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1.  Neurocognitive Functioning in Overweight and Obese Patients With Bipolar Disorder: Data From the Systematic Treatment Optimization Program for Early Mania (STOP-EM) 
Obesity is frequent in people with bipolar I disorder (BD I) and has a major impact on the course of the illness. Although obesity negatively influences cognitive function in patients with BD, its impact in the early phase of the disorder is unknown. We investigated the impact of overweight and obesity on cognitive functioning in clinically stable patients with BD recently recovered from their first manic episode.
Sixty-five patients with BD (25 overweight or obese and 40 normal weight) recently remitted from a first episode of mania and 37 age- and sex-matched healthy control subjects (9 overweight or obese and 28 normal weight) were included in this analysis from the Systematic Treatment Optimization Program for Early Mania (commonly referred to as STOP-EM). All subjects had their cognitive function assessed using a standard neurocognitive battery. We compared cognitive function between normal weight patients, overweight–obese patients, and normal weight healthy control subjects.
There was a negative affect of BD diagnosis on the domains of attention, verbal memory, nonverbal memory, working memory, and executive function, but we were unable to find an additional effect of weight on cognitive functioning in patients. There was a trend for a negative correlation between body mass index and nonverbal memory in the patient group.
These data suggest that overweight–obesity does not negatively influence cognitive function early in the course of BD. Given that there is evidence for a negative impact of obesity later in the course of illness, there may be an opportunity to address obesity early in the course of BD.
PMCID: PMC4304583  PMID: 25702364
bipolar disorder; mania; obesity; overweight; body mass index; cognitive function
2.  Correlation between Peripheral Levels of Brain-Derived Neurotrophic Factor and Hippocampal Volume in Children and Adolescents with Bipolar Disorder 
Neural Plasticity  2015;2015:324825.
Pediatric bipolar disorder (PBD) is a serious mental disorder that affects the development and emotional growth of affected patients. The brain derived neurotrophic factor (BDNF) is recognized as one of the possible markers of the framework and its evolution. Abnormalities in BDNF signaling in the hippocampus could explain the cognitive decline seen in patients with TB. Our aim with this study was to evaluate possible changes in hippocampal volume in children and adolescents with BD and associate them to serum BDNF. Subjects included 30 patients aged seven to seventeen years from the ProCAB (Program for Children and Adolescents with Bipolar Disorder). We observed mean right and left hippocampal volumes of 41910.55 and 41747.96 mm3, respectively. No statistically significant correlations between peripheral BDNF levels and hippocampal volumes were found. We believe that the lack of correlation observed in this study is due to the short time of evolution of BD in children and adolescents. Besides studies with larger sample sizes to confirm the present findings and longitudinal assessments, addressing brain development versus a control group and including drug-naive patients in different mood states may help clarify the role of BDNF in the brain changes consequent upon BD.
PMCID: PMC4444584  PMID: 26075097
3.  Validation of the Italian Version of the Biological Rhythms Interview of Assessment in Neuropsychiatry (BRIAN): Some Considerations on its Screening Usefulness 
Abnormalities in biological rhythms (BR) may have a role in the pathophysiology of Bipolar Disorders (BD). The objective of this study is to validate the Italian version of the Biological Rhythms Interview of Assessment in Neuropsychiatry (BRIAN), a useful tool in studying BR, and measure its accuracy in discriminating BD.
44 outpatients with DSM-IV-TR diagnosis of BD and 38 controls balanced for sex and age were consecutively recruited. The discriminant validity of BRIAN for the screening of BD and its test re-test reliability in two evaluations were assessed.
BD patients scored 22.22±11.19 in BRIAN against 7.13±5.6 of the control group (P<0.0001). BRIAN showed a good accuracy to screen between BD non-BD at cutoff 16, a sensitivity was 68.2 and specificity was 92.5. The test-retest stability measured using Pearson’s coefficient found very high r values for each section and the total score, thus indicating a correlation at the two times of statistical significance in all measures. Cohen’s Kappa varied from 0.47 in the sociality section to 0.80 in the sleep section, with a total K mean of 0.65.
The results show that the Italian version of BRIAN has good discriminant validity in detecting BD from healthy controls and shows good test-retest reliability. The study suggests the possibility of developing mixed screening tools by introducing items on dysregulation of biological rhythms to the usual measures of mood.
PMCID: PMC4076616  PMID: 24987447
Biological rhythms; bipolar disorders; BRIAN; Italian screening; validation.
4.  Bipolar Disorder Affects Behavior and Social Skills on the Internet 
PLoS ONE  2013;8(11):e79673.
Bipolar disorder (BD) is a significant cause of functional, cognitive, and social impairment. However, classic studies of functioning and social skills have not investigated how BD may impact behavior on the Internet. Given that the digital age has been changing the way people communicate, this study aims to investigate the pattern of Internet use in patients with BD.
This cross-sectional study assessed 30 patients with BD I or II and 30 matched controls. Patients were not in an acute mood episode, according to DSM-IV. A standard protocol examined sociodemographic variables and social behavior on the Internet, assessed by Facebook number of friends (FBN) and lifetime estimated number of offline contacts (social network number, SNN).
SNN (p<0.001) and FBN (p = 0.036) of patients with BD were significantly lower than those of controls. Also, variables related with Internet use were significantly lower in patients, e.g., close contacts on Facebook (p = 0.021), Internet experience (p = 0.020), and knowledge of terms associated with social networking sites (p = 0.042). Also, patients showed lower rates of the expected pattern of Internet use (based on their age generation), including a poorer knowledge of SNS (p = 0.018) and a lower frequency of Internet use (p = 0.010).
This study suggests that patients with BD show smaller social networks both in real-world settings and on the Internet. Also, patients tend to use the Internet and social networking sites less frequently and show a poorer knowledge of Internet and social media than healthy controls, below the expected for their generation. These significant differences between patients and controls suggest that the effects of BD on social relationships and functioning extend to electronic media.
PMCID: PMC3823569  PMID: 24244541
5.  Maintenance N-acetyl cysteine treatment for bipolar disorder: A double-blind randomized placebo controlled trial 
BMC Medicine  2012;10:91.
N-acetyl cysteine (NAC) is a glutathione precursor that has been shown to have antidepressant efficacy in a placebo-controlled trial. The current study aimed to investigate the maintenance effects of NAC following eight weeks of open-label treatment for bipolar disorder.
The efficacy of a double blind randomized placebo controlled trial of 2 g/day NAC as adjunct maintenance treatment for bipolar disorder was examined. Participants (n = 149) had a Montgomery Asberg Depression Rating Score of ≥12 at trial entry and, after eight weeks of open-label NAC treatment, were randomized to adjunctive NAC or placebo, in addition to treatment as usual. Participants (primarily outpatients) were recruited through public and private services and through newspaper advertisements. Time to intervention for a mood episode was the primary endpoint of the study, and changes in mood symptoms, functionality and quality of life measures were secondary outcomes.
There was a substantial decrease in symptoms during the eight-week open-label NAC treatment phase. During the subsequent double-blind phase, there was minimal further change in outcome measures with scores remaining low. Consequently, from this low plateau, between-group differences did not emerge on recurrence, clinical functioning or quality of life measures.
There were no significant between-group differences in recurrence or symptomatic outcomes during the maintenance phase of the trial; however, these findings may be confounded by limitations.
Trial Registration
The trial was registered with the Australian New Zealand Clinical Trials Registry (ACTRN12607000074493).
PMCID: PMC3482580  PMID: 22891797
N-acetyl cysteine; depression; bipolar disorder; maintenance; mania; oxidative
6.  The Role of BDNF as a Mediator of Neuroplasticity in Bipolar Disorder 
Psychiatry Investigation  2010;7(4):243-250.
The cognitive impairment and neuroanatomical changes that takes place among patients with bipolar disorder (BD) patients has been well described. Recent data suggest that changes in neuroplasticity, cell resilience and connectivity are the main neuropathological findings in BD. Data from differential lines of research converges to the brain-derived neurotrophic factor (BDNF) as an important contributor to the neuroplasticity changes described among BD patients. BDNF serum levels have been shown to be decreased in depressive and manic episodes, returning to normal levels in euthymia. BDNF has also been shown to decrease as the disorder progresses. Moreover, factors that negatively influence the course of BD, such as life stress and trauma have been shown to be associated with a decrease in BDNF serum levels. These findings suggest that BDNF plays a central role in the progression of BD. The present review discusses the role of BDNF as a mediator of the neuroplastic changes that occur in portion with mood episodes and the potential use of serum BDNF as a biomarker in BD.
PMCID: PMC3022310  PMID: 21253407
Bipolar disorder; Brain-derived neurotrophic factor; Neuroplasticity; Stress; Neurotrophins
7.  A double-blind, Randomized, Placebo-Controlled 4-Week Study on the Efficacy and Safety of the Purinergic Agents Allopurinol and Dipyridamole Adjunctive to Lithium in Acute Bipolar Mania 
The Journal of clinical psychiatry  2008;69(8):1237-1245.
The therapeutics for Bipolar Disorders (BD) is still far from adequate and new options with improved effectiveness, safety and tolerability in a wide range of patients are necessary. Preliminary data have suggested a role for dysfunctions targeting at the purinergic system in mood disorders. This study aimed to evaluate the efficacy and tolerability of the purinergic agents allopurinol and dipyridamole combined with lithium in bipolar mania.
A randomized, placebo-controlled, double-blind study was performed in adult inpatients (n=180) with a DSM-IV-TR diagnosis of bipolar disorder, current episode manic with or without psychotic features (rapid cyclers and mixed episodes were not included). No antipsychotic agent was used during the study. Subjects were given fixed oral doses of either allopurinol 600 mg/day (n=60), dipyridamole 200 mg/day (n=60), or placebo (n=60) added to lithium for 4 weeks. Subjects were rated at baseline and days 7, 14, 21 and 28 using the Young Mania Rating Scale (YMRS) as the primary efficacy measure. The study was conducted between September 2003 and September 2006.
Allopurinol resulted in greater mean reductions in YMRS scores from baseline to day 21 (p<.001) and day 28 (p=.003) compared with placebo using a linear model analysis (d=0.32, 95% C.I. = 0.07 to 0.57). Remission rates were significantly higher for allopurinol compared to dipyridamole and placebo (p=0.008). Lithium showed a significant antimanic efficacy even in the placebo group. Decrease in plasma uric acid levels showed a significant positive association with antimanic effects in the allopurinol group (p<0.001).
Allopurinol is clinically effective and well-tolerated adjunctively with lithium in manic episodes and may represent an alternative approach in the treatment of acute mania, especially for those presenting tolerability and safety issues with antipsychotics. The present results strongly support the involvement of the purinergic system in the pathophysiology and therapeutics of Bipolar Disorder. Further placebo-controlled studies with allopurinol compared with standard mood-stabilizers in mania and maintenance are warranted.
PMCID: PMC2727594  PMID: 18681754
adenosine; allopurinol; purinergic; mania; bipolar disorder; lithium; treatment; trial; purines; depression; uric acid
8.  3-Nitrotyrosine and glutathione antioxidant system in patients in the early and late stages of bipolar disorder 
There has been an increasing interest in the role of oxidative stress in the pathophysiology of bipolar disorder. To explore this further, we evaluated the activity of glutathione peroxidase (GPx), glutathione reductase (GR) and glutathione S-transferase (GST), as well as 3-nitrotyrosine levels and carbonyl content in patients in the early (within 3 years of illness onset) and late (a minimum of 10 years of illness) stages of bipolar disorder.
We matched 30 patients in the early stage and 30 patients in the late stage of bipolar disorder, diagnosed according to DSM-IV criteria, with 60 healthy controls (30 matched for each group of patients). We measured symptomatic status using the Hamilton Rating Scale for Depression and the Young Mania Rating Scale.
We found a significant increase in 3-nitrotyrosine levels among patients in the early (p < 0.010) and late (p < 0.010) stages of bipolar disorder. The activity of GR and GST was increased only among patients in the late stage of illness. Glutathione peroxidase activity and carbonyl content did not differ among the groups.
Limitations of our study include its cross-sectional design, which did not allow us to examine direct causative mechanisms or the effects of progression of illness, and the potential environmental bias introduced by comparing patient groups recruited from different regions of the world.
Our data indicate a possible tyrosine nitration-induced damage in patients with bipolar disorder that is present from the early stage of illness. Our data also indicate that patients in the late stage of illness demonstrate enhanced activity of GR and GST, which could suggest the involvement of a compensatory system in bipolar disorder.
PMCID: PMC2702443  PMID: 19568477
9.  Effects of mood stabilizers on DNA damage in an animal model of mania 
Recent studies have suggested that oxidative stress and DNA damage may play a role in the pathophysiology of bipolar disorder (BD). We investigated the effects of the mood stabilizers lithium and valproate on amphetamine-induced DNA damage in an animal model of mania and their correlation with oxidative stress markers.
In the first experiment (reversal model), we treated adult male Wistar rats with D-amphetamine (AMPH) or saline for 14 days; between the 8th and 14th days, rats also received lithium, valproate or saline. In the second experiment (prevention model), rats received either lithium, valproate or saline for 14 days; between the 8th and 14th days, we added AMPH or saline. We evaluated DNA damage using single-cell gel electrophoresis (comet assay), and we assessed the mutagenic potential using the micronucleus test. We assessed oxidative stress levels by lipid peroxidation levels (TBARS) and antioxidant enzyme activities (superoxide dismutase and catalase). We assessed DNA damage and oxidative stress markers in blood/plasma and hippocampal samples. We evaluated mutagenesis in fresh lymphocytes.
In both models, we found that AMPH increased peripheral and hippocampal DNA damage. The index of DNA damage correlated positively with lipid peroxidation, whereas lithium and valproate were able to modulate the oxidative balance and prevent recent damage to the DNA. However, lithium and valproate were not able to prevent micronucleus formation.
Our results support the notion that lithium and valproate exert central and peripheral antioxidant-like properties. In addition, the protection to the integrity of DNA conferred by lithium seems to be limited to transient DNA damage and does not alter micronuclei formation.
PMCID: PMC2575759  PMID: 18982174
models, animal; bipolar disorder; lithium; DNA damage; dopamine; oxidative stress

Results 1-9 (9)