regulated in response to ER stress, including homocysteine. Herp stabilizes neuronal Ca(2+) homeostasis and is involved in improving the balance of the folding capacity and protein loading in the ER. In patients with alcoholism, we observed a significant decrease in Herp mRNA expression, and an increase of Herp promoter DNA methylation, which was associated with elevated homocysteine levels. Therefore, we studied the mechanism of Herp CpG islands regulation by luciferase assays and mRNA analysis in neuronal SH-SY5Y (human neuroblastoma cell line) and HEK 293T (human embryonic kidney 293T) cells. Acute homocysteine treatment caused transient demethylation of the Herp promoter and an increase in Herp mRNA level. Global DNA methylation was increased over the following 48 h period. We identified the transcription factor binding site AARE (amino acid response element) by mutational analysis involved in Herp induction in SH-SY5Y cells, and the more significant role of the CREB binding site (cyclic AMP response element-binding protein) compared to AARE in HEK 293T cells. Stimulation with SAM (S-adenosyl methionine) and homocysteine led to an increase in Herp promoter methylation, which correlated to an acute decrease in luciferase expression in SAM, but not in homocysteine stimulated cells. Complete methylation of the CpG islands resulted in suppressed gene expression.

Different allele-distribution of mthfr 677 C -> T and mthfr -393 C -> a in patients classified according to subtypes of Lesch's typology.

AIMS: The typology by Lesch distinguishes between four subtypes: type 1 (model of allergy), type 2 (model of anxiety or conflict), type 3 (alcohol as an antidepressant), and type 4 (alcohol as adaptation). Taking into account that alcohol dependence is associated with elevated homocysteine levels, this study was undertaken to investigate different MTHFR (methylenetetrahydrofolate reductase) genotypes related to homocysteine metabolism in patients with alcohol dependence who were classified according to Lesch's typology (LT). SUBJECTS AND METHODS: 134 non-abstinent chronic alcoholics (112 males, 22 females; mean age 44.2 (SD 8.9) years) were classified according to LT and divided into four groups: LT 1 (n = 26), LT 2 (n = 65), LT 3 (n = 58), and LT 4 (n = 18). Total plasma homocysteine levels and MTHFR genotypes -393, 677, and 1,793 were determined. RESULTS: We observed a significantly higher frequency of the thermolabile MTHFR 677 C-->T variant (TT) in patients classified as subtype LT4 when compared with subtypes LT2 and LT3 (P = 0.005). Furthermore, for the MTHFR -393 C --> A-polymorphism, significantly more AC/AA variants were found in subtype LT4 (P = 0.034). No differences in allele-distribution were detected for MTHFR 1793. CONCLUSION: To our knowledge, this is the first study evaluating MTHFR genotypes in patients who were classified according to LT. Significantly different distributions of MTHFR 677 and -393 variants within Lesch Type 4 as compared with Types 2 and 3 hint at genetic determination of Lesch subtypes.

Epigenetic DNA hypermethylation of the HERP gene promoter induces down-regulation of its mRNA expression in patients with alcohol dependence.

BACKGROUND: Elevated plasma homocysteine concentrations can influence genomic and gene-specific DNA methylation in peripheral blood cells. The aim of this study was to investigate in patients with alcohol dependence, who show chronically elevated homocysteine levels, whether DNA methylation pattern within the HERP (homocysteine-induced endoplasmic reticulum protein) promoter region and expression of HERP mRNA is altered. METHODS: The HERP mRNA expression level was measured by quantitative PCR in the blood of 66 male alcoholic patients and 55 nondrinking healthy controls. Epigenetic genomic DNA methylation status and HERP promoter methylation were measured with a nonradioactive elongation assay. RESULTS: We observed a significant increase (7.6%) in the HERP promoter DNA methylation in patients with alcohol dependence (t test, t = -2.45, p < 0.02) when compared with healthy controls (80.4%, SD 14.5), which was significantly associated with their elevated homocysteine levels (multiple linear regression, p < 0.007). Furthermore, we found a significantly lower HERP mRNA expression in patients with alcohol dependence (t test, -7.61 DeltaCT; SD 1.87, p < 0.001) when compared with healthy controls (-6.04 DeltaCT; SD 2.41). The lowered HERP mRNA expression in alcoholic patients was best explained by the hypermethylation of the regulatory HERP gene promoter (regression analysis, p = 0.004). CONCLUSIONS: To our knowledge, this is the first study evaluating HERP mRNA expression and its specific gene promoter methylation in alcoholic patients. As hypermethylation of DNA is an important epigenetic factor in the down-regulation of gene expression, and as HERP has been considered to play an essential role within the intracellular defense system, these findings may be useful in the understanding and treatment of different disease conditions associated with alcohol dependence.

Light-induced exocytosis in cell development and differentiation.

Calcium-dependent exocytosis of fluorescently labeled single secretory vesicles in PC12 cells and primary embryonic telencephalon cells can be triggered by illumination with visible light and imaged by TIRF or epifluorescence microscopy. Opsin 3 was identified by quantitative PCR expression analysis as the putative light receptor molecule for light-induced exocytosis. In primary chicken telencephalon cells, light-induced exocytosis is restricted to a specific period during embryonic development, and involves fusion of rather large vesicles. Strictly calcium-dependent exocytosis starts after a delay of a few seconds of illumination and lasts for up to 2 min. We analyzed the frequency, time course and spatial distribution of exocytotic events. Exocytosis in PC12 cells and telencephalon cells occurs at the periphery or the interface between dividing cells, and the duration of single secretion events varies considerably. Our observation strongly supports the idea that light induced exocytosis is most likely a mechanism for building plasma membrane during differentiation, development and proliferation rather than for calcium-dependent neurotransmitter release.

Recurrent detoxifications are associated with craving in patients classified as type 1 according to Lesch's typology.

AIMS: Recurrent detoxifications have been suggested to be associated with elevated alcohol craving. The aim of this investigation was to study the influence of preceding detoxifications on craving in patients with alcoholism classified according to Lesch's typology. METHODS: We examined 192 patients (154 men, 38 women) after admission for detoxification treatment. Craving was assessed using the Obsessive Compulsive Drinking Scale, and patients were classified into one of the four subgroups of Lesch's typology. The number of preceding detoxifications was assessed with a structured interview. RESULTS: Lesch's typology type 4 patients showed significantly higher craving scores than type 1-3 patients (Mann-Whitney U-Test; P < 0.05). With respect to the influence of recurrent detoxifications, we found a significant correlation between the number of preceding detoxifications and the extent of craving for the whole population (Spearman's rho r = 0.241, P = 0.001, N = 192), particularly for patients of Lesch's type 1 (Spearman's rho r = 0.534, P = 0.001, N = 37). No significant association was found for patients of the other subgroups (Lesch's type 2-4). CONCLUSION: The influence of recurrent detoxifications on craving is especially important in patients with Lesch's type 1. Our results underline the importance of the kindling effect particularly in this group of patients, possibly mediated by an increase of glutamatergic neurotransmission. Furthermore, our results emphasize the need to classify patients with alcohol-dependency in addiction research.