Mood disorders and prospective suicidality in young adults: a population-based cohort study.

OBJECTIVE: To assess the prospective associations of mood disorders and suicidality in a community sample of young adults from south Brazil. METHOD: Prospective population-based cohort study. Young adults (18-24 years old) were recruited and followed up on 5 years later; people were interviewed at their homes. Suicidality, as well as mood and anxiety disorders, was assessed using the Mini-International Neuropsychiatric Interview. The impact of mood episodes on suicidality was both evaluated when they occurred in the same wave (a current episode) and when suicidality occurred prospectively, with suicidality measured at follow-up (a past episode). RESULTS: The sample included 1560 young adults at baseline, with 1244 reassessed at follow-up (80.6%). Depressive episodes, both current and past, had a significant impact on suicidality in the final multivariable model. Manic episodes, however, were less consistently associated with suicidality. CONCLUSION: Depressive episodes have a strong, independent, and robust association with prospective suicidality. The association between manic episodes and suicidality, on the other hand, was dependent on the analysis and deserves further exploration.

Differential expression of transcriptional regulatory units in the prefrontal cortex of patients with bipolar disorder: potential role of early growth response gene 3.

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.

Childhood trauma, family history, and their association with mood disorders in early adulthood.

OBJECTIVE: To assess the prevalence of childhood trauma and types of trauma on mood disorders among young adults in a population-based sample. We further gathered data on family history of mood disorders to test the hypothesis that childhood trauma is a mediating factor for the association between family history of mood disorder and mood disorder in adulthood. METHOD: This is a cross-sectional study, including young adults with bipolar disorder, major depressive disorder, and matched controls without any mood disorder. Childhood trauma was assessed using the Childhood Trauma Questionnaire (CTQ). The Hicks and Tingley implementation was employed to assess whether trauma is a mediator of the effect of family history on diagnosis of any mood disorder. RESULTS: All types of trauma were associated with both major depression and bipolar disorder, with the exception of sexual abuse, which was only associated with bipolar disorder. Moreover, family history of psychiatric illness was also associated with mood disorder in adulthood and with childhood trauma. Using the presence of any mood disorder as the outcome, a third of the effect of having any family history of mood disorder was mediated via childhood trauma. CONCLUSION: This investigation provides further support, in a population-based sample of young adults, of the association between childhood trauma and mood disorders, with sexual abuse being specifically linked with bipolar disorder. The hypothesis that childhood trauma would function as a partial mediator of the association between family history of mood disorder and mood disorder in adulthood was also confirmed.

The association between biological rhythms, depression, and functioning in bipolar disorder: a large multi-center study.

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, R2  = 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.

Brain-derived neurotrophic factor and inflammatory markers in school-aged children with early trauma.

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-1ß 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.

Age at onset, course of illness and response to psychotherapy in bipolar disorder: results from the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD).

BACKGROUND: The 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. METHOD: Embedded 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. RESULTS: Independently 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. CONCLUSIONS: Number of previous mood episodes and illness duration are associated with the likelihood and speed of recovery among bipolar patients receiving psychosocial treatments for depression.

Staging systems in bipolar disorder: an International Society for Bipolar Disorders Task Force Report.

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.

Staging bipolar disorder: clinical, biochemical, and functional correlates.

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.

Val66Met polymorphism and serum brain-derived neurotrophic factor in bipolar disorder: an open-label trial.

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.

Gender-based differences in oxidative stress parameters do not underlie the differences in mood disorders susceptibility between sexes.

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.

Systemic illness moderates the impact of N-acetyl cysteine in bipolar disorder.

OBJECTIVES: Bipolar disorder (BD) is intricately associated with chronic clinical conditions. Medical comorbidity is not only more prevalent in mood disorders, but is associated with increased costs, cognitive impairment and, ultimately, premature mortality. Oxidative stress and inflammation may mediate part of this association. To further investigate the association between medical comorbidity status and clinical improvement with adjuvant N acetyl cysteine (NAC) in the context of a placebo-controlled trial. METHODS: Placebo-controlled randomized clinical trial assessing the effect of NAC over 24 weeks. Symptomatic and functional outcomes were collected over the study period. Medical comorbidities were self-reported, and we took special interest in cardiovascular and endocrine conditions. We evaluated change from baseline to endpoint and the interaction between change and reported medical comorbidities. RESULTS: Fifty-one percent of patients reported have a cardiovascular or endocrine comorbidity. Although not found for depressive symptoms or quality of life, a significant interaction between medical comorbidity and change scores was consistently found for all functional outcomes. This indicated an advantage of NAC over placebo in those with a clinical comorbidity. CONCLUSION: Systemic illness moderated only the effect of NAC on functioning, not on depression. Demonstrating an improvement in functional outcomes with an agent that modulates redox and inflammatory pathways, this study lends empirical support to the idea that medical and psychiatric comorbidity are additive in contributing to allostatic states. One intriguing possibility is that comorbid clinical illness could be a marker for more severe oxidative stress states--and thus guide antioxidant use--in BD.

Illness burden and medical comorbidity in the Systematic Treatment Enhancement Program for Bipolar Disorder.

OBJECTIVE: Coexisting chronic medical conditions are common in bipolar disorder. Here, we report the prevalence and correlates of medical comorbidity in patients enrolled in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD). We were particularly interested in associations between variables reflecting illness chronicity and burden with comorbid medical conditions. METHOD: We used intake data from the open-label component of the STEP-BD. History of medical comorbidity was obtained from the affective disorders evaluation, and its presence was the outcome of interest. The sample size in analyses varied from 3399 to 3534. We used multiple Poisson regression to obtain prevalence ratios. RESULTS: The prevalence of any medical comorbidity in the sample was 58.8%. In addition to demographic variable, several clinical characteristics were associated with the frequency of medical comorbidity. Having more than 10 previous mood episodes, childhood onset, smoking, lifetime comorbidity with anxiety, and substance use disorders were independently associated with having a medical comorbidity in the final multivariate model. CONCLUSION: The results presented here reveal strong associations between variables related to illness chronicity and medical burden in bipolar disorder. This lends further support to recent multidimensional models incorporating medical morbidity as a core feature of bipolar disorder.

Pathways underlying neuroprogression in bipolar disorder: focus on inflammation, oxidative stress and neurotrophic factors.

There is now strong evidence of progressive neuropathological processes in bipolar disorder (BD). On this basis, the current understanding of the neurobiology of BD has shifted from an initial focus on monoamines, subsequently including evidence of changes in intracellular second messenger systems and more recently to, incorporating changes in inflammatory cytokines, corticosteroids, neurotrophins, mitochondrial energy generation, oxidative stress and neurogenesis into a more comprehensive model capable of explaining some of the clinical features of BD. These features include progressive shortening of the inter-episode interval with each recurrence, occurring in consort with reduced probability of treatment response as the illness progresses. To this end, emerging data shows that these biomarkers may differ between early and late stages of BD in parallel with stage-related structural and neurocognitive alterations. This understanding facilitates identification of rational therapeutic targets, and the development of novel treatment classes. Additionally, these pathways provide a cogent explanation for the efficacy of seemingly diverse therapies used in BD, that appear to share common effects on oxidative, inflammatory and neurotrophic pathways.

N-acetyl cysteine add-on treatment for bipolar II disorder: a subgroup analysis of a randomized placebo-controlled trial.

BACKGROUND: The evidence base for the pharmacological treatment of bipolar II disorder is limited. In bipolar disorder, there is evidence for glutathione depletion and increased oxidative stress, as well as dysregulation of glutamate; N-acetyl cysteine (NAC) has effects on both of these systems. Add-on NAC has been shown to have a significant benefit on depressive symptoms in a randomized placebo-controlled trial. In this report, we explore the effects of this compound in a subset of patients with bipolar II disorder from that trial. METHODS: Individuals were randomized to NAC or placebo in addition to treatment as usual, in a double-blind fashion. Mood and functional outcomes were assessed up to 24 weeks of treatment. RESULTS: Fourteen individuals were available for this report, seven in each group. Six people achieved full remission of both depressive and manic symptoms in the NAC group; this was true for only two people in the placebo group (χ(2)=4.67, p=0.031). LIMITATIONS: Subgroup analyses in a small subsample of patients. Not all participants had elevated depression scores at baseline. CONCLUSION: Notwithstanding all the limitations that subgroup analysis of trials carry, this data could serve as a hypothesis-generating stimulus for further clinical trials of pharmacologic treatment for bipolar II depression.

Stigma and functioning in patients with bipolar disorder.

OBJECTIVE: The aim of this study was to investigate the impact of self-rated stigma and functioning in patients with bipolar disorder in Latin-America. METHODS: Two-hundred and forty-one participants with bipolar disorder were recruited from three Latin American countries (Argentina, Brazil, and Colombia). Functional impairment was assessed with the Functioning Assessment Short Test (FAST) and experiences with and impact of perceived stigma was evaluated using the Inventory of Stigmatizing Experiences (ISE). RESULTS: Higher scores of self-perceived stigma were correlated with lower scores of functioning. After multiple regression analysis, being on disability benefit, current mood symptoms and functioning were associated with self-perceived stigma. CONCLUSIONS: This is the first study to demonstrate an association between stigma and poor functioning in bipolar disorder. Possible implications of such findings for practitioners are discussed. LIMITATIONS: The main limitation of this study is that the Inventory of Stigmatizing Experiences has not yet been validated in a population of bipolar patients in our countries. The sample size and heterogeneous clinical subjects from different countries and cultures limit the generalization of the present findings.

Birth-cohort and dual diagnosis effects on age-at-onset in Brazilian patients with bipolar I disorder.

OBJECTIVE: Substance use disorders and birth-cohort have been associated with an earlier onset in bipolar disorder (BD). This study aimed at evaluating the inter-relations of these factors in age-at-onset in bipolar illness. METHOD: Two-hundred and thirty patients with bipolar I disorder were cross-sectionally evaluated. Patients were categorized into four age groups for analysis. Lifetime comorbidity and age-at-onset were derived from the Structured Clinical Interview for DSM-IV. RESULTS: There was a strong linear association between age group and age-at-onset. Lifetime alcohol and drug use disorders were also associated with age-at-onset. Illicit drug and alcohol use disorders and age group remained significant in the multivariate model. No interactions appeared. CONCLUSION: Both age group and dual diagnoses had strong and independent impacts on age-at-onset in out-patients with BD. Substance abuse may be partly accountable for earlier symptom onset, but other features of BD in younger generations are still in need to be accounted for.

Two studies on suicidality in the postpartum.

OBJECTIVE: Research in the prevalence of and risk factors for suicidality in the postpartum is extremely limited. We present here data on the prevalence of and factors associated with suicidality from two postpartum samples. METHOD: The first sample (SC) comprised 317 women consecutively screened for a trial of psychotherapy for postpartum depression. The second sample was a population-based (PB) sample of 386 women. We used the Mini-International Neuropsychiatric Interview (MINI) to assess suicidality in the SC sample and the self-harm question of the Beck Depression Inventory (BDI9) in the PB sample. RESULTS: According to the MINI and the BDI9, prevalence of high suicide risk was 5.7% and 11.1%, respectively, in the SC sample. Previous suicide attempts and a positive BDI were retained as predictors of suicidality. The BDI9 indicated suicidality in 8.3% of the 386 women in the PB sample; a positive BDI was retained in the multivariate analysis as a risk of suicidality. CONCLUSION: Clinicians should enquire vigorously about suicidality in women presenting with depressive symptoms or previous suicide attempts in the postpartum.

Is paternal postpartum depression associated with maternal postpartum depression? Population-based study in Brazil.

OBJECTIVE: To describe the prevalence of paternal postpartum depression (PPD) as well as its association with maternal PPD. METHOD: A population-based random sample of 386 couples was assessed from the sixth to the 12th week postpartum for demographic characteristics, alcohol misuse (AUDIT) and depressive symptoms [Beck Depression Inventory (BDI)]. Logistic regression was employed to control for potential confounders. RESULTS: In the BDI, 26.3% of mothers and 11.9% of fathers scored above the selected threshold of 10. Mild maternal depression [odds ratio (OR) 3.31, 95% CI 1.52-7.20] and moderate to severe maternal depression (OR 8.44, 95% CI 3.53-20.21) were associated with paternal PPD. CONCLUSION: Paternal PPD is a clinically meaningful phenomenon. Fathers should be evaluated for mood disorders in the postpartum, especially when their partner is depressed.