Intervention Review

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Aripiprazole alone or in combination for acute mania

  1. Rachel Brown1,*,
  2. Matthew J Taylor2,
  3. John Geddes3

Editorial Group: Cochrane Common Mental Disorders Group

Published Online: 17 DEC 2013

Assessed as up-to-date: 31 JUL 2013

DOI: 10.1002/14651858.CD005000.pub2


How to Cite

Brown R, Taylor MJ, Geddes J. Aripiprazole alone or in combination for acute mania. Cochrane Database of Systematic Reviews 2013, Issue 12. Art. No.: CD005000. DOI: 10.1002/14651858.CD005000.pub2.

Author Information

  1. 1

    Oxford Health NHS Foundation Trust, Clinical Pharmacy Support Unit, Oxford, UK

  2. 2

    Institute of Psychiatry, King's College London, Department of Psychosis Studies, London, UK

  3. 3

    University of Oxford/Warneford Hospital, Department of Psychiatry, Oxford, UK

*Rachel Brown, Clinical Pharmacy Support Unit, Oxford Health NHS Foundation Trust, Unit 46, Sandford Lane, Kennington, Oxford, OX1 5RW, UK. rachel.brown@oxfordhealth.nhs.uk.

Publication History

  1. Publication Status: New
  2. Published Online: 17 DEC 2013

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Characteristics of included studies [ordered by study ID]
CN138-007

MethodsRandomised controlled trial

Multinational (56 centres in US, Argentina and Mexico)

Three weeks

16.3.2000 to 13.7.2001


ParticipantsN = 401

Age: 18 to 74 years old (mean age not stated)

Males 48%, females 52%

Bipolar I disorder, manic or mixed (DSM-IV criteria) with YMRS total score of ≥ 20 and in acute relapse

Participants were hospitalised for at least the first two weeks of treatment

Exclusion criteria: delirium, dementia, amnestic or other cognitive disorder, schizophrenia, schizoaffective disorder, first manic episode or current episode longer than four weeks, substance abuse disorder, non-response to clozapine, suicide or homicide risk, unstable thyroid pathology, history of neuroleptic malignant syndrome


InterventionsAripiprazole 15 mg fixed dose (N = 136), aripiprazole 30 mg fixed dose (N = 134), placebo (N = 134)


OutcomesPrimary: mean change from baseline on YMRS total score

Secondary: CGI-bipolar version, PANSS, MADRS, response (> 50% decrease in YMRS)


NotesManufacturer sponsored


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNo details, merely stated as randomised (synopsis page 1)

Allocation concealment (selection bias)Unclear riskNo details of method

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskSome missing data, without explanation/details. Likely low impact

Selective reporting (reporting bias)Unclear riskNot all outcomes were included in the unpublished clinical report synopsis, but thy were supplied upon request. However, we did not have access to a published protocol

Other biasUnclear riskNo suggestion of other biases from the data and content of the synopsis report; however, assigned as an unclear risk, as the study has not been published and was kept as data on file

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskNo details of method

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNo details of method

Findling 2009

MethodsRandomised controlled trial

Multicentre (59 US centres)

Four weeks

March 2005 and February 2007


ParticipantsN = 296

Age: 10 to 17 years old (mean age 13.4, SD 2.2)

Males 53.7%, females 46.3%

Bipolar I, current episode manic or mixed with or without psychotic features (DSM-IV criteria) and YMRS total score of ≥ 20

Participants were outpatients, hospitalised or partially hospitalised

Comorbid ADHD, conduct disorder, oppositional defiant disorder or anxiety disorder (except PTSD) allowed

Exclusion criteria: bipolar II, bipolar NOS, PDD, schizophrenia, schizoaffective disorder, substance misuse, pregnancy, suicide risk


InterventionsAripiprazole fixed dose 10 mg (N = 98), aripiprazole fixed dose 30 mg (N = 99), placebo (N = 99)

After screening and washout, aripiprazole 10 mg or 30 mg or placebo for four weeks

Aripiprazole initiated as 2 mg/d (day one and day two), 5 mg/d (day three and day four), 10 mg/d (day five), and if in 30 mg group, titration continued as 10 mg/d (day five and day six), 15 mg/d (day seven and day eight), 20 mg/d (day nine and day 10), 25 mg/d (day nine and day 10) and 30 mg/d (day 13 onwards)


OutcomesPrimary: mean change on YMRS total score from baseline

Secondary: response (≥ 50% decrease in total YMRS), CGI-bipolar version (severity of mania, depression and overall bipolar illness), CGAS, CDRS-R, GBI (abbreviated version), parent questionnaire on home behaviours version of the ADHD Rating Scale-Version IV (ADHD-RS-VI), Pediatric Quality of Life Enjoyment and Satisfaction Questionnaire (P-LES-Q)—all assessed at weeks one, two, three, and four (apart from P-LES-Q, which was administered at baseline and at week four) and time to discontinuation


NotesManufacturer sponsored


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNo details, merely stated as randomised (page 1442)

Allocation concealment (selection bias)Unclear riskNo details of method

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskSome missing data because rating scales were not completed. Likely low impact

Selective reporting (reporting bias)Unclear riskAll stated outcomes are reported on, with the exception of P-QLES-Q, a secondary outcome. It is commented on that no significant difference was seen at week four, but data are not presented (page 1444). However, we did not have access to a published protocol

Other biasUnclear riskNo suggestion of other biases (baseline characteristics balanced; table 1, page 1445); however, this was a manufacturer-sponsored study

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskStated as double-blind, but no details of method provided (page 1442)

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNo details of method

Keck 2003

MethodsRandomised controlled trial

Multicentre (38 US centres)

Three weeks

Study dates not stated


ParticipantsN = 262
Age: ≥ 18 years old (range not stated); mean age: 40.5, SD 12.2
Males 44%, females 56%

Bipolar I, manic or mixed episode (DSM-IV criteria) with YMRS ≥ 20 and experiencing an acute relapse requiring hospitalisation

Participants were hospitalised for at least the first two weeks of treatment. At end of week two, discharged if CGI-bipolar version: severity of illness score ≥ 3 and change from preceding phase ≥ two. If not meeting these criteria, patients remained hospitalised for the remaining week
Participants not responding at end of week two (change from preceding phase score of four to seven) were discontinued from double-blind treatment and were offered the option of open-label aripiprazole during week three
Exclusion criteria: pregnant or lactating women, delirium, dementia, amnestic, other cognitive disorders, schizophrenia or schizoaffective disorder, experiencing first manic episode, duration of current mania > four weeks, non-response to clozapine, probable need for prohibited concomitant treatment, psychoactive substances/substance use disorder, at screening: lithium > 0.6 mmol/L and/or divalproex sodium > 50 microgram/mL (therapeutic levels), suicide or homicide risk, history of NMS or seizure disorder, clinically significant abnormal lab results, vitals, ECG, previous enrolment in an aripiprazole trial


InterventionsAripiprazole variable dose (N = 130) and placebo (N = 132)

After a one- to seven-day screening period to assess patient eligibility and to allow for elimination of existing psychotropics, participants were allocated to 30 mg aripiprazole or placebo for three-week treatment period. Aripiprazole was initiated at 30 mg/d—reduced if needed to 15 mg/d. Average dose at endpoint 27.9 mg


OutcomesPrimary: mean change in total YMRS
Secondary: response (≥ 50% decrease in total YMRS), CGI-bipolar version scale (severity and change from preceding phase) for mania, depression and overall illness, time to discontinuation due to lack of efficacy or entry into open-label aripiprazole treatment

All assessed at days four, seven, 10, 14 and 21


NotesManufacturer sponsored


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskMerely states that participants were "randomly assigned" (page 1652)

Allocation concealment (selection bias)Unclear riskNo details of methods

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNot all participants allocated treatment were included in the analysis. Likely low impact. Table included that lists reasons and numbers of participants discontinuing (table 2, page 1653). LOCF used when possible

Selective reporting (reporting bias)Unclear riskStated outcomes reported on; however, we did not have access to a published protocol

Other biasUnclear riskNo suggestion of other biases—baseline characteristics balanced (table 1, page 1653); however, this was a manufacturer-sponsored study

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskStated as double-blind (page 1652), no details of methods

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNo details of methods

Keck 2009

MethodsRandomised controlled trial

Multicentre (49 US centres)

12 weeks

April 2004 and July 2006


ParticipantsN = 488

18- to 65-year-olds (mean ages: placebo 39.8 (SD 11.3), lithium 39.6 (SD 10.5), aripiprazole 39.6 (SD 10.6))

Males 52%, females 48%

Bipolar I disorder (DSM-IV criteria), acute manic or mixed episode with or without psychotic features and YMRS ≥ 20 requiring hospitalisation

Exclusions include cognitive or psychotic disorders other than mania, bipolar II, bipolar NOS, rapid cycling, known non-response to antimanic agents, substance or alcohol abuse, medical conditions exposing to undue harm


InterventionsAripiprazole (N = 155), lithium (N = 160) or placebo (N = 165)

Three parallel groups

Following washout period, participants were allocated 1:1:1 to aripiprazole, lithium or placebo

Participants requiring hospitalisation beyond three weeks were discontinued

After three weeks, participants in the placebo group were switched to aripiprazole for remaining nine weeks of the study but were excluded from the analysis beyond week three

After 12 weeks, participants could enter a 40-week extension phase


OutcomesPrimary: mean change from baseline on YMRS total score (days two and four, weeks one, two, three, four, five, six, eight, 10 and 12)

Secondary: response (≥ 50% decrease in total YMRS), remission (YMRS ≤ 12) at three weeks and at 12 weeks, CGI-bipolar version severity of illness (mania, depression, overall) and change from preceding phase (mania) (days two and four, weeks one, two, three, four, five, six, eight, 10 and 12), PANSS mean change (total, cognitive, hostility) at three weeks and at 12 weeks, MADRS mean change (days two and four, weeks one, two, three, four, five, six, eight, 10 and 12)


NotesManufacturer sponsored

Third phase of study is still ongoing. Participants could continue double-blind on aripiprazole or lithium for additional 40 weeks


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNo details—merely stated as randomised (page 38)

Allocation concealment (selection bias)Unclear riskNo details of method

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskFigure 1 (page 41) provides the disposition of participants during the study but some missing data. Likely low impact. LOCF used

Selective reporting (reporting bias)Unclear riskStated outcomes are reported on; however, we did not have access to a published protocol

Other biasUnclear riskNo suggestion of other biases—baseline characteristics balanced (table 1, page 40); however, this was a manufacturer-sponsored study

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskDetails/methods lacking

Sham lithium levels are stated as having been reported in the aripiprazole and placebo arms, but the exact method is unclear (page 38) (e.g. Were blood samples taken, How were sham levels given?)

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNo details of method

NCT00665366

MethodsRandomised controlled trial

Multicentre (73 sites in Europe, South Africa and Russia)

12 weeks

June 2008 to October 2011


ParticipantsN = 370

18 years and older—age range not stated (mean age: 44.65 ± 12.57)

Males 46%, females 54%

Bipolar I mania, manic or mixed with or without psychotic features

Current ongoing treatment with lithium or valproate

Therapeutic lithium or valproate levels and YMRS ≥ 16

Exclusions include women of child-bearing potential; delirium, dementia, amnesia or other cognitive disorder, or a psychotic disorder; bipolar II or NOS, or any other primary psychiatric disorder other than bipolar I mania; thyroid pathology; cocaine abuse; history of NMS; refractory manic symptoms; previous non-response to aripiprazole; significant risk of suicide


InterventionsAripiprazole (N = 181) or placebo (N = 189) in combination with valproate or lithium

Participants partially non-responsive (YMRS ≥ 16) to therapeutic levels of lithium or valproate entered 12 weeks of double-blind treatment, during which they were allocated aripiprazole or placebo in a 1:1 ratio. Aripiprazole was given at 5 mg daily (week one), then at 10 mg daily (weeks two and three), then at 15 mg daily (weeks four to six). Flexible dosing of 15 mg or 30 mg daily was administered during weeks seven to 12. The dose could be reduced during weeks seven to 12 to 10 mg daily if necessary for tolerability


OutcomesPrimary: mean change from baseline on YMRS total score at week 12

Secondary: response (≥ 50% decrease in total YMRS), remission (YMRS < 12), CGI-bipolar version scale (severity) for mania, depression and overall illness, FAST—change from baseline in total and subscale scores, LIFE-RIFT—change from baseline in total score, PGI-I

Measurements taken at three, six, nine and 12 weeks


NotesManufacturer sponsored


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNo details—merely stated as randomised

Allocation concealment (selection bias)Unclear riskNo details of methods

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNot all participants allocated treatment were included in all the analyses. Likely low impact. Table included that lists reasons and numbers of participants discontinuing. LOCF used when possible

Selective reporting (reporting bias)Unclear riskStated outcomes reported on; however, we did not have access to a published protocol

Other biasUnclear riskNo suggestion of other biases (baseline characteristics balanced—participant flow table); however, this was a manufacturer-sponsored study

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskStated as double-blind, no details of methods

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNo details of methods

Sachs 2006

MethodsRandomised controlled trial

Multicentre (29 US centres)

Three weeks

Study dates not stated


ParticipantsN = 272
Age: ≥ 18 years (age range not stated), mean age: 38.8 (SE 0.7)

Males 49%, females 51%
Bipolar I disorder (DSM-IV criteria), acute manic or mixed episode requiring hospitalisation with baseline YMRS ≥ 20
Exclusion criteria: delirium, dementia, amnestic or other cognitive disorders, schizophrenia or schizoaffective disorder, experiencing first manic episode, duration of episode > four weeks, unresponsive to clozapine, possibility that the patient would require prohibited concomitant medication, use of psychoactive substances, substance use disorder, lithium > 0.6 mmol/L or divalproex sodium > 50 microgram/mL (therapeutic levels) at screening, suicide or homicide risk, history of neuroleptic malignant syndrome or seizure disorder, clinically significant laboratory test results, vital signs, ECG, or previous enrolment in aripiprazole trial


InterventionsAripiprazole variable dose (N = 137) and placebo (N = 135)

Following a one- to seven-day screening period, participants were allocated to aripiprazole 30 mg daily (with option to reduce to 15 mg for tolerability) or to placebo for three weeks
Participants remained hospitalised for a minimum of two weeks. 85% remained on 30-mg dose at endpoint


OutcomesPrimary: YMRS mean change from baseline
Secondary: response (≥ 50% decrease in YMRS), CGI-bipolar version severity of illness and change from preceding phase for mania, depression and overall illness, mean change in PANSS-total and hostility subscale, MADRS and rate of discontinuation due to lack of efficacy

All assessed at days two, four, seven, 10, 14 and 21


NotesManufacturer sponsored


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNo details—merely stated as randomised (page 537)

Allocation concealment (selection bias)Unclear riskNo details of methods

Incomplete outcome data (attrition bias)
All outcomes
Unclear risk272 randomly assigned, three did not take medication and were excluded from analysis, one discontinued early (page 538). Likely low impact. LOCF used

Selective reporting (reporting bias)Unclear riskStated outcomes are reported on; however, we did not have access to a published protocol

Other biasUnclear riskNo suggestion of other biases—baseline characteristics balanced (table 1, page 539); however, this was a manufacturer-sponsored study

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskStated as double-blind (page 537), no details of methods

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNo details of methods

Tramontina 2009

MethodsRandomised controlled trial

One centre in Brazil

Six weeks

January 2005 to November 2007


ParticipantsN = 43

Eight- to 17-year-olds (mean ages: aripiprazole 11.72 (SD 2.71), placebo 12.16 (SD 2.75))

Males 46.5%, females 53.5%

Bipolar I or II disorder (DSM-IV criteria), acute manic or mixed state (YMRS ≥ 20)

Comorbid with DSM-IV ADHD (clear reports of ADHD symptom onset preceding any mood symptoms)

Outpatients

Exclusions include IQ < 70, medication use during the previous four weeks, PDD < schizophrenia, substance abuse, suicide/homicide risk, previous aripiprazole use, pregnancy, acute/chronic diseases that may interfere with the study


InterventionsAripiprazole variable dose (N = 18) or placebo (N = 25)

Starting dose > 50 kg = 5 mg/d, < 50 kg = 2 mg/d

Dose increased according to response/adverse effects to a max 20 mg/d


OutcomesPrimary: mean change in YMRS

Secondary: response (≥ 50% decrease in YMRS), remission (YMRS ≤ 12), CGI severity of illness, Child Mania Rating Scale—parent version, Brazilian version of Child's Depression Rating Scale, Kutcher Adolescent Rating Scale

Assessed at weeks one, two, three, four, five and six


NotesNot manufacturer sponsored


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComputer-derived sequence algorithm—Epi-Info (page 757)

Allocation concealment (selection bias)Unclear riskIndependent third party performed group allocation. No further details (page 737)

Incomplete outcome data (attrition bias)
All outcomes
Low riskAll participants accounted for, ITT analysis and none excluded/missing (figure 1, page 760)

Selective reporting (reporting bias)Unclear riskAll outcomes reported in the published study; however, we did not have access to a published protocol

Other biasLow riskNo suggestion of other biases—baseline characteristics balanced (table 1, page 761)

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskStated as blind (page 757), no details of methods

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNo details of methods

Vieta 2005

MethodsRandomised controlled trial.

Multicentre (76 international centres).

12 weeks

Study dates not stated.


ParticipantsN = 347
Age range: 18 to 68 years (mean age: 41.8 (SD 0.6))

Males 38%, females 62%
Bipolar I disorder (DSM-IV criteria), acute manic or mixed episode and YMRS baseline ≥ 20

Inpatients or outpatients
Exclusion criteria: rapid cycling bipolar I, current manic episode of > four weeks, Proven substance misuse, unresponsive to antipsychotics, significant risk of suicide, recent treatment with long-acting antipsychotics, lithium or divalproate, use of psychotropic medications (other than benzodiazepines) within one day of randomisation, use of fluoxetine within past four weeks, previous enrolment in an aripiprazole study


InterventionsAripiprazole variable dose (N = 175) or haloperidol variable dose (N = 172)

After a one- to three-day washout period, participants were allocated to aripiprazole 15 mg daily (with an option to increase to 30 mg if poor response at end of week one or two) or haloperidol 10 mg daily (with an option to increase to 15 mg if poor response at end of week one or two). Average aripiprazole dose: at three weeks = 22.6 mg and at 12 weeks = 21.6 mg. Average haloperidol dose: at three weeks = 11.6 mg and at 12 weeks = 11.1 mg.
At the end of week three, if CGI-BP (mania) severity scale ≥ 4 or MADRS ≥ 18, participants were discontinued from the study
Participants remaining from four to 12 weeks continued on the dose prescribed in week three (dose decreases were allowed for tolerability)


OutcomesPrimary: response (≥ 50% decrease in YMRS from baseline)

Secondary: remission (YMRS ≤ 12), mean change in YMRS, CGI-bipolar version—severity of illness for mania, depression and overall illness, MADRS, time to discontinuation for any reason

All assessed at days four and seven and 10 and at weeks two, three, four, five, six, eight, 10 and 12


NotesManufacturer sponsored


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskStated as a fixed randomisation schedule in a 1:1 ratio between treatment arms, but no details of methods provided (page 235)

Allocation concealment (selection bias)Unclear riskNo details of method

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskCONSORT diagram (figure 1, page 236) and numbers balanced across intervention groups. LOCF used. One participant randomly assigned to haloperidol but treated with aripiprazole. Likely low impact

Selective reporting (reporting bias)Unclear riskResults for all stated outcomes appear in the text; however, we did not have access to a published protocol

Other biasUnclear riskNo suggestion of other biases—baseline characteristics balanced (table 1, page 237). However, this was a manufacturer-sponsored study

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskStated as double-blind (page 235), no details of methods

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNo details of methods

Vieta 2008

MethodsRandomised controlled trial

Multicentre (number not stated)

Six weeks

Study dates not stated


ParticipantsN = 384

Age: 18 years or older (mean ages: aripiprazole 42.2 (SD 11.6), placebo 41.7 (SD 12.1))

Males 46%, females 54%

Bipolar I (DSM-IV criteria), manic or mixed episode with or without psychotic symptoms

Participants were required to have lithium levels of 0.6 to 1.0 mmol/L or valproate levels of 50 to 125 microg/mL

Exclusion criteria include hospitalisation for current episode of longer than three weeks, previous non-response to antimanics, bipolar II, rapid cycling, substance use, suicide risk, use of long-acting antipsychotics


InterventionsAripiprazole (N = 253) or placebo (N = 131) in combination with valproate or lithium

Phase one: three-day to four-week washout of medication other than lithium or valproate

Phase two: Participants not already taking lithium or valproate were started on one of these treatments, then a two-week period followed to confirm whether participants were partially non-responsive to lithium or valproate

If partially non-responsive (YMRS ≥ 16), participants entered phase three, which was a six-week double-blind phase during which they were allocated aripiprazole or placebo in a 2:1 ratio. Aripiprazole was started at 15 mg daily and could be increased from day seven to a max of 30 mg if required


OutcomesPrimary: mean change in YMRS

Secondary: response (≥ 50% decrease in YMRS from baseline), remission (YMRS ≤ 12), CGI-bipolar version—mean change in severity of illness and change from preceding phase for mania, depression and overall illness, MADRS, PANSS total and positive, negative, cognitive and hostility subscales, Time to discontinuation for any reason

All assessed at day four, weeks one, two, three, four, five and six


NotesManufacturer sponsored

Fourth phase of study: Participants could enter a 46-week open-label extension with aripiprazole and lithium or valproate


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskMerely stated as randomised (page 1317), no details of methods provided

Allocation concealment (selection bias)Unclear riskNo details of methods

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskLOCF data used, but some data missing. Likely low impact. CONSORT diagram included (figure 1, page 1318)

Selective reporting (reporting bias)Unclear riskStated outcomes are reported on; however, we did not have access to a published protocol

Other biasUnclear riskUnclear how study personnel allocated participants in phase two to lithium or valproate. Unclear how drug levels were blinded and how they were dealt with during the double-blind phase. Also, manufacturer sponsored

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskPhases one and two were open-label; phase three stated as double-blind, but no details of methods (page 1317)

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNo details of methods

Young 2009

MethodsRandomised controlled trial

Multicentre (59 international centres)

Three weeks

Study dates not stated


ParticipantsN = 485

Age: 18 years or older (range not stated); mean age: 40.8

Males 44%, females 56%

Bipolar I (DSM-IV) with an acute manic or mixed episode with or without psychotic features requiring hospitalisation with YMRS ≥ 20 (< 25% increase from screening to baseline) and MADRS total ≤ 17 at end of phase one (no more than a four-point increase between screening and baseline with measures at least two days apart)

Exclusions include delirium, dementia, amnestic or other cognitive disorders, schizophrenia, schizoaffective disorder, first manic/mixed episode, personality disorder, serious unstable medical illness, hospitalisation for current episode of > three weeks, previously unresponsive to antimanics, bipolar II, rapid cycling, substance misuse, suicide risk, long-acting antipsychotics, antidepressants during the previous two to four weeks, ECG during three previous weeks, long-acting antipsychotics


InterventionsAripiprazole (N = 167), haloperidol (N = 165), placebo (N = 153)

Phase one: two- to 14-day screening and washout

Phase two: double-blind treatment with aripiprazole, haloperidol or placebo in a 1:1:1 ratio for three weeks. After three weeks, those receiving placebo were offered open-label aripiprazole. All participants continued until week 12

Aripiprazole was started at 15 mg on day one of phase two. On day four, it was increased to 30 mg if required (mean dose at three weeks = 23.6 mg/d, at 12 weeks = 22.0 mg/d). Haloperidol was started at 5 mg/d on day one. Dose could increase to 10 mg on day four and 15 mg on day seven if required (mean dose at three weeks = 5.8 mg/d, 12 weeks = 7.4 mg/d)


OutcomesPrimary: mean change from baseline in YMRS total score

Secondary: response (≥ 50% decrease in YMRS from baseline), response (YMRS ≤ 12), mean change in CGI-bipolar version—severity and change from preceding phase for mania, CGI-BP severity of illness, mean change in PANSS total and cognitive, hostility, positive and negative subscales, MADRS total mean change, LIFE-RIFT

All assessed at days two, four, seven, 10, weeks two, three, four, five, six, eight, 10 and 12


NotesManufacturer sponsored


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskMerely stated as randomised with no details of methods (page 40)

Allocation concealment (selection bias)Unclear riskNo details of methods

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskLOCF used. Some missing data (figure 1, page 42 gives the flow of participants through the study and includes reasons for discontinuing). Likely low impact

Selective reporting (reporting bias)Unclear riskPrespecified outcomes have been reported on; however, we did not have access to a study protocol

Other biasUnclear riskBaseline characteristics are stated as similar between groups, but this information was not available, and it is stated as reported online in a table (DS2) separately from the published report (page 41). Manufacturer sponsored

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskStated as double-blind but no details of methods (page 40)

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNo details of methods

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

CN138077Did not produce any results

CN138189Data could not be used from phase two of the study, as it did not include a comparison arm

NCT00484471It was not possible to use data from the acute phase, as it had no comparison arm and was open-label

NCT00606229Open-label study

NCT01567527Acute phases of treatment were open-label or single-blind

Woo 2011Not possible to use data from the acute phase, as it had no comparison arm and was open-label

Zeni 2009Not a study assessing the effect of aripiprazole on acute mania

Zimbroff 2007Indication for treatment was immediate relief of acute agitation (rapid tranquillisation)

 
Characteristics of studies awaiting assessment [ordered by study ID]
Kanba 2012

MethodsA multicentre, randomised, double-blind, placebo-controlled, parallel-group comparison trial

ParticipantsPatients aged 18 to 65 who meet DSM-IV-TR criteria for manic or mixed episodes

InterventionsAripiprazole 24 mg per day versus placebo

OutcomesPrimary: Young Mania Rating Scale (YMRS); secondary: Clinical Global Impression-Bipolar Version (CGI-BP)

NotesManufacturer sponsored

 
Comparison 1. Aripiprazole versus placebo

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Mean change in YMRS from baseline at three weeks61819Mean Difference (IV, Random, 95% CI)-3.66 [-5.28, -2.05]

    1.1 Aripiprazole variable dose versus placebo as monotherapy
41146Mean Difference (IV, Random, 95% CI)-3.69 [-5.01, -2.38]

    1.2 Aripiprazole 10 mg versus placebo as monotherapy
1142Mean Difference (IV, Random, 95% CI)-5.80 [-8.88, -2.72]

    1.3 Aripiprazole 15 mg versus placebo as monotherapy
1192Mean Difference (IV, Random, 95% CI)0.11 [-3.17, 3.39]

    1.4 Aripiprazole 30 mg versus placebo as monotherapy
2339Mean Difference (IV, Random, 95% CI)-3.82 [-9.92, 2.27]

 2 Mean change in YMRS from baseline at day four2510Mean Difference (IV, Random, 95% CI)-2.83 [-4.52, -1.14]

    2.1 Aripiprazole variable dose versus placebo as monotherapy
2510Mean Difference (IV, Random, 95% CI)-2.83 [-4.52, -1.14]

 3 Mean change in YMRS from baseline week four1287Mean Difference (IV, Fixed, 95% CI)-7.16 [-9.44, -4.88]

    3.1 Aripiprazole 10 mg versus placebo as monotherapy
1142Mean Difference (IV, Fixed, 95% CI)-6.0 [-9.24, -2.76]

    3.2 Aripiprazole 30 mg versus placebo as monotherapy
1145Mean Difference (IV, Fixed, 95% CI)-8.3 [-11.51, -5.09]

 4 Mean change in YMRS from baseline at week six2420Mean Difference (IV, Random, 95% CI)-4.38 [-9.13, 0.37]

    4.1 Aripiprazole versus placebo as add-on to lithium or valproate
1377Mean Difference (IV, Random, 95% CI)-2.61 [-4.25, -0.97]

    4.2 Aripiprazole versus placebo as monotherapy
143Mean Difference (IV, Random, 95% CI)-7.70 [-13.45, -1.95]

 5 Mean change in YMRS from baseline to week 121Mean Difference (IV, Random, 95% CI)Totals not selected

    5.1 Aripiprazole versus placebo as add-on to lithium or valproate
1Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

 6 Response (≥ 50% decrease in total YMRS from baseline) at three weeks41230Risk Ratio (M-H, Random, 95% CI)1.70 [1.23, 2.34]

    6.1 Aripiprazole variable dose versus placebo
2534Risk Ratio (M-H, Random, 95% CI)1.83 [1.43, 2.34]

    6.2 Aripiprazole 10 mg versus placebo as monotherapy
1147Risk Ratio (M-H, Random, 95% CI)2.44 [1.24, 4.81]

    6.3 Aripiprazole 15 mg versus placebo
1198Risk Ratio (M-H, Random, 95% CI)1.06 [0.73, 1.55]

    6.4 Aripiprazole 30 mg versus placebo
2351Risk Ratio (M-H, Random, 95% CI)1.87 [0.64, 5.45]

 7 Response (≥ 50% decrease in total YMRS from baseline) at four weeks1295Risk Ratio (M-H, Random, 95% CI)2.18 [1.50, 3.16]

    7.1 Aripiprazole 10 mg versus placebo
1147Risk Ratio (M-H, Random, 95% CI)1.79 [1.04, 3.08]

    7.2 Aripiprazole 30 mg versus placebo
1148Risk Ratio (M-H, Random, 95% CI)2.60 [1.55, 4.34]

 8 Response (≥ 50% decrease in total YMRS from baseline) at six weeks2420Risk Ratio (M-H, Random, 95% CI)1.40 [1.09, 1.80]

    8.1 Aripiprazole versus placebo as add-on to lithium or valproate
1377Risk Ratio (M-H, Random, 95% CI)1.29 [1.06, 1.58]

    8.2 Aripiprazole versus placebo as monotherapy
143Risk Ratio (M-H, Random, 95% CI)1.71 [1.13, 2.58]

 9 Remission (YMRS total score ≤ 12) at six weeks3782Risk Ratio (M-H, Random, 95% CI)1.28 [0.98, 1.69]

    9.1 Aripiprazole versus placebo as monotherapy
143Risk Ratio (M-H, Random, 95% CI)2.26 [1.19, 4.28]

    9.2 Aripiprazole versus placebo as add-on to lithium or valproate
2739Risk Ratio (M-H, Random, 95% CI)1.18 [0.96, 1.44]

 10 CGI-Bipolar Version: severity (mania)—mean change at three weeks72262Mean Difference (IV, Random, 95% CI)-0.41 [-0.66, -0.16]

    10.1 Aripiprazole variable dose versus placebo as monotherapy
41142Mean Difference (IV, Random, 95% CI)-0.43 [-0.61, -0.25]

    10.2 Aripiprazole 10 mg versus placebo as monotherapy
1188Mean Difference (IV, Random, 95% CI)-0.60 [-0.92, -0.28]

    10.3 Aripiprazole 15 mg versus placebo as monotherapy
1190Mean Difference (IV, Random, 95% CI)-0.12 [-0.55, 0.31]

    10.4 Aripiprazole 30 mg versus placebo as monotherapy
2385Mean Difference (IV, Random, 95% CI)-0.64 [-1.56, 0.28]

    10.5 Aripiprazole versus placebo as add-on to lithium or valproate
1357Mean Difference (IV, Random, 95% CI)0.04 [-0.18, 0.26]

 11 CGI-Bipolar Version: severity (mania)—mean change at four weeks1287Mean Difference (IV, Random, 95% CI)-1.05 [-1.54, -0.56]

    11.1 Aripiprazole 10 mg versus placebo
1142Mean Difference (IV, Random, 95% CI)-0.8 [-1.21, -0.39]

    11.2 Aripiprazole 30 mg versus placebo
1145Mean Difference (IV, Random, 95% CI)-1.3 [-1.71, -0.89]

 12 CGI-Bipolar Version: improvement (mania)—mean change at three weeks51529Mean Difference (IV, Random, 95% CI)-0.41 [-0.62, -0.21]

    12.1 Aripiprazole variable dose versus placebo
41143Mean Difference (IV, Random, 95% CI)-0.52 [-0.70, -0.34]

    12.2 Aripiprazole 15 mg versus placebo
1192Mean Difference (IV, Random, 95% CI)-0.06 [-0.52, 0.40]

    12.3 Aripiprazole 30 mg versus placebo
1194Mean Difference (IV, Random, 95% CI)-0.06 [-0.50, 0.38]

 13 CGI-Bipolar Version: severity (depression)—mean change at three weeks61905Mean Difference (IV, Random, 95% CI)-0.09 [-0.18, 0.01]

    13.1 Aripiprazole variable dose versus placebo as monotherapy
3878Mean Difference (IV, Random, 95% CI)0.06 [-0.13, 0.24]

    13.2 Aripiprazole 10 mg versus placebo as monotherapy
1142Mean Difference (IV, Random, 95% CI)-0.30 [-0.70, 0.10]

    13.3 Aripiprazole 15 mg versus placebo as monotherapy
1190Mean Difference (IV, Random, 95% CI)-0.12 [-0.42, 0.18]

    13.4 Aripiprazole 30 mg versus placebo as monotherapy
2338Mean Difference (IV, Random, 95% CI)-0.25 [-0.49, -0.01]

    13.5 Aripiprazole versus placebo as add-on to lithium or valproate
1357Mean Difference (IV, Random, 95% CI)-0.08 [-0.22, 0.06]

 14 CGI-Bipolar Version: severity (depression)—mean change at four weeks1287Mean Difference (IV, Random, 95% CI)-0.30 [-0.61, 0.01]

    14.1 Aripiprazole 10 mg versus placebo
1142Mean Difference (IV, Random, 95% CI)-0.30 [-0.74, 0.14]

    14.2 Aripiprazole 30 mg versus placebo
1145Mean Difference (IV, Random, 95% CI)-0.30 [-0.74, 0.14]

 15 CGI-Bipolar Version: improvement (depression)—mean change at three weeks2632Mean Difference (IV, Random, 95% CI)-0.19 [-0.45, 0.07]

    15.1 Aripiprazole variable dose versus placebo as monotherapy
1246Mean Difference (IV, Random, 95% CI)-0.40 [-0.71, -0.09]

    15.2 Aripiprazole 15 mg versus placebo as monotherapy
1192Mean Difference (IV, Random, 95% CI)0.05 [-0.31, 0.41]

    15.3 Aripiprazole 30 mg versus placebo as monotherapy
1194Mean Difference (IV, Random, 95% CI)-0.18 [-0.55, 0.19]

 16 CGI-Bipolar Version: severity (overall)—mean change at three weeks51549Mean Difference (IV, Random, 95% CI)-0.52 [-0.75, -0.29]

    16.1 Aripiprazole variable dose versus placebo as monotherapy
3879Mean Difference (IV, Random, 95% CI)-0.44 [-0.61, -0.26]

    16.2 Aripiprazole 10 mg versus placebo as monotherapy
1142Mean Difference (IV, Random, 95% CI)-0.7 [-1.05, -0.35]

    16.3 Aripiprazole 15 mg versus placebo as monotherapy
1190Mean Difference (IV, Random, 95% CI)-0.24 [-0.65, 0.17]

    16.4 Aripiprazole 30 mg versus placebo as monotherapy
2338Mean Difference (IV, Random, 95% CI)-0.65 [-1.55, 0.26]

 17 CGI-Bipolar Version: severity (overall)—mean change at six weeks2419Mean Difference (IV, Random, 95% CI)-0.08 [-0.72, 0.56]

    17.1 Aripiprazole versus placebo as add-on to lithium or valproate
1376Mean Difference (IV, Random, 95% CI)-0.3 [-0.56, -0.04]

    17.2 Aripiprazole variable dose versus placebo as monotherapy
143Mean Difference (IV, Random, 95% CI)0.41 [-0.49, 1.31]

 18 CGI-Bipolar Version: improvement (overall)—mean change at three weeks2633Mean Difference (IV, Random, 95% CI)-0.37 [-0.82, 0.08]

    18.1 Aripiprazole variable dose versus placebo as monotherapy
1247Mean Difference (IV, Random, 95% CI)-0.80 [-1.20, -0.40]

    18.2 Aripiprazole 15 mg versus placebo as monotherapy
1192Mean Difference (IV, Random, 95% CI)-0.11 [-0.57, 0.35]

    18.3 Aripiprazole 30 mg versus placebo as monotherapy
1194Mean Difference (IV, Random, 95% CI)-0.17 [-0.61, 0.27]

 19 Mean change in MADRS from baseline to week three2635Mean Difference (IV, Random, 95% CI)-0.43 [-2.08, 1.22]

    19.1 Aripiprazole variable dose versus placebo as monotherapy
2635Mean Difference (IV, Random, 95% CI)-0.43 [-2.08, 1.22]

 20 Mean change in PANSS total score at week three3863Mean Difference (IV, Random, 95% CI)-3.22 [-5.26, -1.19]

    20.1 Aripiprazole 15 mg versus placebo
1145Mean Difference (IV, Random, 95% CI)0.56 [-4.00, 7.12]

    20.2 Aripiprazole 30 mg versus placebo
1137Mean Difference (IV, Random, 95% CI)-1.45 [-8.16, 5.26]

    20.3 Aripiprazole variable dose versus placebo as monotherapy
2581Mean Difference (IV, Random, 95% CI)-3.87 [-6.13, -1.62]

 21 Mean change in PANSS-hostility subscale score at week three3827Mean Difference (IV, Random, 95% CI)-1.17 [-1.68, -0.66]

    21.1 Aripiprazole variable dose versus placebo
1246Mean Difference (IV, Random, 95% CI)-1.39 [-2.41, -0.37]

    21.2 Aripiprazole variable dose versus placebo as monotherapy
2581Mean Difference (IV, Random, 95% CI)-1.10 [-1.69, -0.51]

 22 Mean change in PANSS cognitive subscale score at week three3863Mean Difference (IV, Random, 95% CI)-0.77 [-1.38, -0.15]

    22.1 Aripiprazole 15 mg versus placebo
1145Mean Difference (IV, Random, 95% CI)0.58 [-1.19, 2.35]

    22.2 Aripiprazole 30 mg versus placebo
1137Mean Difference (IV, Random, 95% CI)-0.45 [-4.61, 3.71]

    22.3 Aripiprazole variable dose versus placebo as monotherapy
2581Mean Difference (IV, Random, 95% CI)-0.97 [-1.63, -0.30]

 23 Requirement for anticholinergics2730Risk Ratio (M-H, Random, 95% CI)3.28 [1.82, 5.91]

    23.1 Aripiprazole variable dose versus placebo
1384Risk Ratio (M-H, Random, 95% CI)2.70 [1.37, 5.34]

    23.2 Aripiprazole 10 mg versus placebo as monotherapy
1148Risk Ratio (M-H, Random, 95% CI)2.81 [0.65, 12.18]

    23.3 Aripiprazole 30 mg versus placebo as monotherapy
1198Risk Ratio (M-H, Random, 95% CI)8.5 [2.02, 35.82]

 24 Requirement for lorazepam2638Risk Ratio (M-H, Random, 95% CI)0.99 [0.88, 1.12]

 25 Numbers completing double-blind treatment82216Risk Ratio (M-H, Random, 95% CI)1.03 [0.95, 1.12]

    25.1 Aripiprazole variable dose versus placebo as monotherapy
51217Risk Ratio (M-H, Random, 95% CI)1.10 [0.94, 1.29]

    25.2 Aripiprazole 10 mg versus placebo as monotherapy
1147Risk Ratio (M-H, Random, 95% CI)1.11 [0.93, 1.31]

    25.3 Aripiprazole 30 mg versus placebo as monotherapy
198Risk Ratio (M-H, Random, 95% CI)1.0 [0.81, 1.24]

    25.4 Aripiprazole versus placebo as add-on to lithium or valproate
2754Risk Ratio (M-H, Random, 95% CI)0.94 [0.87, 1.02]

 26 Failure to complete treatment—dropouts: adverse drug reaction82621Risk Ratio (M-H, Random, 95% CI)1.26 [0.97, 1.63]

    26.1 Aripiprazole variable dose versus placebo as monotherapy
41174Risk Ratio (M-H, Random, 95% CI)1.20 [0.83, 1.74]

    26.2 Aripiprazole 10 mg versus placebo as monotherapy
1147Risk Ratio (M-H, Random, 95% CI)2.0 [0.23, 17.42]

    26.3 Aripiprazole 15 mg versus placebo as monotherapy
1197Risk Ratio (M-H, Random, 95% CI)2.52 [0.90, 7.07]

    26.4 Aripiprazole 30 mg versus placebo as monotherapy
2349Risk Ratio (M-H, Random, 95% CI)1.44 [0.53, 3.90]

    26.5 Aripiprazole versus placebo as add-on to lithium or valproate
2754Risk Ratio (M-H, Random, 95% CI)1.17 [0.69, 2.00]

 27 Failure to complete treatment—dropouts: lack of efficacy82609Risk Ratio (M-H, Random, 95% CI)0.61 [0.44, 0.84]

    27.1 Aripiprazole variable dose versus placebo as monotherapy
41174Risk Ratio (M-H, Random, 95% CI)0.48 [0.30, 0.77]

    27.2 Aripiprazole versus placebo as add-on to lithium or valproate
2754Risk Ratio (M-H, Random, 95% CI)0.99 [0.53, 1.85]

    27.3 Aripiprazole 10 mg versus placebo as monotherapy
1147Risk Ratio (M-H, Random, 95% CI)0.25 [0.05, 1.32]

    27.4 Aripiprazole 15 mg versus placebo as monotherapy
1192Risk Ratio (M-H, Random, 95% CI)0.69 [0.40, 1.20]

    27.5 Aripiprazole 30 mg versus placebo as monotherapy
2342Risk Ratio (M-H, Random, 95% CI)0.62 [0.18, 2.12]

 28 Participants meeting criteria for treatment as outpatients2534Risk Ratio (M-H, Random, 95% CI)1.67 [1.19, 2.34]

 29 Simpson Angus Scale41233Mean Difference (IV, Random, 95% CI)0.75 [0.20, 1.30]

    29.1 Aripiprazole variable dose versus placebo as monotherapy
2561Mean Difference (IV, Random, 95% CI)0.07 [-0.77, 0.90]

    29.2 Aripiprazole 10 mg versus placebo as monotherapy
1141Mean Difference (IV, Random, 95% CI)0.66 [0.18, 1.14]

    29.3 Aripiprazole 15 mg versus placebo as monotherapy
1192Mean Difference (IV, Random, 95% CI)0.86 [0.09, 1.63]

    29.4 Aripiprazole 30 mg versus placebo as monotherapy
2339Mean Difference (IV, Random, 95% CI)1.51 [0.86, 2.15]

 30 Barnes Akathisia Scale51498Mean Difference (IV, Random, 95% CI)0.20 [0.09, 0.31]

    30.1 Aripiprazole variable dose versus placebo as monotherapy
3825Mean Difference (IV, Random, 95% CI)0.27 [0.08, 0.46]

    30.2 Aripiprazole 10 mg versus placebo as monotherapy
1142Mean Difference (IV, Random, 95% CI)0.02 [-0.19, 0.23]

    30.3 Aripiprazole 15 mg versus placebo as monotherapy
1192Mean Difference (IV, Random, 95% CI)0.35 [0.02, 0.68]

    30.4 Aripiprazole 30 mg versus placebo as monotherapy
2339Mean Difference (IV, Random, 95% CI)0.15 [-0.04, 0.35]

 31 Abnormal Involuntary Movement Scale41068Mean Difference (IV, Random, 95% CI)0.02 [-0.10, 0.15]

    31.1 Aripiprazole variable dose versus placebo as monotherapy
2494Mean Difference (IV, Random, 95% CI)0.04 [-0.15, 0.24]

    31.2 Aripiprazole 10 mg versus placebo as monotherapy
1142Mean Difference (IV, Random, 95% CI)0.0 [-0.25, 0.25]

    31.3 Aripiprazole 15 mg versus placebo as monotherapy
1147Mean Difference (IV, Random, 95% CI)-0.17 [-0.78, 0.44]

    31.4 Aripiprazole 30 mg versus placebo as monotherapy
2285Mean Difference (IV, Random, 95% CI)0.05 [-0.19, 0.29]

 32 Manic reaction2663Risk Ratio (M-H, Random, 95% CI)1.05 [0.40, 2.78]

    32.1 Aripiprazole variable dose versus placebo as monotherapy
1262Risk Ratio (M-H, Random, 95% CI)7.11 [0.37, 136.24]

    32.2 Aripiprazole 15 mg versus placebo as monotherapy
1198Risk Ratio (M-H, Random, 95% CI)1.02 [0.26, 3.96]

    32.3 Aripiprazole 30 mg versus placebo as monotherapy
1203Risk Ratio (M-H, Random, 95% CI)0.66 [0.15, 2.85]

 33 Hypertension2663Risk Ratio (M-H, Random, 95% CI)3.17 [0.83, 12.14]

    33.1 Aripiprazole variable dose versus placebo as monotherapy
1262Risk Ratio (M-H, Random, 95% CI)3.05 [0.13, 74.09]

    33.2 Aripiprazole 15 mg versus placebo as monotherapy
1198Risk Ratio (M-H, Random, 95% CI)4.09 [0.52, 32.04]

    33.3 Aripiprazole 30 mg versus placebo as monotherapy
1203Risk Ratio (M-H, Random, 95% CI)2.46 [0.29, 20.67]

 34 Headache72305Risk Ratio (M-H, Random, 95% CI)1.02 [0.87, 1.21]

    34.1 Aripiprazole variable dose versus placebo as monotherapy
3854Risk Ratio (M-H, Random, 95% CI)1.05 [0.85, 1.30]

    34.2 Aripiprazole 10 mg versus placebo as monotherapy
1148Risk Ratio (M-H, Random, 95% CI)0.96 [0.46, 2.01]

    34.3 Aripiprazole 15 mg versus placebo as monotherapy
1198Risk Ratio (M-H, Random, 95% CI)1.16 [0.73, 1.86]

    34.4 Aripiprazole 30 mg versus placebo as monotherapy
2352Risk Ratio (M-H, Random, 95% CI)1.01 [0.68, 1.51]

    34.5 Aripiprazole versus placebo as add-on to lithium or valproate
2753Risk Ratio (M-H, Random, 95% CI)0.69 [0.36, 1.31]

 35 Anxiety3935Risk Ratio (M-H, Random, 95% CI)1.21 [0.86, 1.71]

    35.1 Aripiprazole variable dose versus placebo as monotherapy
2534Risk Ratio (M-H, Random, 95% CI)1.33 [0.86, 2.05]

    35.2 Aripiprazole 15 mg versus placebo as monotherapy
1198Risk Ratio (M-H, Random, 95% CI)1.02 [0.46, 2.27]

    35.3 Aripiprazole 30 mg versus placebo as monotherapy
1203Risk Ratio (M-H, Random, 95% CI)1.05 [0.48, 2.30]

 36 Insomnia41416Risk Ratio (M-H, Random, 95% CI)1.13 [0.82, 1.55]

    36.1 Aripiprazole variable dose versus placebo as monotherapy
1262Risk Ratio (M-H, Random, 95% CI)1.40 [0.77, 2.54]

    36.2 Aripiprazole versus placebo as add-on to lithium or valproate
2753Risk Ratio (M-H, Random, 95% CI)1.33 [0.72, 2.46]

    36.3 Aripiprazole 15 mg versus placebo as monotherapy
1198Risk Ratio (M-H, Random, 95% CI)0.98 [0.50, 1.90]

    36.4 Aripiprazole 30 mg versus placebo as monotherapy
1203Risk Ratio (M-H, Random, 95% CI)0.81 [0.40, 1.61]

 37 Light-headedness3932Risk Ratio (M-H, Random, 95% CI)1.08 [0.74, 1.57]

    37.1 Aripiprazole variable dose versus placebo as monotherapy
2534Risk Ratio (M-H, Random, 95% CI)1.09 [0.62, 1.91]

    37.2 Aripiprazole 15 mg versus placebo as monotherapy
1197Risk Ratio (M-H, Random, 95% CI)1.18 [0.47, 2.92]

    37.3 Aripiprazole 30 mg versus placebo as monotherapy
1201Risk Ratio (M-H, Random, 95% CI)0.90 [0.35, 2.32]

 38 Akathisia72305Risk Ratio (M-H, Random, 95% CI)3.16 [2.25, 4.43]

    38.1 Aripiprazole variable dose versus placebo as monotherapy
3854Risk Ratio (M-H, Random, 95% CI)2.75 [1.72, 4.41]

    38.2 Aripiprazole 10 mg versus placebo as monotherapy
1148Risk Ratio (M-H, Random, 95% CI)2.04 [0.45, 9.25]

    38.3 Aripiprazole 15 mg versus placebo as monotherapy
1198Risk Ratio (M-H, Random, 95% CI)9.21 [1.26, 67.48]

    38.4 Aripiprazole 30 mg versus placebo as monotherapy
2352Risk Ratio (M-H, Random, 95% CI)3.91 [1.20, 12.77]

    38.5 Aripiprazole versus placebo as add-on to lithium or valproate
2753Risk Ratio (M-H, Random, 95% CI)3.62 [2.00, 6.55]

 39 Nausea72305Risk Ratio (M-H, Random, 95% CI)1.50 [1.20, 1.88]

    39.1 Aripiprazole variable dose versus placebo as monotherapy
3854Risk Ratio (M-H, Random, 95% CI)1.56 [1.17, 2.08]

    39.2 Aripiprazole 10 mg versus placebo as monotherapy
1148Risk Ratio (M-H, Random, 95% CI)1.53 [0.43, 5.40]

    39.3 Aripiprazole 15 mg versus placebo as monotherapy
1198Risk Ratio (M-H, Random, 95% CI)1.31 [0.64, 2.66]

    39.4 Aripiprazole 30 mg versus placebo as monotherapy
2352Risk Ratio (M-H, Random, 95% CI)1.20 [0.63, 2.26]

    39.5 Aripiprazole versus placebo as add-on to lithium or valproate
2753Risk Ratio (M-H, Random, 95% CI)1.74 [0.91, 3.34]

 40 Dyspepsia3930Risk Ratio (M-H, Random, 95% CI)1.31 [0.89, 1.92]

    40.1 Aripiprazole variable dose versus placebo as monotherapy
2534Risk Ratio (M-H, Random, 95% CI)1.77 [1.17, 2.68]

    40.2 Aripiprazole 15 mg versus placebo as monotherapy
1198Risk Ratio (M-H, Random, 95% CI)0.98 [0.50, 1.90]

    40.3 Aripiprazole 30 mg versus placebo as monotherapy
1198Risk Ratio (M-H, Random, 95% CI)0.84 [0.42, 1.67]

 41 Vomiting41232Risk Ratio (M-H, Random, 95% CI)1.47 [0.87, 2.48]

    41.1 Aripiprazole variable dose versus placebo as monotherapy
2534Risk Ratio (M-H, Random, 95% CI)1.69 [1.04, 2.76]

    41.2 Aripiprazole 10 mg versus placebo as monotherapy
1148Risk Ratio (M-H, Random, 95% CI)0.82 [0.28, 2.37]

    41.3 Aripiprazole 15 mg versus placebo as monotherapy
1198Risk Ratio (M-H, Random, 95% CI)7.16 [0.96, 53.29]

    41.4 Aripiprazole 30 mg versus placebo as monotherapy
2352Risk Ratio (M-H, Random, 95% CI)1.23 [0.27, 5.61]

 42 Constipation41255Risk Ratio (M-H, Random, 95% CI)1.75 [1.23, 2.49]

    42.1 Aripiprazole variable dose versus placebo as monotherapy
3854Risk Ratio (M-H, Random, 95% CI)1.72 [1.14, 2.61]

    42.2 Aripiprazole 15 mg versus placebo as monotherapy
1198Risk Ratio (M-H, Random, 95% CI)1.94 [0.76, 4.98]

    42.3 Aripiprazole 30 mg versus placebo as monotherapy
1203Risk Ratio (M-H, Random, 95% CI)1.68 [0.65, 4.35]

 43 Diarrhoea41319Risk Ratio (M-H, Random, 95% CI)0.82 [0.58, 1.17]

    43.1 Aripiprazole variable dose versus placebo as monotherapy
2534Risk Ratio (M-H, Random, 95% CI)0.94 [0.57, 1.55]

    43.2 Aripiprazole versus placebo as add-on to lithium or valproate
1384Risk Ratio (M-H, Random, 95% CI)0.71 [0.29, 1.73]

    43.3 Aripiprazole 15mg versus placebo as monotherapy
1198Risk Ratio (M-H, Random, 95% CI)0.83 [0.36, 1.91]

    43.4 Aripiprazole 30 mg versus placebo as monotherapy
1203Risk Ratio (M-H, Random, 95% CI)0.62 [0.25, 1.49]

 44 Pain extremity2673Risk Ratio (M-H, Random, 95% CI)2.01 [1.07, 3.78]

    44.1 Aripiprazole variable dose versus placebo as monotherapy
1272Risk Ratio (M-H, Random, 95% CI)1.64 [0.74, 3.62]

    44.2 Aripiprazole 15 mg versus placebo as monotherapy
1198Risk Ratio (M-H, Random, 95% CI)2.56 [0.58, 11.34]

    44.3 Aripiprazole 30 mg versus placebo as monotherapy
1203Risk Ratio (M-H, Random, 95% CI)3.20 [0.74, 13.78]

 45 Somnolence3970Risk Ratio (M-H, Random, 95% CI)1.85 [0.94, 3.65]

    45.1 Aripiprazole variable dose versus placebo as monotherapy
1272Risk Ratio (M-H, Random, 95% CI)1.72 [0.98, 3.04]

    45.2 Aripiprazole 10 mg versus placebo as monotherapy
1148Risk Ratio (M-H, Random, 95% CI)4.85 [1.18, 19.99]

    45.3 Aripiprazole 15 mg versus placebo as monotherapy
1198Risk Ratio (M-H, Random, 95% CI)0.85 [0.32, 2.24]

    45.4 Aripiprazole 30 mg versus placebo as monotherapy
2352Risk Ratio (M-H, Random, 95% CI)2.38 [0.34, 16.79]

 46 Tremor31105Risk Ratio (M-H, Random, 95% CI)1.45 [0.89, 2.34]

    46.1 Aripiprazole versus placebo as add-on to lithium or valproate
1384Risk Ratio (M-H, Random, 95% CI)1.49 [0.68, 3.24]

    46.2 Aripiprazole variable dose versus placebo as monotherapy
1320Risk Ratio (M-H, Random, 95% CI)1.42 [0.62, 3.27]

    46.3 Aripiprazole 15 mg versus placebo as monotherapy
1198Risk Ratio (M-H, Random, 95% CI)1.53 [0.43, 5.48]

    46.4 Aripiprazole 30 mg versus placebo as monotherapy
1203Risk Ratio (M-H, Random, 95% CI)1.31 [0.36, 4.79]

 47 EPS31001Risk Ratio (M-H, Random, 95% CI)2.24 [1.47, 3.42]

    47.1 Aripiprazole versus placebo as add-on to lithium or valproate
1384Risk Ratio (M-H, Random, 95% CI)1.93 [1.22, 3.07]

    47.2 Aripiprazole variable dose versus placebo as monotherapy
1320Risk Ratio (M-H, Random, 95% CI)1.82 [1.12, 2.98]

    47.3 Aripiprazole 10 mg versus placebo as monotherapy
1148Risk Ratio (M-H, Random, 95% CI)5.87 [1.44, 23.89]

    47.4 Aripiprazole 30 mg versus placebo as monotherapy
1149Risk Ratio (M-H, Random, 95% CI)5.05 [1.23, 20.75]

 48 Weight gain (≥ 7% increase from baseline)51596Risk Ratio (M-H, Random, 95% CI)0.72 [0.47, 1.10]

    48.1 Aripiprazole variable dose versus placebo as monotherapy
3854Risk Ratio (M-H, Random, 95% CI)0.61 [0.36, 1.03]

    48.2 Aripiprazole variable dose versus placebo as add-on to lithium or valproate
2742Risk Ratio (M-H, Random, 95% CI)0.97 [0.48, 2.00]

 
Comparison 2. Aripiprazole versus other drug treatment

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Mean change in YMRS from baseline at week three3972Mean Difference (IV, Random, 95% CI)0.07 [-1.24, 1.37]

    1.1 Versus haloperidol
2663Mean Difference (IV, Random, 95% CI)0.42 [-1.19, 2.03]

    1.2 Versus lithium
1309Mean Difference (IV, Random, 95% CI)-0.61 [-2.83, 1.61]

 2 Mean change in YMRS from baseline at week 122645Mean Difference (IV, Random, 95% CI)-1.75 [-3.60, 0.11]

    2.1 Versus haloperidol
1336Mean Difference (IV, Random, 95% CI)-1.71 [-4.48, 1.06]

    2.2 Versus lithium
1309Mean Difference (IV, Random, 95% CI)-1.78 [-4.27, 0.71]

 3 Response ≥ 50% decrease in YMRS from baseline at week three3990Risk Ratio (M-H, Random, 95% CI)1.12 [0.77, 1.63]

    3.1 Versus haloperidol
2675Risk Ratio (M-H, Random, 95% CI)1.26 [0.73, 2.16]

    3.2 Versus lithium
1315Risk Ratio (M-H, Random, 95% CI)0.89 [0.64, 1.25]

 4 CGI-Bipolar Version: severity (mania)—mean change at week three3971Mean Difference (IV, Random, 95% CI)-0.04 [-0.20, 0.13]

    4.1 Versus haloperidol
2664Mean Difference (IV, Random, 95% CI)0.02 [-0.19, 0.24]

    4.2 Versus lithium
1307Mean Difference (IV, Random, 95% CI)-0.14 [-0.42, 0.14]

 5 CGI-Bipolar Version: severity (mania)—mean change at week 122644Mean Difference (IV, Random, 95% CI)-0.22 [-0.44, -0.00]

    5.1 Versus haloperidol
1337Mean Difference (IV, Random, 95% CI)-0.31 [-0.67, 0.05]

    5.2 Versus lithium
1307Mean Difference (IV, Random, 95% CI)-0.17 [-0.45, 0.11]

 6 CGI-Bipolar Version: severity (depression)—mean change at week 122644Mean Difference (IV, Random, 95% CI)-0.08 [-0.25, 0.09]

    6.1 Versus haloperidol
1337Mean Difference (IV, Random, 95% CI)-0.07 [-0.28, 0.14]

    6.2 Versus lithium
1307Mean Difference (IV, Random, 95% CI)-0.10 [-0.38, 0.18]

 7 CGI-Bipolar Version: severity (overall)—mean change at week 122644Mean Difference (IV, Random, 95% CI)-0.29 [-0.50, -0.07]

    7.1 Versus haloperidol
1337Mean Difference (IV, Random, 95% CI)-0.41 [-0.74, -0.08]

    7.2 Versus lithium
1307Mean Difference (IV, Random, 95% CI)-0.20 [-0.48, 0.08]

 8 CGI-Bipolar Version: improvement (mania)—mean change at week three2Mean Difference (IV, Fixed, 95% CI)Totals not selected

    8.1 Versus haloperidol
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

    8.2 Versus lithium
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

 9 Mean change in MADRS from baseline at week three3971Mean Difference (IV, Random, 95% CI)-0.55 [-2.03, 0.92]

    9.1 Versus haloperidol
2662Mean Difference (IV, Random, 95% CI)-0.39 [-2.59, 1.82]

    9.2 Versus lithium
1309Mean Difference (IV, Random, 95% CI)-1.0 [-2.66, 0.66]

 10 Mean change in MADRS from baseline at week 122644Mean Difference (IV, Random, 95% CI)-1.05 [-2.39, 0.30]

    10.1 Versus haloperidol
1335Mean Difference (IV, Random, 95% CI)-1.25 [-2.94, 0.44]

    10.2 Versus lithium
1309Mean Difference (IV, Random, 95% CI)-0.7 [-2.92, 1.52]

 11 Mean change in PANSS-total at week three2582Mean Difference (IV, Random, 95% CI)-0.64 [-3.62, 2.34]

    11.1 Versus haloperidol
1314Mean Difference (IV, Random, 95% CI)0.60 [-2.17, 3.37]

    11.2 Versus lithium
1268Mean Difference (IV, Random, 95% CI)-2.5 [-6.38, 1.38]

 12 Mean change in PANSS-cognitive subscale score at week three2582Mean Difference (IV, Random, 95% CI)-0.08 [-0.75, 0.59]

    12.1 Versus haloperidol
1314Mean Difference (IV, Random, 95% CI)0.10 [-0.73, 0.93]

    12.2 Versus lithium
1268Mean Difference (IV, Random, 95% CI)-0.40 [-1.51, 0.71]

 13 Mean change in PANSS-hostility subscale score at week three2582Mean Difference (IV, Random, 95% CI)-0.10 [-0.88, 0.68]

    13.1 Versus haloperidol
1314Mean Difference (IV, Random, 95% CI)0.30 [-0.53, 1.13]

    13.2 Versus lithium
1268Mean Difference (IV, Random, 95% CI)-0.5 [-1.33, 0.33]

 14 Simpson Angus Scale LOCF at week 122646Mean Difference (IV, Random, 95% CI)-2.09 [-7.11, 2.93]

    14.1 Versus haloperidol
1333Mean Difference (IV, Random, 95% CI)-4.68 [-5.87, -3.49]

    14.2 Versus lithium
1313Mean Difference (IV, Random, 95% CI)0.44 [-0.09, 0.97]

 15 Barnes Akathisia Scale LOCF at week 122646Mean Difference (IV, Random, 95% CI)-0.17 [-0.76, 0.41]

    15.1 Versus haloperidol
1333Mean Difference (IV, Random, 95% CI)-0.48 [-0.73, -0.23]

    15.2 Versus lithium
1313Mean Difference (IV, Random, 95% CI)0.12 [-0.07, 0.31]

 16 Abnormal Involuntary Movement Scale LOCF at week 122634Mean Difference (IV, Random, 95% CI)-0.31 [-0.97, 0.36]

    16.1 Versus haloperidol
1321Mean Difference (IV, Random, 95% CI)-0.67 [-1.07, -0.27]

    16.2 Versus lithium
1313Mean Difference (IV, Random, 95% CI)0.01 [-0.17, 0.19]

 17 Akathisia2Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

    17.1 Versus haloperidol (over 12 weeks)
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    17.2 Versus lithium (over 12 weeks)
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 18 Headache2657Risk Ratio (M-H, Random, 95% CI)1.01 [0.72, 1.42]

    18.1 Versus haloperidol (over 12 weeks)
1344Risk Ratio (M-H, Random, 95% CI)0.92 [0.51, 1.66]

    18.2 Versus lithium (over 12 weeks)
1313Risk Ratio (M-H, Random, 95% CI)1.06 [0.71, 1.60]

 19 Tremor2657Risk Ratio (M-H, Random, 95% CI)0.67 [0.41, 1.09]

    19.1 Versus haloperidol (over 12 weeks)
1344Risk Ratio (M-H, Random, 95% CI)0.68 [0.34, 1.38]

    19.2 Versus lithium (over 12 weeks)
1313Risk Ratio (M-H, Random, 95% CI)0.65 [0.33, 1.30]

 20 Numbers completing at end of week three3994Risk Ratio (M-H, Random, 95% CI)1.12 [0.90, 1.39]

    20.1 Versus haloperidol
2679Risk Ratio (M-H, Random, 95% CI)1.19 [0.88, 1.60]

    20.2 Versus lithium
1315Risk Ratio (M-H, Random, 95% CI)0.97 [0.77, 1.22]

 21 Numbers completing the trial (at end of week 12)3994Risk Ratio (M-H, Random, 95% CI)1.12 [0.73, 1.71]

    21.1 Versus haloperidol
2679Risk Ratio (M-H, Random, 95% CI)1.30 [0.74, 2.31]

    21.2 Versus lithium
1315Risk Ratio (M-H, Random, 95% CI)0.80 [0.57, 1.13]

 22 Failure to complete treatment: dropouts—lack of efficacy at three weeks2647Odds Ratio (M-H, Random, 95% CI)0.51 [0.19, 1.40]

    22.1 Versus haloperidol (over three weeks)
1332Odds Ratio (M-H, Random, 95% CI)0.88 [0.35, 2.23]

    22.2 Versus lithium (over three weeks)
1315Odds Ratio (M-H, Random, 95% CI)0.32 [0.14, 0.70]

 23 Failure to complete treatment: dropouts—adverse event at end of three weeks3994Odds Ratio (M-H, Random, 95% CI)0.79 [0.22, 2.76]

    23.1 Versus haloperidol (over three weeks)
2679Odds Ratio (M-H, Random, 95% CI)0.64 [0.09, 4.56]

    23.2 Versus lithium (over three weeks)
1315Odds Ratio (M-H, Random, 95% CI)1.22 [0.64, 2.32]

 
Summary of findings for the main comparison. Aripiprazole versus placebo for an acute manic or mixed episode

Aripiprazole versus placebo for an acute manic or mixed episode

Patient or population: patients with an acute manic or mixed episode
Settings: inpatients and outpatients
Intervention: aripiprazole

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

ControlAripiprazole versus placebo

Mean change in YMRS from baseline at three weeks
Young Mania Rating Scale (YMRS): an 11-item questionnaire to assess the severity of core symptoms of mania. Scale from 0 to 60
Follow-up: three weeks
Mean change in YMRS from baseline at three weeks ranged across control groups from
-3.4 to -10.12 points
Mean change in YMRS from baseline at three weeks in the intervention groups was
3.66 lower
(5.28 to 2.05 lower)
1819
(six studies)
⊕⊕⊕⊝
moderate1

≥ 50% decrease in total YMRS from baseline at three weeks
Young Mania Rating Scale (as above)
Follow-up: three weeks
Study populationRR 1.70
(1.23 to 2.34)
1230
(four studies)
⊕⊕⊕⊝
moderate1

263 per 1000446 per 1000
(323 to 614)

Moderate

243 per 1000413 per 1000
(299 to 569)

Numbers completing double-blind treatment
Number of participants
Follow-up: three to 12 weeks
Study populationRR 1.03
(0.95 to 1.12)
2216
(eight studies)
⊕⊕⊕⊝
moderate2

610 per 1000628 per 1000
(579 to 683)

Moderate

744 per 1000766 per 1000
(707 to 833)

Requirement for anticholinergics
number of participants requiring medication for extrapyramidal side effects
Follow-up: four to six weeks
Study populationRR 3.28
(1.82 to 5.91)
730
(two studies)
⊕⊕⊕⊕
high

46 per 1000152 per 1000
(85 to 274)

Moderate

40 per 1000131 per 1000
(73 to 236)

Akathisia
Participant report
Follow-up: three to 12 weeks
Study populationRR 3.16
(2.25 to 4.43)
2305
(seven studies)
⊕⊕⊕⊕
high

41 per 1000128 per 1000
(91 to 180)

Moderate

22 per 100070 per 1000
(50 to 97)

Nausea
Participant report
Follow-up: three to 12 weeks
Study populationRR 1.50
(1.2 to 1.88)
2305
(seven studies)
⊕⊕⊕⊕
high

101 per 1000152 per 1000
(122 to 191)

Moderate

118 per 1000177 per 1000
(142 to 222)

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio.

GRADE Working Group grades of evidence.
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

 1Not all the study confidence intervals overlapped, moderately high I2 value, and low P value. Heterogeneity may be explained by differences in study design—variable-dose aripiprazole versus fixed-dose aripiprazole.
2High I2 value, low P value. Heterogeneity might be explained by differences in study design—one study discontinued non-responders from the trial at the end of week two and offered open-label aripiprazole, excluding them from the analysis.
 
Summary of findings 2. Aripiprazole versus other drug treatment for an acute manic or mixed episode

Aripiprazole versus other drug treatment for an acute manic or mixed episode

Patient or population: patients with an acute manic or mixed episode
Settings: inpatients and outpatients
Intervention: aripiprazole

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

ControlAripiprazole versus other drug treatment

Mean change in YMRS from baseline at week three
Young Mania Rating Scale: an 11-item questionnaire to assess the severity of the core symptoms of mania. Scale from 0 to 60
Follow-up: 12 weeks
Mean change in YMRS from baseline at week three ranged across control groups from
-15.65 to -12.03 points
Mean change in YMRS from baseline at week three in the intervention groups was
0.07 higher
(1.24 lower to 1.37 higher)
972
(three studies)
⊕⊕⊕⊝
moderate1

≥ 50% decrease in YMRS from baseline at week three
Young Mania Rating Scale (YMRS): as above
Follow-up: 12 weeks
Study populationRR 1.12
(0.77 to 1.63)
990
(two studies)
⊕⊕⊕⊝
moderate1

320 per 1000359 per 1000
(247 to 522)

Moderate

81 per 100091 per 1000
(62 to 132)

Numbers completing the trial (at end of week three)
Number of participants
Follow-up: 12 weeks
Study populationRR 1.13
(1.03 to 1.24)
994
(three studies)
⊕⊕⊝⊝
low1,2

592 per 1000668 per 1000
(609 to 734)

Moderate

338 per 1000382 per 1000
(348 to 419)

Barnes Akathisia Scale LOCF at week 12
A physician-assessed rating scale to assess the severity of drug-induced akathisia Scale from 0 to 14
Follow-up: 12 weeks
Mean Barnes Akathisia Scale LOCF at week 12 ranged across control groups from
0.06 to 0.8
Mean Barnes Akathisia Scale LOCF at week 12 in the intervention groups was
0.17 lower
(0.76 lower to 0.41 higher)
646
(two studies)
⊕⊕⊝⊝
low1,3

Abnormal Involuntary Movement Scale LOCF at week 12
A physician-administered rating scale with 12 items to measure tardive dyskinesia Scale from 0 to 40
Follow-up: 12 weeks
Mean Abnormal Involuntary Movement Scale LOCF at week 12 ranged across control groups from
-0.06 to 0.81
Mean Abnormal Involuntary Movement Scale LOCF at week 12 in the intervention groups was
0.31 lower
(0.97 lower to 0.36 higher)
634
(two studies)
⊕⊕⊝⊝
low1,3

Simpson Angus Scale LOCF at week 12
A physician-administered rating scale to measure drug-induced Parkinsonism Scale from 0 to 40.
Follow-up: 12 weeks
Mean Simpson Angus Scale LOCF at week 12 ranged across control groups from
0.18 to 5.7
Mean Simpson Angus Scale LOCF at week 12 in the intervention groups was
2.09 lower
(7.11 lower to 2.93 higher)
646
(two studies)
⊕⊕⊝⊝
low1,3

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio.

GRADE Working Group grades of evidence.
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

 1Wide confidence intervals and minimal quantity of directly comparative data.
2Significant heterogeneity present. Differences in study design could explain the heterogeneity—the lithium comparator and one of the haloperidol comparator studies were placebo and active drug controlled. Also a difference in the average dose of haloperidol at the 12-week endpoint— 11.2 mg/d in one study and 7.4 mg/d in the other.
3Heterogeneity might be explained by the different side effect profiles of lithium and haloperidol.
 
Table 1. Adverse effects

Control drugBody systemSide effectsN of comparisonN of participantsAdverse event rate (%) in aripiprazole groupAdverse event rate (%) in comparison group

Versus placeboCardiovascularQTc interval ≥ 450 msec and ≥ 10% increase from baseline126200.8

Chest discomfort126200.8

Syncope126200.8

DermatologicalUrticaria126200.8

NeuropsychiatricAgitation126200.8

Dizziness12965.03.0

Fatigue129611.16.0

Asthenia140111.97.5

Dystonia12962.52.0

Depression13707.82.7

EndocrineProlactin below normal (< 2 ng/mL) male adolescents115950.419.6

Prolactin below normal (< 3 ng/mL) female adolescents113927.011.6

OtherOverdose of sedatives12620.80

Accidental injury126213.86.1

Blurred vision12968.12.0

Salivary hypersecretion12965.52.0

Increased appetite12963.55.0

Decreased appetite12964.55.0

Upper abdominal pain12964.55.0

Versus haloperidolCardiovascularQTc interval ≥ 450 msec and ≥ 10% increase from baseline13472.34.7

NeuropsychiatricTreatment-emergent depression measured by CGI-BP depression subscore worsening by ≥ two points134712.021.5

Insomnia134713.78.7

Depression134711.415.7

Extrapyramidal syndrome13479.136.6

Versus lithiumGastrointestinalConstipation131511.011.3

Nausea131523.223.8

NeuropsychiatricAkathisia131511.65.6

Headache131523.920.6

Tremor13157.710.6

Sedation131512.37.5