[A Reversible Case of Korsakoff Syndrome in an Alcohol Dependent Patient]. / Der interessante klinische Fall ­ reversibles amnestisches Syndrom bei einem Patienten mit Alkoholabhängigkeit.

Alcohol dependent patients represent a high-risk group for vitamin deficiency, which could lead to variable cognitive dysfunctions and, as an extreme example, to an amnestic-confabulatory syndrome. In this case report, we report about an alcohol dependent 58-year-old patient without focal neurological symptoms with an amnestic-confabulatory syndrome. After substitution of thiamine, vitamin B12 and folic acid, cognitive symptoms completely vanish within a 22-month period of observation.

5-HT3 receptor influences the washing phenotype and visual organization in obsessive-compulsive disorder supporting 5-HT3 receptor antagonists as novel treatment option.

A role of the HTR3A-E genes in obsessive-compulsive disorder (OCD) can be expected based on promising effects of 5-HT3 receptor antagonists as adjunctive treatment of OCD. We therefore genotyped six common coding or promoter variants within the HTR3A-E genes in a case-control-sample consisting of N=236 OCD patients and N=310 control subjects and in N=58 parent-child-trios. Given the heterogeneous OCD phenotype, we also investigated OCD symptom dimensions and cognitive endophenotypes in subsamples. OCD patients scoring high for the washing subtype were significantly more likely to carry the c.256G-allele of the HTR3E variant rs7627615 (p=0.0001) as compared to OCD patients low for this symptom dimension. Visual organization was impaired in OCD patients and unaffected relatives as compared to healthy control subjects and carriers of the HTR3E c.256G/c.256G-genotype performed significantly worse (p=0.007). The case-control analyses revealed a nominal significant association of the HTR3D variant rs1000592 (p.H52R) with OCD (p=0.029) which was also evident after combination of the case-control and the trio-results (p=0.024). In male subjects, the variant rs6766410 (p.N163K) located in the HTR3C was significantly associated with OCD (p=0.007). The association findings of the HTR3C and the HTR3E remained significant after correction for the number of variants investigated. These findings indicate a role of common variants of the HTR3A-E genes in OCD and OCD-related phenotypes and further support the use of 5-HT3 receptor antagonists as novel treatment options. The HTR3E gene is a novel candidate gene impacting on the individual expression of OC symptoms and OCD-related cognitive dysfunction.

The functional coding variant Asn107Ile of the neuropeptide S receptor gene (NPSR1) influences age at onset of obsessive-compulsive disorder.

Neuropeptide S (NPS) is a novel central acting neuropeptide that modulates several brain functions. NPS has shown strong anxiolytic-like effects and interactions with other central transmitter systems, including serotonin and glutamate. A coding variation (Asn107Ile) of the NPS receptor gene (NPSR1) was associated with panic disorder and schizophrenia. Based on these encouraging findings, the present study aimed at exploring a potential role of NPSR1 in obsessive­compulsive disorder (OCD). A sample of 232 OCD patients was successfully genotyped for the NPSR1 Asn107Ile variant (rs324981). Age at onset was taken into account to address the heterogeneity of the OCD phenotype. The NPSR1 genotype significantly affected age at onset of the OCD patients, with a mean age at onset approximately 4 yr earlier in homozygous carriers of the low-functioning Asn107 variant compared to patients with at least one Ile107 variant (p=0.032). Case­control analyses with 308 healthy control subjects reveal a highly significant association of the Asn107 variant with early onset OCD (odds ratio=2.36, p=0.0004) while late onset OCD or the OCD group as a whole were unrelated to the NPSR1 genotype. Based on our association finding relating NPSR1 genotype to early onset OCD, we suggest a differential role of the NPS system in OCD. In particular, the early onset OCD subtype seems to be characterized by a genetically driven low NPS tone, which might affect other OCD-related transmitter systems, including the serotonin and glutamate systems. In agreement with preclinical research, we suggest that NPS may be a promising pharmacological candidate with anti-obsessional properties.

Sustained incentive value of heroin-related cues in short- and long-term abstinent heroin users.

Models of addiction and addiction memory propose that drug-associated cues elicit incentive effects in drug users, which play an important role in maintenance of drug use and relapse. Incentive effects have been demonstrated for smoking and alcohol-related cues but evidence for heroin-related cues has been inconclusive. Furthermore, it is unknown whether appetitive effects of heroin-related cues persist after prolonged abstinence, although heroin addiction is known to have high relapse rates. Therefore, we investigated implicit and explicit valence of heroin-related cues in dependent users at different stages of abstinence using affective startle modulation. In Study I, 15 current heroin users were measured before and after detoxification. Correspondingly, 15 healthy control participants were tested twice at an interval of 14 days. In Study II, 14 long-term abstinent heroin users were additionally measured in a single session. Implicit processing of drug-related stimuli was assessed using affective startle modulation by pictures of heroin and smoking scenes. Explicit reactions were measured using ratings of valence and craving. In contrast to controls, heroin-dependent participants showed a clear reduction of startle response during heroin-related pictures (p<0.05). Detoxification did not significantly change their startle responses to heroin-cues. No difference between non-detoxified current and long-term abstinent heroin users was found in implicit reactions to heroin-cues, whereas explicit measures differed between both groups (all p<0.05). After detoxification and even after prolonged abstinence, heroin cues still exert implicit appetitive effects in heroin users. This implies that drug-induced adaptations of reward circuits are long-lasting, resulting in a highly stable addiction memory.

A promoter variant of SHANK1 affects auditory working memory in schizophrenia patients and in subjects clinically at risk for psychosis.

Mutations in postsynaptic scaffolding genes contribute to autism, thus suggesting a role in pathological processes in neurodevelopment. Recently, two de novo mutations in SHANK3 were described in schizophrenia patients. In most cases, abnormal SHANK3 genotype was also accompanied by cognitive disruptions. The present study queries whether common SHANK variants may also contribute to neuropsychological dysfunctions in schizophrenia. We genotyped five common coding or promoter variants located in SHANK1, SHANK2 and SHANK3. A comprehensive test battery was used to assess neuropsychological functions in 199 schizophrenia patients and 206 healthy control subjects. In addition, an independent sample of 77 subjects at risk for psychosis was analyzed for replication of significant findings. We found the T allele of the SHANK1 promoter variant rs3810280 to lead to significantly impaired auditory working memory as assessed with digit span (12.5 ± 3.6 vs. 14.8 ± 4.1, P < .001) in schizophrenia cases, applying strict Bonferroni correction for multiple testing. This finding was replicated for forward digit span in the at-risk sample (7.1 ± 2.0 vs. 8.3 ± 2.0, P = .044). Previously, altered memory functions and reduced dendritic spines and postsynaptic density of excitatory synapses were reported in SHANK1 knock-out mice. Moreover, the atypical neuroleptic clozapine was found to increase SHANK1 density in rats. Our findings suggest a role of SHANK1 in working memory deficits in schizophrenia, which may arise from neurodevelopmental changes to prefrontal cortical areas.

The functional coding variant Asn107Ile of the neuropeptide S receptor gene (NPSR1) is associated with schizophrenia and modulates verbal memory and the acoustic startle response.

Recently, the neuropeptide S (NPS) neurotransmitter system has been identified as a promising psychopharmacological drug target given that NPS has shown anxiolytic-like and stress-reducing properties and memory-enhancing effects in rodent models. NPS binds to the G-protein-coupled receptor encoded by the neuropeptide S receptor gene (NPSR1). A functional variant within this gene leads to an amino-acid exchange (rs324981, Asn107Ile) resulting in a gain-of-function in the Ile107 variant which was recently associated with panic disorder in two independent studies. A potential psychopharmacological effect of NPS on schizophrenia psychopathology was demonstrated by showing that NPS can block NMDA antagonist-induced deficits in prepulse inhibition. We therefore explored a potential role of the NPSR1 Asn107Ile variation in schizophrenia. A case-control sample of 778 schizophrenia patients and 713 healthy control subjects was successfully genotyped for NPSR1 Asn107Ile. Verbal declarative memory and acoustic startle response were measured in subsamples of the schizophrenia patients. The case-control comparison revealed that the low-functioning NPSR1 Asn107 variant was significantly associated with schizophrenia (OR 1.19, p=0.017). Moreover, specifically decreased verbal memory consolidation was found in homozygous Asn107 carriers while memory acquisition was unaffected by NPSR1 genotype. The schizophrenia patients carrying the Ile107 variant demonstrated significantly reduced startle amplitudes but unaffected prepulse inhibition and habituation. The present study confirms findings from rodent models demonstrating an effect of NPS on memory consolidation and startle response in schizophrenia patients. Based on these findings, we consider NPS as a promising target for antipsychotic drug development.

The effects of combined acamprosate and integrative behaviour therapy in the outpatient treatment of alcohol dependence: a randomized controlled trial.

AIMS: The aim of this randomized, controlled, multisite trial was to evaluate the efficacy of combined treatment with integrative behaviour therapy (IBT) and acamprosate on drinking behaviour in detoxified alcohol-dependent patients. METHODS: A total of 371 patients were randomized to one of the three treatment conditions: IBT plus acamprosate, IBT plus placebo, or supportive counselling ('treatment as usual', TAU) plus acamprosate. The main outcome was success rate, i.e., rate of abstinence plus improvement according to the criteria of Feuerlein and Küfner (1989), at the end of the six-month treatment phase and at the subsequent six-month follow-up. Drinking status was validated by blood parameters (CDT, GGT, and MCV). Data were analyzed by an intent-to-treat model and missing data were classified as relapse. RESULTS: The success rates at the end of treatment under both TAU plus acamprosate (37.7%) and IBT plus placebo (48%) almost reached the levels derived from the literature. However, adding acamprosate to IBT did not result in the expected increase in success rate (IBT plus acamprosate: 47.6%), and success rates did not differ significantly between groups. Similarly, there was no significant difference between treatment success rates at follow-up. CONCLUSION: The results suggest that the combination of acamprosate and IBT is not more effective than treatment with either IBT or acamprosate alone. However, the two acamprosate conditions differed in success rate by about 10%, which might constitute a clinically relevant though statistically non-significant effect.

The opioid peptides enkephalin and beta-endorphin in alcohol dependence.

BACKGROUND: Experimental evidence indicates that the endogenous opioid system influences stress responses as well as reinforces effects of addictive drugs. Because stress is an important factor contributing to drug dependence and relapse, we have now studied ethanol preference in enkephalin- and beta-endorphin-deficient mice under baseline conditions and after stress exposure. METHODS: In the present study we used a two-bottle choice paradigm to study ethanol consumption and stress-induced ethanol preference. To examine alcohol withdrawal symptoms the forced drinking procedure was employed. We performed an association analysis in two case-control samples of alcohol addicts to determine whether these opioid peptides also contribute to ethanol dependence in humans. RESULTS: Ethanol consumption was significantly reduced in the absence of beta-endorphins, particularly in female knockout animals. Stress exposure results in an increased ethanol consumption in wild-type mice but did not influence ethanol-drinking in beta-endorphin knockouts. Enkephalin-deficient mice showed no difference from wild-type mice in baseline ethanol preference but also showed no stress-induced elevation of ethanol consumption. Interestingly, we found a two-marker haplotype in the POMC gene that was associated with alcohol dependence in females in both cohorts. CONCLUSIONS: Together these results indicate a contribution of beta-endorphin to ethanol consumption and dependence.

Association of DNA polymorphisms in the synaptic vesicular amine transporter gene (SLC18A2) with alcohol and nicotine dependence.

The brain synaptic vesicular amine transporter SLCA18A2 is a key component for the uptake of monoamines like dopamine or serotonin into vesicles. We have analyzed seven DNA polymorphisms located in the genomic region of SLC18A2 for association with alcohol- and nicotine dependence, using a family-based design. Our sample comprised 131 families with alcohol-dependent offspring and 96 families with at least one nicotine-dependent offspring. For the alcohol-dependent sample, we found statistical significant association for two single markers (rs363387, P=0.03; rs363333, P=0.0066) as well as for several haplotypes (minimal P=0.0038). When the sample with alcohol dependence was stratified according to gender, we observed increased association for the male subgroup (rs363387, P=0.0011). None of the markers showed association in the sample of families with nicotine dependence. However, analysis of a combined sample of alcohol and nicotine-dependent families resulted in single markers as well as several haplotypes showing statistical significant association with substance dependence (minimal P=0.0044). We conclude that DNA polymorphisms located in SLC18A2 might contribute to the development of substance dependence.