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BackgroundThe course of bipolar disorder progressively worsens in some patients. Although responses to pharmacotherapy appear to diminish with greater chronicity, less is known about whether patients' prior courses of illness are related to responses to psychotherapy.MethodEmbedded in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) was a randomized controlled trial of psychotherapy for bipolar depression comparing the efficacy of intensive psychotherapy with collaborative care (a three-session psycho-educational intervention). We assessed whether the number of previous mood episodes, age of illness onset, and illness duration predicted or moderated the likelihood of recovery and time until recovery from a depressive episode in patients in the two treatments.ResultsIndependently of treatment condition, participants with one to nine prior depressive episodes were more likely to recover and had faster time to recovery than those with 20 or more prior depressive episodes. Participants with fewer than 20 prior manic episodes had faster time to recovery than those with 20 or more episodes. Longer illness duration predicted a longer time to recovery. Participants were more likely to recover in intensive psychotherapy than collaborative care if they had 10-20 prior episodes of depression [number needed to treat (NNT) = 2.0], but equally likely to respond to psychotherapy and collaborative care if they had one to nine (NNT = 32.0) or >20 (NNT = 9.0) depressive episodes.ConclusionsNumber of previous mood episodes and illness duration are associated with the likelihood and speed of recovery among bipolar patients receiving psychosocial treatments for depression.

In this study, we evaluated the impact of defense style (DS) on outcome and its relation to the therapeutic alliance. Women with postpartum depression were allocated to a brief psychotherapeutic intervention. To evaluate DS and the therapeutic alliance, the Defense Style Questionnaire and the Working Alliance Inventory were employed. The main outcome was the Edinburgh Postnatal Depression Scale score at end point; anxiety and retention in treatment were also evaluated. Fifty-nine patients were included; 46 completed the therapy and 65.4% responded (Edinburgh Postnatal Depression Scale score <10). Intense use of immature defenses was related to persistence of depression and anxiety symptoms at end point, even when controlled for potential confounders. Results tended to confirm a hierarchy of DSs independently of the alliance. Clinicians should be aware of possible differential responses to brief psychotherapies related to DS. [ABSTRACT FROM AUTHOR]

Objective: The term "mood stabilizer" is controversial in the literature and criticized for being imprecise and overly inclusive, having its retirement suggested to avoid misuse. Nevertheless, it continues to be employed as it may still carry important meaning., Methods: We employed document analysis for reviewing relevant definitions of mood stabilizer employed in the literature. Then, we clarify the meanings associated with the term by employing evolutionary concept analysis. Based on its results, we present a theoretical model for a mood stabilizer and further match it with evidence gathered from published meta-analyses and other sources for drugs used in the treatment of bipolar disorder., Results: Concept analysis unearthed four attributes of a mood stabilizer that were nested into the following ascending hierarchy: "not worsening," "acute effects," "prophylactic effects," and "advanced effects." "Prophylactic effects" were often considered the core aspect of a legitimate mood stabilizer., Conclusion: The proposed model uses a hierarchy of attributes that take into account the complexity of the term and help to determine whether a drug is a mood stabilizer. Prophylaxis is pivotal to the concept, whose utility lies in implying a drug able to truly treat bipolar disorder, as opposed to merely targeting symptoms. Consistent use of the term could encourage investigation of drugs that modify long-term outcomes and illness trajectory, instead of simply approaching symptom clusters., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The pathophysiology of bipolar disorder remains incompletely elucidated. The purinergic receptor, P2X7 (P2X7R), plays a central role in neuroinflammation, the establishment, and maintenance of microglial activation and neuronal damage/death, all characteristics of bipolar disorder pathology. The present study aims to explore the participation of the P2X7R in a preclinical pharmacological model of mania. We analyzed the modulatory effects of the P2X7R antagonist, brilliant blue, on behavior, monoamines, gene expression, serum purine levels, and cell typing in a pharmacological model of mania induced by D-amphetamine (AMPH) in mice. Our results corroborate an association between the P2X7 receptor and the preclinical animal model of mania, as demonstrated by the decreased responsiveness to AMPH in animals with pharmacologically blocked P2X7R. This study further suggests a possible dopaminergic mechanism for the action of P2X7 receptor antagonism. Additionally, we observed increased peripheral levels of adenosine, a neuroprotective molecule, and increased central expression of Entpd3 and Entpd1 leading to the hydrolysis of ATP, a danger signal, possibly as an attempt to compensate for the damage induced by AMPH. Lastly, P2X7R antagonism in the AMPH model was found to potentially modulate astrogliosis. Our results support the hypothesis that P2X7R plays a vital role in the pathophysiology of mania, possibly by modulating the dopaminergic pathway and astrogliosis, as reflected in the behavioral changes observed. Taken together, this study suggests that a purinergic system imbalance is associated with the AMPH-induced preclinical animal model of mania. P2X7R may represent a promising molecular therapeutic target for bipolar disorder.

Objective: The purpose of this study was to assess the efficacy and tolerability of tianeptine as an adjunctive maintenance treatment for bipolar depression., Methods: This is a multicenter double-blind randomized placebo-controlled maintenance trial of adjunctive tianeptine 37.5 mg/day. Participants ( n=161) had a Montgomery-Asberg Depression Rating Scale ⩾12 at entry. After eight weeks of open-label tianeptine treatment, those who responded to tianeptine ( n=69) were randomized to adjunctive tianeptine ( n=36) or placebo ( n=33) in addition to usual treatment. Kaplan-Meier estimates and the Mantel-Cox log-rank test were used to evaluate differences in time to intervention for a mood episode between the tianeptine and placebo groups. We also assessed overall functioning, biological rhythms, quality of life, rates of manic switch and serum brain-derived neurotrophic factor levels., Results: There were no differences between adjunctive tianeptine or placebo regarding time to intervention or depression scores in the 24-week double-blind controlled phase. Patients in the tianeptine group showed better performance in the letter-number sequencing subtest from the Wechsler Adult Intelligence Scale at the endpoint ( p=0.014). Tianeptine was well tolerated and not associated with higher risk for manic switch compared to placebo., Conclusion: Tianeptine was not more effective than placebo in the maintenance treatment of bipolar depression. There is preliminary evidence suggesting a pro-cognitive effect of tianeptine in working memory compared to placebo.

Although the etiology of Bipolar Disorder (BD) remains unknown, a strong genetic component to the pathogenesis and risk for this disorder has been widely hypothesized. Several risk genes for BD have been identified; of these, the purinergic P2 × 7 receptor (P2 × 7R) constitutes a pro-inflammatory receptor and a potential risk gene candidate. The purpose of the present study was to assess the frequency of the 1513 A > C P2RX7 polymorphism (rs3751143; Glu496Ala), which leads to receptor loss-of-function, in 154 BD patients versus 184 control subjects. The existence of a differential modulation of P2 × 7R was also analyzed in 22 euthymic BD patients, in comparison to 18 healthy controls. Our data show a decrease in 1513C allele frequency (p = 0.045) and a potential increase in 1513 A A/AC (p = 0.055) genotype frequency in BD patients, compared to controls, indicating an enhanced function of the pro-inflammatory P2 × 7 receptor in BD subjects. Interestingly, no differences in P2RX7 gene and protein expression were found between euthymic BD patients and matched healthy controls. In conclusion, our results suggest that P2 × 7R might play a role in the pathophysiology of BD and add new information regarding this receptor as a potential biomarker for the prediction and diagnosis of the disorder., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Objective: To identify the association of metabolic syndrome (MetS) and psychiatric disorders in young adults in southern Brazil., Methods: This population based cross-sectional study involved a total of 1,023 young adults between the ages of 21 and 32 years. Current episodes of psychiatric disorders were assessed using the Mini International Neuropsychiatric Interview - Plus version. MetS was evaluated using the National Cholesterol Education Program Adult Treatment Panel III (NCEP/ATP III)., Results: Of the 1,023 participants, 24.3% were identified with MetS, 13.5% were diagnosed with anxiety disorders, 7.5% with current depression, 3.9% with bipolar disorders and 10.1% were at risk of suicide. MetS was associated with ethnicity (p = 0.022), excess weight (p < 0.001), current anxiety disorders (p < 0.001), current mood disorders (bipolar disorder in mood episode and current depression) (p < 0.001), and suicide risk (p < 0.001)., Conclusions: MetS was associated with psychiatric disorders. Awareness of factors associated with MetS can help identify high-risk individuals and stimulate disease prevention and control programs, as well as lifestyle changes.

Objective: This study aimed to explore effects of adjunctive treatment with N-acetyl cysteine (NAC) on markers of inflammation and neurogenesis in bipolar depression., Methods: This is a secondary analysis of a placebo-controlled randomised trial. Serum samples were collected at baseline, week 8, and week 32 of the open-label and maintenance phases of the clinical trial to determine changes in interleukin (IL)-6, IL-8, IL-10, tumour necrosis factor-α (TNF-α), C-reactive protein (CRP) and brain-derived neurotrophic factor (BDNF) following adjunctive NAC treatment, and to explore mediation and moderator effects of the listed markers., Results: Levels of brain-derived neurotrophic factor (BDNF), tumour necrosis factor-α (TNF-α), C-reactive protein (CRP), interleukins (IL) -6, 8, or 10 were not significantly changed during the course of the trial or specifically in the open-label and maintenance phases. There were no mediation or moderation effects of the biological factors on the clinical parameters., Conclusion: The results suggest that these particular biological parameters may not be directly involved in the therapeutic mechanism of action of adjunctive NAC in bipolar depression.

Objective: To assess the association between peripheral levels of inflammatory cytokines and functional impairment in subjects with Bipolar Disorder (BD), Major Depressive Disorder (MDD) and population controls., Methods: This was a cross-sectional study with a matched sample of drug-free young adults with BD (n=48), MDD (n=48) and population controls (n=48). Mood disorder was confirmed by a certified psychologist using the Structured Clinical Interview for DSM-IV (SCID-I). Functional impairment was assessed using the Functional Assessment Short Test (FAST). Serum levels of IL-6 and IL-10 were measured by ELISA., Results: Peripheral levels of IL-6 and IL-10 were not significantly different between subjects with BD, MDD compared to controls. Higher levels of functional impairment were verified in subjects with BD and MDD compared to population controls (p≤0.001). In addition, IL-6 and IL-10 levels were positively correlated with functional impairment in subjects with BD (IL-6: r=0.349, p=0.016; and IL-10: r=0.351, p=0.016)., Conclusion: Inflammatory dysregulation was associated with functional impairment among drug-free subjects with BD. This finding suggests that inflammatory dysregulation may be involved in the neuroprogression of BD., (Copyright © 2017. Published by Elsevier B.V.)

Objectives:: To describe the frequency of brain tissue donation for research purposes by families of individuals that committed suicide., Methods:: All requests for brain tissue donation to a brain biorepository made to the families of individuals aged 18-60 years who had committed suicide between March 2014 and February 2016 were included. Cases presenting with brain damage due to acute trauma were excluded., Results:: Fifty-six cases of suicide were reported. Of these, 24 fulfilled the exclusion criteria, and 11 others were excluded because no next of kin was found to provide informed consent. Of the 21 remaining cases, brain tissue donation was authorized in nine (tissue fragments in seven and the entire organ in two)., Conclusions:: Donation of brain tissue from suicide cases for research purposes is feasible. The acceptance rate of 42.8% in our sample is in accordance with international data on such donations, and similar to rates reported for neurodegenerative diseases.

Bipolar disorder is a recurrent and highly incapacitating illness, related to inflammation and changes in the insulin-like growth factor 1 (IGF-1). The objective of this study was to evaluate serum levels of IGF-1 in bipolar disorder patients and its relation to inflammation. We included 31 patients with bipolar disorder and 33 healthy controls. Serum concentrations of IGF-1, growth hormone (GH), insulin and tumor necrosis factor α (TNF-α) were analyzed. The serum levels of IGF-1 seem to be increased in bipolar disorder patients (248.84±104.91ng/mL) compared to controls (169.18±74.16ng/mL). Comparing reference values of IGF serum concentrations between groups, we found that 32% of patients had increased IGF-1 serum concentrations while only 3% of subjects are above normal range. We did not find statistically significant differences between groups in the concentration of insulin, GH, and TNF-α. This study suggests an association between IGF-1 in the pathophysiology of bipolar disorder. It is possible that this peripheral increase is related to a central nervous system increased resistance to IGF-1, thus reducing its neuroprotective action., (Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.)

In regard to mental illness, brain donation is essential for the biological investigation of central pathology. Nevertheless, little is known about the thoughts of people with mental disorders on tissue donation for research. Here, our objective was to understand the attitudes and opinions of people treated for bipolar disorder and their relatives regarding donation in general, and particularly donation for research. This is a qualitative study that used in-depth interviews to determine the thoughts of participants regarding tissue donation for research. Theoretical sampling was used as a recruitment method. Grounded theory was used as a framework for content analyses of the interviews. A semi-structured interview guide was applied with the topics: donation in general; donation for research; mental health and body organs; opinion regarding donation; feelings aroused by the topic. Although all participants were aware of organ donation for transplant, they were surprised that tissue could be donated for research. Nevertheless, once they understood the concept they were usually in favor of the idea. Although participants demonstrated a general lack of knowledge on donation for research, they were willing to learn more and viewed it as a good thing, with altruistic reasons often cited as a motive for donation. We speculate that bridging this knowledge gap may be a fundamental step towards a more ethical postmortem tissue donation process.

This study examined whether sleep disturbance predicted or moderated responses to psychotherapy in participants who participated in STEP-BD, a national, multisite study that examined the effectiveness of different treatment combinations for bipolar disorder. Participants received either a brief psychosocial intervention called collaborative care (CC; n = 130) or intensive psychotherapy (IP; n = 163), with study-based pharmacotherapy. Participants (N = 243) were defined as current (past week) short sleepers (<6 hours/night), normal sleepers (6.5-8.5 hours/night), and long sleepers (≥9 hours/night), according to reported average nightly sleep duration the week before randomization. Sleep disturbances did not predict the likelihood of recovery nor time until recovery from a depressive episode. There was no difference in recovery rates between IP versus CC for normal sleepers, and medium effect sizes were observed for differences in short and long sleepers. In this study, sleep did not play a major role in predicting or moderating response to psychotherapy in bipolar disorder.

Background: It is known that sleep disturbance has been considered a trait-marker of mood disorders. However, the role of disruptions in biological rhythms, such as eating, activity, and social patterns, needs to be better understood., Aim: To assess the differences in biological rhythms in subjects with bipolar disorder, major depressive disorder, and healthy controls. We also tested the association between disruptions of biological rhythms and circadian preferences., Methods: A cross-sectional, population-based study with a representative sample of 1023 young adults. Bipolar disorder and depression were diagnosed using The Mini International Neuropsychiatric Interview - PLUS and DSM Structured Clinical Interview. Self-reported biological rhythms and circadian preference were assessed using the Biological Rhythm Interview of Assessment in Neuropsychiatry (BRIAN)., Results: Bipolar disorders and depression subjects presented higher rates of disruption in biological rhythms when compared to healthy controls even after adjusting for sex, socioeconomic status, alcohol, tobacco, illicit drug use, anxiety disorder and psychotropic medication use. Euthymic subjects showed higher biological rhythm disruption when compared to controls. Higher disruption in biological rhythms was observed in subjects with evening preferences., Conclusion: Higher disruption in biological rhythms occurs in individuals with depression and bipolar disorder even on periods of euthymia., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Objective: To assess circadian preference among a community sample of people with bipolar disorder, major depression and without any mood disorders. Secondly, we investigated the association of circadian preference with cytokines interleukin-6 (IL-6), interleukin-10 (IL-10) and, tumor necrosis factor alpha (TNF-α) and oxidative stress assessed by thiobarbituric acid reactive substances (TBARS), uric acid and Protein Carbonyl Content (PCC)., Method: A cross-sectional study nested in a population-based sample. Caseness was confirmed with the Structured Clinical Interview for DSM-IV. A sample of 215 participants, in whom we measured circadian preferences, IL-6, IL-10, TNF-α, TBARS, uric acid, PCC. Biological rhythms were evaluated using the Biological Interview of Assessment in Neuropsychiatry., Results: Bipolar group presented a higher alteration in biological rhythms (40.40±9.78) when compared with the major depression group (36.35±9.18) and control group (27.61±6.89) p<0.001. Subjects with bipolar disorder who were active at night and had a day/night cycle reverse showed decreased levels of IL-6 (t, 44=2.096; p=0.042), (t, 44=2.213; p=0.032), respectively. In the bipolar disorder group subjects who presented day/night cycle reverse had lower TBARS levels (t, 41=2.612; p=0.013). TNF-α were decreased in subjects more active at night with bipolar disorder., Conclusion: Lower serum levels of IL-6, TNF-α and TBARS were associated with evening preference in bipolar disorder group. These findings suggest that chronotype may alter the levels of interleukins and oxidative stress levels in bipolar and healthy subjects. A better understanding of the role of circadian preferences in levels of interleukins and oxidative stress are needed., (Copyright © 2016 Elsevier B.V. All rights reserved.)

The purpose of this study was to assess the disruption in biological rhythms and metabolic syndrome (MetS) in individuals with depressive episode. This was a cross-sectional, population-based study with a representative sample of 905 young adults. Current depressive episode were confirmed by a psychologist using the Mini International Neuropsychiatric Interview (MINI)-Plus. Self-reported biological rhythms were assessed using the Biological Rhythms Interview of Assessment in Neuropsychiatry (BRIAN). MetS was defined using modified NCEP/ATPIII criteria. Significant main effects of current depressive episode (p<0.001, η(2)=0.163) and MetS (p=0.001, η(2)=0.011) were observed on total BRIAN score. There was a significant interaction between depression and MetS in total biological rhythm scores (p=0.002, η(2)=0.011) as well as sleep (p=0.001, η(2)=0.016) and social domains (p<0.001, η(2)=0.014). In the depressive group, subjects with MetS had a higher disruption in total BRIAN scores (p=0.010), sleep domain (p=0.004), social domain (p=0.005) and in the eating pattern domain approached the level of significance (p=0.098), when compared to subjects with no MetS. The results of the present study showed that self-reported disruptions in biological rhythms are associated with key components of the MetS in community adults with MDD. The understanding of the complex interactions between biological rhythms, MetS and depression are important in the development of preventive and therapeutic strategies., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Objectives: Depressive symptoms are associated with worse outcomes in patients with bipolar disorder (BD). However, scarce data are available regarding neurocognitive profiles across different areas of functioning among BD patients with moderate and severe depression. Our objective was to assess cognition and global functioning in a group of patients with bipolar depression., Methods: Data were available for 100 patients with bipolar depression (78% female) and 70 controls (64% female) paired by age and education level. Cognitive function was assessed with a neuropsychological test battery. Functioning was assessed with the Functioning Assessment Short Test., Results: In patients, severe depression was associated with poorer cognitive performance on measures of executive function. Patients with severe depression showed worse global functioning than those with moderate depression (z = 2.54, p = 0.011). In patients with severe depression, lower global functioning was associated with lower scores in working memory (r = -0.200, p = 0.010), and executive function (r = -0.210, p = 0.007; and r = 0.293, p < 0.001)., Conclusion: Our findings suggest cognitive impairment and global functioning impairment are associated with the severity of depressive symptoms in bipolar depression. Intensive treatment of depressive symptoms in patients with BD is crucial to improve cognitive functioning and, consequently, functional outcomes.

Background: Little is known about specific mood symptoms that may confer risk for suicidal ideation (SI) among patients with bipolar disorder (BD). We evaluated prospectively whether particular symptoms of depression and mania precede the onset or worsening of SI, among adults with or without a history of a suicide attempt., Methods: We examined prospective data from a large (N = 2,741) cohort of patients participating in the Systematic Treatment Enhancement Program for BD (STEP-BD). We evaluated history of suicide attempts at baseline, and symptoms of depression and mania at baseline and follow-up visits. Hierarchical linear modeling tested whether specific mood symptoms predicted subsequent levels of SI, and whether the strength of the associations differed based on suicide attempt history, after accounting for the influence of other mood symptoms and current SI., Results: Beyond overall current depression and mania symptom severity, baseline SI, and illness characteristics, several mood symptoms, including guilt, reduced self-esteem, psychomotor retardation and agitation, increases in appetite, and distractibility predicted more severe levels of subsequent SI. Problems with concentration, distraction, sleep loss and decreased need for sleep predicted subsequent SI more strongly among individuals with a suicide attempt history., Conclusions: Several specific mood symptoms may confer risk for the onset or worsening of SI among treatment-seeking patients with BD. Individuals with a previous suicide attempt may be at greater risk in part due to greater reactivity to certain mood symptoms in the form of SI. However, overall, effect sizes were small, suggesting the need to identify additional proximal predictors of SI., (© 2016 Wiley Periodicals, Inc.)

Bipolar disorder (BD) is a severe mental illness with a strong genetic component. Despite its high degree of heritability, current genetic studies have failed to reveal individual loci of large effect size. In lieu of focusing on individual genes, we investigated regulatory units (regulons) in BD to identify candidate transcription factors (TFs) that regulate large groups of differentially expressed genes. Network-based approaches should elucidate the molecular pathways governing the pathophysiology of BD and reveal targets for potential therapeutic intervention. The data from a large-scale microarray study was used to reconstruct the transcriptional associations in the human prefrontal cortex, and results from two independent microarray data sets to obtain BD gene signatures. The regulatory network was derived by mapping the significant interactions between known TFs and all potential targets. Five regulons were identified in both transcriptional network models: early growth response 3 (EGR3), TSC22 domain family, member 4 (TSC22D4), interleukin enhancer-binding factor 2 (ILF2), Y-box binding protein 1 (YBX1) and MAP-kinase-activating death domain (MADD). With a high stringency threshold, the consensus across tests was achieved only for the EGR3 regulon. We identified EGR3 in the prefrontal cortex as a potential key target, robustly repressed in both BD signatures. Considering that EGR3 translates environmental stimuli into long-term changes in the brain, disruption in biological pathways involving EGR3 may induce an impaired response to stress and influence on risk for psychiatric disorders, particularly BD.

Background: Little is known about predictors of recovery from bipolar depression., Aims: We investigated affective instability (a pattern of frequent and large mood shifts over time) as a predictor of recovery from episodes of bipolar depression and as a moderator of response to psychosocial treatment for acute depression., Method: A total of 252 out-patients with DSM-IV bipolar I or II disorder and who were depressed enrolled in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) and were randomised to one of three types of intensive psychotherapy for depression (n= 141) or a brief psychoeducational intervention (n= 111). All analyses were by intention-to-treat., Results: Degree of instability of symptoms of depression and mania predicted a lower likelihood of recovery and longer time until recovery, independent of the concurrent effects of symptom severity. Affective instability did not moderate the effects of psychosocial treatment on recovery from depression., Conclusions: Affective instability may be a clinically relevant characteristic that influences the course of bipolar depression., (© The Royal College of Psychiatrists 2015.)

Background: There is accumulating evidence that progressive changes in brain structure and function take place as schizophrenia unfolds. Among many possible candidates, oxidative stress may be one of the mediators of neuroprogression, grey matter loss and subsequent cognitive and functional impairment. Antioxidants are exogenous or endogenous molecules that mitigate any form of oxidative stress or its consequences. They may act from directly scavenging free radicals to increasing anti-oxidative defences. There is evidence that current treatments impact oxidative pathways and may to some extent reverse pro-oxidative states in schizophrenia. The existing literature, however, indicates that these treatments do not fully restore the deficits in antioxidant levels or restore levels of oxidants in schizophrenia. As such, there has been interest in developing interventions aimed at restoring this oxidative balance beyond the benefits of antipsychotics in this direction. If antioxidants are to have a place in the treatment of this serious condition, the relevant and up-to-date information should be available to clinicians and investigators., Objectives: To evaluate the effect of antioxidants as add-on treatments to standard antipsychotic medication for improving acute psychotic episodes and core symptoms, and preventing relapse in people with schizophrenia., Search Methods: We searched the Cochrane Schizophrenia Group's Study-Based Register of Trials which is based on regular searches of CINAHL, BIOSIS, AMED, Embase, PubMed, MEDLINE, PsycINFO, and registries of clinical trials. There are no language, time, document type, or publication status limitations for inclusion of records in the register. We ran this search in November 2010, and again on 8 January 2015. We also inspected references of all identified studies for further trials and contacted authors of trials for additional information., Selection Criteria: We included reports if they were randomised controlled trials (RCTs) involving people with schizophrenia who had been allocated to either a substance with antioxidant potential or to a placebo as an adjunct to standard antipsychotic treatment., Data Collection and Analysis: We independently extracted data from these trials and we estimated risk ratios (RR) or mean differences (MD), with 95% confidence intervals (CI). We assessed risk of bias for included studies and created a 'Summary of findings' table using GRADE., Main Results: The review includes 22 RCTs of varying quality and sample size studying Ginkgo biloba, N-acetyl cysteine (NAC), allopurinol, dehydroepiandrosterone (DHEA), vitamin C, vitamin E or selegiline. Median follow-up was eight weeks. Only three studies including a minority of the participants reported our a priori selected primary outcome of clinically important response. Short-term data for this outcome (measured as at least 20% improvement in scores on Positive and Negative Syndrome Scale (PANSS)) were similar (3 RCTs, n = 229, RR 0.77, 95% CI 0.53 to 1.12, low quality evidence). Studies usually reported only endpoint psychopathology rating scale scores. Psychotic symptoms were lower in those using an adjunctive antioxidant according to the PANSS ( 7 RCTS, n = 584, MD -6.00, 95% CI -10.35 to -1.65, very low quality evidence) and the Brief Psychiatric Rating Scale (BPRS) (8 RCTS, n = 843, MD -3.20, 95% CI -5.63 to -0.78, low quality evidence). There was no overall short-term difference in leaving the study early (16 RCTs, n = 1584, RR 0.73, 95% CI 0.48 to 1.11, moderate quality evidence), or in general functioning (2 RCTs, n = 52, MD -1.11, 95% CI -8.07 to 5.86, low quality evidence). Adverse events were generally poorly reported. Three studies reported useable data for 'any serious adverse effect', results were equivocal (3 RCTs, n = 234, RR 0.65, 95% CI 0.19 to 2.27, low quality evidence). No evidence was available for relapse, quality of life or service use., Authors' Conclusions: Although 22 trials could be included in this review, the evidence provided is limited and mostly not relevant to clinicians or consumers. Overall, although there was low risk of attrition and selective data reporting bias within the trials, the trials themselves were not adequately powered and need more substantial follow-up periods. There is a need for larger trials with longer periods of follow-up to be conducted. Outcomes should be meaningful for those with schizophrenia, and include measures of improvement and relapse (not just rating scale scores), functioning and quality of life and acceptability and, importantly, safety data.

Objective: We examined the relationship between biological rhythms and severity of depressive symptoms in subjects with bipolar disorder and the effects of biological rhythms alterations on functional impairment., Method: Bipolar patients (n = 260) and healthy controls (n = 191) were recruited from mood disorders programs in three sites (Spain, Brazil, and Canada). Parameters of biological rhythms were measured using the Biological Rhythms Assessment in Neuropsychiatry (BRIAN), an interviewer administered questionnaire that assesses disruptions in sleep, eating patterns, social rhythms, and general activity., Results: Multivariate analyses of covariance showed significant intergroup differences after controlling for potential confounders (Pillai's F = 49.367; df = 2, P < 0.001). Depressed patients had the greatest biological rhythms disturbance, followed by patients with subsyndromal symptoms, euthymic patients, and healthy controls. Biological rhythms and HAMD scores were independent predictors of poor functioning (F = 12.841, df = 6, P < 0.001, R 2  = 0.443)., Conclusion: Our study shows a dose-dependent association between the severity of depressive symptoms and degree of biological rhythms disturbance. Biological rhythms disturbance was also an independent predictor of functional impairment. Although the directionality of this relationship remains unknown, our results suggest that stability of biological rhythms should be an important target of acute and long-term management of bipolar disorder and may aid in the improvement of functioning., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Aim: To assess the functional impairment of young adults with bipolar disorder with substance abuse/dependence comorbidity., Method: Cross-sectional study within a community sample. Bipolar Disorder was assessed by qualified psychologists using The Mini International Neuropsychiatric Interview - PLUS (MINI-PLUS). Substance abuse and dependence was assessed using the "Alcohol, Smoking and Substance Involvement Screening Test" (ASSIST). Functional impairment was assessed using the Functional Assessment Short Test (FAST)., Results: The sample included 1259 young adults. The prevalence of Bipolar Disorder (BD) without Substance Abuse/Dependence (SAD) comorbidity was 5.9% (n=74), and the prevalence of bipolar disorder with substance abuse/dependence comorbidity was 1.4% (n=17). Both groups showed higher impairment in overall functioning, interpersonal relationship, and leisure time as compared to controls. In addition, BD+SAD showed higher impairment in the cognitive functioning domain of FAST., Limitation: A battery of neuropsychological tests was not performed., Conclusion: Functional impairment is associated with BD, independently of substance abuse or dependence. In addition, BD+SAD present a more severe impairment in the cognitive domain of FAST as compared to controls., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Background: Studies investigating inflammatory markers in post-traumatic stress disorder (PTSD) have yielded mixed results. The aim of our study was to compare concentrations of inflammatory markers in patients with PTSD compared with healthy controls., Methods: We did a meta-analysis and meta-regression of studies comparing inflammatory markers between patients with PTSD and healthy controls by searching PubMed, Embase, Scopus, Web of Science, and PsycINFO for articles published between Jan 1, 1960, and April 7, 2015. From eligible studies (ie, cross-sectional studies or baseline data from longitudinal studies of peripheral blood cytokine concentrations that compared adults with PTSD with healthy controls), we extracted outcomes of interest, such as mean and SD of peripheral blood cytokines, the time of day blood was collected, whether the study allowed patients with comorbid major depressive disorder in the PTSD group, whether patients were medication free, and severity of PTSD symptoms. We undertook meta-analyses whenever values of inflammatory markers were available in two or more studies. A random-effects model with restricted maximum-likelihood estimator was used to synthesise the effect size (assessed by standardised mean difference [SMD]) across studies., Findings: 8057 abstracts were identified and 20 studies were included. Interleukin 6 (SMD 0.88; p=0.0003), interleukin 1β (SMD 1.42; p=0.045), and interferon γ (SMD 0.49; p=0.002) levels were higher in the PTSD group than in healthy controls. Subgroup meta-analysis of patients who were not given medication showed higher tumour necrosis factor α (TNFα; SMD 0.69, 95% CI 0.35-1.02; p<0.0001) in the PTSD group than the control group in addition to the aforementioned cytokines. TNFα (SMD 1.32, 0.13-2.50; p=0.003), interleukin 1β (SMD 2.35, 0.01-4.68; p=0.048), and interleukin 6 (SMD 1.75, 0.97-2.53; p<0.0001) levels remained increased in the PTSD group in a subgroup meta-analysis of studies that excluded comorbid major depressive disorder. Illness duration was positively associated with interleukin 1β levels (b=0.33, p<0.0001) and severity with interleukin 6 (b=0.02, p=0.042). A model composed of several variables-presence of comorbid major depressive disorder, use of psychotropic medications, assay used, and time of day blood was collected-explained the large amount of heterogeneity between interleukin 1β, interleukin 6, and C-reactive protein studies. Egger's linear regression test revealed a potential publication bias for interleukin 1β. Additionally, for most inflammatory markers, study heterogeneity was reported to be high (I(2)>75%)., Interpretation: PTSD is associated with increased interleukin 6, interleukin 1β, TNFα, and interferon γ levels. This information might be useful for consideration of chronic low-grade inflammation as a potential target or biomarker in PTSD treatment. Use of psychotropic medication and presence of comorbid major depressive disorder were important moderators that might explain the inconsistency between results of previous studies. Our search strategy used a range of databases and we made exhaustive effort to acquire data by contacting the authors. Notably, high levels of between-study heterogeneity were recorded for most cytokine variables measured in our analysis. However, meta-regression analysis could explain a large amount of this heterogeneity., Funding: None., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Objective: To investigate peripheral levels of interleukin-10 (IL-10) in patients with major depressive disorder (MDD) and bipolar disorder (BD) and evaluate the relationship between IL-10, age of disease onset, and duration of illness., Methods: Case-control study nested in a population-based cohort of 231 individuals (age 18-24 years) living in Pelotas, state of Rio Grande do Sul, Brazil. Participants were screened for psychopathology using the Mini-International Neuropsychiatric Interview (MINI) and the Structured Clinical Interview for DSM-IV (SCID-I). Serum IL-10 was measured using commercially available immunoassay kits., Results: Peripheral levels of IL-10 were not significantly different in individuals with MDD or BD as compared to controls. However, higher IL-10 levels were found in MDD patients with a later disease onset as compared with controls or early-onset patients. In addition, IL-10 levels correlated negatively with illness duration in the MDD group. In the BD group, age of onset and duration of illness did not correlate with IL-10 levels., Conclusion: Higher levels of IL-10 are correlated with late onset of MDD symptoms. Moreover, levels of this cytokine might decrease with disease progression, suggesting that an anti-inflammatory balance may be involved in the onset of depressive symptoms and disease progression in susceptible individuals.

Progression of bipolar disorder (BD) has been associated with cognitive impairment and changes in neuroplasticity, including a decrease in serum brain-derived neurotrophic factor (BDNF). However, no study could examine BDNF levels directly in different brain regions after repeated mood episodes to date. The proposed animal model was designed to mimic several manic episodes and evaluate whether the performance in memory tasks and BDNF levels in hippocampus, prefrontal cortex, and amygdala would change after repeated amphetamine (AMPH) exposure. Adult male Wistar rats were divided into subchronic (AMPH for 7 days) and chronic groups (35 days), mimicking manic episodes at early and late stages of BD, respectively. After open field habituation or inhibitory avoidance test, rats were killed, brain regions were isolated, and BDNF mRNA and protein levels were measured by quantitative real-time PCR and ELISA, respectively. AMPH impaired habituation memory in both subchronic and chronic groups, and the impairment was worse in the chronic group. This was accompanied by increased Bdnf mRNA levels in the prefrontal cortex and amygdala region, as well as reduced BDNF protein in the hippocampus. In the inhibitory avoidance, AMPH significantly decreased the change from training to test when compared to saline. No difference was observed between subchronic and chronic groups, although chronically AMPH-treated rats presented increased Bdnf mRNA levels and decreased protein levels in hippocampus when compared to the subchronic group. Our results suggest that the cognitive impairment related to BD neuroprogression may be associated with BDNF alterations in hippocampus, prefrontal cortex, and amygdala., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Objectives: The primary objective of this study was to assess the relationship between countertransference (CT) and therapeutic alliance (TA) during the early stages of psychodynamic psychotherapy. A secondary objective is to assess associations between CT and variables related to therapist and patient and between CT and other patient variables investigated, which were defense mechanisms, symptomology and functionality., Methodology: This was a cross-sectional study that enrolled 30 patients treated by 17 different therapists at the psychotherapy clinics of two psychiatry centers. Assessments of each patient-therapist pair were conducted between their fourth and 10th sessions., Results: The CT distance domain exhibited a moderate negative correlation with TA, particularly its sub-dimension representing the patient's capacity for work in therapy. Moderate positive correlations were observed between CT distance and the splitting defense mechanism and between CT closeness and suppression defenses, in addition to moderate negative correlation between CT indifference and the fantasy defense mechanism. Another finding was higher scores for CT indifference in association with socioeconomic classes D and E., Conclusions: The quality of CT may provide a source of information about TA. A high degree of CT distance represents a low level of TA, particularly with relation to the patient's working capacity, although presence of the splitting defense mechanism can affect CT, to the extent that it constitutes a confounding variable. The concept of CT is useful to psychotherapists, providing a source of information about the patient's internal world and about certain elements of therapy, such as the quality of TA, which is important for good treatment results.

Objective: To assess the relationship between crack cocaine use and dimensions of quality of life and social functioning in young adults., Methods: This was a cross-sectional, population-based study involving 1,560 participants in Pelotas, Brazil. Crack cocaine use and abuse were investigated using the Alcohol, Smoking and Substance Involvement Screening Test (ASSIST) inventory. Outcomes of interest were quality of life, religiosity, and social functioning in terms of education, occupational status, family structure, and medical treatment history., Results: Lifetime crack cocaine use was associated with poor quality of life, worse functioning, impaired academic performance, and lower religious involvement. A greater maternal presence and higher paternal absence were more also more pronounced in crack cocaine users, who were also more likely to seek psychological and psychiatric treatment than the general population., Conclusion: Quality of life was severely impacted by crack cocaine use, especially in terms of general and physical health. Social functioning also differed between the general population and crack users, who had lower educational attainment and religious involvement. Maternal presence, paternal absence, and mental health-seeking behaviors were also more frequent among crack cocaine users, although these individuals reported lower rates of treatment satisfaction. Crack cocaine users also had significant social impairment, so that interventions involving family management and a greater focus on general health, quality of life, and functioning may make crucial contributions to the recovery of this group.

Objective: The impact of childhood trauma (CT) on brain-derived neurotrophic factor (BDNF) and cytokines levels remains unclear. We investigated the association between CT and changes in BDNF and cytokines plasma levels in children., Method: We recruited 36 children with trauma (CT+) and 26 children without trauma (CT-). The presence of CT was based on a clinical interview and by Criteria A of DSM-IV criteria for PTSD. Blood samples were drawn from all children to assess BDNF and cytokines. ancova was performed with psychiatric symptoms and BMI as covariates to evaluate group differences in plasma levels., Results: CT+ showed increased levels of BDNF and TNF-α after excluding children with history of inflammatory disease (P<0.05) when compared with those CT-. IL-12p70, IL-6, IL-8, IL-10, and IL-1β levels were not statistically different between groups., Conclusion: CT+ showed increased BDNF and proinflammatory cytokines levels. The increase in BDNF levels may be an attempt to neutralize the negative effects of CT, while an increase in TNF-a levels be associated with a proinflammatory state after CT. How these changes associated with trauma relate to other biological changes and illness trajectory later in life remain to be further studied., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: We discuss the rationale behind staging systems described specifically for bipolar disorders. Current applications, future directions and research gaps in clinical staging models for bipolar disorders are outlined., Method: We reviewed the literature pertaining to bipolar disorders, focusing on the first episode onwards. We systematically searched data on staging models for bipolar disorders and allied studies that could inform the concept of staging., Results: We report on several dimensions that are relevant to staging concepts in bipolar disorder. We consider whether staging offers a refinement to current diagnoses by reviewing clinical studies of treatment and functioning and the potential utility of neurocognitive, neuroimaging and peripheral biomarkers., Conclusion: Most studies to date indicate that globally defined late-stage patients have a worse overall prognosis and poorer response to standard treatment, consistent with patterns for end-stage medical disorders. We believe it is possible at this juncture to speak broadly of 'early'- and 'late'-stage bipolar disorder. Next steps require further collaborative efforts to consider the details of preillness onset and intermediary stages, and how many additional stages are optimal., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Mood disorders are a consequence of the interaction between environmental and biological factors. The objective of this study was to identify associations between stressful life events (LEs) and mood disorders in a community sample of young people in southern Brazil. It is a cross-sectional population-based study on young people between 18 and 24 years of age. The selection of the sample was conducted via conglomerates. Mini International Neuropsychiatric Interviews were used to evaluate mood disorders, and the Social Readjustment Rating Scale to assess stressful life events. The sample included 1172 young people. Of the total sample, the proportion of stressful life events in the last year in each category was: 53.8% work, 42.4% loss of social support, 63.8% family, 50.9% environmental changes, 61.1% personal difficulties, and 38.7% finances. A significant relationship was found between categories of stressful life events and mood disorder episodes. A higher incidence of stressful life events was found among young people in a mixed episode compared to young people in a depressive, (hypo)maniac episode with controls. This finding suggests a psychosocial interaction between stressful life events and the occurrence of mood disorders.

Objective: To estimate the prevalence of lifetime use of crack cocaine and to assess associations with violent and sexual behaviors in young adults selected from the general population of Pelotas, Southern Brazil., Methods: This cross-sectional population-based study included 1,560 participants aged 18-24 years. The use of alcohol and other substances, including crack cocaine, was assessed using the alcohol, smoking and substance involvement screening test. Other variables included violent behaviors, firearm possession, and sexual risk behaviors. The frequency of antisocial personality disorder was also investigated. Associations were analyzed using a crude model and models adjusted for sex, social class, and the use of snorted cocaine., Results: Lifetime prevalence of crack cocaine use was 2.51 %, and it was higher among males and individuals coming from more vulnerable social classes (D or E). In the final multivariate models, lifetime use of crack cocaine was associated with episodes of aggression and firearm possession, as well as with a higher chance of not having used condom in the last sexual intercourse. In less conservative models, crack cocaine use was associated with other violent and sexual risk behaviors., Discussion: The strong association observed between lifetime use of crack cocaine and different violent and sexual risk behaviors underscores relevant characteristics of people who use crack cocaine. Improving our understanding of possible causal chains leading to such associations should be a priority in future studies.

Objective: To assess the association between lifetime crack cocaine use and psychiatric (post-traumatic stress disorder, current depression, current dysthymia, generalized anxiety disorder, panic disorder with agoraphobia, social phobia, as well as SRQ scores and suicide risk) and substance-use disorders (tobacco, alcohol, cannabis, cocaine, amphetamine, inhalants, sedatives, hallucinogens and opioids) in youth in the general population of the city of Pelotas, RS., Method: This was a cross-sectional population-based study, involving 1560 participants between 18 and 24 ears old. Lifetime substance use and abuse were investigated using the ASSIST inventory. Psychiatric comorbidities were assessed using the Mini-International Neuropsychiatric Interview and symptoms of common mental disorders were evaluated with the Self-Reported Questionnaire (SRQ)., Results: The prevalence of lifetime crack cocaine use in the sample was 2.5%. Its use was associated with total SRW scores and the presence of post-traumatic stress disorder, antisocial personality disorder and suicide risk in the final regression model. Tobacco, alcohol, cannabis, cocaine, amphetamine and cocaine dependence were also associated with lifetime use of crack cocaine., Discussion: Youth with a history of crack cocaine use had a higher prevalence of psychiatric conditions such as post-traumatic stress disorder, as well as an increased risk of tobacco, alcohol, cannabis, cocaine, amphetamine and inhalant use and dependence., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Objective: There are several models of staging in bipolar disorder (BD), but none has been validated. The aims of this study were to empirically investigate clinical variables that may be useful to classify patients in clusters according to stage and study the association with biomarkers as biological validators., Method: This was a historical cohort study. Patients (n = 115) diagnosed with BD and not in an acute episode and first-degree relatives of patients diagnosed with BD (n = 25) were recruited. Sociodemographic, clinical, and functional data were collected. Serum cytokines, brain-derived neurotrophic factor, and biomarkers of lipid and protein oxidation were assessed. Cluster analysis was carried out to build a model of staging, and logistic regression was conducted to study associations between the model and biomarkers., Results: Cluster analysis divided the sample into two equitable groups, denominated early and late stage, with empirical cutoffs for the Functioning Assessment Short Test score, number of episodes, age at onset of the disorder, and time elapsed since first episode. In the logistic regression, IL-6 was associated with late stage (P = 0.029)., Conclusion: This study supports that clinical, functional, and biochemical variables may help to define a classification of staging in BD., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Caregiver burden has been associated with caregivers' mental disorders and need for support and information. However, the lack of quantitative studies and formal interventions aiming to lower burden levels in this population reflect the current negligence regarding this important issue., Aim: To identify burden levels and associated factors in caregivers of young adults with bipolar and unipolar mood disorder., Method: This is a cross-sectional study nested within a population-based cross-sectional study with young adults. Caregiver burden was assessed through the Burden Interview. Information about caregiver mental disorders (Axis I) and alcohol abuse were obtained through the Mini International Neuropsychiatric Interview (MINI) and the Cut-Down, Annoyed, Guilty and Eye-Opener (CAGE) questionnaire, respectively., Results: Caregiver burden was associated to caregiver's mood and anxiety disorders, suicide risk and being the caregiver of young adults with depression disorder and bipolar disorder. Also, burden was higher among caregivers of bipolar individuals. When excluding the control group from the analysis, only mood and anxiety disorders remained associated to caregiver burden., Conclusions: Caregivers are affected by the young adult's disorder even before a diagnosis has been given, with serious impairments in their lives. Thus, this is a subject in need of designing relevant strategies aiming to provide them with care., (© The Author(s) 2013.)

Objective: Brain-derived neurotrophic factor (BDNF) is consistently associated with acute mood episodes in bipolar disorder, but there is a lack of longitudinal data to support this hypothesis. In this 16-week open-label clinical trial, we tested the predictive role of BDNF Val66Met polymorphism on serum BDNF levels and the relationship of serum BDNF and clinical response in people with bipolar disorder during an acute illness episode., Method: Sixty-four people with bipolar disorder who were medication-free at baseline and in an acute mood episode were recruited. They were matched with 64 healthy controls. Clinical evaluation, serum BDNF, and BDNF Val66Met polymorphism were determined at baseline, and change in serum BDNF was assessed in patients at weeks 2, 4, 8 and 16., Results: There were no differences between patients and controls in serum BDNF or in frequencies of the BDNF Val66Met polymorphism genotype at baseline. The multivariable model showed that Met carriers had a significantly different change in BDNF levels compared with Val homozygotes. Not achieving a complete remission was also associated with lower prospectively assessed BDNF levels., Conclusion: This study provides the first longitudinal evidence that both the BDNF Val66Met polymorphism and remission status predict change in circulating BDNF levels., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: Clinical staging has increasingly been considered suitable for psychiatric disorders such as bipolar disorder. A staging model of bipolar disorder could help clinicians understand the mechanisms underlying the course of the illness and guide prognosis and therapy. This study aimed to investigate differences in functional status and cognitive functioning in patients in different clinical stages of bipolar disorder., Method: Subjects who met DSM-IV criteria for bipolar disorder (n = 54) were recruited from the Bipolar Disorders Program at Hospital de Clínicas de Porto Alegre (Brazil) from October 2012 to October 2013. All patients had been in remission (score < 7 on the 17-item HDRS and the YMRS) for at least 1 month before assessment. They were classified into 4 clinical stages according to the model described by Kapczinski et al and compared to 43 healthy controls. Functional status was assessed by using the Functioning Assessment Short Test (FAST). Neuropsychological measures were performed to investigate cognitive functioning., Results: Significant differences in functional status were found between patients in all stages compared to controls (F = 33.014, P < .001), except for stage I (P = .104). Additionally, a very strong linear association was found between FAST scores and clinical stages, with FAST scores increasing from stage I to IV (F = 149.55, P < .001). In the bipolar group, stage I was associated with better occupational functioning than stage II (F = 48.344, P = .003). Stage IV patients experienced greater impairment in autonomy than stage III patients (F = 26.646, P = .004), and stage III patients experienced poorer autonomy than those in stage II (P = .004). With regard to cognitive measures, patients in late stages (stages III and IV) were more impaired than healthy controls (P < .001). A similar performance was found between patients in early stages (stages I and II) and healthy controls., Discussion: This study showed progressive functional changes from stage I to stage IV of bipolar disorder, with a greater impairment in patients in later stages of the illness. FAST scores seem to have a good discriminant ability to distinguish between patients in early versus late stages of bipolar disorder and could therefore contribute to the development of a bipolar disorder staging system., (© Copyright 2014 Physicians Postgraduate Press, Inc.)

Objective: At least 50% of individuals with bipolar disorder have a lifetime anxiety disorder. Individuals with both bipolar disorder and a co-occurring anxiety disorder experience longer illness duration, greater illness severity, and poorer treatment response. The study explored whether comorbid lifetime anxiety in bipolar patients moderates psychotherapy treatment outcome., Method: In the Systematic Treatment Enhancement Program randomized controlled trial of psychotherapy for bipolar depression, participants received up to 30 sessions of intensive psychotherapy (family-focused therapy, interpersonal and social rhythm therapy, or cognitive-behavioral therapy) or collaborative care, a three-session comparison treatment, plus pharmacotherapy. Using the number needed to treat, we computed effect sizes to analyze the relationship between lifetime anxiety disorders and rates of recovery across treatment groups after 1 year., Results: A total of 269 patients (113 women) with a comorbid lifetime anxiety disorder (N=177) or without a comorbid lifetime anxiety disorder (N=92) were included in the analysis. Participants with a lifetime anxiety disorder were more likely to recover with psychotherapy than with collaborative care (66% compared with 49% recovered over 1 year; number needed to treat=5.88, small to medium effect). For patients without a lifetime anxiety disorder, there was no difference between rates of recovery in psychotherapy compared with collaborative care (64% compared with 62% recovered; number needed to treat=50, small effect). Participants with one lifetime anxiety disorder were likely to benefit from intensive psychotherapy compared with collaborative care (84% compared with 53% recovered; number needed to treat=3.22, medium to large effect), whereas patients with multiple anxiety disorders exhibited no difference in response to the two treatments (54% compared with 46% recovered; number needed to treat=12.5, small effect)., Conclusions: Depressed patients with bipolar disorder and comorbid anxiety may be in particular need of additional psychotherapy for treating acute depression. These results need to be replicated in studies that stratify bipolar patients to treatments based on their anxiety comorbidity status.

The present study aimed to determine whether any gender-related difference exists concerning oxidative stress parameters in a population of 231 subjects, and if these changes might be related to gender-associated differences in major depressive disorder (MDD) or bipolar disorder (BD) vulnerability. This is a case-control nested in a population-based study. The initial psychopathology screen was performed with the Mini-International Neuropsychiatric Interview and the diagnostic was further confirmed with the Structured Clinical Interview for DSM-IV. Blood samples were obtained after the interview and the oxidative stress parameters such as uric acid, advanced oxidation protein product (PCC) and lipid hydroperoxides (TBARS) were determined. Our results indicated a higher prevalence of MDD and BD in women when compared to men. In addition, significant gender differences were found in the levels of PCC (0.27±0.27 vs. 0.40±0.31nmol CO/mg protein, men vs. women, respectively; P=0.02) and uric acid (4.88±1.39mg/dL vs. 3.53±1.02mg/dL, men vs. women, respectively; P=0.0001), but not in TBARS (0.013±0.01nmol/mg of protein vs. 0.017±0.02nmol/mg of protein, men vs. women respectively; P=0.243). After sample stratification by gender, no association was found between oxidative stress parameters and clinical diagnosis of MDD and BD for women (P=0.516 for PCC; P=0.620 for TBARS P=0.727 for uric acid) and men (P=0.367 for PCC; P=0.372 for TBARS P=0.664 for uric acid). In this study, women seem more susceptible to oxidative stress than male. However, these gender-based differences do not seem to provide a biochemical basis for the epidemiologic differences in mood disorders susceptibility between sexes., (Copyright © 2013 Elsevier Masson SAS. All rights reserved.)

Background: Relatively little is known about psychological predictors of the onset of mania among individuals with bipolar disorder, particularly during episodes of depression. In the present study we investigated attributional style as a predictor of onset of hypomanic, manic or mixed episodes among bipolar adults receiving psychosocial treatment for depression. We hypothesized that "extreme" (i.e., excessively pessimistic or optimistic) attributions would predict a greater likelihood of developing an episode of mood elevation., Method: Outpatients with DSM-IV bipolar I or II disorder (N = 105) enrolled in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) were randomly allocated to one of three types of intensive psychotherapy for depression or a brief psychoeducational intervention. Patients completed a measure of attributional style at baseline and were followed prospectively for up to one year. All analyses were by intent to treat., Results: Logistic regressions and Cox proportional hazards models indicated that extreme (both positively- and negatively-valenced) attributions predicted a higher likelihood of (and shorter time until) transition from depression to a (hypo)manic or mixed episode (ps < .04), independent of the effects of manic or depressive symptom severity at baseline. Extreme attributions were also retrospectively associated with more lifetime episodes of (hypo)mania and depression (ps < .05)., Conclusions: Evaluating extreme attributions may help clinicians to identify patients who are at risk for experiencing a more severe course of bipolar illness, and who may benefit from treatments that introduce greater cognitive flexibility., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Recent studies highlight the presence of systemic toxicity as an integral dimension of bipolar disorder pathophysiology, possibly linking this mood disorder with other medical conditions and comorbidities. This review summarizes recent findings on possible peripheral biomarkers of illness activity, with a focus on neurotrophins, inflammation and oxidative stress. The possible mechanisms underlying the systemic toxicity associated with acute episodes in bipolar disorder are also discussed. Finally, the authors outline novel therapies that emerge from this new research and the assessment of multiple biomarkers as a potential approach to improving management strategies in bipolar disorder.

A growing body of evidence suggests that crack cocaine misuse has widespread systemic and cognitive consequences, but little attention has been given to its systemic pathophysiology. We report here changes in inflammation markers, oxidative damage and brain derived neurotrophic factor in a sample of outpatients with crack cocaine use disorders. Fifty-three outpatients were recruited for this cross-sectional study and matched with fifty control subjects. The focus of this report is in between group differences in cytokines, oxidative damage and brain-derived neurotrophic factor (BDNF). Crack cocaine use was associated with higher BDNF levels when compared to controls, present only in those who used crack cocaine in the last month. Patients also had higher circulating levels of IL-1β, TNF-α and IL-10 when compared to controls. There were no significant differences in oxidative damage between patients and controls. These results represent a first demonstration that crack cocaine use disorders entail an activation of the reward, immune and inflammatory systems., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Objective: Oxidative imbalance has emerged as a treatment target in bipolar disorder. As very limited data are available on the clinical use of antioxidants for mania, we report here results from a post hoc and exploratory subgroup analysis of a randomized, placebo-controlled trial of N-acetyl cysteine (NAC)., Methods: This was a placebo-controlled, randomized, clinical trial assessing the effect of NAC over 24 weeks in mania or hypomania. Symptomatic and functional outcomes were collected over the study period., Results: Fifteen participants were available for this report; two participants in each group failed to complete all assessments. Within-group analyses pointed to an improvement in the NAC group on manic symptoms and worsening in the placebo group on depressive symptoms at endpoint., Conclusions: Although the sample size was small, these results indicated within-group efficacy for this glutathione precursor as compared to placebo. Future trials specifically designed to demonstrate the efficacy of NAC in mania are needed.

Objective: To assess quality of life among Brazilian young adults who are 18-24 years old and who experience depressive, manic/hypomanic, and mixed episodes., Method: This is a cross-sectional population-based study. The sample was selected in clusters. Mood disorders were assessed using a short, structured diagnostic interview-the Mini International Neuropsychiatric Interview (MINI) for DSM-IV and ICD-10 psychiatric disorders. Quality of life was assessed by the MOS 36-item Short-form General Health Survey (SF-36)., Results: The sample comprised 1560 young adults. The prevalence ratio of mood disorder episodes were as follows: 10.0% depressive episode, 2.3% manic/hypomanic episode, and 2.4% mixed episode. Lower scores were found in all domains of quality of life among young adults who experience mood disorder episodes when compared to the general population (p<0.001 in the eight domains of the SF-36). Moreover, the impact on quality of life was higher among young adults with mixed episodes, followed by depressive episodes., Conclusion: Young adults with mood disorders, even without a previous diagnosis of bipolar disorder, have an impaired quality of life in comparison to the general population., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Objective: Bipolar disorder (BD) is associated with significant morbidity and mortality due to comorbid general medical conditions, particularly cardiovascular disease. This study is the first report of the Brazilian Research Network in Bipolar Disorder (BRN-BD) that aims to evaluate the prevalence and clinical correlates of cardiovascular risk factors among Brazilian patients with BD., Methods: A cross-sectional study of 159 patients with DSM-IV BD, 18 years or older, consecutively recruited from the Bipolar Research Program (PROMAN) in São Paulo and the Bipolar Disorder Program (PROTAHBI) in Porto Alegre. Clinical, demographic, anthropometric, and metabolic variables were systematically assessed., Results: High rates of smoking (27%), physical inactivity (64.9%), alcohol use disorders (20.8%), elevated fasting glucose (26.4%), diabetes (13.2%), hypertension (38.4%), hypertriglyceridemia (25.8%), low HDL-cholesterol (27.7%), general (38.4%) and abdominal obesity (59.1%) were found in the sample. Male patients were more likely to have alcohol use disorders, diabetes, and hypertriglyceridemia, whereas female patients showed higher prevalence of abdominal obesity. Variables such as medication use pattern, alcohol use disorder, and physical activity were associated with selected cardiovascular risk factors in the multivariable analysis., Conclusion: This report of the BRN-BD provides new data regarding prevalence rates and associated cardiovascular risk factors in Brazilian outpatients with BD. There is a need for increasing both awareness and recognition about metabolic and cardiovascular diseases in this patient population.

Objective: To verify the prevalence and clinical impact of excessive daytime sleepiness (EDS) in outpatients with bipolar disorder., Methods: Eighty-one outpatients with bipolar disorder and 79 healthy control subjects were recruited. Patients were required not to be acutely manic or depressed. We used the Epworth Sleepiness Scale, the Pittsburgh Sleep Quality Index and the Functioning Assessment Short Test to assess sleepiness, sleep problems and functioning, respectively., Results: Patients had a higher prevalence of sleepiness (40%) than the control group (18%). Sleepiness and sleep disturbance had independent impacts on disability in the multivariable model., Conclusions: This study suggests that EDS is a relevant clinical dimension in patients with bipolar disorder. It is a frequent symptom that often overlaps with other sleep disturbances. This study also reveals that once present it has the potential to increase functional impairment.