Christoph Klawe

The HTR1B 861G>C receptor polymorphism among patients suffering from alcoholism, major depression, anxiety disorders and narcolepsy

The HTR1B receptor gene has been linked to antisocial alcoholism in a Finnish population and an American Indian tribe [Lappalainen et al. , Arch. Gen. Psychiatry, 55 (1998) 989]. Using a candidate gene approach, we genotyped 209 patients with alcoholism, 108 patients with major depression, 32 patients with panic disorder, 50 patients with generalized anxiety disorder, 58 patients with narcolepsy and 74 healthy volunteers for the HTR1B 861G>C polymorphism. There was a higher frequency of the HTR1B 861G alleles among the alcohol-dependent patients as compared to the control subjects (chi(2)=4.02, d.f.=2, P=0.04). However, the association resulted from higher frequencies of the opposite alleles (HTR1B 861G), as originally reported by Lappalainen et al. (1998). Although the association in our study might be due to a type I error, the higher degree of HTR1B allele sharing within both populations could also argue for another alcoholism-relevant gene within the proximity of the HTR1B gene on human chromosome 6.

Serotonergic polymorphisms in patients suffering from alcoholism, anxiety disorders and narcolepsy

1. Alterations in the serotonergic neurotransmission have been frequently described for patients suffering from alcoholism, anxiety disorders and narcolepsy. 2. The authors tested for association of the 5-HT2A receptor polymorphism (T102C) and the intron 7 tryptophan hydroxylase (TPH) polymorphism (A218C) among 176 alcohol dependent patients, 35 patients with panic disorder, 50 patients with generalized anxiety disorder, 55 patients with narcolepsy and 87 healthy controls. 3. Allele and genotype frequencies of the 5-HT2A receptor polymorphism (T102C), the intron 7 TPH polymorphism (A218C) were almost similar between the patients suffering from alcohol dependence, panic disorder, generalized anxiety disorder and narcolepsy. 4. There was no association between the 5-HT2A receptor polymorphism (T102C), the intron 7 TPH (A218C) polymorphisms and alcohol dependence, panic disorder, generalized anxiety disorder and narcolepsy in our subsets of German patients.

Sex differences in allelic frequencies of the 5-HT2C Cys23Ser polymorphism in psychiatric patients and healthy volunteers: findings from an association study.

&NA; Polymorphisms in the serotonergic system are believed to play a role in the etiology and treatment of different psychiatric illnesses. The 5‐HT2C receptor gene is X‐linked, with a frequent mutation at nucleotide 68 leading to a Ser→Cys transition at amino acid 23. Recent studies have demonstrated an impaired function of 5‐HT2C receptors and an increased production of the major noradrenergic metabolite 3‐methoxy‐4‐hydroxyphenylethyleneglycol in the cerebrospinal fluid among the subjects carrying the Ser23 allele (Lappalainen et al., 1999). Biol. Psychiatry 46:821). We genotyped patientswith alcohol dependence, panic disorder without agoraphobia, generalized anxiety disorder, narcolepsy and normal healthy volunteers for the 5‐HT2C Cys23Ser polymorphism. 5‐HT2C Cys23Ser allele frequencies and genotypes did not differ among patients with alcohol dependence, panic disorder, generalized anxiety disorder, narcolepsy and normal healthy volunteers. In an overall analysis, female subjects (n = 173) displayed a higher frequency of 5‐HT2C Ser23 alleles as compared to males (n = 298, P = 0.0178). The potential mechanisms of the observed gender difference in allele frequencies, including transmission ratio distortion, are discussed.

Polymorphisms in the NMDA subunit 2B are not associated with alcohol dependence and alcohol withdrawal-induced seizures and delirium tremens

AbstractObjectiveEthanol–inhibited glutamatergic neurotransmission has been shown to mediate pathophysiological mechanisms in the development of alcoholism, including withdrawal symptoms. NMDA–receptor 2B (NR2B) is a subunit that confers a high sensitivity to ethanol–induced inhibition. Previously we had reported a lack of association between the single nucleotide polymorphism (SNP) rs1806201 in the NR2B gene (GRIN2B) and alcoholism. Shortly thereafter, an association between the polymorphism and early–onset alcoholism has been reported. One aim of the present study was to test whether the association between the GRIN2B polymorphism rs1806201 and early–onset alcoholism can be replicated in a larger sample. Moreover, we hypothesized that another genetic variation within GRIN2B (rs1806191) may have an effect in the etiology of alcoholism or withdrawal–related traits.MethodsWe extended our original study sample to a size of 377 patients and 464 healthy volunteers and performed a replication study, including the second GRIN2B SNP. Associations between allele, genotype and haplotype frequencies of the two polymorphisms and alcoholism as well as with patients’ phenotypes were investigated.ResultsNo associations were found between any of the two polymorphisms, tested individually or as haplotypes, and alcoholism, respectively withdrawal–related traits.ConclusionNeither the analyzed SNPs nor any of their haplotypes likely modify susceptibility to alcohol dependence or withdrawal–related phenotypes.

Symptom-triggered versus standard chlormethiazole treatment of inpatient alcohol withdrawal: clinical implications from a chart analysis.

To evaluate clinical effectiveness and safety of 2 different detoxification treatment protocols, a chart analysis of hospital inpatients consecutively admitted for alcohol withdrawal during one year was undertaken. Records of 33 patients receiving symptom-triggered treatment (using a modified version of the revised Clinical Institute Withdrawal Assessment for Alcohol Scale) were compared with those of patients treated by applying a fixed-dose regimen (n = 32). Patients (45.3 ± 9.8 years, 21% female) of both groups were comparable regarding illness severity, epidemiologic parameters as well as complications during the observed treatment period. Under symptom-triggered therapy, chlormethiazole (CMZ) treatment duration (4.2 ± 3.5 vs. 7.5 ± 3.3 days, Mann-Whitney U test: p = 0.0003) and cumulative CMZ dosage (4,352 ± 4,589 vs. 9,921 ± 6,599 mg, Mann-Whitney U test: p = 0.0004) were significantly reduced. The daily CMZ dose was significantly lower at days 1–5 in the group receiving symptom-triggered treatment. There was no influence of age on the outcome parameters of either treatment group. In conclusion, an individualized symptom-triggered treatment of alcohol withdrawal with CMZ seems to be equally safe but more efficient than a scheduled regimen.

Add-on combination and maintenance treatment: case series of five obese patients with different eating behavior.

Obesity is a general medical condition associated with an increase in morbidity and mortality. Although it would be desirable to use efficacious prevention programs, the success rates reported to date have been rather disappointing. In this observational study, a new drug treatment regimen was evaluated in five obese patients with a mean age of 39.6 ± 4.2 years and an initial body mass index between 34.5 and 38.3 kg/m2 for a period of 96 weeks. The patients showed restrained and unrestrained eating patterns according to a German version of the Three-Factor Eating Questionnaire and were treated in an add-on regimen with the combination of three drugs with different anorectic properties that were consecutively introduced in an interval of 16 weeks. First, orlistat (120 mg three times a day) was given as a monotherapy. Sibutramine (15 mg in the morning) and then topiramate (in a dose dependent on appetite suppression and side effects) were added for a total duration of 48 weeks. A 48-week maintenance and relapse prevention treatment period with topiramate monotherapy followed the discontinuation of orlistat and sibutramine. This outpatient treatment procedure was tolerated well, although side effects occurred in all patients depending on th phase of the treatment regimen. After 96 weeks, the mean body mass index was 25.7 ± 1.2 kg/m2. Moreover, a normalization of eating patterns according to the Three-Factor Eating Questionnaire could be noticed. Factor 3, hunger, was significantly reduced. This treatment plan may be highly effective and safe in a subpopulation of obese patients.

Furosemide Action on Cerebellar GABAA Receptors in Alcohol-Sensitive ANT Rats

Furosemide increases the basal tert-[35S]butylbicyclophosphorothionate ([35S]TBPS) binding and reverses the inhibition of the binding by gamma-aminobutyric acid (GABA) in the cerebellar GABA(A) receptors containing the alpha6 and beta2/beta3 subunits. These effects are less pronounced in the alcohol-sensitive (ANT) than in the alcohol-insensitive (AT) rat line. The difference between the rat lines in the increase of basal [35S]TBPS binding was removed after a longer preincubation with ethylendiaminetetraacetic acid (EDTA) containing buffer, but long preincubation did not reduce the GABA content of the incubation fluid or remove the difference in GABA antagonism by furosemide. The GABA sensitivity of the [35S]TBPS binding did not differ between the rat lines. There was no nucleotide sequence difference in the beta2 or beta3 subunits between the rat lines and similar beta2/3 subunit-dependent agonistic actions by methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM) in the rat lines were detected. The data suggest that there are still unknown structural alterations in the cerebellar GABA(A) receptors between the AT and ANT rat lines, possibly associated with differential alcohol sensitivity.

Speicherkrankheiten an Gelenken: Pathogenese und Histopathologie

Wenngleich lysosomale Speichererkrankungen mit Manifestation in Gelenken und im Bewegungsapparat zu den seltenen Erkrankungen gehören, sind diese aufgrund des geweblichen Schädigungsmusters in die Differenzialdiagnosen von wesentlich häufigeren Erkrankungen, beispielsweise aseptische Knochen-nekrosen, Osteoporose und rheumatoide Arthritis, einzubeziehen. Die Primärdiagnostik orientiert sich an Befunden der bildgebenden Verfahren und insbesondere in Abhängigkeit des Speichererkrankungstypus an der Bestimmung von Enzymaktivitäten in Leukozyten und im Plasma. Im Fall einer Gewebeentnahme bei klinisch unklaren Gelenk- und Knochenläsionen sollte jedoch nach den auffälligen morphologischen Veränderungen von Speichererkrankungen gesucht werden.