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Abstract: Introduction: As several lines of evidence point to irregular biological rhythms in bipolar disorder, and its disruption may lead to new illness episodes, having an instrument that measures biological rhythms is critical. This report describes the validation of a new instrument, the Biological Rhythms Interview of Assessment in Neuropsychiatry (BRIAN), designed to assess biological rhythms in the clinical setting. Methods: Eighty-one outpatients with a diagnosis of bipolar disorder and 79 control subjects matched for type of health service used, sex, age and educational level were consecutively recruited. After a pilot study, 18 items evaluating sleep, activities, social rhythm and eating pattern were probed for discriminant, content and construct validity, concurrent validity with the Pittsburgh Sleep Quality Index (PSQI), internal consistency and test-retest reliability. Results: A three-factor solution, termed sleep/social rhythm factor, activity factor and feeding factor, provided the best theoretical and most parsimonious account of the data; items essentially loaded in factors as theoretically intended, with the exception of the sleep and social scales, which formed a single factor. Test–retest reliability and internal consistency were excellent. Highly significant differences between the two groups were found for the whole scale and for each BRIAN factor. Total BRIAN scores were highly correlated with the global PSQI score. Discussion: The BRIAN scale presents a consistent profile of validity and reliability. Its use may help clinicians to better assess their patients and researchers to improve the evaluation of the impact of novel therapies targeting biological rhythm pathways. [Copyright &y& Elsevier]

Introduction: Suicide is one of the leading causes of death, with a trend for its increase in Brazil in past decades. This study aimed to review the characteristics of suicides in Brazilian postmortem studies. Methods: Studies investigating suicide deaths in Brazil, and based on autopsy or psychological autopsy were included. Proportions were pooled across studies with the use of random and fixed effects models. Results: 6777 references were retrieved from six databases (searches up to January, 2023), and 45 studies included. In autopsy studies (k = 37, n = 16,231), substance use at toxicological analysis was found in 36.42% of cases (95% CI: 30.05–43.32), previous suicide attempts in 23.92% (95% CI: 6.73–57.78). In psychological autopsy studies (k = 8, n = 139), previous suicide attempts were reported in 28.09% (95% CI: 19.74–38.28), psychiatric conditions/symptoms in 90.67% (95% CI: 67.79–97.82), family history of suicidality in 21.33% (95% CI: 13.5–32.03). Most suicide deaths were reported in males and took place at the victim's home, hanging was the most frequent suicide method. Included studies presented significant limitations in quality assessment. Conclusion: Future studies should present more robust methodology, including bigger samples, the use of controls, and validated methodology. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response a letter regarding the pharmacological treatment of postpartum depression (PPD).

National Health Service use the Community Mental Health Service User Questionnaire (NHS-CMH) to assess care quality. However, its reliability and internal validity is uncertain. To test the NHS-CMH structure, reliability and item-level characteristics. We used data from 11,373 participants who answered the 2017 NHS-CMH survey. First, we estimated the NHS-CMH structure using Exploratory Factor Analysis (EFA) in half of the dataset. Second, we tested the best EFA-derived model with Confirmatory Factor Analysis (CFA). We tested the internal validity, construct reliability (omega – ω), explained common variance of each factor (ECV), and item thresholds. EFA suggested a 4-factor solution. The structure derived from the EFA was confirmed, demonstrating good reliability for the four correlated dimensions: "Relationship with Staff" (ω = 0.952, ECV = 40.1%), "Organizing Care" (ω = 0.855, ECV = 21.4%), "Medication and Treatments" (ω = 0.837, ECV = 13.3%), and "Support and Well-being" (ω = 0.928, ECV = 25.3%). A second-order model with a high-order domain of "Quality of Care" is also supported. The NHS-CMH can be used to reliably assess four user-informed dimensions of mental health care quality. This model offers an alternative for its current use (item-level and untested sum scores analysis). [ABSTRACT FROM AUTHOR]

A letter to the editor is presented regarding the article "Affective instability as rapid cycling: theoretical and clinical implications for borderline personality and bipolar spectrum disorders," by D. F. MacKinnon and R. Pies in the February 2006 issue.

The authors discuss information about femicide in early adolescence and the potential role of girl-child marriage as a risk factor. Topics mentioned include the countries with the highest prevalence of girl-child marriage, percentage of child brides who give birth before the age of 20, and case study of a White 13-year-old female stabbed to death by her 25-year-old partner who mentioned jealousy as the motivation of the crime.

Abstract: 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 &y& Elsevier]

Family-related factors play a crucial role in the onset, development, and maintenance of drug misuse and addiction. To investigate the hypothesis that families with a cocaine addicted son display more dysfunction than control families, we applied the Personal Authority in the Family System and the Self-Report Measure of Family Functioning to 67 case triads (child–father–mother) in which the son was an inpatient with a primary diagnosis of cocaine abuse or dependence and to 67 matched control triads from the community (Pelotas, Brazil) in 2000. Case children, mothers, and fathers were significantly more likely to present nuclear family triangulation than their matched control subjects. In addition, case triads had a significantly greater chance of perceiving family functioning as enmeshment. These results suggest both structural and functional differences in these families. We argue for the need of interventions in the family as a whole and for further research in this area. [ABSTRACT FROM AUTHOR]

Even though psychotic depression is related to worse outcomes than nonpsychotic depression, there is increasing evidence that this greater severity is not solely explained by the depressive symptoms. We evaluated the socio-demographic and clinical characteristics, as well as the differences in clinical outcomes of psychiatric hospitalization between psychotic and non-psychotic depression. Two-hundred-eighty-eight depressive inpatients were assessed within 72 h after hospitalization and 24 h before discharge. We compared scores of Hamilton Depression Rating Scale 17-items (HDRS-17), Clinical Global Impression (CGI), Brief Psychiatric Rating Scale (BPRS), and Global Assessment of Functioning (GAF) between psychotic and nonpsychotic patients. Instruments were compared both cross-sectionally – on admission and discharge – and longitudinally. Longitudinal outcomes were corrected for potential confounders (sex, age, age at disease onset, years of study, previous history of mania/hypomania, electroconvulsive therapy in current hospitalization, history of attempted suicide, number of suicide attempts, and previous hospitalizations). One-hundred-thirty-one depressive inpatients (45.4%) presented psychotic features. Both groups showed similar HDRS-17 scores at admission and discharge. However, psychotic patients had worse scores on BPRS, CGI, and GAF at both timepoints. Both groups had similar improvement on HDRS-17 (P = 0.75), CGI (P = 0.5), and GAF (P = 0.84), but psychotic patients had greater improvement on BPRS (P < 0.001). Psychotic inpatients showed worse clinical and functional parameters. Nonetheless, the groups did not differ in depressive symptom severity. These findings reinforce the hypothesis that depressive episode with psychotic features is a more severe form of the disease irrespective of intensity of affective symptomatology. • Psychotic depressive inpatients presented more severe psychopathology, worse functionality, and more disability. • These clinical differences were present both at admission and at discharge. • There were no differences in depressive symptom severity between psychotic and nonpsychotic patients. • Psychotic depressive episode is a more severe form of the disease irrespective of intensity of affective symptomatology. [ABSTRACT FROM AUTHOR]

Trauma pathology is not only a sum of risk factors, but emerges as a result of complex causal interaction. The case presented here illustrates the pathway from suicide exposure to the development of fully-fledged treatment-resistant posttraumatic stress disorder (PTSD), demonstrating how recognized risk factors can act in tandem to generate a difficult to treat syndrome. From a clinical perspective, bottom-up approaches that take into account real coping experiences of people bereaved by suicide are more effective to facilitate recovery and prevent adverse outcomes. Finally, even though treatment is often implemented, the diagnosis can be missed further complicating coping and treatment. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate changes in standardized suicide rates in Brazil between 2000 and 2016, stratified by sex and age.Methods: Descriptive analyses of data from the Brazilian Mortality Information System were performed.Results: 156,292 suicides were registered in the period, with a standardized rate of 4.82/100,000. The risk for males was 3.81 times higher than for females, without meaningful regional variations. This ratio was 8.2 at the 80+ group. An increase from 2000 to 2016 was demonstrated in nearly all subgroups over the 17, especially men aged 20-39 and women aged 40-59.Conclusions: Suicide rates continue to rise in Brazil, especially among young men and middle-aged women. Older men remain exposed to the highest absolute risk. [ABSTRACT FROM AUTHOR]

• Childhood trauma is much reported by subjects with bipolar disorder. • Worse clinical outcomes in bipolar with trauma as compared to bipolar without trauma. • Highest functional impairment in individuals with bipolar disorder and early trauma. Childhood trauma is a complex experience, much reported by subjects with bipolar disorder. There are still few studies that assess its consequences in a community sample of bipolar in early stage. The aim of the present study is to assess the association between childhood trauma and clinical outcomes, including the global functioning, in a community sample of young adults with bipolar disorder. This is a cross-sectional study with a community sample of subjects with bipolar disorder, from 23 to 30 years old, with and without childhood trauma. The trauma experiences during childhood were assessed by Childhood Trauma Questionnaire (CTQ). The functioning was assessed by Functioning Assessment Short Test (FAST). Ninety subjects with bipolar disorder were included in the study (30 with childhood trauma and 60 without childhood trauma). Young adults with bipolar disorder and childhood trauma showed higher prevalence of current suicide risk, higher severity of depressive symptoms, and higher functioning impairment as compared to subjects with bipolar disorder without childhood trauma. The childhood trauma experiences appear to be an environmental risk factor for worse clinical outcomes and higher functional impairment. [ABSTRACT FROM AUTHOR]

Highlights • MetS was more prevalent among subjects with depression and anhedonia. • Subjects with depression and anhedonia have a worse metabolic profile. • Anhedonia may contribute to development of MetS. Abstract The aim of this study was to assess the association between anhedonia and metabolic syndrome (MetS) in a well-characterized community sample of individuals with a current depressive episode. This is a cross-sectional study with young adults aged 24–30 years old. Depressive episode and the presence of anhedonia was assessed using the Mini International Neuropsychiatric Interview – Plus version (MINI Plus). The MetS was assessed using the National Cholesterol Education Program Adult Treatment Panel III (NCEP/ATP III). The sample included 931 subjects, being 22 had depression without anhedonia, whereas 55 had depression with anhedonia. MetS was more prevalent among subjects with depression and anhedonia (43.6%) when compared to individuals without anhedonia and population control group. Moreover, subjects with depression and anhedonia have a significant increase of levels of glucose, triglycerides, total-cholesterol and LDL-cholesterol, as well as significant decreased in the HDL-cholesterol level. The present study showed that individuals with depression and anhedonia present higher prevalence of MetS. Our study suggests that the use of the concept of anhedonia may contribute to a better understanding of the complex relationship between depression and metabolic syndrome. [ABSTRACT FROM AUTHOR]

Highlights • There is a high prevalence of Premenstrual Dysphoric Disorder in a young adult sample. • The high prevalence found should be interpreted considering the retrospective assessment. • PMDD is associated with older age, lower economic status, and no current occupation. • PMDD presents comorbidity with mood and anxiety disorder, and with suicide risk. • Clinicians should be alert to PMDD symptoms, specially in young adult women. Abstract Premenstrual Dysphoric Disorder (PMDD) was recently included in DSM-5 as a full diagnostic category. Few studies have investigated PMDD in a community sample of young adults, especially in Brazil. Thus, the objective of this study was to evaluate the prevalence and the factors associated with PMDD in a community sample of 727 young adult women between the 18 and 24 years of age in southern Brazil. This was a cross-sectional population-based study. The data were collected from 2012 to 2014. PMDD was assessed using the Mini International Neuropsychiatry Interview (M.I.N.I. – Plus). The prevalence of PMDD was 17.6%. PMDD was significantly higher among older women, and in women from lower socio-economic status. A trend towards significance was found for women without a current occupation (study or work). The comorbidities significantly associated with PMDD were current major depression disorder, agoraphobia, bipolar disorder, current suicide risk, generalized anxiety disorder, social phobia, and specific phobia. The high prevalence found in the present study should be interpreted considering a retrospective report. However, our data showed that clinicians should be alert for PMDD symptoms, especially among young adult women. [ABSTRACT FROM AUTHOR]

Objective To assess the differences in the prevalence of the metabolic syndrome (MetS) and their components in young adults with bipolar disorder (BD) and major depressive disorder (MDD) in a current depressive episode. Methods This was a cross-sectional study with young adults aged 24–30 years old. Depressive episode (bipolar or unipolar) was assessed using the Mini International Neuropsychiatric Interview – Plus version (MINI Plus). The MetS was assessed using the National Cholesterol Education Program Adult Treatment Panel III (NCEP/ATP III). Results The sample included 972 subjects with a mean age of 25.81 (±2.17) years. Both BD and MDD patients showed higher prevalence of MetS compared to the population sample (BD = 46.9%, MDD = 35.1%, population = 22.1%, p < 0.001). Higher levels of glucose, total cholesterol and LDL cholesterol, Body Mass Index, low levels of HDL cholesterol, and a higher prevalence of abdominal obesity were observed in both BD and MDD individuals with current depressive episode compared to the general population. Moreover, there was a significant difference on BMI values in the case of BD and MDD subjects (p = 0.016). Conclusion Metabolic components were significantly associated with the presence of depressive symptoms, independently of the diagnosis. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Recent evidence points to the involvement of the purinergic signaling in the pathophysiology of bipolar disorder. The aim of this study was to assess the serum levels of adenosine and to evaluate its relation to functioning in 24 euthymic patients with bipolar disorder type I and in 25 matched healthy controls. Subjects were evaluated using the functioning assessment short test. Serum purine levels were measured by high pressure liquid chromatography. Our results show a decrease in serum adenosine levels in bipolar disorder patients compared with controls (t= −4.8, df= 43.96, p<0.001). Moreover, a significant negative correlation was found between patient adenosine levels and depression scale scores (r= −0.642, p= 0.001). Higher functional impairment was linked to lower levels of adenosine in patients (rho= −0.551, p= 0.008). Taken together, our results provide evidence for a purinergic imbalance in bipolar disorder, specifically an adenosinergic dysfunction. Our results also indicate a relation between adenosine levels and the functional impairment caused by the disorder, which could demonstrate a potential relation of adenosine levels in worsening of symptoms. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Abstract: Bipolar disorder (BD) is associated with considerable higher chronic medical comorbidities, overweight and obesity. Adipokines are adipocyte-derived secretory factors which have functions in immune response and seem to be associated with both BD and overweight. The aim of this study was to evaluate the plasma levels of adipokines (adiponectin, resistin and leptin) and TNF-α and its receptors (sTNFR1 and sTNFR2) in BD overweight patients in comparison with overweight controls. Thirty euthymic BD type-I patients and thirty controls matched by age, gender and body-mass index (BMI) were assessed by Mini-International Neuropsychiatric Interview, Young Mania and Hamilton Depression rating scales (YMRS and HDRS, respectively). Plasma levels of adiponectin, resistin, leptin, TNF-α and its soluble receptors were measured by ELISA. BD patients presented increased plasma levels of adiponectin (p < 0.001), leptin (p < 0.001) and sTNFR1 (p = 0.01). Plasma levels of adipokines were not correlated neither with clinical parameters nor TNF-α, sTNFR1 and sTNFR2 plasma levels. This study provides further support to the hypothesis of the immune/inflammatory imbalance in BD. [Copyright &y& Elsevier]

Abstract: Schizophrenia is a complex and heterogeneous psychiatric disorder. Auditory verbal hallucinations occur in 50–70% of patients with schizophrenia and are associated with significant distress, decreased quality of life and impaired social functioning. This study aimed to investigate the effects of active compared with sham 1-Hz repetitive transcranial magnetic stimulation (rTMS) applied to the left temporal-parietal cortex in patients with schizophrenia treated with clozapine. Symptom dimensions that were evaluated included general psychopathology, severity of auditory hallucinations, quality of life and functionality. Seventeen right-handed patients with refractory schizophrenia experiencing auditory verbal hallucinations and treated with clozapine were randomly allocated to receive either active rTMS or sham stimulation. A total of 384 min of rTMS was administered over 20 days using a double-masked, sham-controlled, parallel design. There was a significant reduction in Brief Psychiatric Rating Scale (BPRS) scores in the active group compared with the sham group. There was no significant difference between active and sham rTMS on Quality of Life Scale (QLS), Auditory Hallucinations Rating Scale (AHRS), Clinical Global Impressions (CGI) and functional assessment staging (FAST) scores. Compared with sham stimulation, active rTMS of the left temporoparietal cortex in clozapine-treated patients showed a positive effect on general psychopathology. However, there was no effect on refractory auditory hallucinations. Further studies with larger sample sizes are needed to confirm these findings. [Copyright &y& Elsevier]

Abstract: Objective: To evaluate the prevalence of episodes of mania and hypomania, as well as associated factors and comorbidities among adults 18 to 24years old in the city of Pelotas, Brazil. Method: This is a cross-sectional population-based study. The sample was selected through conglomerates, and episodes of mania and hypomania were assessed using the Mini International Neuropsychiatric. Results: The sample consisted of 1560 subjects. The lifetime prevalence of manic and hypomanic episodes was 7.5% and 5.3%, respectively. Subjects with (hypo)manic episodes had a higher prevalence of anxiety disorders, substance abuse and suicidality. Limitation: The high rate of (hypo)mania may to some extent reflect diagnostic error. Conclusion: Such high prevalence of (hypo)mania may nonetheless be valid as it was associated with corresponding rates of comorbidity and suicidality. [Copyright &y& Elsevier]

• Treatment of neuronal cells with ATP induces cellular death through apoptosis • Lithium is able to prevent the cellular toxicity induced by ATP • ATP activates microglial cells via P2 × 7R • Lithium couldn't prevent microglial M1-phenotype switch induced by ATP Lithium is the mainstay of pharmacotherapy for treating bipolar disorder (BD). However, despite its wide use for over 60 years in the clinic, its mechanisms of action are not yet well defined. Elucidating lithium's mechanism of action will not only shed light on the pathophysiology of BD, but also potentially uncover new treatment targets. Previous studies suggest that the purinergic system may be involved in lithium's neuroprotective action; thus, the specific aim of this study is to better understand the neuroprotective action of lithium against ATP-induced cellular effect in both neuronal and microglial cellular lineages. We used PC12 neuronal and N9 microglial cells, evaluating cell death by cell counting and Annexin/PI cytometry assay, P2 × 7R immunocontent and ectonucleotidases activity, together with cytokine and nitrite assessment for microglial activity determination. Our results indicate that cells of different neural origins are responsive to ATP, in the sense of neuronal excitotoxicity and microglial switch into an activated M1-like phenotype respectively. Lithium, in turn, modulates the response in neuronal PC12 cells, preventing ATP-induced cell death. On the other hand, in N9 microglial cells, lithium was unable to prevent ATP-induced activation via P2 × 7R, indicating that lithium protective action against the effects of ATP more likely occurs in neurons rather than in microglia. Further studies are needed to better characterize the involvement of the purinergic system in the mechanism of action of lithium against neuronal death and microglial activation, in order to uncover new therapeutic adjunctive targets, such as antagonism of P2 × 7R, as potential approach for bipolar disorder treatment. [ABSTRACT FROM AUTHOR]