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BackgroundRelatively few studies have investigated whether relatives of patients with bipolar disorder show brain functional changes, and these have focused on activation changes. Failure of de-activation during cognitive task performance is also seen in the disorder and may have trait-like characteristics since it has been found in euthymia.MethodA total of 20 euthymic patients with bipolar disorder, 20 of their unaffected siblings and 40 healthy controls underwent functional magnetic resonance imaging during performance of the n-back working memory task. An analysis of variance (ANOVA) was fitted to individual whole-brain maps from each set of patient–relative–matched pair of controls. Clusters of significant difference among the groups were used as regions of interest to compare mean activations/de-activations between them.ResultsA single cluster of significant difference among the three groups was found in the whole-brain ANOVA. This was located in the medial prefrontal cortex, a region of task-related de-activation in the healthy controls. Both the patients and their siblings showed significantly reduced de-activation compared with the healthy controls in this region, but the failure was less marked in the relatives.ConclusionsFailure to de-activate the medial prefrontal cortex in both euthymic bipolar patients and their unaffected siblings adds to evidence for default mode network dysfunction in the disorder, and suggests that it may act as a trait marker. [ABSTRACT FROM PUBLISHER]

The present work focuses on the so-called dual diagnosis (DD): bipolar disorder (BD) associated with substance use disorders (SUD). Although the psychiatrists who treat patients with BD and physicians in charge of patients with SUD frequently find this association with DD, unfortunately there are few scientific works that have studied this association. The Spanish Working Group on Bipolar Disorders in Dual Diagnosis reviewed the published material using a Medline search and selected the most relevant articles. Following this, the Work Group developed an expert consensus in DD and finally, a survey was performed among a group of experts in this disorder to cover the areas that were not fully addressed by the scientific evidence or in those areas in which the Work Group was unable to reach a consensus. We conclude that, in view of the above, establishment of a consensus is a valid tool to complement the current scientific evidence. [ABSTRACT FROM AUTHOR]

Despite decades of research, the pathophysiology of bipolar disorder (BD) is still not well understood. Structural brain differences have been associated with BD, but results from neuroimaging studies have been inconsistent. To address this, we performed the largest study to date of cortical gray matter thickness and surface area measures from brain magnetic resonance imaging scans of 6503 individuals including 1837 unrelated adults with BD and 2582 unrelated healthy controls for group differences while also examining the effects of commonly prescribed medications, age of illness onset, history of psychosis, mood state, age and sex differences on cortical regions. In BD, cortical gray matter was thinner in frontal, temporal and parietal regions of both brain hemispheres. BD had the strongest effects on left pars opercularis (Cohen's d=-0.293; P=1.71 × 10 -21 ), left fusiform gyrus (d=-0.288; P=8.25 × 10 -21 ) and left rostral middle frontal cortex (d=-0.276; P=2.99 × 10 -19 ). Longer duration of illness (after accounting for age at the time of scanning) was associated with reduced cortical thickness in frontal, medial parietal and occipital regions. We found that several commonly prescribed medications, including lithium, antiepileptic and antipsychotic treatment showed significant associations with cortical thickness and surface area, even after accounting for patients who received multiple medications. We found evidence of reduced cortical surface area associated with a history of psychosis but no associations with mood state at the time of scanning. Our analysis revealed previously undetected associations and provides an extensive analysis of potential confounding variables in neuroimaging studies of BD.

Lithium (Li) and valproate (VPA) are used in the treatment of bipolar disorder (BD), with narrow therapeutic window requiring periodic control of serum levels. This prevents intoxication, lack of efficacy due to low serum concentrations, and allows monitoring adherence. We aimed at evaluating the bioequivalence of salivary and blood levels of LI or VPA in a sample of adult BD patients. Secondarily, lithium bioequivalence was evaluated across different patients' lifespans. BD patients treated with either Li or VPA underwent contemporary standard serum and salivary measurements. Blood levels of both drugs were taken according to standard procedures. Li salivary levels were performed by an adapted potentiometric method on the AVL9180 electrolyte analyzer. VPA salivary levels were taken with an immune-assay method with turbidimetric inhibition. A total of 50 patients (38 on Li, 12 on VPA) were enrolled. Blood-saliva bioequivalence for VPA was not found due to a high variability in salivary measures. Li measures resulted in a high correlation (r=0.767, p<0.001), showing no partial correlation with age (r=0.147, p=0.380). Li salivary test is a reliable method of measuring Li availability and is equivalent to serum levels. Potential advantages of Li salivary testing are its non-invasive nature and the possibility of doing the test during the usual appointment with the psychiatrist., (Copyright © 2017 Elsevier B.V. and ECNP. All rights reserved.)

Bipolar patients (BP) are at high risk of suicide. Causal factors underlying suicidal behavior are still unclear. However, it has been shown that lithium has antisuicidal properties. Genes involved in its putative mechanism of action such as the phosphoinositol and the Wnt/β-catenine pathways could be considered candidates for suicidal behavior (SB). Our aim was to investigate the association of the IMPA1 and 2, INPP1, GSK3α and β genes with suicidal behavior in BP. 199 BP were recruited. Polymorphisms at the IMPA1 (rs915, rs1058401 and rs2268432) and IMPA2 (rs66938, rs1020294, rs1250171 and rs630110), INPP1 (rs3791809, rs4853694 and 909270), GSK3α (rs3745233) and GSK3β (rs334558, rs1732170 and rs11921360) genes were genotyped. All patients were grouped and compared according to the presence or not of history of SB (defined as the presence of at least one previous suicidal attempt). Single SNP analyses showed that suicide attempters had higher frequencies of AA genotype of the rs669838-IMPA2 and GG genotype of the rs4853694-INPP1gene compared to non-attempters. Results also revealed that T-allele carriers of the rs1732170-GSK3β gene and A-allele carriers of the rs11921360-GSK3β gene had a higher risk for attempting suicide. Haplotype analysis showed that attempters had lower frequencies of A:A haplotype (rs4853694:rs909270) at the INPP1 gene. Higher frequencies of the C:A haplotype and lower frequencies of the A:C haplotype at the GSK-3β gene (rs1732170:rs11921360) were also found to be associated to SB in BP. Therefore, our results suggest that genetic variability at IMPA2, INPP1 and GSK3β genes is associated with the emergence of SB in BP., (Copyright © 2013 Elsevier B.V. and ECNP. All rights reserved.)

Background: there is a lack of scientific data regarding speed of action of antimanic treatments, a relevant issue in clinical practice., Objective: to assess differences in the speed of onset of antimanic efficacy between haloperidol (as most studied first-generation antipsychotic) and second-generation antipsychotics., Experimental Procedures: meta-analysis of double-blind randomized clinical trials in acute mania, comparing treatment with haloperidol and with second-generation antipsychotics. Search was conducted in MEDLINE and CENTRAL databases (last search: September 2011). Differences in mania scale score reduction at week 1 were assessed., Results: 8 randomized clinical trials fulfilled inclusion criteria and 1 of them was excluded due to low methodological quality. 2037 Manic patients had been treated with antipsychotics in the 7 trials. Haloperidol was found to be significantly more efficacious in the reduction of the mania scale score at week 1. The effect size was small, the Standardized Mean Difference (SMD) being 0.17, with a 95% Confidence Interval ranging from 0.01 to 0.32. Haloperidol was significantly more efficacious than olanzapine (SMD: 0.40 [0.21, 0.59]) and ziprasidone (0.39 [0.18, 0.61]). A non-significant trend towards superiority of haloperidol was found over aripiprazole (SMD: 0.13 [-0.02, 0.19]). There were no significant differences between haloperidol and quetiapine (0.17 [-0.11, 0.44]), and haloperidol and risperidone (SMD: -0.10 [0.30, 0.09])., Conclusions: haloperidol shows a faster onset of antimanic action than second-generation antipsychotics. This difference may be related to D2 affinity. Haloperidol may be considered a treatment option in severely ill manic patients who require urgent relief of symptoms., (Copyright © 2012 Elsevier B.V. and ECNP. All rights reserved.)

Background: Treatment of acute mania with second-generation antipsychotics has been claimed to involve a lower risk of switch to depression than haloperidol. However, clinical guidelines clearly state that this is not a proven fact., Methods: Meta-analysis of double-blind randomized controlled trials in acute mania, comparing rates of switch to depression with atypical antipsychotics and with haloperidol. Search was conducted in MEDLINE and CENTRAL databases (last search: September 2011)., Results: 8 randomized clinical trials fulfilled inclusion criteria. 2 of them were excluded because of low methodological quality or lack of data. 5 second-generation antipsychotics (aripiprazole, olanzapine, quetiapine, risperidone, and ziprasidone) were compared to haloperidol. In the mixed effects model the Risk Ratio for depressive switch was 0.71 (0.52, 0.96) favouring atypical antipsychotics. In the random effects model the difference did not reach statistical significance. In the heterogeneity analysis, exclusion of an outlying aripiprazole trial yielded a Risk Ratio of 0.58 (0.42, 0.82) with a non-significant heterogeneity test. Although no atypical antipsychotic was individually significantly superior to haloperidol, a trend could be seen favouring olanzapine (RR=0.56 [0.29, 1.08]), quetiapine (RR=0.36 [0.10, 1.33]), and ziprasidone (RR=0.51 [0.22, 1.18])., Limitations: All trials were industry supported, with some variability in dosage of haloperidol. Switch to depression was not the primary outcome of the trials. Heterogeneity could be explained as a lack of class-effect for atypicals., Conclusions: Treating acute mania with atypicals is associated to 42% less risk of switch to depression than with haloperidol. Nevertheless, caution should be taken when considering this a class effect, as only olanzapine, quetiapine, and ziprasidone may show a better profile., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Background: Deficits in memory and executive performance are well-established features of bipolar disorder and schizophrenia. By contrast, data on cognitive impairment in schizoaffective disorder are scarce and the findings are conflicting., Method: We used the Wechsler Memory Scale (WMS-III) and the Behavioural Assessment of the Dysexecutive Syndrome (BADS) to test memory and executive function in 45 schizophrenic patients, 26 schizomanic patients and 51 manic bipolar patients in comparison to 65 healthy controls. The patients were tested when acutely ill., Results: All three patient groups performed significantly more poorly than the controls on global measures of memory and executive functioning, but there were no differences among the patient groups. There were few differences in memory and executive function subtest scores within the patient groups. There were no differences in any test scores between manic patients with and without psychotic symptoms., Conclusions: Schizophrenic, schizomanic and manic patients show a broadly similar degree of executive and memory deficits in the acute phase of illness. Our results do not support a categorical differentiation across different psychotic categories with regard to neuropsychological deficits.

Objective: To provide empirical evidence of the effect of subthreshold symptomatology (both depressive and manic) on psychosocial functioning, neurocognition and quality of life in bipolar disorder., Methods: A total of 133 participants were enrolled for this study (bipolar patients, n=103; healthy controls, n=30). Patients were divided into two groups according to their levels of subthreshold symptomatology: the subsyndromic group was constituted by those patients with upper levels of subthreshold symptomatology (HDRS≥4 and YMRS≥3) and the asymptomatic group represented the patients with lower scores (HDRS≤3 and YMRS≤2). All participants were administered a comprehensive neuropsychological battery. Moreover the patients answered the SF-36 (Quality of Life, QoL) and were interviewed with the WHODAS-2 (Psychosocial functioning and disability). One-way ANOVA were used in order to compare the differences between the three groups., Results: The analyses revealed that both patients groups, albeit free of acute symptoms of mania or depression, differed in terms of functioning and disability assessed with the WHODAS-2. Specifically, the total global score of disability was higher for the subsyndromic group indicating more impairment (p=0.008). The same pattern of impairment was found for three of its domains: "understanding and communicating" (p=0.013); "self-care" (p=0.035) and "getting along with others" (p=0.024). The subsyndromic group also scored lower when compared to their counterparts in the Mental Component of QoL of the SF-36 (p=0.045). Finally, in the neuropsychological performance verbal learning and memory was found to be impaired regardless the levels of subthreshold symptomatology, suggesting that this variable is a robust indicator of neuropsychological impairment in BD patients., Conclusions: This report presents empirical data suggesting a moderate impact of subthreshold symptoms on functioning/disability and QoL and a discrete impact on neuropsychological impairment., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Background: Impulsivity is substantially higher in bipolar patients (BP) and may be associated with a more severe course of illness, but no studies have so far examined the relationship between impulsivity and functional outcome in BP. Our goal was to investigate the functional impact of trait-impulsivity in BP., Methods: 138 euthymic BP were recruited. All patients were assessed using an interview based on the Structured Clinical Interview for DSM Disorders (SCID). The Functioning Assessment Short Test (FAST) and the Barratt Impulsiveness Scale (BIS-11) were used to assess functional outcome and impulsivity, respectively. Seven multiple linear regressions, with each individual FAST subscale scores and overall FAST score as dependant variables, were conducted in order to evaluate the predictive role of trait-impulsivity on functional outcome., Results: After a multiple linear regression model, with the FAST total score as dependent variable, we found that depressive symptoms (β=1.580; p<0.001), number of hospitalizations (β=0.837; p=0.019) and impulsivity (β=0.319; p=0.004) were independently associated with overall functional impairment (F=6.854, df=9, p<0.001, adjusted R2=0.311)., Limitations: The cross-sectional design of the study., Conclusions: Our results indicate that impulsivity, as well as depressive symptoms and the number of hospitalizations, is associated with overall functional impairment in BP. The assessment and treatment of impulsivity may be useful in improving functional outcome in BP., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Introduction: DSM course modifiers should be based on enough evidence on his impact in the clinical prognosis of patients presenting with a certain clinical feature. The presence of postpartum onset of a mood episode in bipolar disorders has not been sufficiently studied. This is the first prospective clinical study comparing female bipolar patients with and without lifetime history of postpartum mood episode., Methods: Systematic prospective follow-up (12 years) of 200 female bipolar I or II patients with or without history of postpartum episodes. Postpartum mood episode was defined according to DSM-IV criteria. Patients with and without postpartum onset of a mood episode were compared regarding clinical and sociodemographic variables., Results: Lifetime history of postpartum episode was present in 43 patients and absent in 137 patients. Twenty patients were excluded from the study because lack of agreement of the two independent psychiatrist. Both groups showed almost no differences regarding clinical features, functioning or severity., Limitations: The present study does not take account of potential factors that may influence the outcome of a postpartum episode, including obstetric complications and social support before delivery. Similarly, dimensional and qualitative aspects of bipolar disorder were not included in our analysis., Conclusion: The role of postpartum onset as a DSM course modifier should be reconsidered, as it seems to have no impact on prognosis or functioning., (Copyright 2010 Elsevier B.V. All rights reserved.)

Background: Bipolar II represents a significant subgroup of bipolar patients. However, there is limited evidence regarding the efficacy of pharmacological and/or psychosocial therapies., Method: Post-hoc analyses were undertaken using data on 20 (out of 120) patients who fulfilled DSM-IV criteria for BP II who had participated in a single-blind randomized controlled treatment trial (RCT) exploring the acute and long-term efficacy of group psychoeducation plus standard pharmacological treatment as compared with unstructured support groups plus standard pharmacological treatment. Eight BP II subjects had been randomized to a psychoeducation group and 12 to an unstructured support group., Results: Psychoeducated, as compared to control group bipolar II patients, had significantly better 5-year outcomes, with lower mean number of BP episodes (p<.02), hypomanic episodes (p<.03) and depressive episodes (p<.03), fewer days spent in mood episodes (p=.004) and higher mean levels of functioning (p<.05)., Conclusions: Although these findings should be treated with caution, it appears that psychoeducation plus medication can benefit bipolar II subjects. Dedicated treatment trials will need to clarify whether these therapies require modifications in duration and/or content to meet the needs of bipolar II patients.

The present work focuses on the so-called dual diagnosis (DD): bipolar disorder (BD) associated with substance use disorders (SUD). Although the psychiatrists who treat patients with BD and physicians in charge of patients with SUD frequently find this association with DD, unfortunately there are few scientific works that have studied this association. The Spanish Working Group on Bipolar Disorders in Dual Diagnosis reviewed the published material using a Medline search and selected the most relevant articles. Following this, the Work Group developed an expert consensus in DD and finally, a survey was performed among a group of experts in this disorder to cover the areas that were not fully addressed by the scientific evidence or in those areas in which the Work Group was unable to reach a consensus. We conclude that, in view of the above, establishment of a consensus is a valid tool to complement the current scientific evidence.

Background: Identifying and modifying burdensome aspects might reduce the level of burden and their negative effects both on caregivers and patients' outcome. Most studies evaluate acutely ill patients, whereas the most relevant problems may be related to subthreshold symptoms and long-term outcome. The aims of the present study were to assess caregiver's subjective burden, to analyse which were the most burdensome aspects for caregivers and to study which variables could explain the caregiver's subjective burden., Methods: Caregivers of 86 euthymic bipolar patients completed the subjective burden subscale from an adapted version of the Social Behaviour Assessment Schedule., Results: Caregivers showed a moderate level of subjective burden. The highest levels of distress were reported regarding the patient's behaviour; the most distressing behaviours were hyperactivity, irritability, sadness and withdrawal. Regarding the patient's role performance, the most worrying aspects were those associated with the patient's work or study and social relationships. Regarding adverse effects on others, caregivers were especially distressed by the way the illness had affected their emotional health and their life in general. Poorer social and occupational functioning, an episode in the last 2 years, history of rapid cycling and the caregiver being responsible for medication intake explained a quarter of the variance of the caregiver's subjective burden., Limitations: This was a cross-sectional study focused only on primary caregivers, there was no control group of non-bipolar patients., Conclusions: This study provides relevant data concerning the burden of caregivers of stable bipolar patients, pointing at potential targets for psychosocial interventions.

Introduction: The development of treatment guidelines emerged as an important element so as to standardize treatment and to provide clinicians with algorithms, which would be able to carry research findings to the everyday clinical practice., Material and Method: The MEDLINE was searched with the combination of each one of the key words 'mania', 'manic', 'bipolar', 'manic-depression', 'manic-depressive' with 'treatment guidelines'., Results: The search was updated until March 1st, 2004 and returned 224 articles. Twenty-seven papers concerning the publication of treatment algorithms were traced., Discussion: Despite supposedly being evidence-based, guidelines for the treatment of bipolar disorder vary significantly across committees or working groups. Overall, however, at the first stage of the mania/hypomania algorithm, monotherapy with lithium, divalproex sodium or olanzapine is generally recommended. At latter stages combination therapy is strongly recommended. It is clearly stated that in bipolar depression antidepressants should be used only in combination with antimanic agents in order to avoid switching of phases. During the maintenance phase all patients should receive antimanic agents, while some may need the addition of antidepressants. The most recent guidelines emphasize the use of atypical antipsychotics for mania and lamotrigine for depression. The main problem with guidelines is that they are rapidly outdated and that the evidence base relies mainly on registration monotherapy trials that hardly reflect treatment in routine clinical conditions., Conclusion: Treatment guidelines may be useful to avoid non-evidence-based treatment decisions, but they are quickly out-of-date and may not fully apply to the clinical setting. The more recent guidelines point the value of atypical antipsychotics, lithium, and valproate in the treatment of mania; the role of lithium, lamotrigine, and olanzapine as options for maintenance therapy; and the scarcity of options for the treatment of bipolar depression. Psychoeducation is also supported by most guidelines as an adjunctive treatment.

Introduction: In 1984, Rosenthal et al. described the seasonal affective disorder as a cyclic pattern of depressive episodes appearing in autumn and winter, showing atypical symptoms as hypersomnia, overeating, and carbohydrate craving. They also introduced the self-applied Seasonal Pattern Assessment Questionnaire, which includes a seasonality index. A children and adolescent version was also introduced later too. In this paper the test retest reliability and internal consistency of both the adult and the children and adolescent SPQA version are presented., Methods: 30 adults y 30 adolescents filled out the corresponding questionnaires in an interval of one week. Kappa and intraclass correlation coefficients were applied. Internal consistency was measured with Cronbach alpha., Results: The adult version obtained coefficients between 0.47 y 0.81, and a Cronbach alpha of 0.85 for the seasonality index. The children and adolescent version included several items with low reliability, which were then rewritten. The renewed version was tested again in a new 30 subjects sample. Coefficients ranged from 0.50 to 0.83, with a Cronbach's alpha of 0.69 for the seasonality index., Conclusions: The Spanish version of the SPAQ (Both Adult and Children-Adolescent) showed good reliability values and also appropriate internal consistency coefficients. Therefore, they are ready to be used in clinical and epidemiological research.

Background: A number of open studies and preliminary results of unpublished double-blind trials have suggested that the novel antipsychotic risperidone may be effective and well tolerated in the treatment of acute mania in bipolar disorder., Methods: A total of 174 patients entered this large, open, multicentre trial. Inclusion criteria were: current manic, hypomanic or mixed episode (DSM-IV), and a Young Mania Rating Scale (YMRS) score of >7. Assessments included the YMRS, Positive and Negative Syndrome Scale (PANSS), Hamilton Rating Scale for Depression (HAM-D), Clinical Global Impression (CGI), and Udvalg for Kliniske Undersøgelser (UKU) subscale for neurological side effects., Results: There were significant reductions (P<0.0001) on the YMRS, PANSS and HAM-D scores and a significant improvement (P<0.0001) in CGI ratings at the endpoint. There were no statistically significant increments in the severity of extrapyramidal symptoms according to the UKU. Risperidone was generally well tolerated. The mean dose of risperidone at the endpoint was 4.9+/-2.9 mg/day., Conclusions and Clinical Implications: This open study provides further evidence that risperidone is safe and effective in combination with mood stabilisers in the manic phase of bipolar disorder., Limitations: The open design and the use of concomitant medications make unclear to what extent the positive results were entirely related to risperidone.

Introduction: Recent studies have suggested that the presence of persistent cognitive dysfunctions in bipolar patients is not restricted to acute episodes, but they persist even during remission states. Nevertheless, there are several methodological pitfalls in most studies, such as unclear remission criteria, diagnostic heterogeneity or small sample sizes., Patients and Methods: Several domains of cognitive function were examined in 30 depressed bipolar patients [DSM-IV criteria for major depression, Hamilton Depression Scale (HDRS) > or =17] and 30 euthymic bipolar patients (at least 6 months of remission, HDRS < or =8 and Young Mania Rating Scale, YMRS < or =6). Psychosocial functioning was assessed through General Assessment of Functioning., Results: The two groups showed a similar pattern of neuropsychological performance. However, the depressed group was significantly impaired on the Controlled Oral Word Association Test, FAS (COWAT), a measure of verbal fluency, compared with the euthymic group. On the other hand, functional outcome in euthymic patients was related to verbal fluency, even after controlling for residual depressive symptoms., Conclusions: Neuropsychological performance was similar in both groups, except for verbal fluency, which was lower in the depressed group. Poor verbal fluency was related to a poor social outcome in euthymic patients. Further research including longitudinal designs aimed at evaluating changes in cognition in these patients is warranted., (Copyright 2003 S. Karger AG, Basel)

Background: The goal of this study was to assess the efficacy and safety of risperidone in bipolar and schizoaffective disorders., Method: 541 patients entered this open, multicenter, 6-month study. Patients were entered provided that they fulfilled DSM-IV criteria for bipolar disorder or schizoaffective disorder, bipolar type, during a manic, hypomanic, mixed, or depressive episode. Risperidone was added to any previous mood-stabilizing medication that the patients were taking. Efficacy was assessed with the Young Mania Rating Scale (YMRS), the Hamilton Rating Scale for Depression (HAM-D), the Positive and Negative Syndrome Scale (PANSS), and the Clinical Global Impressions scale (CGI). Extrapyramidal symptoms (EPS) were assessed using the UKU Side Effect Rating Scale., Results: 430 patients completed the study. Addition of risperidone produced highly significant improvements (p < .0001) on the YMRS and HAM-D at both 6 weeks and 6 months and on the CGI and the scales of the PANSS at both 4 weeks and 6 months. There was a significant reduction in UKU total and subscale scores at 6 months. The mean dose of risperidone was 3.9 mg/day. There was no single case of new-emergent tardive dyskinesia, and there was a very low incidence of exacerbation of mania within the first 6 weeks (2%). Adverse events were few and mostly mild. the most frequent being EPS and weight gain., Conclusion: This large study provides additional evidence that risperidone is effective and well tolerated when combined with mood stabilizers in the treatment of bipolar disorder and schizoaffective disorder, bipolar type. Previous concerns about exacerbation of manic symptoms were not confirmed.