Selective DNA methylation of BDNF promoter in bipolar disorder: differences among patients with BDI and BDII.

The etiology of bipolar disorder (BD) is still poorly understood, involving genetic and epigenetic mechanisms as well as environmental contributions. This study aimed to investigate the degree of DNA methylation at the promoter region of the brain-derived neurotrophic factor (BDNF) gene, as one of the candidate genes associated with major psychoses, in peripheral blood mononuclear cells isolated from 94 patients with BD (BD I=49, BD II=45) and 52 healthy controls. A significant BDNF gene expression downregulation was observed in BD II 0.53±0.11%; P<0.05), but not in BD I (1.13±0.19%) patients compared with controls (CONT: 1±0.2%). Consistently, an hypermethylation of the BDNF promoter region was specifically found in BD II patients (CONT: 24.0±2.1%; BDI: 20.4±1.7%; BDII: 33.3±3.5%, P<0.05). Of note, higher levels of DNA methylation were observed in BD subjects on pharmacological treatment with mood stabilizers plus antidepressants (34.6±4.2%, predominantly BD II) compared with those exclusively on mood-stabilizing agents (21.7±1.8%; P<0.01, predominantly BD I). Moreover, among the different pharmacological therapies, lithium (20.1±3.8%, P<0.05) and valproate (23.6±2.9%, P<0.05) were associated with a significant reduction of DNA methylation compared with other drugs (35.6±4.6%). Present findings suggest selective changes in DNA methylation of BDNF promoter in subjects with BD type II and highlight the importance of epigenetic factors in mediating the onset and/or susceptibility to BD, providing new insight into the mechanisms of gene expression. Moreover, they shed light on possible mechanisms of action of mood-stabilizing compounds vs antidepressants in the treatment of BD, pointing out that BDNF regulation might be a key target for their effects.

The MCP-1 gene (SCYA2) and mood disorders: preliminary results of a case-control association study.

The aim of this case-control study was to investigate the potential role of the A-2518G polymorphism of the gene of monocyte chemoattractant protein 1 (MCP-1, a cytokine playing an important role in innate immunity) in conferring susceptibility to mood disorders. The sample studied included 96 outpatients with DSM-IV-TR diagnosis of major depressive disorder, bipolar disorder I (BD I) or BD II and 161 matched healthy controls. All subjects were genotyped for the A-2518G polymorphism of the MCP-1 gene. Genotypic and allelic associations were explored between patients and controls and across the different diagnostic groups (chi(2) tests). No genotypic (chi(2) = 8.215, d.f. = 6, p = 0.223) or allelic (chi(2) = 5.058, d.f. = 3, p = 0.168) association for the A-2518G polymorphism of SCYA2 was found considering cases and controls. Nevertheless, important correlations were observed when patients were divided into diagnostic subgroups. A significantly higher frequency of the AA genotype (chi(2) = 7.233, d.f. = 2, p = 0.027) and of the A allele (chi(2) = 4.730, d.f. = 1, p = 0.030) was observed in subjects with BD. In addition, independently from diagnosis, a higher number of lifetime suicide attempts was found in subjects with the AA genotype of the A-2518G polymorphism of the MCP-1 gene (F = 3.802, p = 0.026). The present preliminary results, though limited by the relatively small sample, suggest a possible role of the SCYA2 in conferring susceptibility to BD and, if confirmed, may represent a biological discriminative influence between mood disorder subtypes.

Cytokine polymorphisms in the pathophysiology of mood disorders.

INTRODUCTION: An increasing amount of data suggests that dysregulation of the immune system, including the cytokine network, is associated with the etiology and pathophysiology of mood disorders. Genes encoding cytokines are highly polymorphic and single nucleotide polymorphisms, associated with increased or reduced cytokine production, have been described. The aim of this study was to define the genetic immunologic scenario associated with major depressive disorder (MDD) and bipolar disorder. METHODS: Eighty-four Italian outpatients affected by bipolar disorder type I, bipolar disorder type II, or MDD, and 363 healthy controls were enrolled into the study. We analyzed allele and genotype distribution of -308 (G/A) tumor necrosis factor-a (TNF-a), +874 (T/A) interferon-g (IFN-g), -174 (G/C) interleukin (IL)-6, and -1082 (G/A) IL-10 promoter polymorphisms by Polymerase Chain Reaction Sequence Specific Primers technique. RESULTS: We observed different genotype and allele distributions of TNF-a, IFN-g, and IL-10 polymorphisms in the three groups of patients analyzed. In particular, bipolar II patients were characterized by an absence of adenine (A) high producer allele of TNF-a (P<.001) and a lower percentage of TT high producer genotype of IFN-g (P<.001); bipolar I individuals showed reduced percentage of AA low producer genotype of IL-10 (P<.001). Both bipolar I and bipolar II patients not carrying guanine (G) high producer IL-6 allele showed a lower mean age at onset (P=.048). CONCLUSION: These data support the existence of a genetic profile related to pro-inflammatory cytokines in patients affected by mood disorders. The differences observed across the three clinical phenotypes suggest the presence of different pathogenetic mechanisms involved in the susceptibility of phenotypically different mood disorders.

Clinical variables related to antidepressant-induced mania in bipolar disorder.

BACKGROUND: The development of mania or hypomania during antidepressant treatment is a serious complication of the clinical management of bipolar disorder (BP). The primary aim of this study was to evaluate the clinical variables related to antidepressant-induced mania or hypomania (AIM) in patients with BP. METHODS: DSM-IV BP-I or BP-II patients who had had at least one depressive episode treated with antidepressants were considered. Patients were subdivided into two groups according to the presence (n = 30) or absence (n = 106) of manic or hypomanic episodes occurring during antidepressant treatment. Possible predictive clinical variables of AIM were considered: gender, diagnostic subtype, age at onset, duration of illness, duration of untreated illness, type of antidepressant administered, number of previous spontaneous hypomanic or manic episodes, number of previous depressive episodes, presence of lifetime suicide attempts, presence of mood stabilizer treatments, presence of psychotic symptoms during spontaneous episodes, family history for psychiatric disorders in first degree relatives. Data were compared between the two groups, with (AIM+) and without (AIM-) antidepressant-induced mania, using Student's t tests and chi-square tests. RESULTS: The lack of mood stabilizer treatments during antidepressant therapy (chi-square = 37.602, df = 1, p < 0.001) and the exposure to tricyclic antidepressants (chi-square = 4.901, df = 1, p < 0.05) resulted significantly associated to the development of AIM. LIMITATIONS: This study was not done under controlled conditions and the relatively small sample studied warrants further replications. CONCLUSIONS: These results point out the risk of mania induction associated to the use of tricyclic antidepressants in BP patients, mainly in absence of adequate mood stabilizers.

The use of atypical antipsychotics beyond psychoses: efficacy of quetiapine in bipolar disorder.

BACKGROUND AND RATIONALE: Atypical antpsychotics have been sucessfully used in the treatment of bipolar disorder (BD), either as adjunctive or as monotherapy. Quetiapine is an atypical antipsychotic extensively used in the treatment of psychotic disorders. It has serotonergic and dopaminergic activity and it appears to be selective for the mesolimbic and mesocortical dopamine system. The aim of this paper was to review the recent literature on the use of quetiapine in the treatment of BD. METHODS: The literature databases currently available online were searched for papers on quetiapine and BD. Papers and reports published between January 1995 and June 2005 were selected and reviewed critically. RESULTS: Augmentative low dose quetiapine was found to be effective in BD partially responsive to conventional mood-stabilizers. Manic and mixed episodes have been the best studied, and quetiapine was found to be effective either as monotherapy or as adjunctive therapy in both randomized clinical trials and open-label studies. Data on the use of quetiapine in bipolar depression showed a significant efficacy and high remission rates. Maintenance data suggested a role of quetiapine as a good alternative to classical mood stabilizers in reducing recurrence rates of BD. A few studies on the efficacy in rapid cycling BD have also been published. CONCLUSIONS: Quetiapine is an effective agent for the short- and long-term treatment of BD. The mechanism of action of quetiapine as a mood stabilizer is still unknown. Some preliminary data suggest the involvement of glutamate pathways but further studies are needed to clarify this issue.

Some biological correlates of drug resistance in schizophrenia: a multidimensional approach.

Drug resistance in schizophrenic disorders treated with an antipsychotic medication is highly problematic, lacking sound criteria to define it, and to discriminate between drug response and clinical remission. This article reviews some neurochemical, psychoimmunological, pharmacogenetic and neuromorphological patterns which can affect drug response and determine drug-resistance phenomena in schizophrenia. Several neurochemical abnormalities have been reported to be relevant for the pathogenesis of schizophrenic disorders and have been related to clinical symptoms as well as to the quality of response to antipsychotics: most of the findings come from studies on DA and 5HT brain metabolism, but more recently other non-dopaminergic pathways have been implicated (e.g., glutamatergic ones). Literature data suggest that schizophrenia may be associated with significant alterations of T-cell functions, showing the activation of the inflammatory response system (IRS), particularly in treatment-resistant schizophrenia, and differential effects on IRS have been reported for conventional and atypical antipsychotics. Furthermore molecular genetic approaches provide a novel method of dissecting the heterogeneity of psychotropic drug response, providing the means of determining the molecular substrates of drug efficacy and drug-induced adverse events. On the other hand, functional neuroimaging techniques, including single photon emission computed tomography (SPECT), positron emission tomography (PET) and functional magnetic resonance imaging (FMRI), providing an in vivo assessment of the expression and function of neuroreceptors, transporters and enzymes, seem to be particularly promising for a better understanding of 'real' drug resistance. Finally, a multidimensional approach taking into account all these variables in the future would likely be the more valuable strategy to optimise response, reducing relapses or resistant clinical situations.