title: AMSTAR 2: a critical appraisal tool for systematic reviews that include randomised or non-randomised studies of healthcare interventions, or both Efficacy and Safety of Aripiprazole Once-Monthly in the Maintenance Treatment of Bipolar I Disorder: A Double-Blind, Placebo-Controlled, 52-Week Randomized Withdrawal Study. Comparison of the prophylactic action of flupenthixol with placebo in lithium treated manic-depressive patients. A long-term prospective study on the outcome of bipolar patients treated with long-acting injectable risperidone Long‐term Depot Neuroleptic Treatment With Perphenazine Decanoate I A randomized, double-blind, placebo-controlled study of maintenance treatment with adjunctive risperidone long-acting therapy in patients with bipolar I disorder who relapse frequently. Clinical features associated with poor pharmacologic adherence in bipolar disorder: results from the STEP-BD study. Flupenthixol decanoate in recurrent manic‐depressive illness Paliperidone palmitate once-monthly reduces risk of relapse of psychotic, depressive, and manic symptoms and maintains functioning in a double-blind, randomized study of schizoaffective disorder. Risperidone Long-Acting Injectable Monotherapy in the Maintenance Treatment of Bipolar I Disorder Clinical factors associated with treatment noncompliance in euthymic bipolar patients. Head-to-head comparison of 1-year aripiprazole long-acting injectable (LAI) versus paliperidone LAI in comorbid psychosis and substance use disorder: impact on clinical status, substance craving, and quality of life Efficacy of olanzapine and olanzapine-fluoxetine combination in the treatment of bipolar I depression. A Pilot, 15-month, randomised effectiveness trial of Risperidone long-acting injection (RLAI) versus oral atypical antipsychotic agents (AAP) in persons with bipolar disorder.
abstract: The number of published systematic review s of studies of healthcare interventions has increased rapidly and these are used extensively for clinical and policy decisions . Systematic review s are subject to a range of biases and increasingly include non-r and omised studies of interventions . It is important that users can distinguish high quality review s. Many instruments have been design ed to evaluate different aspects of review s , but there are few comprehensive critical appraisal instruments . AMSTAR was developed to evaluate systematic review s of r and omised trials . In this paper , we report on the updating of AMSTAR and its adaptation to enable more detailed assessment of systematic review s that include r and omised or non-r and omised studies of healthcare interventions , or both . With moves to base more decisions on real world observational evidence we believe that AMSTAR 2 will assist decision makers in the identification of high quality systematic review s , including those based on non-r and omised studies of healthcare interventions OBJECTIVE To evaluate efficacy , safety , and tolerability of long-acting injectable antipsychotic aripiprazole once-monthly 400 mg ( AOM 400 ) as maintenance treatment for bipolar I disorder ( BP-I ) . METHODS In a double-blind , placebo-controlled , 52-week r and omized withdrawal study conducted from August 2012 to April 2016 , patients with a DSM-IV-TR diagnosis of BP-I currently experiencing a manic episode were stabilized sequentially on oral aripiprazole and AOM 400 and then r and omized to AOM 400 or placebo . The primary end point was time from r and omization to recurrence of any mood episode . Other end points included proportion of patients with recurrence of any mood episode and recurrence by mood episode type . RESULTS Of 266 r and omized patients , 64 ( 48.1 % ) of 133 in the AOM 400 group and 38 ( 28.6 % ) of 133 in the placebo group completed the study .  AOM 400 significantly delayed the time to recurrence of any mood episode compared with placebo ( hazard ratio : 0.45 ; 95 % CI , 0.30 to 0.68 ; P < .0001 ) . Significantly fewer patients ( P < .0001 ) experienced recurrence of any mood episode with AOM 400 ( 35/132 ; 26.5 % ) compared with placebo ( 68/133 ; 51.1 % ) , with the effects observed predominantly on manic episodes ( P < .0001 ) . Patients were not depressed at study entry , and between-group differences in depressive episodes were not significant ( P < .864 ) . The treatment-emergent adverse events ( incidence > 5 % ) that were reported at higher rates with AOM 400 than placebo were weight increase , akathisia , insomnia , and anxiety . CONCLUSIONS AOM 400 delayed the time to and reduced the rate of recurrence of mood episodes and was generally safe and well tolerated . These findings support the use of AOM 400 for maintenance treatment of BP-I. TRIAL REGISTRATION Clinical Trials.gov identifier : NCT01567527 A double-blind cross-over trial of depot flupenthixol in recurrent manic depressive psychosis was carried out . All patients continued on lithium . Eleven patients completed the two-year trial .  Flupenthixol appeared to have no prophylactic effect Background : Risperidone is the first atypical antipsychotic to become available in a long-acting , injectable formulation . This is the first prospect i ve study to assess the effectiveness of long-acting risperidone in a cohort of bipolar patients . Methods : Twenty-nine DSM-IV acutely manic bipolar in patients with a history of poor or partial adherence to medication entered the mirror- design observational study . They received naturalistic treatment for a manic episode plus long-acting , injectable risperidone for a mean period of 2 years . The following measures were used to assess the effectiveness of risperidone  : the number of hospitalizations , the number of manic , mixed , and depressive episodes leading to hospitalization , the mean duration of hospitalizations , time to relapse , treatment adherence , aggression and suicide attempts . The Clinical Global Impressions ( CGI ) was used for clinical relevance as well . Results : During the follow-up , there was a significant decrease in the number of hospitalizations per patient ( Z−2.72 P<0.006 ) , in the number of manic or mixed episodes leading to hospitalization ( Z−2.68 P<0.007 ) but not in the hospitalizations due to depressive episodes , a decrease in the average length of hospitalization per patient ( Z−3.27 P<0.001 ) , a significant increase in the time to any new episode ( first relapse ) ( Z−3.28 , P<0.001 ) , and significant improvements in treatment adherence ( P<0.0001 ) and hetero-aggressive episodes ( P<0.0001 ) , but not suicide attempts ( P = NS ) . At study endpoint 14 patients ( 48 % ) were very much improved according to the CGI . Discussion : This observational long-term study provides support to long-acting injectable risperidone being effective for the maintenance treatment of mania and improving treatment adherence , reducing relapses and re-hospitalization rates In an open , prospect i ve 12 month study of perphenazine decanoate (  PD )  , 42 psyhchotic patients diagnosed according to DSM‐III were treated with a fixed depot interval and an individual dose , guided by gas chromatographic perphenazine plasma concentration monitoring combined with clinical evaluation . Degree of illness was rated using a social‐psychiatric CGI‐scale and extrapyramidal side effects were evaluated by means of a modified Simpson and Angus rating scale . After six months of treatment , a statistically significant improvement was found ( p < 0.001 ) . During the last six months a further slight reduction in mean CGI‐scores was observed . Mild to moderate extrapyramidal side effects occurred in 9 patients ( 21 % ) principally during the initial phase of therapy . No other side effects or changes in blood chemistry were found during the study . Plasma concentrations of perphenazine increased during the initial 3 months and stabilized hereafter . There were however , large intra‐ and inter‐individual variations in the perphenazine plasma concentration/dose ratio . In addition , it was observed that plasma concentrations of perphenazine were significantly higher in patients who had been treated with neuroleptics for more than 10 years compared to those who had been treted 5 years or less . This observation indicates gradual development of tolerance to neuroleptic treatment OBJECTIVE No large controlled trials have evaluated adjunctive maintenance treatment with long-acting injectable antipsychotics in patients with bipolar disorder . This study assessed whether adjunctive maintenance treatment with risperidone long-acting therapy ( RLAT ) , added to treatment-as-usual ( TAU ) medications for bipolar disorder , delays relapse in patients with bipolar disorder type I. METHODS This study included patients with bipolar disorder type I with > or = four mood episodes in the 12 months prior to study entry . Following a 16-week , open-label stabilization phase with RLAT plus TAU , remitted patients entered a 52-week , double-blind , placebo-controlled , relapse-prevention phase . R and omized patients continued treatment with adjunctive RLAT ( 25 - 50 mg every two weeks ) plus TAU ( n = 65 ) or switched to adjunctive placebo injection plus TAU ( n = 59 ) . The primary outcome measure was time to relapse to any mood episode . RESULTS Of 240 enrolled patients , 124 entered double-blind treatment . Time to relapse was longer in patients receiving adjunctive RLAT ( p = 0.010 ) . Relapse rates were 23.1 % ( n = 15 ) with adjunctive RLAT versus 45.8 % ( n = 27 ) with adjunctive placebo ; relative relapse risk was 2.3-fold higher with adjunctive placebo ( p = 0.011 ) . Completion rates were : adjunctive RLAT , 60.0 % ( n = 39 ) and adjunctive placebo , 42.4 % ( n = 25 ; p = 0.050 ) . Adverse event (AE)-related discontinuations were 4.6 % ( n = 3 ) and 1.7 % ( n = 1 ) , respectively . Common AEs ( adjunctive RLAT versus adjunctive placebo ) were : tremor ( 24.6 % versus 10.2 % ) , insomnia ( 20.0 % versus 18.6 % ) , muscle rigidity ( 12.3 % versus 5.1 % ) , weight increased ( 6.2 % versus 1.7 % ) , and hypokinesia ( 7.7 % versus 0.0 % ) . CONCLUSIONS Adjunctive RLAT significantly delayed time to relapse in patients with bipolar disorder type I who relapse frequently . Safety and tolerability of RLAT were generally consistent with that previously observed BACKGROUND Poor medication adherence is common among bipolar patients . METHOD We examined prospect i ve data from 2 cohorts of individuals from the Systematic Treatment Enhancement Program for Bipolar Disorder ( STEP-BD ) study ( 1999 - 2005 ) with bipolar disorder . Clinical and sociodemographic features associated with missing at least 25 % of doses of at least 1 medication were assessed using logistic regression , and a risk stratification model was developed and vali date d. RESULTS Of 3,640 subjects with 48,287 follow-up visits , 871 ( 24 % ) reported nonadherence on 20 % or more study visits . Clinical features significantly associated ( P < .05 ) with poor adherence included rapid cycling , suicide attempts , earlier onset of illness , and current anxiety or alcohol use disorder . Nonadherence during the first 3 months of follow-up was associated with less improvement in functioning at 12-month follow-up ( P < .03 ) . A risk stratification model using clinical predictors accurately classified 80.6 % of visits in an independent validation cohort . CONCLUSION Risk for poor medication adherence can be estimated and may be useful in targeting interventions The hypothesis that flupenthixol decanoate may serve as an alter‐native to prophylactically administered lithium in recurrent manicdepressive illness , bipolar and unipolar type , was tested in two groups of patients . In Group I the patients were allocated r and omly to maintenance treatment with either lithium or flupenthixol decanoate . The patients in Group II had previously been given lithium and were switched to flupenthixol decanoate because of unsatisfactory prophylactic effect of lithium , doubtful tablet compliance , troublesome side effects , or fear of later harmful effects . The flupenthixol decanoate dosage was 20 mg every 2–3 weeks . The study was not blind OBJECTIVE Schizoaffective disorder is a complex illness for which optimal treatment is not well established . Results of the first controlled , relapse-prevention study of paliperidone palmitate once-monthly injectable ( paliperidone monthly ) in schizoaffective disorder are presented . METHOD The study was conducted between September 20 , 2010 , and October 22 , 2013 . Patients with schizoaffective disorder ( confirmed by the Structured Clinical Interview for DSM-IV Axis I Disorders ) experiencing acute exacerbation of psychotic and depressive/manic symptoms were stabilized with paliperidone monthly as monotherapy or as adjunctive therapy to mood stabilizers or antidepressants and r and omly assigned ( 1:1 ) to paliperidone monthly or placebo in a 15-month , double-blind , relapse-prevention phase . R and omization was stratified by administration as monotherapy or adjunctive therapy and by study center . The primary endpoint was time to relapse . RESULTS 334 patients were evaluated .  Paliperidone monthly significantly delayed time to relapse for psychotic , depressive , and manic symptoms compared with placebo ( P < .001 , log-rank test ) . Relapse risk was 2.49 times greater for placebo ( hazard ratio = 2.49 ; 95 % CI , 1.55 to 3.99 ; P < .001 , Cox proportional hazards model ) . Overall relapse rates were 33.5 % for placebo and 15.2 % for paliperidone monthly . For monotherapy , relapse risk was 3.38 times greater with placebo ( P = .002 ) , and for adjunctive treatment it was 2.03 times greater with placebo ( P = .021 ) . Paliperidone monthly was superior to placebo in maintaining functioning as measured by the Personal and Social Performance scale ( P = .014 , mixed-model repeated- measures analysis ) . The most common adverse events ( placebo , paliperidone monthly ) were increased weight ( 4.7 % , 8.5 % ) , insomnia ( 7.1 % , 4.9 % ) , schizoaffective disorder ( 5.9 % , 3.0 % ) , headache ( 3.5 % , 5.5 % ) , and nasopharyngitis ( 3.5 % , 5.5 % ) . Incidence of any extrapyramidal-related adverse event was 7.1 % for placebo and 8.5 % for paliperidone monthly . CONCLUSIONS Paliperidone monthly as monotherapy or adjunctive therapy significantly delayed psychotic , depressive , and /or manic relapses ; reduced their risk ; and better maintained functioning in patients with schizoaffective disorder . Results support the value of maintenance treatment with paliperidone monthly in schizoaffective disorder . TRIAL REGISTRATION Clinical Trials.gov identifier : NCT01193153 BACKGROUND Treatment adherence is a significant problem in patients with bipolar disorder . This study was design ed to determine the efficacy of risperidone long-acting injectable ( LAI ) in the maintenance treatment of bipolar I disorder . METHODS Eligible patients with current or recent manic or mixed episodes ( n = 559 , aged 18 - 65 years ) were treated with open-label oral risperidone for 3 weeks ( period II ) and open-label risperidone LAI for 26 weeks ( n = 501 ; period III ) . Patients who maintained response ( n = 303 ) were r and omly allocated 1:1 to placebo injections ( n = 149 ) or to continue risperidone LAI ( n = 154 ) for up to 24 months ( period IV ) . RESULTS Most ( 77 % ) patients on risperidone LAI received a dose of 25 mg every 2 weeks during period IV . Time to recurrence for any mood episode ( primary outcome variable ) was significantly longer in the risperidone LAI group versus placebo ( p < .001 ) ; the difference was significant for time to recurrence of elevated-mood episode ( p < .001 ) but not time to recurrence of depressive episode ( p = .805 ) . Weight gains > or = 7 % ( compared with the period 's baseline ) occurred in 15 % of patients in period III ; in 12 % of patients on risperidone LAI and 3 % of patients on placebo in period IV . CONCLUSIONS Risperidone LAI monotherapy significantly delayed the time to recurrence of mood episodes , versus placebo , in this controlled , r and omized study in patients with bipolar I disorder . Risperidone LAI was tolerable and no new safety concerns emerged compared with previous studies of risperidone LAI BACKGROUND Noncompliance with medication is a very common feature among bipolar patients . Rates of poor compliance may reach 64 % for bipolar disorders , and noncompliance is the most frequent cause of recurrence . Knowledge of the clinical factors associated with noncompliance would enhance clinical management and the design of strategies to achieve a better outcome for bipolar patients . Although most patients withdraw from medication during maintenance treatment , compliance studies in euthymic bipolar sample s are scarce . METHOD Compliance treatment and its clinical correlates were assessed at the end of 2-year follow-up in 200 patients meeting Research Diagnostic Criteria for bipolar I or bipolar II disorder by means of compliance-focused interviews , measurements of plasma concentrations of mood stabilizers  , and 2 structured interviews : the Schedule for Affective Disorders and Schizophrenia and the Structured Clinical Interview for DSM-III-R Axis II disorders . Well-compliant patients and poorly compliant patients were compared with respect to several clinical and treatment variables . RESULTS The rate of mildly and poorly compliant patients was close to 40 % . Comorbidity with personality disorders was strongly associated with poor compliance . Poorly compliant patients had a higher number of previous hospitalizations , but reported fewer previous episodes . The type of treatment was not associated with compliance . CONCLUSION Clinical factors , especially comorbidity with personality disorders , are more relevant for treatment compliance than other issues such as the nature of pharmacologic treatment . Compliant patients may have a better outcome in terms of number of hospitalizations , but not necessarily with respect to the number of episodes . Bipolar patients , especially those with personality disorders , should be monitored for treatment compliance Background To overcome nonadherence in patients with psychosis switch to long-acting injectable ( LAI ) antipsychotic formulations is adopted . Most oral versus LAI comparisons showed similar antipsychotic responses . Psychoses often overlap with substance use disorder ( SUD ) . Head-to-head LAI comparisons have hitherto focused only on non-comorbid population s. Objective The objective of this study was to compare two LAIs , administered for 12 months , in initially hospitalized patients with psychosis comorbid with SUD in their clinical and quality of life ( QoL ) outcomes . Patients and methods In patients were recruited during 2016 and switched r and omly to 400 mg intramuscular aripiprazole monohydrate ( AM ) ( N=50 ) or to 100 mg intramuscular paliperidone palmitate ( PP ) once-monthly ( N=51 ) ; patients were discharged and followed up for 12 months . Patients were rated at baseline and after 1 year through the Clinical Global Impression scale – severity ( CGIs ) , substance craving intensity was rated through a visual analog scale for substance craving , and QoL through the World Health Organization ( WHOQOL-BREF ) scale . We addressed confounders with backward stepwise logistic regression and three-way analysis of variance . Results PP were older and had more cases of schizophrenia spectrum and less bipolar disorders than AM , but AM had a stronger craving for substances at baseline . Both LAIs were associated with significant improvements in all outcomes , with AM displaying stronger effect sizes than PP . The two groups did not differ on baseline WHOQOL-BREF scores in any domain , but at the 1-year follow-up , AM fared better on all domains . The two groups did not differ in final severity , but PP scored higher than AM in craving at the 1-year endpoint . Limitation : The CGIs is not a refined tool for severity and the substance craving may be subject to recall bias . Conclusion 1-year AM and PP was followed by improved clinical status and QoL and reduced substance craving in a population with psychosis and SUD comorbidity . AM , compared to PP , improved craving and QoL at the 1-year follow-up BACKGROUND Despite the longer duration of the depressive phase in bipolar disorder and the frequent clinical use of antidepressants combined with antipsychotics or mood stabilizers , relatively few controlled studies have examined treatment strategies for bipolar depression . OBJECTIVE To examine the use of olanzapine and olanzapine-fluoxetine combination in the treatment of bipolar I depression . DESIGN Double-blind , 8-week , r and omized controlled trial . SETTING Eighty-four sites ( inpatient and outpatient ) in 13 countries . Patients A total of 833 r and omized adults with bipolar I depression with a Montgomery-Asberg Depression Rating Scale ( MADRS ) score of at least 20 . Intervention Patients were r and omly assigned to receive placebo ( n = 377 ) ; olanzapine , 5 to 20 mg/d ( n = 370 ) ; or olanzapine-fluoxetine combination , 6 and 25 , 6 and 50 , or 12 and 50 mg/d ( n = 86 ) . MAIN OUTCOME MEASURE Changes in MADRS total scores using mixed-effects model repeated- measures analyses . RESULTS During all 8 study weeks , the olanzapine and olanzapine-fluoxetine groups showed statistically significant improvement in depressive symptoms vs the placebo group ( P<.001 for all ) . The olanzapine-fluoxetine group also showed statistically greater improvement than the olanzapine group at weeks 4 through 8 . At week 8 , MADRS total scores were lower than at baseline by 11.9 , 15.0 , and 18.5 points in the placebo , olanzapine , and olanzapine-fluoxetine groups , respectively . Remission criteria were met by 24.5 % ( 87/355 ) of the placebo group , 32.8 % ( 115/351 ) of the olanzapine group , and 48.8 % ( 40/82 ) of the olanzapine-fluoxetine group . Treatment-emergent mania ( Young Mania Rating Scale score < 15 at baseline and > or = 15 subsequently ) did not differ among groups ( placebo , 6.7 % [ 23/345 ] ; olanzapine , 5.7 % [ 19/335 ] ; and olanzapine-fluoxetine , 6.4 % [ 5/78 ] ) . Adverse events for olanzapine-fluoxetine therapy were similar to those for olanzapine therapy but also included higher rates of nausea and diarrhea . CONCLUSIONS Olanzapine is more effective than placebo , and combined olanzapine-fluoxetine is more effective than olanzapine and placebo in the treatment of  bipolar I depression without increased risk of developing manic symptoms UNLABELLED Chengappa KNR , Turkin SR , Schlicht PJ , Murphy SL , Brar JS , Fagiolini A , Houck PR , Garbutt RG , Fredrick N. A Pilot , 15-month , r and omised effectiveness trial of Risperidone long acting injection ( RLAI ) versus oral atypical antipsychotic agents ( AAP ) in persons with bipolar disorder . OBJECTIVE Long-acting injectible antipsychotic agents are rarely considered in the treatment of bipolar patients [ bipolar disorder ( BPD ) ] . We posited that BPD patients receiving risperidone long-acting injections  [ Risperidone long-acting injections ( RLAIs ) ] would experience fewer negative clinical events than those receiving oral atypical antipsychotic agents ( AAP ) . METHODS Adult BPD patients in a hypomanic , manic or mixed episode were r and omised to either oral risperdone followed by RLAI ( n = 23 ) or an AAP ( n = 25 ) for 15 months . Any mood stabilizers were continued . An independent clinician board declared any clinical events that occurred but the treatment assignment was concealed . RESULTS Nine of the 48 patients who participated in this study did not improve , leaving 39 patients in 1-year extension . RLAI patients received the following bi-weekly dosages : 25 mg ( n = 9 ) , 37.5 mg ( n = 8) , and 50 mg ( n = 6 ) . The AAP group included aripiprazole ( n = 11 , 15 - 30 mg/day ) , quetiapine ( n = 8 , 300 - 700 mg/day ) , olanzapine ( n = 5 , 15 - 25 mg/day ) , and ziprasidone , ( n = 1 , 160 mg/day ) . In total , 47 clinical events were declared . The RLAI-treated group experienced significantly fewer clinical events ( mean : 0.86 ± 0.73 ) compared with the AAP group ( 1.61 ± 1.29 ) , t = 2.29 , d.f . = 37 , p = 0.028 ( 95 % CI = 0.087 - 1.421 ) . Of all , 50 % of the AAP subjects gained ≥ 7 % of their baseline body weight as did 38 % of the RLAI-treated patients . CONCLUSIONS RLAI-treated patients experienced significantly fewer negative clinical events . Further exploration should focus on which subtypes of BPD patients might benefit from RLAI treatment . Weight gain in BPD subjects requires clinical attention . Limitations include an open design , small sample size and the inability to conclude on whether this strategy is useful for depressive episodes
target: Risperidone long-acting injectable was found to be effective in protecting from any mood/manic symptom compared to placebo , but not from depressive recurrences .
  Add-on or monotherapy paliperidone palmitate in SAD patients  protected from psychotic , depressive , and manic symptoms .
  In patients with BD-I with a manic episode at study enrolment , aripiprazole monohydrate significantly delayed time to recurrence of manic episodes without inducing depressive episodes .
  LAIs  are effective and well-tolerated maintenance treatments for BD and SAD .
  They showed better efficacy in preventing mania than depression .
  LAIs may be first-line for BD-I and SAD patients with a manic predominant polarity and with non-adherence problems
background: Long-Acting Injectable Antipsychotics ( LAIs ) are used to overcome non-compliance in psychoses , mainly schizophrenia spectrum disorders .
  We aim ed to summarize available evidence of studies comparing the efficacy of LAIs to placebo or oral medications for Bipolar Disorder ( BD ) and /or Schizoaffective Disorder ( SAD ) .