Jürgen Seifert

No association of CNR1 gene variations with susceptibility to schizophrenia.

Schizophrenia is one of the most common psychiatric disorders. There is a growing body of evidence associating dysregulation of the endogenous cannabinoid system with the pathogenesis of schizophrenia. In order to test the hypothesis that mutations in the central cannabinoid receptor-1 (CNR1) gene confer susceptibility to the development of schizophrenia, we performed an association study in a group of 104 German patients with schizophrenia and 140 healthy controls, using three polymorphisms within and flanking the coding exon of CNR1 (rs6454674, rs1049353, AL136096). In addition, we analyzed the whole coding region of the CNR1 gene of 50 of the patients by capillary sequencing to detect rare mutations. Our adequately powered study failed to reveal a statistically significant segregation of CNR1 polymorphisms to the diseased or control group. Furthermore, capillary sequencing of CNR1 in a subgroup of study subjects did not show any non-synonymous mutations predicting malfunction of CNR1 in patients with schizophrenia. In conclusion, we could not detect a statistically significant association between mutations in the CNR1 gene and the predisposition to develop schizophrenia. However, further studies are necessary to unravel the relationship between mutations in the CNR1 gene and the genetic susceptibility for the manifestation of certain subtypes or schizophrenia i.e. the predominance of negative or positive symptoms or as predictors of the clinical course.

The cannabinoid receptor gene (CNR1) is not affected in German i.v. drug users

The aim of the study was to investigate a possible contribution of the cannabinoid receptor gene (CNR1) to the development of i.v. drug addiction. Allele and genotype frequencies of a previously associated flanking triplet repeat polymorphism were compared between patients and controls, and the whole coding region of the CNR1 gene of all patients were screened for presence of mutations. The study took place at the Addiction Treatment Unit of the Medical School Hannover, and two outpatients departments in Hannover, Germany. Forty German unrelated opioid addicts (27 males and 13 females; mean age 37.9 years; range 16–53 years), took part, all of them satisfying ICD‐10 and DSM‐IV diagnostic criteria for opioid dependence and 81 age‐ and sex‐matched controls (German blood donors). Measurements used were lengths of alleles, genotyping and single strand conformation polymorphism (SSCP) analysis. Neither the ≥ 5 alleles of the extragenic triplet repeat (AAT) marker nor the alleles of an intragenic biallelic CNR1 polymorphism (1359G/A) were associated with i.v. drug use in our study group. In addition, we did not detect any sequence variation within the CNR1 gene which could confer susceptibility to i.v. drug abuse. In contrast to previous investigations, we found no evidence for an involvement of the CNR1 gene in i.v. drug addiction.

Short-term cognitive improvement in schizophrenics treated with typical and atypical neuroleptics.

Objective: Atypical neuroleptics seem to be more beneficial than typical ones with respect to long-term neuropsychological functioning. Thus, most studies focus on the long-term effects of neuroleptics. We were interested in whether atypical neuroleptic treatment is also superior to typical drugs over relatively short periods of time. Methods: We studied 20 schizophrenic patients [10 males, mean age 35.5 years, mean Brief Psychiatric Rating Scale (BPRS) score at entry 58.9] admitted to our hospital with acute psychotic exacerbation. Nine of them were treated with typical and 11 with atypical neuroleptics. In addition, 14 healthy drug-free subjects (6 males, mean age 31.2 years) were enrolled in the study and compared to the patients. As neuropsychological tools, a divided attention test, the Vienna reaction time test, the Benton visual retention test, digit span and a Multiple Choice Word Fluency Test (MWT-B) were used during the first week after admission, within the third week and before discharge (approximately 3 months). Results: Patients scored significantly worse than healthy controls on nearly all tests (except Vienna reaction time). Clinical ratings [BPRS and Positive and Negative Symptom Scale for Schizophrenia (PANSS)] improved markedly (p < 0.01), without a significant difference between typical and atypical medication. Clinical improvement (PANSS total score) correlated with less mistakes on the Benton test (r = 0.762, p = 0.017) and an improvement on the divided attention task (r = 0.705, p = 0.034). Neuropsychological functioning (explicit memory, p < 0.01; divided attention, p < 0.05) moderately improved for both groups under treatment but without a significant difference between atypical and typical antipsychotic drugs. Conclusions: Over short periods of time (3 months), neuropsychological disturbances in schizophrenia seem to be moderately responsive to both typical and atypical neuroleptics.

Mood and affect during detoxification of opiate addicts: a comparison of buprenorphine versus methadone

Twenty‐six in‐patients with Diagnostic and Statistical Manual version IV (DSM‐IV) criteria for opioid dependence were selected at random to receive either a combination of an 11‐day low‐dose buprenorphine and a 14‐day carbamazepine regimen (n = 14) or a combination of an 11‐day methadone and a 14‐day carbamazepine regimen (n = 12) in a double‐blind, randomized 14‐day in‐patient detoxification treatment. Patients with buprenorphine and carbamazepine showed a significantly better psychological state after the first and second weeks of treatment. Above all, the buprenorphine‐treated patients demonstrated a less marked tiredness, sensitiveness and depressive state as well as a more prominent elevated mood during the detoxification process. Seven non‐completers (after 7 days: four of 12 = 33.3%; after 14 days: seven of 12 = 58.3%) were treated with methadone and carbamazepine and five non‐completers (after 7 days: two of 14 = 14.3%; after 14 days: five of 14 = 35.7%) received buprenorphine and carbamazepine. The difference in the overall dropout rate after day 14 was not significant. The present study supports the hypothesis that the combination of buprenorphine and carbamazepine leads to a better clinical outcome than does a combination of methadone and carbamazepine in the detoxification of opioid addicts with additional multiple drug abuse. The buprenorphine and carbamazepine‐regimen provides a more effective short‐term relief of affective disturbances than does methadone and carbamazepine. No severe side effects occurred during the treatment period in both groups.

Treatment of alcohol withdrawal: chlormethiazole vs. carbamazepine and the effect on memory performance--a pilot study.

Although relatively little attention has been paid to the question how acute alcohol withdrawal might affect cognitive functions, this factor remains of particular interest because it influences psychotherapeutic treatment during detoxification. The clinical outcome and neuropsychological state of 37 inpatients with alcohol withdrawal was investigated in a randomized single‐blind approach. Two different medical strategies [chlormethiazole (CMZ) vs. carbamazepine (CBZ)] in the treatment of inpatients with alcohol withdrawal syndrome were compared. Among comparable groups (related to gender, age, initial alcohol level, severity of abuses, severity of initial withdrawal symptoms such as tremor, perspiration, psychomotor agitation, hallucinations, orientation, intelligence, patient demographics), CBZ is just as potent as CMZ in therapy of withdrawal symptoms (circulatory function, vegetative function, psychomotor activity). Patients in both groups showed initial impairments in some neuropsychological tests (d2, Zahlen‐Verbundings test, Beck Depression Inventory, Anxiety Sensitivity Index) with significant improvement during detoxification. Additionally, CBZ‐treated patients showed significantly better verbal memory performance during the first days of treatment. Without any addictive potential, CBZ therapy could be very supportive in alcohol detoxification. In addition a higher verbal memory performance state could be favourable for a psychotherapeutic approach.

Buprenorphine and carbamazepine as a treatment for detoxification of opiate addicts with multiple drug misuse: a pilot study

The growing tendency of opioid addicts to misuse multiple other drugs leads to the investigation of new pharmacostrategies to prevent patients from suffering life‐threatening complications and minimize the withdrawal symptoms. The short‐term efficacy of a 10‐day low‐dose buprenorphine/19‐day carbamazepine regime (n = 15) to a 14‐day oxazepam/19‐day carbamazepine regime (n = 12) in an open‐labelled 21‐day inpatient detoxification treatment was compared. Twenty‐seven men and women dependent on opioids and misusing other drugs admitted to a detoxification unit were included in this protocol. Eighteen of 27 patients (67%) completed the study. Four non‐completers (27%) received buprenorphine/carbamazepine (four of 15) and five non‐completers (42%) were treated with oxazepam/carbamzepine (five of 12), but the difference in the dropout rate between the two treatment strategies was not significant.The buprenorphine/carbamazepine regime provided significantly more effective relief of withdrawal symptoms during the first week of treatment. No severe side effects occurred during treatment in both groups. The present study supports the hypothesis that buprenorphine/carbamazepine is more effective than oxazepam/carbamazepine in rapid opioid detoxification in patients with additional multiple drug misuse and both regimens were safe with no unexpected side effects.

Effects of acute alcohol withdrawal on memory performance in alcohol-dependent patients: a pilot study.

Studies on the neuropsychological performance in detoxified alcoholic patients often begin by acknowledging that there is a cognitive impairment to be found. Only little attention has been paid to date to the question as to how acute alcohol withdrawal might affect cognitive functions. Twenty‐nine alcohol‐dependent inpatients, nine in moderate alcohol withdrawal, treated with carbamazepine (group 1), 10 in mild alcohol withdrawal without pharmacological treatment (group 2), 10 in mild alcohol withdrawal with carbamazepine treatment (group 3) and 31 healthy subjects as controls (group 4) underwent repeated investigations using memory tests. The tests were performed on the first, third, seventh and fourteenth days of withdrawal. Immediate free recall of a word‐list was impaired in the three patient groups in comparison with the control group on the 1st day. Thereafter no significant differences could be revealed between patients and controls. In a word‐list recognition test the memory functions were not impaired in group 1 and group 2 in comparison with the control subjects. However, patients in group 3 showed impairment in this recognition test in comparison with the healthy subjects on the first and third days. The present study suggests that acute alcohol withdrawal impairs memory functions, especially free recall. This should be considered in treatment interventions in the early days of withdrawal.

Detoxifikation polytoxikomaner Patienten mit Buprenorphin Auswirkungen auf Affektivität, Angst und Entzugssymptomaik

ZusammenfassungDie vorliegende prospektive offene kontrollierte Studie vergleicht die Effizienz einer 10-tägigen Buprenorphin-/19-tägigen Carbamazepin-Entgiftungsmedikation (BPN/CBZ) in der Prüfgruppe versus einer 14-tägigen Oxazepam-/19-tägigen Carbamazepin-Entgiftungsmedikation (OXA/CBZ) in der Kontrollgruppe bei 27 opioidabhängig-polytoxikomanen Patienten hinsichtlich der Behandlung akuter Entzugssymptome. Prüfgrößen waren die somatischen und psychischen Entzugssymptome, die mit den Skalen ASI, HAMD, SCL-90-R und SOWS erfasst wurden, sowie die Abbruchquote.Von den 15 Patienten der BPN/CBZ-Gruppe und 12 Patienten der OXA/CBZ-Gruppe, schlossen 18 (67%) die Studie am 21. Tag ab. Von den 9 Studienabbrechern bekamen 4 (27%) Buprenorphin/Carbamazepin und 5 (42%) Oxazepam/Carbamazepin. Der SOWS-Gesamt-Score zeigte einen signifikanten Gruppenunterschied über den Testzeitraum zugunsten der BPN/CBZ-Gruppe. Der HAMD-Score unterschied sich am Aufnahmetag nicht (BPN/CBZ 11,6; OXA/CBZ 11,0), am 14. Tag jedoch hochsignifikant (BPN/CBZ 3,0; OXA/CBZ 6,1). Bei 3 von 9 Faktoren des SCL-90-R zeigte sich ein Trend zugunsten des BPN/CBZ. Die ASI-Testung ergab für BPN/CBZ am 7. und 14. Behandlungstag einen hochsignifikant bzw. signifikant geringeren Score im Vergleich zu OXA/CBZ. In beiden Gruppen traten keine ernsten Nebenwirkungen auf.Das Behandlungsschema mit BPN/CBZ zeigt gegenüber dem Behandlungsschema OXA/CBZ eine signifikant bessere Wirkung auf Angst, Depressivität und Entzugssymptome während der Opioidentgiftung sowie einen Trend zu einer geringeren Abbruchquote. Die Eignung von Buprenoprphin zur Detoxifikation wird anhand seiner pharmakologischen Eigenschaften (κ-Antagonismus, partieller μ-Agonismus) diskutiert.AbstractWe used an open-labeled, 21-day inpatient detoxification treatment to compare the short-term effects of a 10-day buprenorphine plus 19-day carbamazepine regimen (n=15) to a 14-day oxazepam plus 19-day carbamazepine regimen (n=12) during rapid detoxification from opioids and other abused drugs. Somatic and psychopathological changes were assessed using the following rating scales: ASI, HAMD, SCL-90-R, and SOWS. Eighteen of 27 patients (67%) completed the study. Four dropouts (27%) were treated with buprenorphine/carbamazepine (BPN/CBZ) and the other five dropouts (42%) were treated with oxazepam/carbamazepine (OXA/CBZ). Repeated measures analysis of variance showed that SOWS scores were significantly less pronounced with BPN-CBZ than with OXA/CBZ. On the first day of admission, no significant difference in HAMD scores was detected (BPN/CBZ 11.6, BPN/CBZ 1.0). On day 14, HAMD was significantly less pronounced in BPN/CBZ (3.0) than in OXA/CBZ (6.1). BPN/CBZ showed a significant improvement in the ASI score on days 7 and 14 compared with OXA/CBZ. Three of nine items of the SCL-90-R showed a trend toward less pronounced outcome in BPN-CBZ. No severe side effects occurred during treatment in either group. The buprenorphine/carbamazepine regimen provided significantly more effective relief from affect disturbances and withdrawal syndromes than the oxazepam/carbamazepine regimen. The pharmacological basis of these effects of buprenorphine (κ-antagonism activity, μ-agonism activity) are discussed.