P2X7 Purinergic Receptor Is Involved in the Pathophysiology of Mania: a Preclinical Study.

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.

Bipolar disorder and 1513A>C P2RX7 polymorphism frequency.

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.

Inflammatory cytokines and functional impairment in drug-free subjects with mood disorder.

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.

Mood disorders and biological rhythms in young adults: A large population-based study.

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.

Circadian preferences, oxidative stress and inflammatory cytokines in bipolar disorder: A community study.

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.

A cluster analytic approach to identifying predictors and moderators of psychosocial treatment for bipolar depression: Results from STEP-BD.

BACKGROUND: We sought to address how predictors and moderators of psychotherapy for bipolar depression - identified individually in prior analyses - can inform the development of a metric for prospectively classifying treatment outcome in intensive psychotherapy (IP) versus collaborative care (CC) adjunctive to pharmacotherapy in the Systematic Treatment Enhancement Program (STEP-BD) study. METHODS: We conducted post-hoc analyses on 135 STEP-BD participants using cluster analysis to identify subsets of participants with similar clinical profiles and investigated this combined metric as a moderator and predictor of response to IP. We used agglomerative hierarchical cluster analyses and k-means clustering to determine the content of the clinical profiles. Logistic regression and Cox proportional hazard models were used to evaluate whether the resulting clusters predicted or moderated likelihood of recovery or time until recovery. RESULTS: The cluster analysis yielded a two-cluster solution: 1) "less-recurrent/severe" and 2) "chronic/recurrent." Rates of recovery in IP were similar for less-recurrent/severe and chronic/recurrent participants. Less-recurrent/severe patients were more likely than chronic/recurrent patients to achieve recovery in CC (p=.040, OR=4.56). IP yielded a faster recovery for chronic/recurrent participants, whereas CC led to recovery sooner in the less-recurrent/severe cluster (p=.034, OR=2.62). LIMITATIONS: Cluster analyses require list-wise deletion of cases with missing data so we were unable to conduct analyses on all STEP-BD participants. CONCLUSIONS: A well-powered, parametric approach can distinguish patients based on illness history and provide clinicians with symptom profiles of patients that confer differential prognosis in CC vs. IP.

Affective instability and the course of bipolar depression: results from the STEP-BD randomised controlled trial of psychosocial treatment.

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.

Medical burden, body mass index and the outcome of psychosocial interventions for bipolar depression.

OBJECTIVE: Individuals with bipolar disorder experience a disproportionately high incidence of medical co-morbidity and obesity. These health-related problems are a barrier to recovery from mood episodes and have been linked with unfavorable responses to pharmacological treatment. However, little is known about whether and how these characteristics affect responses to adjunctive psychotherapy. METHOD: Embedded in the Systematic Treatment Enhancement Program for Bipolar Disorder was a randomized controlled trial of psychotherapy for bipolar depression comparing the efficacy of intensive psychotherapy plus pharmacotherapy with collaborative care (a three-session psycho-educational intervention) plus pharmacotherapy. We conducted a post-hoc analysis to evaluate whether medical burden and body mass index predicted and/or moderated the likelihood of recovery and time until recovery from a depressive episode among patients in the two treatments. RESULTS: Participants who had medical co-morbidity and body mass index data constituted 199 of the 293 patients in the original Systematic Treatment Enhancement Program for Bipolar Disorder trial. Higher medical burden predicted a lower likelihood of recovery from depression in both treatment conditions (odds ratio = 0.89), but did not moderate responses to intensive psychotherapy vs collaborative care. Intensive psychotherapy yielded superior recovery rates for individuals of normal body mass index (odds ratio= 2.39) compared with collaborative care, but not among individuals who were overweight or obese. CONCLUSION: Medical co-morbidity and body weight impacts symptom improvement and attention to this co-morbidity may inform the development of more personalized treatments for bipolar disorder.

Extreme attributions predict the course of bipolar depression: results from the STEP-BD randomized controlled trial of psychosocial treatment.

OBJECTIVE: Little is known about predictors of recovery from bipolar depression or moderators of treatment response. In the present study, we investigated attributional style (a cognitive pattern of explaining the causes of life events) as a predictor of recovery from episodes of bipolar depression and as a moderator of response to psychotherapy for bipolar depression. METHOD: 106 depressed outpatients with DSM-IV bipolar I or II disorder who were enrolled in the Systematic Treatment Enhancement Program for Bipolar Disorder were randomly assigned to intensive psychotherapy for depression (n = 62) or to collaborative care (n = 44), a minimal psychoeducational intervention. The primary outcome was recovery status at each study visit as measured by the Clinical Monitoring Form. Attributional style was measured at baseline using the Attributional Style Questionnaire. Data were collected between 1998 and 2005. RESULTS: All analyses were by intention to treat. Extreme attributions predicted a lower likelihood of recovery (P < .01; OR = 0.93; 95% CI, 0.88-0.98) and longer time until recovery (P < .01; OR = 0.96; 95% CI, 0.93-0.99), independent of the effects of initial depression severity. Among individuals with more pessimistic attributional styles, higher initial depression severity predicted a lower likelihood of recovery (P = .01; OR = 0.64; 95% CI, 0.45-0.91) and longer time until recovery (P < .001; OR = 0.76; 95% CI, 0.66-0.88). There was no difference in recovery rates between intensive psychotherapy and collaborative care (OR = 0.90; 95% CI, 0.40-2.01) in the full sample. CONCLUSIONS: These results suggest that extreme, rigid attributions may be associated with a more severe course of depression and that evaluating attributional style may help clinicians to identify patients who are at risk for experiencing a more severe course of depression. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00012558.

Quality of life and mood disorder episodes: community sample.

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.

Concurrent Validity and Reliability of the Brazilian Version of the Functioning Assessment Short Test in Patients with Schizophrenia.

OBJECTIVE: Many studies have documented the high rates of functional impairment among patients with schizophrenia. The majority of the available instruments used to assess functioning, however, focus on global measures of functional recovery rather than specific domains of psychosocial functioning. Most of these instruments have important limitations regarding use in psychiatry. The aim of the present study was to evaluate the psychometric properties of the Brazilian version of the Functioning Assessment Short Test (FAST) in patients with schizophrenia. METHODS: A convenience sample of 107 chronic outpatients with schizophrenia and 108 controls was assessed in a university hospital (Hospital de Clínicas de Porto Alegre, Brazil). Psychometric properties of FAST (internal consistency, concurrent validity, and test-retest reliability) were analyzed. RESULTS: The internal consistency obtained was high; the Cronbach's alpha was 0.89. FAST total score was higher in patients than in the control group (Z = 11.95; P<0.001). FAST test-retest agreement was excellent (intraclass correlation coefficient = 0.93; 95% confidence interval 0.81-0.97). In addition, FAST displayed a positive correlation with the Brief Psychiatric Rating Scale (ρ = 0.41; P<0.001) and a negative correlation with the Global Assessment of Functioning scale (ρ =-0.71; P = 0.001). CONCLUSIONS: Psychotic symptoms, comorbidity, and functional and cognitive impairment contribute to the decreased quality of life of patients with schizophrenia. It is important to obtain a valid and reliable instrument that is capable of evaluating the functional domains in this pathology. In this context, FAST showed accurate psychometrics properties and was able to detect functional differences between patients with the diagnosis of schizophrenia and healthy subjects.

Psychopathology of cocaine dependent patients in a therapeutic community.

OBJECTIVE AND METHODS: Male patients in a therapeutic community (n=102) from a city in southern Brazil, with a primary diagnosis of cocaine dependence, were evaluated with Exner's Comprehensive System for the Rorschach, with the objective of describing personality psychopathology. RESULTS: High lambdas were present in 62% of patients. 60.8% of the patients scored positive in the Coping Deficit Index; 22.5% in the Depression Index. Other constellations were infrequently present (<5%). CONCLUSIONS: A positive CDI, a measure of difficulty in the management of complexities and poor social skills, may have treatment-matching implications, such as the selection of interventions targeted at interpersonal difficulties. Personality assessment should be considered in such patients.