Randomized, placebo-controlled trial of quetiapine XR and divalproex ER monotherapies in the treatment of the anxious bipolar patient. A review of aripiprazole in the treatment of patients with schizophrenia or bipolar I disorder Daily electronic self-monitoring of subjective and objective symptoms in bipolar disorder—the MONARCA trial protocol (MONitoring, treAtment and pRediCtion of bipolAr disorder episodes): a randomised controlled single-blind trial Family-focused treatment for adolescents with bipolar disorder. Treatment of suicide attempters with bipolar disorder: a randomized clinical trial comparing lithium and valproate in the prevention of suicidal behavior. Randomized, placebo-controlled trial of risperidone for acute treatment of bipolar anxiety. Factors associated with suicide attempts in 648 patients with bipolar disorder in the Stanley Foundation Bipolar Network. The effects of physical activity in the acute treatment of bipolar disorder: a pilot study. Anxiety disorder comorbidity in bipolar disorder patients: data from the first 500 participants in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD). The Stanley Foundation Bipolar Treatment Outcome Network. I. Longitudinal methodology. Pramipexole for bipolar II depression: a placebo-controlled proof of concept study High Behavioral Approach System (BAS) sensitivity, reward responsiveness, and goal-striving predict first onset of bipolar spectrum disorders: a prospective behavioral high-risk design. N-acetyl cysteine add-on treatment for bipolar II disorder: a subgroup analysis of a randomized placebo-controlled trial. Antimanic response to aripiprazole in bipolar I disorder patients is independent of the agitation level at baseline. Co-morbid disruptive behavior disorder and aggression predict functional outcomes and differential response to risperidone versus divalproex in pharmacotherapy for pediatric bipolar disorder. The Stanley Foundation Bipolar Treatment Outcome Network. II. Demographics and illness characteristics of the first 261 patients. The efficacy of N-acetylcysteine as an adjunctive treatment in bipolar depression: an open label trial. Divalproex in the treatment of bipolar depression: a placebo-controlled study. The study protocol of the Norwegian randomized controlled trial of electroconvulsive therapy in treatment resistant depression in bipolar disorder Clinical, psychological and environmental predictors of prospective suicide events in patients with Bipolar Disorder. Minocycline and aspirin in the treatment of bipolar depression: a protocol for a proof-of-concept, randomised, double-blind, placebo-controlled, 2×2 clinical trial Aripiprazole augmentation in treatment-resistant bipolar depression: Early response and development of akathisia Development of an online intervention for bipolar disorder. www.moodswings.net.au
BACKGROUND Anxiety disorders complicate the treatment of bipolar disorder but are seldom the focus of bipolar treatment studies . METHODS The anxiolytic effect of quetiapine XR 50 - 300 mg/day compared to divalproex ER ( 500 - 3000 mg/day ) was tested in an 8-week , double-blind , placebo-controlled , r and omized clinical trial in 149 patients with bipolar disorder and a co-occurring panic disorder or GAD . The primary efficacy measure was the Clinician Global Improvement-21 Anxiety Scale ( CGI-21 ) . Secondary measures included the Hamilton Anxiety Scale ( HAM-A ) and Sheehan Panic Disorder Scale ( SPS ) . RESULTS Repeated measures last-observation-carried-forward ( LOCF ) analyses of variance demonstrated significant treatment-by-time interaction effects on 3 of the 4 anxiety measures .  Quetiapine XR at a mean endpoint dose of 186 mg/day produced rapid sustained improvements relative to baseline , divalproex ER and placebo on anxiety . Mean baseline-to-endpoint improvement was significantly greater for quetiapine XR compared to divalproex ER and placebo on the HAM-A and SPS . Both active medications were well tolerated , but weight gain was higher on quetiapine XR . LIMITATIONS The study was limited to 8 weeks and to patients with bipolar disorder and comorbid panic disorder or GAD . The results may not be applicable to quetiapine XR as an add-on treatment to mood stabilizers or to bipolar disorder comorbid with other anxiety disorders . CONCLUSIONS Quetiapine XR in a dose range of 50 - 300 mg/day appears to reduce anxiety in bipolar patients with comorbid panic disorder or GAD treated for 8 weeks . The efficacy of other second-generation antipsychotics and mood stabilizers in patients with bipolar disorder and a co-occurring anxiety disorder should be investigated in double-blind , placebo-controlled studies Aripiprazole has been approved by regulatory agencies for the treatment of schizophrenia and bipolar I disorder . Although it is a dopamine partial agonist , it also has substantial binding affinity for the serotonin 5HT2A receptor . Several double-blind r and omized clinical trials have established the efficacy and tolerability of aripiprazole within the dose range of 10–30 mg/day for schizophrenia , and 15–30 mg/day for manic or mixed states associated with bipolar I disorder . Relatively few comparative trials with other second-generation antipsychotics have been published for schizophrenia , with none available for bipolar disorder . The evidence so far suggests that in terms of efficacy for schizophrenia , aripiprazole is superior to placebo and haloperidol ( long term ) , similar to perphenazine and risperidone , and inferior to olanzapine .  Its tolerability profile in patients with schizophrenia appears superior to haloperidol , perphenazine , risperidone , and olanzapine .  Efficacy in treating manic or mixed states was established in placebo-controlled trials . Among some patients with bipolar disorder  , akathisia and gastrointestinal ( GI ) complaints can emerge at the start of treatment ; however , the GI symptoms were time-limited in many instances . Appropriate dosing may also be important in individualizing therapy to improve tolerability , with lower starting doses becoming more important when adding to , or switching from , another antipsychotic . Aripiprazole appears to have a low propensity for weight gain , a favorable metabolic profile , and no association with hyperprolactinemia Introduction Electronic self-monitoring of affective symptoms using cell phones is suggested as a practical and inexpensive way to monitor illness activity and identify early signs of affective symptoms . It has never been tested in a r and omised clinical trial whether electronic self-monitoring improves outcomes in bipolar disorder . We are conducting a trial testing the effect of using a Smartphone for self-monitoring in bipolar disorder . Methods We developed the MONARCA application for And roid-based Smartphones , allowing patients suffering from bipolar disorder to do daily self-monitoring — including an interactive feedback loop between patients and clinicians through a web-based interface . The effect of the application was tested in a parallel-group , single-blind r and omised controlled trial so far including 78 patients suffering from bipolar disorder in the age group 18–60 years who were given the use of a Smartphone with the MONARCA application ( intervention group ) or to the use of a cell phone without the application ( placebo group ) during a 6-month study period . The study was carried out from September 2011 . The outcomes were changes in affective symptoms ( primary ) , social functioning , perceived stress , self-rated depressive and manic symptoms , quality of life , adherence to medication , stress and cognitive functioning ( secondary and tertiary ) . Analysis Recruitment is ongoing . Ethics Ethical permission has been obtained . Dissemination Positive , neutral and negative findings of the study will be published . Registration details The trial is approved by the Regional Ethics Committee in The Capital Region of Denmark ( H-2 - 2011 - 056 ) and The Danish Data Protection Agency ( 2013 - 41 - 1710 ) . The trial is registered at Clinical Trials.gov as NCT01446406 BACKGROUND Research has begun to eluci date the optimal pharmacological treatments for pediatric-onset bipolar patients , but few studies have examined the role of psychosocial interventions as adjuncts to pharmacotherapy in maintenance treatment . This article describes an adjunctive family-focused psychoeducational treatment for bipolar adolescents ( FFT-A ) . The adult version of FFT has been shown to be effective in forestalling relapses in two r and omized clinical trials involving bipolar adults . METHODS FFT-A is administered to adolescents who have had an exacerbation of manic , depressed , or mixed symptoms within the last 3 months . It is given in 21 outpatient sessions of psychoeducation , communication enhancement training , and problem solving skills training . We describe modifications to the adult FFT model to address the developmental issues and unique clinical presentations of pediatric-onset patients . RESULTS An open treatment trial involving 20 bipolar adolescents ( 11 boys , 9 girls ; mean age 14.8+/-1.6 ) found that the combination of FFT-A and mood stabilizing medications was associated with improvements in depression symptoms , mania symptoms , and behavior problems over 1 year . LIMITATIONS These early results are based on a small-scale open trial . CONCLUSIONS Results from an ongoing r and omized controlled trial will clarify whether combining FFT-A with pharmacotherapy improves the 2-year course of adolescent bipolar disorder . If the results are positive , then a structured manual-based psychosocial approach will be available for clinicians who treat adolescent bipolar patients in the community OBJECTIVE Bipolar disorder is associated with high risk for  suicidal acts . Observational studies suggest a protective effect of lithium against suicidal behavior . However , testing this effect in r and omized clinical trials is logistically and ethically challenging . The authors tested the hypothesis that lithium offers bipolar patients with a history of suicide attempt greater protection against suicidal behavior compared to valproate . METHOD Patients with bipolar disorder and past suicide attempts ( N=98 ) were r and omly assigned to treatment with lithium or valproate , plus adjunctive medications as indicated , in a double-blind 2.5-year trial . An intent-to-treat analysis was performed using the log-rank test for survival data . Two models were fitted : time to suicide attempt and time to suicide event ( attempt or hospitalization or change in medication in response to suicide plans ) . RESULTS There were 45 suicide events in 35 participants , including 18 suicide attempts made by 14 participants , six from the lithium group and eight from the valproate group . There were no suicides . Intent-to-treat analysis using the log-rank test showed no differences between treatment groups in time to suicide attempt or to suicide event . Post hoc power calculations revealed that the modest sample size , reflective of challenges in recruitment , only permits detection of a relative risk of 5 or greater . CONCLUSIONS Despite the high frequency of suicide events during the study , this r and omized controlled trial detected no difference between lithium and valproate in time to suicide attempt or suicide event in a sample of suicide attempters with bipolar disorder . However , smaller clinical ly significant differences between the two drugs were not ruled out BACKGROUND The treatment of bipolar disorder is often complicated by the presence of a co-occuring anxiety disorder . Although second generation antipsychotics are being used with increasing frequency in bipolar patients , their anxiolytic effects have not been well studied in this population . METHODS The anxiolytic effect of risperidone 0.5 - 4 mg/day was tested in an 8-week , double-blind , placebo-controlled , r and omized clinical trial in 111 patients with bipolar disorder and a co-occuring panic disorder or generalized anxiety disorder ( GAD ) . The primary outcome measure was the Clinician Global Improvement-21 Anxiety scale ( CGI-21 Anxiety ) . Secondary measures included the Hamilton Anxiety Scale ( HAM-A ) and the Sheehan Panic Disorder Scale . RESULTS On the last-observation-carried forward analysis of repeated measures analysis of variance ( ANOVA ) , risperidone was not more effective than placebo for the CGI-21 Anxiety score or the other anxiety outcome measures .  Risperidone was well tolerated , with only two patients withdrawing because of adverse events . LIMITATIONS The  risperidone treated group had more patients with mixed states and lifetime panic disorder at r and omization than the placebo group . The study was limited to 8 weeks and to individuals with bipolar and comorbid panic disorder or GAD . The results may not be applicable to risperidone as an add-on treatment to mood stabilizers , or to bipolar disorder comorbid with anxiety disorders other than panic disorder or GAD . CONCLUSIONS Risperidone monotherapy was not an effective anxiolytic for bipolar patients with comorbid panic disorder or GAD in doses of 0.5 - 4 mg/day over 8 weeks of treatment . The efficacy of other second generation antipsychotics and mood stabilizers on anxiety in patients with bipolar disorder and a co-occuring anxiety disorder should be investigated in double-blind , placebo-controlled studies BACKGROUND Clinical factors related to suicide and suicide attempts have been studied much more extensively in unipolar depression compared with bipolar disorder . We investigated demographic and course-of-illness variables to better underst and the incidence and potential clinical correlates of serious suicide attempts in 648 out patients with bipolar disorder . METHOD Patients with bipolar I or II disorder ( DSM-IV criteria ) diagnosed with structured interviews  were evaluated using self-rated and clinician-rated question naires to assess incidence and correlates of serious suicide attempts prior to study entry .  Clinician prospect i ve ratings of illness severity were compared for patients with and without a history of suicide attempt . RESULTS The 34 % of patients with a history of suicide attempts , compared with those without such a history , had a greater positive family history of drug abuse and suicide ( or attempts ) ; a greater personal history of early traumatic stressors and more stressors both at illness onset and for the most recent episode ; more hospitalizations for depression ; a course of increasing severity of mania ; more Axis I , II , and III comorbidities ; and more time ill on prospect i ve follow-up . In a hierarchical logistic regression , a history of sexual abuse , lack of confidant prior to illness onset , more prior hospitalizations for depression , suicidal thoughts when depressed , and cluster B personality disorder remained significantly associated with a serious suicide attempt . CONCLUSION Our retrospective findings , supplemented by prospect i ve follow-up , indicate that a history of suicide attempts is associated with a more difficult course of bipolar disorder and the occurrence of more psychosocial stressors at many different time domains . Greater attention to recognizing those at highest risk for suicide attempts and therapeutic efforts aim ed at some of the correlates identified here could have an impact on bipolar illness-related morbidity and mortality BACKGROUND Physical activity has demonstrated efficacy in depression and anxiety , but its potential in the management of bipolar disorder is yet unexplored . This study is a pilot investigation into the effectiveness of an adjunctive walking program in the acute treatment of  bipolar disorder  . METHODS This is a retrospective cohort study of all patients admitted over a 24-month period to a private psychiatric unit with a primary diagnosis of bipolar disorder ( ICD-10 ) . All patients were invited to participate voluntarily in a walking group during their admissions . Those who reliably attended the walking group ( participants ) were compared against those who did not attend ( non- participants ) , using the clinician-rated Clinical Global Impression Severity ( CGI-S ) and Improvement ( CGI-I ) scales and the self-reported 21-item Depression Anxiety Stress Scales ( DASS ) as primary outcome measures . RESULTS There were 24 admissions for participants and 74 admissions for non- participants . The two groups did not differ significantly in patient demographics or admission CGI and DASS measures , except for a lower DASS Stress subscore for participants ( p=0.049 ) . At discharge , the inter-group differences in CGI measures remained non-significant , but participants had significantly lower scores than non- participants for DASS ( p=0.005 ) and all its subscales ( Depression p=0.048 , Anxiety p=0.002 , Stress p=0.01 ) . LIMITATIONS Method ological limitations include a retrospective design , small sample size , lack of r and omisation or control , and indirect measure of manic symptoms . CONCLUSIONS The results of this trial provide preliminary support for a therapeutic role of physical activity in bipolar disorder , and warrant further investigation with r and omised controlled trials OBJECTIVE The authors provide a detailed perspective on the correlates of comorbid anxiety in a large , well-characterized sample of bipolar disorder patients . METHOD Anxiety and its correlates were examined in a cross-sectional sample from the first 500 patients with bipolar I or bipolar II disorder enrolled in the Systematic Treatment Enhancement Program for Bipolar Disorder , a multicenter project funded by the National Institute of Mental Health design ed to evaluate the longitudinal outcome of patients with bipolar disorder . RESULTS Lifetime comorbid anxiety disorders were common , occurring in over one-half of the sample , and were associated with younger age at onset , decreased likelihood of recovery , poorer role functioning and quality of life , less time euthymic , and greater likelihood of suicide attempts . Although substance abuse disorders were particularly prevalent among patients with anxiety disorders , comorbid anxiety appeared to exert an independent , deleterious effect on functioning , including history of suicide attempts ( odds ratio=2.45 , 95 % CI=1.4 - 4.2 ) . CONCLUSIONS An independent association of comorbid anxiety with greater severity and impairment in bipolar disorder patients was demonstrated , highlighting the need for greater clinical attention to anxiety in this population , particularly for enhanced clinical monitoring of suicidality . In addition , it is important to determine whether effective treatment of anxiety symptoms can lessen bipolar disorder severity , improve response to treatment of manic or depressive symptoms , or reduce suicidality The NIMH-Stanley Foundation Bipolar Treatment Outcome Network , a multisite clinical trials network , has been established to address many of the neglected areas of research in bipolar illness . The Network was design ed so that it would be able to conduct r and omized clinical trials at several different levels of method ologic rigor ( blinded and open-label ) both in academic and community practice setting s in order to better assess long-term efficacy of existing treatments and develop new ones . In this fashion , large numbers of representative patients with bipolar disorder have been enrolled with an additional focus of elucidating possible clinical and biological predictors of treatment response . The unique focus of the Network is its systematic longitudinal approach to illness so that patients can be assessed comprehensively over the long-term in sequential r and omized clinical trials at critical clinical decision points where data on relative efficacy are inadequate . Bipolar I and bipolar II patients with a range of illness variants and comorbidities are included . Daily prospect i ve ratings of severity of mania and depression and associated degree of functional impairment are completed on the NIMH-Life Chart Method and a modified Clinical Global Impressions Scale for Bipolar Illness ( CGI-BP ) is utilized . More detailed cross-sectional ratings for depression ( Inventory of Depressive Symptomatology ) , mania ( Young Mania Rating Scale ) , and psychosis ( Positive and Negative Syndrome Scale ) are additionally used at academic centers . This article describes the rationale for the Network , its guiding principles , methods , and study design to systematic ally assess the highly variable course of bipolar illness and its response to current and future treatments BACKGROUND The original serotonergic and noradrenergic hypotheses do not fully account for the neurobiology of depression or mechanism of action of effective antidepressants . Research implicates a potential role of the dopaminergic system in the pathophysiology of bipolar disorder . The current study was undertaken as a proof of the concept that dopamine agonists will be effective in patients with bipolar II depression . METHODS In a double-blind , placebo-controlled study , 21 patients with DSM-IV bipolar II disorder , depressive phase on therapeutic levels of lithium or valproate  were r and omly assigned to treatment with pramipexole ( n = 10 ) or placebo ( n = 11 ) for 6 weeks . Primary efficacy was assessed by the Montgomery-Asberg Depression Rating Scale . RESULTS All subjects except for one in each group completed the study . The analysis of variance for total Montgomery-Asberg Depression Rating Scale scores showed a significant treatment effect . A therapeutic response ( > 50 % decrease in Montgomery-Asberg Depression Rating Scale from baseline ) occurred in 60 % of patients taking pramipexole and 9 % taking placebo ( p = .02 ) . One subject on pramipexole and two on placebo developed hypomanic symptoms . CONCLUSIONS The dopamine agonist pramipexole was found to have significant antidepressant effects in patients with bipolar II depression A prospect i ve , behavioral high-risk design provided a theoretically guided examination of vulnerability to first onset of bipolar spectrum disorder based on the Behavioral Approach System ( BAS ) model . Adolescents ( ages 14 - 19 ) at an " age of risk " for bipolar disorder onset were screened on BAS sensitivity by interviewers blind to current symptoms , lifetime history , and family history of psychopathology . Participants were selected with high versus moderate levels of BAS sensitivity and administered a lifetime diagnostic interview . Those with a bipolar spectrum disorder , psychosis , or hypomanic episode with onset prior to the BAS sensitivity assessment were excluded . High BAS ( n = 171 ) and moderate BAS ( n = 119 ) sensitivity participants in the final sample completed baseline measures of symptoms , goal - setting , and reward responsiveness and were followed prospect ively with semistructured diagnostic interviews every 6 months . Consistent with the vulnerability hypothesis of the BAS model of bipolar disorder , high BAS participants had a greater likelihood , and shorter time to onset , of bipolar spectrum disorder than moderate BAS participants across an average of 12.8 months of follow-up ( 12.9 % vs. 4.2 % ) , controlling for baseline depressive and hypomanic symptoms , and family history of bipolar disorder . High reward responsiveness on a behavioral task and ambitious goal -striving for popular fame and financial success ( but not impulsivity ) also predicted first onset of bipolar spectrum disorder controlling for the covariates and BAS risk group , and ambitious goal -striving partially mediated the BAS risk group effect . We discuss implication s of the findings for the BAS model of bipolar disorder and early intervention efforts BACKGROUND The evidence base for the pharmacological treatment of bipolar II disorder is limited . In bipolar disorder , there is evidence for glutathione depletion and increased oxidative stress , as well as dysregulation of glutamate ; N-acetyl cysteine ( NAC ) has effects on both of these systems . Add-on NAC has been shown to have a significant benefit on depressive symptoms in a r and omized placebo-controlled trial . In this report , we explore the effects of this compound in a subset of patients with bipolar II disorder from that trial . METHODS Individuals were r and omized to NAC or placebo in addition to treatment as usual , in a double-blind fashion . Mood and functional outcomes were assessed up to 24 weeks of treatment . RESULTS Fourteen individuals were available for this report , seven in each group . Six people achieved full remission of both depressive and manic symptoms in the NAC group ; this was true for only two people in the placebo group ( χ(2)=4.67 , p=0.031 ) . LIMITATIONS Subgroup analyses in a small sub sample of patients . Not all participants had elevated depression scores at baseline . CONCLUSION Notwithst and ing all the limitations that subgroup analysis of trials carry , this data could serve as a hypothesis-generating stimulus for further clinical trials of pharmacologic treatment for bipolar II depression OBJECTIVE To examine the antimanic efficacy of the relatively nonsedating antipsychotic aripiprazole in patients with bipolar I disorder and high or low baseline levels of agitation . METHOD Data were pooled for this post hoc analysis from two 3-week , placebo-controlled trials of aripiprazole in acute mania ( DSM-IV ) . Patients r and omly assigned to aripiprazole 30 mg/day ( N = 259 ) or placebo ( N = 254 ) were classified as having either high ( Positive and Negative Syndrome Scale [ PANSS ] Excited Component [ PEC ] score of > or=14 and a score of > or= 4 on at least one PEC item ) or low ( PEC < 14 ) levels of agitation at baseline .  Efficacy measures were changes in Young Mania Rating Scale ( YMRS ) scores , Clinical Global Impressions-Bipolar ( CGI-BP ) scores , and PEC scores . Efficacy and agitation measurements were assessed by analysis of covariance . RESULTS From the first week of therapy onward , aripiprazole-treated subjects had significantly greater reduction from baseline in YMRS total scores than placebo-treated subjects in both the high- and low-agitation groups ( p < .05 for both groups ) and significantly improved CGI-BP scores vs. placebo at end point ( p < .05 for both ) . In highly agitated patients receiving aripiprazole , PEC scores were significantly decreased versus placebo at end point ( p < .05 ) . In patients with low agitation receiving aripiprazole , no increases in PEC scores were seen , and a significant reduction in agitation symptoms was apparent after adjustment for baseline PEC scores . CONCLUSIONS Aripiprazole was superior to placebo in reducing the severity of both mania and agitation in highly agitated patients with bipolar I disorder and showed significant antimanic activity in patients with low levels of agitation without increasing agitation . These findings suggest that aripiprazole 's antimanic effect is specific and not limited to control of agitation through sedation OBJECTIVE Co-morbid diagnoses , such as disruptive behavior disorders ( DBDs ) and high levels of aggression , are extremely common among youth with pediatric bipolar disorder ( PBD ) and may interfere with treatment response ; however , they have rarely been examined as predictors of response to pharmacotherapy . The current study examines co-morbid DBD and aggression prospect ively as predictors of pharmacotherapy outcome , as well as potential moderators of response to a specific medication ( risperidone vs. divalproex ) , among children with PBD . METHODS Data are from a prospect i ve 6-week double-blind , placebo-controlled , r and omized outpatient medication treatment trial of risperidone versus divalproex for manic episodes in 65 children 8 - 18 with PBD . Outcome measures were administered at pretest , post-test , and weekly during the 6 weeks of treatment . Mixed-effects regression models were used to examine pharmacotherapy response . RESULTS Results indicated that youth with co-morbid DBD experienced greater improvement in manic symptoms in response to risperidone versus divalproex , whereas youth with non-co-morbid DBD experienced similar trajectories of symptom improvement in both medication groups . In addition , the non-DBD group experienced greater improvement in global functioning over time as compared with youth with co-morbid-DBD , and this gap increased over the course of treatment . Results also indicated that high-aggression youth experienced worse global functioning by end treatment versus low-aggression youth . CONCLUSIONS In conclusion , a co-morbid diagnosis of DBD and /or high levels of aggressive symptoms in youth with PBD may be important clinical predictors of variation in treatment response to pharmacotherapy . These findings may help research ers and clinicians develop tailored treatment approaches that optimize symptom and functional outcomes BACKGROUND Since recent NIMH Bipolar Disorder Workshops highlighted the dearth of longitudinal and controlled studies of bipolar illness , the Stanley Foundation Bipolar Network ( SFBN ) has recruited a large cohort of patients with bipolar disorder to begin to address these issues . This report describes the demographics and course of illness characteristics of this study population . METHODS The first 261 out patients to be diagnosed by the Structured Clinical Interview for DSM-IV ( SCID ) and complete a detailed patient and a brief clinician question naire are described . All patients met DSM-IV criteria for bipolar I ( n=211 ) , bipolar II ( n=42 ) , or NOS ( n=5 ) or schizoaffective ( n=3 ) , bipolar type . Chi-square and t-tests were used to examine statistically significant associations among important demographic and descriptive items . RESULTS The general demographic and illness characteristics were similar to those in many bipolar clinical sample s and not dissimilar from those reported in epidemiological surveys . The majority of patients had been hospitalized , with almost half reporting a worsening of illness over time , and two-thirds were not asymptomatic between episodes . First treatment for patients had been delayed by an average of 10 years from illness onset ( by SCID ) . Almost a third of patients had attempted suicide at least once , and 30 % reported current suicidal ideation at study entry . A total of 62 % reported moderate to severe impact of the illness on occupational functioning . Early onset bipolar illness ( < or = 17 years old ) was associated with increased frequency of mood switches , worsening course of illness , and history of early abuse ( physical , verbal , or sexual ) . CONCLUSION The SFBN represents a sample of predominantly BP I patients largely recruited from the community who will be followed in detail longitudinally , participate in clinical trials , and thus help advance our underst and ing and treatment of this life-threatening medical disorder . While there is a broad range of illness characteristics and severity , the majority of patients have been severely impacted by their illness despite the availability of multiple conventional treatment approaches in the community . These data further underscore the need for development of new and earlier treatment interventions . LIMITATION The SFBN population is limited by the lack of r and om selection and represents a cohort willing to be treated and followed intensively in academic tertiary referral centers . While its characteristics are similar to many clinical study population s , the generalizability to non-clinic population s remains uncertain BACKGROUND Evidence is accumulating to support the presence of redox dysregulation in a number of psychiatric disorders , including bipolar disorder . This dysregulation may be amenable to therapeutic intervention . Glutathione is the predominant non-enzymatic intracellular free radical scavenger in the brain , and the most generic of all endogenous antioxidants in terms of action . N-acetylcysteine ( NAC ) is a glutathione precursor that effectively replenishes brain glutathione . Given the failure of almost all modern trials of antidepressants in bipolar disorder to demonstrate efficacy , and the limited efficacy of mood stabilisers in the depressive phase of the disorder , this is a major unmet need . METHOD This study reports data on the treatment of 149 individuals with moderate depression during the 2 month open label phase of a r and omised  placebo controlled clinical trial of the efficacy of 1 g BID of NAC that examined the use of NAC as a maintenance treatment for bipolar disorder . RESULTS In this trial , the estimated mean baseline Bipolar Depression Rating Scale ( BDRS ) score was 19.7 ( SE=0.8 ) , and the mean BDRS score at the end of the 8 week open label treatment phase was 11.1 ( SE=0.8 ) . This reduction was statistically significant ( p<0.001 ) . Improvements in functioning and quality of life were similarly evident . CONCLUSION These open label data demonstrate a robust decrement in depression scores with NAC treatment . Large placebo controlled trials of acute bipolar depression are warranted BACKGROUND The treatment of bipolar disorder in the depressed phase is complicated by a tendency for conventional antidepressant drugs to worsen the course of the illness by precipitating a manic episode or increasing cycle frequency . Thus , the potential antidepressant efficacy of mood stabilizers , such as divalproex , which is an effective treatment for the manic phase of bipolar disorder , is of considerable interest . METHODS The clinical efficacy of divalproex ( valproate , Depakote ) was tested in an 8-week , double-blind , placebo-controlled , r and omized clinical trial in 25 out patients with bipolar I depression . The primary outcome measure was the 17-item Hamilton Rating Scale for Depression , and secondary measures included the Hamilton Rating Scale for Anxiety , the Clinician Administered Rating Scale for Mania , and the Clinical Global Impression scale . RESULTS Using repeated measures ANOVA with last observation carried forward , divalproex was more effective than placebo in improving symptoms of depression ( p = 0.0002 ) and symptoms of anxiety ( p = 0.0001 ) than placebo . LIMITATIONS The sample size was small , and most patients were male . CONCLUSIONS These pilot results indicate that divalproex is effective in reducing the symptoms of depression and anxiety in bipolar I , depressed phase . These positive results support the need to perform a larger , multisite study of divalproex treatment for bipolar depression Background The treatment of depressive phases of bipolar disorder is challenging . The effects of the commonly used antidepressants in bipolar depression are question able . Electroconvulsive therapy is generally considered to be the most effective treatment even if there are no r and omized controlled trials of electroconvulsive therapy in bipolar depression . The safety of electroconvulsive therapy is well documented , but there are some controversies as to the cognitive side effects . The aim of this study is to compare the effects and side effects of electroconvulsive therapy to pharmacological treatment in treatment resistant bipolar depression .  Cognitive changes and quality of life during the treatment will be assessed . Methods / Design A prospect i ve , r and omised controlled , multi-centre six- week acute treatment trial with seven clinical assessment s. Follow up visit at 26 weeks or until remission ( max 52 weeks ) . A neuropsychological test battery design ed to be sensitive to changes in cognitive function will be used . Setting : Nine study centres across Norway , all acute psychiatric departments . Sample : n = 132 patients , aged 18 and over , who fulfil criteria for treatment resistant depression in bipolar disorder , Montgomery Åsberg Depression Rating Scale Score of at least 25 at baseline . Intervention : Intervention group : 3 sessions per week for up to 6 weeks , total up to 18 sessions . Control group : algorithm-based pharmacological treatment as usual . Discussion This study is the first r and omized controlled trial that aims to investigate whether electroconvulsive therapy is better than pharmacological treatment as usual in treatment resistant bipolar depression . Possible long lasting cognitive side effects will be evaluated . The study is investigator initiated , without support from industry . Trial registration Patients with Bipolar Disorder ( BD ) have high rates of suicide compared to the general population . The present study investigates the predictive power of baseline clinical , psychological and environmental characteristics as risk factors of prospect i ve suicide events ( attempts and completions ) . Data was collected from the Systematic Treatment Enhancement Program for Bipolar Disorder ( STEP-BD ) study . 3083 bipolar patients were included in this report , among these 140 ( 4.6 % ) had a suicide event  ( 8 died by suicide and 132 attempted suicide ) .  Evaluation and assessment forms  were used to collect clinical , psychological and socio-demographic information . Chi-square and independent t-tests were used to evaluate baseline characteristics . Potential prospect i ve predictors were selected on the basis of prior literature and using a screening analysis of all risk factors that were associated with a history of suicide attempt at baseline and were tested using a Cox regression analysis . The strongest predictor of a suicide event was a history of suicide attempt ( hazard ratio = 2.60 , p-value < 0.001 ) in line with prior literature . Additional predictors were : younger age , a high total score on the personality disorder question naire and a high percentage of days spent depressed in the year prior to study entry . In conclusion , the present findings may help clinicians to identify patients at high risk for suicidal behavior upon presentation for treatment Introduction New medication classes are needed to improve treatment effectiveness in the depressed phase of bipolar disorder ( BD ) . Extant evidence suggests that BD is characterised by neural changes such as dendritic remodelling and glial and neuronal cell loss . These changes have been hypothesised to result from chronic inflammation . The principal aims of the proposed research is to evaluate the antidepressant efficacy in bipolar depression of minocycline , a drug with neuroprotective and immune-modulating properties , and of aspirin , at doses expected to selectively inhibit cyclooxygenase 1 ( COX-1 ) . Methods and analysis 120 out patients between 18 and 55 years of age , who meet DSM-IV-TR criteria for BD ( type I or II ) and for a current major depressive episode will be recruited to take part in a r and omised , double-blind , placebo-controlled , parallel-group , proof-of-concept clinical trial following a 2 × 2 design . As adjuncts to existing treatment , subjects will be r and omised to receive one of the four treatment combinations : placebo-minocycline plus placebo-aspirin , active-minocycline plus placebo-aspirin , placebo-minocycline plus active-aspirin or active-minocycline plus active-aspirin . The dose of minocycline and aspirin is 100 mg twice daily and 81 mg twice daily , respectively . Antidepressant response will be evaluated by assessing changes in the Montgomery – Asberg Depression Rating Scale scores between baseline and the end of the 6-week trial . As secondary outcome measures , the anti-inflammatory effects  of minocycline and aspirin will be tested by measuring pre-treatment and post-treatment levels of C reactive protein and inflammatory cytokines . Ethics and dissemination Minocycline has been widely used as an antibiotic in doses up to 400 mg/day . Low-dose aspirin has been safely used on a worldwide scale for its role as an antithrombotic and thrombolytic . The study progress will be overseen by a Data , Safety and Monitoring Board , which will meet once every 6 months . Results of the study will be published in peer- review ed publications . Trial registration number Clinical Trials.gov : NCT01429272 There is growing evidence that atypical antipsychotics may be effective in the treatment of acute bipolar depression . Results from r and omized , placebo-controlled trials support the use of quetiapine monotherapy and a combination of olanzapine-fluoxetine in the depressed phase of bipolar disorder , while only limited data exists regarding the use of aripiprazole in this population . To assess the potential effectiveness of aripiprazole in treating acute bipolar depression , a chart review was conducted on 12 patients with treatment-resistant bipolar disorder ( I , II , and not otherwise specified [ NOS ] ) who received aripiprazole augmentation for the relief of an acute major depressive episode . After 8 weeks of treatment , 4 of 12 ( 33 % ) patients demonstrated a response , defined as a 50 % reduction in the Montgomery-Asberg Depression Rating Scale ( MADRS ) score . In addition , 5 of 12 ( 42 % ) patients newly developed akathisia . This report , though limited by its small sample size and naturalistic design , suggests that the usefulness of aripiprazole in the treatment of bipolar depression may be limited by akathisia We describe the development process and completed structure , of a self-help online intervention for bipolar disorder , known as MoodSwings ( www.moodswings.net.au ) . The MoodSwings program was adapted as an Internet intervention from an efficacious and vali date d face-to-face , group-based psychosocial intervention . The adaptation was created by a psychologist , who had previously been involved with the validation of the face-to-face program , in collaboration with website design ers . The project was conducted under the supervision of a team of clinician research ers . The website is available at no cost to registered participants . Self-help modules are accessed sequentially . Other features include a mood diary and a moderated discussion board . There has been an average of 1,475,135 hits on the site annually ( 2008 and 2009 ) , with some 7400 unique visitors each year . A r and omised controlled trial based on this program has been completed . Many people with bipolar disorder are accepting of the Internet as a source of treatment and , once engaged , show acceptable retention rates . The Internet appears to be a viable means of delivering psychosocial self-help strategies
Placebo response in bipolar disorder trials is more likely to occur in patients who are mildly ill , bipolar II , mixed-episode , first-episode , rapid cycling , atypical , non-psychotic , substance abusers and medically ill .
The use of concomitant medication such as benzodiazepines , a high frequency of visits , a high number of treatment groups and sites , fixed-dose design s , and the concomitant use of psychotherapy are likely to increase placebo response .
There are a number of clinical and method ological variables that are associated with placebo response
Background :  Placebo response is high in bipolar disorder trials .
This is a challenge for research ers and an enigma for clinicians .
This article will attempt to aid in the comprehension of the ethical questions and method ologies related to the use of placebo in bipolar disorder .
Results : Placebo has a very important role in the study of bipolar disorders .
From a method ological point of view , and given the limitations of non-inferiority design s , the use of placebo is necessary to evaluate the sensitivity of the study and ensure that the drug under investigation is really effective .