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The exact role of the enzyme glycogen synthase kinase 3beta (GSK-3beta) in mood disorders is still unknown. GSK-3beta has been mapped to chromosome 3q13.3, a potential susceptibility locus for bipolar disorder. The -50T/C polymorphism, falling within the promoter region of the gene coding for GSK-3beta, was previously reported to be associated with age at onset, therapeutic response to lithium salts and total sleep deprivation in bipolar patients. In the present study we investigated the association between the -50T/C polymorphism and both symptomatic and personality features in mood disorders. The sample comprised 365 inpatients affected by major depressive disorder and bipolar disorder, genotyped for the GSK-3beta-50 polymorphism and assessed with the Operational Criteria Checklist for Psychotic Illness (OPCRIT). Ninety-five subjects were also evaluated with the Temperament and Character Inventory (TCI). The GSK-3beta-50 polymorphism showed a positive association with delusional symptomatology and with the personality features linked to Self-Transcendence. Finally, GSK-3beta-50 and personality showed an interactive effect on delusional scores. In conclusion, our findings support the role of GSK-3beta-50 in both normal and psychopathological aspects of human cognition and further suggest a possible interaction between genes and personality in the liability to psychotic disorders.

Transcranial magnetic stimulation (TMS) has been extensively studied as a treatment for Major Depression. However, no data are available about the role of genetic variables on the response to this treatment. We analysed the role of two polymorphisms that influence the response to antidepressants: the polymorphisms of the serotonin transporter promoter region (SERTPR) and of the 5-HT(1A) serotonergic receptor promoter region (-1019C/G). Ninety-nine patients from two double-blind, randomised, sham-controlled TMS trials were enrolled. There was a significant influence (p=0.016) of the SERTPR polymorphism on treatment outcome, without differences between active and sham stimulation. Conversely, there was a significant (p=0.014) interaction between 5-HT(1A) genotype and type of stimulation: C/C patients showed a higher difference between active and sham stimulation, indicating that these patients benefited more by TMS than C/G and G/G subjects. Our sample has not the power to control for the possible influence of different medications on these results.

The action of multiple liability genes is responsible for complex phenotypes at the same time, a single gene, could control several phenotypic features. This is the case of human period 3 gene (hper3), mainly involved in the setting of the biologic clock. Some variants of this gene, besides being associated with the Delayed Sleep Phase Syndrome, showed a key role in determining evening preference rather than morning one. According to this rationale, we hypothesized that this gene could influence circadian mood fluctuations, in mood disorders. Our study demonstrated that rare genetic variants of hper3 are significantly associated to a number of mood disorders features, such as age of onset, response to SSRIs treatment, circadian mood oscillations and characteristics of temperament. These preliminary results could shed further light on the involvement of circadian genes in various aspects of physiological and psychopathological mechanisms of the brain., (2007 Elsevier B.V and ECNP)

Background: Mucus plugging and hypersecretion have been associated with an increased relative risk of death in patients with bronchiectasis who may or may not have chronic obstructive pulmonary disease (COPD), which is of prognostic relevance in the elderly. However, chest physiotherapy and/or the use of mucoactive agents is considered to be an effective therapeutic model in treating patients with COPD and bronchiectasis., Objective: The objective of this study was to test the effectiveness of oral erdosteine in treating elderly patients with bronchiectasis and chronic mucus hypersecretion who have been referred to a pulmonary rehabilitation program., Methods: In this 15-day, prospective, parallel, open label, pilot study, elderly patients with bronchiectasis, hypersecretion, a noncurrent smoking status, who had been consecutively enrolled at Ospedale Villa Pineta's Pulmonary Rehabilitation Center, Pavullo-Modena, Italy, were randomized into 2 treatment groups. Group 1 consisted of those patients receiving PO erdosteine 225 mg BID and chest physiotherapy; group 2 comprised those patients receiving chest physiotherapy alone. Forced lung volumes, arterial blood gases, respiratory muscle strength, walking capacity (as measured by 6-minute walking test [6MWT]), and visual analog scale (VAS) symptoms (cough and dyspnea) were recorded at enrollment and at the conclusion of the study. Mucus density (MD), mucus purulence (MP), and mucus volume produced (MVP) were assessed using a 3-point scale (0 = best or low; 1 = moderate; and 2 = worst or high) at baseline and at 5-day time points during the study period. All measurements were assessed by personnel blinded and not directly associated with the study administration., Results: Thirty patients (21 [70%] male and 9 [30%] female; mean [SD] age, 71 [11] years; and mean [SD] weight, 66 [3] kg) were enrolled. Characteristics were similar in the 2 groups at baseline. At day 15, significant improvements were observed in 6MWT, VAS cough, and VAS dyspnea (P < 0.01) in both groups. However, a significant improvement in forced expiratory volume in 1 second and forced vital capacity (in milliliters) was observed only in group i (0.2 [0.3]; P < 0.05). At day 15, improvement was observed in mean (SD) in MD, MP, and MVP scores for both groups. Significant changes, however, were observed in all 3 measurements in group 1 (-0.80 [0.22], -0.71 [0.51], and 1.01 [0.39], respectively), whereas a significant improvement was observed only in MD (-0.55 [0.44]) and MVP (0.45 [0.62]) in group 2. The improvement in MVP observed in group 1 was significantly better than that observed in group 2 (P < 0.05)., Conclusion: This pilot study found that a regimen of PO erdosteine 225 mg BID in addition to routine chest physiotherapy provided some physiologic and clinical benefits in the treatment of these elderly patients with bronchiectasis and chronic mucus hyper-secretion.

Context: Total sleep deprivation combined with light therapy causes rapid amelioration of bipolar depression. A polymorphism in the promoter for the serotonin transporter influences both antidepressant response and the structure and function of specific brain areas., Objective: To determine whether antidepressant therapy or the genotype of the serotonin transporter influence the pattern of neural response to a task targeting the depressive biases in information processing (moral valence decision)., Design: Before-and-after trial studying the biologic correlates of response to treatment., Setting: University hospital. Patients Twenty inpatients with bipolar depression. Intervention Repeated total sleep deprivation combined with light therapy for 1 week., Main Outcome Measures: Brain blood oxygen level-dependent functional magnetic resonance imaging using a 3.0-T scanner before and after treatment. Self-ratings and observer ratings of mood (visual analog scale 3 times daily and Hamilton Depression Rating Scale) before and after treatment., Results: We found significant interactions of treatment (before and after), response to treatment (Hamilton Depression Rating Scale score <8), and moral valence of the stimuli (positive or negative) in the anterior cingulate cortex, dorsolateral prefrontal cortex, insula, and parietal cortex. In these areas, responders changed their blood oxygen level-dependent responses to emotional stimuli in a pattern opposite of that in nonresponders. Genotype of the promoter for the serotonin transporter predicted response to treatment and influenced baseline neural responses in the anterior cingulate cortex and the dorsolateral prefrontal cortex., Conclusion: Multiple factors that affect or are affected at the individual level by major depressive episodes in the course of bipolar disorder significantly interact in influencing brain cortical activity in specific areas.

The short variant of the serotonin transporter gene (SERTPR) has been consistently associated with a poorer response to treatment with various selective serotonin reuptake inhibitors (SSRIs). Antidepressant response is not a unitary phenomenon, however, and we here hypothesized that the SERTPR effect could be specific to some types of symptomatology. The sample comprised 281 inpatients affected by mood disorders and treated for major depression with SSRIs. The total depressive scores for all patients were analyzed in previous reports, but symptomatologic clusters were not examined previously. The 21-item Hamilton Rating Scale for Depression (HAM-D) was administered to evaluate depressive symptoms at baseline and weekly over 6 weeks of treatment. All patients were genotyped for the SERTPR polymorphism. Compared with patients with the SERTPR l/l and l/s polymorphisms, s/s patients showed a selective and slower improvement of depressive "core" and somatic anxiety symptoms, but they did not differ from other patients regarding other symptomatologic clusters such as insomnia and motor retardation. These findings support the view that response to SSRIs is not a unitary phenomenon and that improvement of symptomatologic clusters as, at least in part, genetically driven. SERTPR may be hypothesized as concurrently participating to the activity of anatomic brain regions differentially involved in depression and somatic symptoms of anxiety; however, further studies are required to examine these complex interactions.

Recently, an association between serotonin 1A receptor binding potential and self-transcendence scores at the temperament and character inventory (TCI) has been reported. We tested involvement of 5-HT(1A) gene in this trait, in a sample of 40 remitted mood disorder patients. Subjects with the 5-HT(1A)*C/C genotype showed significantly lower scores at the total self-transcendence and at the sub-scales of transpersonal identification and spiritual acceptance. Our preliminary results further support the involvement of the serotoninergic pattern in the self-transcendence character trait., ((c) 2005 Wiley-Liss, Inc.)

The molecular mechanisms driving the biological clock in the suprachiasmatic nucleus of the hypothalamus may play a role in mood disorders. A single nucleotide polymorphism (SNP) (-50 T/C) falling into the effective promoter region (nt -171 to +29) of the gene coding for glycogen synthase kinase 3-beta (GSK3-beta) has been linked with different age at onset of bipolar illness and with different antidepressant effects of total sleep deprivation. GSK3-beta codes for an enzyme which is a target for the action of lithium and possibly of valproic acid. We studied the effect of this polymorphism on the therapeutic response to lithium salts of 88 bipolar type I patients. Data about recurrence rate of mood episodes were collected for at least 2 years before lithium and 2 years on lithium. Results showed that homozygotes for the wild variant did not change their recurrence index while carriers of the mutant allele improved, thus supporting the hypothesis that GSK is a target for the therapeutic action of lithium. Results warrant interest for the variants of genes pertaining to the molecular clock as possible endophenotypes of bipolar disorder, but caution ought to be taken in interpreting these preliminary results and future replication studies must be awaited because of the low frequency of the GSK3-beta*C/C genotype in the studied populations.

The molecular mechanisms driving the biological clock in the suprachiasmatic nucleus of the hypothalamus may play a role in mood disorders. A single nucleotide polymorphism (SNP) (-50T/C) falling into the effective promoter region (nt -171 to +29) of the gene coding for glycogen synthase kinase 3-beta (GSK3-beta) has been linked with different age at onset of bipolar illness. GSK3-beta codes for an enzyme which is a target for the action of lithium and valproic acid, and the inhibition of which causes antidepressant-like behaviors in a preclinical model. We studied the effect of this polymorphism on the acute response to total sleep deprivation of 60 depressed bipolar type I inpatients. Homozygotes for the mutant allele of GSK3-beta promoter (-50T/C) SNP showed a later onset of bipolar illness, and better acute effects of TSD treatment on perceived mood (as rated on VAS). Overall, these observations suggest a protective role for this genotype in respect to bipolar illness. Results warrant interest for the variants of genes pertaining to the molecular clock as possible endophenotypes of bipolar disorder, and for GSK3-beta as a target of a new class of antidepressant drugs, but caution ought to be taken in interpreting these preliminary results and future replication studies must be awaited because of the low frequency of the GSK3-beta*C/C genotype in the studied populations.

Genetic studies in medicine exploited age of onset as a criterion to delineate subgroups of illness. Bipolar patients stratified with this criterion were shown to share clinical characteristics and patterns of inheritance of illness. The molecular mechanisms driving the biological clock in the suprachiasmatic nucleus of the hypothalamus may play a role in mood disorders. A single nucleotide polymorphism (SNP) (-50 T/C) falling into the effective promoter region (nt -171 to +29) of the gene coding for glycogen synthase kinase 3-beta (GSK3-beta) has been identified. GSK3-beta codes for an enzyme which is a target for the action of lithium and which is also known to regulate circadian rhythms in Drosophila. We studied the effect of this polymorphism on the age at onset of bipolar disorder type I. A homogeneous sample of 185 Italian patients affected by bipolar disorder was genotyped. Age at onset was retrospectively ascertained with best estimation procedures. No association was detected between GSK3-beta -50 T/C SNP and the presence of bipolar illness. Homozygotes for the wild variant (T/T) showed an earlier age at onset than carriers of the mutant allele (F=5.53, d.f.=2,182, P=0.0047). Results warrant interest for the variants of genes pertaining to the molecular clock as possible endophenotypes of bipolar disorder, but caution ought to be taken in interpreting these preliminary results and future replication studies must be awaited.

Recent studies showed that a polymorphism (T to C nucleotide substitution) in the 3' flanking region of the human CLOCK gene is associated with diurnal preferences of human healthy subjects, with higher "eveningness" in subjects carrying at least one copy of the C allele. We investigated the possible role of CLOCK gene polymorphism in the regulation of diurnal mood fluctuations during a major depressive episode. Sample (n = 101) was collected, in the context of previously reported trials, among patients affected by bipolar disorder type I, depressive episode without psychotic features, free of psychotropic medications. Perceived mood levels were assessed three times a day with self-administered visual analogue scales. Genotype groups showed no significant difference in diurnal mood fluctuations. When stratifying the sample by including only patients with an adequate period of observation (duration of illness higher than 5 years, n = 69), we post-hoc observed a significantly higher recurrence rate in homozygotes for the C variant, which was almost double than that of the other genotype groups. This preliminary observation leads to hypothesize a role for the CLOCK gene polymorphism in the regulation of long-term illness recurrence in bipolar disorder. Given the post-hoc nature of the finding, replication in independent samples is necessary to confirm it., (Copyright 2003 Wiley-Liss, Inc.)

Background: In order to evaluate the factors associated with change in exercise capacity after comprehensive inpatient Pulmonary Rehabilitation (IPR) we studied 132 consecutive adults with Chronic Obstructive Pulmonary Disease (COPD) recovering from an acute exacerbation., Material/methods: Lung function, arterial blood gases, and respiratory muscle strength were measured at baseline. Perceived breathlessness (B), 6-minute walk distance (6MWD), dyspnea at rest and post-exertion (D), hospital anxiety and depression (HAD), and health-related quality of life were assessed before (T0) and after (T1) IPR. The patients were divided into two groups depending on the change in 6MWD: Improvers (IM at least +54 meters after IPR, n=81) or Non-Improvers (NIM, less than 54 meters or no change, n=51)., Results: At T1 61% of the patients showed improvement as here defined. The IM group showed lower 6MWD and higher B and resting-D at T0 than NIM (p<0.05). A stepwise multiple regression analysis was performed using 6MWD change as the dependent variable. and anthropometric and physiological measures at T0 as the independent variables. This regression model explained 26% of the 6MWD-change; 6MWD and PaO2 significantly contributed to this model., Conclusions: In COPD patients recovering from an acute exacerbation, the predicted change in exercise capacity using anthropometric, demographic, clinical, and physiological variables after 2 weeks of comprehensive IPR is likely to be low. The baseline level of exercise performance and arterial oxygenation show the most consistent correlation with change in walking ability in these patients.