The combined polymorphisms of interleukin-6-174GG genotype and interleukin-10 ATA haplotype are associated with a poor quality of life in patients with chronic hepatitis C.

PURPOSE: Chronic hepatitis C (CHC) is associated with a decreased health-related quality of life (HRQOL). More recent studies have pointed toward a genetic basis of patient-reported quality of life outcomes. Taking into account that the influence of single-nucleotide polymorphisms (SNPs) on the HRQOL of CHC patients has not been studied, we investigated the combined IL10-1082G/A, - 819C/T, and - 592C/A SNPs, and IL6-174G/C SNP. We also evaluated the association between demographic, clinical, psychiatric, virological, and genetic variables with domains and summaries of HRQOL in CHC patients. METHODS: 132 consecutive CHC patients and 98 controls underwent psychiatric evaluation by using the Mini International Neuropsychiatric Interview. HRQOL was assessed by a generic questionnaire, the Medical Outcomes Study 36-Item Short Form Health Survey (SF-36), and by the specific Liver Disease Quality of Life Questionnaire (LDQOL). IL6 and IL10 polymorphisms were evaluated by Taqman SNP genotyping assay. Multivariate analysis was used to evaluate the associations. RESULTS: Major depressive disorder was associated with lower SF-36 and LDQOL scores in seven and ten domains, respectively. Diabetes and hypertension were also associated with reduced HRQOL. CHC patients carrying the combination of IL10 ATA haplotype/IL6-GG genotype had lower scores in the SF-36-physical functioning domain, and reduced scores in the LDQOL effects of liver disease on activities of daily living, quality of social interaction, and sexual function domains than the non-carriers of the combined haplotype/genotype. CONCLUSION: This is the first study to demonstrate that combined IL6 high-producer GG genotype and IL10 low-producer ATA haplotype is associated with poorer HRQOL in CHC patients.

Significant sleep disturbances in euthymic bipolar patients.

OBJECTIVE: A growing amount of data suggests that sleep dysfunction is frequently observed in bipolar disorder (BD) patients even when they do not fulfill the criteria for major mood episodes. Thus, we performed a case-control study assessing sleep status in a group of euthymic BD patients and a group of health controls. METHODS: A total of 209 subjects (104 health controls and 105 BD patients) were enrolled in the study. The Pittsburgh Sleep Quality Index (PSQI) was used for sleep assessment. Inclusion criteria for the BD group were a diagnosis of BD, following DSM-IV-TR criteria, according to the MINI-plus structured clinical interview. Euthymia was established as a score lower than 7 both in the Hamilton Depression Rating Scale (HDRS) and in the Young Mania Rating Scale (YMRS). Health controls were also interviewed using the MINI-plus and included in this study if they were free of any current or past DSM-IV-TR axis I psychiatric disorder as well the actual use of psychopharmacological medications. RESULTS: While 21.2 % of the control group displayed poor sleep quality according to the global PSQI-BR score, 82.9 % of the euthymic BD patients had poor sleep quality (p=0.000). PSQI sleep duration subcomponent showed comparable results in the two groups (p=0.535), even though BD patients had significant disruptions in sleep latency (p=0.000) and sleep efficiency (p=0.000) subcomponents. CONCLUSION: We were able to show that BD patients, even in euthymic phase, exhibit a significantly worse sleep quality as compared with health controls as assessed by PSQI total score and five of its seven subcomponents.

Increased plasma levels of soluble TNF receptor I in patients with bipolar disorder.

Bipolar disorder (BD) has been associated with a proinflammatory state in which TNF-α seems to play a relevant role. The aim of the present study was to evaluate the plasma levels of TNF-α and its soluble receptors (sTNFR1 and sTNFR2) in BD patients in mania and euthymia in comparison with control subjects. We evaluated 53 BD patients (34 in mania and 19 in euthymia) and 38 healthy subjects. All subjects were assessed by the Mini-International Neuropsychiatry Interview (MINI-Plus). Patients were also evaluated by the Young Mania Rating Scale (YMRS) and by Hamilton Depression Rating Scale (HDRS). Plasma TNF-α and its soluble receptors were measured by ELISA. The plasma TNF-α and sTNFR2 levels did not differ between groups, but higher sTNFR1 levels were found in BD patients. Of note, BD patients in mania had higher sTNFR1 levels than BD patients in euthymia and controls. The sTNFR1 and sTNFR2 levels correlated with BD duration, and sTNFR2 levels correlated with age of patients. Our data indicate a proinflammatory status in BD patients during mania and further suggest that inflammatory mechanisms may be involved with the physiopathology of BD.

The role of genetic variation of BDNF gene in antidepressant-induced mania in bipolar disorder.

The occurrence of mania during antidepressant treatment is a key issue in the clinical management of bipolar disorder (BD). Brain-derived neurotrophic factor (BDNF) has been implicated in the pathogenesis of mood disorders. Moreover, antidepressants increase the expression of BDNF and its overactivity may be involved in the mechanism of development of the manic state. The aim of the present study was to test the influence of BDNF gene alterations in antidepressant-induced mania in bipolar patients. A case-control study was performed to analyse genotype and allele frequencies for the BDNF polymorphisms between two groups [37 patients with antidepressant-induced mania (AIM+) and 55 patients without antidepressant-induced mania (AIM-)]. No significant differences were found between AIM+ and AIM- groups. Our results did not support the BDNF gene link to antidepressant-induced mania, like a previous study with a smaller sample has already suggested.

Suicide behavior and neuropsychological assessment of type I bipolar patients.

BACKGROUND: Neuropsychological deficits are often described in patients with bipolar disorder (BD). Some symptoms and/or associated characteristics of BD can be more closely associated to those cognitive impairments. We aimed to explore cognitive neuropsychological characteristics of type I bipolar patients (BPI) in terms of lifetime suicide attempt history. METHOD: We studied 39 BPI outpatients compared with 53 healthy controls (HC) matched by age, educational and intellectual level. All subjects were submitted to a neuropsychological assessment of executive functions, decision-making and declarative episodic memory. RESULTS: When comparing BDI patients, regardless of suicide attempt history or HC, we observed that bipolar patients performed worse than controls on measures of memory, attention, executive functions and decision-making. Patients with a history of suicide attempt performed worse than non-attempters on measures of decision-making and there were a significant negative correlation between the number of suicide attempts and decision-making results (block 3 and net score). We also found significant positive correlation between the number of suicide attempts and amount of errors in Stroop Color Word Test (part 3). LIMITATIONS: The sample studied can be considered small and a potentially confounding variable - medication status - were not controlled. CONCLUSION: Our results show the presence of neuropsychological deficits in memory, executive functions, attention and decision-making in BPI patients. Suicide attempts BPI scored worse than non-suicide attempt BPI on measures of decision-making. More suicide attempts were associated with a worse decision-making process. Future research should explore the relationship between the association between this specific cognitive deficits in BPIs, serotonergic function and suicide behavior in bipolar patients as well other diagnostic groups.

The role of 5-HTTLPR polymorphism in antidepressant-associated mania in bipolar disorder.

BACKGROUND: The occurrence of mania during antidepressant treatment is a key issue in the clinical management of bipolar disorder (BD). The serotonin transporter gene is a candidate to be associated with antidepressant-associated mania (AAM) in some patients. This gene has a polymorphism within the promoter region (5-HTTLPR) with two allelic forms, the long (L) and the short (S) variants. METHODS: We performed a case-control study to compare 5-HTTLPR genotype and allelic frequencies between 43 patients with a DSM-IV diagnosis of BD, with at least one manic/hypomanic episode associated with treatment with proserotonergic antidepressants (AAM+) and 69 unrelated, matched bipolar patients, who had been exposed to proserotonergic antidepressants without development of manic symptoms (AAM-(*)). Furthermore, we performed this comparison between a subgroup of 23 AAM+ patients that, when they presented AAM, were not using mood stabilizer (AAM+(*)) and 25 AAM- patients who used antidepressant without the concomitant use of a mood stabilizer (AAM-(*)). 5-HTTLPR genotyping was performed using PCR. RESULTS: No significant differences were found between AAM+ and AAM-. Within the subgroups, our results show that S-carriers (LS+SS Genotypes) are more prone to make a manic/hypomanic episode associated with antidepressant (P=0.017). LIMITATIONS: Our study is retrospective. CONCLUSIONS: The 5-HTTLPR polymorphism may be considered a predictor of abnormal response to antidepressant in patients with BP, but this action is influenced by the presence of a mood stabilizer. Such observations reinforce that a correct diagnosis of bipolarity before the beginning of the treatment is essential, mainly for S-carriers patients.

Bipolar disorder first episode and suicidal behavior: are there differences according to type of suicide attempt?

OBJECTIVE: The objective of this study was to test the hypothesis that the polarity of the first mood episode may be a marker for suicidal behavior, particularly the violent subtype. METHOD: One hundred and sixty-eight patients diagnosed with bipolar disorder (DSM-IV) were grouped according to type of first episode: depression or manic/hypomanic. Groups were compared for demographic and clinical variables. We performed logistic regression in order to test the association between first episode polarity and suicidal behavior. RESULTS: We found that depressed patients have a lifetime history of more suicide attempts. However, univariate analysis of number of suicide attempts showed that the best model fits the bipolar II subtype (mean square = 15.022; p = 0.010) and lifetime history of psychotic episodes (mean square = 17.359; p = 0.021). Subgrouping the suicide attempts by subtype (violent or non-violent) revealed that manic/hypomanic patients had a greater tendency toward attempting violent suicide (21.2 vs. 14.7%, X(2) = 7.028, p = 0.03). Multiple logistic regression analysis confirmed this result. CONCLUSION: Depressed patients had more suicide attempts over time, which could be explained by the higher prevalence of bipolar II subtype in this group, whereas manic/hypomanic patients had a lifelong history of more frequent violent suicide attempts, not explained by any of the variables studied. Our results support the evidence that non-violent suicide attempters and violent suicide attempters tend to belong to different phenotypic groups.

Interleukin-10 promoter gene polymorphisms are associated with the first major depressive episode in chronic hepatitis C patients.

AIMS: To investigate the association of IL10 SNPs in chronic hepatitis C (CHC) patients with and without the first major depressive episode (MDE), as well as their association with plasma levels of target cytokines. METHODS: A hundred and thirty two CHC patients (32 with and 100 without first MDE) and 98 controls were prospectively enrolled in this cross-sectional study. MDE was diagnosed by a psychiatrist, using the Mini International Neuropsychiatric Interview Plus 5.0. IL10 polymorphisms (-1082 G/A, -819C/T and -592C/A IL10 SNPs) were evaluated by Taqman SNP genotyping assay. Plasma concentrations of IL-2, IL-6, IL-10, IFN-γ and TNF-α were determined using the Human Th1/Th2 Cytometric Bead Array kit. The associations were investigated by logistic models. RESULTS: The frequencies of the studied IL10 SNPs did not differ between the CHC patients and controls. The first MDE was positive and independently associated with the IL10-1082*A, IL10-819*T and IL10-592*A (ATA) low producer haplotype (OR = 1.50; 95% CI = 1.11-2.04; P = 0.009) and current alcohol misuse (OR = 4.29; 95% CI = 1.22-15.05; P = 0.02), and inversely associated with increasing age (OR = 0.94; 95% CI = 0.91-0.98; P = 0.006). In addition, plasma level of TNF-α was significantly higher in the carriers than in the non-carriers of the IL10 ATA haplotype in patients with the first MDE. The IL-10 and IL-2 plasma levels were significantly higher in the carriers than in non-carriers of the IL10 GCC high producer haplotype, demonstrating the functionality of the studied IL10 polymorphisms. CONCLUSIONS: This is the first study to demonstrate that the IL10 low producer ATA haplotype is associated with the first MDE in patients with CHC.

Genetic Association of the PERIOD3 (Per3) Clock Gene with Bipolar Disorder.

OBJECTIVE: Circadian rhythms have been linked to psychiatric disorders such as Depression and Bipolar Disorder (BD). Given previous evidences of sleep/circadian disturbances as well as the genetic susceptibility for BD, we decided to investigate the possible link between the PERIOD3 (Per3) circadian gene and BD. METHODS: This is a genetic association case (BD) vs. control study of the Per3 gene. We further subdivided our BD sample into "good sleepers" (PSQI ≤5) and "poor sleepers" (PSQI>5) according to the Pittsburgh Sleep Quality Index (PSQI) global score, and then we assessed genetic association of the Per3 gene with sleep quality in the BD group. RESULTS: There were 209 cases and 213 controls in our sample. The GT genotype of the SNP rs707467 significantly associated with BD (χ2=8.80; p-value=0.01; adjusted residual=±2.6). We also found significant association of the SNP rs10462020 allele T with BD (χ2=5.81; p-value=0.01) as well as the genotype TT (χ2= 6.01; p-value=0.04; adjusted residual=±2.4). CONCLUSION: In this study we demonstrated evidences of genetic association between the Per3 gene and BD. The results of association between the Per3 gene and BD in our sample may bring additional evidence to the former findings of association between the Per3 gene and BD.

Analysis of telomere attrition in bipolar disorder.

BACKGROUND: Telomeres can be considered a marker of biological aging. Studies have suggested that telomere shortening may be associated with aging related diseases and also psychiatric disorders. OBJECTIVES: Investigate whether bipolar disorder (BD) and its clinical specificities are associated with telomere shortening. METHODS: Eighty-five BD patients and 95 healthy controls were paired for age, sex and educational level. Volunteers were submitted to a psychiatric interview and clinical evaluation. Patients and controls were compared as a whole sample and within specific telomere range (short and long telomeres). Intrapatients group comparison involved type of BD and comorbidities. A Real Time Quantitative PCR was performed in order to verify leukocytes telomere length. RESULTS: Bipolar disorder patients presented shorter telomeres when compared to controls (p<0.001). However, there was no significant difference in telomere length between different BD subtypes. When two groups of patients (long and short telomeres) were compared, only panic disorder showed an association with telomere categories (χ(2)=6.91; p=0.009; OR=4.27). LIMITATIONS: It was not possible to collect information about time since diagnosis, which limited conclusions regarding BD chronicity and telomere length. Furthermore, medication interference upon telomere length was not controlled. CONCLUSIONS: Results suggest that BD is associated with reduced telomere length. Also, panic comorbidity may represent an additive risk factor. Understanding aspects that contribute to determination of telomere size in bipolar patients allows us to understand what the impact on telomeres size is, which is a health vulnerability marker.

Affective temperaments and antidepressant response in the clinical management of mood disorders.

BACKGROUND: The aim of this study was to investigate the presence of a relationship between affective temperament and antidepressant treatment response in mood disorder patients. METHODS: The lifetime history of antidepressant response of 90 bipolar disorder patients and 88 major depressive disorder patients were retrospectively evaluated and then assigned to one of four subgroups: complete response (CR), partial response (PR), no response (NR), and antidepressant associated mania response (AAMR). Using TEMPS-Rio de Janeiro - the brief Brazilian version of TEMPS-A - we compared affective temperament subscale scores across these groups. RESULTS: We observed a statistically significant relationship between depressive and anxious affective temperaments and no antidepressant response. In bipolar disorder patients, cyclothymic temperament (p<0.01) and hyperthymic temperament (p<0.05) were associated with antidepressant-associated mania. Hyperthymic temperament was associated with complete antidepressant responses in major depressive disorder patients. LIMITATIONS: The evaluation of antidepressant response was retrospective. CONCLUSIONS: Our data are consistent with the theory that affective temperament traits are factors that can influence the antidepressant response and the recovery from depressive episodes, but more longitudinal studies are needed to confirm this theory and our findings.

Affective temperaments: familiality and clinical use in mood disorders.

BACKGROUND: The affective temperament profiles among patients with mood disorders may be an important parameter in the clinical evaluation of these patients. It has been proposed that temperament traits have familiality and may represent vulnerability markers to identify the risk to developing specific clinical type of mood disorders. To test these theories, measures of temperament were examined in bipolar patients (BP), unipolar major depressive patients (UP), healthy relatives of these patients (HRP) and normal controls (NC). METHODS: We compared affective temperament scores, using the brief Brazilian version of TEMPS-A--TEMPS-Rio de Janeiro, between 90 BP, 88 UP, 132 HRP and 136 NC. A MANCOVA model was constructed. Dependent variables were the six subscales of the TEMPS-RJ (depressive, cyclothymic, irritable, hyperthymic, anxious and worrying temperaments). The effects of age and gender were adjusted as covariates. Furthermore, we performed a comparison between a subgroup of 68 HRP, relatives of bipolar patients (HRBP), and the remainders 64 HRP, relatives of unipolar patients (HRUP) and controls. RESULTS: The clinical group (BP, UP) showed higher temperament scores than NC, except for hyperthymic scores. BP showed higher cyclothymic (p<0.001), hyperthymic (p<0.001) and lower anxious (p<0.01) temperament scores than UP. HRP showed lower scores than clinical groups. HRBP scored higher cyclothymic subscale than HRUP and NC groups. LIMITATIONS: Bipolar I and II subjects were placed in the same group. CONCLUSIONS: The cyclothymic and hyperthymic traits were associated with bipolarity in patients and cyclothymic temperament could be a characteristic trait of the healthy relatives of bipolar patients. Our data support that affective temperament might become a useful tool for clinical evaluation and research purposes in mood disorders.

A kinematic analysis of the association between impulsivity and manual aiming control.

Two characteristics usually found in impulsive behavior are deficits in response inhibition and the inability to delay gratification. The former behavior is called motor impulsivity, and the second is called cognitive impulsivity. This study investigates the association of motor and cognitive impulsivity with manual aiming control. We administered two neuropsychological tests to 81 healthy participants to measure their levels of motor and cognitive impulsivity. A manual aiming motor task was also applied. Subsequently, from the initial group of 81 participants, two subgroups of 27 individuals were selected by their scores on (1) motor impulsivity and (2) cognitive impulsivity, and their motor performances were compared. While a group was comprised by the top 33.3% high-impulsive participants, the other was comprised by the bottom 33.3% low-impulsives participants. The results indicate that motor impulsivity is more related to motor control than cognitive impulsivity. Differences between motor impulsivity groups were found in the duration of the primary submovement, peak velocity, score of response inhibition errors and incorrect hits score. It was found that in situations in which the temporal and spatial demands to the motor system were high, the impulsivity had a functional, adaptive effect on motor control.

Impaired nerve growth factor homeostasis in patients with bipolar disorder.

OBJECTIVE: Neuro-trophins are critically involved in neuro-plasticity, the impairment of which is a major role-player in bipolar disorder (BD), and their altered levels have been recently advocated in the patho-physiology of this affective malady. The aim of this study, therefore, was to evaluate the plasma levels of nerve growth factor (NGF) in BD patients in comparison with control subjects. METHODS: Forty-nine BD type-I individuals (30 in mania and 19 in euthymia) and 36 healthy controls were assessed by Mini-plus, Young mania and Hamilton depression rating scales. NGF levels were detected by ELISA. RESULTS: Plasma NGF concentrations were decreased in BD patients when compared to that seen with controls. BD individuals in mania had lower NGF levels than euthymic patients or controls. NGF levels were negatively correlated with the severity of mania. CONCLUSIONS: This is the first study to evaluate NGF levels in BD patients, providing further support to the hypothesis of impaired neuro-plasticity in BD. These data also suggest that NGF measurement could be used for the biological marker for manic state.

The role of BDNF genetic polymorphisms in bipolar disorder with psychiatric comorbidities.

BACKGROUND: Bipolar disorder (BD) is a complex disorder where genetic factors play a major role in its etiology. Probably, no other axis I diagnosis has a co-morbidity prevalence as high as BD. Since BDNF is involved in different ways in various psychiatric disorders we hypothesized that its genetic polymorphisms could be associated with the co-morbidity phenomenon in BD. METHODS: We studied 320 subjects (160 BD patients and 160 healthy controls). Genotyping was performed using made-to-order TaqMan genotyping assays (rs4923463, rs6265, rs2049045, and rs7103411). Statistical analyses were performed using UNPHASED version 3.0.12 and Haploview 4.1. RESULTS: No genotypic, allelic or haplotype differences were found between bipolar patients and healthy controls. Concerning exclusively the rs4923463 (G/G) there was a significant association with alcoholism (p=0.009), smoking (p=0.006) and violent suicide attempt (p=0.03). We further found that the G-G haplotype (rs4923463-rs2049045) (adjusted p=0.029) and the G-T haplotype (rs4923463-rs7103411) (adjusted p=0.029) were significantly more frequent in the group with alcoholism co-morbidity when compared with the group without this co-morbidity. LIMITATIONS: Sample size and retrospective assessment of suicide behavior and psychiatric comorbidities. CONCLUSIONS: The results obtained in our study indicate that BDNF variants may confer susceptibility to additional psychiatric diagnosis in BD.

The 5-HTTLPR polymorphism, impulsivity and suicide behavior in euthymic bipolar patients.

BACKGROUND: Suicide behavior is very frequent in Bipolar Disorder (BD) and they are both closely associated with impulsivity. Furthermore they are, impulsivity, BD and suicide behavior, associated with serotonergic function, at least partially, under genetic determinism and somewhat associated with the serotonin transporter gene polymorphism, the 5-HTTLPR. We aimed to assess different impulsivity components in BD sub-grouped by suicidal attempt and healthy controls. We hypothesized that the non-planning/cognitive impulsivity, could be more closely associated with suicidal behavior. We further associated 5-HTTLPR genotypes with neuropsychological results to test the hypothesis that this polymorphism is associated with cognitive impulsivity. METHOD: We assessed 95 euthymic bipolar patients sub-grouped by suicidal attempt history in comparison with 94 healthy controls. All subjects underwent a laboratory assessment of impulsivity (Continuous Performance Test and Iowa Gambling Test). Furthermore the genotyping of 5-HTTLPR was performed in all subjects. RESULTS: We found that bipolar patients are more impulsive than healthy controls in all impulsivity dimensions we studied. Furthermore bipolar patients with a suicide attempt history have a greater cognitive impulsivity when compared to both bipolar patients without such a history as well when compared to healthy controls. No association was found between 5-HTTLPR genotypes and neuropsychological measures of impulsive behavior. LIMITATIONS: The sample studied can be considered small and a potentially confounding variable - medication status - was not controlled. CONCLUSION: A lifetime suicide attempt seems associated with cognitive impulsivity independently of the socio-demographic and clinical variables studied as well with 5-HTTLPR genotype. Further studies in larger samples are necessary.