title: An open-label study of lamotrigine adjunct or monotherapy for the treatment of adolescents with bipolar depression. A Pilot Study of Antidepressant-Induced Mania in Pediatric Bipolar Disorder: Characteristics, Risk Factors, and the Serotonin Transporter Gene A prospective open-label treatment trial of ziprasidone monotherapy in children and adolescents with bipolar disorder. Evidence-based guidelines for treating bipolar disorder: Revised third edition recommendations from the British Association for Psychopharmacology Double-blind, randomized, placebo-controlled long-term maintenance study of aripiprazole in children with bipolar disorder. Aripiprazole augmentation in treatment-resistant depression. Post-acute effectiveness of lithium in pediatric bipolar I disorder. Risperidone for the treatment of acute mania in children and adolescents with bipolar disorder: a randomized, double-blind, placebo-controlled study. A double-blind, randomized, placebo-controlled trial of divalproex extended-release in the treatment of bipolar disorder in children and adolescents. Double-blind 18-month trial of lithium versus divalproex maintenance treatment in pediatric bipolar disorder. Efficacy and safety of extended-release quetiapine fumarate in youth with bipolar depression: an 8 week, double-blind, placebo-controlled trial. A Prospective Open‐Label Trial of Lamotrigine Monotherapy in Children and Adolescents with Bipolar Disorder An open-label trial of risperidone in children and adolescents with bipolar disorder. Maintenance treatment of adolescent bipolar disorder: open study of the effectiveness and tolerability of quetiapine Olanzapine/Fluoxetine combination in children and adolescents with bipolar I depression: a randomized, double-blind, placebo-controlled trial. Efficacy, long-term safety, and tolerability of ziprasidone in children and adolescents with bipolar disorder. Efficacy and safety of quetiapine in children and adolescents with mania associated with bipolar I disorder: a 3-week, double-blind, placebo-controlled trial. Co-morbid disruptive behavior disorder and aggression predict functional outcomes and differential response to risperidone versus divalproex in pharmacotherapy for pediatric bipolar disorder. Combination lithium and divalproex sodium in pediatric bipolarity. Combination lithium and divalproex sodium in pediatric bipolar symptom re-stabilization. A pilot controlled trial of topiramate for mania in children and adolescents with bipolar disorder. Dopamine D2 receptor occupancy in vivo by the novel atypical antipsychotic olanzapine — a123 IBZM single photon emission tomography (SPET) study Ziprasidone treatment of children and adolescents with Tourette's syndrome: a pilot study. Divalproex sodium for pediatric mixed mania: a 6-month prospective trial. Lithium in the Acute Treatment of Bipolar I Disorder: A Double-Blind, Placebo-Controlled Study A double-blind randomized pilot study comparing quetiapine and divalproex for adolescent mania. Open-label prospective trial of risperidone in combination with lithium or divalproex sodium in pediatric mania. A prospective open-label trial of extended-release carbamazepine monotherapy in children with bipolar disorder. Olanzapine versus placebo in the treatment of adolescents with bipolar mania. A one-year open-label trial of risperidone augmentation in lithium nonresponder youth with preschool-onset bipolar disorder. Lithium treatment of acute mania in adolescents: a placebo-controlled discontinuation study. Methylphenidate combined with aripiprazole in children and adolescents with bipolar disorder and attention-deficit/hyperactivity disorder: a randomized crossover trial. A double-blind, placebo-controlled pilot study of quetiapine for depressed adolescents with bipolar disorder. A double-blind, randomized, placebo-controlled study of quetiapine as adjunctive treatment for adolescent mania. Aripiprazole augmentation in treatment-resistant bipolar depression: Early response and development of akathisia A prospective open-label trial of quetiapine monotherapy in preschool and school age children with bipolar spectrum disorder. Efficacy of Topiramate, Valproate, and Their Combination on Aggression/Agitation Behavior in Patients With Psychosis An open-label study of aripiprazole in children with a bipolar disorder. Open-Label, 8-Week Trial of Olanzapine and Risperidone for the Treatment of Bipolar Disorder in Preschool-Age Children Lithium treatment of acute mania in adolescents: a large open trial. Aripiprazole in children and adolescents with bipolar disorder comorbid with attention-deficit/hyperactivity disorder: a pilot randomized clinical trial. A 12-week single-blind trial of quetiapine for the treatment of mood symptoms in adolescents at high risk for developing bipolar I disorder. Acute treatment of pediatric bipolar I disorder, manic or mixed episode, with aripiprazole: a randomized, double-blind, placebo-controlled study. An open-label trial of aripiprazole monotherapy in children and adolescents with bipolar disorder. Double-blind randomized trial of risperidone versus divalproex in pediatric bipolar disorder. A revised anchored version of the BPRS-C for childhood psychiatric disorders. Divalproex monotherapy in the treatment of bipolar offspring with mood and behavioral disorders and at least mild affective symptoms. An open-label trial of divalproex in children and adolescents with bipolar disorder. A randomized controlled trial of risperidone, lithium, or divalproex sodium for initial treatment of bipolar I disorder, manic or mixed phase, in children and adolescents.
abstract: OBJECTIVE The treatment of pediatric bipolar depression has not been well studied . The authors wished to prospect ively study the efficacy of lamotrigine as adjunctive or monotherapy in adolescents with bipolar disorder who were experiencing a depressive episode . METHOD This was an 8-week open-label trial of lamotrigine with 20 adolescents ages 12 - 17 years ( mean age 15.8 ; 7 boys , 13 girls ) with diagnoses of bipolar disorder I , II , or not otherwise specified , who were experiencing a depressive episode .  Lamotrigine was begun at 12.5 to 25 mg/day . Primary response criteria was a 1 or a 2 on the Clinical Global Impression-Improvement at week 8 . A secondary criterion was at least a 50 % decrease in Children 's Depression Rating Scale-Revised scores . RESULTS Nineteen subjects completed the trial . The mean final dose was 131.6 mg/day . Seven subjects were taking other psychotropic medications . Sixteen subjects ( 84 % ) responded by primary criteria , and 12 ( 63 % ) responded to our secondary criteria . Eleven subjects ( 58 % ) were considered in remission at week 8 . Young Mania Rating Scale and Overt Aggression Scale-Modified scores also decreased significantly during the trial . There was no significant weight change , rash , or other adverse effects during the trial . CONCLUSIONS Adolescents with bipolar depression appeared to respond to lamotrigine treatment , whether as adjunctive therapy or monotherapy , with decreases in depression , mania , and aggression . Larger , placebo-controlled studies of lamotrigine are needed in this population BACKGROUND Antidepressant-induced mania ( AIM ) has been described in bipolar disorder ( BD ) and has been associated with the short-allele of the serotonin transporter gene ( 5-HTT ) . We wished to investigate the frequency of and risk factors for AIM in pediatric patients with or at high risk for BD . METHODS Fifty-two children and adolescents ( 30 with BD and 22 with subthreshold manic symptoms , 15.1 + /- 3.4 years old ) , all with a parent with BD , were interviewed with their parents for manic/depressive symptoms occurring before and after past antidepressant treatment .  The 47 subjects with serotonin reuptake inhibitor ( SSRI ) exposure  were genotyped for the 5-HTT polymorphism . RESULTS Fifty percent of subjects were AIM + and 25.5 % had new onset of suicidal ideation . The AIM + and AIM - groups did not differ significantly in relation to allele ( p = .36 ) or genotype ( p = .53 ) frequencies of the 5-HTT polymorphism . The AIM + subjects were more likely to have more comorbidities ( 3.2 vs. 2.4 ; p = .02 ) and be BD type I ( p = .04 ) than AIM - subjects . CONCLUSIONS Youth with or at high risk for BD may be particularly vulnerable to SSRI AIM and thus should be monitored if given SSRIs . In this preliminary study , we did not find that the 5-HTT polymorphism significantly influenced vulnerability to AIM OBJECTIVE To assess the effectiveness and tolerability of ziprasidone for treating pediatric mania . METHODS This was an eight-week , open-label , prospect i ve study of ziprasidone monotherapy ( 57.3 + /- 33.9 mg/day ) in 21 bipolar youth [ manic , mixed , or bipolar not otherwise specified ( NOS ) ; 6 - 17 years old ] . Assessment s included the Young Mania Rating Scale ( YMRS ) , Clinical Global Impressions-Improvement scale ( CGI-I ) , and Brief Psychiatric Rating Scale ( BPRS ) . Adverse events were assessed through spontaneous self-reports , vital signs , weight monitoring , and laboratory analysis . RESULTS Fourteen of the 21 youth ( 67 % ) completed the study .  Ziprasidone treatment was associated with clinical ly and statistically significant improvement in mean YMRS scores ( -10.8 + /- 8.4 , p < 0.0001 ) and 57 % had a CGI-I < or=2 at endpoint . Ziprasidone was well tolerated with no statistically significant increase in body weight ( 0.6 + /- 0.4 kg , p = 0.2 ) or QTc interval ( -3.7 + /- 4.7 , p = 0.5 ) . CONCLUSIONS Open-label ziprasidone treatment was associated with a significant short-term improvement of symptoms of pediatric bipolar disorder . Future placebo-controlled , double-blind studies are warranted The British Association for Psychopharmacology guidelines specify the scope and targets of treatment for bipolar disorder . The third version is based explicitly on the available evidence and presented , like previous Clinical Practice Guidelines , as recommendations to aid clinical decision making for practitioners : it may also serve as a source of information for patients and carers , and assist audit . The recommendations are presented together with a more detailed review of the corresponding evidence . A consensus meeting , involving experts in bipolar disorder and its treatment , review ed key areas and considered the strength of evidence and clinical implication s. The guidelines were drawn up after extensive feedback from these participants . The best evidence from r and omized controlled trials and , where available , observational studies employing quasi-experimental design s was used to evaluate treatment options . The strength of recommendations has been described using the GRADE approach . The guidelines cover the diagnosis of bipolar disorder , clinical management , and strategies for the use of medicines in short-term treatment of episodes , relapse prevention and stopping treatment . The use of medication is integrated with a coherent approach to psychoeducation and behaviour change BACKGROUND This study evaluates the long-term efficacy of aripiprazole compared to placebo in children with bipolar disorders . METHOD Out patients aged 4 to 9 years meeting DSM-IV criteria for a bipolar disorder ( I , II , not otherwise specified , cyclothymia ) were eligible to receive up to 16 weeks of open-label treatment with  aripiprazole ( phase 1 ) . Patients were r and omized into the 72-week double-blind phase of the study once they met a priori response criteria for stabilization ( phase 2 ) . During phase 2 , patients either remained on their current aripiprazole regimen or began a double-blind taper with aripiprazole discontinued and switched to placebo . The primary outcome measure for phase 2 was time to discontinuation due to a mood event . RESULTS Patients were recruited between May 2004 and November 2008 . Following phase 1 , in which 96 patients received aripiprazole , 30 patients ( mean age = 7.1 years ) were r and omly assigned to continue aripiprazole and 30 patients ( mean age = 6.7 years ) were r and omly assigned to placebo . The mean ( SD ) dose of aripiprazole prior to r and omization for these patients was 6.4 ( 2.1 ) mg/d . Patients r and omly assigned to aripiprazole were enrolled significantly longer until time to study discontinuation due to a mood event ( 6.14 median weeks , SE ± 11.88 weeks ; P = .005 ) and discontinuation for any reason ( including mood events ) ( 4.00 median weeks , SE ± 3.91 weeks ; P = .003 ) than those r and omly assigned to placebo ( mood event , 2.29 median weeks , SE ± 0.38 weeks ; any reason , 2.00 median weeks , SE ± 0.31 weeks ) . Regardless of r and om assignment , both the aripiprazole and placebo groups showed substantial rates of withdrawal from maintenance treatment over the initial 4 weeks ( 15/30 [ 50 % ] for aripiprazole ; 27/30 [ 90 % ] for placebo ) , suggesting a possible nocebo effect ( ie , knowledge of possibly switching from active medication to placebo increasing concern about relapse ) . The most frequently reported adverse events during double-blind aripiprazole therapy included stomach pain ( n = 10 , 33 % ) , increased appetite ( n = 9 , 30 % ) , and headaches ( n = 9 , 30 % ) . CONCLUSIONS Despite the possibility of a nocebo effect , these results suggest that aripiprazole may be superior to placebo in the long-term treatment of pediatric patients following stabilization with open-label aripiprazole . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00194077 BACKGROUND Evidence is accumulating to support the use of atypical neuroleptics as adjunctive treatment for refractory mood disorders , although there are currently no published data on the efficacy of an atypical neuroleptic in treatment-resistant depression when a previous trial of drug from the same class has failed . The authors hypothesized that aripiprazole would be efficacious in augmenting antidepressant treatment in resistant patients with non-psychotic unipolar depression who had previously failed a trial of another atypical neuroleptic . METHODS This study was a retrospective chart review of the efficacy of aripiprazole augmentation in 30 treatment-resistant unipolar depression patients who had failed multiple previous antidepressant trials and had also failed augmentation with at least one other atypical neuroleptic .  Prospect i ve Global Assessment of Functioning and Clinical Global Impressions-Improvement scores were completed on each patient throughout treatment . RESULTS Utilizing an intent-to-treat analysis ( including 9 patients who dropped out prior to completion of 6 weeks ) , 46.7 % ( 14/30 ) patients were rated much improved or very much improved with treatment . This improvement negatively correlated with Thase-Rush staging of treatment resistance . GAF scores also showed a significant improvement . Six of the 14 patients who initially improved subsequently relapsed ( yielding a long-term net response rate of 26.7 % ) . CONCLUSION Aripiprazole may be effective as an antidepressant augmentation agent in highly treatment resistant patients who had failed a prior trial of another atypical neuroleptic OBJECTIVE This study examined the long-term effectiveness of lithium for the treatment of pediatric bipolar disorder within the context of combination mood stabilizer therapy for refractory mania and pharmacological treatment of comorbid psychiatric conditions . METHODS Out patients , ages 7 - 17 years , meeting American Psychiatric Association , diagnostic and statistical manual of mental disorders , 4th ed . ( DSM-IV ) diagnostic criteria for bipolar disorder I ( BP-I ) ( manic or mixed ) who demonstrated at least a partial response to 8 weeks of open-label treatment with lithium ( phase I ) were eligible to receive open-label lithium for an additional 16 weeks ( phase II ) . Up to two adjunctive medications could be prescribed to patients experiencing residual symptoms of mania or comorbid psychiatric conditions , following a st and ardized algorithm . RESULTS Forty-one patients received continued open-label long-term treatment with lithium for a mean of 14.9 ( 3.0 ) weeks during phase II . The mean weight-adjusted total daily dose at end of phase II was 27.8 ( 6.7 ) mg/kg/day , with an average lithium concentration of 1.0 ( 0.3 ) mEq/L. Twenty-five of the 41 patients ( 60.9 % ) were prescribed adjunctive psychotropic medications for residual symptoms . The most frequent indications for adjunctive medications were refractory mania ( n=13 ; 31.7 % ) and attention-deficit/hyperactivity disorder ( ADHD ) ( n=15 ; 36.6 % ) . At the end of this phase 28 ( 68.3 % ) patients met a priori criteria for response ( ≥50 % reduction from phase I baseline in young mania rating scale [ YMRS ] summary score and a clinical global impressions-improvement [ CGI-I ] score of 1 or 2 ) , with 22 ( 53.7 % ) considered to be in remission ( YMRS summary score≤12 and CGI-severity score of 1 or 2 ) . These data suggest that patients who initially responded to lithium  maintained mood stabilization during continuation treatment , but partial responders did not experience further improvement during Phase II , despite the opportunity to receive adjunctive medications . The most commonly reported ( ≥20 % ) adverse events associated with lithium treatment were vomiting , headache , abdominal pain , and tremor .  CONCLUSIONS Lithium may be a safe and effective longer-term treatment for patients with pediatric bipolar disorder who respond to acute treatment with lithium . Partial responders to acute lithium did not appear to experience substantial symptom improvement during the continuation phase , despite the possibility that adjunctive medications could be prescribed OBJECTIVES To evaluate the efficacy , safety , and tolerability of risperidone monotherapy for the treatment of an acute mixed or manic episode in children and adolescents with bipolar I disorder . METHODS This r and omized , placebo-controlled , double-blind , 3-arm study ( N = 169 ) included children and adolescents ( ages 10 - 17 years ) with a DSM-IV diagnosis of bipolar I disorder , experiencing a manic or mixed episode . Study participants were r and omized to placebo ( n = 58 ) , risperidone 0.5 - 2.5 mg/day ( n = 50 ) , or risperidone 3 - 6 mg/day ( n = 61 ) for 3 weeks . The primary efficacy measure was change in Young Mania Rating Scale ( YMRS ) total score from baseline to end point . Safety assessment s included adverse event ( AE ) monitoring and scores on extrapyramidal symptom rating scales . RESULTS Improvement in mean YMRS total score was significantly greater in risperidone-treated subjects than in placebo-treated subjects [ mean change ( SD ) -9.1 ( 11.0 ) for placebo ; -18.5 ( 9.7 ) for risperidone 0.5 - 2.5 mg ( p < 0.001 ) ; -16.5 ( 10.3 ) for risperidone 3 - 6 mg ( p < 0.001 ) ] . The most common risperidone-associated  AEs were somnolence , headache , and fatigue . Mean ( SD ) weight gain was 0.7 ( 1.9 ) kg , 1.9 ( 1.7 ) kg , and 1.4 ( 2.4 ) kg in the placebo , risperidone 0.5 - 2.5 mg , and risperidone 3 - 6 mg groups , respectively , during this 3-week study . CONCLUSIONS At daily doses of 0.5 - 2.5 mg and 3 - 6 mg , risperidone was effective and well tolerated in children and adolescents experiencing acute manic or mixed episodes of bipolar I disorder . Results indicate that risperidone 0.5 - 2.5 mg has a better benefit-risk profile than risperidone 3 - 6 mg OBJECTIVE To compare the efficacy and safety of divalproex extended-release ( ER ) to placebo in a 28-day double-blind study of bipolar disorder in children and adolescents and evaluate the safety of divalproex ER in a 6-month open-label extension study . METHOD In the double-blind study , 150 patients ( manic or mixed episode , aged 10 - 17 years ) with baseline Young Mania Rating Scale ( YMRS ) score of 20 or higher were r and omized to once-daily placebo or divalproex ER , which was titrated to clinical response or serum valproate concentration of 80 to 125 microg/mL. Sixty-six patients enrolled in the extension study . RESULTS In the double-blind study , a treatment effect was not observed with divalproex ER based on change in mean YMRS score  ( divalproex ER -8.8 [ n = 74 ] ; placebo -7.9 [ n = 70 ] ) or secondary measures . Divalproex was similar to placebo based on incidence of adverse events . Four subjects treated with divalproex ER and three treated with placebo discontinued because of adverse events . Mean ammonia levels increased in the divalproex ER group , but only one patient was symptomatic . In the long-term study , YMRS scores decreased modestly ( 2.2 points from baseline ) . The most common adverse events were headache and vomiting . CONCLUSIONS The results of the study do not provide support for the use of divalproex ER in the treatment of youths with bipolar I disorder , mixed or manic state . Further controlled trials are required to confirm or refute the findings from this study OBJECTIVE To determine whether divalproex sodium ( DVPX ) was superior to lithium carbonate ( Li+ ) in the maintenance monotherapy treatment of youths diagnosed with bipolar disorder who had been previously stabilized on combination Li+ and DVPX ( Li+/DVPX ) pharmacotherapy . METHOD Youths ages 5 - 17 years with bipolar I or II disorder were initially treated with Li /DVPX . Patients meeting remission criteria for four consecutive weeks were then r and omized in a double-blind fashion to treatment with either Li+ or DVPX for up to 76 weeks . Study participation ended if the subject required additional clinical intervention or if the subject did not adhere to study procedures . RESULTS Patients were recruited between July 1998 and May 2002 . One hundred thirty-nine youths with a mean ( SD ) age of 10.8 ( 3.5 ) years were initially treated with Li+/DVPX for a mean ( SD ) duration of 10.7 ( 5.4 ) weeks . Sixty youths were then r and omized to receive monotherapy with Li+ ( n = 30 ) or DVPX ( n = 30 ) . The Li+ and DVPX treatment groups did not differ in survival time until emerging symptoms of relapse ( p = .55 ) or survival time until discontinuation for any reason ( p = .72 ) . CONCLUSIONS DVPX was not found to be superior to Li+ as maintenance treatment in youths who stabilized on combination Li+/DVPX pharmacotherapy OBJECTIVE Quetiapine is an atypical antipsychotic with demonstrated efficacy in the treatment of adolescent schizophrenia and pediatric bipolar mania . Large , placebo-controlled studies of interventions in pediatric bipolar depression are lacking . The current study investigated the efficacy and safety of quetiapine extended-release ( XR ) in patients 10 - 17 years of age , with acute bipolar depression . METHODS This multicenter , double-blind , r and omized , placebo-controlled study investigated quetiapine XR ( dose range , 150 - 300 mg/day ) in pediatric out patients with an American Psychiatric Association , Diagnostic and Statistical Manual of Mental Disorders , 4th ed . , Text Revision ( DSM-IV-TR ) diagnosis of bipolar I or bipolar II disorder ( current or most recent episode depressed ) treated for up to 8 weeks ( Clinical Trials.gov identifier : NCT00811473 ) . The primary study outcome was mean change in Children 's Depression Rating Scale-Revised ( CDRS-R ) total score . Secondary efficacy outcomes included CDRS-R-based response and remission rates . RESULTS Of 193 patients r and omized to treatment , 144 patients completed the study ( 75.3 % of quetiapine XR group [ n=70 ] ; 74.0 % of placebo  group [ n=74 ] ) . Least squares mean changes in CDRS-R total score at week 8 were : -29.6 ( SE , 1.65 ) with quetiapine XR and -27.3 ( SE , 1.60 ) with placebo , a between-treatment group difference of -2.29 ( SE , 1.99 ; 95 % CI , -6.22 , 1.65 ; p=0.25 ; mixed-model for repeated measures analysis ) . Rates of response and remission did not differ significantly between treatment groups . The safety profile of quetiapine XR was broadly consistent with the profile reported previously in adult studies of quetiapine XR and pediatric studies of quetiapine immediate-release ( IR ) . Potentially clinical ly significant elevations in clinical chemistry values included triglycerides ( 9.3 % , quetiapine XR ; 1.4 % , placebo group ) and thyroid stimulating hormone ( 4.7 % , quetiapine XR ; 0 % , placebo group ) . An adverse event potentially related to diabetes mellitus occurred in 3.3 % of the quetiapine XR versus no adverse events in the placebo group . CONCLUSIONS Quetiapine XR did not demonstrate efficacy relative to placebo in this 8 week study of pediatric bipolar depression . Quetiapine XR was generally safe and well tolerated Aim : To evaluate the safety and efficacy of lamotrigine monotherapy as an acute treatment of bipolar mood elevation in children with bipolar spectrum disorders . Method : This was a 12‐week , open‐label , prospect i ve trial of lamotrigine monotherapy to assess the effectiveness and tolerability of this compound in treating pediatric bipolar disorder . Assessment s included the Young Mania Rating Scale ( YMRS ) , Clinical Global Impressions‐Improvement scale ( CGI‐I ) , Children 's Depression Rating Scale ( CDRS ) , and Brief Psychiatric Rating Scale ( BPRS ) . Adverse events were assessed through spontaneous self‐reports , vital signs weight monitoring , and laboratory analysis . Results : Thirty‐nine children with bipolar disorder ( YMRS at entry : 31.6 ± 5.5 ) were enrolled in the study and 22 ( 56 % ) completed the 12‐week trial . Lamotrigine was slowly titrated to an average endpoint dose of 160.7 ± 128.3 in subjects < 12 years of age ( N = 22 ) and 219.1 ± 172.2 mg/day in children 12–17 years of age ( N = 17 ) . Treatment with lamotrigine was associated with statistically significant levels of improvement in mean YMRS scores ( −14.9 ± 9.7 , P < 0.001 ) at endpoint . Lamotrigine treatment also result ed in significant improvement in the severity of depressive , attention‐deficit/hyperactivity disorder ( ADHD ) , and psychotic symptoms  . Lamotrigine was generally well tolerated with marginal increase in body weight ( 47.0 ± 18.0 kg vs. 47.2 ± 17.9 kg , P= 0.6 ) and was not associated with abnormal changes in laboratory parameters . Several participants were discontinued due to skin rash ; in all cases , the rash resolved shortly after discontinuation of treatment . No patient developed Steven Johnson syndrome . Conclusions : Open‐label lamotrigine treatment appears to be beneficial in the treatment of bipolar disorder and associated conditions in children . Future placebo‐controlled , double‐blind studies are warranted to confirm these findings OBJECTIVE The aim of this study was to evaluate the potential of risperidone as a treatment of  pediatric bipolar disorder .  METHODS This was an 8-week , open-label , prospect i ve study of risperidone monotherapy ( 1.25 + /- 1.5 mg/d ) for 30 bipolar youths ( manic , mixed , or hypomanic ; 6 - 17 years of age ) . RESULTS Twenty-two of the 30 youths ( 73 % ) completed the study . Using predefined criteria for improvement ( a Clinical Global Impressions Improvement in Mania score of < or = 2 at endpoint ) , the response rate for manic symptoms was 70 % . The significant reduction in symptoms of mania result ed in a mean Young Mania Rating Scale ( YMRS ) score 13.5 at endpoint , indicating mild residual symptoms . Weight increased significantly from baseline ( 2.1 + /- 2.0 kg ; p < 0.001 ) and there was a four-fold increase in prolactin levels from baseline ( p < 0.001 ) . CONCLUSIONS Open-label risperidone treatment was associated with a significant shortterm improvement of symptoms of pediatric bipolar disorder . Future placebo-controlled , double-blind studies are needed to confirm these preliminary results Background The purpose of the study was to determine the effectiveness and tolerability of quetiapine as a maintenance treatment preventing against relapse or recurrence of acute mood episodes in adolescent patients diagnosed with bipolar disorder . Methods Consenting patients meeting DSM-IV lifetime criteria for a bipolar disorder and clinical ly appropriate for maintenance treatment were enrolled in a 48-week open prospect i ve study . After being acutely stabilized ( CGI-S ≤ 3 for 4 consecutive weeks ) , patients were started or continued on quetiapine and other medications were weaned off over an 8-week period . Quetiapine monotherapy was continued for 40-weeks and other mood stabilizers or antidepressants were added if clinical ly indicated . A neurocognitive test battery assessing the most reliable findings in adult patients was administered at fixed time points throughout the study to patients and matched controls . Results Of the 21 enrolled patients , 18 completed the 48-week study . Thirteen patients were able to be maintained without relapse or recurrence in good quality remission  on quetiapine monotherapy , while 5 patients required additional medication to treat impairing residual depressive and /or anxiety symptoms . According to symptom ratings and global functioning scores , the quality of remission for all patients was very good . Neurocognitive test performance over treatment was equivalent to that of a matched control group of never ill adolescents . Quetiapine was generally well tolerated with no serious adverse effects . Conclusion This study suggests that a proportion of adolescent patients diagnosed with bipolar disorder can be successfully maintained on quetiapine monotherapy . The good quality of clinical remission and preserved neurocognitive functioning underscores the importance of early diagnosis and effective stabilization . Clinical Trials OBJECTIVE To assess the efficacy and safety of olanzapine/fluoxetine combination ( OFC ) for the acute treatment of bipolar depression in children and adolescents . METHOD Patients 10 to 17 years of age with bipolar I disorder ( BP-I ) , depressed episode , baseline Children 's Depression Rating Scale-Revised ( CDRS-R ) total score ≥40 , Young Mania Rating Scale ( YMRS ) total score ≤15 , and YMRS-item 1 ≤2 were r and omized to OFC ( 6/25 - 12/50 mg/day olanzapine/fluoxetine ; n = 170 ) or placebo ( n = 85 ) for up to 8 weeks of double-blind treatment . The primary efficacy measure was mean change in CDRS-R using mixed-model repeated- measures methodology . RESULTS Baseline-to-week-8 least-squares mean change in CDRS-R total score was greater for OFC-treated patients than for placebo-treated patients ( -28.4 versus -23.4 , p = .003 ; effect size = .46 ) , with between-group differences statistically significant at week 1 ( p = .02 ) and all subsequent visits ( all p < .01 ) . Rates of and times to response and remission were statistically significantly greater for OFC- than for placebo-treated patients . The most frequent treatment-emergent adverse events in the OFC group were weight gain , increased appetite , and somnolence . Mean weight gain at patient 's endpoint was significantly greater for OFC- than for placebo-treated patients ( 4.4 kg versus 0.5 kg , p < .001 ) . Treatment-emergent hyperlipidemia was very common among OFC-treated patients . Abnormal increases in hepatic analytes , prolactin , and corrected QT interval ( QTc ) were also common or very common but generally not clinical ly significant . CONCLUSION In this study , OFC was superior to placebo , and has been approved by the US Food and Drug Administration ( FDA ) for the acute treatment of bipolar I depression in patients 10 to 17 years of age . Benefits should be weighed against the risk of adverse events , particularly weight gain and hyperlipidemia . Clinical trial registration information-A Study for Assessing Treatment of Patients Ages 10 - 17 with Bipolar Depression ; http:// clinical trials.gov ; NCT00844857 OBJECTIVE The purpose of this study was to evaluate the short- and long-term efficacy and safety of ziprasidone in children and adolescents with bipolar I disorder . METHODS Subjects 10 - 17 years of age with a manic or mixed episode associated with bipolar I disorder participated in a 4 week , r and omized , double-blind , placebo-controlled multicenter trial ( RCT ) followed by a 26 week open-label extension study ( OLE ) . Subjects were r and omized 2:1 to initially receive flexible-dose ziprasidone ( 40 - 160 mg/day , based on weight ) or placebo . Primary outcome was the change in Young Mania Rating Scale ( YMRS ) scores from baseline . Safety assessment s included weight and body mass index ( BMI ) , adverse events ( AEs ) , vital signs , laboratory measures , electrocardiograms , and movement disorder ratings . RESULTS In the RCT , 237 subjects were treated with ziprasidone ( n=149 ; mean age , 13.6 years ) or placebo ( n=88 ; mean age , 13.7 years ) . The estimated least squares mean changes in YMRS total ( intent-to-treat population ) were -13.83 ( ziprasidone ) and -8.61 ( placebo ; p=0.0005 ) at RCT endpoint . The most common AEs in the ziprasidone group were sedation ( 32.9 % ) , somnolence ( 24.8 % ) , headache ( 22.1 % ) , fatigue ( 15.4 % ) , and nausea ( 14.1 % ) . In the OLE , 162 subjects were enrolled , and the median duration of treatment was 98 days . The mean change in YMRS score from the end of the RCT to the end of the OLE ( last observation carried forward ) was -3.3 ( 95 % confidence interval , -5.0 to -1.6 ) . The most common AEs were sedation ( 26.5 % ) , somnolence ( 23.5 % ) , headache ( 22.2 % ) , and insomnia ( 13.6 % ) . For both the RCT and the OLE , no clinical ly significant mean changes in movement disorder scales , BMI z-scores , liver enzymes , or fasting lipids and glucose were observed . One subject on ziprasidone in the RCT and none during the OLE had Fridericia-corrected QT interval ( QTcF ) ≥ 460 ms . CONCLUSION These results demonstrate that ziprasidone is efficacious for treating children and adolescents with bipolar disorder .  Ziprasidone was generally well tolerated with a neutral metabolic profile . CLINICAL TRIALS REGISTRY NCT00257166 and NCT00265330 at Clinical Trials.gov OBJECTIVE To evaluate the efficacy and safety of quetiapine monotherapy in children and adolescents with mania associated with bipolar I disorder . METHOD Patients aged 10 to 17 years , with a DSM-IV-TR diagnosis of a manic episode associated with bipolar I disorder and Young Mania Rating Scale ( YMRS ) total score ≥ 20 were r and omized to 3 weeks of quetiapine ( 400 or 600 mg/d ) or placebo . The primary efficacy measure was change in YMRS total score . The study was conducted at 34 centers in the United States between August 2004 and July 2006 . RESULTS The intent-to-treat population included 277 patients . Least squares mean change in YMRS score from baseline to end point by mixed-model , repeated- measures analysis was -14.25 , -15.60 , and -9.04 for quetiapine 400 mg/d , quetiapine 600 mg/d , and placebo , respectively ( P < .001 , each quetiapine dose vs placebo ) . Significant improvement in YMRS score versus placebo was first observed at day 4 ( P = .015 ) with quetiapine 400 mg/d and day 7 ( P < .001 ) with quetiapine 600 mg/d . Mean changes in body weight at day 21 ( observed cases ) were 1.7 kg for both quetiapine doses and 0.4 kg for placebo . Numerically larger mean increases in total cholesterol , low-density lipoprotein cholesterol , and triglycerides were observed with quetiapine than placebo . Adverse events associated with quetiapine were mostly mild to moderate in intensity . CONCLUSIONS In this 3-week study , quetiapine was significantly more effective than placebo in improving manic symptoms in youth with mania associated with bipolar disorder . Treatment was generally well tolerated and adverse events were broadly consistent with the known profile of quetiapine in adults with bipolar disorder . TRIAL REGISTRATION Clinical Trials.gov identifier : NCT00090311 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 OBJECTIVE Lithium carbonate ( Li ) or divalproex sodium ( DVPX ) may be effective for some juveniles with bipolar disorder . Many youths with bipolar disorder do not respond to DVPX or Li monotherapy . An open-label study was conducted to examine the effectiveness of combination DVPX and Li therapy with youths diagnosed with bipolar disorder . METHOD Patients meeting DSM-IV criteria for bipolar I or bipolar II disorder , ages 5 to 17 years , were treated prospect ively for up to 20 weeks with DVPX + Li . Assessment s included the Young Mania Rating Scale ( YMRS ) , Children 's Depression Rating Scale-Revised ( CDRS-R ) , and the Children 's Global Assessment Scale ( CGAS ) . The a priori definition of clinical remission utilized included four contiguous weekly ratings of YMRS < /=12.5 , CDRS-R < /=40 , CGAS > /=51 , clinical stability , and no evidence of mood cycling . RESULTS Ninety patients ( 66 males , 24 females ) were treated . Significant improvement ( p < .0001 ) in all outcome measures was observed by week 8 as well as at the end of study . The mean time in study was 11.3 weeks . Forty-seven percent ( n = 42 ) met a priori criteria for remission . CONCLUSIONS Symptoms of mania and depression in juvenile bipolar disorder may be safely and effectively treated acutely with DVPX + Li OBJECTIVE It has been reported that bipolar disorder may become less responsive to previously effective treatment with each symptomatic relapse . The primary goal of this study was to assess the rate of re-stabilization after the resumption of lithium ( Li ) plus divalproex ( DVPX ) following relapse on either agent as monotherapy . METHOD This is a prospect i ve , 8-week , open-label outpatient Li/DVPX combination therapy trial . Patients ages 5 to 17 years with bipolar disorder type I or II , who had achieved symptom remission with Li/DVPX combination therapy and subsequently relapsed during treatment with Li or DVPX monotherapy were enrolled between January 1999 and January 2003 . RESULTS Thirty-eight patients with a mean age of 10.5 years entered the study . Thirty-four ( 89.5 % ) patients responded to treatment with Li/DVPX mood stabilizer therapy alone , but four patients required adjunctive antipsychotic treatment to address residual symptomatology . Overall , reinitiation of Li/DVPX combination therapy was well tolerated with no subjects discontinuing because of a medication-related adverse event . CONCLUSIONS It appears that most youths with bipolar disorder who stabilize on combination Li/DVPX therapy and subsequently relapse during monotherapy can safely and effectively be re-stabilized with the reinitiation of Li/DVPX combination treatment OBJECTIVE To assess the efficacy of topiramate monotherapy for acute mania in children and adolescents with bipolar disorder type I. METHOD This double-blind , placebo-controlled study was discontinued early when adult mania trials with topiramate failed to show efficacy . Efficacy end points included the Young Mania Rating Scale ( YMRS ) , Brief Psychiatric Rating Scale for Children , Children 's Depression Rating Scale , Children 's Global Assessment Scale , and Clinical Global Impressions-Improvement . RESULTS Fifty-six children and adolescents ( 6 - 17 years ) with a diagnosis of bipolar disorder type I received topiramate ( n=29 , 52 % ) or placebo ( n=27 , 48 % ) . The only statistically significant differences in efficacy measures between treatment groups were the difference between slopes of the linear mean profiles of the YMRS ( p=.003 ) using a post hoc repeated measures regression and the change in Brief Psychiatric Rating Scale for Children at day 28 ( -14.9 versus-5.9 , p=.048 ) using observed data . Adverse events with topiramate included decreased appetite , nausea , diarrhea , and paresthesia . CONCLUSIONS Topiramate was well tolerated ; however , the results are inconclusive because of premature termination result ing in a limited sample size . Adequately powered controlled trials are necessary to determine whether topiramate has efficacy in reducing symptoms of acute mania in children and adolescents We have studied striatal D2 dopamine binding in schizophrenic patients treated with the novel atypical antipsychotic drug , olanzapine.123I iodobenzamide ( IBZM ) single photon emission tomography ( SPET ) was used to estimate striatal dopamine D2 receptor binding in vivo . Patients were recruited from a prospect i ve , double blind controlled trial of olanzapine versus haloperidol treatment . In vivo striatal D2 binding data from olanzapine treated patients ( n=6 ) were compared with previously reported data from typical antipsychotic responsive ( n=10 ) ; clozapine ( n=10 ) ; and risperidone ( n=6 ) treated patient groups .  Mean % Brief Psychiatric Rating Scale score ( BPRS ) improvement following olanzapine treatment was 49 % ( SD 44 ) . The hypothesis that clinical improvement in olanzapine treated patients would be associated with higher mean striatal D2 binding of123I IBZM ( reflecting lower levels of D2 occupancy ) than typical antipsychotic ( 1.25±0.05 ) or risperidone ( 1.24±0.04 ) treatment was confirmed . Olanzapine treated patients had similar levels of striatal D2 binding in vivo ( 1.41±0.06 ) as those treated with clozapine ( 1.49±0.04 ) . This preliminary evidence suggests olanzapine is another atypical antipsychotic drug in which therapeutic response is not associated with a high degree of striatal D2 receptor occupancy in vivo OBJECTIVE To evaluate the efficacy and tolerability of ziprasidone in children and adolescents with Tourette 's syndrome and chronic tic disorders . METHOD Twenty-eight patients aged 7 to 17 years were r and omly assigned to ziprasidone or placebo for 56 days . Ziprasidone was initiated at a dose of 5 mg/day and flexibly titrated to a maximum of 40 mg/day . RESULTS Ziprasidone was significantly more effective than placebo in reducing the Global Severity ( p = .016 ) and Total Tic ( p = .008 ) scores on the Yale Global Tic Severity Scale . Compared with placebo , ziprasidone significantly reduced tic frequencies as determined by blind videotape tic counts ( p = .039 ) . The mean ( + /- SD ) daily dose of ziprasidone during the last 4 weeks of the trial was 28.2 + /- 9.6 mg . Mild transient somnolence was the most common adverse event . No clinical ly significant effects were observed on specific ratings of extrapyramidal symptoms , akathisia , or tardive dyskinesia . CONCLUSIONS In this limited sample , ziprasidone ( 5 - 40 mg/day ) appears to be effective and well tolerated in the treatment of Tourette 's syndrome . Ziprasidone may be associated with a lower risk of extrapyramidal side effects in children . However , additional studies are necessary to evaluate more fully its safety and efficacy in children with tic disorders OBJECTIVE This prospect i ve 6-month open trial examined the effectiveness and safety of divalproex sodium ( DVPX ) in pediatric mixed mania . METHOD Thirty-four subjects with a mean age of 12.3 ( SD = 3.7 ) years , DSM-IV diagnosis of a current mixed episode and a baseline Young Mania Rating Scale ( YMRS ) score > 20 were treated with DVPX monotherapy .  The primary outcome measures were the YMRS and the Child Depression Rating Scale-Revised . Secondary measures were the Clinical Global Impression Scale for Bipolar Disorder ( CGI-BP ) and the Children 's Global Assessment of Functioning Scale ( C-GAS ) . Measures of safety and tolerability were also administered . RESULTS Effect size ( Cohen 's d ) based on change scores from baseline was 2.9 for the YMRS and 1.23 for the CDRS-R. Response rate ( > or = 50 % change from baseline YMRS score and < or = 40 score on CDRS-R at the end of study ) was 73.5 % . The remission rate ( > or = 50 % change from baseline on YMRS , < or = 40 on CDRS-R , CGI-BP-Improvement subscale of < or = 2 , and > or = 51 CGAS score ) was 52.9 % . Significant improvements ( p < 0.001 ) from baseline were seen for mean scores on all outcome measures ( i.e. , YMRS , CGI-BP , CDRS-R , and C-GAS ) .  DVPX was safe and well tolerated with no serious adverse events during the 6-month trial . CONCLUSION This study provides evidence for the effectiveness and safety of DVPX in the treatment of pediatric mixed mania over a 6-month period . Placebo-controlled , r and omized trials involving larger sample s will ultimately shed light on the efficacy of this agent BACKGROUND : Lithium is a benchmark treatment for bipolar disorder in adults . Definitive studies of lithium in pediatric bipolar I disorder ( BP-I ) are lacking . METHODS : This multicenter , r and omized , double-blind , placebo-controlled study of pediatric participants ( ages 7–17 years ) with BP-I/manic or mixed episodes compared  lithium ( n = 53 )  versus placebo ( n = 28 ) for up to 8 weeks . The a priori primary efficacy measure was change from baseline to the end of study ( week 8/ET ) in the Young Mania Rating Scale ( YMRS ) score , based on last-observation-carried-forward analysis . RESULTS : The change in YMRS score was significantly larger in lithium-treated participants ( 5.51 [ 95 % confidence interval : 0.51 to 10.50 ] ) after adjustment for baseline YMRS score , age group , weight group , gender , and study site ( P = .03 ) . Overall Clinical Global Impression – Improvement scores  favored lithium ( n = 25 ; 47 % very much/much improved ) compared with placebo ( n = 6 ; 21 % very much/much improved ) at week 8/ET ( P = .03 ) . A statistically significant increase in thyrotropin concentration was seen with lithium ( 3.0 ± 3.1 mIU/L ) compared with placebo ( –0.1 ± 0.9 mIU/L ; P < .001 ) . There was no statistically significant between-group difference with respect to weight gain . CONCLUSIONS : Lithium was superior to placebo in reducing manic symptoms in pediatric patients treated for BP-I in this clinical trial . Lithium was generally well tolerated in this patient population and was not associated with weight gain , distinguishing it from other agents commonly used to treat youth with bipolar disorder OBJECTIVE To determine the comparative efficacy of quetiapine and divalproex for the treatment of adolescent mania . METHOD Fifty adolescents ( ages 12 - 18 years ) with bipolar I disorder , manic or mixed episode , were r and omized to quetiapine ( 400 - 600 mg/day ) or divalproex ( serum level 80 - 120 microg/mL ) for 28 days for this double-blind study , which was conducted from July 2002 through January 2004 . The primary efficacy measure was change in Young Mania Rating Scale ( YMRS ) score across the study period . RESULTS Repeated measures analysis of variance using the last-observation carried forward data indicated no statistically significant group difference in YMRS scores across the 28 days of the study ( p = 0.3 ) . Mixed regression analyses ( comparison of slopes ) revealed that improvement in YMRS scores occurred more rapidly in the quetiapine than in the divalproex group for both the last-observation carried forward ( p = 0.01 ) and observed data ( p = 0.03 ) . Response and remission rates were significantly greater in the quetiapine than in the divalproex group ( p < .03 ) . Rates of adverse events did not differ significantly between groups . CONCLUSIONS The results suggest that quetiapine is at least as effective as divalproex in the treatment of acute manic symptoms associated with adolescent bipolar disorder ; however , a quicker reduction of manic symptoms may occur with quetiapine as compared with divalproex . Quetiapine may be useful as monotherapy for the treatment of adolescents with manic or mixed episodes , although placebo-controlled studies are necessary OBJECTIVE This prospect i ve 6-month open trial examined the safety and efficacy of two combination therapies for manic or mixed episodes of pediatric bipolar disorder : ( 1 ) divalproex sodium plus risperidone ( DVPX+Risp ) , or ( 2 ) lithium plus risperidone ( Li+Risp ) . METHODS Thirty-seven ( 37 ) subjects aged 5 and 18 ( age=12.1+/-3.5 years ) with DSM IV current mixed or manic episode and Young Mania Rating Scale ( YMRS ) score > 20 were sequentially assigned to either DVPX+Risp or Li+Risp in a 6-month , prospect i ve open-label trial . Outcome measures included the YMRS , Clinical Global Impression Scale for Bipolar Disorder ( CGI-BP ) , Child Depression Rating Scale-Revised ( CDRS-R ) as well as measures of safety and tolerability . RESULTS Effect sizes ( Cohen 's d ) based on change of YMRS scores from baseline were 4.36 for DVPX+Risp and 2.82 for Li+Risp .  Response rates ( > or=50 % change from baseline YMRS score at the end of study ) were 80 % for DVPX+Risp and 82.4 % for Li+Risp . Both combination treatments were well tolerated . Significant improvements ( p<0.001 ) from baseline were seen for mean scores on all efficacy measures , i.e. , YMRS , CGI-BP , and CDRS-R. There were no significant group differences in safety or tolerability , and no serious adverse events during the 6-month trial . CONCLUSION Both DVPX+Risp and Li+Risp show strong effects coupled with safety and tolerability in treating children and adolescents with manic or mixed episodes associated with type I bipolar disorder OBJECTIVE The aim of this study was to evaluate the safety and efficacy of extended release carbamazepine ( CBZ-ER ) monotherapy in the treatment of pediatric bipolar disorder ( BD ) . METHOD This was an 8-week , open-label , prospect i ve trial of CBZ-ER monotherapy ( 788 + /- 252 mg/day ) to assess the effectiveness and tolerability of this compound in treating pediatric bipolar spectrum disorders . Assessment s included the Young Mania Rating Scale ( YMRS ) , Clinical Global Impressions-Improvement scale , Children 's Depression Rating Scale , and Brief Psychiatric Rating Scale . Adverse events were assessed through spontaneous self-reports , vital signs weight monitoring , and laboratory analysis . RESULTS Of the 27 participating children with BD , 16 ( 59.% ) completed the study .  CBZ-ER treatment was associated with statistically significant , but modest , levels of improvement in mean YMRS scores ( -10.1 + /- 10.2 , p < 0.001 ) with end-point mean YMRS score ( 21.8 + /- 12.2 ) suggesting a lack of complete resolution of mania . CBZ-ER treatment also result ed in significant improvement in the severity of depressive , attention-deficit/hyperactivity disorder , and psychotic symptoms . With the exception of 2 participants who discontinued due to skin rash , CBZ-ER was well tolerated with marginal increase in body weight ( 0.8 + /- 2.5 kg , p = 0.04 ) and was not associated with any abnormal changes in laboratory parameters . CONCLUSIONS Open-label CBZ-ER treatment was beneficial for the treatment of BD in children . Future controlled trials are warranted OBJECTIVE The purpose of this study was to evaluate the efficacy and safety of olanzapine for the treatment of acute manic or mixed episodes associated with bipolar disorder in adolescents . METHOD A 3-week multicenter , parallel , double-blind , r and omized placebo-controlled trial was conducted at 24 sites in the United States and two sites in Puerto Rico . The participants were outpatient and inpatient male and female adolescents 13 - 17 years of age with an acute manic or mixed episode . Subjects received either olanzapine  ( 2.5 - 20 mg/day [ N=107 ] ) or placebo ( N=54 ) . The mean change from baseline to endpoint in the Young Mania Rating Scale total score was the primary outcome measure . RESULTS The mean baseline-to-endpoint change in the Young Mania Rating Scale total score was significantly greater for patients receiving olanzapine relative to patients receiving placebo , and a greater proportion of olanzapine-treated patients met response and remission criteria ( 44.8 % versus 18.5 % and 35.2 % versus 11.1 % , respectively ) . The mean baseline-to-endpoint weight change was significantly greater for patients receiving olanzapine relative to patients receiving placebo ( 3.7 kg versus 0.3 kg ) , and the incidence of treatment-emergent weight gain > or = 7 % of baseline was higher for olanzapine-treated patients ( 41.9 % versus 1.9 % ) . The mean baseline-to-endpoint changes in prolactin , fasting glucose , fasting total cholesterol , uric acid , and the hepatic enzymes aspartate transaminase and alanine transaminase were significantly greater in patients treated with olanzapine relative to patients receiving placebo . CONCLUSIONS Olanzapine was effective in the treatment of bipolar mania in adolescent patients . Patients treated with olanzapine , however , had significantly greater weight gain and increases in the levels of hepatic enzymes , prolactin , fasting glucose , fasting total cholesterol , and uric acid OBJECTIVE The aim of this study was to assess the safety and efficacy of risperidone augmentation of lithium in preschool-onset bipolar disorder ( BD ) among youth who insufficiently respond to lithium monotherapy .  METHOD Thirty-eight subjects between the ages of 4 and 17 years ( mean age = 11.37 + /- 3.8 years ) with onset of BD in preschool years ( manic or mixed episode ) entered this 12-month trial . All subjects received lithium monotherapy . Patients who failed to adequately respond to lithium monotherapy after 8 weeks and those who relapsed after an initial response were given risperidone augmentation for up to 11 months . The Young Mania Rating Scale ( YMRS ) was the primary outcome measure . Response was defined as a > or = 50 % decrease from baseline . Additional data were collected on diagnostic comorbidity , family history , number of hospitalizations , perinatal risk factors , history of physical or sexual abuse , Child Depression Rating Scale-Revised ( CDRS-R ) , Clinical Global Impression ( CGI ) scale for BD ( CGI-BP ) , Children 's Global Assessment Scale ( C-GAS ) , and adverse medication effects . RESULTS Of the 38 subjects treated with lithium monotherapy , 17 responded , whereas 21 required augmentation with risperidone .  Response rate in the youths treated with lithium + risperidone was 85.7 % ( n = 18/21 ) . Significant predictors of inadequate response to lithium monotherapy requiring augmentation were : ( 1 ) attention-deficit/hyperactivity disorder ( ADHD ) , ( 2 ) severity at baseline , ( 3 ) history of sexual or physical abuse , and ( 4 ) preschool age . Combination treatment of lithium and risperidone was found to be safe and well tolerated . CONCLUSIONS A substantial proportion of youth with a history of preschool-onset BD treated with lithium  were either nonresponders or partial responders . Subsequent augmentation of lithium with risperidone in these cases was well tolerated and efficacious . Potential predictors of lithium nonresponse identified in this study may guide the choice of medications earlier in the treatment process OBJECTIVE There are no published placebo-controlled studies of any agent in the treatment of acute mania in children or adolescents . This is the first placebo-controlled study of lithium 's efficacy in the treatment of acute mania in adolescents . METHOD In this discontinuation study , participants received open treatment with lithium at therapeutic serum levels ( mean 0.99 mEq/L ) for at least 4 weeks . Responders were r and omly assigned to continue or discontinue lithium during a 2-week double-blind , placebo-controlled phase . This study had 80 % power to detect a 40 % difference in exacerbation rates between groups ( 10 % on lithium versus 50 % on placebo ) . RESULTS Twenty-three of 40 protocol participants ( 57.5 % ) experienced a clinical ly significant symptom exacerbation during the 2-week double-blind phase . However , the slightly lower exacerbation rate in the group maintained on lithium ( 10/19 or 52.6 % ) versus the group switched to placebo ( 13/21 or 61.9 % ) did not reach statistical significance . CONCLUSIONS This study does not support a large effect for lithium continuation treatment of adolescents with acute mania , mostly due to the unexpectedly high rate of exacerbations in the group that continued on lithium . Further studies are warranted to clarify whether acute mania in adolescents is lithium responsive In clinical sample s , juvenile bipolar disorder ( JBPD ) is frequently accompanied by co-morbid attention-deficit/hyperactivity disorder ( ADHD ) . Clinical trials assessing combined psychopharmacological interventions in this population are scarce , and methylpheni date ( MPH ) may worsen manic symptoms . We conducted a r and omized crossover trial with MPH and placebo ( 2 weeks each ) combined with aripiprazole in children and adolescents ( n = 16 ; 8 - 17 years old ) with JBPD and ADHD who had a significant response in manic symptoms with aripiprazole but still presented clinical ly significant symptoms of ADHD .  ADHD , manic , and depressive symptoms were assessed by means of st and ard scales . Fourteen out of the 16 subjects completed the trial . No significant differences between the effects of methylpheni date and placebo were detected in ADHD ( F(1 , 43.22 ) = 0.00 ; p = 0.97 ) or manic ( F(1 , 40.19 ) = 0.93 ; p = 0.34 ) symptoms . Significant improvement in depressive symptoms was observed in the MPH group ( F(1,19.03 ) = 7.75 ; p = 0.01 ) according to a secondary self-reported outcome measure . One patient using aripiprazole  and MPH discontinued the trial due to the onset of a severe mixed episode . No other significant adverse events were observed . Although MPH did not worsen manic symptoms , it was not more effective than placebo in improving ADHD symptoms in children and adolescents with JBPD co-morbid with ADHD stabilized with aripiprazole . Further investigations are warranted . This study is registered at www . clinical trials.gov under the identifier NCT00305370 OBJECTIVE To conduct a pilot study comparing the effects of quetiapine and placebo for the treatment of depressive episodes in adolescents with bipolar I disorder . METHOD Thirty-two adolescents ( ages 12 - 18 years ) with a depressive episode associated with bipolar I disorder were r and omized to eight weeks of double-blind treatment with  quetiapine , 300 - 600 mg/day , or placebo . This two-site study was conducted from March 2006 through August 2007 . The primary efficacy measure was change in Children 's Depression Rating Scale-Revised Version ( CDRS-R ) scores from baseline to endpoint . Secondary efficacy measures included change in CDRS-R scores over the eight-week study period ( PROC MIXED ) , changes from baseline to endpoint in Hamilton Anxiety Rating Scale ( HAM-A ) , Young Mania Rating Scale ( YMRS ) , and Clinical Global Impression-Bipolar Version Severity ( CGI-BP-S ) scores , as well as response and remission rates . Safety and tolerability were assessed weekly . RESULTS There was no statistically significant treatment group difference in change in CDRS-R scores from baseline to endpoint ( p = 0.89 , effect size = -0.05 , 95 % confidence interval : -0.77 - 0.68 ) , nor in the average rate of change over the eight weeks of the study ( p = 0.95 ) . Additionally , there were no statistically significant differences in response ( placebo = 67 % versus quetiapine = 71 % ) or remission ( placebo = 40 % versus quetiapine = 35 % ) rates , or change in HAM-A , YMRS , or CGI-BP-S scores ( all p > 0.7 ) between treatment groups . Dizziness was more commonly reported in the quetiapine ( 41 % ) than in the placebo ( 7 % ) group ( Fisher 's exact test , p = 0.04 ) . CONCLUSIONS The results suggest that quetiapine monotherapy is no more effective than placebo for the treatment of depression in adolescents with bipolar disorder . However , limitations of the study , including the high placebo response rate , may have contributed to our findings and should be considered in the design of future investigations of pharmacological interventions for this population OBJECTIVES This r and omized , double-blind , placebo-controlled study examined the efficacy and tolerability of quetiapine in combination with divalproex ( DVP ) for acute mania in adolescents with bipolar disorder . It was hypothesized that DVP in combination with quetiapine would be more effective than DVP alone for treating mania associated with adolescent bipolar disorder . Furthermore , it was hypothesized that quetiapine would be well tolerated . METHOD Thirty manic or mixed bipolar I adolescents ( 12 - 18 years ) received an initial DVP dose of 20 mg/kg and were r and omly assigned to 6 weeks of combination therapy with quetiapine , which was titrated to 450 mg/day ( n = 15 ) or placebo ( n = 15 ) . Primary efficacy measures were change from baseline to endpoint in Young Mania Rating Scale ( YMRS ) score and YMRS response rate . Safety and tolerability were assessed weekly . RESULTS The DVP + quetiapine group demonstrated a statistically significantly greater reduction in YMRS scores from baseline to endpoint than the DVP + placebo group ( F(1,27 ) = 5.04 , p = .03 ) . Moreover , YMRS response rate was significantly greater in the DVP + quetiapine group than in the DVP + placebo group ( 87 % versus 53 % ; Fisher exact test , p = .05 ) . No significant group differences from baseline to endpoint in safety measures were noted . Sedation , rated as mild or moderate , was significantly more common in the DVP + quetiapine group than in the DVP + placebo group . CONCLUSIONS The findings of this study indicate that quetiapine in combination with DVP is more effective for the treatment of adolescent bipolar mania than DVP alone . In addition , the results suggest that quetiapine is well tolerated when used in combination with DVP for the treatment of mania 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 BACKGROUND Although bipolar disorder frequently onsets in the preschool years , treatment studies to guide management of these highly dysfunctional children are limited . This study evaluates the response to quetiapine monotherapy in preschool and school age children with bipolar spectrum disorder ( BSD ) . METHOD Two eight-week , prospect i ve , open-label trials utilizing identical methodology to assess the effectiveness and tolerability of quetiapine monotherapy in the treatment of BSD in preschool ( age 4 - 6 years ) and school age children ( age 6 - 15 years ) . RESULTS Forty-nine children ( 30 preschool and 19 school age ) with BSD ( Young Mania Rating Scale [ YMRS ] at entry : 34.5±5.5 and 30±6.5 respectively ) were enrolled and 34 ( 20 preschool and 14 school age ) completed the trial . Quetiapine was titrated to a mean endpoint dose of 175.8±63.8 mg/day in preschool and 248.7±153.1 mg/day in school age children . At endpoint , treatment with quetiapine was associated with similar and statistically significant improvement in mean YMRS scores in preschool ( -14.5±11.5 , p<0.001 ) and school age ( -13±9.8 , p<0.001 ) children . Quetiapine was generally well tolerated with treatment limiting adverse-events observed in 3/30 preschool and 1/19 school age children . Quetiapine monotherapy in preschool and school age children was associated with significant weight gain ( + 3.1±1.8 and + 7.4±7.7 lb respectively , p<0.001 ) and with clinical ly insignificant changes in vital signs . LIMITATIONS As an uncontrolled study , the assessment s were not blind to treatment and the effects of treatment can not be separated from time . CONCLUSIONS Open-label quetiapine treatment was beneficial for the treatment of BSD in preschool and school age children . Further controlled trials are warranted Abstract : Topiramate is an antiepileptic drug , recently also used in the treatment of psychiatric diseases . Inasmuch as topiramate and valproate , which are currently used for aggressive behavior , share several pharmacological mechanisms ( positive modulatory effect on the GABA activity and negative modulatory effect on glutamatergic neurotransmission ) , the objective of the present study was to compare the pharmacological effects of topiramate with those of valproate and their combination in patients with psychiatric disorders showing marked aggression and agitation . A retrospective , case-controlled , mirror-image study was carried out in a sample of 45 in patients affected by schizophrenia , schizoaffective and bipolar disorder , and hospitalized in a maximum-security Canadian psychiatry hospital .  Overt Aggression Scale , Agitation-Calmness Evaluation Scale , number and intensity of psychotic episodes , number of episodes of withdrawal from group activities per week , and number of therapeutic isolation per week and of strict surveillance intervention per week were evaluated before and after the treatments . Results indicate that patients treated with topiramate show a decrease in the average score of the Overt Aggression Scale , a decrease of episodes of agitation and of strict surveillance interventions . This effect was similar to the group treated with valproate or with the combination of valproate-topiramate . However , valproate therapy , but not topiramate therapy , decreased the intensity of agitation episodes measured by the Agitation-Calmness Evaluation Scale ;  valproate and the combination topiramate-valproate decreased the number of psychotic disorganization episodes as well . These results suggest that topiramate could be a valid medicine in the control of aggression in psychosis . Double-blind , r and omized , placebo-controlled studies need to further assess this pharmacological indication OBJECTIVE The purpose of this open-label study was to describe the effectiveness of aripiprazole ( APZ ) in the treatment of children with bipolar disorders suffering from manic symptomatology . METHOD Symptomatic out patients ( Young Mania Rating Scale [ YMRS ] score ≥15 ) meeting strict , unmodified , Diagnostic and Statistical Manual of Mental Disorders , 4th edition , diagnostic symptom criteria for a bipolar disorder , ages 4 - 9 years , were eligible . Subjects were treated prospect ively with flexible doses of APZ ( maximum daily dose of 15 mg/day ) , for up to 16 weeks or until a priori response criteria were met . Outcome measures included the YMRS , Clinical Global Impressions Scale-Severity , Children 's Global Assessment Scale ( CGAS ) , and the Children 's Depression Rating Scale-Revised ( CDRS-R ) . A priori response criteria consisted of 3 of 4 consecutive weeks with ( 1 ) CDRS-R < 29 ; ( 2 ) YMRS < 10 ; and ( 3 ) CGAS > 50 . RESULTS Ninety-six children ( 62 males ; mean age of 6.9 ( SD = 1.7 ) , received APZ for an average length of treatment of 12.5 ( SD = 3.9 ) weeks . Significant improvements in YMRS , CDRS-R , CGAS , and Clinical Global Impressions Scale-Severity scores ( p < 0.001 ) were noted at the end of study participation . Sixty of the subjects ( 62.5 % ) met a priori response criteria at study 's end . The most common side effects noted were stomachache , increased appetite , and headache . Two subjects were removed from the study due to side effects [ epistaxis ( n = 1 ) ; akathisia ( n = 1 ) ] . Subjects experienced an average weight gain of 2.4 ( SD = 1.9 ) kg . CONCLUSION APZ may be effective in the acute treatment of symptoms of children with bipolar illnesses BACKGROUND To evaluate short-term safety and efficacy of atypical antipsychotics in a single-site , prospect i ve , open-label , 8-week study of risperidone and olanzapine monotherapy in preschoolers with bipolar disorder ( BPD ) . METHODS Risperidone was initiated at an open-label dose of .25 mg/day , increased weekly according to response and tolerability to a maximum does of 2.0 mg/day . Olanzapine was initiated at 1.25 mg/day and increased to no more than 10 mg/day . RESULTS Thirty-one children aged 4 - 6 years were treated with olanzapine ( n = 15 , 6.3 + /- 2.3 mg/day ) or risperidone ( n = 16 , 1.4 + /- .5 mg/day ) . At study end point ( week 8 or last observation carried forward ) , there was a 18.3 + /- 11.9 point ( t = -5.6 , p < .001 ) reduction in risperidone-treated subjects and a 12.1 + /- 10.4 point ( t = -4.4 , p < .001 ) reduction in Young Mania Rating Scale ( YMRS ) scores in olanzapine-treated subjects that did not differ between groups ( t = 1.4 , p = .2 ) . Response criteria ( Clinical Global Impression improvement of " Much " or " Very Much " improved or a YMRS change of > or= 30 % or more ) indicated no difference in rate of response with risperidone and olanzapine ( 69 % vs. 53 % , chi(2)((1 ) ) = .8 , p = .4 ) . CONCLUSIONS This prospect i ve open study suggests that treatment with risperidone or olanzapine may result in a rapid reduction of symptoms of mania  in preschool children with BPD . Because of substantial residual symptomatology and adverse effects , however , a pressing need exists to identify additional safe and effective treatments for the management of BPD in this high-risk population OBJECTIVE To examine initial response to treatment in a large sample of acutely manic bipolar I adolescents and to examine potential predictors of nonresponse , such as the presence of prominent depressive features , psychosis , or psychiatric comorbidity . METHOD Adolescents , 12 to 18 years of age , with an acute manic episode were treated with open lithium . Response was defined as a decline in Young Mania Rating Scale total score of > or=33 % and a rating of " much improved " or " very much improved " on the Clinical Global Impressions Improvement item at week 4 . Remission of mania was defined as a Young Mania Rating Scale score of < or=6 . Axis I diagnoses were assessed using the Lifetime Schedule for Affective Disorders and Schizophrenia for Adolescents . RESULTS Of 100 subjects , 63 met response criteria and 26 achieved remission of manic symptoms at the week 4 assessment . Prominent depressive features , age at first mood episode , severity of mania , and comorbidity with attention-deficit/hyperactivity disorder did not distinguish responders from nonresponders . When treated with adjunctive antipsychotic medication , subjects with psychotic features at baseline responded as well as subjects without psychosis . CONCLUSIONS In this largest systematic treatment trial of acutely manic adolescents to date , lithium appears effective for acute stabilization of symptoms . Controlled treatment studies in adolescents with acute mania are needed OBJECTIVE To assess response to treatment with aripiprazole in children and adolescents with bipolar disorder comorbid with attention-deficit/hyperactivity disorder ( ADHD ) . METHOD Children and adolescents were extensively assessed according to DSM-IV criteria for bipolar disorder comorbid with ADHD ( n = 710 ) . Those with this comorbidity who were acutely manic or in mixed states were r and omly assigned in a 6-week double-blind , placebo-controlled trial to aripiprazole ( n = 18 ) or placebo ( n = 25 ) . Primary outcome measures were assessed weekly and included the Young Mania Rating Scale ; the Swanson , Nolan , and Pelham Scale-Version IV ; and weight . Secondary outcome measures were the Clinical Global Impressions-Severity of Illness scale , the Child Mania Rating Scale-Parental Version ( CMRS-P ) , the Children 's Depression Rating Scale-Revised , the Kutcher Adolescent Depression Scale , and adverse events . The trial was conducted at the Hospital de Clínicas de Porto Alegre , Rio Gr and e do Sul , Brazil , from January 2005 to November 2007 . RESULTS The group receiving aripiprazole showed a significantly greater reduction in YMRS scores ( P = .02 , effect size [ ES ] = 0.80 ) , CMRS-P scores ( P = .02 ; ES = 0.54 ) , and CGI-S scores ( P = .04 ; ES = 0.28 ) from baseline to endpoint than the placebo group . In addition , higher rates of response ( P = .02 ) and remission ( P = .01 ) were found for the aripiprazole group . No significant between-group differences were found in weight , ADHD symptoms , and depressive symptoms . Adverse events significantly more frequent in the aripiprazole group were somnolence and sialorrhea . CONCLUSION Aripiprazole was effective in reducing manic symptoms and improving global functioning without promoting severe adverse events or weight gain . No significant treatment effect in ADHD symptoms was observed . Studies are needed to assess psychopharmacologic interventions for improving ADHD symptoms in juvenile bipolar disorder comorbid with ADHD . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00116259 OBJECTIVE To investigate the effectiveness and tolerability of quetiapine for the treatment of adolescents at high risk for developing bipolar I disorder . METHOD Twenty adolescents ( aged 12 - 18 years ) with mood symptoms that did not meet DSM-IV-TR criteria for bipolar I disorder and who had at least one first-degree relative with bipolar I disorder were recruited from August 2003 to June 2005 to participate in a single-blind , 12-week prospect i ve study of quetiapine .  Subjects were diagnosed using the Washington University in St. Louis Kiddie Schedule of Affective Disorders and Schizophrenia and were symptomatic , defined by a Young Mania Rating Scale ( YMRS ) score > or = 12 or a Childhood Depression Rating Scale-Revised Version ( CDRS-R ) score > or = 28 at baseline . The primary effectiveness measure was an endpoint Clinical Global Impressions-Improvement scale ( CGI-I ) score < or = 2 ( " much " or " very much " improved ) . Secondary efficacy measures included change from baseline to endpoint in YMRS and CDRS-R scores . RESULTS Mood disorder diagnoses in the adolescents consisted of bipolar disorder not otherwise specified ( N = 11 ) , dysthymia ( N = 3 ) , bipolar II disorder ( N = 3 ) , cyclothymia ( N = 2 ) , and major depressive disorder ( N = 1 ) . The majority of patients ( N = 12 , 60 % ) were non-responders to previous trials of psychotropic agents . Fifteen subjects ( 75 % ) completed all study visits . Eighty-seven percent of patients were responders ( CGI-I < or = 2 ) to quetiapine at week 12 ( mean + /- SD endpoint dose = 460 + /- 88 mg/day ) . YMRS scores decreased from 18.1 + /- 5.5 at baseline to 8.7 + /- 7.9 at endpoint ( p < .0001 ) , and CDRS-R scores decreased from 38.2 + /- 9.8 to 27.7 + /- 9.3 , ( p = .0003 ) . The most frequently reported adverse events were somnolence , headache , musculoskeletal pain , and dyspepsia . No subjects discontinued study participation due to adverse events . CONCLUSION Although these findings are limited by the small sample size and open-label treatment , the results suggest that quetiapine may be an effective treatment for mood symptoms in adolescents with a familial risk for developing bipolar I disorder OBJECTIVES To determine the efficacy and safety of aripiprazole for the treatment of pediatric bipolar I disorder , manic or mixed episode , with or without psychotic features . METHOD Subjects were enrolled between March 2005 and February 2007 in a r and omized , multicenter , double-blind 4-week study of aripiprazole 10 mg/d , aripiprazole 30 mg/d , and placebo .  Subjects ( n = 296 ) were 10 to 17 years old with a DSM-IV diagnosis of bipolar I disorder with current manic or mixed episodes , with or without psychotic features , and a Young Mania Rating Scale ( YMRS ) score > or = 20 . The primary efficacy variable was change from baseline in the YMRS total score . RESULTS Both doses of aripiprazole were superior to placebo on the YMRS total score beginning at week 1 and continuing through week 4 . Aripiprazole 10 mg and 30 mg were more effective than placebo on global improvement , mania , and overall bipolar illness outcome measures . Response ( > or = 50 % reduction in YMRS total score ) at week 4 was achieved by 44.8 % , 63.6 % , and 26.1 % of subjects in the aripiprazole 10 mg , aripiprazole 30 mg , and placebo groups , respectively ( P < .01 both doses vs placebo ) . Both doses were generally well tolerated . The most common adverse events were extrapyramidal disorder and somnolence ; rates were higher for aripiprazole 30 mg compared with aripiprazole 10 mg . Average weight gain was not significantly different between the aripiprazole 10 mg ( + 0.82 kg ) or 30 mg ( + 1.08 kg ) groups compared with the placebo group ( + 0.56 kg ) ( P = .35 and P = .13 , respectively ) . CONCLUSIONS Aripiprazole in daily doses of 10 mg or 30 mg is an effective and generally well-tolerated acute treatment for pediatric subjects with bipolar I mania or mixed episodes . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00110461 INTRODUCTION Aripiprazole is a novel second-generation antipsychotic approved for the treatment of bipolar disorder in adults but there is no systematic data available in pediatric bipolar disorder . METHODS This was an 8-week , open-label , prospect i ve study of aripiprazole 9.4+/-4.2 mg/day monotherapy to assess the efficacy and tolerability of this compound in treating pediatric bipolar disorder . Assessment s included the Young Mania Rating Scale , Clinical Global Impressions-Improvement scale , and Brief Psychiatric Rating Scale . Adverse events were assessed through spontaneous self-reports , vital signs weight monitoring , and laboratory analysis . RESULTS Fifteen of the 19 bipolar youth ( 79 % ) completed the study .  Aripiprazole treatment was associated with clinical ly and statistically significant improvement in mean Young Mania Rating Scale scores ( -18.0+/-6.9 , P<.0001 ) . With the important exception of two cases of extrapyramidal symptoms that precipitated dropout , aripiprazole was well tolerated with no statistically significant increase in body weight ( 1.8+/-1.7 kg , P=.2 ) . CONCLUSION Open-label aripiprazole treatment was beneficial in the treatment of mania in youth with bipolar disorder . Future placebo-controlled , double-blind studies are warranted OBJECTIVE To determine the relative effects of risperidone and divalproex in pediatric mania . METHODS This is a double-blind , r and omized , outpatient clinical trial with 66 children and adolescents ( mean age= 10.9 ± 3.3 years ; age range= 8 - 18 years ) with mania who were r and omly assigned to either risperidone ( 0.5 - 2 mg/day , n= 33 ) or divalproex ( 60 - 120 μg/mL , n= 33 ) for a six-week period . Measures included the Young Mania Rating Scale ( YMRS ) and Child Depression Rating Scale-Revised ( CDRS-R ) . RESULTS Mixed-effects regression models , with interaction between time and the active drug as predictors , found that the risperidone group had more rapid improvement than the divalproex group ( p < 0.05 ) , although final scores did not differ significantly between groups . Mixed models using only those subjects who completed the six-week study found similar results . The response rate on YMRS was 78.1 % for risperidone and 45.5 % for divalproex ( p < 0.01 ) . The remission rate for risperidone was 62.5 % , compared with 33.3 % for divalproex ( p < 0.05 ) . Improvement on the CDRS-R was significantly higher for the risperidone group relative to the divalproex group ( p < 0.05 ) . There were no significant differences between groups in safety , but subject retention was significantly higher at study endpoint in the risperidone group ( p < 0.01 ) . Dropout rate was 24 % in the risperidone group and 48 % in the divalproex group , with increased irritability being the most common reason for dropout in the latter . There was no significant weight gain in either group . CONCLUSION Results suggest that risperidone was associated with more rapid improvement and greater reduction in manic symptoms compared to divalproex . Although the results suggest that both drugs are safe , risperidone 's lower attrition rate and lower rate of adverse events may suggest better toleration . Clinical trials with larger sample s are required to confirm these preliminary findings The Brief  Psychiatric Rating Scale  for Children ( BPRS-C ) is increasingly used as an outcome measure in research , managed care , and public sector child/adolescent clinical setting s. The BPRS-C was developed to provide a descriptive profile of symptoms applicable to a broad range of child and adolescent psychiatric disorders . Its use frequently includes trained and untrained clinician raters with differing degrees of experience and training in child and adolescent disorders . Unfortunately , this latter approach leads to a large amount of variability in scores and consequently reduces its overall reliability . This study reports on a revised BPRS-C with the addition of clinical descriptive anchors design ed to improve reliability and validity for both trained and untrained raters . A sample of 4,733 children and adolescents seen in 10 public sector facilities was administered the BPRS-C along with other st and ard clinical measures ( Child Behavior Checklist and Global Assessment of Functioning ) . Additional reliability data were gathered in a University Medical Center child and adolescent research site with both trained and untrained raters . The data indicated improvement in overall reliability and validity scores , good internal consistency , and improved factor scores . The addition of an overall total severity score may prove to be a useful outcome measure for assessment of treatment response BACKGROUND Offspring of parents with bipolar disorder , by virtue of their high-risk status for developing bipolar disorder , merit an investigation of the efficacy of treatment with mood stabilizers . Behavioral and mood difficulties in this population may represent prodromal forms of bipolar disorder . We studied the efficacy of divalproex in treating child and adolescent bipolar offspring with mood or behavioral disorders who did not yet meet criteria for bipolar I or II disorder . METHOD We studied 24 children aged 6 - 18 years ( mean = 11.3 years ; 17 boys/7 girls ) with at least 1 biological parent with bipolar disorder . Participants were diagnosed by the Washington University in St. Louis Kiddie Schedule for Affective Disorders and Schizophrenia with at least 1 of the following DSM-IV disorders : major depressive disorder , dysthymic disorder , cyclothymic disorder , or attention-deficit/hyperactivity disorder . Subjects all had at least moderate affective symptoms ( 28-item Hamilton Rating Scale for Depression or Young Mania Rating Scale score > 12 ) . After a 2-week washout period , subjects were treated with divalproex for 12 weeks , titrated to achieve serum levels of 50 - 120 micro g/mL ( mean final dose = 821 mg/day ; mean final serum level = 79.0 micro g/mL ) . RESULTS One subject discontinued after 2 weeks due to continuation of symptoms . Of the remaining 23 subjects , 18 ( 78 % ) were considered responders by primary outcome criteria ( " very much improved " or " much improved " on the Clinical Global Impressions-Improvement scale ) . Divalproex was well tolerated with no discontinuations due to adverse effects . CONCLUSION Bipolar offspring with mood or behavioral disorders and at least mild affective symptoms may respond to divalproex treatment . Our study was limited by the open treatment , lack of a placebo group , and the heterogeneous nature of the sample . Controlled studies are warranted in the use of divalproex in symptomatic bipolar offspring OBJECTIVE This study evaluated the safety and effectiveness of divalproex sodium ( Depakote ) in the treatment of youths with bipolar disorder . METHOD Forty bipolar disorder patients aged 7 to 19 years , with a manic , hypomanic , or mixed episode , enrolled in an open-label study of  divalproex ( 2 - 8 weeks ) , followed by a double-blind , placebo-controlled period ( 8 weeks ) . RESULTS Twenty-two subjects ( 61 % ) showed > or = 50 % improvement in Mania Rating Scale ( MRS ) scores during the open-label period . Significant ( < .001 ) improvements from baseline were seen for mean scores of all efficacy measures , including the MRS , Manic Syndrome Scale , Behavior and Ideation Scale , Brief Psychiatric Rating Scale , Clinical Global Impressions Severity scale , and Hamilton Rating Scale for Depression . Of the 23 subjects who discontinued the study during the open-label period , 6 ( 15 % ) discontinued for ineffectiveness , 6 ( 15 % ) for intolerance , 6 ( 15 % ) for noncompliance , and 6 ( 15 % ) for other reasons . Adverse events were generally mild or moderate in severity , with the most common being headache , nausea , vomiting , diarrhea , and somnolence . Laboratory data results were unremarkable . Too few subjects participated in the double-blind period for statistical analysis . CONCLUSION This study provides preliminary support for the safety and effectiveness of divalproex in the treatment of bipolar disorder in youths CONTEXT There was a paucity of comparative pharmacological research for initial treatment of bipolar I disorder , manic or mixed phase , in children and adolescents . OBJECTIVE To investigate which medication to administer first to antimanic medication-naive subjects . DESIGN , SETTING , AND PARTICIPANTS The Treatment of Early Age Mania ( TEAM ) study recruited 6- to 15-year-old children and adolescents with DSM-IV bipolar I disorder ( manic or mixed phase ) at 5 US sites from 2003 to 2008 into a controlled , r and omized , no-patient-choice , 8-week protocol . Blinded , independent evaluators conducted all baseline and end-point assessment s. INTERVENTIONS Subjects received a titrated schedule of lithium , divalproex sodium , or risperidone . Medications were increased weekly only if there was inadequate response , and no dose-limiting adverse effects , to maximum doses of lithium carbonate ( 1.1 - 1.3 mEq/L ) , divalproex sodium ( 111 - 125 μg/mL ) , and risperidone ( 4 - 6 mg ) . MAIN OUTCOME MEASURES Primary outcome measures were the Clinical Global Impressions for Bipolar Illness Improvement-Mania and the Modified Side Effects Form for Children and Adolescents . RESULTS There were 279 antimanic medication-naive subjects ( mean [ SD ] age , 10.1 [ 2.8 ] years ; 50.2 % female ) who had the following characteristics : 100 % elated mood and /or gr and iosity , 77.1 % psychosis , 97.5 % mixed mania , 99.3 % daily rapid cycling , and mean ( SD ) mania duration of 4.9 ( 2.5 ) years .  The mean ( SD ) titrated lithium level was 1.09 ( 0.34 ) mEq/L , and the mean ( SD ) divalproex sodium level was 113.6 ( 23.0 ) μg/mL. The mean ( SD ) titrated risperidone dose was 2.57 ( 1.21 ) mg . Higher response rates occurred with risperidone vs lithium ( 68.5 % vs 35.6 % ; χ(2)(1 ) = 16.9 , P < .001 ) and vs divalproex sodium ( 68.5 % vs 24.0 % ; χ(2)(1 ) = 28.3 , P < .001 ) . Response to lithium vs divalproex sodium did not differ . The discontinuation rate was higher for lithium than for risperidone ( χ(2)(1 ) = 6.4 , P = .011 ) . Increased weight gain , body mass index , and prolactin level occurred with risperidone vs lithium ( F(1,212 ) = 45.5 , P < .001 ; F(1,212 ) = 39.1 , P < .001 ; and F(1,213 ) = 191.4 , P < .001 , respectively ) and vs divalproex sodium ( F(1,212 ) = 34.7 , P < .001 ; F(1,212 ) = 45.3 , P < .001 ; and F(1,213 ) = 209.4 , P < .001 , respectively ) . The thyrotropin level increased in subjects taking lithium ( t(62 ) = 11.3 , P < .001 ) . CONCLUSIONS Risperidone was more efficacious than lithium or divalproex sodium for the initial treatment of childhood mania but had potentially serious metabolic effects . TRIAL REGISTRATION clinical trials.gov Identifier :
target: RESULTS There is sufficient evidence for a Grade A recommendation of the use of olanzapine plus fluoxetine at reducing depressive symptoms in bipolar depression and of quetiapine at high doses for depressive symptoms occurring during mixed episodes .
  These results mostly overlap with the approved treatments for bipolar depression in adults
background: BACKGROUND The management of depressive and mixed symptoms in children and adolescents with bipolar disorder ( BD ) remains a matter of debate .
  The goal of this review is , thus , to systematic ally examine the impact of atypical antipsychotics ( AAPs ) and mood stabilisers in the treatment of bipolar depression and /or mixed states .