Zolpidem is a short-acting imidazopyridine hypnotic that is an agonist at the gamma-aminobutyric acid A type (GABAA) receptor. It has been suggested that it acts selectively on alpha1 subunit-containing GABAA benzodiazepine (BZ1) receptors presenting (contrary to classic benzodiazepines) low or no affinity for other subtypes. Therefore, it has been proposed that it lacks the benzodiazepines-like side-effects, having minimal abuse and dependence potential. Nevertheless, there is a considerable number of zolpidem dependence case reports in the literature. We present eight cases of zolpidem abuse and dependence without criminal record, without history of substance abuse (except for one alcohol abuser), with minor psychiatric disorders, who took zolpidem after physicians prescription in order to deal with their insomnia. However, they became zolpidem abusers not craving its sedative, but its anxiolytic and stimulating action, which helped them to cope with everyday activities. It is possible that, in the high doses that our patients used, zolpidem abandons its selectivity for BZ1 receptors and demonstrates all the actions of classic benzodiazepines. Molecular biology, via possible mutations on GABA receptors, may provide some answers as to why our eight patients (who did not differ much from the thousands of insomniacs who use zolpidem) and other zolpidem abusers, raised the dose progressively, and sought something from the drug other than hypnotic action.
We previously reported an association between the functional polymorphism in the upstream regulatory region of the serotonin transporter gene (SERTPR) and the prophylactic efficacy of lithium in a sample of 201 Italian subjects affected by Mood disorders. The aim of the present study was to replicate analyses on an independent sample. In total, 83 subjects affected by Bipolar disorder were recruited in the Mood Disorders Clinic of the Eginition Hospital of the Athens University, Medical School Department of Psychiatry. All patients were administered with lithium as prophylactic therapy and they were prospectively observed for at least 3 years. Subjects were typed for their SERTPR variant using polymerase chain reaction techniques. SERTPR variants were associated with lithium outcome among those subjects who had few manic episodes before lithium treatment and, as a trend, among subjects who received a high daily dose of lithium (X1200 mg/die). In both cases, subjects with the l/l variant showed a higher probability to develop an illness episode within 3 years of prophylactic treatment with lithium. The present study confirmed our previous observation of a better response of SERTPR*l/s carriers, but could not confirm a poor efficacy in subjects with the SERTPR*s/s genotype. Notwithstanding the conflicting results, SERTPR variants are a possible liability factor for lithium long-term efficacy in mood disorders. Further studies on independent and large samples are required to determine the reliability and direction of the possible association between SERTPR variants and lithium outcome. INTRODUCTIONLithium is an effective prophylactic agent in mood disorders but not all patients equally respond to lithium therapy. Clinical predictors account for less than half of the variance, 1-8 and there are evidences suggesting that genetic factors play a substantial role in lithium prophylaxis effectiveness. [9][10][11][12][13][14][15][16][17][18][19][20] A large number of studies reported an association between prophylactic lithium response and a family history of bipolar disorder, 10,[12][13][14]17 although not unequivocally confirmed. [21][22][23][24][25] Recently, Grof et al 26 reported that lithium response in a sample of relatives of responder probands was 67% compared to 30% in the comparison group.
Interleukin-1 (IL1) can contribute to pathophysiology of Alzheimer's disease (AD) by promoting deposition of amyloid-beta in the brain. The gene encoding IL1 alpha (IL1A) has a common polymorphism in its 5' regulatory region (rs1800587) with possible functional effects. IL1A T/T genotype has been associated with AD but the overall effect is modest and negative studies have been published. The aim of this study was to investigate the association of the IL1A rs1800587 polymorphism with AD in two independent case-control groups from Greece (Athens) and Italy (Faenza and Granarolo). Preliminary results from the ongoing sample (110 patients with sporadic AD and 130 nonpsychiatric controls) showed no association between IL1A variants and AD, however C/T heterozygotes had more severe depression in AD (Cornell Scale for Depression in Dementia) compared to other genotypes (F = 4.56, d.f = 1, p = 0.037) after controlling for age, illness duration and cognitive impairment (MMSE). Despite the small sample size and the possibility of a false negative finding, our preliminary data support the hypothesis the IL1A rs1800587 variants are not associated with AD. The effect of the IL1A on depressive symptomatology warrants further investigations, however the lack of a gene-dose relationship would suggest a false positive.
Alzheimer's disease (AD) has been associated with up-regulation of pro-inflammatory cytokines (e.g., specific gene variants for TNF-alpha; IL-6; IFN-gamma) and low plasma levels of cyanocobalamin (vitamin B12). Our goal was to relate B12 levels to AD symptoms and to expression of pro-inflammatory cytokines. Clinical manifestations were investigated for a case series of fifty-five outpatients using the MMSE, Neuropsychiatric Inventory (NPI) and Cornell Scale for Depression in Dementia (CDDS). Plasma B12 levels were measured by radioligand binding assay. Basal and PMA-stimulated levels of IFN-gamma, TNF-alpha, and IL-6 were measured by ELISPOT (PBMC culture supernatant). 47 patients were genotyped for APOE. Ten patients (18%) had their B12 levels below < 250 pg/ml. They did not statistically differ from those 45 who had normal levels in most demographic and clinical features; their MMSE scores were lower (14.7 vs 19.6 p=0.03) but not after adjustment for disease duration. A greater basal production of IL-6 was reported in patients who had low B12 levels compared to normal B12 subjects (1333 pg/ml vs 976 p< 0.01); this association was confirmed after controlling for age of onset and APOE genotype. In conclusion, low B12 level is associated with greater production of IL-6 in peripheral blood mononuclear cells. Further research is warranted to elucidate whether this neuroinflammatory effect of cobalamin is implicated in the pathophysiology of AD.
These preliminary findings suggest the involvement of inflammatory response in the pathogenic effect of the APOE epsilon-4 allele in AD, although their replication in larger samples is mandatory. The modest correlations between pro-inflammatory cytokines released at peripheral level and AD features emphasizes the need for further research to elucidate the role of neuroinflammation in pathophysiology of AD.
The objective of the present study was to determine whether a combined psychotherapeutic-psychopharmacological (with mirtazapine) treatment of collateral anxiety and depressive symptomatology during the post-withdrawal phase of alcoholism facilitates the process of alcohol detoxification, which is a decisive stage in the treatment of alcohol-dependent individuals. For that purpose, the rate of remission of anxiety and depressive symptoms over a 4-week detoxification period was evaluated between two groups: the first group followed a standard detoxification protocol (n = 33) and the second group was assigned to mirtazapine in addition to standard treatment (n= 35). A marked reduction of anxiety and depressive symptoms was demonstrated in both groups. However, patients on mirtazapine improved more and at a faster rate compared to controls. Thus, mirtazapine, used adjunctively to short-term psychotherapy, may help the detoxification process by minimizing physical and subjective discomfort. Consequently, it may improve patient compliance in alcohol detoxification programs and facilitate the initial phase treatment of alcohol abuse dependence.
There is evidence that GABAergic anticonvulsants can be efficacious in the treatment of alcohol dependence and in the prevention of alcohol relapse because these agents act on the substrate that is involved in alcoholism. Tiagabine, a selective GABA transporter1 reuptake inhibitor, may be a promising candidate for the treatment of alcohol-dependent individuals. In this randomized, open pilot study, we aimed to investigate the efficacy and tolerability of tiagabine as adjunctive treatment of alcohol-dependent individuals (N = 60) during the immediate post-detoxification period and during a 6-month follow-up period following alcohol withdrawal. A control non-medicated group of alcohol-dependent individuals (N = 60) was used for comparisons in terms of anxiety and depressive symptoms, craving and drinking outcome. Although a steady improvement in terms of psychopathology, craving and global functioning was observed in both groups throughout the study, subjects on tiagabine improved significantly more compared to the control subjects (P < 0.001). Furthermore, the relapse rate in the tiagabine group was lower than in the control group (7 vs 14.3%). Tiagabine was well tolerated and only a minority of the participants reported some adverse effects in the beginning of tiagabine treatment. Results from this study suggest that tiagabine is a safe and effective medication for the management of alcohol dependence when given adjunctively to a standard psychotherapy treatment. Further studies are warranted before definite conclusions can be reached.
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