What we learn about bipolar disorder from large-scale neuroimaging: Findings and future directions from the ENIGMA Bipolar Disorder Working Group.

MRI-derived brain measures offer a link between genes, the environment and behavior and have been widely studied in bipolar disorder (BD). However, many neuroimaging studies of BD have been underpowered, leading to varied results and uncertainty regarding effects. The Enhancing Neuro Imaging Genetics through Meta-Analysis (ENIGMA) Bipolar Disorder Working Group was formed in 2012 to empower discoveries, generate consensus findings and inform future hypothesis-driven studies of BD. Through this effort, over 150 researchers from 20 countries and 55 institutions pool data and resources to produce the largest neuroimaging studies of BD ever conducted. The ENIGMA Bipolar Disorder Working Group applies standardized processing and analysis techniques to empower large-scale meta- and mega-analyses of multimodal brain MRI and improve the replicability of studies relating brain variation to clinical and genetic data. Initial BD Working Group studies reveal widespread patterns of lower cortical thickness, subcortical volume and disrupted white matter integrity associated with BD. Findings also include mapping brain alterations of common medications like lithium, symptom patterns and clinical risk profiles and have provided further insights into the pathophysiological mechanisms of BD. Here we discuss key findings from the BD working group, its ongoing projects and future directions for large-scale, collaborative studies of mental illness.

SIGMA-VB: Validity and reliability of the Brazilian Portuguese version of the Montgomery-Åsberg Depression Rating Scale using the Structured Interview Guide for the MADRS

Objective: The Montgomery-Åsberg Depression Rating Scale (MADRS) is widely used to assess depression severity. The Structured Interview Guide for the MADRS (SIGMA) was created to standardize MADRS assessment. The objective of this study was to translate and validate the original SIGMA into a Brazilian Portuguese version (SIGMA-VB). Methods: We translated and cross-culturally validated the original SIGMA into the SIGMA-VB, and assessed its psychometric properties using data from 93 adult outpatients enrolled in the Integral Assessment in Unipolar Depression (AIUNI) trial. Participants were assessed by two raters on five visits over 8 weeks. We calculated multiple interrater reliability indexes for the SIGMA-VB and used the Hamilton Depression Hating Scale (HAM-D) for validation purposes. Results: According to the SIGMA-VB, participants had moderate depression at baseline followed by mild depression at 8 weeks. We found over 90% of correlation between scores attributed by different raters using the SIGMA-VB. Correlations between the SIGMA-VB and the HAM-D were above 66%. Conclusion: Our findings confirm that the SIGMA-VB is a valid and reliable instrument to assess depression severity in clinical research and practice. Its interrater reliability was similar to that of a previously published Japanese version of the SIGMA.

SIGMA-VB: Validity and reliability of the Brazilian Portuguese version of the Montgomery-Åsberg Depression Rating Scale using the Structured Interview Guide for the MADRS.

OBJECTIVE: The Montgomery-Åsberg Depression Rating Scale (MADRS) is widely used to assess depression severity. The Structured Interview Guide for the MADRS (SIGMA) was created to standardize MADRS assessment. The objective of this study was to translate and validate the original SIGMA into a Brazilian Portuguese version (SIGMA-VB). METHODS: We translated and cross-culturally validated the original SIGMA into the SIGMA-VB, and assessed its psychometric properties using data from 93 adult outpatients enrolled in the Integral Assessment in Unipolar Depression (AIUNI) trial. Participants were assessed by two raters on five visits over 8 weeks. We calculated multiple interrater reliability indexes for the SIGMA-VB and used the Hamilton Depression Hating Scale (HAM-D) for validation purposes. RESULTS: According to the SIGMA-VB, participants had moderate depression at baseline followed by mild depression at 8 weeks. We found over 90% of correlation between scores attributed by different raters using the SIGMA-VB. Correlations between the SIGMA-VB and the HAM-D were above 66%. CONCLUSION: Our findings confirm that the SIGMA-VB is a valid and reliable instrument to assess depression severity in clinical research and practice. Its interrater reliability was similar to that of a previously published Japanese version of the SIGMA.

Increased Brain Lactate During Depressive Episodes and Reversal Effects by Lithium Monotherapy in Drug-Naive Bipolar Disorder: A 3-T 1H-MRS Study.

OBJECTIVE: Mitochondrial dysfunction and energy metabolism impairment are key components in the pathophysiology of bipolar disorder (BD) and may involve a shift from aerobic to anaerobic metabolism. Measurement of brain lactate in vivo using proton magnetic resonance spectroscopy (H-MRS) represents an important tool to evaluate mitochondrial and metabolic dysfunction during mood episodes, as well as to monitor treatment response. To date, very few studies have quantified brain lactate in BD. In addition, no study has longitudinally evaluated lactate using H-MRS during depressive episodes or its association with mood stabilizer therapy. This study aimed to evaluate cingulate cortex (CC) lactate using 3-T H-MRS during acute depressive episodes in BD and the possible effects induced by lithium monotherapy. METHODS: Twenty medication-free outpatients with short length of BD (80% drug-naive) in a current major depressive episode were matched with control subjects. Patients were treated for 6 weeks with lithium monotherapy at therapeutic doses in an open-label trial (blood level, 0.48 ± 0.19 mmol/L). Cingulate cortex lactate was measured before (week 0) and after lithium therapy (week 6) using H-MRS. Antidepressant efficacy was assessed with the 21-item Hamilton Depression Rating Scale as the primary outcome. RESULTS: Subjects with BD depression showed a significantly higher CC lactate in comparison to control subjects. Furthermore, a significant decrease in CC lactate was observed after 6 weeks of lithium treatment compared with baseline (P = 0.002). CC Lactate levels was associated with family history of mood disorders and plasma lithium levels. CONCLUSIONS: This is the first report of increased CC lactate in patients with bipolar depression and lower levels after lithium monotherapy for 6 weeks. These findings indicate a shift to anaerobic metabolism and a role for lactate as a state marker during mood episodes. Energy and redox dysfunction may represent key targets for lithium's therapeutic actions.

A Longitudinal (6-week) 3T (1)H-MRS Study on the Effects of Lithium Treatment on Anterior Cingulate Cortex Metabolites in Bipolar Depression.

The anterior cingulate cortex (ACC) is a key area in mood regulation. To date, no longitudinal study has specifically evaluated lithium׳s effects on ACC metabolites using (1)H-MRS, as well as its association with clinical improvement in bipolar depression. This (1)H-MRS (TE=35ms) study evaluated 24 drug-free BD patients during depressive episodes and after lithium treatment at therapeutic levels. Brain metabolite levels (N-acetyl aspartate (NAA), creatine (tCr), choline, myo-inositol, and glutamate levels) were measured in the ACC at baseline (week 0) and after lithium monotherapy (week 6). The present investigation showed that ACC glutamate (Glu/tCr) and glutamate+glutamine (Glx/tCr) significantly increased after six weeks of lithium therapy. Regarding the association with clinical improvement, remitters showed an increase in myoinositol levels (mI/tCr) after lithium treatment compared to non-remitters. The present findings reinforce a role for ACC glutamate-glutamine cycling and myoinositol pathway as key targets for lithium׳s therapeutic effects in BD.

Decreased AKT1/mTOR pathway mRNA expression in short-term bipolar disorder.

Strong evidence implicates intracellular signaling cascades dysfunction in the pathophysiology of Bipolar Disorder (BD). Regulation of AKT/mTOR pathway is a critical signaling pathway in synaptic neurotransmission and plasticity, also modulating cell proliferation and migration. Gene expression of the AKT/mTOR pathway was assessed in 25 BD (DSM-IV-TR criteria) unmedicated depressed individuals at baseline and after 6 weeks of lithium therapy and 31 matched healthy controls. Decreases in blood AKT1 and mTOR mRNA expression, as well as in BAD/BCL-2 expression ratio were observed in short-term BD patients during depressive episodes in comparison to healthy controls. There was no significant change in the expression of AKT1, mTOR, BCL-2, BAD and NDUFA6 after lithium therapy in the total group of BD subjects. However, the changes in AKT1 expression after lithium treatment were positively correlated with depression improvement. An integrated activity within this pathway was observed at both baseline and post-treatment. The present results support an integrated AKT/mTOR signaling pathway activity in a similar fashion to the described in previous human postmortem and rodents brain studies. Overall, the results reinforce a role for AKT1 and mTOR in the pathophysiology of BD and support the relevance of blood mRNA expression as a valid surrogate biological source to study brain intracellular signaling cascades changes and convergent molecular pathways in psychiatric disorders.

Role of quetiapine beyond its clinical efficacy in bipolar disorder: From neuroprotection to the treatment of psychiatric disorders (Review).

The aim of the present review was to discuss the following aspects of treatment with quetiapine in psychiatric disorders: i) Neurocognition and functional recovery in bipolar disorder (BD); ii) neuroprotective profile in different models; and iii) potential off-label indications. A PubMed search was conducted of articles published in English between 2000 and 2012 on quetiapine, cross-referenced with the terms 'anxiety', 'attention deficit disorder', 'borderline personality disorder', 'dementia', 'insomnia', 'major depressive disorder' (MDD), 'obsessive-compulsive disorder', 'post-traumatic stress disorder', 'remission', 'cognition', 'neurobiology', 'neuroprotection', 'efficacy' and 'effectiveness'. Articles were selected from meta-analyses, randomized clinical trials and open trials, and the results were summarized. Quetiapine, when studied in off-label conditions, has shown efficacy as a monotherapy in MDD and general anxiety disorder. Quetiapine also appears to exhibit a small beneficial effect in dementia. The review of other conditions was affected by methodological limitations that precluded any definitive conclusions on the efficacy or safety of quetiapine. Overall, the present review shows evidence supporting a potential role for quetiapine in improving cognition, functional recovery and negative symptoms in a cost-effective manner in BD. These benefits of quetiapine are potentially associated with its well-described neuroprotective effects; however, further studies are clearly warranted.

Treatment implications of predominant polarity and the polarity index: a comprehensive review.

BACKGROUND: Bipolar disorder (BD) is a serious and recurring condition that affects approximately 2.4% of the global population. About half of BD sufferers have an illness course characterized by either a manic or a depressive predominance. This predominant polarity in BD may be differentially associated with several clinical correlates. The concept of a polarity index (PI) has been recently proposed as an index of the antimanic versus antidepressive efficacy of various maintenance treatments for BD. Notwithstanding its potential clinical utility, predominant polarity was not included in the DSM-5 as a BD course specifier. METHODS: Here we searched computerized databases for original clinical studies on the role of predominant polarity for selection of and response to pharmacological treatments for BD. Furthermore, we systematically searched the Pubmed database for maintenance randomized controlled trials (RCTs) for BD to determine the PI of the various pharmacological agents for BD. RESULTS: We found support from naturalistic studies that bipolar patients with a predominantly depressive polarity are more likely to be treated with an antidepressive stabilization package, while BD patients with a manic-predominant polarity are more frequently treated with an antimanic stabilization package. Furthermore, predominantly manic BD patients received therapeutic regimens with a higher mean PI. The calculated PI varied from 0.4 (for lamotrigine) to 12.1 (for aripiprazole). CONCLUSIONS: This review supports the clinical relevance of predominant polarity as a course specifier for BD. Future studies should investigate the role of baseline, predominant polarity as an outcome predictor of BD maintenance RCTs.

Lithium efficacy in bipolar depression with flexible dosing: A six-week, open-label, proof-of-concept study.

Lithium has a narrow therapeutic index with a subtle balance between effectiveness and adverse effects. Current guidelines recommend the use of lithium as a treatment for acute bipolar depression; however, the therapeutic range for the treatment has not been fully defined. Recently, the adjunctive lower lithium dose in bipolar depression has revealed potential efficacy; however, no study has investigated it predominantly in monotherapy. In this open-label, proof-of-concept study, 31 individuals with bipolar disorder during a depressive episode were randomized and 29 were followed up for six weeks with flexible lithium dosing. All subjects had a 21-item Hamilton Rating Scale for Depression (HAM-D) score of ≥18 at baseline. Subjects were divided into two groups, with higher (Li ≥0.5 mEq/l) or lower (Li <0.5 mEq/l) blood lithium levels. Response and remission rates were evaluated using the HAM-D scores. Following 6 weeks of lithium treatment, the remission rate for all patients was 62.0%. The plasma lithium levels did not impact the clinical response. However, subjects with higher blood lithium levels had an increased prevalence of nausea, restlessness, headaches and cognitive complaints. The results indicate that the lithium dose for the treatment of bipolar depression in an individual should be based on the clinical efficacy and side-effects. In the context of personalized psychiatric treatments, it is necessary to evaluate the therapeutic action of lithium with individual regimens in order to develop more tolerable and effective treatment approaches.

Screening for bipolar depression in family medicine practices: prevalence and clinical correlates.

BACKGROUND: To compare individuals in primary care (PC) who screen positive for bipolar depression to those who screened positive for unipolar depression on mental health care ouctomes, PC service utilization, medical comorbidities, suicidal ideation, health-related quality of life (HRQoL) and psychosocial functioning. METHODS: In this cross-sectional study, participants (N=1197) answered self-reported measures of depressive symptoms (Center for epidemiologic studies depression scale), HRQoL (World Health Organization Quality of Life instrument-Abbreviated version), medical comorbidity (functional comorbidity index) and functioning (Functional Assessment Short test). Participants were partitioned into 'bipolar' and 'unipolar' depression groups based on a predefined cutoff on the Brazilian mood disorder questionnaire. RESULTS: The prevalence of bipolar depression was in PC was 4.6% (95% CI: 3.4-5.8). Participants with bipolar depression were more likely to endorse suicidal ideation, present with more medical comorbidities, report a worse physical HRQoL and have a higher rate of PC services utilization as compared to participants who screened positive for unipolar depression. Only six (10.9%) participants were recognized by the general practitioner as having a diagnosis of bipolar depression. LIMITATIONS: The cross-sectional design prevents firm causal inferences from being drawn. A positive screen for BD does not substantiate the actual diagnosis. Co-morbid mental disorders were not accessed. CONCLUSIONS: Bipolar depression is common and under-recognized in Brazilian PC services. A positive screen for bipolar depression was associated with worse clinical outcomes and greater PC service utilization.

Multiple levels of impaired neural plasticity and cellular resilience in bipolar disorder: developing treatments using an integrated translational approach.

OBJECTIVES: This paper reviews the neurobiology of bipolar disorder (BD), particularly findings associated with impaired cellular resilience and plasticity. METHODS: PubMed/Medline articles and book chapters published over the last 20 years were identified using the following keyword combinations: BD, calcium, cytokines, endoplasmic reticulum (ER), genetics, glucocorticoids, glutamate, imaging, ketamine, lithium, mania, mitochondria, neuroplasticity, neuroprotection, neurotrophic, oxidative stress, plasticity, resilience, and valproate. RESULTS: BD is associated with impaired cellular resilience and synaptic dysfunction at multiple levels, associated with impaired cellular resilience and plasticity. These findings were partially prevented or even reversed with the use of mood stabilizers, but longitudinal studies associated with clinical outcome remain scarce. CONCLUSIONS: Evidence consistently suggests that BD involves impaired neural plasticity and cellular resilience at multiple levels. This includes the genetic and intra- and intercellular signalling levels, their impact on brain structure and function, as well as the final translation into behaviour/cognitive changes. Future studies are expected to adopt integrated translational approaches using a variety of methods (e.g., microarray approaches, neuroimaging, genetics, electrophysiology, and the new generation of -omics techniques). These studies will likely focus on more precise diagnoses and a personalized medicine paradigm in order to develop better treatments for those who need them most.

Major depressive disorder in breast cancer: a critical systematic review of pharmacological and psychotherapeutic clinical trials.

BACKGROUND: While women with breast cancer often face varying levels of psychological distress, there is a subgroup whose symptomatology reaches a threshold for diagnosis of major depressive disorder (MDD). Major depressive disorder is known to influence patient outcomes, such as health-related quality of life and treatment adherence. There are no systematic reviews that evaluate pharmacological and psychotherapeutic treatment trials for MDD among individuals with breast cancer. METHODS: Two authors independently searched MEDLINE, EMBASE, Cochrane and Clinical Trials.gov databases through February 20, 2013 without language restrictions. Core journals, reference lists and citation tracking were also searched. Articles on breast cancer patients were included if they (1) included participants with a diagnosis of MDD; (2) investigated pharmacological or psychotherapeutic treatments for MDD compared to placebo or usual care in a randomized controlled trial (RCT). RESULTS: Two RCTs on antidepressant treatment met inclusion criteria. However, no RCTs investigating the effects of psychological treatments for MDD in breast cancer were identified. Notwithstanding the paucity of data investigating the effects of psychological treatments for MDD in breast cancer, numerous psychotherapeutic strategies targeting depressive symptoms were identified. Mianserin had significant antidepressant effects when compared to placebo in a 6-week, parallel-group, RCT of Stage I-II breast cancer in women with MDD. Desipramine and paroxetine were reported to be no more efficacious than placebo in a 6-week, RCT of Stage I-IV breast cancer in women with MDD. CONCLUSIONS: The evidence reviewed herein underscores the paucity of data available to guide clinicians in treatment decisions for MDD in individuals with breast cancer. Therefore, the treatment of MDD in breast cancer is primarily based on clinical experience. Some antidepressants (for example, paroxetine) should be avoided in women concurrently taking tamoxifen due to relevant interactions involving the cytochrome CYP2D6.

Affective temperaments and ego defense mechanisms associated with somatic symptom severity in a large sample.

BACKGROUND: Several complex mechanisms including biological, psychological and social factors may contribute to the development of bodily symptoms. Affective temperaments may represent heritable subclinical manifestations of mood disorders, and the concept of ego defense mechanisms has also provided a model for the comprehension of psychopathology. The relationship between affective temperaments, defensive functioning and somatic symptom severity remains unknown. METHODS: We obtained data from a subsample of the Brazilian Internet Study on Temperament and Psychopathology (BRAINSTEP). Participants completed the Affective and Emotional Temperament Composite Scale (AFECTS), the Defense Style Questionnaire (DSQ-40) and the Symptom Checklist-90-Revised (SCL-90-R). SCL-90-R Somatization scale was used as outcome variable. RESULTS: Among 9937 participants (4472 male; 45%), individuals with dysphoric, cyclothymic and depressive temperaments and those who adopted displacement, somatisation and passive aggression as their predominant defense mechanisms presented high somatic symptom severity. Participants with dysphoric temperament and those with higher displacement scores were more likely to endorse numerous bodily symptoms after controlling for age, gender, education and depressive symptoms. Moderator analysis showed that the relationship of dysphoric temperament with somatic symptom severity was much more powerful in people who adopted displacement as their predominant defense. LIMITATIONS: The data was collected from a convenience web-based sample. The study was cross-sectional. There was no information on the presence of established physical illness. CONCLUSIONS: Affective temperaments and defense mechanisms are associated with somatic symptom severity independently of depressive symptoms. These two personality theories provide distinct but interacting views for comprehension of somatic symptom formation.

Early improvement with lithium in classic mania and its association with later response.

OBJECTIVES: Despite lithium's clinical efficacy in treating mania in bipolar disorder (BD), studies evaluating early improvement and subsequent treatment response are sparse. This study investigated whether early improvement (within one week) to lithium monotherapy predicted later response and remission in individuals with BD mania. METHODS: BD-I patients (n=46) experiencing a manic episode received lithium monotherapy for four weeks (initial dose: 600mg/d, adjusted to therapeutic levels); individuals experiencing a mixed episode, rapid cyclers, previous non-responders to lithium, and those with current drug abuse/dependence were excluded. Symptoms were rated using the Young Mania Rating Scale (YMRS) at baseline and at Days 7, 14, 21, and 28. RESULTS: Thirty-three percent of the total sample responded to lithium within the first week of treatment, defined as a ≥50% decrease from baseline YMRS scores; 63% responded by study endpoint. In addition, 39% of the total sample showed early improvement (at least 20% decrease in YMRS scores) after one week of treatment. In this group, 79% responded to lithium by study endpoint. Among those showing less than 20% improvement at Week 1, only 23% responded to lithium by study endpoint. LIMITATIONS: History of episodes sequence was not assessed. CONCLUSIONS: Early improvement in response to lithium monotherapy in subjects with BD mania predicted later response and remission. Most patients who did not show early improvement in response to lithium during the first week of treatment showed no response after one month. The findings provide a valuable clinical tool for early identification of those patients most likely to benefit from lithium in clinical practice.

Early improvement of psychotic symptoms with lithium monotherapy as a predictor of later response in mania.

Although lithium has been the first line agent in the treatment of bipolar disorder (BD), few studies have evaluated lithium's efficacy in mania with psychosis and its association with later response. Furthermore, given the widespread concern about antipsychotic side effects, answering a question about whether lithium alone can manage to treat both psychotic and non-psychotic mania seems a very relevant one. The present study addresses the antipsychotic efficacy of lithium monotherapy in acute mania and early improvement of psychotic symptoms as a predictor of later response of manic symptoms. Forty-six patients presenting a manic episode (32 with psychotic features and 14 subjects without psychotic features) were treated for 4 weeks with lithium monotherapy and evaluated weekly using the Young Mania Rating Scale (YMRS). Subjects with rapid cycling, substance abuse/dependence, or mixed episodes were excluded. The overall antimanic efficacy of lithium in psychosis vs. non-psychosis groups was evaluated. In addition, early improvement of psychotic symptoms and its prediction of subsequent response (>50% decrease in total YMRS scores) or remission were evaluated. Lithium showed a similar efficacy in both psychosis and non-psychosis mania. Early improvement of psychotic symptoms was associated with clinical response and remission at endpoint.

Plasma cortisol in first episode drug-naïve mania: differential levels in euphoric versus irritable mood.

BACKGROUND: Dysregulation of HPA axis has been widely described in subjects with bipolar disorder (BD), including changes in cortisol levels during mood episodes and euthymia. However, most of the studies were done with medicated BD patients with variable length of illness, which was shown to interfere on peripheral cortisol levels. Therefore, the present study aims to evaluate plasma cortisol levels in drug-naïve BD subjects during the first manic episode, as well as investigate the relationship between plasma cortisol levels and manic symptomatology. METHODS: Twenty-six drug-naïve patients were enrolled meeting criteria for a first manic episode in bipolar I disorder. Severity of mania was assessed using the Young Mania Rating Scale (YMRS). The control group included 27 healthy subjects matched by age and gender. Cortisol was quantified using a direct radioimmunoassay. RESULTS: Plasma cortisol levels were decreased during first manic episode compared to healthy controls. Higher cortisol levels were positively associated with the presence of irritability (dysphoria), while elated mania showed lower cortisol levels compared to controls. LIMITATION: Data including larger samples are lacking. CONCLUSION: Higher cortisol in dysphoric mania compared to predominantly elated/euphoric mania may indicate a clinical and neurobiological polymorphic phenomenon, potentially involving a higher biological sensitivity to stress in the presence of irritable mood. The present findings highlight the importance to add a dimensional approach to the traditional categorical diagnosis for future neurobiological studies in BD.

Effects of lithium on oxidative stress parameters in healthy subjects.

Increased neuronal oxidative stress (OxS) induces deleterious effects on signal transduction, structural plasticity and cellular resilience, mainly by inducing lipid peroxidation in membranes, proteins and genes. Major markers of OxS levels include the thiobarbituric acid reactive substances (TBARS) and the enzymes superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase. Lithium has been shown to prevent and/or reverse DNA damage, free-radical formation and lipid peroxidation in diverse models. This study evaluates OxS parameters in healthy volunteers prior to and following lithium treatment. Healthy volunteers were treated with lithium in therapeutic doses for 2-4 weeks. Treatment with lithium in healthy volunteers selectively altered SOD levels in all subjects. Furthermore, a significant decrease in the SOD/CAT ratio was observed following lithium treatment, which was associated with decreased OxS by lowering hydrogen peroxide levels. This reduction in the SOD/CAT ratio may lead to lower OxS, indicated primarily by a decrease in the concentration of cell hydrogen peroxide. Overall, the present findings indicate a potential role for the antioxidant effects of lithium in healthy subjects, supporting its neuroprotective profile in bipolar disorder (BD) and, possibly, in neurodegenerative processes.

LICAVAL: combination therapy in acute and maintenance treatment of bipolar disorder.

BACKGROUND: The challenge of Bipolar Disorder (BD) treatment is due to the complexity of the disease. Current guidelines represent an effort to help clinicians in their everyday practice but still have limitations, specially concerning to long term treatment. LICAVAL (efficacy and tolerability of the combination of LIthium and CArbamazepine compared to lithium and VALproic acid in the treatment of young bipolar patients) study aim to evaluate acute and maintenance phase of BD treatment with two combined drugs. METHODS: LICAVAL is a single site, parallel group, randomized, outcome assessor blinded trial. BD I patients according to the DSM-IV-TR, in depressive, manic,/hypomanic or mixed episode, aged 18 to 35 years are eligible. After the diagnostic assessments, the patients are allocated for one of the groups of treatment (lithium + valproic acid or lithium + carbamazepine). Patients will be followed up for 8 weeks in phase I (acute treatment), 6 months in phase II (continuation treatment) and 12 months in phase III (maintenance treatment). Outcome assessors are blind to the treatment. The main outcome is the evaluation of changes in mean scores on CGI-BP-M between baseline and endpoint at the end of each phase of the study. RESULTS: LICAVAL is currently in progress, with patients in phase I, II or III. It will extended until august 2012. CONCLUSIONS: Trials comparing specific treatments efficacy in BD (head to head) can show relevant information in clinical practice. Long term treatment is an issue of great important and should be evaluated carefully in more studies as long as BD is a chronic disease. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00976794.