|Kecka ||Randomised, double-blind, parallel-group, placebo-controlled, multicentre study, enrolling patients from 76 centres in three countries (Argentina, Mexico, US) from March 2000 to June 2003. During a stabilisation phase, patients received open-label treatment with aripiprazole for 6–18 weeks. Patients remained in this phase until their symptoms were stable (YMRS score ≤10 and MADRS score ≤13 over a minimum of 6 weeks). A total of 633 patients were enrolled in the study; 567 entered the stabilisation phase, including 333 who had participated in earlier studies of aripiprazole for acute mania. Of the 567 participants, 206 (36%) completed the stabilisation phase and 361 (64%) discontinued, mainly because adverse events (22%), lack of efficacy (12%), or withdrawal of consent (12%). A total of 161 patients (28%) who completed the stabilisation phase were randomly assigned to receive either aripiprazole or placebo. Study duration: 6 months||All study participants met DSM-IV criteria for bipolar I disorder. Patients (men and women aged 18 years and older) could enter the stabilisation phase if they recently completed a 3-week, placebo-controlled, acute mania study of aripiprazole; if they met eligibility criteria for an acute mania study but declined participation; or they experienced a manic or mixed episode requiring hospitalisation and treatment within the previous 3 months. Exclusion criteria: pregnancy or lactation; history or symptoms of a cognitive disorder, schizophrenia or schizoaffective disorder, psychotic symptoms better explained by another medical condition or attributed to substance abuse, allergy or hypersensitivity to aripiprazole or other quinolinones, history of neuroleptic malignant syndrome, seizure disorder, participation in a clinical trial with another investigational agent within the past month or electroconvulsive therapy within the past 2 months||Study medications were administered orally, once a day, at approximately the same time each day. During the stabilisation phase, patients received open-label treatment with aripiprazole at a starting dose of 30 mg/day. The dose could be decreased o 15 mg/day at any time for tolerability. Subsequently, patients were randomised to the aripiprazole dose they were taking at the end of stabilisation phase or to PBO. At any time during the double-blind phase, the dose of aripiprazole or placebo could be increased or decreased to 30 or 15 mg, respectively, based on the investigator's assessment of therapeutic effect and tolerability. During the whole study, all psychotropic medications except lorazepam and anticholinergic agents were excluded||Time to relapse for a mood episode (whether manic, depressive or mixed) during the double-blind phase. Relapse was defined by a discontinuation of the study attributed to lack of efficacy (i.e. hospital admission, new psychotropic drug for manic and/or depressive symptoms). Randomisation in a 1 : 1 ratio (no other details about randomisation or blinding were reported). Aripiprazole was not tapered in patients randomly assigned to placebo. The double-blind period was designed a priory to consist of an initial 26-week phase, followed by a prospective, 74-week extension phase. Patients who completed the initial 26-week period without a relapse were offered to continue a further 74 weeks of double-blind treatment under the same treatment regimen to allow them a total of 100 weeks of double-blind treatment |
|Tohenb || |
Randomised, double-blind, placebo-controlled, parallel study. In the open-label phase, patients who met the enrolment criteria after a 2- to 7-day screening period received open-label olanzapine in a flexible dose (5–20 mg/day) for 6–12 weeks. Patients unable to tolerate the minimum dose were discontinued. During the first 3 weeks of open-label treatment, additional antimanic medications were tapered. After the third week, concomitant psychotropic medications were discontinued, excluded the benzodiazepines (not to exceed 6 mg/day of lorazepam equivalents). Beginning with week 6 (and no later than week 12), patients in symptomatic remission for at least 2 consecutive weekly visits became eligible for randomisation to the maintenance phase.
Study duration: 12 months
|Bipolar disorder patients with symptomatic remission after open-label acute treatment with olanzapine for an index manic or mixed episode. In- and out-patients (at least 18 years old) were recruited at 44 sites in the US and five sites in Romania. 361 participants entered the double-blind phase (225 with olanzapine; 136 with placebo). The patients met the DSM-IV criteria for an index manic or mixed episode of bipolar I disorder on the basis of the SCID-IV and were required to have a YMRS total score ≥20 at screening and at the start of open-label acute treatment. In addition, patients had to have experienced at least two prior manic or mixed episodes within 6 years of study entry||Olanzapine: from 5 to 20 mg/day. During double-blind treatment, study drugs were initially dispensed at a dose that was equivalent to that received at the end of open-label treatment. After 1 day, the daily dose could be adjusted within the allowed dose range (5–20 mg/day). Dose decreases in any number of tablets were permitted in response to adverse events. Benzodiazepines were permitted during the double-blind phase but could not exceed 4 mg/day of lorazepam equivalents during the first week and could not exceed 2 mg/day of lorazepam equivalents during the remainder of the study period (total duration of benzodiazepines use could not exceed 60 cumulative days). Anticholinergic use was permitted||Time to and incidence of symptomatic relapse into any mood episode. Symptomatic relapse (any mood episode): YMRS total score ≥15, HAMD score ≥15, or hospitalisation for manic, mixed or depressive episode. Patients were randomly assigned in a 2 : 1 ratio to double-blind maintenance treatment with either 5–20 mg/day of olanzapine or placebo. This assignment ratio minimised the number of patients receiving placebo|
|Tohenc || |
Randomised, double-blind, controlled trial. Four study periods:
Screening (two visits over 2–7 days)
Open-label cotreatment (6–12 weeks; twice weekly visits for the first 2 weeks, weekly thereafter)
Double-blind taper (4 weeks; weekly visits)
Double-blind monotherapy (48 weeks; biweekly during the first 4 weeks, monthly thereafter).
From 87 in-patient and out-patient settings across Western Europe, Canada, South Africa, Israel, Australia, and New Zealand between August 1999 and June 2002. Four hundred and thirty-one participants entered the double-blind phase (217 with olanzapine; 214 with lithium). Study duration: 12 months
|Bipolar disorder patients (aged more than 18 years), meeting DSM-IV criteria for bipolar disorder (current episode manic or mixed) as determined with the SCID-IV. Patients were required to have a YMRS total score ≥20 at baseline and a history of at least two manic or mixed episodes in the preceding 6 years. Patients were excluded from the study if they had a serious, unstable medical illness; met DSM-IV substance dependence criteria (nicotine or caffeine excepted) within the past 30 days; had been treated with a depot neuroleptic in the previous 6 weeks; were at serious suicide risk; had a history of intolerance, or lack of response, to an adequate trial of lithium or olanzapine as determined by the investigator||Open-label cotreatment: allowed dosages of olanzapine were 5–20 mg/day (starting dose: 15 mg); required to LI target blood level of 0.6–1.2 mEq/l by week 4 (starting dose: 600 mg). Only oral or i.m. haloperidol and zuclopenthixol were permitted for extreme agitation during the open-label period. Benzodiazepines were allowed: maximum 8 mg/day in lorazepam equivalents up to the first 6 weeks of the open-label period, maximum 6 mg/day for the remainder of the open-label period and during the first 2 weeks of the taper period. Up to 4 mg/day for the remaining 2 weeks of the taper period and then to 2 mg/day (for not more than 60 cumulative days) for the double-blind monotherapy period. Anticholinergics were permitted for treatment-emergent extrapyramidal symptoms||Incidence of symptomatic relapse into any mood episode. Symptomatic relapse (any mood episode): YMRS total score ≥15 and/or HAMD score ≥ 15. Randomisation (1 : 1 ratio) by means of a unique drug kit number via a call-in interactive voice response system. Patients, site personnel and sponsor investigators were blind to randomisation codes. During the double-blind taper period, patients remained on their current dose of randomly assigned treatment, and the dose of the discontinued drug was tapered in a blinded, a priori-determined, stepwise manner over 4 weeks. To maintain the blind associated with blood draws, all patients randomly assigned to olanzapine also had blood drawn. For every outlier report generated for a lithium patient, a sham lithium outlier report was sent to an olanzapine patient|
|Tohend || |
Double-blind, randomised, controlled trial. After a screening and washout period (2–7 days), a 6-week double-blind period follows (olanzapine – from 5 to 20 mg/day – plus lithium or valproate vs. placebo and lithium or valproate). After a rerandomisation, there is a 78-week double-blind therapy period for responders (olanzapine – from 5 to 20 mg/day – plus lithium or valproate vs. placebo and lithium or valproate).
Study duration: 18 months
|99 participants, aged 18–70 years (51 with olanzapine plus lithium or valproate; 48 with placebo plus lithium or valproate) with diagnosis of bipolar I disorder, manic or mixed episode, with or without psychotic features, using the SCID–IV, in syndromic remission. In addition, participants had to have experienced at least two previous mood episodes (manic, depressed or mixed) and a documented trial at a therapeutic blood level of lithium or valproate for at least 2 weeks immediately prior to enrolment, demonstrating persistent manic symptoms (YMRS score ≥16). Exclusion criteria: serious and unstable medical illness; DSM–IV substance dependence within the past 30 days (except nicotine or caffeine); pregnancy; documented history of intolerance to olanzapine; and serious suicidal risk||Olanzapine (range 5-20 mg/day; starting dose: 10 mg) in combination with lithium or valproate (combination therapy), or placebo added to lithium or valproate (monotherapy). Patients continued taking the same mood stabiliser that they had received during the acute phase, the choice of which was determined by the site investigator. During this relapse prevention phase of the study, the blood levels of lithium (0.6–1.2 mm) and valproate (50– 125 mg/ml) remained within the therapeutic range. Only benzodiazepines (max. 2 mg lorazepam equivalent per day for max. five consecutive days, or 60 days cumulatively) and anticholinergics (for treatment for extrapyramidal side-effects but not for prophylaxis) were permitted||Time to syndromic relapse of bipolar disorder (either mania or depression) as defined by DSM-IV criteria. Randomisation (unique drug kit number via a call-in interactive voice response system) in a 1 : 1 ratio. Patients, study site personnel and sponsor investigators were masked to the randomisation codes. Only the addition of olanzapine or placebo was conducted under double-masked conditions. To maintain masking, treatment took the form of two 5-mg capsules (either olanzapine or placebo), titrated up in increments of one capsule, or down by any number of decrements at the investigator's discretion, as indicated by each patient's symptom improvement and treatment tolerance|
|Vietae ||Multicentre, randomised, parallel-group, double-blind study, comparing quetiapine with placebo, as adjunct to lithium or valproate in adult patients with bipolar I disorder (both mania and depression). The study was conducted in 37 in the United States and 140 in other countries, including Australia, Europe and South Africa between April 2004 and October 2006. The study consisted of enrolment and two phases, the initial open-label treatment phase (12–36 weeks) and the subsequent randomised treatment phase (up to 104 weeks). To be randomised, patients must have been treated with quetiapine within the range of 400–800 mg/day and lithium or valproate for at least 12 weeks during the open-label treatment phase and also YMRS and MADrS total scores ≤12. Study duration: up to 2 years||Male or female patients, aged 18 years or older, with bipolar I disorder, who had experienced an acute manic, depressed or mixed episode at enrolment; or a past manic, depressed or mixed episode within 26 weeks, as documented by medical records, treated with quetiapine and mood stabiliser (lithium or valproate). The patients should have had at least one manic, depressed or mixed episode in the 2 years prior to the index episode||Oral dose of open-label quetiapine, 400–800 mg/day in divided doses, (recommended target dose: 600 mg/day – doses could be adjusted). After randomisation, open-label 100-mg quetiapine tablets were titrated down and replaced with 100-mg tablets of blinded investigational product at a rate of one tablet per every 2 days. The dose of blinded investigational product could be adjusted as clinically indicated. Patients began or continued on an oral dose of open-label lithium or valproate chosen by the investigator according to clinical judgment. Lithium or valproate dose was adjusted at the discretion of the investigator (target serum concentrations: 0.5–1.2 mEq/l for lithium and 50–125 μg/ml for valproate||Time to recurrence of a mood event. Recurrence was defined as i) initiation of an antipsychotic, antidepressant, mood stabiliser other than the assigned mood stabiliser, anxiolytic other than lorazepam or any other medication to treat a manic, depressed or mixed event, ii) hospitalisation for a manic, depressed or mixed event, iii) YMRS score ≥20 at two consecutive assessments or at the final assessment if the patient discontinues, or MADRS score ≥20 at two consecutive assessments or at the final assessment if the patient discontinues, or iv) discontinuation from the study by the patient if, in the opinion of the investigator, the discontinuation was due to a manic, depressed or mixed event|
|Suppesf || |
Multicentre (127 centres in US and Canada, between March 2004 and September 2006), randomised, double-blind study comparing quetiapine with placebo, as adjunct to lithium or valproate in the maintenance treatment of adult patients with bipolar I disorder (both mania and depression). The design of this study is identical to the study by Vieta et al. .
Study duration: up to 2 years
|The design of this study is identical to the study by Vieta  (see above)||The design of this study is identical to the study by Vieta  (see above)||The design of this study is identical to the study by Vieta  (see above)|
|Weislerg ||Multicentre, randomised, parallel-group, double-blind, placebo-controlled study to evaluate the efficacy and safety of quetiapine and lithium for up to 104 weeks in adult patients with bipolar I disorder. The study was conducted between March 2005 and July 2007. Countries of recruitment: Argentina, Bulgaria, Colombia, India, Lithuania, Malaysia, Mexico, Peru, Philippines, Romania, Russian Federation, Taiwan, Thailand, Ukraine, United States. The study was terminated early after planned interim analysis provided positive results|| |
Male or female patients, aged 18 years or older. Inclusion Criteria:
Diagnosis of bipolar I disorder (current manic, mixed or depressed)
Any mood episode during the last 26 weeks that was treated with quetiapine
Need of reliable method of contraception for female patients.
Substance or alcohol dependence
Use of an experimental drug within 30 days of enrolment
|Patients aged ≥18 years with DSM-IV-diagnosed bipolar I disorder and a current or recent manic, depressive, or mixed episode received open-label quetiapine (300–800 mg/day) for 4–24 weeks. Patients achieving stabilisation were randomised to continue quetiapine or to switch to placebo or lithium (0.6–1.2 mEq/l) for up to 104 weeks in a double-blind trial||Primary outcome: time from randomisation to recurrence of a mood event. Secondary outcomes: time from randomisation to recurrence of a manic or depressed event. Safety assessments included adverse events and laboratory values|
|Bowdenh || |
Subjects with DSM-IV bipolar I disorder with a Mania Rating Scale score ≥14 were enrolled. Subjects achieving ≥8 consecutive weeks of stability with open-label ziprasidone (80–160 mg/day) and lithium or valproate over a period of at least 10 weeks and up to 16 weeks. (period 1) were randomly assigned in the double-blind maintenance period (period 2) to ziprasidone plus mood stabiliser or placebo plus mood stabiliser. The study was conducted from December 2005 to May 2008.
Inclusion criteria: adults meeting DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition) criteria for bipolar I disorder (currently with manic or mixed symptoms)
Exclusion Criteria: Ultra rapid cyclers and subjects with significant cardiovascular disease including history of QT prolongation and/or congenital long QT syndrome
|Patients randomised to ziprasidone continued to receive the same stable treatment regimen achieved during the open-label treatment, that is, either 80, 120 or 16 mg/day for up to 24 weeks of double-blind treatment. Patients randomised to placebo were tapered off the open-label ziprasidone by 40 mg/day every 2 days (in a double-blinded manner) until they were completely off ziprasidone and were on matching placebo capsules for up to 24 weeks of double-blind treatment|| |
Primary outcome: time to intervention for a mood episode. Secondary outcomes:
time to discontinuation for any reason
Change from baseline in Mania Rating Scale
Change from baseline in Clinical Global Impression Severity score
Clinical Global Impression - Improvement
Change from baseline in Montgomery-Asberg Rating Scale Score
Change from baseline in Positive and Negative Syndrome Scale score
|Marcusi || |
Multicentre, randomised, double-blind, placebo-controlled out-patient study.
In Phase 1, patients with acute manic or mixed symptomatology were assigned lithium (0.6–1.0 mm) or valproate (50–125 μg/ml). Patients with a partial non-response (Y-MRS ≥16) were eligible to enter Phase 2, where aripiprazole (10–30 mg/day; starting dose: 15 mg/day) was assigned in single-blind fashion. Three hundred and thirty-seven patients responding to the combination treatment, and maintaining response for 12 weeks, were randomised (1 : 1) double-blind to continuation of aripiprazole plus mood stabiliser or placebo plus mood. Study duration: 12 months
The population included in this study were male and female out-patients, ≥18 years of age, with a diagnosis of bipolar I disorder as defined by DSM-IV-TR who displayed an acute manic or mixed episode as confirmed by the SCID (Y-MRS total score ≥16), with or without psychotic features. Patients who are using lithium or valproate immediately prior to study entry were included as long as they met the criteria
Phase 1 (2–8 weeks): 250- and 300-mg oral lithium tablets or 250-mg valproic acid oral tablets
Phase 2 (13–24 weeks): aripiprazole 10-and 15-mg oral tablets and 250- and 300-mg oral lithium tablets or 250-mg valproic acid oral tablets
Phase 3 (52 weeks): aripiprazole 10- and 15-mg oral tablets and 250- and 300-mg oral lithium tablets or 250-mg valproic acid oral tablets
Primary outcome: time to relapse to any mood episode.
Secondary outcomes: mean change from baseline in the following scales: Y-MRS total score; MADRS total score; CGI-BP severity of illness score; percentage of patients maintaining remission during Phase 3; time to manic relapse; time to depressive relapse.
Safety outcome measures included the frequency and severity of adverse events, serious adverse events (clinical and laboratory) and discontinuations from study due to adverse events, vital signs (supine and standing positions), body weight, electrocardiogram, routine and special laboratory tests
|Carlsonj || |
Subjects with DSM-IV-TR bipolar I disorder with a manic or mixed episode were enrolled. Subjects achieving at least 8 consecutive weeks of stability (YMRS and MADRS total score ≤12) with single-blind aripiprazole (10-30 mg/day) and open-label lamorigine (100-200 mg/day) over a period of 9–24 weeks (stabilisation phase) were randomly assigned to aripiprazole (double-blind) plus lamotrigine (open label) or placebo (double-blind) plus lamotrigine (open label). The study was conducted from December 2005 to July 2009.
Study duration: 52 months
|Inclusion criteria: adults meeting DSM-IV-TR criteria for bipolar I disorder with a manic or mixed episode in the previous 3 months [YMRS ≥ 16], with or without psychotic features and with or without a history of rapid cycling (≥4 but ≤7 mood episodes per year). Exclusion criteria: DSM-IV-TR diagnosis of delirium, dementia, amnestic or other than bipolar I disorder; pregnancy; first manic or mixed episode; treatment refractory manic or mixed episodes; a history of aripiprazole treatment within the previous 3 months; a prestudy lamotrigine dose >200 mg/day that could not be titrated down to 100 or 200 mg/day; risk of committing suicide|| |
Starting dose for single-blind aripiprazole: 10 mg/day, with a target dose of 15 mg/day (then, dose could be adjusted by increments or decrements of 5 mg, between 10–30 mg/day). Open-label lamotrigine (as add-on to aripiprazole) was started at 25 mg/day (target dose of 200 mg/day). Patients stabilised were randomised (1 : 1) to continue treatment with either double-blind aripiprazole or double-blind placebo in combination with open-label lamotrigine.
Doses of aripiprazole and lamotrigine could be adjusted. Clinical assessments: every 2 weeks for the first 8 weeks and then monthly up to Week 52
The criteria for relapse included one or more of the following events: hospitalisation for a manic or mixed episode; a serious adverse event or worsening disease during the study; or discontinuation due to a lack of efficacy (as determined by the investigator).
Secondary endpoints were time to any relapse (manic, mixed, depressive), time to depressive relapse, and time to discontinuation for any reason. Other outcome measures were the mean change from baseline in YMRS and MADRS total scores, and Clinical Global Impression–Bipolar Disorder (CGI-BP) severity of illness score (mania, depression, overall), and mean CGI-BP change from preceding phase score (mania, depression, overall)